Didier Lacombe

Definition of a critical region on chromosome 18 for congenital aural atresia by arrayCGH

Deletions of the long arm of chromosome 18 occur in approximately 1 in 10,000 live births. Congenital aural atresia (CAA), or narrow external auditory canals, occurs in approximately 66% of all patients who have a terminal deletion 18q. The present report describes a series of 20 patients with CAA, of whom 18 had microscopically visible 18q deletions. The extent and nature of the chromosome-18 deletions were studied in detail by array-based comparative genomic hybridization (arrayCGH). High-resolution chromosome-18 profiles were obtained for all patients, and a critical region of 5 Mb that was deleted in all patients with CAA could be defined on 18q22.3-18q23. Therefore, this region can be considered as a candidate region for aural atresia. The array-based high-resolution copy-number screening enabled a refined cytogenetic diagnosis in 12 patients. Our approach appeared to be applicable to the detection of genetic mosaicisms and, in particular, to a detailed delineation of ring chromosomes. This study clearly demonstrates the power of the arrayCGH technology in high-resolution molecular karyotyping. Deletion and amplification mapping can now be performed at the submicroscopic level and will allow high-throughput definition of genomic regions harboring disease genes.

Further delineation of Kabuki syndrome in 48 well-defined new individuals†

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases—providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Toriello-Carey syndrome: evidence for X-linked inheritance.

Toriello-Carey syndrome is characterized by agenesis of the corpus callosum, telecanthus, short palpebral fissures, Robin sequence, abnormal ears, cardiac anomalies, and hypotonia. We describe two patients with Toriello-Carey syndrome and call attention to an unbalanced sex ratio. The first patient, a male, was born at term by Cesarean section and manifests micrognathia, cleft soft palate, hypoplastic right ear, anotia on the left side, cerebellar vermis hypoplasia, hydrocephalus, agenesis of the corpus callosum, and hypoplastic left heart. He died 2 days after birth. The second patient is the male sib of a patient reported previously [Am J Med Genet 42: 374-376; 1992]. He had large fontanelles, telecanthus, a short nose, small and malformed ears, micrognathia, a large ventricular septal defect, and pulmonary stenosis. At age 8 months he has growth retardation and developmental delay. A sister is unaffected. Review documented eight other patients with Toriello-Carey syndrome, six of whom were male. The two female patients are less severely affected and are still alive. Of the other male patients, all are deceased except one who is still alive at age 5 years; he has severe growth retardation (-3 SD), mental retardation (DQ44), severe speech delay, and characteristic anomalies. The predominance of affected males and the milder phenotype in the female patients suggests an X-linked gene or sex influenced gene.

Cutaneous manifestations in Costello and cardiofaciocutaneous syndrome: report of 18 cases and literature review.

Costello syndrome (CS) and cardiofaciocutaneous syndrome (CFCS) are congenital disorders involving the Ras‐MAPK pathway with phenotypic overlap. These two entities are thought to share common cutaneous findings, although so far they have been poorly studied. The objective of this prospective observational study was to describe the spectrum of skin findings in CS and CFCS and to highlight those specific to each of these two diseases. Patients with a confirmed diagnosis of CFCS or CS underwent a systematic skin examination during the annual workshop organized by the French CS association in 2007 and 2009 in Bordeaux, France. Eighteen patients were included in the study. Specific skin abnormalities, including cutis laxa, curly hair, pruritus, and hyperhidrosis, are shared by CFCS and CS, whereas others may help to differentiate between these two syndromes. Acanthosis nigricans, papillomas, and loose thick skin of the dorsum of the hands are characteristic of CS, whereas sparse eyebrows and dry hyperkeratotic skin are suggestive of CFCS. Our results highlight that a systematic cutaneous examination, in addition to dysmorphologic and noncutaneous anomalies, may be helpful in establishing the diagnosis of CFCS and CS. The physiopathologic link between constitutional Ras‐MAPK pathway activation and the observed ectodermal findings remains to be investigated.