Frontonasal Dysplasia 3

A number sign (#) is used with this entry because of evidence that frontonasal dysplasia-3 (FND3) is caused by homozygous mutation in the ALX1 gene (601527) on chromosome 12q21. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of frontonasal dysplasia, see FND1 (136760).

Clinical Features

Uz et al. (2010) described 3 Turkish sibs, born of consanguineous parents, with severe facial clefting and extreme microphthalmia. The male proband was born with hypertelorism, bilateral extreme microphthalmia, upper eyelid colobomata, sparse eyelashes, absence of eyebrows, wide nasal base, hypoplasia of the ala nasi, bilateral nonmidline cleft lip with a prominent glabella, complete cleft palate, and low-set posteriorly rotated ears. The only extracranial finding was a caudal appendage in the sacral region. Orbital and brain MRI showed brachycephaly, bilateral extreme microphthalmia, and a large midline bone defect of the cranium. At 11 years of age, the proband had mild mental retardation but followed commands well and his hearing was normal; however, his facial anatomy prevented sufficient expressive speech and he was only able to say 'mama.' Motor development milestones were normal. The mother had 2 consecutive pregnancies with affected female fetuses that were diagnosed prenatally. Uz et al. (2010) also reported an unrelated Turkish girl with an almost identical phenotype, who had hypertelorism, extreme microphthalmia of the right eye and microphthalmia of the left eye, upper eyelid colobomata, lack of eyelashes and eyebrows, and palpable midline cranial cleft with a soft tissue mass in the left frontal area. She also had a wide nasal bridge with hypoplasia of the ala nasi, bilateral nonmidline cleft lip, very prominent glabella, complete cleft palate, and low-set posteriorly rotated ears. Brain MRI at 4 months of age showed severely delayed myelinization, thin corpus callosum, and asymmetric cerebellar vermis configuration on the left side. Motor development was delayed. She underwent reconstructive surgery but died in infancy from a pulmonary infection. Uz et al. (2010) stated that the phenotype in these patients was borderline between frontofacionasal dysplasia (229400) and Fryns microphthalmia syndrome (600776).

Mapping

Uz et al. (2010) performed genomewide homozygosity mapping of 3 affected sibs with severe frontonasal dysplasia and their unaffected consanguineous parents and identified a single large homozygous stretch spanning approximately 27 Mb on chromosome 12q21.3.

Molecular Genetics

In 3 affected sibs from a consanguineous Turkish family with severe frontonasal dysplasia mapping to chromosome 12q21.3, Uz et al. (2010) detected a mendelian segregation error within a region of homozygosity; analysis of SNP array data revealed a homozygous deletion of the entire region in all affected offspring. The unaffected parents were heterozygous carriers of the deletion, which encompassed 7 genes, including a highly relevant candidate, ALX1. In an unrelated Turkish girl with a nearly identical phenotype, Uz et al. (2010) identified homozygosity at the ALX1 region on 12q21; sequencing ALX1 revealed a homozygous splice site mutation (601527.0001) that was found in heterozygosity in her unaffected parents and was not detected in 171 Turkish controls.