Frontonasal Dysplasia 2

A number sign (#) is used with this entry because of evidence that frontonasal dysplasia-2 (FND2) is caused by homozygous mutation in the ALX4 gene (605420) on chromosome 11p11.

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

Clinical Features

Kayserili et al. (2009) described 2 consanguineous Turkish families with an autosomal recessive form of frontonasal dysplasia characterized by a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, cryptorchidism, agenesis of the corpus callosum, total alopecia, and mental retardation. No limb anomalies were reported. Skin from a biopsy of an affected individual demonstrated a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation.

Kariminejad et al. (2008, 2014) reported a girl, born to consanguineous Iranian parents, with FND2. At age 2 years, she had very sparse hair, eyebrows, and eyelashes, and absence of body hair. Craniofacial abnormalities included hypertelorism, short and upslanting palpebral fissures, telecanthus, wide and flat nasal bridge, thick and broad columella, hypoplasia of the alae nasi, and notched nostrils. Imaging of the skull showed cranium bifidum with parietal foramina and normal facial skeletal bones; brain imaging showed small abnormally shaped occipital lobes and mild abnormalities of the corpus callosum. Skin biopsy showed mild hyperkeratosis and underdeveloped hair follicles. The patient also had reduced lacrimation and reduced sweating. Cognition was normal. The patient's father had bilateral small parasagittal parietal foramina and mild dysplastic changes in the cerebellum. The mother, who had milder cerebellar findings than the father, had impressions on the inner surface of the parasagittal parietal bones.

Clinical Variability

Kayserili et al. (2012) reported a boy, born of consanguineous Turkish parents, with a mild form of FND2. He had hypertelorism, upslanting palpebral fissures, wide nasal bridge and ridge, bifid nasal tip, broad columella, cleft alae nasi, and an upper labiogingival sulcus. Skull and brain imaging showed bilateral parietal foramina and a mildly hypoplastic, kinked body of the corpus callosum and underdevelopment of the vermis. Psychomotor development was normal.

Inheritance

The transmission pattern of FND2 in the family reported by Kariminejad et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

In a Turkish family segregating frontonasal dysplasia, Kayserili et al. (2009) used homozygosity mapping to localize the disease locus to a 19.8-Mb segment on chromosome 11p11.2-q12.3.

Molecular Genetics

In affected members of 2 consanguineous Turkish families segregating frontonasal dysplasia, Kayserili et al. (2009) identified homozygosity for a 793C-T nonsense mutation in the Aristaless-like-4 gene (605420.0008). The mutation was predicted to result in a premature stop codon (R265X), truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Kayserili et al. (2009) concluded that ALX4 plays a critical role in craniofacial development as well as in skin and hair follicle development.

In a boy, born of consanguineous Turkish parents, with a mild form of FND2, Kayserili et al. (2012) identified a homozygous missense mutation in the ALX4 gene (Q225E; 605420.0011). Functional studies were not performed. The parents, who were heterozygous for the mutation, had uncovered bilateral parietal foramina of small size. Kayserili et al. (2012) postulated that the less severe phenotype observed in this patient compared to the patients reported by Kayserili et al. (2009) was due to the missense mutation retaining some functionality.

In a girl, born of consanguineous Iranian parents, with FND2, Kariminejad et al. (2014) identified a homozygous frameshift mutation in the ALX4 gene (605420.0014).