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A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.

ABSTRACT: Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome.A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard deviation). His past medical history was significant for soft cleft palate and bilateral cataracts. He had a flat midface, micrognathia, and limitations in bilateral elbow flexion. Radiographs showed mild spondyloepiphyseal dysplasia. Initially, we suspected Marshall syndrome, but no mutation was identified in COL11A1. At 8 years old, his height was 116.2 cm (-1.89 standard deviation), and his orofacial characteristics appeared unremarkable. We analyzed the COL2A1 gene and found a novel heterozygous mutation (c.1142 G?>?A, p.Gly381Asp).In this case report, we identify a novel missense mutation in the COL2A1 gene in a patient with Stickler syndrome type 1, and we describe age-related changes in the clinical phenotype with regard to orofacial characteristics and height. Genetic analysis is helpful for the diagnosis of this clinically variable and genetically heterogeneous disorder.

SUBMITTER: Higuchi Y

PROVIDER: S-EPMC5574094 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.

Higuchi Yousuke Y Hasegawa Kosei K Yamashita Miho M Tanaka Hiroyuki H Tsukahara Hirokazu H

Journal of medical case reports 20170826 1

<h4>Background</h4>Stickler syndrome is a group of collagenopathies characterized by ophthalmic, skeletal, and orofacial abnormalities, with the degree of symptoms varying among patients. Mutations in the COL2A1, COL11A1, and COL11A2 procollagen genes cause Stickler syndrome. Marshall syndrome, caused by a COL11A1 mutation, has clinical overlap with Stickler syndrome.<h4>Case presentation</h4>A 2-year-old Japanese boy was presented to our hospital with short stature (79.1 cm, -2.52 standard devi ...[more]

PMID: 28841907

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Project description:ObjectiveNoonan syndrome (NS), an autosomal dominant disease known as a RASopathy, is caused by germline mutations in mitogen-activated protein kinase pathway genes. A RIT1 gene mutation has been found to cause NS. The present study summarizes RIT1 gene mutation sites and associated clinical phenotypes.MethodsWe retrospectively analyzed the clinical characteristics of a case of NS caused by RIT1 mutation in our hospital, and searched the PubMed database, China National Knowledge Infrastructure (CNKI) database and Wanfang database with the keywords Noonan syndrome and RIT1. Studies published between May 1, 2014 and July 1, 2021 were retrieved. By reviewing the abstracts and full text of the studies, we screened NS cases associated with RIT1 mutation in children 0-18 years of age. The clinical characteristics of these cases were summarized.ResultsA total of 41 cases were analyzed, including 13 boys and 28 girls. There were 14 premature cases. The age at diagnosis was 4 days to 18 years, and 10 cases were diagnosed at 0-1 years of age. Common amino acid substitution positions included 57 (13/41), 95 (7/41), 82 (8/41), and 90 (4/41). A total of 63.63% cases had abnormal prenatal examination results, manifesting mainly as fetal neck edema, polyhydramnios and cardiac malformation. With respect to abnormal conditions after birth, 70-80% of patients had typical developmental malformations of the face, neck and thorax; 19/35 patients had abnormal lymphatic development; and a portion of patients had short stature and motor development disorders. A total of 87.80% (36/41) patients had cardiac dysplasia, among which hypertrophic cardiomyopathy (HCM) accounted for 58.53%. A total of 84.62% of patients carrying the p.A57G mutation had HCM, but no HCM was found in patients with the p.G95A mutation. A total of 34.15% of patients had pulmonary artery or pulmonary valve stenosis (PVS). In patients with the p.M90I mutation, 75% had PVS. Patients with concurrent HCM and PVS accounted for 19.51 and 48.78% of patients had supraventricular tachycardia.ConclusionA RIT1 gene mutation causing NS was associated with a high rate of abnormal prenatal examination findings. Most patients had typical NS craniofacial deformities, and some have short stature and motor development disorders. The cardiac deformity rate was high, and HCM was common. Some patients had supraventricular arrhythmias. Heart abnormalities showed high heterogeneity, given the various mutation loci.

Project description:Noonan syndrome (NS), a heterogeneous developmental disorder associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity and typical facial features, is caused by activating mutations in genes involved in the RAS-MAPK signaling pathway.Here, we present a clinical and molecular characterization of a small family with Noonan syndrome. Comprehensive mutation analysis of NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS was performed using targeted next-generation sequencing. The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient's father, who also showed signs of NS.We describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS. Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases. Interestingly, 50% of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals. In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly. The clinical and genetic heterogeneity observed in RASopathies is a challenge for genetic testing. However, next-generation sequencing technology, which allows screening of a large number of genes simultaneously, will facilitate an early and accurate diagnosis of patients with RASopathies.

Dataset Information

A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.

Publications

A novel mutation in the COL2A1 gene in a patient with Stickler syndrome type 1: a case report and review of the literature.

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