Brachyphalangy, Polydactyly, And Tibial Aplasia/hypoplasia

Clinical Features

Baraitser et al. (1997) reported 2 unrelated children with an unusual combination of limb anomalies, facial dysmorphism, and genital hypoplasia. The limb defects consisted mainly of very short fingers with absent nails on some digits, and in the lower limbs a combination of absent tibia, complex preaxial polydactyly, syndactyly, and marked brachydactyly. In addition, both patients had micropenis and facial dysmorphism, especially malformed ears. Faravelli et al. (2001) reported similar features in a male infant. Pierson et al. (2001) described a newborn male with total anomalous pulmonary venous connection, malformed ears, hypertelorism, brachyphalangy of the hands, pterygium of the elbows, knees, and wrists, complex lower limb preaxial polydactyly, tibial shortening, clubfeet, horseshoe kidney, and micropenis. His 36-year-old father had similar craniofacial and limb anomalies, suggesting autosomal dominant inheritance.

Wechsler et al. (2004) reported the first female with this syndrome. She had tibial aplasia, mirror image preaxial polydactyly involving her feet, brachyphalangy, genital hypoplasia, and facial dysmorphism including telecanthus, blepharophimosis, flat nasal bridge with a small nose, and small mouth. Consistent with reports in males of a micropenis and hypoplastic scrotum, she had absent labia minora and a very small clitoris. Her father had very minor anomalies suggestive of somatic mosaicism or marked variability.

Bernardi et al. (2009) described a 1-year-old girl who had brachyphalangy, polydactyly, and tibial aplasia/hypoplasia associated with genital hypoplasia. Facial dysmorphism included telecanthus and a carp-shaped mouth, and she had dysplastic and low-set ears. In addition, she displayed features not previously described in this condition, including wormian bones, lacrimal sac fistula, ectopic kidney, and anteriorly placed anus. Bernardi et al. (2009) reviewed the features of previously reported patients and stated that this patient represented the ninth reported case and only the second involving a female.

Molecular Genetics

Because some mouse models affecting limb development are caused by mutations in Alx4 (605420) and related members of the paired homeodomain class, Wechsler et al. (2004) considered the human homologs to be candidate genes for this disorder. Sequencing of the coding exons of ALX4 and ALX3 (606014) in their proband revealed no disease-causing alterations.