Expanding the phenotypic spectrum of Mendelian connective tissue disorders to include prominent kidney phenotypes.

Heritable connective tissue disorders are a group of diseases, each rare, characterized by various combinations of skin, joint, musculoskeletal, organ, and vascular involvement. Although kidney abnormalities have been reported in some connective tissue disorders, they are rarely a presenting feature. Here we present three patients with prominent kidney phenotypes who were found by whole exome sequencing to have variants in established connective tissue genes associated with Loeys-Dietz syndrome and congenital contractural arachnodactyly. These cases highlight the importance of considering connective tissue disease in children presenting with structural kidney disease and also serves to expand the phenotype of Loeys-Dietz syndrome and possibly congenital contractural arachnodactyly to include cystic kidney disease and cystic kidney dysplasia, respectively.

Congenital contractural arachnodactyly suspected by abnormally long extremities by fetal ultrasound.

Congenital contractural arachnodactyly (CCA) is a rare disease with the clinical features of limited extension of multiple joints, arachnodactyly, camptodactyly, thin and long extremities, and so on. In the point of long extremities, CCA resembles Marfan syndrome (MFS). CCA is easily differentiated from MFS after birth due to the flexion of multiple joints, including elbows, knees, hips and fingers. During the fetal period, observation of arachnodactyly and folded fingers by fetal ultrasound is the means of differential diagnosis between these two diseases. We report on a case of CCA diagnosed with prenatal symptoms of long extremities, and introduced physiotherapy in early childhood for a better physical prognosis.

Confirming the involvement of PIEZO2 in the etiology of Marden-Walker syndrome.

Pathogenic heterozygous variants in PIEZO2 typically cause distal arthrogryposis type 5 (DA5) and the closely related Gordon syndrome (GS). Only one case of PIEZO2-related Marden-Walker syndrome (MWS) has been reported to date. We report the phenotypic features of a Saudi female patient with features consistent with MWS in whom we identified a novel de novo likely pathogenic variant in PIEZO2. Our case lends support to the link between PIEZO2 and MWS.

Inclusion of joint laxity, recurrent patellar dislocation, and short distal ulnae as a feature of Van Den Ende-Gupta syndrome: a case report.

BACKGROUND: Van Den Ende-Gupta Syndrome (VDEGS) is an extremely rare autosomal recessive syndrome with less than 20 reported families (approximately 40 patients) in the worldwide literature. CASE PRESENTATION: We have assessed one consanguineous Saudi family with typical features of VDEGS. Two siblings were affected with almost identical features; including blepharophimosis, arachnodactyly, flexion contractures of the elbows, camptodactyly, slender ribs, hooked lateral clavicular ends, and bilateral radial head dislocations. Both patients had several unusual features; including joint laxity, flat feet, recurrent patellar dislocations, and bilateral short distal ulnae. Full sequencing of SCARF2 revealed a homozygous mutation c.773G > A (p. Cys258Tyr) in both affected children. The parents (both with no abnormalities) were heterozygous for the same mutation. CONCLUSION: Joint laxity, recurrent patellar dislocations, and short distal ulnae should be included as part of the clinical spectrum of VDEGS.

Beals syndrome (congenital contractural arachnodactyly): prenatal ultrasound findings and molecular analysis.

We report the prenatal findings in two cases of Beals syndrome. Both pregnancies presented with clinical features of arthrogryposis multiplex congenita/fetal akinesia syndrome (AMC/FAS), including clenched fists and multiple joint contractures on repeat prenatal ultrasound examinations. The first case was diagnosed as having Beals syndrome on physical examination shortly after birth and the diagnosis was confirmed by DNA analysis, shown as a point mutation in the fibrillin 2 (FBN2) gene. The second case was diagnosed with Beals syndrome following microarray analysis on amniocytes, which showed a deletion of the FBN2 gene. Although most cases with AMC/FAS carry a poor prognosis, Beals syndrome is consistent with normal cognitive development and a better prognosis. Thus, making the correct diagnosis is crucial, both pre- and postnatally, for accurate counseling and management.

van den Ende-Gupta syndrome: evidence for genetic heterogeneity.

van den Ende-Gupta syndrome is characterized by craniofacial and skeletal manifestations, mainly malar and/or maxillary hypoplasia, blepharophimosis, distinctive nose, lower lip eversion, arachnodactyly, camptodactyly, and long slender bones of hands and feet. Growth and development are normal. To date only 11 patients, from 8 families, have been described. Autosomal recessive inheritance has been accepted in this condition, supported by the presence of consanguinity in three families and the recurrence of the disorder within the offspring of unaffected couples. In this article we report on a kindred with three affected individuals, two brothers and their half-sister, in which the van den Ende-Gupta syndrome is probably transmitted as an autosomal dominant trait in connection with gonadal mosaicism.

Comparison of computed radiography and multi-detector computed tomography in the detection of post mortem metacarpal index.

BACKGROUND: The sudden, unexpected death of young persons from ruptured thoracic aortic dissection is suggestive of Marfan syndrome (MFS), a genetic disorder of fibrillin. Establishing such a diagnosis is important so that the same fate might be avoided in living relatives. MFS diagnosis is difficult in the deceased but the presence of arachnodactyly, a common morphological feature of MFS, can be established by assessing the metacarpal index (MCI). MCI is routinely determined using radiographic techniques including computed radiography (CR). The wider availability of computed tomography (CT) in the forensic environment provides an alternative method. CT is predicted to produce measurements at least as accurate as CR. The aims of this study therefore were to (1) validate MCI measurements by comparing CT and CR with direct measurement using calipers on human skeletonised hands, and (2) compare cadaveric CT and CR MCI measurements. METHODS: The metacarpals of 12 human skeleton hands were measured using CT and CR, and compared with direct measurement using calipers (the "gold standard"). Fifty randomly selected cadavers between 20 and 40 years had the MCI of both hands measured using CT and CR. RESULTS: CT was found to be more accurate in the measurement of MCI than CR. There were significant differences in the MCIs obtained for CT and CR (females: p=0.01; males: p<0.0001) and between CR and calipers (p=0.004). There were no significant differences between MCIs obtained for CT and calipers (p=0.71). CR was found to consistently overestimate the MCI by an average of 7.97%. CONCLUSION: CT is more accurate in determination of the MCI than CR and should provide the basis for future skeletal measurements.