Mesomelic Dysplasia, Savarirayan Type

Clinical Features

Savarirayan et al. (2000) reported 2 unrelated, sporadic cases of a mesomelic dysplasia characterized by absence of fibulas and severely hypoplastic, triangular-shaped tibias. Moderate mesomelic shortness was present in the upper limbs with proximal widening of the ulnas. An abnormal pelvis and marked bilateral glenoid hypoplasia were other skeletal abnormalities. The authors believed that these cases represented a distinct form of mesomelic dysplasia.

Nakamura et al. (2007) described a father-son pair with a severe form of mesomelic dysplasia that shared many features of the Savarirayan and Nievergelt (163400) types. Radiographs of the son at 6 months of age showed mild mesomelic shortening of the arms with proximal radius hypoplasia and broadening of the distal radius and proximal ulna. The lower limbs showed greater involvement with markedly short, broad tibia and absent fibular ossification. Rudimentary distal ossification occurred with age. The father demonstrated identical abnormalities of the tibia and fibula but had broader radii and ulnae with interosseous bridging on the left. The triad of severely deformed tibia, rudimentary fibula, and mildly affected radius and ulna in the son resembled that of the Savarirayan type. The broad, trapezoidal radius in the father showed greater similarity to the Nievergelt type. Nakamura et al. (2007) suggested that the Savarirayan and Nievergelt types may be allelic autosomal dominant disorders.

Yasui et al. (2000) reported 2 unrelated patients with bilateral partial deficiencies of the tibia and fibula associated with apparently intact femur and tarsal bones, teratologic dislocation of the hips, and subluxation of the radial head. Ultrasound and MRI studies suggested the presence of cartilaginous remnants of the tibia and fibula.

Cytogenetics

Ladinsky et al. (2014) reported a male infant with hypereosinophilic syndrome (607685), lower extremity hemimelia with mesomelic shortening, and sensorineural hearing loss. At birth he had plagiocephaly, upslanting palpebral fissures, depressed nasal bridge, long philtrum, high anteriorly arched palate, and posteriorly rotated ears with over-folded helices. He also had left hip dysplasia and left undescended testicle. Echocardiogram showed a patent foramen ovale versus small secundum atrial septal defect, which closed spontaneously. Renal ultrasound revealed mild bilateral nonprogressive pelviectasis. Computed tomography demonstrated malformed bilateral semicircular canals resulting in sensorineural hearing loss. He had bilateral tibial and fibular hemimelia and significant lower extremity mesomelia. At 3 months of age, the child developed eczematous patches on his cheeks, scalp, and upper extremities. By 10 months of age, the rash had spread over both lower extremities. Skin biopsy of the rash showed superficial dermatitis with perivascular infiltration of both lymphocytes and eosinophils. Bone marrow examination performed at 11 months of age was hypercellular with active and progressive trilineage maturation and marked eosinophilia. Array comparative genomic hybridization studies showed a heterozygous 1.76-Mb deletion on chromosome 6p22.3 that was not identified in the parents by FISH analysis.

Flottmann et al. (2015) performed array comparative genomic hybridization in 3 unrelated patients with mesomelic dysplasia of the Savarirayan type, including patient 1 described by Yasui et al. (2000) and patient 2 described by Savarirayan et al. (2000) and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3. The deletions encompass 4 known genes: MBOAT1 (611732), E2F3 (600427), CDKAL1 (611259) and SOX4 (184430). All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae. Flottmann et al. (2015) identified a fourth patient with an overlapping, slightly larger de novo deletion that also encompassed the flanking gene ID4 (600581); this patient had intellectual disability and no skeletal abnormalities. The authors stated that the DECIPHER database listed 4 other patients with no significant skeletal abnormalities and overlapping, but much larger, deletions, and the ClinVar database listed only one overlapping 12-Mb deletion in a patient with developmental delay (dbVar:nsv530892). Flottmann et al. (2015) suggested that the deletion identified in the patients with mesomelic dysplasia removes 2 regulatory boundaries and brings several potential limb enhancers into close proximity of ID4 resulting in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia.

Molecular Genetics

Steichen-Gersdorf et al. (2008) reported a female infant with mesomelic dysplasia characterized by bilateral fibular absence and short, dysplastic, triangulated tibiae. The femurs were of normal size. The radii and ulnae were slightly short, and the radial heads were subluxed. The feet were in a marked equinovalgus position with postaxial reduction on the right side and abnormally spaced toes on the left. She had respiratory insufficiency and myoclonic jerks, and died at age 4 months. Postmortem examination showed malrotation of the colon, a horseshoe kidney, and ambiguous genitalia. The findings were similar to those described by Savarirayan et al. (2000), with the addition of central nervous system manifestations and urogenital anomalies, but the phenotype was also reminiscent of a severe form of Nievergelt syndrome. Array comparative genomic hybridization studies showed a heterozygous 500-kb deletion on chromosome 2q11.2 containing the LAF4 gene (601464). In situ hybridization studies in mouse embryos showed expression of Laf4 in the developing brain and limb buds. Kraft et al. (2015) reevaluated the patient reported by Steichen-Gersdorf et al. (2008) and determined that she had a 353-kb intragenic deletion in the LAF4 gene encompassing only 9 exons of the gene and resulting in a truncated 850-residue protein lacking a domain predicted to be involved in transcription activation. Homozygous knockout of the Laf1 gene in mice did not result in a recognizable phenotype. However, mice with either the heterozygous or homozygous 353-kb deletion had a short zeugopod in the upper limb as well as lower limb abnormalities that recapitulated part of the human phenotype, including small, triangular ossification center of the tibia and severe hypoplasia of the fibula. The mice also had polydactyly of the feet with incomplete penetrance. Kraft et al. (2015) suggested that the phenotype in the patient was a Nievergelt-like syndrome, and concluded that the truncated protein exerts a dominant-negative effect leading to the abnormalities of bone formation.