RESUMEN
Agnathia-otocephaly complex is a malformation characterized by absent/hypoplastic mandible and abnormally positioned ears. Mutations in two genes, PRRX1 and OTX2, have been described in a small number of families with this disorder. We performed clinical and genetic testing in an additional family. The proband is a healthy female with a complicated pregnancy history that includes two offspring diagnosed with agnathia-otocephaly during prenatal ultrasound scans. Exome sequencing was performed in fetal DNA from one of these two offspring revealing a heterozygous duplication in OTX2: c.271_273dupCAG, p.(Gln91dup). This change leads to the insertion of a glutamine within the OTX2 homeodomain region, and is predicted to alter this signaling molecule's ability to interact with DNA. The same variant was also identified in the proband's clinically unaffected 38-year-old husband and their 9-year-old daughter, who presented with a small mandible, normal ears and velopharyngeal insufficiency due to a short hemi-palate. This unusual presentation of OTX2-related disease suggests that OTX2 might have a role in palatal hypoplasia cases. A previously unreported OTX2 variant associated with extreme intrafamilial variability is described and the utility of exome sequencing as a tool to confirm the diagnosis of agnathia-otocephaly and to inform the reproductive decisions of affected families is highlighted.
Asunto(s)
Anomalías Múltiples/genética , Duplicación de Gen , Factores de Transcripción Otx/genética , Sistemas de Lectura , Insuficiencia Velofaríngea/genética , Anomalías Múltiples/diagnóstico , Adulto , Niño , Femenino , Estudios de Asociación Genética , Heterocigoto , Humanos , Masculino , Modelos Moleculares , Mutación , Factores de Transcripción Otx/química , Linaje , Fenotipo , Conformación Proteica , Insuficiencia Velofaríngea/diagnósticoRESUMEN
OBJECTIVE: We investigated the effect of the bacterial flora of the nose and throat on the outcome of the initial repairs of the cleft palate in the presence of prophylactic antibiotics. DESIGN: A retrospective review of 90 procedures in 66 patients who had cleft palate repair between April 2005 and June 2007 was conducted at Booth Hall Children's Hospital, Manchester, U.K. Both isolated cleft palate and cleft lip and palate patients were included. Exclusion criteria included syndromic cases, other medical disorders, and revisions of previous cleft palate repairs. Nose and throat swabs were taken on admission. Benzyl penicillin and flucloxacillin were given perioperatively. The occurrence of oronasal fistulas was correlated with the bacteria grown on culture. RESULTS: The oronasal fistula rate was 15.9%. The highest fistula rate in procedures with positive swabs was seen with Moraxella catarrhalis. CONCLUSIONS: M. catarrhalis has not been previously recognized as a pathogen in cleft palate repairs. This study demonstrates a higher fistula rate in procedures positive for M. catarrhalis. Other factors that may have contributed to the fistula formation include the severity of the initial cleft and technical factors. Further study is required before a definitive link can be established.