Frontonasal Dysplasia 1

A number sign (#) is used with this entry because frontonasal dysplasia-1 (FND1), also designated frontorhiny, is caused by homozygous mutation in the aristaless-like homeobox-3 gene (ALX3; 606014) on chromosome 1p13.

Description

The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported.

Twigg et al. (2009) characterized frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.

Also see acromelic frontonasal dysplasia (AFND; 603671), frontofacionasal dysplasia (FFND; 229400), oculoauriculofrontonasal syndrome (OAFNS; 601452), the acrofrontofacionasal dysostosis syndromes (201180, 239710), and craniofrontonasal syndrome (304110).

Genetic Heterogeneity of Frontonasal Dysplasia

Frontonasal dysplasia-2 (FND2; 613451) is caused by mutation in the ALX4 gene (605420) on chromosome 11p11. Frontonasal dysplasia-3 (FND3; 613456) is caused by mutation in the ALX1 gene (601527) on chromosome 12q21.

Clinical Features

Twigg et al. (2009) described a particular form of frontonasal dysplasia, which they called frontorhiny, characterized by distinctive facial appearance with hypertelorism, wide nasal bridge, short nasal ridge, splayed nasal bones with bifid nasal tip, broad columella that attaches to the face above the alae, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. Additional recurrent features present in a minority of individuals included upper eyelid ptosis and midline dermoid cysts of craniofacial structures. Twigg et al. (2009) extended their analysis to the sibs reported by Lees et al. (2007), a brother and sister, offspring of consanguineous parents, with ptosis, hypertelorism, long eyelashes, bifid nose, upturned nares, very broad columella, histologically proven intranasal dermoid, and soft tissue swelling of the philtrum. One sib also had a midline cleft lip and lipomas on the forehead, and an MRI showed a lipoma of the posterior corpus callosum. The other sib had narrowing of the posterior choanae and conductive hearing loss. Although neither sib had an abnormal skull shape, Lees et al. (2007) had suggested that the sibs had craniorhiny (123050). Twigg et al. (2009) disagreed with this classification, citing differences in facial morphology, absence of craniosynostosis, and autosomal recessive inheritance. Twigg et al. (2009) also suggested that the proband in the report by Toriello et al. (1985) (see 164000) may have had frontorhiny.

General Craniofacial Features of FND

The craniofacial features of frontonasal dysplasia include anterior cranium bifidum, ocular hypertelorism, orofacial clefting, and notching or clefting of the alae nasi (Sedano et al., 1970).

Moreno Fuenmayor (1980) reported a consanguineous Venezuelan family in which 3 members had frontonasal dysplasia. Fifteen other members of the pedigree had hypertelorism and/or bifid nose.

Fryburg et al. (1993) observed a black family from the Bahamas in which the mother, 2 of her sons, and her brother had variable manifestations of frontonasal dysplasia. The mother had very mild expression but her brother and 2 sons were more severely affected. The affected brother and 4 other members of the mother's sibship, 2 female and 2 male, had postaxial polydactyly. The authors considered postaxial polydactyly to be a separate autosomal dominant trait segregating in this family because the trait is a frequent isolated finding and is often seen in relatives of patients without FND. In addition, none of the affected family members had any malformations involving other parts of their bodies. The mother had only slight increase in interpupillary distance, wide nose with a broad nasal tip, and diastasis of the central incisors. She had had extra digits removed bilaterally. The mother's brother had a bifid nasal tip with a short columella. One of the sons was mildly affected, the other very severely affected.

Associated Features of FND

De Moor et al. (1987) reported 3 unrelated children with frontonasal dysplasia associated with tetralogy of Fallot. All had true hypertelorism and a median nasal groove, with absence of the nasal tip. None had mental deficiency. Multifactorial inheritance was proposed.

Meinecke and Blunck (1989) described a single case of frontonasal dysplasia associated with congenital heart defect and pointed to similarities to the patients reported by De Moor et al. (1987).

Lees et al. (1998) described 3 males and 3 females with hypertelorism, midline facial cleft, sphenoethmoidal encephalocele, agenesis of the corpus callosum, optic disc anomalies (peripapillary staphyloma, hypoplastic optic discs, absent optic chiasm, and morning glory disc anomaly), and pituitary dysfunction (growth hormone deficiency, hypothyroidism, diabetes insipidus, and hypoadrenalism). One of the males had previously been described by Leitch and Winter (1996). Lees et al. (1998) suggested that these patients represent a distinct entity, which lies within the spectrum of the frontonasal dysplasia syndrome.

Nevin et al. (1999) described a 2-year-old girl with anterior cranium bifidum occultum, lipoma of the genu and anterior part of the corpus callosum, and hypertelorism. The mother had a history of a 'nasal drip' at birth caused by a defect in the cribriform plate. This required surgery at the age of 5.5 years. At the age of 31 years, the only clinical signs in the mother were a widow's peak, mild hypertelorism, and a left nostril slightly smaller than the right.

Lopes et al. (2004) described a 15-month-old girl with frontonasal dysplasia, frontal and nasal hemangiomas, optic disc anomalies (salt-and-pepper retina, megalopapillae, and iris synechiae), hearing loss, lymphedema of upper and lower limbs, neuronal migration error, and mild neuropsychomotor delay. Lopes et al. (2004) suggested that this child had a previously unrecognized syndrome.

Guion-Almeida and Richieri-Costa (2009) described 10 Brazilian male patients with frontonasal dysplasia, cleft lip/palate, mental retardation, lack of language acquisition, and midline central nervous system anomalies, mainly agenesis of the corpus callosum, large interhemispheric cysts, gyral anomalies, and occasional neuronal heterotopias. Guion-Almeida and Richieri-Costa (2009) suggested that these patients represent a newly recognized recurrent-pattern syndrome of unknown cause previously subsumed under frontonasal dysplasia.

Reviews

Wu et al. (2007) reviewed 104 cases of FND, grouped FND patients into 7 different phenotypic subtypes in addition to isolated FND, and provided references for the cases in each category.

Inheritance

The patients with FND1 reported by Twigg et al. (2009) exhibited autosomal recessive inheritance.

Gonzales-Ramos (1981) reviewed a considerable number of cases, all sporadic. He described the case of a woman with severe frontonasal dysplasia, all of whose 7 children were normal. He concluded that reports of dominant inheritance (e.g., Friede, 1954) may have represented Greig syndrome (145400).

Autosomal recessive inheritance was suggested by the inbred kindred reported by Moreno Fuenmayor (1980).

The findings in the family reported by Fryburg et al. (1993) are consistent with autosomal or X-linked dominant inheritance.

Mohammed et al. (2004) reported 5 sets of same-sex twins in which only a single twin was affected with frontonasal dysplasia. Zygosity testing established monozygosity in all 5 sets of twins with a probability of greater than 99:1. Mohammed et al. (2004) concluded that the observed malformations were nongenetic in origin and, by extrapolation, proposed that most singleton cases of frontonasal dysplasia also arise from true errors of early development and that occult monozygotic twinning may be a predisposing factor.

Cytogenetics

Stevens and Qumsiyeh (1995) described a 4-year-old boy with typical frontonasal dysostosis and an apparently balanced de novo translocation involving chromosomes 3, 7, and 11, with a total of 4 breakpoints. The child had a widow's peak, marked hypertelorism, absence of the nasal tip, and widely separated nares. He also had an atrial septal defect, micropenis, small testes, clubfeet, scoliosis, block C2-4 vertebrae, and structural brain abnormalities on MRI. Stevens and Qumsiyeh (1995) proposed that search for a gene underlying this disorder should focus on 4 chromosome bands: 3q23, 3q27, 7q21, and 11q21.

Pathogenesis

Brugmann et al. (2010) showed that excessive Hedgehog activity, caused by truncating the primary cilia on cranial neural crest cells, caused hypertelorism and frontonasal dysplasia. Elimination of the intraflagellar transport protein Kif3a (604683) led to excessive Hedgehog responsiveness in facial mesenchyme, which was accompanied by broader expression domains of Gli1 (165220), Ptch1 (601309), and Shh (600725), and reduced expression domains of Gli3 (165240). Broader domains of Gli1 expression corresponded to areas of enhanced neural crest cell proliferation in the facial prominences of Kif3a conditional knockouts. Avian Talpid embryos that lack primary cilia exhibited similar molecular changes and similar facial phenotypes. Brugmann et al. (2010) hypothesized that a severe narrowing of the facial midline and excessive expansion of the facial midline may both be attributable to disruptions in Hedgehog pathway activity.

Molecular Genetics

Assuming recessive inheritance, Twigg et al. (2009) mapped the locus in 3 families with frontorhiny to chromosome 1 and identified mutations in the ALX3 gene (606014) on chromosome 1p13.3. Twigg et al. (2009) identified a total of 7 different homozygous pathogenic mutations in 7 families. One of these families had been reported by Lees et al. (2007). These mutations comprised missense substitutions at critical positions within the conserved homeodomain as well as nonsense, frameshift, and splice site mutations, all predicting severe or complete loss of function. Twigg et al. (2009) confirmed that there were no mutations in the ALX1 (601527) or ALX4 (605420) genes in these patients.