Agnathia-Otocephaly Complex

A number sign (#) is used with this entry because agnathia-otocephaly complex (AGOTC) can be caused by heterozygous mutation in the PRRX1 gene (167420) on chromosome 1q24. One patient with a homozygous mutation in PRRX1 has been reported.

Description

Agnathia-otocephaly is a rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal (review by Faye-Petersen et al., 2006).

Clinical Features

Pauli et al. (1983) described an agnathia-holoprosencephaly syndrome in 2 stillborn sisters. One sister also had cardiac anomalies, stage-2 malrotation of the gut with a common mesentery, and a hypoplastic right kidney. The other sister had complete agenesis of the olfactory bulbs.

Ozden et al. (2000) reported a premature male infant with this syndrome who died soon after delivery. The infant had synophthalmia with frontal proboscis and agnathia. He also had aglossia, and his ears were extremely low set but not fused in the midline. At autopsy, situs inversus totalis was found. Alobar holoprosencephaly and agenesis of the corpus callosum were present. The karyotype was 46,XY.

Erlich et al. (2000) stated that 17 cases of nonsyndromic dysgnathia had been reported since 1961 and that only 2 had survived past infancy. They described an infant who had been noted prenatally by ultrasound to have severe micrognathia and, after birth, was found to have abnormal ears with canal stenosis and noncontiguous lobules located dorsally to the rest of the pinnae, normal zygomata, severe jaw immobility, and microstomia with an opening of only 4 to 5 mm, hypoplastic tongue, and cleft palate. The 21-year-old mother was born with severe micrognathia requiring tracheostomy, microglossia, cleft palate with filiform alveolar bands, abnormal pinnae, and decreased conductive hearing. Dysgnathia is thought to result from a defect in the development of the first branchial arch.

Guion-Almeida et al. (2002) compared the findings in patients with auriculocondylar syndrome (602483) with those in the mother and daughter reported by Erlich et al. (2000) as having the dysgnathia complex. They concluded that the patients of Erlich et al. (2000) actually had auriculocondylar syndrome.

Schiffer et al. (2002) reported detailed findings from a sporadic case of agnathia-otocephaly complex. Ultrasonography at 30 weeks' gestation showed polyhydramnios with micrognathia, low-set ears, and malformed feet. Spontaneous fetal death occurred 5 days later. Postmortem examination showed lack of mandible, hypoplasia of the maxilla, plump low-set ears that were almost fused in the midline, microstomia with persistence of the buccopharyngeal membrane, a small tongue, anal atresia, and pes equinovarus. The hyoid bone was intact, and there were no brain abnormalities. The authors also reported 2 additional cases of agnathia-otocephaly. Schiffer et al. (2002) postulated that a malformation occurred at Carnegie stage 11 (embryonic days 23 to 26).

Puvabanditsin et al. (2006) reported 2 unrelated infants with otocephaly. Features included absence of the mandible, small mouth, cleft palate, hypotelorism, and low-set ears. One infant had pulmonary hypoplasia, and the other had a 3-lobed left lung and 2-lobed right lung. The latter infant also had holoprosencephaly, situs inversus, and transposition of the great arteries.

Faye-Petersen et al. (2006) reported 5 new cases; one had holoprosencephaly and situs inversus, and 2 presented with unexplained polyhydramnios.

Celik et al. (2012) reported a female infant with otocephaly, born of consanguineous parents, who died shortly after birth from respiratory distress. Postmortem examination showed downslanting palpebral fissures, synotia, a hypoplastic oropharynx with a blind-ended and small stoma, hypoplastic and retropositioned tongue, hypoplastic and dysmorphic larynx and epiglottis, agenesis of the trachea-oropharynx connection, and a blind-ended proximal trachea. Agnathia was confirmed by cranial imaging. Other anomalies included open and atretic external auditory canals, tracheomalacia, bilateral pulmonary hypoplasia, and an atrial septal defect.

Donnelly et al. (2012) reported a patient with agnathia-otocephaly diagnosed by prenatal ultrasound at 33 weeks' gestation. The infant was born prematurely and died 15 minutes later due to airway obstruction. Postmortem examination showed severely dysmorphic facial features, with marked microstomia with a pinpoint opening into the oropharynx and a less than 1 mm nasopharyngeal passage. The mandible was absent, the tongue markedly hypoplastic, and the palate was abnormally shaped with a central cleft. Both ears were bilaterally malformed, low set, and posteriorly rotated. The remainder of the internal examination was normal with no evidence of situs inversus, central nervous system, or cardiac abnormalities.

Dasouki et al. (2013) reported an Indonesian girl, born of unrelated parents, with agnathia-otocephaly caused by a heterozygous truncating mutation in the PRRX1 gene (167420.0004). Severe retrognathia was detected prenatally. After birth, she showed small oral cavity, narrow auditory canals, and unilateral moderate hearing loss. Maxillofacial CT examination showed severe retrognathia with a rudimentary condyle bilaterally, no ramus, and a small angle, body, and symphysis, as well as a retrognathic base of the tongue. The child was alive at age 9 months. An older brother with similar gross features died on the second day of life from severe airway obstruction.

Pathogenesis

Puvabanditsin et al. (2006) noted that otocephaly is an extreme case of first branchial arch anomalies and is often associated with field defects involving midline structures.

Gekas et al. (2010) reviewed the embryonic, genetic, and teratogenic causes of AGOTC, noting that it is considered a defect of blastogenesis that results from failed mesenchymal migration of the maxillary prominence and atrophy in development of the mandibular prominences. Because craniofacial development during embryogenesis and fetogenesis involves the complex interactions of several developmental molecular pathways, genetic heterogeneity of AGOTC is likely. However, teratogens have also been linked to the induction of abnormalities of facial development, and reports of discordant clinical features within the otocephalic spectrum in dizygotic twins, monozygotic diamnionic twins, and even conjoined twins, support the influence of nongenetic factors in AGOTC.

Cytogenetics

Pauli et al. (1983) originally suggested an autosomal recessive etiology of the agnathia-holoprosencephaly syndrome in 2 stillborn sisters. However, repeat prometaphase chromosome studies showed a balanced translocation in the father of the affected individuals and an unbalanced translocation in the second of the 2 sibs. One of the breakpoints was at 18p, which is known to be a locus for holoprosencephaly.

Krassikoff and Sekhon (1989) described agnathia-holoprosencephaly in 3 infants, offspring of a man who, like his mother and brother, had a balanced t(6;18). All 3 infants were thought to have duplication of 6p and monosomy of 18p.

Inheritance

Erlich et al. (2000) suggested autosomal dominant inheritance because of the finding of dysgnathia in mother and daughter. They raised the possibility of a defect in the OTX2 gene (600037) as the basis of the disorder.

Dasouki et al. (2013) reported a family in which 2 sibs had agnathia-otocephaly due to paternal germline mosaicism for a heterozygous dominant-negative mutation in the PRRX1 gene (167420.0003). The parents were not related.

Molecular Genetics

In a fetus with agnathia-otocephaly complex reported by Schiffer et al. (2002), Sergi and Kamnasaran (2011) identified a heterozygous loss-of-function mutation in the PRRX1 gene (F113S; 167420.0001). The PRRX1 gene was selected for sequencing because of its known role in mandibular-facial development.

Celik et al. (2012) identified a homozygous loss-of-function mutation in the PRRX1 gene (A231P; 167420.0002) in a female infant, born of consanguineous parents, with agnathia-otocephaly complex.

In a patient with agnathia-otocephaly complex detected by prenatal 3-dimensional ultrasound, Donnelly et al. (2012) identified a de novo heterozygous truncating mutation in the PRRX1 gene (c.267delA; 167420.0003). Dasouki et al. (2013) identified a heterozygous 4-bp duplication (c.266dupA; 167420.0004) in an affected patient. The mutations in the patients reported by Donnelly et al. (2012) and Dasouki et al. (2013) occurred in a polyA tract in exon 2 of PRRX1, suggesting replication slippage as the mechanism.

Population Genetics

Faye-Petersen et al. (2006) stated that otocephaly is identified in less than 1 in 70,000 births.

Animal Model

Evidence for a genetic basis for dysgnathia is found in animals, including the guinea pig (Wright, 1934) and mouse (Juriloff et al., 1985; Suda et al., 1999). The work by Wright (1934) on inbred strains of guinea pigs describes a spectrum of severity in the phenotype seen within the same sibship, ranging from a small mandible to agenesis of the mandible with severe defects of the nose, eyes, and brain. This implies a common genetic cause for nonsyndromic dysgnathia and agnathia-holoprosencephaly.

Martin et al. (1995) generated a loss-of-function mutation in the mouse Pmx1 gene. Mice homozygous for the mutant allele died soon after birth and exhibited defects of skeletogenesis, which involved the loss or malformation of craniofacial, limb, and vertebral skeletal structures. The affected skeletal elements derived from the cranial neural crest, as well as somitic and lateral mesoderm. Further analysis demonstrated defects in the formation and growth of chondrogenic and osteogenic precursors. Martin et al. (1995) concluded that Pmx1 regulates the formation of preskeletal condensations from undifferentiated mesenchyme.