👤 Evrim Cifci Sunamak

Hereditary multiple osteochondromas is an autosomal dominant disorder caused by heterozygous pathogenic variants in EXT1 or EXT2. We aimed to evaluate the clinical and molecular findings of a Turkish cohort with hereditary multiple osteochondroma. Thirty-two patients aged 1.3-49.6 years from 22 families were enrolled. Genetic analyses were made by EXT1 and/or EXT2 sequencing and chromosomal microarray analyses. We found 17 intragenic pathogenic variants in EXT1 (13/17) and EXT2 (4/17), 12 of which are novel. Four probands had EXT1 deletions, including 2 patients with partial EXT1 microdeletions involving exons 2-11 and 5-11, and 2 patients with whole-gene deletions. In 21 variants, the frequency of truncating and missense variants was 76.1% and 23.8%, respectively. Two families had no detectable variants in EXT1 and EXT2. All patients had multiple osteochondromas at the long bones, mainly at the tibia, forearm, femur, and humerus. Bowing deformity of the forearms (9/32) and the lower extremities (2/32), and scoliosis (6/32) were observed. The clinical severity was not different between patients with EXT1 or EXT2 variants. One patient with an EXT2 variant and another with an EXT1 microdeletion had the most severe phenotype with class III disease. Four patients with no EXT1 or EXT2 variants had milder phenotypes. Intrafamilial variability in disease severity was not observed. We report a hereditary multiple osteochondroma cohort with clinical and molecular data including 12 novel intragenic variants in EXT1 or EXT2, and 4 microdeletions involving EXT1. Taken together, our data expand the existing knowledge of the phenotype-genotype spectrum in hereditary multiple osteochondroma. Show less

Trichorhinophalangeal syndrome is a rare autosomal dominant disorder characterized by distinctive craniofacial and skeletal abnormalities. This study aimed to delineate the trichorhinophalangeal syndrome phenotype and to compare the clinical and molecular findings between trichorhinophalangeal syndrome types I and II. A total of 22 trichorhinophalangeal syndrome patients aged 0.9-45 years from 17 families were enrolled. Nineteen patients were diagnosed with trichorhin ophalangeal syndrome I and 3 with trichorhinophalangeal syndrome II. Genetic analyses were made by TRPS1 sequencing and/or chromosomal microarray analyses. A novel frameshift variant (c.531₅₃₂del), a known missense variant, and whole-gene deletions were the pathogenic TRPS1 variants detected in trichorhinophalangeal syndrome I. Three trichorhinophalangeal syndrome II patients had large deletions with variable breakpoints involving the TRPS1-EXT1 interval. All patients had the typical craniofacial findings of trichorhinophalangeal syndrome such as a pear-shaped nose, long philtrum, and thin upper lip, as well as cone-shaped epiphyses. Sparse hair and eyebrows (20/22), short metacarpals and metatarsals (20/22), and small hands (19/22) were common. While craniofacial and limb abnormalities were similar in trichorhinophalangeal syndrome I and II, 3 of 19 trichorhinophal angeal syndrome I patients had mild, and 2 of 3 trichorhinophalangeal syndrome II patients had severe intellectual disability. Three trichorhinophalangeal syndrome II patients including the patient with the EXT1 deletion beginning from exon 2 had exostoses. In trichorhinophal angeal syndrome II, although microdeletion sizes and facial or skeletal features were not correlated, patients with larger deletions had severe intellectual disability. This study has expanded the existing knowledge on the phenotype-genotype spectrum in trichorhinophalangeal syndrome. We suggest including the EXT1 gene partially in the minimal critical region for trichorhinophalangeal syndrome II. Show less

Koolen-de Vries syndrome (KdVS) is a rare multisystemic disorder caused by a microdeletion on chromosome 17q21.31 including KANSL1 gene or intragenic pathogenic variants in KANSL1 gene. Here, we describe the clinical and genetic spectrum of eight Turkish children with KdVS due to a de novo 17q21.31 deletion, and report on several rare/new conditions. Eight patients from unrelated families aged between 17 months and 19 years enrolled in this study. All patients evaluated by a clinical geneticist, and the clinical diagnosis were confirmed by molecular karyotyping. KdVS patients had some common distinctive facial features. All patients had neuromotor retardation, and speech and language delay. Epilepsy, structural brain anomalies, ocular, ectodermal, and musculoskeletal findings, and friendly personality were remarkable in more than half of the patients. Hypertension, hypothyroidism, celiac disease, and postaxial polydactyly were among the rare/new conditions. Our study contributes to the clinical spectrum of patients with KdVS, while also provide a review by comparing them with previous cohort studies. Show less