Acromelic Frontonasal Dysostosis

A number sign (#) is used with this entry because of evidence that acromelic frontonasal dysostosis (AFND) is caused by heterozygous mutation in the ZSWIM6 gene (615951) on chromosome 5q12.

Description

Verloes et al. (1992) described a rare variant of frontonasal dysplasia (see FND1, 136760), designated acromelic frontonasal dysplasia (AFND), in which similar craniofacial anomalies are associated with variable central nervous system malformations and limb defects including tibial hypoplasia/aplasia, talipes equinovarus, and preaxial polydactyly of the feet.

Clinical Features

A dominant form of frontonasal dysplasia with associated spinal anomalies was suggested by Reich et al. (1977).

Prescott et al. (1989) described a subgroup of cases of median cleft face consisting of 2 new cases and 6 from the literature. The distinctive feature was the association of skeletal abnormalities and mental retardation. The patients were at the severe end of the group. They showed agenesis of the nasal root, marked separation of slitlike nares, tibial aplasia, hallucal polydactyly, and varus deformity. Males and females were equally represented.

Slaney et al. (1999) reported 3 male and 2 female infants with acromelic frontonasal dysostosis. All 5 had a frontonasal malformation of the face and nasal clefting associated with striking symmetric preaxial polysyndactyly of the feet and variable tibial hypoplasia. The frontonasal malformations have overlap with acrocallosal (200990) and Greig (175700) syndromes, but the significant hypertelorism and bifid nasal tip distinguish them. All 8 patients previously described (Sedano et al., 1970; Calli, 1971; Edwards et al., 1971; Warkany et al., 1973; Toriello et al., 1986; Verloes et al., 1992; and Sueldo and Fernandes, 1993), as well as the 5 discussed by Slaney et al. (1999), had wide fontanels and sutures resulting from cranial defects. There was only occasional mild involvement of the hands. Most males had bilateral cryptorchidism. Three of the cases were the product of consanguineous unions, as were previously reported cases (Verloes et al., 1992), suggesting that acromelic frontonasal dysostosis may be an autosomal recessive disorder.

Hing et al. (2004) reported 2 unrelated boys, aged 8 and 9, with classic features of AFND in whom CT studies showed strikingly similar findings of brachycephaly, orbital hypertelorism, midline maxillary cleft, large anterior fontanel with an interfrontal bone, and posterior parietal foramina. The authors stated that these boys were the oldest living individuals with AFND described in the literature. One child had a family history of AFND with vertical transmission from father to son suggesting autosomal dominant inheritance, with variable expressivity and reduced penetrance. The father had brachycephaly, hypertelorism, mild bifurcation and increased breadth of nasal columella and tip, and broad feet; a paternal uncle died in the newborn period with clinical features similar to the proband, whereas the paternal grandmother was clinically unaffected. The father had a maternal second cousin with significant hypertelorism. Hing et al. (2004) analyzed genotype markers at candidate AFND loci in this family and identified 3 potential loci, but mutation analysis of several candidate genes revealed no coding mutations.

Kocak and Ceylaner (2009) reported a 3-generation Turkish family segregating autosomal dominant frontonasal dysplasia with additional features. The proband was a 3.5-year-old girl with a severe phenotype, including frontal balding, convex profile of nose, notching of nostrils, cleft lip and palate, aplasia of uvula, and oligodontia. Limb defects in the proband included clubbed thumbs, bilateral talipes equinovarus, overriding toes, bilateral clubbed and thickened nails of halluces, and vertical creases on the plantar surface between the first and second toes. Brain MRI showed ventricular dilation and an encephalomalacic region in the left hemisphere. The proband's mother had a widow's peak, hypertelorism, broad nasal root, tip, and base, wide philtral groove, and diastasis of the upper central incisors. Examination of photos of the mother's father, half-brother, half-sister, and her half-sister's son revealed that all had hypertelorism, broad nose, and wide philtral groove.

Over a 20-year period, Smith et al. (2014) followed 4 unrelated children with classic features of AFND who were later found to have mutations in the ZSWIM6 gene (see MOLECULAR GENETICS). Each child presented with neurocognitive and motor delays, severe symmetric frontonasal dysplasia with median cleft face, carp-shaped mouth, widely spaced nasal alae, hypertelorbitism, variable parietal foramina, interhemispheric lipoma, and unilateral or bilateral tibial hemimelia with preaxial polydactyly. Other variable features included periventricular nodular heterotopia, aplastic or hypoplastic corpus callosum, absent olfactory bulbs, vertical clivus, patellar hypoplasia, hypopituitarism, and cryptorchidism. The neurocognitive delays were severe, and the affected individuals were unable to live independently as adults. Severe upper airway obstruction and facial malformation required tracheostomy and gastrostomy in 3 of the 4 probands, and 1 proband had a seizure disorder.

Twigg et al. (2016) reported 2 sporadic patients with frontonasal dysplasia and a mildly affected woman with a severely affected son. The mother, who had undergone multiple surgeries to reshape the frontonasal region, exhibited hypertelorism and a short broad nose with a bifid tip, but had normal intelligence and no extracranial features. Her 7-year-old son was born with a severe frontonasal malformation and limb anomalies, and had severe neurocognitive and motor delay, being unable to walk or communicate with words. One of the sporadic patients was a 12-year-old boy with frontonasal dysplasia and severe psychomotor delay, but no limb anomalies. The second sporadic patient was a female fetus with abnormalities detected on prenatal ultrasound at 19 weeks' gestation, including facial malformation with hypertelorism, broad glabella, nasal hypoplasia, and bilateral talipes equinovarus. After termination, postmortem examination revealed median facial cleft and bilateral tibial hypoplasia.

Molecular Genetics

Smith et al. (2014) performed whole-exome sequencing in 3 unrelated patients with acromelic frontonasal dysostosis and identified the same de novo missense mutation in the ZSWIM6 gene (R1163W; 615951.0001) in all 3 patients. The mutation was confirmed to be de novo by Sanger sequencing in the 3 parent-child trios; it was also detected in a fourth unrelated AFND patient, for whom parental DNA was not available. In the latter patient, who had a milder phenotype, the mutation was present at a 60:40 ratio of wildtype to mutant allele, suggestive of mosaicism.

In a cohort of 27 individuals with frontonasal dysplasia, Twigg et al. (2016) screened for the ZSWIM6 R1163W mutation and identified heterozygosity for the variant in 2 sporadic patients and in the severely affected son of his mildly affected mother. Mosaicism was suspected in the mother; deep sequencing of DNA revealed the mutant variant to be present at varying levels in all 5 tissues tested: approximately 11% in buccal scrapings, 3% in saliva, 2% in urine and blood, and 1% in skin. The mother as well as 1 of the sporadic patients had normal limbs, establishing that limb anomalies are not an absolute requirement for the diagnosis.