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Rare Presentation of Neurofibromatosis and Turner Syndrome in a Pediatric Patient

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Natalie Gengel
Natalie Gengel
Natalie Gengel
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Ian Marshall at Rutgers-Robert Wood Johnson Medical School
Ian Marshall
  • Rutgers-Robert Wood Johnson Medical School
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Abstract

Neurofibromatosis type 1 (NF1) is classically defined by the presence of multiple c afé-au-lait macules as one of the diagnostic criteria. Turner syndrome (TS) can also present with café-au-lait macules along with short stature. Our patient is the fifth reported with both NF1 and TS and the first who has been on growth hormone for short stature associated with TS.
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[page 14] [Pediatric Reports 2017; 9:6810]
Rare presentation of
neurofibromatosis and Turner
syndrome in a pediatric patient
Natalie Gengel, Ian Marshall
Department of Pediatrics, Rutgers-
Robert Wood Johnson Medical School,
New Brunswick, NJ, USA
Abstract
Neurofibromatosis type 1 (NF1) is clas-
sically defined by the presence of multiple
café-au-lait macules as one of the diagnos-
tic criteria. Turner syndrome (TS) can also
present with café-au-lait macules along
with short stature. Our patient is the fifth
reported with both NF1 and TS and the first
who has been on growth hormone for short
stature associated with TS.
Introduction
Solitary café-au-lait macules are com-
mon birthmarks,1which can vary in color
from light to dark brown, with borders that
can be smooth or irregular. When multiple
café-au-lait macules are present, neurofi-
bromatosis type 1 (NF1) should be consid-
ered. NF1 is an autosomal dominant disor-
der due to loss-of-function mutations in the
tumor suppressor NF1 gene (neurofibromin
1).2The worldwide incidence of NF1 is
estimated to be 1 in 2500 to 3000 individu-
als.3,4 It is a clinical diagnosis based on the
presence of at least 2 of 7 diagnostic crite-
ria.5One of the 7 criteria include 6 or more
café-au-lait macules ≥5 mm in diameter in
pre pubertal, and ≥15 mm in post pubertal
children.5
Turner syndrome (TS) can also present
with café-au-lait macules.6TS occurs due
to loss of either all or part of the X chromo-
some, with an incidence of at least 1 in 2500
live births.7
Four patients with overlapping pheno-
typic features of both NF1 and TS have
been previously reported.8-10 We report the
fifth girl diagnosed with NF1 and TS who
presented with café-au-lait macules.
Case Report
An 8-year-old female presented to our
clinic for continued evaluation of short
stature due to TS. She had been diagnosed
with TS when chromosome analysis at age
6 for short stature revealed 45X karyotype
(Universidad Autónoma de Santo Domingo,
Dominican Republic). She was started on
growth hormone (GH) therapy to promote
linear growth. Initially 3 café-au-lait mac-
ules were reported on clinical examination.
At age 8 years, a clinical diagnosis of NF1
was made based on presence of more than 6
café-au-lait macules measuring >5 mm in
diameter, axillary freckling, and Lisch nod-
ules on ophthalmologic examination. A
novel heterozygous p.M1149V variant of
uncertain significance was identified by
genetic testing (Center for Human Genetics,
Inc., Cambridge, MA, USA). It was predict-
ed that this variant would not be tolerated
based on SIFT (http://sift.jvci.org), and
probably damaging using Polymorphism
Phenotyping v2 (PolyPhen2) (http://gene-
tics.bwh. Harvard.edu/pph2). As the amino
acid was conserved amongst species, and
p.M1149I variant had been reported as dis-
ease causing, it was concluded that
p.M1149V variant was likely pathogenic.
Discussion
NF1 is a RASopathy, a class of develop-
mental disorders caused by germline muta-
tions in genes that regulate the Ras/mito-
gen-activated protein kinase (MAPK) path-
way.11 RASopathies produce a group of
phenotypically overlapping syndromes,
which, in addition to NF1, include Noonan
syndrome (NS) and Noonan-like
syndrome.11 Another RASopathy called
Neurofibromatosis-Noonan syndrome
(NFNS), first recognized in 1985 by
Allanson et al.12 shows phenotypic overlap
between NF1 and NS. Although NS and TS
share phenotypic similarities, which result-
ed in patients with NS previously diagnosed
with a form of TS, they are distinct genetic
conditions. Our patient is the fifth reported
with clinical features of both NF1 and TS.
Interestingly, the same pathogenic variant,
p.M1149V, that was identified in NF-1 in
our patient has been reported in another
patient with NF1,13 who was also diagnosed
with mitochondrial complex I deficiency
based on investigation for progressive
microcephaly. This again was presumed to
be coincidental. Our patient was prescribed
GH therapy for the FDA approved indica-
tion of short stature due to TS.14 Short
stature, and GH deficiency (GHD) have
also been reported as more common in chil-
dren with NF1 than the general popula-
tion.15 The exact incidence and cause of
GHD have not been clearly defined.
However, as NF1 has an increased risk for
development of benign and malignant
tumors, there has been a long-standing con-
cern about the safety of GH therapy in NF1
patients. Review of data from 102 NF1 chil-
dren on GH therapy16 showed the incidence
of intracranial tumor occurrence was com-
parable to that in NF1 patients not treated
with GH.17-19 Interestingly, in NF1 patients,
GH receptor (GHR) expression was identi-
fied in plexiform neurofibromas,20 which
are common precursors of malignant
peripheral nerve sheath tumors in NF1.21
Although this does not prove a role of GH
in development of these neurofibromas and
a link to malignant transformation, the pres-
ence of GHR suggests that these tumors
may respond to GH.
Conclusions
Although the 2 distinct genetic syn-
dromes in our patient are presumably a
chance occurrence, it remains important for
clinicians to recognize that the presence of
one genetic condition that can explain a
specific clinical presentation, does not
exclude a second. We plan to monitor our
patient closely both clinically and biochem-
ically due to the potential risk of malignant
transformation of her fibromas on GH ther-
apy.
References
1. Shah KN. The diagnostic and clinical
significance of café-au-lait macules.
Pediatric Reports 2017; volume 9:6810
Correspondence: Ian Marshall, Department of
Pediatrics, Rutgers-Robert Wood Johnson
Medical School, 89 French Street, New
Brunswick, NJ, 08901, USA.
Tel.: +1.732.235.9378 - Fax: +1.732.235.5002
E-mail: marshaia@rutgers.edu
Key words: Neurofibromatosis type 1; Turner
syndrome; Growth hormone.
Contributions: NG, collection of data, and wrote
first draft; IM, final revision including discus-
sion.
Conflict of interest: the authors declare no poten-
tial conflict of interest.
Received for publication: 29 July 2016.
Revision received: 19 January 2017.
Accepted for publication: 28 March 2017.
This work is licensed under a Creative
Commons Attribution NonCommercial 4.0
License (CC BY-NC 4.0).
©Copyright N. Gengel and I. Marshall, 2017
Licensee PAGEPress, Italy
Pediatric Reports 2017; 9:6810
doi:10.4081/pr.2017.6810
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Brief Report
... Среди моногенных синдромов, которые описаны в комплексе с хромосомными аномалиями, одним из наиболее частых является нейрофиброматоз. В литературе имеются описания случаев сочетания нейрофиброматоза и других генетических синдромов, включая частые хромосомные синдромы [1][2][3]. Нейрофиброматоз 1-го типа является частым, хорошо изученным моногенным синдромом с аутосомно-доминантным типом наследования и частотой 1:2500 [4]. Заболевание обусловлено мутациями в гене-супрессоре опухолей NF1, который локализуется в перицентромерном регионе длинного плеча хромосомы 17 (17q11.2) и кодирует белок нейрофибромин [4]. ...
... Различные хромосомные аномалии также встречаются с нейрофиброматозом [1,3]. ...
... [1] и Шерешевского-Тернера [3]. ...
View
... To the best of our knowledge, only five cases of coexistent TS and NF1 are reported in literature as of this writing and almost all of them presented with classic clinical features of both NF1 and TS. [1][2][3][4] In this report, we describe the case of a girl who did not have the classic presenting features of TS or NF1, but genetic tests revealed both these disorders and therefore required close supervision while receiving hormonal replacement. The case highlights important clinical considerations in the diagnosis and management of this dual pathology. ...
... Due to phenotypic similarities between the two syndromes like café-au-lait macules, many of the published cases presented as diagnostic dilemmas. [2][3][4] However, in all these cases, the diagnosis of NF1 could be made using the NIH diagnostic criteria. ...
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