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At a glance

Striking malformation syndrome with hypo- or agnathia, holoprosencephaly and other, severe and mainly facial anomalies. Most often lethal in the first hours or days of life is due to respiratory complications (airway obstruction, asphyxia).

Synonyms

Dysgnathia Complex; Agnathia-Otocephaly.

Incidence

The incidence for cytogenetically normal holoprosencephaly has been cited as approximately 1.2 in 10,000 births, but the incidence of holoprosencephaly among pregnancies terminated before 20 weeks of gestation has been reported to be over 30 times higher than that of pregnancies that progress beyond 20 weeks. The incidence of otocephaly is significantly lower with an estimate of approximately 1 in 70,000 live births and the combination of otocephaly with holoprosencephaly is exceedingly rarer than that.

Genetic inheritance

Agnathia-holoprosencephaly may be genetically determined as an autosomal recessive trait. Most cases, however, are sporadic. Few reported cases had duplications of 6q and monosomy 18p. The Paired-Related Homeobox 1 (PRRX1) gene, mapped to chromosome 1q24.2, and more recently the Orthodenticle homeo-box 2 (OTX2) gene, mapped to chromosome 14q22.3, have been cited by some authors as the possible sites of mutations responsible for this disorder.

Pathophysiology

The defect most likely results from the first pharyngeal arch as a consequence of failed prechordal mesenchymal migration of the neural crest mesenchyme into the maxillary prominence and atrophy of the mandibular prominences. (All five prominences involved in forming the face are produced by proliferation of neural crest cells that migrate into the arches from the neural crest during the fourth week of gestational development.) Medications during pregnancy (eg, salicylate, antiasthmatics [theophylline], amidopyrine, phenytoin, mycophenolate), maternal diabetes mellitus, maternal alcohol abuse, and/or environmental factors have been blamed for some of the cases.

Diagnosis

Based on the striking clinical findings.

Clinical aspects

Agnathia-holoprosencephaly is a developmental field complex anomaly that affects the development of the face and brain and can be associated with situs inversus and other visceral anomalies. Isolated craniofacial (no cerebral) anomalies has been referred to as otocephaly (Agnathia-Microstomia-Synotia Syndrome), which is one of the most severe forms of the first branchial arch syndromes. In the syndrome complex of otocephaly, four different types can be distinguished:

  • Isolated agnathia

  • Agnathia with holoprosencephaly

  • Agnathia with situs inversus and visceral anomalies

  • Agnathia, holoprosencephaly, situs inversus, and other visceral anomalies

Four different types can also be distinguished based on the dominant craniofacial anomalies:

  • Cyclopia: Single median eye with or without proboscis.

  • Ethmocephaly: Hypotelorism with proboscis between the eyes.

  • Cebocephaly: Hypotelorism with a single-nostril nose below the eyes.

  • Less severe agnathia: Facial features (including hypotelorism) with median cleft lip and agnathia.

These babies presents with agnathia or severe mandibular hypoplasia, maxillary hypoplasia with choanal stenosis or atresia, high-arched or ...

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