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Acromesomelic dysplasia type Maroteaux (AMDM, OMIM #602875) is an autosomal recessive disorder characterized by severe short stature, shortened middle and distal segments of the limbs, redundant skin of fingers, radial head subluxation or dislocation, large great toes and cranium, and normal intelligence. Only the skeletal system appears to be consistently affected. AMDM is caused by biallelic loss-of-function variants in the natriuretic peptide receptor B (NPRB or NPR2, OMIM #108961) which is involved in endochondral ossification and longitudinal growth of limbs and vertebrae. In this study, we investigated 26 AMDM patients from 22 unrelated families and revealed their genetic etiology in 20 families, via Sanger sequencing or exome sequencing. A total of 22 distinct variants in NPR2 (14 missense, 5 nonsense, 2 intronic, and 1 one-amino acid deletion) were detected, among which 15 were novel. They were in homozygous states in 19 patients and in compound heterozygous states in four patients. Parents with heterozygous NPR2 variants were significantly shorter than the control. Extra-skeletal abnormalities, including global developmental delay/intellectual disability, nephrolithiasis, renal cyst, and oligodontia were noted in the patient cohort. The high parental consanguinity rate might have contributed to these findings, probably associated with other gene variants. This study represents the largest cohort of AMDM from Turkey and regional countries and further expands the molecular and clinical spectrum of AMDM.

Mucopolysaccharidosis type III (MPS III) is a neurodegenerative disorder. In MPS III patients, heparan sulfate accumulates in many tissues especially the central nervous system. There are limited data regarding bone involvement in MPS III compared to other MPS types. The aim of this study was to evaluate bone mineral density (BMD) and the prevalence of low bone mass, and to explore the association between BMD, vitamin D levels, bone fracture, and patient characteristics in MPS III. A clinical assessment and interview was held to obtain data about family history, height, weight, body mass index (BMI), nutrition, walking capacity, bone fracture, epilepsy, and medical therapy of 15 patients with MPS III. Height, weight, and BMI z scores were calculated. Laboratory tests including 25-hydroxyvitamin D (25-OH-D) were measured. BMD measurements for the lumbar spine were obtained using dual-energy X-ray absorptiometry (DXA). BMD z scores were adjusted for height-for-age z score (HAZ) to provide correction for height deficits. Lumbar spine BMD z score was low (<−1) in five patients for chronological age and normalized in two of five patients after adjustment for HAZ. Three patients continued to have low BMD; these were older than the other patients and one had a history of long bone fracture. Two of these patients were observed to have lost walking capacity at 10 and 14 years, and the other was walking with support. Six patients had deficient, and three patients had insufficient levels of 25-OH-D. Two osteoporotic patients had significantly lower levels of 25-OH-D. We found that older patients with immobility are at high risk of osteoporosis and bone fracture, and vitamin D deficiencies/insufficiencies are widely seen. We recommend monitoring BMD by DXA and checking vitamin D metabolism to assess low bone mass and fracture risk in older MPS III patients with immobility.

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7 −/− mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7 −/− mouse cartilage and patient fibroblasts. Finally, we find an abnormal N -glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development. The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.

Purpose Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2 , encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing. Methods In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2 -positive ( n  = 44) and FBN2 -negative group ( n  = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups. Results The total score was significantly different between the groups ( P  < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups. Conclusions Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.

Background This study presents an adult 7p21 deletion patient, including a literature review specific to 7p21 deletion, and concludes recommendations toward such patients. A 47-year-old male with moderate-to-severe learning disability and significant dysmorphic features was seen in our Medical Genetics clinic. Initially, a chromosome analysis was requested considering a pre-diagnosis of Down syndrome with adult age, and other chromosomal abnormalities. Results In karyotype analysis, one chromosome 7 was observed to have a deletion on its short arm. Subsequently, single nucleotide polymorphism array (SNP Array) analysis was pursued to confirm the abnormality seen in the chromosome analysis and to elucidate its details. The results indicated a 16-megabase loss in the 7p21.3-p15.3 regions. Conclusions Patients with deletions of the short arm of chromosome 7 may exhibit various phenotypic features, including case-specific anomalies. Common abnormalities often linked to the heterozygous loss of 7p21 include a wide nasal bridge and ear shape abnormalities. Our 47-year-old patient presented with macroglossia and dysmorphic traits, suggesting macroglossia as a potential clinical finding for follow-up in adults. Further research is needed to confirm if all such specific anomalies are due to 7p genetic material loss.

Tow bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. The exact prevalence of TRPS is unknown; the estimated prevalence is Q.2-1/100,000.1'2 It was first described in 1966 by Giedion, and less than 250 TRPS patients have been reported.34 There are two clinical subtypes of TRPS; one of them is TRPS type 1 (TRPS1) (OMIM #190350) caused by pathogenic variants in the TRPS1 gene located on chromosome 8q23.3, and the other one is TRPS type 2 (Langer-Giedion syndrome, LGS), (OMIM #150230), a contiguous gene deletion syndrome is caused by submicroscopic deletion of the chromosomal segment 8q23.3-8q24.11, containing TRPS1, RAD21, and EXT1. A different subtype of TRPS has also been described; however, TRPS type 3 is now accepted within the spectrum of TRPS1 with more severe brachydactyly and short stature.25 TRPS1 gene is a zinc finger transcription factor expressed in cartilage, kidneys, and hair follicles that represses GATA-regulated genes and regulates bone perichondrium mineralization, chondrocyte proliferation, differentiation, and apoptosis.6/7TRPSl has high penetrance and wide phenotypic variability. Molecular Analysis Molecular karyotyping was performed using the DNA samples of patients obtained from peripheral whole blood.

Thrombocytopenia-absent radius (TAR) syndrome is a rare congenital syndrome in which thrombocytopenia and the absence of radius can be accompanied by various organ anomalies. Bilateral phocomelia is the most severe form in this clinic. Thumbs are always present. The deletion of the RNA-binding motif protein 8A (RBM8A) gene on chromosome 1q21.1 in Array Comparative Genomic Hybridization confirms the diagnosis of TAR syndrome. Thrombocytopenia, which can cause complications, tends to resolve in the first year of life. Although there are delays in motor development, mental retardation is not one of the common clinical findings of this syndrome. In the differential diagnosis of severe radial defects, TAR syndrome, Holt-Oram syndrome, Roberts syndrome, Fanconi anemia, and VACTERL association are included. The presence of key findings of each syndrome is important in the differential diagnosis. Here, we aimed to evaluate the approach to the differential diagnosis of severe radial anomalies in a patient with TAR syndrome and neuromotor retardation.

Background. Tricho-rhino-phalangeal syndrome (TRPS) is a rare, autosomal dominant disorder characterized by typical craniofacial features, ectodermal and skeletal findings. TRPS type 1 (TRPS1) is caused by pathogenic variations in the TRPS1 gene, which relates to the vast majority of cases. TRPS type 2 (TRPS2) is a contiguous gene deletion syndrome involving loss of functional copies of the TRPS1, RAD21, and EXT1. Herein, we reported the clinical and genetic spectrum of seven TRPS patients with a novel variant. We also reviewed the musculoskeletal and radiological findings in the literature. Methods. Seven Turkish patients (three female, four male) from five unrelated families aged between 7 to 48 years were evaluated. The clinical diagnosis was confirmed by either molecular karyotyping or TRPS1 sequencing analysis via next-generation sequencing. Results. Both TRPS1 and TRPS2 patients had some common distinctive facial features and skeletal findings. All patients had a bulbous nose with hypoplastic alae nasi, brachydactyly, short metacarpals and phalanges in variable stages. Low bone mineral density (BMD) was identified in two TRPS2 family members presenting with bone fracture, and growth hormone deficiency was detected in two patients. Skeletal X-ray imaging revealed cone-shaped epiphysis of the phalanges in all, and multiple exostoses were present in three patients. Cerebral hamartoma, menometrorrhagia and long bone cysts were among the new/rare conditions. Three pathogenic variants in TRPS1 were identified in four patients from three families, including a frameshift (c.2445dup, p.Ser816GlufsTer28), one missense (c.2762G > A), and a novel splice site variant (c.2700+3A > G). We also reported a familial inheritance in TRPS2 which is known to be very rare. Conclusions. Our study contributes to the clinical and genetic spectrum of patients with TRPS while also providing a review by comparing with previous cohort studies.

Celiac disease is an autoimmune, gastrointestinal disorder characterized by intolerance to the dietary grain protein gluten. An increased prevalence of celiac disease has been reported in Down syndrome and Turner syndrome, but there has been only few previous reports with respect to the association of celiac disease in Williams-Beuren syndrome. The aim of this study was to evaluate the frequency of celiac disease in our 24 Williams-Beuren syndrome patients. Gastrointestinal problems and celiac disease symptoms of patients were noted. All patients were analyzed by the titer of tissue transglutaminases IgA and IgG. HLA genotyping and intestinal biopsy was performed to the patients with positive serology. We also performed gluten free diet in the presence of compatible symptoms, serology, HLA genotyping and intestinal biopsy. In our study, two patients had positive tTG antibodies, but only one had positive biopsy finding for celiac disease. The frequency of celiac disease in patients with Williams-Beuren syndrome was estimated as 1/24 (4.1%). Though the number of participants in this study was limited, the results show that the frequency of celiac disease is higher in Williams-Beuren syndrome compared to the general population. We suggest that a high suspicion and testing for celiac disease should be recommended at certain intervals in all cases with Williams-Beuren syndrome to detect the cause of growth retardation and gastrointestinal problems.