Agnathia-Otocephaly Complex Due to a De Novo Deletion in the OTX2 Gene

Abstract

Agnathia-otocephaly complex (AOC) is a rare and usually lethal malformation typically characterized by hypoplasia or the absence of the mandible, ventromedial and caudal displacement of the ears with or without the fusion of the ears, a small oral aperture with or without a tongue hypoplasia. Its incidence is reported as 1 in 70,000 births and its etiology has been attributed to both genetic and teratogenic causes. AOC is characterized by a wide severity clinical spectrum even when occurring within the same family, ranging from a mild mandibular defect to an extreme facial aberration incompatible with life. Most AOC cases are due to a de novo sporadic mutation. Given the genetic heterogeneity, many genes have been reported to be implicated in this disease but to date, the link to only two genes has been confirmed in the development of this complex: the orthodenticle homeobox 2 (OTX2) gene and the paired related homeobox 1 (PRRX1) gene. In this article, we report a case of a fetus with severe AOC, diagnosed in routine ultrasound scan in the first trimester of pregnancy. The genetic analysis showed a novel 10 bp deletion mutation c.766_775delTTGGGTTTTA in the OTX2 gene, which has never been reported before, together with a missense variant c.778T>C in cis conformation.

Otocephaly: A Case Report of a Rare Congenital Anomaly

“…Another related condition known as agnathia otocephaly complex is diagnosed when an underdeveloped or absent mandible, misplaced ears with or without auricular fusion, and a small mouth with oroglossal hypoplasia or aglossia are present. The prognosis can be significantly influenced by additional features such as holoprosencephaly, cyclopia, anencephaly, meningomyelocele, situs inversus, lung and genitourinary anomalies, and skeletal and cardiovascular abnormalities [2].…”

“…Otocephaly is an uncommon abnormality characterized by the absence or underdevelopment of the mandible (agnathia), misplacement of the ears towards the front (melotia), a small mouth (microstomia), and the absence or underdevelopment of the tongue (aglossia or microglossia) [1]. This infrequent anomaly affects the frontal part of the first brachial arch and occurs due to improper migration of neural crest cells from the hindbrain [1,2]. Its origin has been linked to both genetic and teratogenic causes.…”

“…Its origin has been linked to both genetic and teratogenic causes. Factors such as salicylates, theophylline, radiation, and alcohol exposure during pregnancy have been reported as potential causes [2]. Respiratory problems are common in affected individuals, and the spectrum of malformation is often lethal.…”