Ann Child Neurol Search


Ann Child Neurol > Volume 31(2); 2023 > Article
Lee, Jo, Kim, and Kim: Hypochondroplasia with Acanthosis Nigricans and Moyamoya Disease
Mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3) cause a variety of disorders, including achondroplasia, hypochondroplasia (HCH), Crouzon syndrome with acanthosis nigricans (CAN), Muenke syndrome, and thanatophoric dysplasia [1]. Acanthosis nigricans (AN) is a skin condition characterized by velvety and pigmented hyperkeratosis in body folds and creases. It typically affects the neck folds, armpits, groin, and other areas, and is commonly observed in children with obesity, type 2 diabetes, drug-induced conditions, and inherited conditions, including FGFR3 mutations [2,3]. Recent genome-wide association studies have identified the ring finder protein 213 gene (RNF213) as an important susceptibility gene for moyamoya disease (MMD). Here, we describe the first known case of co-occurrence of HCH with AN and MMD, caused by mutations in FGFR3 and RNF213.
An 18-year-old girl was referred to the pediatric department for an evaluation of progressive hyperpigmentation of her skin since the age of 8 years. She was born through normal vaginal delivery at term, and the pregnancy of her mother was uncomplicated. The patient’s family history was unremarkable, motor and intellectual development were normal, and she had not experienced seizures, hemiparesis, or loss of consciousness. On physical examination, she did not have a dysmorphic face, macrocephaly, brachydactyly, lordosis, or a limited range of motion at the elbows. Her skin showed extensive AN at the flexion sites, neck, upper trunk, and groin. Her height was 145.5 cm (0th percentile), and her weight was within the normal range. A skin biopsy revealed no specific findings other than hyperkeratosis. This case was reviewed and approved by the Institutional Review Board of Pusan National University Hospital (IRB No. 2203-007-112). Informed consent was obtained from the parents. The patient’s medical records and other data were anonymized to ensure confidentiality.
Upon an initial analysis of the results of diagnostic exome sequencing (DES), we identified a heterozygous c.1949A>C (p.Lys650Thr) mutation in FGFR3, which has been reported to be associated with CAN and HCH. For further evaluation, a three-dimensional computed tomography (CT) scan of the skull and magnetic resonance imaging (MRI) of the brain were performed. CT showed no craniosynostosis (Fig. 1A). Brain MRI revealed MMD-specific findings, including bilateral distal internal carotid artery stenosis, no visible middle and anterior cerebral arteries, and collateral vessels at the bilateral posterior cerebral arteries and deep gray matter (Fig. 1B and C). We reanalyzed the DES data and identified an additional pathogenic variant of RNF213 (c.14429G>A, p.Arg4810Lys) associated with MMD. Sanger sequencing tests were performed to validate the two variants of FGFR3 and RNF213 in DNA samples from the proband and parents. The parents did not carry FGFR3 c.1949A>C, which had occurred de novo. The patient inherited RNF213 c.14429G>A from her mother (Fig. 1D and E), who was a carrier without MMD on brain MRI.
HCH is a form of short-limbed dwarfism, like achondroplasia, but with milder features. It is characterized by short stature, short arms and legs, broad, short hands and feet, macrocephaly, lordosis, and a limited range of motion. These symptoms are less prominent than those of achondroplasia and may not be diagnosed until adolescence or adulthood. FGFR3 encodes a transmembrane tyrosine kinase receptor located on the cell surface of fibroblasts and keratinocytes, and is involved in a variety of activities, including mitogenesis, angiogenesis, and wound healing [1,4]. Gain-of-function mutations in FGFR3 result in the activation, proliferation, and differentiation of fibroblasts and keratinocytes, which cause the development of the AN phenotype. To date, several FGFR3 mutations have been reported in patients with HCH. p.Asn540Lys was the most common, and p.Lys650Asn and p.Lys650Gln were associated with a milder skeletal dysplasia phenotype [4]. Only 10 cases have been reported of AN with or without HCH due to the FGFR3 p.Lys650Thr mutation [5-8]. The present patient had the FGFR3 p.Lys650Thr mutation and exhibited AN and a mild HCH phenotype with only short stature and no skeletal dysplasia.
After receiving the first result of the FGFR3 mutation in DES, MMD was diagnosed during the evaluation to confirm deep phenotyping. A reanalysis of the DES data identified a heterozygous c.14429A>C, p.Arg4810Lys mutation in RNF213. MMD is characterized by occlusion of the supraclinoid internal carotid artery and the development of a fine vascular network. Recent advances have enhanced our understanding of the genetic factors associated with MMD. RNF213 has been identified as a novel susceptibility gene for MMD in East Asian people [9]. A case-control study demonstrated a strong association of p.Arg4810Lys with MMD in an East Asian population, with an odds ratio of 111.8 [9]. The frequency of p.Arg4810Lys in the general population in Japan is 1.4% to 2.7%, with incomplete penetrance [10]. A carrier may not exhibit MMD.
To our knowledge, this is the first case of HCH co-occurring with AN and MMD. Additional diagnostic tests or a reanalysis of results is essential for a final and accurate diagnosis, even after a thorough physical examination, phenotyping, and molecular genetic testing. Therefore, to understand the concept of an “evolving” molecular interpretation, education for physicians and patients is essential.

Conflicts of interest

No potential conflict of interest relevant to this article was reported.


Author contribution

Conceptualization: YJL, YHJ, MBK, and YMK. Methodology: YHJ. Project administration: MBK. Writing-original draft: YJL. Writing-review & editing: YMK.


This work was supported by a clinical research grant from Pusan National University Hospital in 2022.

Fig. 1.
(A) Three-dimensional computed tomography of the skull is normal. (B) T2-weighted axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrates poor visualization of both internal carotid arteries (arrows) and middle cerebral arteries (arrowheads). (C) Magnetic resonance angiography shows bilateral stenosis of the internal carotid, anterior cerebral, and middle cerebral arteries. (D) Sequencing of fibroblast growth factor receptor 3 (FGFR3) identified a heterozygous c.1949A>C mutation in the proband, but not in the parental DNA. (E) Ring finder protein 213 gene (RNF213) sequencing demonstrated a heterozygous c.14429A>C mutation in the proband and the mother’s DNA, but not in the father’s DNA.


1. MedlinePlus. FGFR3 gene [Internet]. Bethesda: US National Library of Medicine; 2022 [cited 2022 Dec 26]. Available from:

2. Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: a practical approach to evaluation and management. Dermatol Online J 2008;14:2.
3. Berk DR, Spector EB, Bayliss SJ. Familial acanthosis nigricans due to K650T FGFR3 mutation. Arch Dermatol 2007;143:1153-6.
crossref pmid
4. Bellus GA, Spector EB, Speiser PW, Weaver CA, Garber AT, Bryke CR, et al. Distinct missense mutations of the FGFR3 lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet 2000;67:1411-21.
crossref pmid pmc
5. Fu J, Zhao Y, Wang T, Zhang Q, Xiao X. Acanthosis nigricans in a Chinese girl with FGFR3 K650 T mutation: a case report and literature review. BMC Med Genet 2019;20:8.
crossref pmid pmc pdf
6. Muguet Guenot L, Aubert H, Isidor B, Toutain A, Mazereeuw-Hautier J, Collet C, et al. Acanthosis nigricans, hypochondroplasia, and FGFR3 mutations: findings with five new patients, and a review of the literature. Pediatr Dermatol 2019;36:242-6.
crossref pmid pdf
7. Fukuchi K, Tatsuno K, Matsushita K, Kubo A, Ito T, Tokura Y. Familial acanthosis nigricans with p.K650T FGFR3 mutation. J Dermatol 2018;45:207-10.
crossref pmid pdf
8. Ichiyama S, Kubo A, Matayoshi T, Saeki H, Funasaka Y. Effects of glycolic acid peeling on the cutaneous manifestation of generalized acanthosis nigricans caused by FGFR3 mutation: a report of one sporadic and two familial cases. J Dermatol 2017;44:e250-1.
crossref pmid pdf
9. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 2011;6:e22542.
crossref pmid pmc
10. Cao Y, Kobayashi H, Morimoto T, Kabata R, Harada KH, Koizumi A. Frequency of RNF213 p.R4810K, a susceptibility variant for moyamoya disease, and health characteristics of carriers in the Japanese population. Environ Health Prev Med 2016;21:387-90.
crossref pmid pmc pdf
Share :
Facebook Twitter Linked In Google+ Line it
METRICS Graph View
  • 0 Crossref
  •   Scopus 
  • 1,392 View
  • 34 Download
Related articles in Ann Child Neurol


Browse all articles >

Editorial Office
101, Daehak-ro, Jongno-gu, Seoul 03080, Korea
Tel: +82-2-2072-2364    Fax: +82-2-743-3455    E-mail:                

Copyright © 2024 by Korean Child Neurology Society.

Developed in M2PI

Close layer
prev next