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CONSENSUS STATEMENT
Rare diseases in clinical endocrinology: a taxonomic classification
system
G. Marcucci •L. Cianferotti •P. Beck-Peccoz •M. Capezzone •F. Cetani •A. Colao •M. V. Davı
`•
E. degli Uberti •S. Del Prato •R. Elisei •A. Faggiano •D. Ferone •C. Foresta •L. Fugazzola •E. Ghigo •
G. Giacchetti •F. Giorgino •A. Lenzi •P. Malandrino •M. Mannelli •C. Marcocci •L. Masi •F. Pacini •
G. Opocher •A. Radicioni •M. Tonacchera •R. Vigneri •M. C. Zatelli •M. L. Brandi
Received: 19 August 2014 / Accepted: 17 October 2014
ÓItalian Society of Endocrinology (SIE) 2014
Abstract
Purpose Rare endocrine–metabolic diseases (REMD)
represent an important area in the field of medicine and
pharmacology. The rare diseases of interest to endocri-
nologists involve all fields of endocrinology, including rare
diseases of the pituitary, thyroid and adrenal glands, par-
aganglia, ovary and testis, disorders of bone and mineral
metabolism, energy and lipid metabolism, water metabo-
lism, and syndromes with possible involvement of multiple
endocrine glands, and neuroendocrine tumors. Taking
advantage of the constitution of a study group on REMD
within the Italian Society of Endocrinology, consisting of
basic and clinical scientists, a document on the taxonomy
of REMD has been produced.
Methods and results This document has been designed to
include mainly REMD manifesting or persisting into
adulthood. The taxonomy of REMD of the adult comprises
a total of 166 main disorders, 338 including all variants and
subtypes, described into 11 tables.
Conclusions This report provides a complete taxonomy
to classify REMD of the adult. In the future, the creation of
registries of rare endocrine diseases to collect data on
cohorts of patients and the development of common and
standardized diagnostic and therapeutic pathways for each
rare endocrine disease is advisable. This will help planning
G. Marcucci (&)L. Cianferotti M. L. Brandi
Head, Bone Metablic Diseases Unit, Department of Surgery and
Translational Medicine, University of Florence, Viale Pieraccini
6, 50139 Florence, Italy
e-mail: gemma.marcucci@libero.it
M. L. Brandi
e-mail: marialuisa.brandi@unifi.it
P. Beck-Peccoz L. Fugazzola
Department of Clinical Sciences and Community Health,
University of Milan and Endocrine Unit, Fondazione IRCCS Ca’
Granda, Milan, Italy
M. Capezzone
Section of Endocrinology and Metabolism, Department of
Internal Medicine, Endocrinology and Metabolism and
Biochemistry, University of Siena, Policlinico Santa Maria alle
Scotte, Siena, Italy
F. Cetani R. Elisei M. Tonacchera
Unit of Endocrinology, Department of Clinical and Experimental
Medicine, University of Pisa, Pisa, Italy
A. Colao A. Faggiano
Dipartimento di Medicina Clinica e Chirurgia, Universita
`
Federico II di Napoli, Naples, Italy
M. V. Davı
`
Section D, Department of Medicine, Clinic of Internal Medicine,
University of Verona, Verona, Italy
E. degli Uberti M. C. Zatelli
Section of Endocrinology, Department of Medical Sciences,
University of Ferrara, Ferrara, Italy
S. Del Prato
Section of Metabolic Diseases and Diabetes, Department of
Endocrinology and Metabolism, University of Pisa, Pisa, Italy
D. Ferone
Endocrinology, Department of Internal Medicine and Medical
Specialties and Center of Excellence for Biomedical Research,
IRCCS AOU San Martino-IST, University of Genoa, Genoa,
Italy
C. Foresta
Department of Medicine and Centre for Human Reproduction
Pathology, University of Padova, Padua, Italy
E. Ghigo
Division of Endocrinology, Diabetology and Metabolism
Department of Medical Sciences, University Hospital Citta
`
Salute e Scienza, Turin, Italy
123
J Endocrinol Invest
DOI 10.1007/s40618-014-0202-6
and performing intervention studies in larger groups of
patients to prove the efficacy, effectiveness, and safety of a
specific treatment.
Keywords Taxonomy Endocrinopathy Orphan
disease Endocrine glands Neuroendocrine tumors
Abbreviations
ACA Abs Adrenal cortex antibodies
AFP Alpha fetoprotein
ALP Alkaline phosphatase
Apo B Apolipoprotein B
AVP Arginine vasopressin
BAP Bone alkaline phosphatase
BB-CK Brain-specific creatine kinase isoenzyme
b-HCG b-Human chorionic gonadotropin
Ca Calcium
cAMP Cyclic adenosine monophosphate
CaSR Calcium-sensing receptor
CEA Carcino-embryonic antigen
CgA Chromogranin A
CK Creatin kinase
DDAVP Desmopressin
DHEA Dehydroepiandrosterone
DHEA-s Dehydroepiandrosterone-sulfate
DHT Dihydrotestosterone
DIT Di-iodinated tyrosine
DOC Deoxycorticosterone
FGF23 Fibroblast growth factor 23
FPG Fasting plasma glucose
GAD Abs Glutamic acid decarboxylase antibodies
GIST Gastro-intestinal stromal tumors
Gs G-protein alpha subunit
hCG Human chorionic gonadotropin
HDL High-density lipoprotein
5-HIAA 5-Hydroxyindoleacetic acid
5-HT 5-Hydroxytryptophan
IA2 Abs Tyrosine phosphatase antibodies
IDL Intermediate-density lipoprotein
IGF-1 Insulin-like growth factor
K Potassium
LDL Low-density lipoprotein
LPL Lipoprotein lipase
Mg Magnesium
MIT Mono-iodinated tyrosine
MPC Abs Melanin-producing cells antibodies
Na Sodium
NSE Neuron-specific enolase
21OH Abs 21 hydroxylase antibodies
17-OHP 17 OH progesterone
17a-OH Abs 17 alpha-hydroxylase antibodies
P Phosphorus
PCA Abs Parietal cell antibodies
PP Pancreatic polypeptide
PRL Prolactin
PTHrP Parathyroid hormone-related protein
SCC Abs Side-chain cleavage enzyme antibodies
G. Giacchetti
Division of Endocrinology, Azienda Ospedaliero-Universitaria,
Ospedali Riuniti Umberto I-GM Lancisi-G Salesi, Universita
`
Politecnica delle Marche, Ancona, Italy
F. Giorgino
Section of Internal Medicine, Endocrinology, Andrology and
Metabolic Diseases, Department of Emergency and Organ
Transplantation, University of Bari Aldo Moro, Bari, Italy
A. Lenzi
Chair of Endocrinology, Section Medical Pathophysiology, Food
Science and Endocrinology, Department Exp. Medicine,
Sapienza University of Rome, Policlinico Umberto I, Rome,
Italy
P. Malandrino
Endocrinology, Department of Clinical and Molecular
Biomedicine, Garibaldi-Nesima Medical Center, University of
Catania, Catania, Italy
M. Mannelli
Endocrinology Unit, Department of Experimental and Clinical
Biomedical Sciences, University of Florence, Florence, Italy
C. Marcocci
Department of Endocrinology and Metabolism, University of
Pisa, Pisa, Italy
L. Masi
Department of Orthopedic, Metabolic Bone Diseases Unit
AOUC-Careggi Hospital, Largo Palagi, 1, Florence, Italy
F. Pacini
Section of Endocrinology and Metabolism, University of Siena,
Siena, Italy
G. Opocher
Familial Cancer Clinic and Oncoendocrinology, Veneto Institute
of Oncology, IRCCS, Padua, Italy
G. Opocher
Department of Medicine DIMED, University of Padova, Padova,
Italy
A. Radicioni
Department of Experimental Medicine, Sapienza University of
Rome, Rome, Italy
R. Vigneri
Department of Clinical and Molecular Biomedicine, University
of Catania, and Humanitas Catania Center of Oncology, Catania,
Italy
J Endocrinol Invest
123
SS Somatostatin
StCA Abs Steroid-producing cell antibodies
TmP/GFR Renal tubular reabsorption of phosphate
tTGA Abs Tissue transglutaminase antibodies
TPO Abs Thyroid peroxidase antibodies
UFC Urinary free cortisol
Ur. Ca Urinary calcium
Ur. K Urinary potassium
Ur. Na Urinary sodium
Ur. P Urinary phosphorus
VIP Vasoactive intestinal polypeptide
VLCFA Very long chain fatty acids
Introduction
Rare endocrine–metabolic diseases (REMD) represent an
important area in the field of medicine and pharmacology
and constitute a major challenge for the clinical endocri-
nologist. Indeed, adult endocrinologists have to constantly
face and/or rule out rare diseases in the differential diag-
noses of clinical endocrine disorders more than any other
medical specialist outside the pediatric field.
The rare diseases of interest to endocrinologists involve
all fields of endocrinology, encompassing those of the
pituitary, thyroid, and adrenal glands, paraganglia, ovary
and testis, disorders of bone and mineral metabolism,
energy and lipid metabolism, water metabolism, and syn-
dromes with possible involvement of multiple endocrine
glands. The estimated total average prevalence of rare
endocrine diseases in a million inhabitants is around
20–50/1,000,000. To date REMD are not organized into an
itemized taxonomy.
There is no single, widely accepted definition for rare
disease. In general, a rare disease, also referred to as
‘‘orphan disease’’, is any disorder whose prevalence is
lower than a given cutoff encoded by the legislation of each
country. In the United States, a 1984 amendment to the
1983 Orphan Drug Act (a USA law designed to facilitate
the development and commercialization of drugs to treat
rare diseases) defines rare disease as ‘‘any disease or con-
dition that affects\200,000 people at any given time in the
United States’’ or any disease whose prevalence is \7.5/
100,000 [1]. This definition is also included in the 2002
Rare Disease Act, which established the Office of Rare
Disease as the coordinating federal authority on this matter
[2, reviewed in 3]. The European Commission on Public
Health, which officially addressed this issue in 1999 in the
view of ‘‘adopting a programme of Community action on
rare diseases’’, defines these disorders as ‘‘life-threatening
or chronically debilitating diseases which are of such low
prevalence that special combined efforts are needed to
address them’’, along with a prevalence of \5/10,000 [4].
This definition has been recently confirmed in the Report
on the State of the Art of Rare Disease in Europe in 2013
[5].
The European Organization for rare diseases (EUROR-
DIS) estimates that as many as 5,000–7,000 distinct rare
diseases exist, and as much as 6–8 % of the population of
the European Union is affected by at least one [6]. Only
about 400 rare diseases have targeted therapies. About
80 % have a genetic component, according to the Rare
Genomics Institute. Therefore, despite the low prevalence
of each rare disease, the total number of people affected by
rare diseases in the EU is estimated to be between 27 and
36 million [5,7,8]. Among these, the majority suffer from
even more uncommon diseases with a prevalence of B1/
100,000 [8].
Rare diseases can vary in prevalence between popula-
tions, so a disease that is rare in some populations may be
common in others. This is especially true for genetic dis-
eases, for which the founder effect can result in a disease
that is very rare worldwide being prevalent within a smaller
community.
The geographic dispersion of a relatively small number
of patients affected by rare diseases leads to many unique
and complicated issues that are exclusive to these groups.
These include difficulties in finding providers with the
appropriate knowledge of the disorder to be able to plan
proper diagnostic algorithms and procedures, and to pre-
scribe safe and effective treatments. Funding to conduct
investigations to assess the natural history, etiology
(including genetic testing), and effectiveness of pharma-
cological therapies is also an important issue [9,10].
Although a rare disease affects no more than 200,000
persons, many of them share similar symptoms and take
advantage of the same treatments. Indeed, a critical com-
ponent of advancing rare disease research centers relies on
the establishment of disease registries and associated data
[11–14].
EURORDIS estimates that at least 80 % of rare diseases
have a genetic origin [6,15]. Symptoms of some rare
disorders may be revealed at birth or in childhood, whereas
others only appear later in life, up to the fourth or fifth
decade. Rare diseases require early diagnosis, and fre-
quently, a multifaceted approach and follow-up by expert
medical teams. Many rare diseases are complex, chronic,
severe, and disabling, leading to reduced quality of life and
life expectancy. In addition, these patients are often par-
ticularly isolated and vulnerable. The lack of specific
health policies for rare diseases and the scarcity of exper-
tise translate into delayed diagnoses and difficult access to
care [9]. Misdiagnosis and non-diagnosis are the main
hurdles that must be overcome to improve the quality of
J Endocrinol Invest
123
life for thousands of rare disease patients. A translational
approach characterized by scientific cooperation between
clinicians and researchers is mandatory to increase
knowledge about rare diseases and plan screening and
management protocols. For many, rare disease treatment
poses a challenge due to limited scientific data and poor
commercial interest on behalf of pharmaceutical industries
[16]. For these reasons, today rare diseases are a priority
area for action in public health programs. In 2010 the 5th
European Conference on rare diseases (ECRD) focused on
the state-of-art health policies relevant to rare diseases, and
released recommendations on: national plans and strategies
for rare diseases, European reference networks and centers
of expertise for rare disease, science from the bench to the
bedside, medicine for people living with a rare disease and
information, help lines, empowerment, and medical edu-
cation [17]. Several Countries endorse and support specific
plans to overcome these issues. In Europe and North
America, several projects on rare diseases are ongoing, and
thematic networks have been created with new calls that
are launched yearly [18,19]. In 2011, a joint consortium
between the USA and Europe, the International Rare Dis-
eases Research Consortium (IRDiRC, http://www.irdirc.
org), initiated and endorsed by the European Commission
and the US National Institute of Health Research, was
launched to foster collaboration in this field. The ambitious
goal of this consortium is to develop a diagnostic tool for
every known rare disease and to deliver at least 200 new
therapies for these disorders by 2020. The consortium
acknowledges that correct classification of rare diseases is
of preliminary importance to this purpose.
Awareness and empowerment of patients with rare dis-
eases are crucial [17]. Thus, non-profit national and inter-
national organizations and related coalitions, often
supported by related foundations, have been created for
rare diseases as a whole, as well as for specific disorders.
Cooperation between researchers/clinicians and patients,
endorsed and pursued by specific organizations such as the
National Organization for Rare Disorders (NORD, https://
www.rarediseases.org) in North America, is critical to
better address the everyday challenges of these patients
through the development of specific approaches. On the
other hand, scientific societies can support these efforts
beginning with the categorization and classification of
diseases.
Taking advantage of the constitution of a study group on
REMD within the Italian Society of Endocrinology (SIE),
including basic and clinical scientists, a document on the
taxonomy of REMD of the adult has been produced. This
extensive and as complete as possible document has been
designed to include mainly REMDs which manifest or
persist into adulthood. Although this instrument is
addressed primarily to clinical endocrinologists to serve as
a tool for use in clinical practice for an improved catego-
rization of patients, it is advisable that in the future it could
also be used for specific drug development and policy-
making in public health [20].
Materials and methods
The taxonomy of REMD has been built taking advantage
of evidence based on the available literature and position
statements. Main reviews and reference papers have been
included.
For genetically determined disorders, the Online Men-
delian Inheritance in Men (OMIM, http://www.omim.org)
database has been used, retrieving phenotype numbers and
gene/locus numbers [21]. The nomenclature for disease
acronyms used is the one approved by the Gene Nomen-
clature Committee belonging to the Human Genome
Organization (HUGO-HGNC) [22]. For non-genetically
determined REMD, Orphanet nomenclature has been used
[23].
The results have been summarized in 11 tables, divided
according to endocrine gland or metabolic disorder (pitui-
tary, thyroid gland, bone and mineral metabolism, axis
PTH/PTHrP–PTHR1, glucose and lipids metabolism,
metabolism of water, adrenal glands and paraganglia,
ovary, testis, rare diseases with possible involvement of
multiple endocrine glands, and neuroendocrine tumors).
For each disease, the following have been specified:
disease name and related acronym, OMIM phenotype
number, mutated gene(s) and OMIM gene/locus number
(related genes), phenotypic traits, typical metabolic bio-
markers, incidence, prevalence, age range of expression,
and the most significant references, where available. These
essential data are sufficient to frame a rare endocrine dis-
ease by clinical endocrinologists.
Since the specific purpose of this taxonomic study is to
classify REMD, we refer to further literature for general
and specific descriptions of the different disorders and
related therapy.
Results and discussion
The taxonomy of REMD of the adult comprises a total of
169 main disorders and 346 with all variants and subtypes,
distributed in 11 tables: 90 % are genetically determined.
Among these, in 93 % of the cases the specific gene/locus
has been identified. For the remaining 10 % a monogenic
cause has not been established.
REMD (main disorders, with all variants and subtypes)
have been subdivided as follows: (Table 1) 24 rare pitui-
tary diseases, (Table 2) 24 rare thyroid diseases, (Table 3)
J Endocrinol Invest
123
Table 1 Rare pituitary diseases
Disorder OMIM
phenotype
number
OMIM
gene/
locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
1) Pituitary
adenoma, GH-
secreting
# 102200 AIP
(605555)
Gigantism in juveniles or acromegaly in
adults
Coarsened facial appearance, acral
enlargement, increased skin thickness
and soft tissue hyperplasia
Other manifestations: Increased
sweating, goiter, joint involvement,
carpal tunnel syndrome, visual
abnormalities, headache, colon polyps,
sleep apnea, reproductive disorders
The excessive secretion of GH and IGF-
1 leads to severe complications in the
cardiovascular, respiratory, metabolic,
skeletal, and integumentary systems
High GH and IGF-1 levels
The standard method for diagnosing
acromegaly is the measurement of the
GH nadir during an oral glucose
tolerance test, which is undetectable in
normal individuals, while
acromegalics fail to suppress GH
levels
3–4/
1,000,000
40–130/
1,000,000
Variable [24]
2) Pituitary
adenoma, TSH-
secreting
– – Hyperthyroidism, goiter High TSH, FT3, and FT4 levels Unknown Unknown Variable [25]
3) Pituitary
adenoma, ACTH-
secreting
# 219090 – Cushing’s syndrome:
Moon face, buffalo hump, obesity, skin
thinning, large and purple abdominal
striae, ecchymotic lesions or purpura,
lower limb edema, muscle atrophy,
osteoporosis, hypertension and
cardiovascular complications,
hirsutism, gonadal dysfunction,
psychic disturbances
High ACTH, and UFC levels 1–3/
1,000,000
40/
1,000,000
Variable [26]
4) Pituitary
adenoma, LH-
secreting
– – Pituitary adenoma High LH levels Unknown Unknown Variable [27]
5) Pituitary
adenoma, FSH-
secreting
– – Pituitary adenoma High FSH levels Unknown Unknown Variable [28]
J Endocrinol Invest
123
Table 1 continued
Disorder OMIM
phenotype
number
OMIM
gene/
locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
6) Familial isolated
pituitary adenomas
(FIPA), Familial
isolated
somatotropinoma
(IFS)
–
# 102200
—
AIP
(605555)
Acromegaly, gigantism
Macroadenomas:
Invasive and somatostatin analogs—
resistant
FIPA: high GH and IGF1 levels or high
PRL levels or high ACTH and cortisol
levels
IFS: High GH and IGF-1 levels
Unknown Pituitary
adenomas
(PA):
1/1,000
FIPA: 5 %
di PA
IFS:
Unknown
\18–40
years
[29]
7) Congenital hypopituitarism
7a)
Hypogonadotropic
hypogonadism 1
with or without
anosmia; HH1
# 308700 KAL 1
(300836)
Anosmia due to agenesis of the
olfactory lobes, hypogonadism
secondary to deficiency of
hypothalamic gonadotropin-releasing
hormone. Transmitting females have
partial or complete anosmia. Renal
agenesis, bimanual synkinesia, pes
cavus, high-arched palate, and
cerebellar ataxia
Low FSH, LH, T, 17b-estradiol levels 1/
10,000–1/
86,000
Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7b)
Hypogonadotropic
hypogonadism 2
with or without
anosmia; HH2
# 147950 FGFR1
(136350)
Hypogonadotropic hypogonadism,
anosmia, midline cranial anomalies,
cleft lip, cleft palate and imperfect
fusion
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7c)
Hypogonadotropic
hypogonadism 3
with or without
anosmia; HH3
# 244200 PROKR2
(607123)
Hypogonadotropic hypogonadism,
anosmia, midline, cranial fusion
defect, cleft lip, cleft palate,
hypotelorism, unilateral renal agenesis
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7d)
Hypogonadotropic
hypogonadism 5
with or without
anosmia; HH5
# 612370 CHD7
(608892)
Hypogonadotropic hypogonadism,
anosmia, cleft palate, and
sensorineural hearing loss
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
J Endocrinol Invest
123
Table 1 continued
Disorder OMIM
phenotype
number
OMIM
gene/
locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
7e)
Hypogonadotropic
hypogonadism 9
with or without
anosmia; HH9
# 614838 NSMF
(608137)
Hypogonadotropic hypogonadism,
anosmia, cleft palate, and
sensorineural hearing loss
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7f)
Hypogonadotropic
hypogonadism 10
with or without
anosmia; HH10
# 614839 TAC3
(162330)
Hypogonadotropic hypogonadism,
anosmia, cleft palate, and
sensorineural hearing loss
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7g)
Hypogonadotropic
hypogonadism 12
with or without
anosmia; HH12
# 614841 GnRH1
(152760)
Hypogonadotropic hypogonadism,
anosmia, cleft palate, and
sensorineural hearing loss
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7h)
Hypogonadotropic
hypogonadism 13
with or without
anosmia; HH13
# 614842 KiSS1
(603286)
Hypogonadotropic hypogonadism,
anosmia, cleft palate, and
sensorineural hearing loss
Low FSH, LH, T, 17b-estradiol levels Unkonwn Male:
1/8,000
Female:
1/40,000
Adolescence [30]
7i) Laurence–Moon
syndrome
# 245800 – Neurological symptoms: cognitive
impairment, ataxia, progressive
spastic paraplegia
Oftalmologic signs: retinitis pigmentosa
and blindness. Endocrinological signs:
hypogonadotropic hypogonadism with
hypogenitalism, obesity and growth
delay. Polydactyly, renal dysfunction
Low FSH, LH, T, 17b-estradiol levels,
dyslipoproteinemia, hyperglycemia
Unknown Unknown Variable [31]
7l) Prader–Willi
syndrome; PWS
#176270 NDN
(602117)
SNRPN
(182279)
Reduced fetal movement, hypotonia,
feeding difficulties, intellectual delay,
hyperphagia, cryptorchidism, GH
deficiency, mixed hypogonadism,
delayed puberty, behavioral problems,
dysmetabolism, osteoporosis
Low FSH, LH, T, 17b-estradiol, GH,
IGF-1 levels, high LDL levels, low
HDL levels, normal levels of
triglicerides, no insulin resistance
1/
25,000–1/
10,000
1–9/100,000 Variable [32]
J Endocrinol Invest
123
Table 1 continued
Disorder OMIM
phenotype
number
OMIM
gene/
locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
7m) Alstrom
syndrome; ALMS
#203800 ALMS1
(606844)
Obesity, nystagmus, photodysphoria,
blindness in adulthood, bilateral
sensorineural hearing loss throughout
childhood. Dilated cardiomyopathy,
renal, pulmonary and hepatic
disturbances. Diabetes mellitus Type
2, hypothyroidism, GH deficiency,
primary hypogonadism in males,
hyperandrogenism in females
Hyperinsulinemia,
hypertriglicerydemia, hyperuricemia,
hypotiroidism, low FSH, LH, T, 17b-
estradiol, GH, IGF-1 levels
Unknown 1–9/
1,000,000
Variable [33]
8) Pituitary hormone deficiency, combined
8a) Pituitary
hormone
deficiency,
combined 1;
CPHD1
# 613038 POU1F1
(173110)
Severe growth deficiency,
hypothyroidism, prominent forehead,
marked midfacial, hypoplasia, severe
mental retardation, preserved
production of FSH, LH and ACTH
Low GH, PRL TSH, FT3 and FT4
levels. Normal ACTH, LH and FSH
levels
Unknown Unknown Variable [34]
8b) Pituitary
hormone
deficiency,
combined 2;
CPHD2
# 262600 PROP1
(601538)
Growth failure, failure to thrive,
hypothyroidism, incomplete
secondary sexual development,
infertility, small penis, ACTH
deficiency (less common)
Low GH, IGF-1, TSH, FT3, FT4, LH,
FSH, T, 17b-estradiol, PRL, ACTH,
cortisol levels
Unknown Unknown Variable [35]
8c) Pituitary
hormone
deficiency,
combined 3;
CPHD3
# 221750 LHX3
(600577)
Rigidity of the cervical spine, mild
sensorineural hearing loss, deficiency
of all anterior pituitary hormones
except ACTH, with consequent
clinical manifestations
Low GH, IGF-1, IGF-I binding protein-
3, TSH, FT4, LH, FSH, testosterone,
17b-estradiol and PRL levels
Unknown \1/
1,000,000
Variable [36]
8d) Pituitary
hormone
deficiency,
combined 4;
CPHD4
# 262700 LHX4
(602146)
Poorly developed sella turcica with
PRL, TSH and GH. Deficiency corpus
callosum, hypoplasia ectopic
neurohypophysis
Low GH, IGF-1, TSH, FT3, FT4 and
PRL levels
Unknown \
1/
1,000,000
Variable [37]
8e) Pituitary
hormone
deficiency,
combined 5;
CPHD5 (Septo-
optic dysplasia)
# 182230 HESX1
(601802)
Optic nerve hypoplasia, pituitary gland
hypoplasia, midline abnormalities of
the brain, absence of the corpus
callosum and septum pellucidum
Low GH, ACTH, TSH, FT3, FT4, FSH,
LH, IGF1, T, 17b-estradiol, levels.
Neonatal hypoglycemia
1/10,000 Unknown Variable [38]
J Endocrinol Invest
123
Table 1 continued
Disorder OMIM
phenotype
number
OMIM
gene/
locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
9) Isolated growth
hormone
deficiency, type 1a;
IGHD1A
# 262400 GH1
(139250)
Proportionate short stature, decreased
growth velocity, micropenis, fasting
hypoglycemia, truncal obesity, high-
pitched voice, pubertal delay
(gonadotropin independent)
Low GH and IGF1 levels, fasting
hypoglycemia, high cholesterol levels
Unknown Unknown Since the
second/
third year
of life
[39]
10) Pituitary tumors
(Carney complex,
type 1)
#160980 PRKAR1A
(188830)
Spotty skin, cardiac myxomas,
pigmentation, precocious puberty,
Cushing’s syndrome, caused by
primary pigmented nodular adrenal
dysplasia, skin pigmented lesions,
pituitary tumors precocious, thyroid
and testes tumors, other myxoid
tumors
Variable, 20–30 % hypercortisolism
with low ACTH levels, less frequently
high levels of PRL, GH or IGF-1, or
high levels of T, high serum FT4, FT3
levels, low TSH level
Unknown \1/
1,000,000
Neonatal/
infancy
[40]
Table 2 Rare thyroid diseases
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
1) Sporadic medullary
thyroid carcinoma
(MTC)
–RET
(164761)
Thyroid nodules with possible lymph
node or distant metastases, diarrhea
High CEA and calcitonin levels 0.5 of all
thyroid
cancers
1–9/100,000 Adulthood [41]
2) Familial medullary thyroid carcinoma
2a) Familial medullary
thyroid carcinoma
(MTC)
# 155240 RET
(164761)
NTRK1
(191315)
Thyroid nodules with possible lymph
node or distant metastases, diarrhea.
Four or more family members across
at least two or more generations
have isolated medullary thyroid
carcinoma
High CEA and calcitonin levels Unknown Unknown Adulthood
(if no
screened)
[42]
2b) Familial medullary
thyroid carcinoma
(multiple endocrine
neoplasie: MEN2A)
# 171400 RET
(164761)
Medullary thyroid carcinoma,
pheochromocytoma, parathyroid
adenomas. Associated characteristic
features: cutaneous lichen
amyloidosis, Hischprung’s disease
rarely prominent corneal nerves
High serum basal levels and
stimulated calcitonin, elevated
catecholamines and
catecholamine metabolites, high
serum Ca and PTH levels
Unknown 1/30,000 3–25 years [42]
J Endocrinol Invest
123
Table 2 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
3) Anaplastic thyroid
carcinoma
– – Rapidly growing thyroid mass
invading surrounding structures with
compressive symptoms. Cervical
lymph nodes enlargement and
distant metastases frequently
None Unknown 1–9/1,000,000 Adulthood
([60
years)
[44]
4) Familial differentiated thyroid cancer
4a) Familial
differentiated thyroid
cancer (Carney
complex, type 1)
# 160980 PRKAR1A
(188830)
Spotty skin pigmentation, cardiac
myxomas, endocrine overactivity,
acromegaly, Cushing’s syndrome,
caused by primary pigmented
nodular adrenal dysplasia, pituitary
tumors and thyroid and testes
tumors, other myxoid tumors
None Unknown Unknown Neonatal/
infancy
[45]
4b) Familial
differentiated thyroid
cancer (Cowden
syndrome 1)
# 158350 PTEN
(601728)
Multiple hamartomas in the skin,
breast, thyroid, digestive tract,
endometrium and the brain, high risk
of malignant tumors (breast,
endometrium and follicular thryoid
cancer)
None Unknown 1/200,000 Neonatal/
infancy
[46]
4c) Familial
differentiated thyroid
cancer (Gardner
syndrome)
# 175100 APC
(611731)
Patients may begin to develop
multiple polyps in the colon. Unless
the colon is removed, these polyps
will become malignant (cancerous)
None 1/8,300 1/
11,300–37,600
Second
decade of
life
[47]
5) Familial nonmedullary
thyroid cancer,
papillary
# 188550 TRIM33
(605769)
TRIM24
(603406)
PCM1
(600299)
NCOA4
(601984)
CCDC6
(601985)
GOLGA5
(606918)
Thyroid nodule, usually single, fixed,
freely moveable. Hoarseness,
dysphagia, cough and dyspnea are
signs of the advanced stages of the
disease. Two or more family
members across at least 2 or more
generations have isolated papillary
thyroid cancer
None Unknown Unknown Variable [48]
6) Thyroglossal duct
cyst, familial
# 188455 – Growing thyroid mass in the median
region of the neck
None Unknown Unknown Variable [49]
J Endocrinol Invest
123
Table 2 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
7) Thyroid hormone
resistance, generalized,
autosomal dominant;
GRT
# 188570 THRB
(190160)
Goiter, clinically euthyroid, delayed
speech development, childhood
attention-deficit/hyperactivity
disorder
High FT3 and FT4 levels,
inappropriate secretion of TSH
1/50,000 Unknown Neonatal/
infancy
[50]
8) Hypothyroidism,
Congenital,
Nongoitrous, 6;
CHNG6
# 614450 THRA Growth retardation, delayed mental
and bone development, and
constipation
Normal TSH levels, low-normal
FT4 and high normal FT3 levels
Unknown Unknown Neonatal/
infancy
[51]
9) Permanent congenital hypothyroidism
9a) Permanent congenital
hypothyroidism
(Allan–Herndon–
Dudley syndrome;
AHDS)
# 300523 SLC16A2
(300095)
Mental retardation, congenital
hypotonia, generalized muscle
weakness
High FT3 levels, low to below
normal FT4 levels and levels of
TSH within the range
1/4,000 \1/1,000,000 Neonatal [52]
9b) Permanent congenital
hypothyroidism
(Hypothyroidism,
athyroidal, with spiky
hair and cleft palate)
# 241850 FOXE1
(602617)
Athyroidal hypothyroidism cleft
palate, spiky hair, choanal atresia,
bifid epiglottis
High FT3 levels, low to below
normal FT4 levels and TSH
levels within the range
Unknown \1/1,000,000 Neonatal [53]
9c) Hypothyroidism,
congenital,
nongoitrous, 1;
CHNG1 (TSH
resistance)
# 275200 TSHR
(603372)
Rare hypoparathyroidism, hypoplastic
thyroid glands
High TSH levels, low FT4 levels Unknown Unknown Neonatal [54]
9d) Pendred syndrome;
PDS
# 274600 SLC26A4
(605646)
Bilateral sensorineural hearing loss
(with variable degree), euthyroid
goiter
None Unknown 1–9/100,000 Neonatal/
Infancy
[55]
9e) Hypothyroidism,
congenital,
nongoitrous, 2;
CHNG2
# 218700 PAX 8
(167415)
Hypothyroidism with thyroid
agenesis, hypoplastic, ectopy,
normal sized thyroid gland
Low FT4 and FT3 levels, high
TSH levels
Unknown 2/100,000 Neonatal [56]
9f) Choreoathetosis and
congenital
hypothyroidism with or
without pulmonary
dysfunction; CAHTP
# 610978 NKX2–1
(600635)
Hypothyroidism with thyroid
agenesis, hypoplasia, normal sized
thyroid gland, respiratory distress,
neurological disorders
(choreoathetosis)
Low FT4 and FT3 levels, high
TSH levels
Unknown Unknown Neonatal [57]
10) Inherited Thyroxine-
binding globulin
deficiency
–SERPINA7
(314200)
Clinically euthyroid individuals with
partial to complete TBG deficiency
Low total FT4 levels, normal
TSH and FT4 levels, low to
undetectable TBG levels
1:5,000
newborns
(1:2,800
in males)
1–5/100,000 Variable [58]
J Endocrinol Invest
123
Table 2 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range
of
expression
References
11) Thyroid dyshormonogenesis
11a) Thyroid
dyshormonogenesis 1;
TDH1
# 274400 SLC5A5
(601843)
Hypothyroidism with diffuse or
nodular goiter
Low FT4 and FT3 levels, high
TSH levels, low saliva/plasma
(123)I ratio
Unknown Unknown Variable [59]
11b) Thyroid
dyshormonogenesis
2A; TDH2A
# 274500 TPO
(606765)
Hypothyroidism with diffuse or
nodular goiter
Low FT4 and FT3 levels, high
TSH levels
Unknown 1/66,000 Neonatal [60]
11c) Thyroid
Dyshormonogenesis 3;
TDH3
# 274700 TG
(188450)
Hypothyroidism with diffuse or
nodular goiter
Low FT4 and FT3 levels, high
TSH levels, urinary excretion of
iodopeptides
Unknown 1/100,000 Variable [61]
11d) Thyroid
dyshormonogenesis 4;
TDH4
# 274800 IYD
(612025)
Permanent hypothyroidism with goiter Low FT4 and FT3 levels, high
TSH levels, urinary excretion of
MIT and DIT
Unknown Unknown Neonatal [62]
11e) Thyroid
dyshormonogenesis 6;
TDH6
# 607200 DUOX2
(606759)
Permanent or transient
hypothyroidism with normal sized
thyroid gland or goiter
Normal or low FT4 and FT3
levels, high TSH levels
Unknown Unknown Neonatal [63]
Table 3 Rare mineral and bone diseases
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
1) Osteogenesis imperfecta; OI
1a) Osteogenesis
imperfecta type 1
# 166200 COL1A1
(120150)
Mild form
Blue sclera, no dentinogenesis imperfecta,
minimal bony deformity, risk of
vertebral and long bone fractures,
normal height, minimal functional
limitations
None Unknown The overall prevalence
of OI is estimated at
between 1/10,000 and
1/20,000, but the
prevalence of type I is
unknown
Childhood [64]
1b) Osteogenesis
Imperfecta type 3
# 259420 COL1A1
(120150)
COL1A2
(120160)
The most severe form
Risk of perinatal lethality, multiple long
bone deformities, fractures at birth (over
50 % are wheelchair dependent at an
early stage, very short stature with adult
height ranging from 90 to 120 cm,
possible respiratory compromise), blue
or grey sclera, severe dentinogenesis
imperfecta and triangular faces
None Unknown Unknown Neonatal/
infancy
[64]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
1c) Osteogenesis
Imperfecta type 4
# 166220 COL1A1
(120150)
COL1A2
(120160)
Moderate severity. The patients range
from being fully mobile to completely
wheelchair dependent. Scoliosis, severe
osteoporosis, ligament laxity, blue
sclera at a young age and white in
adults, no dentinogenesis imperfecta,
triangular faces
None Unknown Unknown Neonatal/
infancy
[64]
1d) Osteogenesis
Imperfecta type 5
# 610967 IFITM5
(614757)
Distinctive phenotype with moderate to
severe bone fragility. Hypertrophic
callus formation and early calcification
of the interosseous membrane between
the bones of the forearm. Limits of
pronation and supination, radial head
dislocation. The lamellar organization
of the bone: irregular mesh-like
appearance. No blue sclera and
dentinogenesis imperfecta
None Unknown \1/1,000,000 Neonatal/
infancy
[64]
1e) Osteogenesis
Imperfecta type 6
# 613982 SERPINF1
(172860)
Moderate to severe skeletal deformity and
fragility. Bone biopsy specimens: fish
scale-like appearance of the bone
lamellae and the presence of excessive
osteoid. No blue sclera or
dentinogenesis imperfecta
None Unknown Unknown Neonatal/
Infancy
[64]
2) Cystic angiomatosis
of bone
– – Disseminated multifocal hemangiomatous
and/or lymphangiomatous lesions of the
skeleton, in both the axial and
appendicular skeleton, with possible
visceral organ involvement. The process
can be monostotic or polyostotic,
isolated skeletal involvement is very
rare
Laboratory findings
are unremarkable,
although increases
in ALP activity have
been noted
Unknown Unknown The first
decade of
life, it is
usually
manifested
by the age
of puberty,
with a
range
extending
to the third
decade
[65]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
3) Cystic angiomatosis
of bone, diffuse;
GSD
# 123880 – The most severe form of cystic
angiomatosis of bone. Severe
debilitation, resorption of most or all of
a bone associated with a proliferation of
vascular channels. Histologically
compared to cystic angiomatosis of
bone, it produces significantly more
destruction with osteolysis and tends to
involve one bone only
Laboratory findings
are unremarkable,
although increases
in ALP have been
noted
Unknown Unknown Variable [66]
4) Vitamin d hydroxylation-deficient rickets
4a) Vitamin d
hydroxylation-
deficient rickets, type
1a; VDDR1A
# 264700 CYP27B1
(609506)
Rickets, tetany, convulsions, seizures,
muscle weakness, and poor growth.
Enamel hypoplasia is occasionally
observed
Low serum Ca levels,
very low/
undetectable 1–25
OH
2
D
3
levels,
normal 25 OH D
3
levels, slightly high
PTH levels,
high BAP levels
Unknown 1/2,700 in Quebec
Rare in other countries
Soon after
birth
[67]
4b) Vitamin d
hydroxylation-
deficient rickets, type
1b; VDDR1B
# 600081 CYP2R1
(608713)
Hypotonia, muscle weakness, difficulty in
walking, difficulty in standing, rickets,
increased fractures, bone pain, sparse
bone trabeculae, thin bony cortex,
delayed opacification of the epiphyses,
widened, distorted epiphyses, frayed,
irregular metaphyses, lower limb
deformities, bowing of the legs
Curvatures of the femur, tibia, fibula,
enlargement of the wrists, enlargement
of the ankles
Low serum Ca and P
levels, high 1–25
OH
2
D
3
levels,
normal 25 OH D
3
levels, markedly
high PTH and BAP
levels
Unknown 1/2,358, in the
Saguenay-Lac-Saint-
Jean region of Quebec
province
Rare in other countries
Infancy [68]
4c) Vitamin
d-dependent rickets,
type 2a;VDDR2A
# 277440 VDR
(601769)
Growth retardation, muscle weakness,
convulsion for hypocalcemia, bone pain
at the lower extremities that delays their
development of walking, fracture and
pseudo-fractures, fracture and pseudo-
fractures sparse bone trabeculae thin
bony cortex, delayed opacification of
the epiphyses, subperiosteal erosions
due to secondary hyperparathyroidism
dental caries or hypoplasia of the teeth,
scalp and body alopecia
Low serum Ca and P
levels, high 1–25
OH
2
D
3
levels,
normal 25 OH D
3
levels, markedly
high PTH and BAP
levels
Unknown Unknown First 6
months of
life
[69]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
5) Tumoral calcinosis
5a) Tumoral calcinosis,
hyperphosphatemic,
familial; HFTC
# 211900 GALNT3
(601756)
FGF23
(605380)
KL
(604824)
Altered skeletal mineralization, ectopic
calcifications around large joints, soft
tissue masses around the hips, the
shoulders and the elbows
Low Ur. P levels, high
serum P levels and
TmP/GFR, normal
serum Ca, Ur. Ca,
PTH, and 25 OH D
3
levels,
inappropriately high
1–25 OH
2
D
3
, low
intact serum FGF23
levels
Unknown 1/20,000 Unknown [70]
5b) Tumoral calcinosis,
normophosphatemic,
familial; NFTC
# 610455 SMAD9
(610456)
Reddish to hyperpigmented skin lesions,
soft tissue masses at the extremities,
severe conjunctivitis, and severe
gingivitis
Normal Ur. P and
serum P levels
Unknown Unknown Unknown [71]
6) Hypophosphatemic
rickets, X-linked
dominant; XLHR
# 307800 PHEX
(300550)
Rickets/osteomalacia short stature, late
dentition, tooth abscesses
High Ur. P levels, low
serum P and renal
TmP/GFR levels,
normal serum Ca
levels, low Ur. Ca
levels, normal PTH
and 25 OH D
3
levels,
inappropriately low
or normal 1–25 OH
2
D
3
levels, high BAP
intact FGF23 levels,
low serum GH (not
always)
1/25,000 1–9/100,000 Within 1
year of life
[72]
7) Hypophosphatemic
rickets, autosomal
dominant; ADHR
# 193100 FGF23
(605380)
Rickets/osteomalacia, short stature,
fatigue and weakness
High Ur. P levels, low
serum P and renal
TmP/GFR levels,
normal serum Ca
levels, low Ur. Ca
levels, normal PTH
and 25 OH D
3
levels,
inappropriately low
or normal 1–25 OH
2
D
3
levels, high BAP
intact FGF23 levels
Unknown \1/1,000,000 1–3 years [73]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
8) Hypophosphatemic
rickets with
hypercalciuria,
hereditary; HHRH
# 241530 SLC34A3
(609826)
Rickets/osteomalacia, kidney stone,
nephrocalcinosis
High Ur. P levels, low
serum P levels, low
Renal TmP/GFR,
high Ur.Ca levels,
normal/high serum
Ca levels, high 1–25
OH
2
D
3
levels,
normal 25 OH D
3
and PTH levels
Unknown \1/1,000,000 1–3 years [72]
9) Osteoglophonic
dysplasia; OGD
# 166250 FGFR1
(136350)
Rickets/osteomalacia, severe craniofacial
abnormalities, bone dysplasia,
macroglossia, and hypertrophy of the
gums, severe dwarfism, mandibular
prognathism, frontal bossing, and
proptosis
High Ur. P levels, low
serum P and renal
TmP/GFR, normal
Ur. Ca, serum Ca,
PTH, 25 OH D
3
levels, normal/low
1–25 OH
2
D
3
levels,
high serum intact
FGF23 levels
Unknown Unknown Newborns [74]
10) Hypophosphatemic
rickets, autosomal
recessive; ARHR1
# 241520 DMP1
(600980)
High bone density at the base of skull,
clavicles and ribs anomalies,
enthesopathies, short stature, limited
movement of spine and hip,
calcification of the ligaments at the
bony insertions sites
High Ur. P levels, low
serum P and renal
TmP/GFR levels,
low Ur. Ca levels,
normal serum Ca,
PTH levels, high
BAP, extremely
high intact serum
FGF23 levels
Unknown Unknown 1–3 years [72]
11) Nephrolithiasis/
osteoporosis,
hypophosphatemic,
1; NPHLOP1
# 612286 SLC34A1
(182309)
Kidney stones, nephrocalcinosis,
osteoporosis
High Ur. P levels, low
serum P and renal
TmP/GFR levels,
high Ur. Ca levels,
normal serum Ca,
PTH levels, high
1–25 OH
2
D
3
levels,
low/normal high
serum intact FGF23
levels
Unknown \1/1,000,000 Variable [72]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
12) Hypophosphatemic
rickets and
hyperparathyroidism
% 612089 – Rickets, kidney stones High Ur.P, low levels
renal TmP/GFR,
and serum P levels,
high serum Ca
levels,
inappropriately
normal 1–25 OH
2
D
3
levels, high PTH,
serum intact FGF23,
and serum a-Klotho
levels
Unknown Unknown 10 years [75]
13) Osteopetrosis
13a) Osteopetrosis,
autosomal recessive
1; OPTB1
# 259700 TCIRG1
(604592)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometimes hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible,
generalized high bone mass, sclerotic
cranial base, loss of trabecular structure,
poor definition between cortical and
medullary bone, short stature,
macrocephaly, frontal bossing, genus
valgum, ‘‘rugger-Jersey’’ spine
(vertebral endplate thickening)
Low serum Ca levels,
high PTH, 1–25
OH
2
D
3
, BB-CK,
and acid
phosphatase levels,
anemia
1/200,000
live
births
1–9/1,000,000 Neonatal/
infancy
[76]
13b) Osteopetrosis,
autosomal recessive
2; OPTB2
# 259710 TNFSF11
(602642)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometime hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible,
generalized high bone mass, sclerotic
cranial base, loss of trabecular structure,
poor definition between cortical and
medullary bone, short stature,
macrocephaly, frontal bossing, genus
valgum
Low serum Ca levels,
high PTH, 1–25
OH
2
D
3
, BB-CK,
and acid
phosphatase levels,
anemia
1/200,000
live
births
1–9/1,000,000 Neonatal/
infancy
[76]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
13c) Osteopetrosis,
autosomal recessive
3; OPTB3
# 259730 CA2
(611492)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometime hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible, cerebral
calcification, mental retardation,
generalized high bone mass, sclerotic
cranial base, loss of trabecular structure,
poor definition between cortical and
medullary bone, short stature,
macrocephaly, frontal bossing, genus
valgum, fractures very common
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels,
immunodeficiency,
anemia, tubular
renal acidosis
Unknown \1/1,000,000 Neonatal/
infancy
[76]
13d) Osteopetrosis,
autosomal recessive
4; OPTB4
# 611490 CLCN7
(602727)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometime hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible,
generalized high bone mass, sclerotic
cranial base, loss of trabecular structure,
poor definition between cortical and
medullary bone, short stature,
macrocephaly, frontal bossing, genus
valgum, ‘‘rugger-Jersey’’ spine
(vertebral endplate thickening)
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels, anemia
1/200,000
live
births
1–9/1,000,000 Neonatal/
infancy
[76]
13e) Osteopetrosis,
autosomal recessive
5; OPTB5
# 259720 OSTM1
(607649)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometime hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible,
generalized high bone mass, sclerotic
cranial base, loss of trabecular structure,
poor definition between cortical and
medullary bone, short stature,
macrocephaly, frontal bossing, genus
valgum, ‘‘rugger-Jersey’’ spine
(vertebral endplate thickening)
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels, anemia
Unknown \1/1,000,000 Neonatal/
Infancy
[76]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
13f) Osteopetrosis,
autosomal recessive
6; OPTB6
# 611497 PLEKHM1
(611466)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometime hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible, facial
palsy due to cranial nerve VII
compression, bone marrow failure (in
some patients), generalized high bone
mass, sclerotic cranial base, loss of
trabecular structure, poor definition
between cortical and medullary bone,
short stature, macrocephaly, frontal
bossing, genus valgum, ‘‘rugger-Jersey’’
spine (vertebral endplate thickening),
hip osteoarthritis
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels, anemia
Unknown Unknown Childhood [76]
13g) Osteopetrosis,
autosomal recessive
7; OPTB7
# 612301 TNFRSF11A
(603499)
Hearing loss, blindness (retinal
degeneration or increase of intracranical
pressure), sometime hydrocephalus,
hypersplenism, dental problems,
osteomyelitis of the mandible
generalized high bone mass, sclerotic
cranial base, loss of trabecular structure,
poor definition between cortical and
medullary bone, short stature,
macrocephaly, frontal bossing, genus
valgum
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels, anemia
Unknown \1/1,000,000 Unknown [76]
13h) Osteopetrosis,
autosomal dominant
1; OPTA1
# 607634 LRP5
(603506)
Increase in bone density that affects
mainly the cranial vault, chronic
skeletal pain and disorders of the cranial
nerves (trigeminal neuralgia, facial
paralysis, deafness)
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels, anemia
Unknown \1/1,000,000 Adolescence/
young
adulthood
[77]
13i) Osteopetrosis,
autosomal dominant
2; OPTA2
# 166600 CLCN7
(602727)
The typical radiographic sign is
‘‘sandwich vertebrae’’ (dense bands of
sclerosis parallel to the vertebral
endplates). The main complications are
confined to the skeleton, including
fractures, scoliosis, hip osteoarthritis
and osteomyelitis, particularly affecting
the mandible in association with dental
abscess or caries. Cranial nerve
compression is a rare but important
complication, with hearing and visual
loss affecting around 5 % of individuals
Low serum Ca levels,
high PTH, 1–25
OH
2
D3, BB-CK,
acid phosphatase
levels, anemia
Unknown 1–9/100,000 Childhood [78]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
14) Pycnodysostosis # 265800 CTSK
(601105)
Dolichocephaly, open fontanel,
generalized high bone mass, bone
fragility, short stature, clavicular
dysplasia, obtuse angle of mandible,
short terminal phalanges
Low GH and IGF-I
levels
Unknown 1–1.7/1,000,000 Infancy/early
childhood
[79]
15) Osteopoikilosis # 166700 LEMD3
(607844)
Disseminate connective tissue nevi with
both elastic-type nevi
(juvenile elastoma) and collagen-type
nevi (dermatofibrosis lenticularis
disseminate), osteosclerotic foci in
epimethaphysal regions of long bones
Unknown Unknown 1/50,000 Childhood/
adulthood
[76]
16) Endosteal hyperostosis
16a) Hyperostosis
corticalis generalisata
# 239100 SOST
(605740)
Progressive asymmetrical enlargement of
the jaw that occurs during puberty. The
adult mandible is markedly thickened
with a wide angle, dental malocclusion
is uncommon. Recurrent facial nerve
palsy, deafness and optic atrophy from
narrowing of cranial foramina are
common and can begin as early as
infancy. Long bones may become
painful with applied pressure, but there
are no fractures
ALP activity in serum
may be increased
Unknown Unknown Variable [80]
16b) Hyperostosis
corticalis
generalisata, benign
form of worth, with
torus palatinus
# 144750 LRP5
(603506)
The clinical manifestations and the
radiological signs, including wide
mandibular bone, can be identical to
Van Buchem disease and sclerostenosis.
The absence of fractures, increased
thickness of the cortices of the long
bones, and increased density of the axial
skeleton. Metamorphosis of the face
occurs during adolescence as the
forehead flattens, the mandibules
become elongated and the gonial angle
decreases. Taurus palatinus (osseous
prominance of the palate vault)
There is a homogenous increase in bone
mass without sclerotic bands, and the
cranial vault rather than the basis is
dense. Fractures are unusual
ALP activity in serum
may be increased
Unknown Unknown Variable [80]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
17) Camurati–
Engelmann disease;
CAEND
# 131300 TGFb1
(190180)
Leg pain, muscular weakness, diaphyseal
dysplasia, hyperostosis of the skull base,
cortical bone thickening and sclerosis of
the diaphysis of the long tubular bones
by both endosteal and periosteal bone
proliferation
Anemia Unknown Unknown Childhood [80]
18) Craniometaphyseal
dysplasia, autosomal
dominant; CMDD
# 123000 ANKH
(605145)
Impaired vision, hearing loss, facial nerve
paralysis, metaphyseal flaring,
hyperostosis and sclerosis of the cranial
bones, thick bony wedge over the bridge
of the nose and glabella (first signs)
Unknown Unknown \1/1,000,000 Childhood [81]
19) Melorheostosis % 155950 LEMD3
(607844)
Sporadically joint contractures,
sclerodermatous skin lesions, muscle
atrophy, hemangiomas, lymphedema,
linear hyperostosis of the cortex of long
bones reminiscent of dripping candle
wax
There is no definitive
diagnostic
laboratory test for
melorheostosis and
the results of
complete blood
count, as well as
serum P and ALP
tests are typically
normal
Unknown \1/1,000,000 Variable [82]
20) Hypophosphatasia:
20a) Hypophosphatasia
perinatal
# 241500 ALPL
(171760)
Extreme skeletal demineralization,
irritability, periodic apnea with
cyanosis, bradycardia, fever,
myelophthisic anemia, intracranical
hemorrhage
High serum Ca levels,
low PTH, 1–25 OH
2
D
3
, and ALP levels,
high serum
pyridoxal-50-
phosphate
monohydrate levels
Unknown Unknown In utero [83]
20b) Hypophosphatasia
infantile
# 241500 ALPL
(171760)
Rickets, skeletal demineralization with
fracture and thoracic deformity,
inadeguate weight gain, hypotonia,
seizures, nephrocalcinosis
High serum Ca levels,
high Ur. Ca levels,
low PTH, 1–25 OH
2
D
3
, ALP levels, high
serum pyridoxal-50-
phosphate
monohydrate levels
Unknown Unknown Postnatally
but before
6 months
[83]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
20c) Hypophosphatasia
childhood
# 241510 ALPL
(171760)
Rickets, progressive premature loss of
teeth (before 5 years), premature fusion
of cranial sutures with craniosinostosis,
short stature, waddling gait
Normal serum Ca
levels; normal Ur.
Ca levels, high
serum P levels (in
50 % of patients),
high TmP/GFR, low
ALP levels, high
serum pyridoxal-50-
phosphate
monohydrate levels
Unknown Unknown After 6
months
[83]
20d) Hypophosphatasia
adult
# 146300 ALPL
(171760)
Recurrent metatarsal fractures, femoral
pseudo-fractures, osteopenia,
chondrocalcinosis
Normal serum Ca
levels, normal Ur.
Ca levels, high
serum P levels (in
50 % of patients),
high TmP/GFR
levels, low ALP
levels, high serum
pyridoxal-50-
phosphate
monohydrate levels
Unknown Unknown Adulthood [83]
21) Familial expansile
osteolysis; FEO
# 174810 TNFRSF11A
(603499)
Focal skeletal changes, with
predominantly peripheral distribution
Progressive osteoclastic resorption
accompanied by medullary expansion
led to severe, painful, disabling
deformity and a tendency to pathologic
fracture, associated deafness and loss of
dentition
Serum ALP and
urinary
hydroxyproline are
elevated to a
variable degree,
possible high serum
Ca levels
Unknown Unknown Childhood/
second
decade
[84]
22) Hyperphosphatasia with mental retardation syndrome
22a)
Hyperphosphatasia
with mental
retardation syndrome
type 1; HPMRS1
# 239300 PIGV
(610274)
Mental retardation, various neurologic
abnormalities such as seizures and
hypotonia, hyperphosphatemia, facial
dysmorphism, variable degrees of
brachytelephalangy
High serum ALP
levels
Unknown \1/1,000,000 Neonatal/
infancy
[85]
22b)
Hyperphosphatasia
with mental
retardation syndrome
type 2; HPMRS2
# 614749 PIGO
(614730)
Moderately to severely delayed
psychomotor development, facial
dysmorphism, brachytelephalangy,
additional features, such as cardiac
septal defects or seizures
High serum ALP
levels
Unknown Unknown Neonatal/
infancy
[86]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
22c)
Hyperphosphatasia
with mental
retardation syndrome
type 3; HPMRS3
# 614207 PGAP2
(615187)
Mild to severe mental retardation,
hypotonia with very poor motor
development, sensorineural hearing,
loss seizures, poor speech, mild
microcephaly, disordered sleep pattern
High serum ALP
levels
Unknown Unknown Neonatal/
infancy
[87]
23) Paget disease,
juvenile
# 239000 TNFRSF11B
(602643)
Osteoporosis, expanded long bones,
bowed long bones, and coarse
trabeculations, calvaria markedly
thickened with islands of increased bone
density, muscular weakness may be
striking
Retinal degeneration, premature loss of
teeth and dwarfism mentally retardation
High acid and ALP
levels, high leucine
aminopeptidase, and
hydroxyproline in
blood and urine
levels, high uric
acid, high serum
osteocalcin and
urinary
hydroxyproline and
pyridinoline:
deoxypyridinoline
levels
Rare \1/1,000,000 Childhood [88]
24) McCune–Albright
syndrome; MAS
# 174800 GNAS
(139320)
Cranial foramen impingement, cranio-
facial hyperostosis, facial asymmetry,
deafness, blindness, gastrointestinal
polyps, polyostotic fibrous dysplasia,
pathologic fracture, large cafe au lait
spots with irregular margins, pituitary
adenoma hyperthyroidism,
hyperparathyroidism, Cushing
syndrome, precocious puberty,
acromegaly, hyperprolactinemia
High GH levels and
PRL excess,
hypercortisolism,
suppressed levels of
TSH and elevated
FT3, high serum
estradiol in female,
excess of T in male,
renal P wasting,
with or without
hypophosphatemia
Unknown 1–9/1,000,000 Chilhood [89]
25) Exostoses multiple
25a) Exostoses
multiple type1
# 133700 EXT1
(608177)
Multiple outgrowing cartilage-capped
bony protuberances, mostly located in
the metaphyseal and juxta-metaphyseal
regions of long bones.
Osteochondromas, which can be
asymptomatic or result in pain,
compression of peripheral nerves or
vessels, bony deformity, restricted range
of joint movement, and short stature
Unknown Unknown 1–9/100,000 Childhood [90]
25b) Exostoses
multiple type 2
# 133701 EXT2
(608210)
Malignant transformation of
osteochondroma towards secondary
peripheral chondrosarcoma
Unknown Unknown 1–9/100,000 Childhood [91]
J Endocrinol Invest
123
Table 3 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
26) Fibrodysplasia
ossificans
progressiva; FOP
# 135100 ACVR1
(102576)
Intermittently progressive ectopic
ossification and malformed big toes,
which are often monophalangic (hallux
valgus, malformed first metatarsal, and/
or monophalangism). Sporadic episodes
of painful soft tissue swellings, occur
which are often precipitated by soft
tissue injury, intramuscular injections,
viral infection, muscular stretching, falls
or fatigue. Atypical features (e.g.
intercurrent aplastic anemia,
craniopharyngioma, childhood
glaucoma or growth retardation)
Unknown Unknown \1/1,000,000 Childhood [92]
Table 4 Rare diseases of the PTH/PTHR1 and PTHrP receptors
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
1) Hyperparathyroidism familial isolated:
1a)
Hyperparathyroidism
type 1; HRPT1
# 145000 CDC73
(607393)
Parathyroid adenoma, hyperplasia High PTH and serum Ca
levels, low serum P
levels
Unknown Unknown Variable [93]
1b)
Hyperparathyroidism
type 3; HRPT3
% 610071 – Parathyroid adenoma, hyperplasia High PTH and serum Ca
levels, low serum P
levels
Unknown Unknown Variable [94]
2) Hyperparathyroidism familial not isolated:
2a)
Hyperparathyroidism
familial not isolated
(MEN1)
# 131100 MEN1
(613733)
Parathyroid adenoma/hyperplasia, entero-pancreatic
tumor (gastrinoma, insulinoma, non-functioning
neuroendocrine tumor, glucagonoma, VIP-oma,
somatostatinoma), Foregut carcinoid, thymic
carcinoid, bronchial carcinoid, gastric
enterochromaffin-like non-functioning tumors, anterior
pituitary tumor (PRL, GH ?PRL, GH, non-
functioning, ACTH, TSH), adrenal cortex non-
functioning tumors, pheochromocytoma, lipomas,
facial angiofibromas, collagenomas
High levels of one or
more of the following
markers: PRL, IGF-1,
gastrin, Fasting
glucose, insulin, PP,
glucagon, VIP, CgA,
Ca, PTH
0.2–2/100,000 1–3.3/100,000 5–81 years [95]
J Endocrinol Invest
123
Table 4 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
2b) Hyperparathy-
roidism familial not
isolated (MEN2A-2B)
# 171400
# 162300
RET
(164761)
MEN2A: Medullary thyroid carcinoma,
pheochromocytoma, parathyroid adenomas
Associated characteristic features: cutaneous lichen
amyloidosis, Hischprung’s Disease rarely prominent
corneal nerves
MEN2B: Aggressive medullary thyroid carcinoma,
pheochromocytoma, mucosal neuromas, and thickened
corneal nerves
Associated characteristic physical features: full lips,
thickened eyelids, high-arched palate, marfanoid
habitus
High serum basal levels
and stimulated
calcitonin, elevated
catecholamines and
catecholamine
metabolites, high
serum Ca and PTH
levels
MEN2A: Unknown
MEN2B: \1/
500,000
MEN2A:1/30,000
MEN2B: \1/
100,000
MEN2A:3–25
years
MEN2B:
Childhood
(earlier onset
in first years
of life)
[42,43]
2c) Hyperparathyroidism
familial not isolated
(MEN4)
# 610755 CDKN1B
(600778)
Intermediate features between MEN1 and MEN2 with
presence of neoplasms in at least 2 endocrine glands
High serum Ca,
calcitonin, CEA, PTH,
gastrin, insulin, VIP,
PP, somatostatin,
CgA, PRL, GH, IGF-
1, ACTH, UFC,
serum, and urinary
catecholamines levels.
High or low glycemia,
low serum P levels
Unknown 4/100,000 50–55 years [96]
2d) Hyperparathyroidism
2; HRPT2
(Hyperparathy
-roidism-jaw tumor
syndrome)
#145001 CDC73
(607393)
Parathyroid adenoma/hyperplasia, renal tumors (Wilm
tumors, polycystic kidney disease or renal
harmartomas) and fibro-osseous tumors of the jaw
High PTH and serum Ca
levels, low serum P
levels
Unknown Unknown Variable [97]
3) Primary hyperparathyroidism due to somatic mutations
3a) Primary
hyperparathyroidism
due to somatic
mutations (MEN1)
# 131100 MEN1
(613733)
Tumors of parathyroids, weakness, fatigue, depression,
bone pain, muscle soreness, decreased appetite,
feelings of nausea and vomiting, constipation,
polyuria, polydipsia, cognitive impairment, kidney
stones and osteoporosis
High serum Ca, PTH,
and Ur. Ca levels, low
serum P levels
Unknown 4/100,000 50–55 years [98]
3b) Primary
hyperparathyroidism
due to somatic
mutations (MEN4)
# 610755 CDKN1B
(600778)
Intermediate features between MEN1 and MEN2 with
presence of neoplasms in at least 2 endocrine glands
High serum Ca,
calcitonin, CEA, PTH,
gastrin, insulin, VIP,
PP, somatostatin,
CgA, PRL, GH, IGF-
1, ACTH, UFC, serum
and urinary
catecholamines levels.
High or low glycemia,
low serum P levels
Unknown 4/100,000 50–55 years [99]
J Endocrinol Invest
123
Table 4 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
3c) Primary
hyperparathyroidism
due to somatic
mutations (modifier of
von Hippel–Lindau
syndrome)
#193300 CCND1
(168461)
Adrenal pheochromocytoma, retinal angioma,
hemangioblastoma of the central nervous system,
endolymphatic sac tumor, pancreatic endocrine tumor,
clear cell renal cancer
High metanephrine,
normetanephrine, 3
metossi-thyramine
levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 4–60 years [100]
3d) Primary
hyperparathyroidism
due to somatic
mutations
(Hyperparathy-
roidism-jaw tumor
syndrome)
# 145001 CDC73
(607393)
Adrenal pheochromocytoma,
retinal angioma,
hemangioblastoma of the central nervous system,
endolymphatic sac tumor, pancreatic endocrine tumor,
clear cell renal cancer
High metanephrine,
normetanephrine,
three metossi-
thyramine levels
Unknown Unknown 50–55 years [101]
4) Hyperparathyroidism,
neonatal severe;
NSHPT
# 239200 CASR
(601199)
Hypercalcemia at birth, rib fractures, hypotonia,
respiratory distress, massive increase parathyroids
Urgent total parathyroidectomy
Marked high serum Ca
levels ([16 mg/dl),
relative hypocalciuria,
very high PTH, and
serum Mg levels
Unknown Unknown At birth [102]
5) Parathyroid cancer # 608266 CDC73
(607393)
Typical signs and symptoms of marked hypercalcemia
and high PTH levels: bone pain, fractures, kidney
stone, fatigue, weakness, weight loss, anorexia, nausea,
vomiting, polyuria, and polydipsia, palpable mass in
neck [3 cm (30–70 %)
High serum Ca levels
([14–15 mg/dl), high
serum PTH (3–10
times above the upper
limit of normal range)
levels
Secretion in some
patients of N-terminal
PTH fragment
Abnormally elevated
serum and urinary
levels of hCG and its
malignant
hyperglycosilated
isoform
\1/100 Unknown 50 years [103]
6) Hypocalciuric hypercalcemia, familial
6a) Hypocalciuric
hypercalcemia,
familial type 1; HHC1
# 145980 CASR
(601199)
Hypercalcemia at birth, generally asymptomatic
Mild symptoms: easy fatigue, weakness, polydipsia
Rare pancreatitis and chondrocalcinosis
Little or no increase parathyroids, persistent after
subtotal parathyroidectomy
Mild-moderate
hypercalcemia, normal
serum Mg levels or
modestly elevated,
relative hypocalciuria,
ratio of renal calcium
clearance to creatinine
clearance below 0.01,
PTH normal or
modestly elevated
(5–10 %), normal
1–25 OH
2
D
3
levels
1/10,000–1/100,000 2 % of primary
hyperparathy
-roidism
At birth [104]
J Endocrinol Invest
123
Table 4 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
6b) Hypocalciuric
hypercalcemia,
familial type 2; HHC2
# 145981 GNA11
(139313)
Hypercalcemia at birth, generally asymptomatic High serum Ca levels
and inappropriately
low Ur Ca excretion,
normal or modestly
elevated serum Mg,
normal P/Ca clearance
to creatinine clearance
below 0.01 (in some
cases 0.010–0.011)
normal or modestly
high serum PTH levels
Unknown Unknown Unknown [105]
6c) Hypocalciuric
hypercalcemia,
familial type 3; HHC3
# 600740 AP2S1 Hypercalcemia, osteomalacia (after the age of 30 years) High serum Ca levels
and inappropriately
low Ur Ca excretion,
mild
hypophosphatemia,
modestly high serum
PTH levels
Unknown Unknown Unknown [106]
7) Hypercalcemia
hypocalciuric
acquired
–Ab anti CASR
gene
Hypercalcemia Hypercalcemia and
inappropriately low
urine calcium
excretion
Unknown Unknown Unknown [107]
8) Ectopic
hyperparathyroidism
associated to a clear
cell carcinoma of the
ovary
– – Cell carcinoma of the ovary, hypercalcemia High serum Ca and
PTHrP levels
Unknown Unknown Variable [108]
9) Ectopic
hyperparathyroidism
associated to small
cell lung carcinoma
– – Small cell lung carcinoma, hypercalcemia High serum Ca and PTH
levels
Unknown Unknown Variable [109]
10) Ectopic
hyperparathyroidism
associated to
thymoma
– – Thymoma, hypercalcemia High serum Ca and renal
tubular reabsorption
levels, low P levels,
maximal tubular
reabsorption of P, and
high serum PTH levels
Unknown Unknown Variable [110]
11) Autoimmune
isolated
hypoparathyroidism
– – Hypocalcemia Low serum Ca and PTH
levels, high serum P
levels, CaSR
antibodies and NALP5
antibodies
Unknown Unknown 20–30 years [111]
12) Hypoparathyroidism
polyendocrine
syndrome
–AIRE
(607358)
Candidiasis, hypocorticosurrenalism,
hypoparathyroidism (±other autoimmune diseases)
Low serum Ca and PTH
levels, high serum P
and ACTH levels
Unknown 1/14,000–1/80,000 20–30 years [112]
J Endocrinol Invest
123
Table 4 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
13)
Hypoparathyroidism,
familial isolated; FIH
# 146200 PTH
(168450)
GCM2
(603716)
Severe hypocalcemia Extremely low serum Ca
levels and low
undetectable PTH
levels, and high serum
P levels
Unknown \1/1,000,000 First decade [113]
14) Hypocalcemia, autosomal dominant
14a) Hypocalcemia,
autosomal dominant
1; HYPOC1
# 601198 CASR
(601199)
Mild hypocalcemia, hypercalciuria
(asymptomatic in some patients)
Low serum Ca and Mg
levels and low/normal
PTH levels, normal/
high serum P levels
Unknown \1/70,000 20–40 years [114]
14b) Hypocalcemia,
autosomal dominant
2; HYPOC2
# 615361 GNA11
(139313)
Mild hypocalcemia, hypercalciuria
(asymptomatic in some patients)
Low serum Ca and Mg
levels and low/normal
PTH levels, normal/
high serum P levels
Unknown Unknown Variable [114]
15) X-linked
hypoparathy-
roidism; HYPX
# 307700 – Epilepsy, hypocalcemia
(only males)
Low serum Ca and PTH
levels
Unknown Unknown Infantile onset [115]
16) DiGeorge
syndrome; DGS
# 188400 TBX1
(602054)
Abnormal faces, immunodeficiency, cardiac defects,
ectodermal abnormalities
Very low serum Ca and
PTH levels, high
serum P levels
Unknown 1/2,000–1/4000 10–40 years [116]
17) Hypoparathyroidism,
sensorineural deafness,
and renal disease;
HDR
# 146255 GATA3
(131320)
Hypocalcemia, bilateral deafness, renal dysplasia Low serum Ca and PTH
levels, high serum P
levels
Unknown \1/1,000,000 First decade [117]
18) Kenny–Caffey syndrome
18a) Kenny–Caffey
syndrome, Type 1;
KCS1
# 244460 TBCE
(604934)
Hypocalcemia, bone dysplasia, short stature, dental
abnormalities
Low serum Ca and PTH
levels, high serum P
levels
Unknown \1/1,000,000 First decade [118]
18b) Kenny–Caffey
syndrome, Type 2;
KCS2
# 127000 FAM111A
(615292)
Hypocalcemia, bone dysplasia, short stature, dental
abnormalities
Low serum Ca and PTH
levels, high serum P
levels
Unknown \1/1,000,000 First decade [118]
19)
Hypoparathyroidism–
retardation–
dysmorphism
syndrome; HRD
# 241410 TBCE
(604934)
Hypocalcemia, mental retardation, dysmorphism Low serum Ca and PTH
levels
Unknown \1/1,000,000 First decade [119]
20) Mitochondrial diseases
20a) Kearns–Sayre
syndrome; KSS
# 530000 Mitochondrial
DNA
—
Hypocalcemia, ophthalmoplegia, pigmentary retinal de
generation, cardiomyopathy
Low serum Ca and PTH
levels, high serum P
levels
Unknown Unknown First decade [120]
J Endocrinol Invest
123
Table 4 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
20b) Mitochondrial
myopathy,
encephalopathy, lactic
acidosis, and stroke-
like episodes;
MELAS
# 540000 Mitochondrial
DNA
—
Myopathy, encephalopathy, stroke-like episodes None Unknown Unknown Infancy [121]
20c) Trifunctional
protein deficiency
# 609015 HADHA
(600890)
HADHB
(143450)
Myopathy None Unknown Unknown Unknown [122]
20d) Deficiency of
Acyl-coa
dehydrogenase,
medium-chain;
ACADMD
# 201450 ACADM
(607008)
Myopathy None Unknown Unknown Unknown [123]
21) Pseudohypoparathyroidism
21a) Pseudohypoparathy-
roidism type 1A;
PHP1A
# 103580 GNAS
(139320)
Multiple hormone resistance, short stature, obesity,
round faces, subcutaneous ossifications, brachydactyly,
and other skeletal anomalies
Decreased cellular
cAMP response to
PTH infusion,
decreased erythrocyte
Gs activity, low serum
Ca levels, high serum
P levels
Unknown Unknown Childhood [124]
21b) Pseudohypoparathy-
roidism type 1B;
PHP1B
# 603233 GNAS
(139320)
Renal PTH resistance
No clinical features of Albright hereditary
osteodystrophy (AHO)
Decreased cAMP
response to PTH
infusion, normal
erythrocyte Gs
activity, low serum Ca
levels, high serum P
levels
Unknown Unknown Variable [125]
21c) Pseudohypoparathy-
roidism type 2; PHP2
% 203330 GNAS
(139320)
Isolated renal PTH resistance and lack the features of
AHO
Normal erythrocyte Gs
activity and a normal
cAMP response to
PTH infusion; the
phosphaturic effect of
PTH is deficient, low
serum Ca levels, high
serum P levels, and
increased PTH levels
Unknown Unknown Childhood [126]
22) Pseudopseudo
hypoparathyroidism;
PPHP
# 612463 GNAS
(139320)
Short stature, obesity, round faces, subcutaneous
ossifications, brachydactyly, and other skeletal
anomalies. Some patients have mental retardation
Abnormally high basal
urinary excretion of
cAMP and a normal
increase in urinary
cAMP after PTH
infusion
Unknown Unknown Childhood [127]
J Endocrinol Invest
123
Table 4 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range
of expression
References
23) Metaphyseal
chondrodysplasia,
Jansen type
# 156400 PTH1R
(168468)
High skull vault, flattening of the nose and forehead,
low-set ears, hypertelorism, high-arched palate,
micrognathia, retrognathia
Hyphoscoliosis with bell-shaped thorax and widened
costochondral junctions, metaphyseal enlargement of
the joints, frontonasal hyperplasia
Short legs and relatively long arms
In younger patients: Enlargement of metaphysis with a
wide zone of irregular calcifications (lesions similar to
rickets)
At the puberty partially calcified cartilage that protrude
into diaphysis
Late adolescence cartilaginous tissue in the metaphysis
disappears, sclerosis and thickening of the base of skull
with cranial auditory and optical nerve compression
High serum Ca, Ur. Ca.
and Ur. P. levels, high
Ur. cAMP levels,
undetectable/low PTH
levels
Unknown \1/1,000,000 Neonatal/
infancy
[128]
24) Eiken skeletal
dysplasia
# 600002 PTH1R
(168468)
Multiple epiphyseal dysplasia None Unknown \1/1,000,000 Neonatal/
infancy
[129]
25) Enchondromatosis,
multiple, Ollier type
% 166000 PTH1R
(168468)
Soft tissues hemangiomas (Maffucci Syndrome),
multiple enchondromas with skeletal deformities and
potential risk for malignant change to chondrosarcoma
Slightly high PTH levels Unknown 1–9/100,000 Childhood [130]
J Endocrinol Invest
123
Table 5 Rare metabolic diseases of glucose, lipids, and mucopolysaccharides
Disorder OMIM
phenotype
number
OMIM gene/locus number Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
1) Lipodystrophy, familial
partial; FPLD
# 151660
# 604367
# 613877
# 615238
Type 2: LMNA (150330) Type 3:
PPARG (601487) PPP1R3A
(600917) Type 4: PLIN1 (170290)
Type 5: CIDEC (612120)
Abnormal subcutaneous adipose
tissue distribution, metabolic
abnormalities include insulin-
resistant diabetes mellitus with
acanthosis nigricans and
hypertriglyceridemia; hirsutism
and menstrual abnormalities occur
infrequently
Hypertriglyceridemia Unknown Unknown Late
childhood/
early adult
life
[131]
2) Lipodystrophy,
congenital generalized;
CGL
# 608594
# 269700
# 612526
# 613327
Type 1: AGPAT2 (603100) Type 2:
BSCL2 (606158) Type 3: CAV1
(601047) Type 4: PTRF (603198)
Absence of adipose tissue from birth
or early infancy and severe insulin
resistance. Other clinical and
biologic features include
acanthosis nigricans, muscular
hypertrophy, hepatomegaly, altered
glucose tolerance or diabetes
mellitus, and hypertriglyceridemia
Hyperglycemia and
hypertriglyceridemia
Unknown 1–9/1,000,000 Neonatal/
infancy
[132]
3) Mandibuloacral
dysplasia with type a
lipodystrophy; MADA
# 248370 Type A: LMNA (150330) Type B:
ZMPSTE24 (606480)
Growth retardation, craniofacial
anomalies with mandibular
hypoplasia, skeletal abnormalities
with progressive osteolysis of the
distal phalanges and clavicles, and
pigmentary skin changes. The
lipodystrophy is characterized by a
marked acral loss of fatty tissue
with normal or increased fatty
tissue in the neck and trunk. Some
patients may show progeroid
features. Metabolic complications
can arise due to insulin resistance
and diabetes
Hyperglycemia and
hyperinsulinemia
Unknown \1/1,000,000 Neonatal/
infancy
[133]
4) Diabetes and deafness,
maternally inherited;
MIDD
# 520000 MT-TL1 (590050) MT-TE (590025)
MT-TK (590060)
Onset of sensorineural hearing loss
and diabetes in adulthood. Some
patients may have additional
features observed in mitochondrial
disorders, including pigmentary
retinopathy, ptosis,
cardiomyopathy, myopathy, renal
problems, and neuropsychiatric
symptoms
Hyperglycemia MIDD accounts for 0.5–3
% of diabetes mellitus
1–9/1,000,000 Adulthood [134]
5) Apolipoprotein e,
deficiency or defect of,
included
?107741 Homozygous or compound
heterozygous for apoE2 (–)
Palmar xanthomas and
manifestations of coronary and
peripheral atherosclerosis
High cholesterol,
triglycerides, and IDL
lipoprotein levels
Unknown 0.02/100 Childhood [135]
6) Acyl-coa dehydrogenase
deficiency; ACADVLD
# 201475
# 201450
Very long chain, deficiency ACADVL
(609575) Medium chain, deficiency
ACADM (607008)
Liver (Reye syndrome), heart
(hypertrophic or dilated
cardiomyopathy acute or chronic)
and muscle (moderate or severe
hypotonia or recurrent
rhabdomyolysis); hypoglycemia,
neuropathy, and pigmentary
retinopathy
Low total plasma
carnitine levels
Unknown Unknown Childhood/
adulthood
[136]
J Endocrinol Invest
123
Table 5 continued
Disorder OMIM
phenotype
number
OMIM gene/locus number Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
7) Carnitine
palmitoyltransferase 2
deficiency, late-onset
# 255110 CPT2 (600650) Inherited disorder of mitochondrial
long-chain fatty acid oxidation.
Recurrent episodes of
rhabdomyolysis triggered by
prolonged exercise, fasting, or
febrile illness
High serum muscle
enzymes and
myoglobinuria levels
Unknown Unknown Adolescence/
young
adulthood
[137]
8) Carnitine deficiency,
systemic primary; CDSP
# 212140 SLC22A5 (603377) Defect in the high-affinity carnitine
transporter expressed in muscle,
heart, kidney, lymphoblasts, and
fibroblasts. This results in impaired
fatty acid oxidation in skeletal and
heart muscle. In addition, renal
wasting of carnitine results in low
serum levels and diminished
hepatic uptake of carnitine by
passive diffusion, which impairs
ketogenesis
Low serum carnitine
levels
Unknown 1–9/100,000 Neonatal/
infancy
[138]
9) Carnitine
palmitoyltransferase
deficiency
# 255120
# 600649
Type 1: CTP1A (600528) Type 2:
CPT2 (600650)
Severe episodes of hypoketotic
hypoglycemia usually occurring
after fasting or illness
Hypoglycemia usually
occurring after fasting
or illness
Unknown \1/1,000,000 Infancy/early
childhood
[139]
10) Deficiency of Acyl-Coa
dehydrogenase, short-
chain; ACADSD
# 201470 CTP1B (601987) Clinical features are variable: a
severe form of the disorder can
cause infantile onset of acidosis
and neurologic impairment,
whereas some patients develop
only myopathy. With the advent of
screening for inborn errors of
metabolism, patients with putative
pathogenic mutations but who
remain asymptomatic have also
been identified
None Unknown Unknown Childhood [140]
11) Trifunctional protein
deficiency
# 609015 HADHA (600890) HADHB (143450) Classic trifunctional protein
deficiency can be classified into
three main clinical phenotypes:
neonatal onset of a severe, lethal
condition resulting in sudden
unexplained infant death, infantile
onset of a hepatic Reye-like
syndrome, and late-adolescent
onset of primarily a skeletal
myopathy
None Unknown \1/1,000,000 Neonatal/
infancy
[122]
12) Abetalipoproteinemia;
ABL
# 200100 MTTP (157147) Hypocholesterolemia and
malabsorption of lipid-soluble
vitamins leading to retinal
degeneration, neuropathy, and
coagulopathy. Hepatic steatosis is
also common
Hypocholesterolemia,
low vitamins A, D, E
and K levels
Unknown \1/1,000,000 Neonatal/
infancy
[141]
J Endocrinol Invest
123
Table 5 continued
Disorder OMIM
phenotype
number
OMIM gene/locus number Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
13) Fabry disease # 301500 GLA (300644) The disorder is a systemic disease,
manifests as progressive renal
failure, cardiac disease,
cerebrovascular disease, small-
fiber peripheral neuropathy, and
skin lesions, among other
abnormalities
Determination of the
enzyme alpha-
Galactosidse A activity
1/55,000 1–5/10,000 Childhood [142]
14) Hyperlipoproteinemia
type 1
# 238600 LPL (609708) Hyperchylomicronemia, pancreatitis,
hepatosplenomegaly, eruptive
xanthomas, and lactescence of the
plasma (severe phenotype),
diabetes mellitus
Extreme concentrations
of circulating large
chylomicrons
(chylomicronemia),
low or absent LPL
activity in post-heparin
plasma
1/1,000,000 Unknown Infancy/
childhood
[143]
15) Gaucher Disease # 230800
# 231000
# 231005
# 610539
Type 1, 3, 3a, 3c, Perinatal lethal:
GBA (606463) Gaucher disease,
atypical, due to saposin c
deficiency: PSAP (176801)
Intracellular accumulation of
glucosylceramide in most tissue,
‘Gaucher cells’;
hepatosplenomegaly,
pancytopenia. Type 3: central
nervous system involvement and
neurologic manifestations; ocular
pingueculae, dermal
hyperpigmentation
Clinical severity, ranging from
affected infants to asymptomatic
adults
Deficient activity of beta-
glucocerebrosidase;
chitotriosidase
deficiency
1/60,000 1/40,000 Infancy/
adulthood
[144]
16) Glycogen storage
disease; GSD
# 232200
# 232220
# 232300
#232400
# 232600
# 232800
# 232700
# 306000
# 232800
# 306000
# 261750
# 613027
# 261670
# 612933
# 611881
# 612932
# 612934
# 613507
Type1a: G6PC (613742) Type1b:
SLC37A4 (602671) Type2: GAA
(606800) Type3a, b, c, d: AGL
(610860) Type4: GBE 1 (607839)
Type5: PYGM (608455) Type6:
PYGL (613741) Type9a: PYGL
(613741) Type7: PFKM (610681)
Type9 (9a, 9b, 9c): PHKA2
(306000) PHKB (172490) PHKG2
(172471) Type10: PGAM2
(612931) Type11: LDHA (150000)
Type12: ALDOA (103850) Type13:
ENO3 (131370) Type14: PGM1
(171900) Type15: GYG1 (603942)
Affected tissue liver and muscle,
severe hypoglycemia and
hepatomegaly, growth retardation,
delayed puberty, lactic acidemia,
hyperlipidemia, hyperuricemia
Markedly high
triglycerides levels,
myoglobinuria in GSD
V, high serum lactate,
pyruvate, and creatine
kinase levels, with
myoglobinuria in GSD
type 11
1/100,000–1/300,000
Type 1 is the most
common (25 % of all
GSDs),
1/20,000–43,000
Unknown Infancy [145]
J Endocrinol Invest
123
Table 5 continued
Disorder OMIM
phenotype
number
OMIM gene/locus number Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
17) Lipomatosis, multiple % 151900 – Numerous encapsulated lipomas on
the trunk and extremities
None 0.002/100 Unknown Third or
fourth
decade
[146]
18) Hyperinsulinemic
hypoglycemia, familial;
HHF
# 256450
#601820
# 602485
# 609975
# 609968
# 606762
# 610021
Type 1: ABCC8 (600509)
Type 2: KCNJ11 (600937) Type 3:
GCK (138079) Type 4: HADH
(601609) Type 5: INSR (147670)
Type 6: GLUD1 (138130)
SLC16A1 (600682)
Severe hyperinsulinemic
hypoglycemia, neoformation of
islets of Langerhans from
pancreatic duct epithelium, b-cell
hypertrophy and b-cell hyperplasia,
brain damage
High ammonium and
insulin levels
1/5,000 births (for the
sporadic form), but may
be as high as 1/2,500
births (in societies with
high rates of
consanguinity,
especially in the
Arabian Peninsula)
Unknown Birth/infancy [147]
19) Hypercholesterolemia,
familial
# 143890 LDLR (606945) GSBS (604088)
ITIH4 (600564) APOB (107730)
PCSK9 (607786)
Tendinous xanthomas, corneal arcus,
and coronary artery disease
The phenotype can be altered by a
single nucleotide polymorphism
(SNP) in the modifier genes
(APOA2, EPHX2, GHR)
Homozygotes, including severely
elevated plasma low LDL, tuberous
and tendon xanthomata, and
premature atherosclerosis
LDL [500 mg/dl
HDL C330 mg/dl
Homozygous familial
hypercholesterolemia is
estimated to be
1/1,000,000, where the
heterozygous familial
hypercholesterolemia is
estimated at 1/500
The prevalence is
variable
Homozygous FH
is greater in
specific regions
presumably due
to founder
effects and
isolation of a
population
Birth/early
childhood
[148]
20) Hypercholesterolemia,
autosomal dominant,
type b
# 144010 APOB (107730) Tendinous xanthomas, corneal arcus,
and coronary artery disease
The phenotype can be altered by a
SNP in the modifier genes
(APOA2, EPHX2, GHR)
Homozygotes, including severely
elevated plasma low LDL, tuberous
and tendon xanthomata, and
premature atherosclerosis
LDL [500 mg/dl
HDL C330 mg/dl
Homozygous familial
hypercholesterolemia is
estimated to be
1/1,000,000, where the
heterozygous familial
hypercholesterolemia is
estimated at 1/500
The prevalence is
variable
Homozygous FH
is greater in
specific regions
presumably due
to founder
effects and
isolation of a
population
Birth/early
childhood
[148]
21) Hypercholesterolemia,
autosomal recessive;
ARH
# 603813 LDLRAP1 (605747) Tendinous xanthomas, corneal arcus,
and coronary artery disease
The phenotype can be altered by a
SNP in the modifier genes
(APOA2, EPHX2, GHR)
Homozygotes, including severely
elevated plasma low LDL, tuberous
and tendon xanthomata, and
premature atherosclerosis
LDL [500 mg/dl
HDL C330 mg/dl
Homozygous familial
hypercholesterolemia is
estimated to be
1/1,000,000, where the
heterozygous familial
hypercholesterolemia is
estimated at 1/500
The prevalence is
variable
Homozygous FH
is greater in
specific regions
presumably due
to founder
effects and
isolation of a
population
Birth/early
childhood
[148]
J Endocrinol Invest
123
Table 5 continued
Disorder OMIM
phenotype
number
OMIM gene/locus number Phenotype Typical metabolic
biomarkers
Incidence Prevalence Age range of
expression
References
22) Mucopolysaccha-
ridosis; MPS
# 607016
# 309900
#252900
#252920
#252930
#252940
# 253000
# 253010
# 253200
# 253220
# 601492
Hurler–Scheie syndrome: IDUA
(252800) MPS, type 2: IDS
(300823) MPS type 3a, b, c, d San
Filippo Syndrome a, b, c, d: SGSH
(605270) NAGLU (609701)
HGSNAT (610453) GNS (60766)
AR-MPS type 4a and I4b Morquio
Syndrome A and B: GALNS
(612222) GLB1 (611458) MPS
type 6: B ARSB (611542) MPS type
7: GUSB (611499) MPS type 9:
HYAL1 (607071)
Accumulation of
glycosaminoglycans in nearly all
cell types, tissues, and organs that
lead to organ failure, cognitive
impairment and reduced life
expectancy. Corneal clouding,
mental retardation, hernias,
dysostosis multiplex, and
hepatosplenomegaly
Airway obstruction, skeletal
deformities, cardiomyopathy, and
in most patients, neurologic decline
Urinary excretion of
glycosaminoglycans
1/100,000 Variable Early
childhood
[149]
Table 6 Rare water metabolism diseases
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical biomarkers Incidence Prevalence Age range of
expression
References
1) Diabetes
insipidus,
neurohypophyseal
# 125700
# 304900
AVP
(192340)
X-linked
recessive
(304900)
Polyuria and polydipsia Plasma osmolality [300 mOsm/kg.
Urinary osmolality \300 mOsm/kg,
urine osmolality does not increase after
fluid restriction but increases [50 %
after DDAVP
Unknown 1/25,000 About a year and a
half
[150,151]
2) Wolfram
syndrome 1;
WFS1
# 222300 WFS1
(606201)
Polyuria and polydipsia Plasma osmolality [300 mOsm/kg.
Urinary osmolality \300 mOsm/kg,
urine osmolality does not increase after
fluid restriction but increases [50 %
after DDAVP
Unknown Unknown Childhood [152]
3) Diabetes
insipidus,
nephrogenic
# 304800 AVPR2
(300538)
Polyuria and polydipsia. Episodes
of hypernatremic dehydration
during the first 1 or 2 years of
life. Sometimes low intelligence
quotient
Plasma osmolality [300 mOsm/kg.
Urinary osmolality \300 mOsm/kg,
urinary osmolality does not increase
after fluid restriction and DDAVP
Unknown 1–2/
1,000,000
At birth [153]
J Endocrinol Invest
123
Table 6 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical biomarkers Incidence Prevalence Age range of
expression
References
4) Diabetes
insipidus,
nephrogenic,
autosomal
# 125800 AQP2
(107777)
Polyuria and polydipsia. Episodes
of hypernatremic dehydration
during the first 1 or 2 years of
life. Sometimes low intelligence
quotient
Plasma osmolality [300 mOsm/kg.
Urinary osmolality \300 mOsm/kg,
urinary osmolality does not increase
after fluid restriction and DDAVP
Unknown 1–2/
1,000,000
At birth [154]
5) Nephrogenic
syndrome of
inappropriate
antidiuresis;
NSIAD
# 300539 AVPR2
(300538)
Hypotonic euvolemic
hyponatremia
The main clinical features, seizure
or irritability, appeared to be
linked to the severe
hyponatremia
Plasma osmolality \275 mOsm/kg;
urinary osmolality [100 mOsm/kg;
urinary sodium [30 mmol/l
Undetectable levels of AVP
\1/
1,000,000
\1/
1,000,000
Infancy/adulthood,
but most
diagnoses were
made during the
first 2 years of life
[155]
Table 7 Rare adrenal glands and paraganglia diseases
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
1) Familial hyperaldosteronism
1a) Glucocorticoid-
remediable
aldosteronism; GRA
(hyperaldosteronism,
familial, type 1)
# 103900 CYP11B1
(610613)
Heterogeneous phenotype:
Early severe resistant hypertension, or
normotension
Biological markers of primary
hyperaldosteronism of variable
intensity, abnormal elevated
urinary levels of 18-oxo and 18
hydroxycortisol.
Unknown Unknown Variable [156]
1b) Hyperaldosteronism,
familial, type 2
% 605635 – Early onset and sometimes severe and
resistant, hypertension, polyuria,
polydipsia, non-specific symptoms
of hypokaliemia (weakness, fatigue,
myalgia, constipation, headache)
High level of plasmatic aldosterone
suppressed plasma renin activity,
low or normal serum K levels,
metabolic alkalosis, high hybrid
steroids 18-oxo and
18-hydroxycortisol levels
Unknown Unknown Variable [157]
1c) Hyperaldosteronism,
familial, type 3
# 613677 KCNJ5
(600734)
Early onset and sometimes severe and
resistant hypertension, polyuria,
polydipsia, non-specific symptoms
of hypokaliemia (weakness, fatigue,
myalgia, constipation, headache)
High serum aldosterone levels,
suppressed plasma renin activity,
low or normal K levels, metabolic
alkalosis, high hybrid steroids
18-oxo and 18-hydroxycortisol
levels
Unknown \1/1,000,000 Infancy [158]
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
2) Gitelman syndrome # 263800 SLC12A3
(600968)
Asymptomatic or transient period of
muscle weakness, tetany, vomiting,
abdominal pains chondrocalcinosis
(swelling, local heat, tenderness
over the affected joint), tendency of
low blood pressure, sometimes
delayed growth
Low serum Mg levels, hypokaliemic
alkalosis, low Ur. Ca excretion
secondary hyperaldosteronism
Unknown \1/40,000 Infancy (above
6-year old)/
adolescence/
adulthood
[159]
3) Bartter syndrome
3a) Bartter syndrome,
antenatal, type 1
# 601678 SLC12A1
(600839)
Antenatal: fetal polyuria,
polyhydramnios (between 24 and
30 weeks of gestation), premature
delivery
Neonates/infancy: hyposthenuria,
several salt wasting failure to thrive,
hypotension, nephrocalcinosis,
osteopenia
Moderate hypokaliemic metabolic
alkalosis, high Ur. Ca levels, high
plasma renin activity, high
aldosterone levels, high excretion
of Ur. Na
Unknown Unknown Antenatal/infancy [161]
3c) Bartter syndrome type 3 # 607364 CLCNKB
(602023)
Short stature, normal blood pressure,
hyperplasia and hypertrophy of the
juxtaglomerular cells
Hypokaliemic metabolic alkalosis,
high Ur. Ca levels secondary
hyperaldosteronism, increased
renal prostaglandin production,
occasionally, low serum Mg
levels, high serum Na and
excretion of Ur. K
Unknown Unknown Infancy/
adolescence/
adulthood
[162]
3d) Bartter Syndrome type
4A
# 602522 BSND
(606412)
Short stature, normal blood pressure,
hyperplasia and hypertrophy of the
juxtaglomerular cells
Hypokaliemic metabolic alkalosis,
high Ur. Ca levels secondary
hyperaldosteronism, increased
renal prostaglandin production,
occasionally, low serum Mg
levels, high serum Na and
excretion of Ur. K
Unknown Unknown Infancy/
adolescence/
adulthood
[163]
3e) Bartter syndrome type 4B # 613090 CLCNKA
(602024)
CLCNKB
(602023)
Short stature, normal blood pressure,
hyperplasia, and hypertrophy of the
juxtaglomerular cells
Hypokaliemic metabolic alkalosis,
high Ur. Ca levels secondary
hyperaldosteronism, increased
renal prostaglandin production,
occasionally, low Mg levels, high
serum Na and excretion of Ur. K
Unknown Unknown Infancy/
adolescence/
adulthood
[162]
4) Liddle Syndrome # 177200 SCNN1B
(600760)
SCNN1G
(600761)
Constitutive activation of the renal
epithelial sodium channel
Children: asymptomatic, detection of
early and severe hypertension
Young adult: aspecific symptoms of
hypokaliemia (weakness, fatigue,
myalgia, constipation)
Low serum K levels, metabolic
alkalosis, high serum Na levels,
low rates of Ur. Na, high rates of
Ur. K, low plasma renin activity,
suppressed aldosterone secretion
Unknown \1/1,000,000 Infancy/young
adulthood (\35
years)
[164]
5) Pseudohypoaldosteronism,
type 2a; PHA2A
% 145260 – Hypertension, delayed growth,
weakness, periodic paralysis
High serum K levels, low plasma
renin activity, normal or elevated
level of aldosterone,
hyperchloremic metabolic
acidosis
Unknown Unknown Variable [165]
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
6) Apparent
mineralocorticoid excess;
AME
# 218030 HSD11B2
(614232)
Congenital defect in 11-beta-
dehydrogenase type II
Early onset and severe hypertension,
polyuria, polydipsia, failure to thrive
Low serum K levels, metabolic
alkalosis, high serum Na levels,
low plasma renin activity, low
levels of aldosterone
Unknown \1/1,000,000 Neonatal/infancy
(first year of life)
[166]
7) Sporadic
pheochromocytoma
– – Adrenal pheochromocytoma,
extraadrenal paraganglioma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
0.2 % of
hypertensive
population
4–84 years [167]
8) Familial pheochromocytoma:
8a) Familial
pheochromocytoma
(MEN2A-2B)
# 171400
# 162300
RET
(164761)
MEN2A: Medullary thyroid
carcinoma, pheochromocytoma,
parathyroid adenomas
Associated characteristic features:
cutaneous lichen amyloidosis,
Hischprung’s Disease rarely
prominent corneal nerves
MEN2B: Aggressive medullary
thyroid carcinoma,
pheochromocytoma, mucosal
neuromas, and thickened corneal
nerves
Associated characteristic physical
features: full lips, thickened eyelids,
high-arched palate, marfanoid
habitus
High serum basal levels and
stimulated calcitonin, elevated
catecholamines and
catecholamine metabolites, high
serum Ca and PTH levels
MEN2A:
Unknown
MEN2B: \1/
500,000
MEN2A:1/
30,000
MEN2B: \1/
100,000
MEN2A:3–25 years
MEN2B: Childhood
(earlier onset in
first years of life)
[42,43]
8b) Familial
pheochromocytoma (von
Hippel–Lindau; VHL)
# 193300 VHL
(608537)
Adrenal pheochromocytoma, retinal
angioma, hemangioblastoma of the
central nervous system,
endolymphatic sac tumor,
pancreatic endocrine tumor, clear
cell renal cancer
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 4–60 years [100]
8c) Familial
pheochromocytoma
(neurofibromatosis, type 1)
# 162200 NF1
(613113)
Adrenal pheochromocytoma, Lysch
nodules, caffe-au lat spots,
cutaneous neurofibromas, neural
crest-derived tumors,
gastrointestinal stromal tumor
(GIST)
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 4–84 years [168]
9) Familial pheochromocytoma:
9a) Familial
pheochromocytoma type
1 (Pheochromocytoma)
# 171300 TMEM127
(613403)
Adrenal pheochromocytoma High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 21–72 years [169]
9b) Familial
pheochromocytoma type 2
(Pheochromocytoma)
# 171300 MAX
(154950)
Adrenal pheochromocytoma,
sympathetic paraganglioma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 13–80 years [170]
10) Paragangliomas
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
10a) Paragangliomas 1;
PGL1
# 168000 SDHD
(602690)
Head and neck parasympathetic
paraganglioma, adrenal
pheochromocytoma, sympathetic
paraganglioma, pituitary adenoma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000
(for all types of
pheocromocytoma/
paraganglioma)
Unknown 5–65 years [171]
10b) Paragangliomas 2;
PGL2
# 601650 SDHAF2
(613019)
Head and neck parasympathetic
paraganglioma
None 0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown Unknown [172]
10c) Paragangliomas 3;
PGL3
# 605373 SDHC
(602413)
Head and neck paragangliomas,
adrenal pheochromocytoma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
Unknown Unknown Childhood [173]
10d) Paragangliomas 4;
PGL4
# 115310 SDHB
(185470)
Sympathetic paraganglioma, head and
neck parasympathetic
paraganglioma, renal clear cell
carcinoma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 5–65 years [167]
10e) Paragangliomas 5;
PGL5
# 614165 SDHA
(600857)
Sympathetic paraganglioma, head and
neck parasympathetic
paraganglioma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown Unknown [167]
11) Other paraganglioma
11a) Paraganglioma and
gastric stromal sarcoma
# 606864 SDHB
(185470)
SDHC
(602413)
SDHD
(602690)
Paraganglioma, gastrointestinal
stromal tumor
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
Unknown 12 % of
pediatric
GISTs (1–5/
10 000)
Unknown [174]
11b) Paraganglioma (Carney
Triad)
# 604287 – Paraganglioma, GIST, pulmonary
amartocondroma
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
Unknown Unknown Unknown [175]
12) Adrenal hyperplasia, congenital
12a) Adrenal hyperplasia,
congenital, due to
21-hydroxylase
deficiency
# 201910 CYP21A2
(613815)
Classic salt wasting: females prenatal
virilized
Simple virilizing: females prenatal
virilized
Nonclassic: postnatally
hyperandrogenism
High 17-OHP, DHEA and
androstenedione levels
Classic salt wasting
1/20,000
Simple virilizing
1/60,000
Nonclassic 1/1,000
1–9/100,000 Classic salt wasting:
newborn to
6 months
Simple virilizing:
newborn/2 years
(female),
2–4 years (male)
Nonclassic:
Childhood/
adulthood
[176]
12b) Adrenal hyperplasia,
congenital, due to steroid
11-beta-hydroxylase
deficiency
# 202010 CYP11B1
(610613)
11b-Hydroxylase deficiency:
Virilization, sexual ambiguity,
hypertension
High DOC and 11-deoxycortisol
levels
1/100,000 1–9/1,000,000 Newborn/adulthood [177]
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
12c) Adrenal hyperplasia,
congenital, due to
17-alpha-hydroxylase
deficiency
# 202110 CYP17A1
(609300)
17a-Hydroxilase deficiency:
Impaired adrenal and gonadal
steroidogenesis (disorder of sex
development); hypokalemic
hypertension
Hypergonadotropic hypogonadism,
high DOC and 11-deoxycortisol
levels
Unknown 1/1,000,000 Adolescence [178]
12d) Deficiency of 3-beta-
hydroxysteroid
dehydrogenase, type 2
# 201810 HSD3B2
(613890)
3b-HSD type 2 deficiency:
Impaired adrenal and gonadal
steroidogenesis (ambiguous
genitalia in male; mild virilization in
female), salt wasting
High 17-OH-pregnenolone and
DHEA levels
Unknown \1/1,000,000 Early infancy [179]
12e) Disordered
steroidogenesis due to
cytochrome p450
oxidoreductase deficiency
# 613571 POR
(124015)
P450 Oxidoreductase deficiency:
Disorder of sex development, skeletal
malformations
High pregnenolone, progesterone
and 17-OHP levels
1/150,000 Unknown Puberty [180]
12f) Lipoid congenital
adrenal hyperplasia; LCAH
# 201710 STAR
(600617)
StAR deficiency:
Lipoid adrenal hyperplasia, impaired
adrenal and gonadal steroidogenesis
with no sexual development, salt
wasting
Low steroid values and elevated
plasma renin activity
Unknown Unknown Newborn [181]
12g) Adrenal insufficiency,
congenital, with 46, xy sex
reversal, partial or
complete
# 613743 CYP11A1
(118485)
P450 Side-chain Cleavage deficiency:
Depending on the impairment of
CYP11A1 and ranging from severe
adrenal deficiency to mild disorder
of sex development
Low steroid values and elevated
plasma renin activity
Unknown Unknown Newborn to
childhood
[182]
13) Cushing syndrome
(Pituitary adenoma,
ACTH-secreting)
# 219090 AIP
(605555)
GNAS
(139320)
Truncal and facial obesity, signs of
hypercatabolism (thinned skin,
purple striae, ecchymosis, bruising
with no obvious trauma, proximal
muscle weakness with amyotrophy,
unexplained osteoporosis), weight
gain with decreasing growth
velocity. Other less specific
features: fatigue, high blood
pressure, glucose intolerance,
hypokalemia, acne, hirsutism,
menstrual irregularity, diminished
libido, erectile dysfunction, and
neuropsychological disturbances
High UFC and late night salivary
cortisol, absent cortical
suppression to 1 mg overnight or
48 h: 2 mg dexamethasone test,
abnormal response to
desmopressin test or even CRH
test
1/400,000 1–9/100 000 Variable (peak
incidence at
25–40 years)
[183]
14) Hereditary Cushing
14a) Hereditary Cushing
(Carney Complex
variant/type 1)
# 608837
# 160980
MYH8
(160741)
PRKAR1A
(188830)
Cardiac, endocrine, cutaneous, and
neural myxomatous tumors,
pigmented lesions of the skin and
mucosae
High cortisol, GH and IGF-1 levels,
subtle hyperprolactinemia
Unknown \1/1,000,000 Variable
(it most commonly
presents in the
teen years and
early adulthood)
[184]
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
14b) Hereditary Cushing
(MEN1)
# 131100 MEN
(613733)
Parathyroid adenoma/hyperplasia,
entero-pancreatic tumor
(gastrinoma, insulinoma, non-
functioning neuroendocrine tumor,
glucagonoma, VIP-oma,
somatostatinoma), Foregut
carcinoid, thymic carcinoid,
bronchial carcinoid, gastric
enterochromaffin-like non-
functioning tumors, anterior
pituitary tumor (PRL, GH ?PRL,
GH, non-functioning, ACTH, TSH),
adrenal cortex non-functioning
tumors, pheochromocytoma,
lipomas, facial angiofibromas,
collagenomas
High levels of one or more of the
following markers: PRL, IGF-1,
gastrin, fasting glucose, insulin,
PP, glucagon, VIP, CgA, Ca, PTH
0.2–2/100,000 1–3.3/100,000 5–81 years [95]
14c) Hereditary Cushing
(Pigmented nodular
adrenocortical disease,
primary, PPNAD 2)
# 610475 PDE11A
(604961)
See Cushing syndrome
Associated with Carney Complex and
PPNAD: PDE11A is a genetic
modifying factor for the
development of testicular and
adrenal tumors in patients with
germline PRKAR1A mutation
High cortisol, GH, IGF-1 levels,
subtle hyperprolactinemia
Unknown Unknown Variable
(most commonly in
early adulthood)
[185]
15) Familial adrenocortical tumors
15a) Familial
adrenocortical tumors
(MEN1)
# 131100 MEN
(613733)
Parathyroid adenoma/hyperplasia,
entero-pancreatic tumor
(gastrinoma, insulinoma, non-
functioning neuroendocrine tumor,
glucagonoma, VIP-oma,
somatostatinoma), Foregut
carcinoid, thymic carcinoid,
bronchial carcinoid, gastric
enterochromaffin-like non-
functioning tumors, anterior
pituitary tumor (PRL, GH ?PRL,
GH, non-functioning, ACTH, TSH),
adrenal cortex non-functioning
tumors, pheochromocytoma,
lipomas, facial angiofibromas,
collagenomas
High levels of one or more of the
following markers: PRL, IGF-1,
gastrin, fasting glucose, insulin,
PP, glucagon, VIP, CgA, Ca, PTH
0.2–2/100,000 1–3.3/100,000 5–81 years [95]
15b) Li–Fraumeni syndrome
1; LFS1
#151623 TP53
(191170)
Breast cancer, soft tissue sarcomas,
osteosarcomas, brain tumors, acute
leukemia, adrenocortical
Carcinomas, lung adenocarcinoma,
colon cancer, pancreatic cancer,
prostate cancer, Wilms tumor,
phyllodes tumor
High b-Hcg, alpha-fetoprotein,
17-OHP, T, DHEA-s, and
androstenedione levels
High complete blood count,
erythrocyte sedimentation rate,
lactate dehydrogenase
Unknown Unknown Adulthood [186]
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
15c) Li–Fraumeni syndrome
2; LFS2
# 609265 CHEK2
(604373)
Breast cancer, soft tissue sarcomas,
osteosarcomas, brain tumors, acute
leukemia, adrenocortical
Carcinomas, lung adenocarcinoma,
colon cancer, pancreatic cancer,
prostate cancer, Wilms tumor,
phyllodes tumor
High b-Hcg, alpha-fetoprotein,
17-OHP, T, DHEA-s, and
androstenedione levels
High complete blood count,
erythrocyte sedimentation rate,
lactate dehydrogenase
Unknown Unknown Adulthood [187]
15d) Li–Fraumeni syndrome
3; LFS3
% 609266 – Breast cancer, soft tissue sarcomas,
osteosarcomas, brain tumors, acute
leukemia, adrenocortical
Carcinomas, lung adenocarcinoma,
colon cancer, pancreatic cancer,
prostate cancer, Wilms tumor,
phyllodes tumor
High b-Hcg, alpha-fetoprotein,
17-OHP, T, DHEA-s, and
androstenedione levels
High complete blood count,
erythrocyte sedimentation rate,
lactate dehydrogenase
Unknown Unknown Adulthood [188]
15e) Hereditary Cushing
(Beckwith–Wiedemann
syndrome)
# 130650 CDKN1C
(600856)
KCNQ1O
T1
(604115)
H19
(103280)
NSD1
(606681)
Abdominal wall defects (omphalocele,
umbilical hernia, and diastasis recti),
visceromegaly involving liver,
spleen, pancreas, kidneys, or
adrenals, fetal adrenocortical
cytomegaly, renal anomalies:
primary malformations, renal
medullary dysplasia,
nephrocalcinosis, and
nephrolithiasis, predisposition to
embryonal malignancies
Low glycemia levels Unknown 1–5/10,000 Neonatal/infancy [189]
16) ACTH-independent
macronodular adrenal
hyperplasia; AIMAH
# 219080 GNAS
(139320)
ARMC5
(615549)
An endogenous form of adrenal
Cushing syndrome characterized by
multiple bilateral adrenocortical
nodules that cause a striking
enlargement of the adrenal glands
High cortisol level, low ACTH level Unknown \1/1,000,000 The fifth and sixth
decades of life
[190]
17) Pigmented nodular
adrenocortical disease,
primary, 1; PPNAD1
# 610489 PRKAR1A
(188830)
Clinical features of adrenal Cushing
syndrome, including hypertension
Mildly or clearly high cortisol level,
low ACTH level
Unknown Unknown but
less
2/1,000,000
persons per
year
12–21 years [191]
18) Adrenocortical
hypofunction, chronic
primary congenital
# 103230 – Skin hyperpigmentation, weight loss,
hypotension, fatigue, nausea
Mineral and glucocorticoid
deficiency, electrolyte disorders
(hyponatremia, hyperkalemia)
0.8/100,000 (70–80
% autoimmune
adrenalitis)
4–11/100,000 Childhood/
adulthood
[192]
19) Adrenal hypoplasia,
congenital
# 300200 DAX1
(300473)
Adrenal hypoplasia congenita:
disorders of adrenal cortex, gonads,
and hypothalamus
Mineral and glucocorticoid
deficiency combined with
hypogonadotropic hypogonadism
Rare Unknown Puberty [193]
20) Adrenomyeloneuropathy,
included; ALD
# 300100 ABCD1 Adrenoleukodystrophy: adrenal
deficiency combined with
demyelination within the nervous
system
Mineral and glucocorticoid
deficiency
1/20,000 1–9/100,000 Childhood/
adulthood
[194]
J Endocrinol Invest
123
Table 7 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
21) Glucocorticoid
deficiency 1; GCCD1
# 202200 MC2R
(607397)
MRAP
(609196)
Familial glucocorticoid deficiency
(unresponsiveness to ACTH)
Tall stature, failure to thrive,
hyperpigmentation skin, seizures,
coma, recurrent hypoglycemic
episodes, frequent, severe infections
Low cortisol and normal plasma
renin
Unknown \1/1,000,000 Childhood [195]
22) Adrenocortical
carcinoma, hereditary;
ADCC
# 202300 TP53
(191170)
Adrenal mass with metastatic spread
at diagnosis in up to 75 % of cases,
virilism
High glucocorticoids alone (35 %),
glucocorticoids and androgens (35
%), androgens alone (10 %),
aldosterone (\1 %) levels
1/1,000,000 1–9/1,000,000 3–5 years [196]
Table 8 Rare ovarian diseases
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age rangeof
expression
References
1) Congenital hypogonadism hypergonadotropic (female)
1a) Turner
syndrome
– Monosomy x/partial
deletion of
chromosome X
Short stature, delayed puberty,
primary amenorrhea, or
premature ovarian failure,
hypoplastic left heart,
coarctation of the aorta, low
hairline, low-set ears, small
mandible, multiple pigmented
nevi, cubitus valgus, nail
hypoplasia, hyperconvex
uplifted nails, characteristic
faces, shortening of the fourth
metacarpal, high-arched
palate, recurrent otitis media,
and neurosensory hearing loss
Markedly high FSH level Unknown 1–5/
10,000
Birth [197]
J Endocrinol Invest
123
Table 8 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age rangeof
expression
References
1b) Noonan
syndrome
# 163950
# 609942
# 610733
# 611553
# 613224
# 613706
Type 1:
PTPN11
(176876)
Type 3:
KRAS
(190070)
Type 4:
SOS1
(182530)
Type 5:
RAF1
(164760)
Type 6:
NRAS
(164790)
Type 7:
BRAF
(164757)
Short stature, facial
dysmorphism, a wide
spectrum of congenital heart
defects, multiple skeletal
defects, webbed neck, mental
retardation, bleeding diathesis,
lymphatic dysplasia
Normal GH level, but sometimes
high IGF-1 level, elevated FSH
level
1/1,000–1/2,500 Unknown Variable [198]
2) Premature
ovarian failure;
POF
# 311360
# 300511
# 300604
# 608996
# 611548
# 612310
# 612964
Type 1:
FMR1
(309550)
Type 2a:
DIAPH2
(300108)
Type 2b:
FLJ22792
(300603)
Type 3:
FOXL2
(605597)
Type 5:
NOBOX
(610934)
Type 6:
FIGLA
(608697)
Type 7:
NR5A1
(184757)
Primary amenorrhea, or oligo/
amenorrhea (lasting 4
months), polymenorrhea, or
dysfunctional uterine bleeding
after having attained normal
puberty and having
established regular menstrual
cycles
High FSH level 1/10,000 (by 20 years), 1/1,000
(by 30 years), 1/100 (by 40
years)
[1/1,000 \40 years [199]
J Endocrinol Invest
123
Table 8 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age rangeof
expression
References
3) Ovarian
dysgenesis
# 233300
# 300510
# 614324
Type 1:
FSHR
(136435)
Type 2:
BMP15
(300247)
Type 3:
PSMC3IP
(608665)
Hypergonadotropic ovarian
failure, streak gonads
High FSH and LH level Unknown 1–9/
100,000
[200]
4) Ovarian Sertoli–
Leydig cell
tumors
– – Ovarian tumor. Many tumors
have foci that are of
intermediate differentiation
and other areas that are poorly
differentiated tumors. Well-
differentiated tumors are
almost always pure without
heterologous or retiform
components,
hyperandrogenism with
virilizing features or hirsutism
High androgen level Unknown Unknown Variable (peak
30 years of
age)
[201]
5) Granulosa cell
tumor of the
ovary
– – A solid and cystic tumor with
hemorrhage within cysts, solid
and yellow, or cystic,
either multilocular or unilocular
Hyperestrinism and various
menstrual abnormalities, in
postmenopausal patients,
postmenopausal bleeding
High 17b-estradiol level 0.4–1.7/100,000 Unknown Variable [202]
6) Ovarian germ
cell cancer
# 603737 – Ovarian cancer None Unknown Unknown Variable [203]
J Endocrinol Invest
123
Table 9 Rare testicular diseases
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
1) Congenital hypergonadotropic hypogonadism
1a) 46, XX sex reversal 1;
SRXX1
# 400045 SRY
(480000) (about
80 % are SRY
positive, 20 %
SRY negative)
Male external genitalia ranging from
normal to ambiguous, two testicles,
azoospermia; and absence of Mu
¨llerian
structures. Approximately 80 % of
individuals with 46, XX testicular
Disorders of Sex Development (DSD)
present after puberty with normal pubic
hair and normal penile size, but small
testes, gynecomastia, and azoospermia.
Approximately 20 % present at birth
with ambiguous genitalia. If untreated,
males with 46, XX testicular DSD
experience the consequences of
testosterone deficiency
Hypergonadotropic hypogonadism
secondary to testicular failure
5/100,000 1/20,000 Birth (ambiguous genitalia)
Mid puberty/adulthood
(infertility)
[204]
1b) Myotonic dystrophy 1;
DM1
# 160900 DMPK (CTG repeat)
(605377)
Multisystem disorder that affects skeletal
and smooth muscle as well as the eye,
heart, endocrine system, and central
nervous system. The phenotypes span a
continuum from mild to severe forms
(mild, classic, congenital). Mild DM is
characterized by cataract and mild
myotonia. Classic DM is characterized
by muscle weakness and wasting,
myotonia, cataract, and often cardiac
conduction abnormalities; adults may
become physically disabled and may
have a shortened life span. Congenital
DM is characterized by hypotonia and
severe generalized weakness at birth,
often with respiratory insufficiency and
early death; intellectual disability is
common
High CK levels
Hypergonadotropic hypogonadism
secondary to testicular failure
5/100,000 1/20,000 Birth: 10 years (congenital
forms)
10–30 years (classic forms).
20–70 years (mild forms)
[205]
1c) Leydig cell hypoplasia,
type 1
# 238320 LHCGR
(152790)
Severe forms caused by complete
inactivation of LHCGR are
characterized by complete 46, XY male
pseudohermaphroditism, lack of breast
development, and absent development
of secondary male sex characteristics.
Milder forms caused by partial
inactivation of the gene display a
broader range of phenotypic expression
ranging from micropenis to severe
hypospadias
Hypergonadotropic hypogonadism
secondary to LH resistance. Lack
of responsiveness to hCG
challenge
Unknown Unknown Birth [206]
1d) FSH resistance – FSHR
(136435)
Infertility, small testes High FSH levels Unknown Unknown Adulthood [207]
J Endocrinol Invest
123
Table 9 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
1e) Adrenoleukodystrophy;
ALD
# 300100 ABCD1
(300371)
Wide range of phenotypes. Many
individuals remain asymptomatic until
middle age or even later. Childhood
cerebral forms (*35 % of affected
individuals): it initially resembles
attention-deficit disorder or
hyperactivity; progressive impairment
of cognition, behavior, vision, hearing,
and motor function follow the initial
symptoms and often lead to total
disability within 2 years.
Adrenomyeloneuropathy (*40–45 % of
affected individuals): progressive
stiffness and weakness in the legs,
abnormalities of sphincter control, and
sexual dysfunction. All symptoms are
progressive over decades. Addison
disease only (*10 % of affected
individuals): signs of adrenal
insufficiency, including increased skin
pigmentation
High VLCFA levels 5/100,000 1/20,000–1/
50,000
4–8 years (childhood
cerebral forms)
20–40 years
(adrenomyeloneuropathy)
2–20 (Addison disease
only)
[208]
1f) Testicular regression
syndrome; TRS
%273250 – Regression of testis development between
8 and 14 weeks of gestation. The
phenotype of patients varies depending
on the timing and extent the fetal
testicular regression and ranges from a
female to anorchic male phenotype
among patients with a 46, XY
karyotype. If fetal testicular regression
occurs between 8 and 10 weeks of
gestation, patients may have female
external genitalia with or without
ambiguity, associated with lack of
gonads, hypoplastic uterus, and
rudimentary genital ducts. Regression of
the testes after 12–14 weeks results in
phenotypic males with anorchia or
streak gonads (rudimentary testes).
Intermediary phenotypes occur with
sexual ambiguity associated with
variable degrees of genital duct,
urogenital sinus, and external genitalia
differentiation anomalies. Patients have
either absent or streak gonads
Hypergonadotropic hypogonadism
secondary to absent testes
1–9/
100,000
1–9/100,000 Birth [209]
1g) Spermatogenic failure,
Y-linked, 2; SPGFY2
# 415000 AZF regions
–
Infertility with non-obstructive
azoospermia or severe oligozoospermia
Azoospermia or severe
oligozoospermia
50/100,000 5–10 % of
azoospermia
and severe
oligozoospermia
Variable [210]
J Endocrinol Invest
123
Table 9 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
2) Hypogonadism due to reduced testosterone synthesis or action
2a) Leydig cell
hypoplasia, type 1
# 238320 LHCGR
(152790)
Two types of Leydig cell hypoplasia have
been defined. Type 1, a severe form
caused by complete inactivation of
LHCGR, is characterized by complete
46, XY male pseudohermaphroditism,
lack of breast development, and absent
development of secondary male sex
characteristics. Type 2, a milder form
caused by partial inactivation of the
gene, displays a broader range of
phenotypic expression ranging from
micropenis to severe hypospadias
Low T levels, high LH levels, lack
of responsiveness to LH/CG
challenge
Unknown Unknown Childhood/adolescence [211]
2b) Smith–Lemli–Opitz
syndrome; SLOS
# 270400 DHCR7
(602858)
Prenatal and postnatal growth retardation,
microcephaly, moderate to severe
intellectual disability, and multiple
major and minor malformations include
distinctive facial features, cleft palate,
cardiac defects, underdeveloped
external genitalia in males, hypospadias,
postaxial polydactyly, and 2–3
syndactyly of the toes. The clinical
spectrum is wide and individuals have
been described with normal
development and only minor
malformations
High 7-dehydrocholesterol level
and low cholesterol levels
2–5/
100,000
1/20,000–1/
40,000
Birth–puberty [212]
2c) Lipoid congenital
adrenal hyperplasia;
LCAH
# 201710 STAR
(600617)
Affected individuals are phenotypic
females with a severe salt-losing
syndrome (mineralocorticoid
deficiency) that is fatal if not treated in
early infancy. Severe deficiency of
adrenal and gonadal steroids
Mineralocorticoid and
glucocorticoid primary
deficiency
Unknown Unknown Birth–3 months [213]
2d) Adrenal insufficiency,
congenital, with 46, XY
sex reversal, partial or
complete
# 613743 CYP11A1
(118485)
Acute adrenal insufficiency in infancy or
childhood. Female external genitalia.
Milder forms with only clitoromegaly
and late-onset adrenal failure
Mineralocorticoid and
glucocorticoid primary
deficiency
\1/
1,000,000
\1/1,000,000 Variable [214]
2e) Deficiency of 3-beta-
hydroxysteroid
dehydrogenase, type 2
# 201810 HSD3B2
(613890)
Salt wasting and non-salt wasting forms
with a wide variety of symptoms,
including glucocorticoid deficiency and
male undervirilization manifesting as a
micropenis to severe perineoscrotal
hypospadias
Mineralocorticoid and
glucocorticoid primary
deficiency
\1/
1,000,000
\1/1,000,000 Variable [215]
2f) Deficiency of 17-Beta
hydroxysteroid
dehydrogenase 3
# 264300 HSD17B3
(605573)
Ambiguous external genitalia or complete
female external genitalia at birth. These
children are raised as female, and their
diagnosis is often discovered when there
is absence of menarche (and frequent
finding of inguinal testes in these cases)
Low T levels and high
androstenedione levels
0.5–1/
100,000
1–9/1,000,000 Birth/puberty [216]
J Endocrinol Invest
123
Table 9 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
2g) Pseudovaginal
perineoscrotal
hypospadias; PPSH
# 264600 SRD5A2
(607306)
Incomplete male pseudohermaphroditism
with pseudovaginal perineoscrotal
hypospadias, clitoral-like phallus,
markedly bifid scrotum, cryptorchidism.
The uterus and fallopian tubes are
absent
Baseline and post-hCG-stimulation
elevated T-to-DHT ratio
Unknown Unknown Birth/puberty [217]
2h) Androgen insensitivity
syndrome; AIS
# 300068 AR
(313700)
Female external genitalia. Absent or
rudimentary wolffian duct derivatives.
Cryptorchidism. Short blind-ending
vagina. Scant or absent pubic and/or
axillary hair
High T with high LH levels 2–5/
100,000
Unknown Birth/puberty [218]
2i) Partial androgen
insensitivity syndrome;
PAIS
# 312300 AR
(313700)
Wide range of phenotypes of external
genitalia from predominantly male
(hypospadias, cryptorchidism,
micropenis), to ambiguous, to
predominantly female (clitoromegaly
and labial fusion, vaginal opening)
Normal/high T with normal/high
LH levels
1–2/
100,000
Unknown Birth [219]
2l) Spinal and bulbar
muscular atrophy,
x-linked 1; SMAX1
# 313200 AR (CAG repeat)
(313700)
Gradual and progressive neuromuscular
disorder in which degeneration of lower
motor neurons results in proximal
muscle weakness, muscle atrophy, and
fasciculations. Affected individuals
often show gynecomastia, small testes,
and reduced fertility as a result of mild
androgen insensitivity
Slightly high T 9LH product 1–9/
100,000
1/30,000 Adolescence/adulthood [220]
3) Other 46, XY DSD
3a) 46, XY Sex reversal 1;
SRXY1
# 400044 SRY
(480000) (15 % of
complete gonadal
dysgenesis)
Female external and internal genitalia.
Completely undeveloped (‘‘streak’’)
gonads. Lack of pubertal development
Hypergonadotropic hypogonadism
secondary to testicular failure
Unknown Unknown Adolescence/young
adulthood
[221]
3b) 46, XY Sex reversal 3;
SRXY3
# 612965 NR5A1
(184757) (13 % of
complete gonadal
dysgenesis)
Female external and internal genitalia.
More severe phenotypes include
primary adrenal failure; milder
phenotypes have isolated partial
gonadal dysgenesis
Hypergonadotropic hypogonadism
secondary to testicular failure
Unknown Unknown Adolescence/young
adulthood
[222]
3c) 46, XY Sex reversal 7;
SRXY7
# 233420 DHH
(605423) (50 % of
complete gonadal
dysgenesis)
Female external and internal genitalia.
Completely undeveloped (‘‘streak’’)
gonads. Lack of pubertal development
Hypergonadotropic hypogonadism
secondary to testicular failure
Unknown Unknown Adolescence/young
adulthood
[223]
3c) Campomelic dysplasia # 114290 SOX9
(608160)
Ambiguous genitalia or normal female
external genitalia. Skeletal
(campomelic) dysplasia characterized
by distinctive faces, Pierre Robin
sequence with cleft palate, shortening
and bowing of long bones, and club feet.
Many affected infants die in the
neonatal period
Hypergonadotropic hypogonadism
secondary to testicular failure
0.3/100,000 Unknown Birth [224]
J Endocrinol Invest
123
Table 9 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
3d) Frasier syndrome # 136680 WT1
(607102)
Glomerular nephropathy with normal
female external genitalia. High risk of
gonadoblastoma
Hypergonadotropic hypogonadism
secondary to testicular failure
\1/
1,000,000
Unknown Childhood [225]
4) Denys–Drash syndrome # 194080 WT1
(607102)
Diffuse mesangial sclerosis with nephrotic
syndrome and renal faı
`lure,
pseudohermaphroditism,
nephroblastoma (Wilms tumor)
Hypergonadotropic hypogonadism
secondary to testicular failure
\1/
1,000,000
Unknown Birth/infancy [225]
5) 46, XY Gonadal
dysgenesis, partial, with
minifascicular neuropathy
# 607080 DHH
(605423)
Ambiguous genitalia with partial gonadal
dysgenesis and motor and sensory
neuropathy
Hypergonadotropic hypogonadism
secondary to testicular failure
\1/
1,000,000
Unknown Birth/infancy [226]
6) Testicular germ cell
tumor; TGCT
# 273300 – Classified as seminoma and non-
seminoma, it has no specific phenotype.
Often men with TGCT notice a hard,
painless lump on the testicle or a change
in the size of their testicle
High beta-hCG, AFP, LDH levels 2–9/
100,000
1–2/1,000 15–40 years [227]
7) Testicular Leydig cell
tumor
– – Painless testicular enlargement. When
arising in children it may present with
precocious puberty (androgen
secretion). In boys and adults it may be
associated with gynecomastia and
decreased libido (estrogen secretion)
T or estradiol may be high Unknown 1–3 % of
testicular
tumors
5–10 years, 30–60 years [228]
8) Testicular sertoli cell
tumor
– – Slowing growing testicular mass None Unknown 0.4–1.5 % of
testicular
tumors
45 years (mean age) [229]
9) Gonadoblastoma: GBY # 424500 – It affects dysgenetic gonads (DSD patients
with Y chromosome)
None Unknown 30–60 % of DSD
patients
\30 years [230]
J Endocrinol Invest
123
Table 10 Rare diseases with possible endocrine multiple
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
1) Multiple
endocrine
neoplasia Type 1;
MEN1
# 131100 MEN1
(613733)
Parathyroid adenoma/hyperplasia,
entero-pancreatic tumor
(gastrinoma, insulinoma, non-
functioning neuroendocrine
tumor, glucagonoma, VIP-oma,
somatostatinoma), Foregut
carcinoid, thymic carcinoid,
bronchial carcinoid, gastric
enterochromaffin-like non-
functioning tumors, anterior
pituitary tumor (PRL, GH ?PRL,
GH, non-functioning, ACTH,
TSH), adrenal cortex non-
functioning tumors,
pheochromocytoma, lipomas,
facial angiofibromas,
collagenomas
High levels of one or more of the
following markers: PRL, IGF-
1, gastrin, fasting glucose,
insulin, PP, glucagon, VIP,
CgA, Ca, PTH
0.2–2/100,000 1–3.3/
100,000
5–81 years [95]
2) Multiple
endocrine
neoplasia Type
2A; MEN2A
# 171400 RET
(164761)
Medullary thyroid carcinoma,
pheochromocytoma, parathyroid
adenomas
Associated characteristic features:
cutaneous lichen amyloidosis,
Hischprung’s disease rarely
prominent corneal nerves
High serum basal levels and
stimulated calcitonin, elevated
catecholamines and
catecholamine metabolites,
high serum Ca and PTH levels
Unknown 1/30,000 3–25 years [42]
3) Multiple
endocrine
neoplasia Type 2B;
MEN2B
# 162300 RET
(164761)
Aggressive medullary thyroid
carcinoma, pheochromocytoma,
mucosal neuromas, and thickened
corneal nerves
Associated characteristic physical
features: full lips, thickened
eyelids, high-arched palate,
marfanoid habitus
High serum basal and stimulated
calcitonin levels, high
catecholamines, and
catecholamine metabolites
levels
\1/500,000 \1/100,000 Childhood
(earlier onset
in first years of
life)
[43]
4) Multiple
endocrine
neoplasia Type 4;
MEN4
# 610755 CDKN1B
(600778)
Intermediate features between
MEN1 and MEN2 with the
presence of neoplasms in at least
2 endocrine glands
High serum Ca, calcitonin, CEA,
PTH, gastrin, insulin, VIP, PP,
somatostatin, CgA, PRL, GH,
IGF-1, ACTH, UFC, serum and
urinary catecholamines levels.
High or low glycemia, low
serum P levels
Unknown 4/100,000 50–55 years [99]
J Endocrinol Invest
123
Table 10 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
5) Tuberous
sclerosis; TSC
# 191100
# 613254
Type 1:
TSC1
(605284)
Type 2:
TSC2
(191092)
Skin abnormalities (patches of
light-colored skin, facial
angiofibromas), seizures,
behavioral problems such as
hyperactivity and aggression,
intellectual disability or learning
problems, developmental
disorders, brain tumors, kidney
tumors. Additionally, tumors can
develop in the heart, lungs and
retina
Mutated hamartin and tuberin 1/10,000 8.8/10,000 Childhood but
manifestations
are often mild
in childhood
and overt in
adulthood
[231]
6) Von Hippel–
Lindau; VHL
# 193300 VHL
(608537)
Adrenal pheochromocytoma,
retinal angioma,
hemangioblastoma of the central
nervous system, endolymphatic
sac tumor, pancreatic endocrine
tumor, clear cell renal cancer
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 4–60 years [100]
7) Adrenal
hypoplasia,
congenital; AHC
# 300200 DAX1
(300473)
Congenital adrenal hypoplasia,
hypogonadotropic hypogonadism
High ACTH level, low serum
cortisol, and gonadotropins
levels
1/12,500 Unknown During
childhood
[232]
8)
Neurofibromatosis
type 1; NF1
# 162200 NF1
(613113)
Adrenal pheochromocytoma, Lysch
nodules, caffe-au lat spots,
cutaneous neurofibromas, neural
crest-derived tumors, GIST
High metanephrine,
normetanephrine, 3 metossi-
thyramine levels
0.8/100,000 (for all
types of
pheocromocytoma/
paraganglioma)
Unknown 4–84 years [168]
9) Carney complex
type 1; CNC1
# 160980 PRKAR1A
(188830)
Pigmented micronodular adrenal
dysplasia, Cushing disease,
acromegaly, thyroid follicular
hyperplasia, associated with
cardiac, cutaneous, and neural
myxomatous tumors, pigmented
lesions of the skin and mucosae
Variable, 20–30 %
hypercortisolism with low
ACTH levels, less frequently
high levels of PRL, GH or IGF-
1, or high levels of T, high
serum FT4, FT3 levels, low
TSH level
Unknown On 2010,
500
patients
were
known
Variable [233]
J Endocrinol Invest
123
Table 10 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
10) Autoimmune
polyendocrine
syndrome, type 1,
with or without
reversible
metaphyseal
dysplasia; APS1
# 240300 AIRE
(607358)
Candidiasis (before 5 years)
Hypoparathyroidism (before 10
years)
Addison’s disease (before 15 years)
?
2–3 of the following: insulin-
dependent diabetes, primary
hypogonadism, pernicious
anemia, alopecia, vitiligo,
Hashimoto’s thyroiditis, gastritis,
idiopathic hypopituitarism
Multiple auto-antibodies:
21OH Abs, ACA Abs, Islet cells
Abs, GAD Abs, (optional IA2),
MPC Abs, TPO Abs, H?–K?
ATPase of the parietal cells
Abs, intrinsic factor Abs
High serum TSH, FSH, LH,
glucose levels
Low FT4, T, estradiol, fasting
morning cortisol levels
Assessment of serum Na, K, Ca,
blood cell count and ACTH
stimulation test (when adrenal
antibodies are present) may be
useful
Fasting morning cortisol levels
Anemia
1/100,000 (juvenile)
and 1/20,000
(adult)
From
1/14,000
in Sardinia
to
1/129,000
Poland
5–15 years [234]
11) Autoimmune
polyendocrine
syndrome, type 2;
APS2
% 269200 Polygenic
associated
with HLA-
DR3 and
HLA-DR4
and non-
HLA
genes
MICA
(600169)
PTPN22
(600716)
CTLA4
(123890)
Association between autoimmune
Addison’s disease and either
autoimmune thyroid disease or
type 1 diabetes, or both
Further endocrine (hypogonadism,
hypoparathyroidism), and non-
endocrine component diseases
(autoimmune gastritis, pernicious
anemia, vitiligo, autoimmune
hepatitis, and myasthenia gravis)
may be present
Multiple auto-antibodies:
Islet cells Abs, GAD Abs,
(optional IA2 Abs), TPO Abs,
TSH receptor Abs, Cytochrome
P450 enzymes Abs (especially
21-Hydroxylase), H?–K?
ATPase of the parietal cells
Abs, intrinsic factor Abs, tTGA
Abs, (optional gliadin Abs)
High serum TSH, FSH, LH,
glucose levels
Low FT4, T, estradiol, fasting
morning cortisol levels
Assessment of serum Na, K, Ca,
blood cell count and ACTH
stimulation test (when adrenal
antibodies are present) may be
useful
Unknown 1/20,000 Adulthood
(20–60 years,
mostly in the
third or fourth
decade)
[235]
12) Autoimmune
polyendocrine
syndrome, type 3;
APS3
– – Autoimmune thyroid diseases
associated to other autoimmune
diseases (excluding Addison’s
disease and/or
hypoparathyroidism)
Multiple auto-antibodies Unknown Unknown Variable [236]
J Endocrinol Invest
123
Table 10 continued
Disorder OMIM
phenotype
number
OMIM
gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of
expression
References
13) Autoimmune
polyendocrine
syndrome, type 4;
APS4
–– C2 autoimmune diseases, which do
not fall in types 1, 2 or 3. The
major component of the disease is
Addison disease
Minor autoimmune diseases:
Addison disease, premature
gonadal failure, vitiligo, alopecia,
celiac disease, chronic atrophic
gastritis and Wherlof’s syndrome
Multiple auto-antibodies: 21OH
Abs, ACA Abs, StCA Abs,
17a-OH Abs, SCC Abs, MPC
Abs, tTGA Abs, PCA Abs
High serum, FSH, LH, T,
estradiol, fasting morning
cortisol levels
Assessment of serum Na, K,
blood cell count and ACTH
stimulation test (when adrenal
antibodies are present) may be
useful
Unknown Unknown 6–62 years [237]
Table 11 Rare neuroendocrine tumors
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
1) Vasoactive
intestinal
polypeptide-
secreting tumor
– – Large volume, watery diarrhea,
dehydration, and hypokalemia. The
excess vasoactive intestinal
polypeptide (VIP) secretion also can
result in hyperglycemia (20–50 %),
hypercalcaemia (25–50 %),
hypochlorhydria (20–50 %), and
flushing (15–30 %). Rare in patients
with MEN 1
High serum VIP levels
(usually [500 pg/ml)
(usually \190 pg/ml) ±
high serum CgA levels
0.05–0.2/100,000 Unknown Median onset 40 years
(range 11–75 years)
[238]
2) Pancreatic
polypeptide-
secreting tumor
– – Non-specific abdominal pain High serum PP levels and/or
high serum CgA levels
Unknown Unknown Unknown [239]
3) Sporadic
somatostatinoma
– – Diabetes mellitus, gallbladder disease,
diarrhea, weight loss, and
steatorrhea (SSoma syndrome), but
are cases
With no specific symptoms or found
by chance that demonstrate
immunohistochemical staining for
somatostatin-like-immunoreactivity
High serum SS levels and/or
high serum CgA levels
Unknown Unknown Median onset 54 years
(range 24–84)
[240]
J Endocrinol Invest
123
Table 11 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
4) Familial
somatostatinoma
–MEN1
(613733)
VHL
(608537)
NF1
(613113)
Multiple endocrine neoplasia type 1
Von Hippel–Lindau syndrome
neurofibromatosis type 1
Diabetes mellitus, gallbladder disease,
diarrhea, weight loss, and
steatorrhea (SSoma syndrome), but
are cases with no specific symptoms
or found by chance that demonstrate
immunohistochemical staining for
somatostatin-like-immunoreactivity;
syndrome phenotype
High serum SS levels and/or
serum CgA levels
Unknown Unknown Unknown [240]
5) Sporadic
glucagonoma
– – Weight loss, necrolytic migratory
erythema, diabetes, or glucose
intolerance, mucosal abnormalities
(glossitis, stomatitis), venous
thromboembolism, neuropsychiatric
disturbances (most often depression
and/or psychosis), diarrhea, and
rarely, dilated cardiomyopathy
High serum glucagon levels
with diagnostic levels
generally [500 pg/ml
(\120), anemia
2–4/100,000 Unknown Middle-aged with a median
age at the time of
diagnosis of 53–55 years
(range 43–71)
[241]
6) Familial
glucagonoma
–MEN1
(613733)
See above High serum glucagone levels,
with diagnostic levels
generally [500 pg/ml
(\120), anemia
2–4/100,000
(associated with
MEN 1 5 % of
cases)
Unknown Unknown [242]
7) Sporadic
nonfunctional
pancreatic
neuroendocrine
tumors
– – Incidentally discovered in most cases,
usually advanced disease ([60 %
liver metastases). Symptoms can be
caused by tumor growth: abdominal
pain (40–60 %), weight loss (25–50
%), and jaundice (30–40 %)
High serum CgA levels 0.1–0.4/100,000
(all types of
pancreatic
NET)
Unknown Median age: 57 years (range
23–93)
[243]
8) Familial
nonfunctional
pancreatic
neuroendocrine
tumors
–MEN1
(613733)
VHL
(608537)
NF1
(613113)
TSC1
(613254)
TSC2
(605284)
MEN1
High penetrance 80–90 % at 60 years
of age
VHL
Disease (usually asymptomatic)
Rarely associate with Von
Recklinghausen disease NF-1) and
tuberous sclerosis
Gastrointestinal hemorrhage, biliary or
gastric outlet obstruction, abdominal
mass, and pain can be present at the
time of diagnosis; worse prognosis
compared with functioning tumors
High serum CgA levels Unknown 20–90 % of MEN 1
patients (most common
gastroenteropancreatic
tumor associated with
MEN1)
10–17 % of VHL patients
Variable [244]
J Endocrinol Invest
123
Table 11 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
9) Sporadic
gastrinoma
– – Tumor mass signs and symptoms and/
or Zollinger–Ellison syndrome,
characterized by gastric acid
hypersecretion resulting in severe
peptic disease and gastroesophageal
reflux disease
High serum gastrin and CgA
levels
Both sporadic and
familial
gastrinoma:
0.05–0.2/
100,000
(sporadic type
is about 80 % of
cases)
Unknown Peak of incidence 50–80
years
[245]
10) Familial
gastrinoma
–MEN1
(613733)
Tumor mass signs and symptoms and/
or Zollinger–Ellison syndrome
characterized by gastric acid
hypersecretion resulting in severe
peptic disease and gastroesophageal
reflux disease
MEN1 phenotype in all cases
High serum gastrin and CgA
levels
Both sporadic and
familial
gastrinoma:
5–20/100,000
(familiar type is
about 20 % of
cases)
Gastrinoma in 30 % of
MEN1 patients
From 20 years to adulthood [245]
11) Gastric neuroendocrine tumor (GNET)
11a) Gastric
neuroendo
-crine tumor
type 1
– Loss of heterozygosity
of the MENI (613733)
gene locus on 11q13
has been described in
17–73 %
Chronic atrophic gastritis,
achlorhydria and G cell hyperplasia
High serum gastrin levels,
and CgA levels, increased
gastric pH
0.2/100,000
(including
GNET type 1,
3, 4)
2–2.5/100,000 (70–80 %
of GNET)
Mean 63 years (range
21–96)
[246]
11b) Gastric
neuroendocrine
tumor type 2
–MEN1
(613733)
Hypertrophic fundic gastropathy,
Zollinger–Ellison syndrome
High serum gastrin levels,
high serum CgA levels,
decreased gastric pH
Unknown Unknown Mean 50 years [247]
11c) Gastric
neuroendocrine
tumor type 3
– Loss of heterozygosity
of the MENI (613733)
gene locus on 11q13
has been described in
25–50 %
Sporadic with high malignant
potential
Carcinoid syndrome is a rare
presentation
Normal gastrinemia
They typically produce 5-HT
and/or high serum CgA
levels
0.2/100,000
(including
Gastric
neuroendocrine
tumor type 1, 3,
4)
0.4–0.8/100,000 (14–20
% of GNET)
All gastric neuroendocrine
tumors: mean 60–64 years
(range 21–96)
[246]
11d) Gastric
neuroendocrine
tumor type 4
–TP53
(191170)
Poorly differentiated tumor, highly
aggressive. They may arise from
ACTH or serotonin cells or are of
mixed endocrine–exocrine etiology
Normal gastrinemia and/or
high serum CgA levels
0.2/100,000
(including
Gastric
neuroendocrine
tumor type 1, 3,
4)
Unknown All gastric neuroendocrine
tumors: mean 60–64 years
(range 21–96)
[246]
J Endocrinol Invest
123
Table 11 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
12) Bronchial and
thymic
carcinoids
# 613733 MEN1
(613733)
(in familiar forms)
Typical carcinoid, atypical carcinoid,
large cell neuroendocrine
carcinoma; small cell
neuroendocrine carcinoma
In case of centrally located carcinoids
recurrent infections, chest pain,
cough, dyspnea, and pneumonia
may occur. Peripherally located
ones are generally incidental
findings
High serum CgA levels, and/
or 5-HIAA and NSE (in
poorly differentiated
subtypes)
5.2/100,000 Bronchial or thymic
carcinoids in 7 % of
MEN1 patients
50–56 years [244]
13) Sporadic
insulinoma
– – Syndrome of hypoglycemia (100 %),
usually during fasting, rarely in
post-prandial phase,
neuroglycopenic symptoms (80–100
%), and symptoms of adrenergic
stimulation (80–100 %). It usually
manifests with hunger, fatigue,
nausea, vomiting, paresthesia,
peripheral neuropathy, and blurred
vision
Patients are often overweight. The
most dramatic symptoms of
hypoglycemia, such as
neuropsychiatric manifestations,
oscillating moderate personality
changes, confusion, and coma can
lead to difficulties in diagnosis
Fasting hypoglycemia,
inappropriately high serum,
insulin and C-peptide or
proinsulin levels
0.4/100,000 Unknown Mean 45 year (range 8–82) [248]
14) Familial
insulinoma
–MEN1
(613733)
See above
Multiple pancreatic lesions
Fasting hypoglycemia,
inappropriately high serum,
insulin and C-peptide or
proinsulin levels
0.1/100,000 Insulinoma in 15–20 %
of MEN1 patients
Mean 25 year (range 5–69) [95]
15) Duodenal
neuroendocrine
tumor
–MEN1
(613733)
(in familiar forms)
CDKN1B
(600778)
(recurrent somatic
mutations and
deletions)
Several cancer-related
pathways implicated,
including PI3K/Akt/
mTOR signaling, the
TGF-bpathway,
through alterations in:
SMAD,SRC (190090)
Abdominal pain, often crampy, and
paroxysmal are the most common
symptoms. Abdominal pain and/or
intermittent bowel obstruction may
be due to the mechanical effect of
the intraluminal tumor, or due to
mesenteric lymph node involvement
which can produce a secondary
desmoplastic response. Desmoplasia
can lead to bowel tethering and
kinking as well as mesenteric
ischemia
Duodenal or biliary obstruction
High serum CgA levels 0.19/100,000 Unknown Unknown [249]
J Endocrinol Invest
123
Table 11 continued
Disorder OMIM
phenotype
number
OMIM gene/locus
number
Phenotype Typical metabolic biomarkers Incidence Prevalence Age range of expression References
16) Colonic
neuroendocrine
tumor
– – Most tumors arise in the caecum,
followed by the ileocecal region and
ascending colon. Patients present
with pain, bleeding, altered bowel
habits, weight loss, and anorexia.
With advanced disease they may
present with symptoms of bowel
obstruction, anemia or a palpable
liver
Less than 5 % have carcinoid
syndrome
There is an association between
inflammatory bowel diseases and
colon neuroendocrine tumors NETs
Rarely high serum CgA levels 0.17–0.40/
100,000
Unknown Mean 65 years [250]
17) Rectal
neuroendocrine
tumor
– – Half of all are diagnosed upon routine
lower endoscopy
Symptoms if present are usually rectal
bleeding, constipation or pain, and
tenesmus. Carcinoid syndrome is
very rare
Bowel obstruction or systemic
symptoms only with advanced
disease
Rarely high serum CgA levels 0.1–1.0/100,000 Unknown Mean
56 years
[250]
18) Ileal
neuroendocrine
tumor
–CDKN1B
(600778)
Tumor mass signs and symptoms and/
or:
Typical carcinoid syndrome: diarrhea,
flushing, carcinoid heart disease
and/or
Atypical carcinoid syndrome: flushing,
headache, lacrimation, hypotension,
cutaneous edema,
bronchoconstriction
High serum CgA, serotonin,
urinary 5-HIAA levels
0.29–1.08/
100,000
Unknown Peak of incidence 59–65
years
[251]
19) Jejunal
neuroendocrine
tumor
––
Usually grouped with
either duodenal or ileal
NETs
Poorly characterized and
heterogeneous ‘‘Duodenal-like’’
tumors of the upper jejunum usually
share the same general behavior
than their duodenal counterparts
Jejunal entero chromaffin tumors
share the same presentation and
general clinical behavior than their
ileal counterparts, including a strong
tendency to local invasion, regional
lymph node involvement, and
metastatic dissemination
‘‘Duodenal-like’’ tumors of
the upper jejunum usually
synthesize gastrin
Unknown Unknown Unknown [252]
J Endocrinol Invest
123
48 rare mineral and bone diseases, (Table 4) 41 rare dis-
eases of the PTH/PTHr1 and PTHrp receptors, (Table 5)69
rare metabolic diseases of glucose, lipids and mucopoly-
saccharides, (Table 6) 6 rare water metabolism diseases,
(Table 7) 49 rare adrenal glands and paraganglia diseases,
(Table 8) 20 rare ovarian diseases, (Table 9) 28 rare tes-
ticular diseases, (Table 10) 14 rare diseases with possible
multiple endocrine involvement, and (Table 11) 23 rare
neuroendocrine tumors.
This report provides a complete taxonomy for the
classification of REMDs of the adult. Although it is
limited in terms of information included, it provides a
comprehensive overview of rare disorders of the various
endocrine systems and a primary diagnostic tool. This
document is the starting point from which future studies
can be pursued, such as the creation of registries of rare
endocrine diseases, to collect data on cohorts of patients,
and the development of common and standardized diag-
nostic and therapeutic pathways for each rare endocrine
disease. This will help to plan and perform intervention
studies in larger groups of patients to prove the efficacy,
effectiveness and safety of a certain treatment, thus
achieving the priority of testing and delivering new drugs
for rare diseases by 2020.
Acknowledgments This work was made possible through an
unrestricted grant from F.I.R.M.O. Fondazione Raffaella Becagli.
Conflict of interest All authors have no conflict of interest to
disclose.
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