Gary M. Joffe, MD*, Luis A. Izquierdo, MD, Gerardo O. Del Valle, MD, James F. Smith, MD, George J. Gilson, MD, S. Chaterjee, MD, and Luis B. Curet, MD

Synonyms: Otocephaly, holoprosencephaly-agnathia
Prevalence: Unknown, less than 10 cases described.
Definition: A lethal anomaly characterized by hypoplasia or absence of the mandible with abnormally positioned ears and any form of holoprosencephaly.
Etiology: May be autosomal recessive inheritance.
Pathogenesis: Probably due to failure of migration of neural crest mesenchyme into the maxillary prominence at the fourth to fifth week of gestation (post-conception).
Associated anomalies: Holo­pros­encephaly, cephalocele, dysge­ne­sis of corpus callosum, cerebellar hypoplasia, atresia of third ven­tricle, midline proboscis, hypo­pla­s-tic tongue, tracheoesophageal fis­tula, cardiac anomalies, and adrenal hypoplasia.
Differential diagnosis: agnathia-microstomia-synotia, melotia, oto­­cephaly, Robin anomalad.
Prognosis: Lethal
Recurrence risk: Mendelian inheritance.
Management: As for diseases with fatal outcome.

MESH Brain-abnormalities; Ear-abnormalities; Eye-abnormalities; Face-abnormalities; Jaw -Abnormalities -diagnosis; Skull-abnormalities BDE 2780 MIM 20265 POS 3478 ICD9 744.84-742.2 CDC 744.810

* Address correspondence to: Gary M. Joffe, MD, University of New Mexico, School of Medicine, Dept. of Ob-Gyn. 2211 Lomas Blvd., NE, Albuquerque, NM 87131-5286 Ph: 505-277-8381 (voice), 277-7621 (fax).

Introduction

Agnathia-holoprosencephaly is a complex, lethal anomaly characterized by hypoplasia or absence of the mandible with abnormally positioned ears and holoprosencephaly. When it is not associated with central nervous system malformations it is referred to as “agnathia-microstomia-synotia” (BDE 0028). The cardiac, respiratory, and endocrine systems may be affected as well. We present a case of agnathia-holoprosencephaly followed by a discussion of the embryology, ultrasonographic characteristics, and possible etiology.

Case report

A 26 year old gravida 1 initially presented to the prenatal substance abuse clinic at our institution at twenty-seven weeks from her stated last mens­trual period. Her prenatal course had been significant for heavy consumption of ethanol and amphetamines. She was also noted to have cervicitis secondary to b-streptococcus and tricho­monas.

An ultrasound was ordered which revealed complex anomalies involving the central nervous system and face. These included ven­triculomegaly, absence of the corpus callo­sum, apparent dilatation of the third ventricle, enlarged cisterna magna, and cleft lip (fig. 1, 2, 3).

Fig. 1: Axial scan at the level of the cerebral peduncles and thalami demonstrating ventriculomegaly, absence of midline falx, and enlarged posterior fossa.

Fig. 2: Axial scan taken at a level caudad to Fig. 1 demonstrating cisterna magna measuring 19mm in diameter with apparent absence of cerebellum.

Fig. 3:  Axial scan at level of posterior fossa. Arrow points to cystic structure thought to represent dilatation of third ventricle. Subsequent pathologic examination revealed partial atresia of third ventricle and an arched, distorted aqueduct.

The entire face was incompletely viewed, secondary to fetal position. The remainder of the anatomical survey was completely normal. The patient subsequently underwent amniocentesis, which revealed a 46,XY karyotype.

At thirty weeks of gestation, the patient experienced preterm labor. Fetal distress developed due to umbilical cord prolapse. Because the patient wanted all resuscitative efforts carried out for this infant, she was delivered by cesarean section. The infant was a 1,060g male born with a heartbeat and respiratory effort. The absence of the mandible was evident at delivery and this precluded successful resuscitation. The infant expired forty-five minutes after delivery.

The findings at autopsy included complete absence of the mandible, bilateral cleft lip and palate, cleft of the lower lip, and ears that were fused at the tragus in the midline of the neck (fig.4, 5).

Fig. 4: Gross findings at the time of autopsy revealed ears fused in the midline, complete absence of the mandible, and clefting of both lips.

Fig. 5: X-Ray taken after the cranium was drained of 260cc of serous fluid. Note the absence of the mandible in the lateral view of the head.  

In addition, histologic examination of the brain revealed hydrocephalus involving the late­ral ventricles, dysgenesis of the corpus callosum, atresia of the third ventricle, and severe cerebellar hypoplasia (fig. 6).

Fig. 6: Gross specimen of the brain. Note the hypoplastic cerebellum in the midline with absence of the vermis.

Comments

Agnathia-microstomia-synotia is defined as absence or hypoplasia of the mandible, proximity of the temporal bones, and abnormal position of the ears¹. When complicated by holoprosencephaly, it is referred to as “agnathia-holo­pros­encephaly”.

This is an extremely rare malformation (less than 10 cases reported), and according to the Birth Defect Encyclopedia, the anomaly may represent an autosomal recessive defect¹.

Embryology

Facial development occurs in the human embryo mainly between the fifth and eighth weeks post-conception². Surrounding the primitive stomodeum are the fron­tonasal prominence superiorly, maxillary prominence of the first branchial arch laterally, and the mandibular prominence (also first branchial arch derivatives) inferiorly (fig. 7).

Fig. 7: Schematic representation of facial development at Day 24, Day 33, and Day 48 post-conception. Mesenchymal cells, of neural crest origin migrate into the mandibular prominence forming the precursor of the lower jaw. The ears “migration” to their adult site is actually secondary to rapid proliferation of cells destined to form the mandible and differential growth of the cranium.

The mandible is the first part of the face to form. It is thought to arise from proliferation and migration of mesenchyme, possibly of neural crest origin. The medial ends of the mandibular prominence merge in the midline by the beginning of the fifth week of gestation post-conception.

The maxillae form during the sixth and seventh week of gestation by the merging of the maxillary prominence with each other and the frontonasal prominence along the nasolacrimal groove (fig. 7).

This infant demonstrated both clefting of the upper lip and palate in addition to the rare median cleft of the lower lip. The upper cleft can be explained on the basis of failure of migration of mesenchyme of the maxillary prominence. This resulted in bilateral clefting (fig.4). The cleft of the lower lip is secondary to total absence of development of the mandibular prominence, which also resulted in complete absence of the mandible.

Since the maxillary mesenchymal migration did not occur, the ears did not undergo “migration” to their usual position, and remained in their original embryonic location (fig. 4).

Associated anomalies

This case demonstrated an association of otocephaly with central nervous system malformations. Other malformations noted to occur with this anomaly have included holoprosencephaly, cepha­locele, midline proboscis, hypo­plastic tongue, tracheo-esopha­geal fistula, cardiac anomalies, and adrenal hypoplasia¹.

Differential diagnosis

The differential diagnosis of agnathia-holo­pros­encephaly includes agnathia-­micro­stomia- syn­otia (no holoprosencephaly) and the Robin anomalad. This is another disorder of formation of the mandible, which is characterized by mandibular hypoplasia, posterior cleft palate, and posterior displacement of the tongue. The key to distinguishing agnathia-microstomia-synotia from Robin anomalad using ultrasonography is localization of the ears. The ears remain in the midline over the neck in agnathia-microstomia-synotia, while some degree of “migration” does occur in the Robin anomalad.

In summary, otocephaly is a rare, complex lethal anomaly with unknown etiology. In this case, heavy ethanol and amphetamine usage in early pregnancy might have been associated with this malformation complex. Otoceph­aly is a diagnosis that can be made antenatally by ultrasound by demonstrating absence of the mandible, low set ears, and associated central nervous system anomalies.

References

1. Buyse ML: Birth Defect Encyclopedia. Center for Birth Defects Information Service, Inc. Dover, MA. Published by Blackwell Scientific Publications Cambridge, MA 1990 pp64-5.

2. Moore K: The developing human. Philadelphia, WB Saunders 1982 pp197-201.