Schneckenbecken Dysplasia

A number sign (#) is used with this entry because Schneckenbecken dysplasia (SHNKND) is caused by homozygous or compound heterozygous mutation in the SLC35D1 gene (610804) on chromosome 1p31.

Description

Schneckenbecken dysplasia is a perinatally lethal skeletal dysplasia. The German term 'Schneckenbecken' refers to the distinctive, snail-like appearance of the ilia that results from a medial bone projection from the inner iliac margin. Other hallmarks of the disorder include thoracic hypoplasia, severe flattening of the vertebral bodies, and short, thick long bones (summary by Hiraoka et al., 2007).

Clinical Features

In an Asian family, Knowles et al. (1986) reported a first-cousin marriage that resulted in 13 pregnancies; 4 of the offspring (2 male; 2 female) were normal and 5 were stillborn, short-limbed dwarfs; 3 pregnancies resulted in miscarriage and 1 was terminated for dwarfism detected prenatally. The radiology and histology were unique. The family was reported as probable achondrogenesis (see 200600) by Laxova et al. (1973). The vertebral bodies were hypoplastic with relatively well-preserved posterior arches. Knowles et al. (1986) commented that 'superiorly oriented orbits lend the facial roentgenograms a Mephistophilian appearance.' The authors suggested that achondrogenesis type I (see 200600) has severe shortness and bowing of limb bones with marked spur formation at the expanded metaphyseal ends and virtually unossified vertebral bodies and sacrum. Differences from achondrogenesis type II (200610) and thanatophoric dysplasia (187600) were also noted. The multiple affected sibs reported by Chemke et al. (1971) and Graff et al. (1972) as thanatophoric dysplasia were thought by Knowles et al. (1986) to have this disorder.

Borochowitz et al. (1986) described the same form of neonatal lethal chondrodysplasia under the label of Schneckenbecken dysplasia, from the German for snail-pelvis, because of the radiographic configuration of the hypoplastic iliac bones. Other radiographic features were short, broad long-bones with dumbbell-like appearance, flat and hypoplastic vertebral bodies, short and wide fibula, and precocious ossification of the tarsus. Chondroosseous histology was characterized by hypervascularity, increased cellular density, and normal-sized chondrocytes with a centrally located round nucleus and absence of lacunar space. With a total of 9 cases in 4 families, autosomal recessive inheritance as well as the distinctness of the disorder seems firmly established. Camera et al. (1991) described the clinical and radiologic features of a case occurring in an Italian family.

Nikkels et al. (2001) described a male fetus, with consanguineous Mediterranean parents, who presented with severe hydrops and short-limb skeletal dysplasia at 20 weeks' gestation. The pregnancy was terminated at 22 weeks. Radiographs showed typical findings of Schneckenbecken dysplasia, including platyspondyly with oval-shaped vertebral bodies, extremely short long bones with dumbbell-like appearance, and small ilia with snail-like appearance.

Inheritance

The transmission pattern of Schneckenbecken dysplasia in the families reported by Borochowitz et al. (1986) was consistent with autosomal recessive inheritance.

Molecular Genetics

Because of phenotypic similarities between the Slc35d1 knockout mouse and Schneckenbecken dysplasia, Hiraoka et al. (2007) screened 6 affected patients for SLC35D1 mutations and identified mutations in 2. One patient, who was first described by Nikkels et al. (2001), was homozygous for a 1-bp deletion (610804.0001), and the other patient was compound heterozygous for a nonsense (610804.0002) and a splice site (610804.0003) mutation. All 3 mutations were predicted to produce truncated proteins.

Furuichi et al. (2009) analyzed the SLC35D1 gene in 5 unrelated patients with Schneckenbecken dysplasia and identified homozygous or compound heterozygous mutations in 3 of them (610804.0004-610804.0007, respectively); no SLC35D1 mutations were identified in the remaining 2 patients or in 15 unrelated patients with other severe spondylodysplastic dysplasias. Radiographic features common to the 3 SLC35D1 mutation-positive cases included handlebar clavicle, bell-shaped thorax, narrowing of the interpediculate distance, metaphyseal flaring, severe retardation of vertebral body ossification, relatively preserved ossification of the posterior arch, relatively preserved sacral ossification, pubic ossification, and lack of angular deformity of the humerus. Furuichi et al. (2009) noted that these features were also present in the 2 previously identified Schneckenbecken dysplasia patients with SLC35D1 mutations (Hiraoka et al., 2007).

Animal Model

Hiraoka et al. (2007) generated an Slc35d1-knockout mouse model. Heterozygous mice were phenotypically normal, but Slc35d1 -/- mice did not survive the neonatal period; their crown-rump length was reduced and their limbs were extremely short. Skeletal preparations showed hypoplasia of craniofacial bones, flattening of vertebral bodies, longitudinally short ilia and extremely short long bones. This severe chondrodysplasia, which resembles the phenotype of Schneckenbecken dysplasia, confirmed that Slc35d1 is crucial during prenatal skeletal development in mice.