Mesomelia-Synostoses Syndrome

A number sign (#) is used with this entry because of evidence that mesomelia-synostoses syndrome is a contiguous gene deletion syndrome caused by heterozygous microdeletion on chromosome 8q13.

Description

The Verloes-David-Pfeiffer mesomelia-synostoses syndrome is an autosomal dominant form of mesomelic dysplasia comprising typical acral synostoses combined with ptosis, hypertelorism, palatal abnormality, congenital heart disease, and ureteral anomalies (summary by Isidor et al., 2009).

Mesomelia and synostoses are also cardinal features of the Kantaputra type of mesomelic dysplasia (156232).

Clinical Features

Verloes and David (1995) described a seemingly 'new' dominantly inherited form of mesomelic shortness of stature with severe skeletal changes in the ankles, knees, and elbows. The father and 2 children (a living 4-year-old girl and an aborted 18-week-old fetus) were affected. Skeletal abnormalities included brachymetacarpy and brachymetatarsy of the third to fifth rays, synostoses in these bones, synostoses of metacarpals and metatarsals II to V with the corresponding carpal/tarsal bones, partial fusion in the proximal row of carpal bones, and mild vertebral anomalies. The father and daughter also had downslanting palpebral fissures, beaked nose, hypertelorism, ptosis, microretrognathia, and transverse agenesis of the soft palate. Abnormally short umbilical cord with unusually long skin coverage was present. Mesomelic shortness increased with time, with progressive curvature of the forearm.

A possible further sporadic case was reported independently, with similar facial and skeletal anomalies, nasal speech due to short velum, and hydronephrosis (Pfeiffer et al., 1995).

Day-Salvatore and McLean (1998) described a female infant with microcephaly, hypoplastic frontal ridges, telecanthus, blepharoptosis, blepharophimosis, cleft palate, mild microstomia, micrognathia, abnormally modeled ears, hypoplastic left heart, hypoplastic radii and ulnae with radial subluxation, pseudoarthrotic distal humeri, fused metacarpals, tibial bowing, unusual feet with long halluces, hydronephrosis, patent urachus, and abnormal electroencephalogram. Other cardiovascular abnormalities included patent ductus arteriosus, ventricular septal defect, single coronary artery, and retroesophageal subclavian artery. The electroencephalogram was consistent with moderate to severe, diffuse or multifocal cerebral dysfunction, although overt clinical seizure manifestations were not observed. Neurodevelopmental evaluation at age 35 months showed global developmental delays in expressive language and problem-solving skills as well as gross motor skills.

Leroy et al. (2003) reported a 4-year-old boy with symmetric carpometacarpal and tarsometatarsal synostoses and moderate acromesomelia, resulting in severe impairment of mobility in the upper limbs and gait. Additional features included hypoplastic supraorbital ridges, telecanthus, ptosis, blepharophimosis, beak-like nose, mild retrognathia, hypoplastic soft palate and uvula, atrial septal defect, ventricular septal defect, coarctation of the aorta, and bilateral hydronephrosis due to congenital vesicoureteral junction stenosis. His stature was in the low normal range, and mental development was normal. Leroy et al. (2003) tabulated the similarities to the patients previously reported by Verloes and David (1995) and Pfeiffer et al. (1995), and suggested that the phenotype results from a mutation that disturbs antenatal pattern formation, specifically distal limb segmentation and joint differentiation.

Isidor et al. (2009) reviewed the clinical features of 5 reported patients with the mesomelia-synostoses syndrome (Verloes and David, 1995; Pfeiffer et al., 1995; Day-Salvatore and McLean, 1998; Leroy et al., 2003) and provided follow-up on 3 of the patients. In contrast to other mesomelic syndromes, the clinical course of this mesomelic dysplasia is slowly progressive, at least until adulthood, with development of severe limb deformities despite repeated corrective surgical intervention. Isidor et al. (2009) noted that the unknown mutant gene has at least 2 developmental pathogenic effects, generating congenital malformations and multiple synostoses in early prenatal life, and manifesting in postnatal life as a severe osteochondrodysplasia.

Molecular Genetics

Using whole-genome oligonucleotide array CGH, Isidor et al. (2010) identified a microdeletion on chromosome 8q13 in each of 5 patients with the mesomelia-synostosis syndrome from 4 previously reported families (Verloes and David, 1995; Pfeiffer et al., 1995; Day-Salvatore and McLean, 1998; and Leroy et al., 2003, respectively). The deletions varied from 582 kb to 738 kb, but always encompassed only 2 genes: SULF1 (610012) and SLCO5A1 (613543). Breakpoint sequence analysis in 2 families showed nonrecurrent deletions.