Ann Pediatr Endocrinol Metab Search


Ann Pediatr Endocrinol Metab > Volume 29(2); 2024 > Article
Jeon, Kim, Yoo, Kim, and Cheon: A novel compound heterozygous variant of the COL11A1 gene in a patient with fibrochondrogenesis type I: the first case in Korea


· Fibrochondrogenesis (FBCG1) is a severe, autosomal recessive, short-limbed skeletal dysplasia caused by a variant in the COL11A1 gene. This is the first Korean report of FBCG1 which have a compound heterozygous variant of the COL11A1 gene and may provide insight into the phenotypic spectrum of FBCG1.
To the editor,
Fibrochondrogenesis type 1 (FBCG1, OMIM #228520) is a rare lethal autosomal recessive form of short-limbed skeletal dysplasia [1]. FBCG1 is caused by a mutation in the COL11A1 gene [1]. About 22 cases have been reported worldwide [2,3]. The disease is clinically characterized by short stature, skeletal anomalies, significant shortening of all limb segments, facial dysmorphism, myopia, cataracts, and sensorineural hearing loss [1,4,5]. Radiographically, the long bones are severely short and typically dumbbell-shaped with metaphyseal widening. Flat vertebral bodies and platyspondyly, a distinctive pear-shaped appearance, are observed on lateral view [1,4,5]. The disease was named on the basis of the abnormal morphology of the growth plate, in which the chondrocytes have a fibroblastic appearance and there are regions of fibrous cartilage extracellular matrix [1]. Clinically, patients with FBCG1 exhibit a wide clinical spectrum depending on their genotype.
Here, we report the first case of FBCG1 diagnosed by whole exome sequencing in Korea. A detailed interpretation of the identification of a novel variant in a single case of FBCG1 is included.
The patient was a boy 5 years and 11 month of age who was referred to the outpatient clinic due to short stature and webbed neck. He was delivered vaginally at 37+2 weeks of gestation at a birth weight of 2.66 kg. His father's height was 177 cm and his mother's height was 156 cm. He had a healthy sister and there was nothing noteworthy in the family pedigree.
At the time of the outpatient visit, the patient's height, body weight, and head circumference were 105.0 cm (-2.09 standard deviation score [SDS]), 17 kg (-1.85 SDS), 50.5 cm (-0.79 SDS), respectively. He had a dysmorphic facial appearance (Fig. 1), a narrow thorax, mild micromelia, and clinodactyly of both fifth digits. His bilateral wrist joints were flexed inward. Radiographically, the patient's spine was relatively straight, and the ribs exhibited broad metaphyseal cupping at the distal ends. The lumbar vertebral bodies demonstrated marked platyspondyly. He had achieved normal development milestones and was of normal intelligence.
At the first visit to our outpatient clinic, we performed a gene panel related to Noonan syndrome, with negative results. For further diagnosis, we performed whole exome sequencing (WES). Genomic DNA was extracted from buccal swab samples. All exons of all human genes (~22,000) were captured using Agilent's SureSelect kit (version C2, December 2018) and sequenced using the NovaSeq platform (Illumina, San Diego, CA, USA).
WES revealed bi-allelic variants in the COL11A1 gene. Sequence analysis of COL11A1 gene (NM_080629.2) revealed compound heterozygous variants in c.3478C>G (p.Pro1160Ala) on exon 45 and c.2771C>T (p.Pro924Leu) on exon 35 (Fig. 2), the former of which is a novel variant. The c.3478C>G variant was predicted to damage protein structure/function (REVEL score: 0.649≥0.6) and is absent from both gnomAD v2.1.1and v3 datasets. Initially, we classified this novel variant as a variant of uncertain significance, but later changed our classification to likely pathogenic after segregation analysis (trans). The compound heterozygous variants were derived from both the mother (p.Pro924Leu) and father (p.Pro1160Ala).
After genetic diagnosis, the patient underwent ophthalmologic and audiometric assessments, which re vealed no complications. At the age of 12 years, his height was 145.5 cm (-1.00 SDS) and body weight was 36.9 kg (-1.12 SDS). His bone age was two years advanced relative to chronological age. He showed pubertal development corresponding to Tanner stage III. The patient's predicted adult height was expected to be 157 cm (-3.08 SDS).
The COL11A1 gene encodes the α1 chain of type XI collagen, is located at chromosome 1p21.1, and consists of 67 exons [1,6]. A novel variant for FBCG1, p.Pro1160Ala of the COL11A1 protein, is characterized by the base substitution of C to G at the nucleotide position 3478. This change is conserved across multiple species (Fig. 2). The p.Pro1160 residue is located on the cell surface proteins containing the conserved peptide motif (LPXTG)-anchored collagen-like adhesin Scl2/SclB domain.
Although there is no specific treatment for FBCG1, identification of variants in FBCG1 facilitates diagnostic testing for families and early detection of ophthalmic and hearing problems for parents, siblings, and other family members. Lukas et al. reported that treatment of three cases with COL11A1 mutations with growth hormone was effective, increasing growth velocity to 9.1 cm/year and height to SDS +1.5 during the first year of growth hormone treatment [7].
This is the first Korean report of FBCG1 with compound heterozygous mutations of the COL11A1 gene, and may provide insight into the phenotypic spectrum of FBCG1. If skeletal abnormalities are suspected in patients with short stature, immediate skeletal dysplasia-related next-generation sequencing is recommended.


Conflicts of interest

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


This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Ethics statement

This study was approved by the Institutional Review Board (IRB) of Pusan National University Yangsan Hospital, Yangsan, Korea (IRB No. 05-2023-029). We obtained informed consent from the patient's parents.


This study was supported by a 2022 research grant from Pusan National University Yangsan Hospital.

Fig. 1.
Appearance of the patient at the initial visit. He had a dysmorphic appearance including hypertelorism, right ptosis, midface hypoplasia, long philtrum, low-set and rotated ear, anteverted nares, webbed neck, micrognathia, and triangular facial shape. His bilateral wrist joints were flexed inward.
Fig. 2.
Whole exome sequencing found 2 heterozygous variants in the COL11A1 gene (NM_080629.3). Sequence analysis of the COL11A1 gene revealed compound heterozygous variants, c.3478C>G (p.Pro1160Ala) on exon 45 and c.2771C>T (p.Pro924Leu) on exon 35. Alignment of the predicted amino acid sequence of COL11A1 genes among different species, which is shown in the dotted red box. Sequences were aligned with blastp (


1. Tompson SW, Bacino CA, Safina NP, Bober MB, Proud VK, Funari T, et al. Fibrochondrogenesis results from variants in the COL11A1 type XI collagen gene. The American Journal of Human Genetics 2010;87:708–12.
crossref pmid
2. Bekdache GN, Begam MA, Chedid F, Al-Gazali L, Mirghani H. Fibrochondrogenesis: prenatal diagnosis and outcome. Journal of Obstetrics and Gynaecology 2013;33:663–68.
crossref pmid
3. Al-Gazali LI, Bakir M, Hamid Z, Varady E, Varghes M, Haas D, et al. Erratum: Birth prevalence and pattern of osteochondrodysplasias in an inbred high risk population. Birth Defects Research Part A-Clinical and Molecular Teratology 2003;67:125–32.
4. Dong Z, Ma Q, Zheng C, Huang Y, Dong X, Yang K, et al. Identification of novel heterozygous missense variant in the COL11A1 causing fetal craniofacial anomalies. All Life 2022;15:240–46.
5. Čopíková J, Paděrová J, Románková V, Havlovicová M, Balaščáková M, Zelinová M, et al. Expanding the phenotype spectrum associated with pathogenic variants in the COL2A1 and COL11A1 genes. Annals of Human Genetics 2020;84:380–92.
crossref pmid pdf
6. Hufnagel SB, Weaver KN, Hufnagel RB, Bader PI, Schorry EK, Hopkin RJ. A novel dominant COL11A1 variant resulting in a severe skeletal dysplasia. American Journal of Medical Genetics Part A 2014;164:2607–12.

7. Plachy L, Dusatkova P, Maratova K, Petruzelkova L, Elblova L, Kolouskova S, et al. Familial short stature—a novel phenotype of growth plate collagenopathies. The Journal of Clinical Endocrinology & Metabolism 2021;106:1742–49.
crossref pdf


Browse all articles >

Editorial Office
501-107, 30 Seocho-daero 74-gil, Seocho-gu, Seoul 06622, Republic of Korea
Tel: +82-2-3471-4268    Fax: +82-2-3471-4269    E-mail:                

Copyright © 2024 by Korean Society of Pediatric Endocrinology.

Developed in M2PI

Close layer
prev next