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Case Report: Multiple
prolactinomas in a young
man with Kallmann
syndrome and familial
hypocalciuric hypercalcemia
Mojca Jensterle
1,2
*, Andrej Janež
1,2
, Tina Vipotnik Vesnaver
3
,
Marus
ˇaDebeljak
2,4
, Nika Breznik
4
,
Katarina Trebus
ˇak Podkrajs
ˇek
4,5
, Rok Herman
1,2
, Eric Fliers
6
,
Tadej Battelino
2,7
and Magdalena Avbelj Stefanija
2,7
1
Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana,
Ljubljana, Slovenia,
2
Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia,
3
Clinical Institute
of Radiology, University Medical Centre Ljubljana, Ljubljana, Slovenia,
4
Clinical Institute for Special
Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana,
Ljubljana, Slovenia,
5
Institute of Biochemistry and Molecular Genetics, Medical Faculty, University of
Ljubljana, Ljubljana, Slovenia,
6
Department of Endocrinology and Metabolism, Amsterdam
Gastroenterology, Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam,
Amsterdam, Netherlands,
7
Department of Paediatric Endocrinology, Diabetes and Metabolic Diseases,
University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
Introduction: The occurrence of prolactinomas in sex hormone treated patients
with central hypogonadism is extremely rare.
Case presentation: We present a Caucasian male patient who was diagnosed
with Kallmann syndrome (KS) at age 15 years. Testosterone treatment was started.
At age 26 the patient presented with mild headache. MRI revealed two separate
pituitary adenomas along with the absence of the olfactory bulbs. Given the
presence of marked hyperprolactinemia (17x upper limit of the reference range)
the diagnosis prolactinoma was made and treatment with cabergoline was started
which resulted in a complete biochemical response and in marked reduction of
both adenomas in size. Hypogonadism persisted and testosterone replacement
therapy was continued. Genetic testing of genes associated with pituitary tumors,
Kallmann syndrome and idiopathic hypogonadotropic hypogonadism was
negative. Mild concomitant hypercalcemia in accordance with familial
hypocalciuric hypercalcemia (FHH) prompted mutation analysis of the calcium
receptor (CASR) gene which yielded a pathogenic inactivating variant.
Discussion/conclusion: The presence of two separate prolactinomas in a patient
with KS has not yet been reported in the literature. The effect of sex hormone
treatment of KS patients on the possible development of prolactinoma is
unknown at present. The occurance of multiple prolactinomas in our patient
Frontiers in Endocrinology frontiersin.org01
OPEN ACCESS
EDITED BY
Mian Guo,
The Second Affiliated Hospital of Harbin
Medical University, China
REVIEWED BY
Maria Stamou,
Massachusetts General Hospital and
Harvard Medical School, United States
Daisuke Areiyasu,
Kawasaki Municipal Hospital, Japan
*CORRESPONDENCE
Mojca Jensterle
mojcajensterle@yahoo.com
RECEIVED 26 June 2023
ACCEPTED 17 October 2023
PUBLISHED 30 October 2023
CITATION
Jensterle M, JanežA, Vipotnik Vesnaver T,
Debeljak M, Breznik N, Trebus
ˇak
Podkrajs
ˇek K, Herman R, Fliers E,
Battelino T and Avbelj Stefanija M (2023)
Case Report: Multiple prolactinomas in a
young man with Kallmann syndrome and
familial hypocalciuric hypercalcemia.
Front. Endocrinol. 14:1248231.
doi: 10.3389/fendo.2023.1248231
COPYRIGHT
© 2023 Jensterle, Janež, Vipotnik Vesnaver,
Debeljak,Breznik,Trebus
ˇak Podkrajs
ˇek,
Herman, Fliers, Battelino and Avbelj Stefanija.
This is an open-access article distributed
under the terms of the Creative Commons
Attribution License (CC BY). The use,
distribution or reproduction in other
forums is permitted, provided the original
author(s) and the copyright owner(s) are
credited and that the original publication in
this journal is cited, in accordance with
accepted academic practice. No use,
distribution or reproduction is permitted
which does not comply with these terms.
TYPE Case Report
PUBLISHED 30 October 2023
DOI 10.3389/fendo.2023.1248231
suggests increased susceptibility. Although CaSR is expressed in GnRH neurons
in mouse brain and CaSR deficient mice have a reduced hypothalamic GnRH
neuronal population, the relevance of the CASR gene variant in our patient for the
KS phenotype is unclear at present.
KEYWORDS
Kallmann syndrome, prolactinoma, hypogonadism, sex hormones, familial
hypocalciuric hypercalcemia
1 Introduction
Prolactinomas are the commonest pituitary adenomas,
representing about 50% of pituitary adenomas, with an overall
prevalence of approximately 50:100,000 (1,2). The vast majority of
pediatric prolactinomas are identified in late adolescence (2), while
they are ultra-rare in prepubertal children (3–5). There is a strong
female preponderance, with a peak incidence in childbearing ages
(1). In males, peak incidence is beyond 50 years; however, tumors in
males are on average larger and more aggressive (1). The sex
differences in presentation and biological behavior are associated
with variability in expression of genes involved in the estrogen
signaling pathway (6). Therefore, hormonal homeostasis was
proposed to play an important role in prolactinoma
pathogenesis (3).
Kallmann syndrome (KS) is a congenital form of
hypogonadotropic hypogonadism (HH) associated with
hyposmia/anosmia, that occurs with an incidence of 1:48,000
(1:30,000 males) (7). Genetic variants in various genes underlying
KS are associated with embryonal development and migration of
GnRH neurons along with the development of olfactory neurons
(8). A clinical study in a large group of KS patients showed that
certain clinical features are highly associated with specific genetic
causes, such that synkinesia (ANOS1), dental agenesis (FGF8/
FGFR1), digital bony abnormalities (FGF8/FGFR1), and hearing
loss (CHD7) can be useful for prioritizing genetic screening (9).
We present a young male patient with a rare co-occurrence of
KS and multiple prolactinomas. Genetic screening for KS and for
pituitary adenoma was negative. As the patient showed
concomitant mild hypercalcemia in accordance with familial
hypocalciuric hypercalcemia (FHH) we performed additional
mutation analysis of the calcium receptor (CASR)genewhich
yielded a pathogenic inactivating variant. We are unaware of
earlier reports of the combined occurrence of these rare clinical
features in KS patients.
2 Case presentation
A 15-year-old male Caucasian patient presented with absent
puberty, small testicles (1 ml), osteopenia and anosmia. The flaccid
penile length was 3.6 cm and the lenght of the stretched penis was
5.2 cm. No cryptorchidism or microphallus were reported at birth.
Endocrine assessment, including a gonadotropin-releasing
hormone (GnRH) stimulation test (serum luteinizing hormone
(LH) and follicule-stimulating hormone (FSH) response upon
stimulation with gonadorelin 100 µg intravenously, measured at
0’,20’,30’and 60’min), confirmed HH [basal LH 0.1 U/L (reference
range in 11-15 yo boys 0.2-1.9 U/L (10)], peak LH 3.19 U/L
[reference range in 11-15 yo boys 1.8-12 U/L (10)], basal FSH
0.24 U/L [reference range in 11-15 yo boys 0.3-3.5 U/L (10)], peak
FSH 2.33 U/L [reference range in 11-15 yo boys 1.2-5.5 U/L (10)],
serum testosterone 0.5 nmol/L (reference range in 14.5-17.3 yo boys
0.85-45.62 nmol/L) (11). Prolactin was not determined at the time
of diagnosis until just before testosterone replacement was started at
the age of 15 years old [10.2 mcg/L, upper limit of the reference
range16.1mcg/L(12)]. Based on concomitant olfactory
dysfunction, he was diagnosed with KS. No baseline brain
imaging was performed at that time. Hormonal replacement
treatment was initiated for puberty induction with testosterone
enanthate and then continued with testosterone undecanoate
following the local monitoring protocol. Testosterone levels were
sustained within the normal range and bone mineral density
reached normal adult levels by the age of 21.5 years (femur neck
Z-score -0.5 SD and lumbar spine Z-score -0.8 SD).
At age 26 the patient presented with mild headache. MRI brain
imaging (1,5T Philips Achieva MRI scanner) revealed the absence
of olfactory bulbs (shown in Figure 1)(13). Unexpectedly, there
were two additional abnormal findings in the pituitary region, i.e., a
T1 hypointense, T2 hyperintense lesion, probably adenoma
measuring 10 x 8 mm that enhanced after Gadolinium
enhancement. The lesion expanded the right lobe of the pituitary
gland and extended to the right parasellar region. Additionally, a
second lesion was present in the left lobe of the gland, measuring
5 mm in diameter. The second adenoma was slightly hyperintense
on T1 sequence, T2 hypointense, and after gadolinium it enhanced
less than the rest of the gland (shown in Figures 2,3).
Hormonal evaluation revealed hyperprolactinemia (prolactin
292 mcg/L, upper limit of the reference range for men 17 mcg/l).
Deficiencies of thyrotropin (TSH), adrenocorticotropin (ACTH),
and growth hormone (GH) as well as GH hypersecretion were
excluded. TSH was 3.95 mE/L (reference range 0.55-4.78 mE/L),
fT4 was 14.5 pmol/L (reference range 11.5-22.7 pmol/L), ACTH
was 5.46 pmol/L (reference range up to 10.2 pmol/), basal cortisol
was 406 nmol/l, dehydroepiandrosterone (DHEAS) was 11.10
µmol/L (reference range 7.56-17.28 µmol/L), insulin-like growth
Jensterle et al. 10.3389/fendo.2023.1248231
Frontiers in Endocrinology frontiersin.org02
factor 1 (IGF-1) was 223 mcg/L (reference range 75-274 mcg/L),
insulin-like growth factor-binding protein 3 (IGFBP-3) was 4.69
mg/L (reference range 2.80-6.30 mg/L). Treatment with cabergoline
at an initial dosage of 0.25 mg twice weekly up-titrated to 0.5 mg
twice weekly resulted in a complete biochemical response (prolactin
level 23.9 mcg/L after 3 months, 8.1 mcg/L after 6 months and 2.2
mcg/L at the last check-up 3.5 years after starting cabergoline). Both
pituitary lesions showed a clear reduction in size, and the lesion in
the left lobe almost completely disappeared (shown in Figure 4).
The frequencies of mild headaches have decreased, not necessarily
related to reduction of the lesions. After normalization of prolactin,
we discontinued testosterone undecanoate for 7 months and
reassessed the gonadal axis. During that time he continued to
take cabergoline. Hypogonadism persisted despite prolactin
normalization (testosterone 4.6 nmol/L, reference range 6.9-23.3
nmol/L) and testosterone undecanoate 1000 mg was reintroduced
and applied every 12 weeks to sustain testosterone level within the
normal range. At last follow up visit, the patient reported no
symptoms of hypogonadism, exhibited normal male hair growth
pattern and pseudogynecomastia without notable glandular tissue.
In addition to the endocrine abnormalities the patient had
asymptomatic and mild hypercalcemia (Ca 2.95 mmol/L (ref.
range 2.10-2.60 mmol/L) in the presence of elevated plasma PTH
(PTH 69 ng/L, ref. range 12-65 ng/L). Morphological examinations
of parathyroid glands yielded normal results. A diagnosis of familial
hypocalciuric hypercalcemia (FHH) was made based on the
combination of these laboratory findings and his family history
with a father and sister both known with FHH (shown in Figure 5).
While other family members had timely puberty (menarche at 13
years in the mother and at 14 years in the sister), his father had
anosmia and reportedly shawed his beard regularly at 19 years old.
In the extended family there was a history of a throat carcinoma and
colon carcinoma in two grandaunts on paternal side.
In all four family members whole genome sequencing using
Illumina NovaSeq 6000 System (San Diego, California, USA) was
performed. The analysis was focused on exonic and splicing
variants. Identified genetic variants with coverage >10x and read
frequency >0.3 were annotated and filtered with VarAFT software
(14). The minor allele frequency threshold was set at 1% and all
variants exceeding this value were excluded from further analysis.
Candidate variants were subsequently confirmed with targeted
Sanger sequencing. We used ClinSV framework, that enables the
identification of copy-number-neutral structural variants and
overlapping deletions/duplicationseventsingenome(15).
Targeted analysis of 36 genes associated with neuroendocrine
tumors (Supplementary Table 1), of 63 genes associated with
hypogonadotropic hypogonadism (Supplementary Table 2) and
TSHZ1 gene associated with isolated congenital anosmia (ICA)
did not identify likely pathogenic variants. In an extended panel of
366 candidate genes (Supplementary Table 3)basedontheir
biological function in GnRH neuronal development and action
(16) and in 191 genes (Supplementary Table 4) demonstrated to be
downregulated in prolactinoma cells (17) no pathogenic variants
according to ACMG criteria (18)wereidentified. Also, no
potentially here described disease related de novo variants were
identified in the proband. A few variants of unknown significance
were identified in genes associated with GnRH neuronal
development and action, whose association with KS in our patient
is highly unreliable, taking into account lacking additional clinical
signs expected in certain gene defects and/or uncertain results of the
in silico pathogenicity prediction tools (Supplementary Table 5).
FIGURE 2
T2 weighted image in coronal plane; pituitary adenoma of the right
lobe of the gland, extending to the right parasellar region (white
arrow), rounded adenoma of the left lobe (blue arrow). Pituitary
infundibulum is slightly tilted to the left.
FIGURE 1
T2 weighted image in coronal plane; Absent olfactory bulbs (arrow).
Jensterle et al. 10.3389/fendo.2023.1248231
Frontiers in Endocrinology frontiersin.org03
Familial hypocalciuric hypercalcemia (FHH, OMIM #145980) due
to inactivating heterozygous variant in the calcium-sensing receptor
(CASR NM_000388.4: c.2383C>T, NP_000379.3: p.R795W; a
pathogenic variant fulfilling the following ACMG criteria: PM1,
PP2, PM2, PP3, PP5) was confirmed align with asymptomatic
hypercalcemia and elevated PTH.
3 Discussion
We illustrate a patient with Kallmann syndrome and two
prolactinomas during early adulthood. Multiple separate pituitary
adenomas are generally very rare, identified in only 0.7% of
pituitary adenoma cases (19). While increased frequency of
unspecified microadenomas have been reported in idiopathic HH
patients (20), there is to our knowledge only one anecdotal report of
prolactinoma in KS (21). To our knowledge, the occurrence of two
separate prolactinomas in a patient with KS has not yet been
reported in the literature.
Identification of prolactinomas in our patient first challenged
the diagnosis of KS as the cause of hypogonadism, particularly in
the absence of genetic confirmation. Only about 50% of idiopathic
HH cases are explained by genetic defects (22). We do consider the
cause of HH in our patient to be congenital for the following
arguments: i) small testicular volume at age 15 indicated long
lasting hypogonadism, ii) anosmia with absent olfactory tracts in
the patient and iii) anosmia in a family member suggesting an
inherited cause. Furthermore, the normal prolactin level just before
the start of testosterone replacement strengthens the argument that
the patient’s congenital HH was not due to hyperprolactinemia and
that there were no prolactin-secreting microprolactinomas at the
time of diagnosis. Moreover, hypogonadism was not reversed after
adequate prolactin suppression. Longer-term HPG axis suppression
despite achieving normoprolactinemia is not unusual in men with
macroprolactinomas. According to Sehemby M et al., the likelihood
of HPG axis recovery is associated with baseline prolactin level and
tumor size. Specifically, tumor diameter less than or equal to 3.2 cm
and serum prolactin less than or equal to 2098 ng/mL best predicted
reversal of HH (23). Baseline characteristics of our patient were far
from reaching these limits.
The only pathogenic variant identified in our patient by targeted
phenotype driven analysis was inactivating variant in CASR gene,
previously described in association with familial hypocalciuric
hypercalcemia (FHH) (24). Of note, animal and in vitro data
shows that CaSR is expressed in vivo in GnRH neurons in mouse
brain. Moreover, high Ca2+ induces chemotaxis of GnRH cell lines
acting via the CaSR, and CaSR deficientmicehavemarkedly
reduced GnRH neuronal population in the anterior hypothalamus
(25). This points to a possible role for the CaSR pathogenic variant
in the development of KS in our patient. On the other hand, no
delayed puberty, infertility or central hypogonadism have been
reported in FHH patients (26). Thus, at present, the phenotype in
our patient cannot be fully explained by the CASR variant.
We failed to perform brain or pituitary MRI at baseline in the
present patient, and a recent consensus statement supports cranial
MRI at baseline in the workup of congenital isolated HH patients, not
only to assess inner ear, midline structures and olfactory structures,
but also to identify potential tumors and/or space occupying lesions
(27). Sellar abnormalities such as craniopharyngioma, intracranial
cysts, empty sella, non-functional pituitary adenoma and also
prolactinoma have been reported in patients with KS (21,28–30).
On the other hand, the cost-effectiveness of brain imaging in
FIGURE 3
CE T1 weighted image in coronal plane: enhancement of the lesion
in the right lobe (white arrow), lesser enhancement of the lesion in
the left lobe (blue arrow).
FIGURE 4
The latest MRI assessment 3 years after initiating the cabergoline
treatment: Control T2 weighted image in coronal plane: Size
reduction of the right lobe adenoma (white arrow) and almost
complete disappearance of the lesion in the left lobe (blue arrow).
Jensterle et al. 10.3389/fendo.2023.1248231
Frontiers in Endocrinology frontiersin.org04
congenital isolated HH has been debated as unsuspected structural
lesions of etiological significance were observed in only 1-3% of
patients in a larger cohort (31).
Data on the prevalence of structural pituitary abnormalities in
men presenting with adult-onset isolated HH is scarce (20,28,32–
34). A significant ambiguity still remains about which patient
deserves a magnetic resonance imaging (MRI) scan of the
hypothalamus and pituitary during evaluation and follow-up in
this population (28). One study suggests that the use of routine
hypothalamic-pituitary imaging in the evaluation of adult-onset
isolated HH, in the absence of clinical characteristics of other
hormonal loss, hormonal hypersecretion or sellar compression
symptoms, does not increase the diagnostic yield of sellar
structural abnormalities over that reported in the general
population (32). On the other hand, it was reported that
structural pituitary disease is more common in adult-onset
isolated HH than in the general population, and that current
guidelines do not accurately identify ‘at-risk’individuals (20,33).
A recent report suggested that MRI of the pituitary is not warranted
in all patients with adult-onset isolated HH, as the yield of
identifiable abnormalities is quite low (34). Anatomic lesions were
likely to be present only when low levels of testosterone are found
concomitantly with high levels of prolactin and/or low IGF-1
standard deviation score (34). Based on current European
Academy of Andrology and Endocrine Society clinical practice
guidelines the overall cost-effectiveness of MRI scanning in the
absence of clinical evidence of pituitary mass effects is relatively low,
but should be considered when testosterone concentrations are <6
nmol/L and LH is low or normal (35,36).
We identified one case reporting a prolactinoma in a patient
with KS (21). The imaging diagnostic in that case was not
performed at routine checkup, but only after a life-threatening
complication due to pituitary apoplexy (21). By the same authors,
an adult-onset prolactinoma in a female with PROP1 related
hypopituitarism including central hypogonadism supplemented
with sex hormones was reported (21). The authors speculated
that long lasting therapy with sex steroids initiated at adolescence
may have facilitated the development of the prolactinoma via
epigenetically mediated gene dysregulation (21). Estrogen
receptors are commonly present on prolactinoma cells and their
density diminishes with dopamine antagonists. It is speculated that
the presence of estrogen receptors improves response to dopamine
antagonists (37). Of note, aromatase enzyme is expressed in human
pituitary in men and women with particularly striking
interindividual variance in men (38). As the genetic analysis
results for neuroendocrine tumors in our patient were negative,
additional prolactinoma predisposing factors should be at least
considered. We propose that a potential role for inactivating
variants in the CASR gene deserves further study in relation to
the pathogenesis of KS. Finally, the long-lasting therapy with sex
steroids initiated at adolescence may have facilitated the
development of the prolactinomas as similar cases have been
reported in the literature. Acknowledging such risk would be
important, since sex steroid replacement therapy could mask the
hypogonadism as an early sign of prolactinoma.
4 Conclusion
We present the case of a young male patient with a rare co-
occurrence of KS, multiple prolactinomas and familial
hypocalciuric hypercalcemia (FHH). While genetic background of
KS and of pituitary adenomas remained unclear, FHH was
genetically confirmed by a pathogenic inactivating variant in the
CASR gene. We are unaware of earlier reports of the combination of
these rare clinical features in KS patients and suggest their possible
interrelation deserves further attention.
Data availability statement
The original contributions presented in the study are included
in the article/Supplementary Material. Further inquiries can be
directed to the corresponding author.
Ethics statement
The case study was conducted according to the guidelines of the
Declaration of Helsinki, and approved by the Medical Ethics
Committee of the Republic of Slovenia (#29/06/14 and #132/03/
15). Written informed consent was obtained from the patient for
publication of this case report and any accompanying images.
FIGURE 5
The pedigree and the diagnosis of family history.
Jensterle et al. 10.3389/fendo.2023.1248231
Frontiers in Endocrinology frontiersin.org05
Author contributions
MJ: Conceptualization, Data collection, Analysis and
Interpretation, Literature review, Writing - original draft, Writing
- review and editing; MA: Conceptualization, Data collection,
Analysis and Interpretation, Literature review, Writing - original
draft, Writing - review and editing and Supervision; TV, MD, NB,
KT, and RH: Data collection, Analysis and Interpretation, Writing -
review & editing; AJ, EF, and TB: Analysis and Interpretation,
Literature review and Writing review & editing. All authors
contributed to the article and approved the submitted version.
Funding
The research work was partly funded by the Slovenian research
agency project P3-0298. The planning and conduction of the study,
the interpretation of data, and the writing of the present manuscript
are completely independent of the funder.
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated organizations,
or those of the publisher, the editors and the reviewers. Any product
that may be evaluated in this article, or claim that may be made by its
manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online
at: https://www.frontiersin.org/articles/10.3389/fendo.2023.1248231/
full#supplementary-material
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