Elsevier

European Journal of Medical Genetics

Volume 53, Issue 6, November–December 2010, Pages 358-366
European Journal of Medical Genetics

Review
Current perspectives on the etiology of agnathia-otocephaly

https://doi.org/10.1016/j.ejmg.2010.09.002Get rights and content

Abstract

Agnathia-otocephaly, a rare, sporadic and lethal malformation, is characterized by microstomia (small mouth), aglossia (absence of the tongue), agnathia (absence of the lower jaw) and abnormally positioned ears. It is a principal anomaly derived from the first pharyngeal arch as a consequence of failed mesenchymal migration of the maxillary prominence and atrophy in the development of the mandibular prominences. Unfortunately, these patients have poor prognoses and may succumb to death shortly after birth due to respiratory problems if appropriate airway management is not implemented. Difficulties persist in the prenatal diagnosis of agnathia-otocephalic patients. However, two- and three-dimensional ultrasonography, computed tomography and magnetic resonance imaging technologies now offer significant improvements in refining the resolution of distinctive facial anomalies. This complex disorder can be attributed to both genetic and teratogenic causes, in addition to other unidentifiable factors. Furthermore, studies in model organisms, in particular mice, have unraveled potential genetic pathways that may contribute to the etiology. This article highlights current perspectives on agnathia-otocephaly with a focus on the etiological causes and issues concerning prenatal diagnosis, differential diagnosis, prognosis and genetic counseling. Finally, studies using animal models especially genetically engineered mice are described to comprehend the molecular genetic interactions that may occur during the genesis of this intriguing craniofacial birth defect.

Introduction

Otocephaly, also referred to as agnathia-otocephaly, is a rare, often sporadic and lethal malformation complex characterized primarily by an absent/underdeveloped mandible (micrognathia, agnathia), microstomia, hypoglossia/aglossia and with variable anterior midline fusion of the ears (melotia, synotia) [1], [5], [6], [8], [11], [18], [22], [24], [26], [28], [31], [35], [48], [50], [51], [53], [56], [59], [62], [63] (Fig. 1). The estimated incidence is less than 1 in 70,000 births, with etiologies linked to both genetic and teratogenic factors [1], [5], [6], [8], [11], [18], [22], [24], [26], [28], [31], [35], [43], [48], [50], [53], [56], [59], [62], [63]. During embryogenesis, mandibulofacial development principally originates from the first pharyngeal arch. A defect in blastogenesis or even aberrancies in neural crest cell migration can result in the incomplete development of the medial nasal process of the first pharyngeal arch, giving rise to an otocephalic association of abnormalities involving the ears, mouth and mandible [42], [29]. It is now clear that several molecular pathways and genes appear to impact the survival, proliferation and migration of neural crest cells during early embryonic development. Insults including genetic and teratogenic factors may therefore affect the developing fetus, resulting in aberrancies in normal developmental paradigms [1], [5], [6], [8], [11], [18], [22], [24], [26], [28], [31], [35], [48], [50], [51], [53], [56], [59], [62], [63]. In this article, we highlight current knowledge known on the pathogenesis (embryonic, genetic, teratogenic), prenatal diagnostic methods, prognosis & genetic counseling, experimental animal models, and molecular mechanisms underlying agnathia-otocephaly. Overall, the development of better diagnostic methods, animal models and the study of genetic pathways will collectively assist in an improved understanding of otocephaly biology, and inevitably, to better clinically manage this devastating birth defect.

Section snippets

Embryology of normal facial development in humans

Craniofacial development requires the orchestrated integration of multiple specialized tissues, such as the surface ectoderm, neural crest, mesoderm and pharyngeal endoderm, leading towards the formation of the central and peripheral nervous systems, axial skeleton, musculature, and connective tissues of the head and face (Table 1). The pharyngeal arches participate in patterning the facial structures [27] (Table 1). The face derives from five prominences which encircle the stomodeum. Among

Generalized etiologies of agnathia-otocephaly in humans

Frequent dysmorphologies and complications documented among agnathia-otocephalic patients are summarized in Table 2. Otocephaly is considered a defect of blastogenesis, resulting in the variable dysmorphogenesis of structures principally derived from the first pharyngeal arch derivatives [11], [42]. However, mal-developments in the derivatives from the remaining four arches can also contribute to this malformation [11], [42]. Interestingly, a defect in blastogenesis can further result in the

Prenatal detection methods

Reports on the prenatal diagnosis of a developing fetus with agnathia-otocephaly are very rare [1], [5], [6], [8], [18], [22], [31], [48], [50], [51], [53], [56], [59], [62], [63]. With an estimated incidence of less than 1 in 70,000 births, about 144 affected individuals were described to date since the first reported patient in 1717 by Kerckring [11], [18], [22], [24], [28], [35], [51], [53]. The incidence is almost equal in males and females [1], [5], [6], [8], [11], [18], [22], [24], [26],

Differential diagnosis

If micrognathia is suspected, the sonographer must conduct a careful search for additional anomalies, since more than 200 genetic conditions have been described with micrognathia [15]. The differential diagnoses include: chromosomal abnormalities, neuromuscular abnormalities, skeletal dysplasia, teratogen exposure (retinoic acid, methotrexate/aminopterin, etc), Pierre Robin sequence, isolated or syndrome-associated. Syndromes associated with micrognathia include Deletion 22q11.2 syndrome,

Prognosis and genetic counseling issues

Evidence to date suggests that the majority of patients with agnathia-otocephaly are sporadic cases [1], [5], [6], [8], [11], [18], [22], [23], [26], [28], [31], [35], [43], [48], [50], [51], [53], [56], [59], [62], [63]. Only a few familial cases were reported, but with difficulty in understanding the mode of inheritance [11], [26]. Thus far, there has been a lack of evidence for uniparental disomy or even recurrent non-random chromosome aberrations among affected individuals, leading to no

Understanding molecular interactions during craniofacial development and with relevance to agnathia-otocephaly using genetically engineered mouse models

Craniofacial development during embryogenesis and fetogenesis involves the complex interactions of several developmental molecular pathways. Fig. 2 summarizes key candidate developmental pathways which may contribute to the genetic pathogenesis of agnathia-otocephaly, and will be discussed herein. Firstly, Sonic hedgehog (SHH) signaling is among the most pertinent pathways involved in the patterning of the first pharyngeal arch [29]. Mutations in Shh result in growth retardation and

Spontaneous/chemically induced animals with agnathia-otocephaly

Reports of spontaneous agnathia-otocephaly were documented in sheep, rabbits, guinea pigs, dogs and even in mice [11], [47], [45], [61], [12]. But there is no definitive evidence on the etiology of the otocephalic phenotype among sheep, as being either genetic or teratogenic. However, it must be noted that several examples of affected sheep manifested different gradations of the agnathia-otocephaly spectrum [47]. Canine experiments [12] which previously involved crossing different breeds of

Conclusions

Since the first clinically documented report of a patient with agnathia-otocephaly in 1717, our understanding of the etiology of this disorder is still ongoing. Although this sporadic, congenital malformation is relatively rare, the craniofacial findings are remarkably fascinating to wide academic disciplines ranging from developmental biologists, dysmorphologists, clinical geneticists, obstetricians and pathologists. Based on the current knowledge known on normal craniofacial development, an

Acknowledgments

We are thankful to the families for contributing to examples of agnathia-otocephaly described in this article, Ms Abidin for contributing to the illustration, some tables and their content, and Dr. Kam Kamnasaran for helpful comments on this manuscript. This work is supported to DK by grants from the CHUQ foundation, Fondation des étoiles, Canadian Foundation for Innovation and Fonds de la recherche en santé du Québec.

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