Otocephaly-Dysgnathia Complex: Description of Four Cases and Confirmation of the Role of OTX2.

Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1) genes have recently been identified in some cases. We screened 4 otocephalic cases for these 2 genes and identified OTX2 mutations in 2 of them, thus confirming OTX2 is implicated in otocephaly. No PRRX1 mutation was identified. Interestingly, ocular involvement is not a constant feature in otocephalic cases with an OTX2 mutation. In one case, the mutation was inherited from a microphthalmic mother. The mechanism underlying this intrafamilial phenotypic variability remains unclear, but other genetic factors are likely to be necessary for the manifestation of the otocephalic phenotype.

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated.

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.