Skeletal Defects, Genital Hypoplasia, And Mental Retardation

A number sign (#) is used with this entry because of evidence that a syndrome involving skeletal defects, genital hypoplasia, and mental retardation is caused by mutation in the ZBTB16 gene (176797).

Clinical Features

Wieczorek et al. (2002) described a 5-year-old boy who had bilateral absence of thumbs, right-sided aplasia and left-sided hypoplasia of the radius, bilateral ulnar hypoplasia, bifid right hallux, short stature, microcephaly, cryptorchidism, micropenis, and mental retardation. Additional findings included 13 ribs bilaterally, delayed bone age, and mild facial dysmorphism. Brain and renal ultrasonography, echocardiography, ophthalmologic examination, and MRI of the brain were normal.

Fischer et al. (2008) reexamined the boy originally reported by Wieczorek et al. (2002) at age 12.75 years and found that he had short stature, microcephaly, and severe mental retardation; facial dysmorphism consisted of strabismus, a small mouth with thin lips, and a protruding right ear which had been surgically corrected. Additional clinical findings included a long trunk, hypoplastic right clavicle and scapula, hyperelastic knee joints with hypoplastic and laterally displaced right patella, surgically corrected bifid and medially deviated right great toe, hypoplastic forearms, and oligodactyly with bilateral pollicization of the index fingers. The humeri, femurs, tibias, and fibulas were shortened compared to reference data. MRI scan of the right knee showed a small patella, hypoplastic medial and lateral menisci, a rudimentary posterior cruciate ligament with a cystic structure, and absence of the anterior cruciate ligament. MRI of the brain did not reveal any abnormalities.

Cytogenetics

In a 5-year-old boy with skeletal defects, genital hypoplasia, and mental retardation, Wieczorek et al. (2002) performed G- and C-banded chromosome analysis that revealed a normal male karyotype; high-resolution comparative genomic hybridization (CGH) was also normal.

Molecular Genetics

In a 12.75-year-old boy with skeletal defects, genital hypoplasia, and mental retardation, originally reported by Wieczorek et al. (2002), Fischer et al. (2008) performed array-based CGH and identified an approximately 8-Mb de novo deletion on the paternal chromosome 11, a region containing about 72 genes. Sequence analysis of the candidate gene ZBTB16 (176797) on the maternal allele revealed a missense mutation (176797.0001); functional analysis showed that the mutation impairs ZBTB16 function. The mother, who was a heterozygous carrier of the mutation, had no hand or forearm abnormalities on x-ray examination. No mutations were found in the ZBTB16 gene in 41 patients who had clinical overlap with this patient, including patients with thrombocytopenia-absent radius syndrome (274000), a tentative diagnosis of Holt-Oram syndrome (142900), or severe radial defects.