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

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.

Prenatal Diagnosis of Otocephaly: A Rare Facial Anomaly.

Introduction: Otocephaly is a rare malformation characterized by agnathia (absence of the mandible), melotia (medially displaced ear pinna), aglossia (absence of the tongue) and microstomia (small oral aperture). This results due to failure of migration of the neural crest cells and is a defect of the first branchial arch. It is incompatible with life and early prenatal diagnosis is useful. Case Report: Our patient a primigravida with 19 weeks 6 days gestation was referred for micrognathia and polyhydramnios. On ultrasound examination, she had unilateral mild ventriculomegaly and posterior fossa cyst in the fetal brain. The fetus had agnathia and anophthalmia. There was an echogenic intracardiac focus and echogenic bowel. The stomach was not seen clearly. This could be due to agnathia and microstomia leading to swallowing difficulties. The patient was explained about the guarded prognosis. The pregnancy was terminated. A diagnosis of otocephaly was made. Discussion: Otocephaly is a rare disorder of development of the first branchial arch. The reported incidence is 1 in 70,000. It is mostly lethal due to respiratory difficulties and may be associated with cranial and extracranial malformations. Most case reports have found that it is sporadic and could be due to mutations in the PRRX1 gene. Other anomalies that may be associated with otocephaly are neural tube defects, cephalocele, dysgenesis of corpus callosum, atresia of the third ventricle, midline probocis, hypotelorism, renal ectopia, cyclopia, vertebral and rib abnormalities, tracheo esophageal fistula, cardiac anomalies and adrenal hypoplasia. Most of the cases reported so far were diagnosed in the second or the third trimester. Facial anomaly screening has undergone a huge evolution in the recent years. In addition to the usual facial screening, we recommend mandibular arch screening in the first and early second trimester. If there is a doubt the patient may be called back at 15 to 16 weeks of gestation considering the fact that these anomalies are usually lethal and medical termination is safer earlier in pregnancy than later. MRI may be a handy tool to confirm antenatal diagnosis as it can detect the abnormal ears. Agnathia and polyhydramnios occur together in the third trimester but in the first or second trimester polyhydramnios may not be observed. Conclusion: Otocephaly, though rare, poses a clinical challenge for both patient and the reporting doctor. Considering the time limitation for termination of pregnancy in our country, early prenatal diagnosis is important. A detailed face evaluation in the first trimester can help detect this defect as early as 11-14 weeks. Early diagnosis of lethal anomalies helps in completing the fetal work up and offering a safer termination. Correct diagnosis and work up of fetal anomalies allows for documentation and awareness of the presence of these conditions in our population.

A de novo variant in OTX2 in a lamb with otocephaly.

BACKGROUND: Otocephaly is a rare lethal malformation of the first branchial arch. While the knowledge on the causes of otocephaly in animals is limited, different syndromic forms in man are associated with variants of the PRRX1 and OTX2 genes. CASE PRESENTATION: A stillborn male lamb of the Istrian Pramenka sheep breed showed several congenital craniofacial anomalies including microstomia, agnathia, aglossia, and synotia. In addition, the lamb had a cleft palate, a small opening in the ventral neck region, a cystic oesophagus and two hepatic cysts. The brain was normally developed despite the deformed shape of the head. Taken together the findings led to a diagnosis of otocephaly. Whole-genome sequencing was performed from DNA of the affected lamb and both parents revealing a heterozygous single nucleotide variant in the OTX2 gene (Chr7: 71478714G > A). The variant was absent in both parents and therefore due to a de novo mutation event. It was a nonsense variant, XM_015097088.2:c.265C > T; which leads to an early premature stop codon and is predicted to truncate more than 70% of the OTX2 open reading frame (p.Arg89*). CONCLUSIONS: The genetic findings were consistent with the diagnosis of the otocephaly and provide strong evidence that the identified loss-of-function variant is pathogenic due to OTX2 haploinsufficiency. The benefits of trio-based whole-genome sequencing as an emerging tool in veterinary pathology to confirm diagnosis are highlighted.

Otocefalia: presentación de dos casos / Otocepsahly: report of two cases

Presentar dos casos de otocefalia. Caso 1. Paciente de 32 años de edad, II gesta, I para, con embarazo de 25 semanas, en control en el servicio de alto riesgo obstétrico del Instituto Autónomo Hospital Universitario de Los Andes por antecedente de embarazo con producto malformado. En estudio ecográfico se encontró feto con microcefalia. Se atendió parto por vía vaginal a las 29 semanas, y se obtuvo recién nacido vivo, sexo masculino, con microcefalia y malformaciones en la región facial tipo otocefalia y aprosopia, el cual muere a los pocos minutos de nacido. Caso 2. Paciente de 39 años, VI gesta, IV paras, I aborto, con embarazo de 27 semanas por fecha de última menstruación. Le fue practicada hemilaringectomía durante la tercera semana de embarazo, bajo anestesia endovenosa. A las 27 semanas, se practica ecosonograma y se encontró polihidramnios, meroanencefalia y quistes aracnoideos. Después de parto a las 28 semanas, se obtiene recién nacido vivo, de sexo femenino, con microcefalia y malformaciones faciales dadas por otocefalia y aprosopia, y muere a los dos minutos de nacida. A ambos productos se les realizó estudio morfológico en la Cátedra de Embriología de la Universidad de Los Andes.

To present two cases of otocephaly. Case 1: Patient of 32 years of age, gravida II, I delivery, with a 25 weeks pregnancy, in prenatal care at the service of high obstetrical risk of the "Instituto Autonomo Hospital Universitario de Los Andes", for history of previous pregnancy with a malformed product. The ultrasound study reported fetal microcephaly. She had a premature delivery at 29 weeks, obtaining an alive male new born, with microcephaly and facial malformations like otocephaly and aprosopia, that dies after few minutes of been born. Case 2. Patient of 39 years, gravida VI, V deliveries, I abortion, with pregnancy of 27 weeks for last menstrual period. She had a hemilaringectomy during the third week of pregnancy, under endovenous anesthesia. The ultrasound study at 27 weeks revealed polihydramnios, meroanencephaly and arachnoid cysts. After premature labor at 28 weeks, a female alive new born, with microcephaly and face malformations given by otocefalia and aprosopia was obtained, and dies two minutes after been born. Morphological study was performed to both products in Embriology Unit of The University of Los Andes.