Copy number variation analysis in 98 individuals with PHACE syndrome.

PHACE syndrome is the association of large segmental facial hemangiomas and congenital anomalies, such as posterior fossa malformations, cerebral arterial anomalies, coarctation of the aorta, eye anomalies, and sternal defects. To date, the reported cases of PHACE syndrome have been sporadic, suggesting that PHACE may have a complex pathogenesis. We report here genomic copy number variation (CNV) analysis of 98 individuals with PHACE syndrome as a first step in deciphering a potential genetic basis of PHACE syndrome. A total of 3,772 CNVs (2,507 duplications and 1,265 deletions) were detected in 98 individuals with PHACE syndrome. CNVs were then eliminated if they failed to meet established criteria for quality, spanned centromeres, or did not contain genes. CNVs were defined as "rare" if not documented in the database of genomic variants. Ten rare CNVs were discovered (size range: 134-406 kb), located at 1q32.1, 1q43, 3q26.32-3q26.33, 3p11.1, 7q33, 10q24.32, 12q24.13, 17q11.2, 18p11.31, and Xq28. There were no rare CNV events that occurred in more than one subject. Therefore, further study is needed to determine the significance of these CNVs in the pathogenesis of PHACE syndrome.

A case of ankyloblepharon, ectodermal dysplasia, and cleft lip/palate syndrome with ectrodactyly: are the p63 syndromes distinct after all?

Ectodermal dysplasias are diseases with abnormal development of ectodermally derived tissues such as skin, hair, teeth, and nails. Mutations in the transcription factor p63 have been linked to several syndromes characterized by ectodermal, orofacial, and limb defects. We present the case of an infant with ankyloblepharon, cleft palate, scalp dermatitis, and ectrodactyly. She is unique for having a novel p63 mutation that has not been previously reported. Her case also points to the significant overlap between the p63-associated ectodermal dysplasias and challenges the traditional diagnostic schema for these rare syndromes.

Association of hearing loss with PHACE syndrome.

BACKGROUND: PHACE syndrome describes a spectrum of anomalies associated with large facial infantile hemangiomas and characterized by posterior fossa malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. With improved recognition and imaging practices of infants with PHACE syndrome, additional associations have been identified. To our knowledge, the potential association of ipsilateral hearing loss and PHACE syndrome has not been previously emphasized. OBSERVATIONS: We describe 6 patients, 4 with definite and 2 with probable PHACE syndrome, according to the new diagnostic criteria, and associated auditory deficiencies. One patient had isolated conductive hearing loss; 2 patients had isolated sensorineural hearing loss; 1 patient had mixed hearing loss (both conductive and sensorineural components); and 1 patient had hearing loss that was inconclusive at the time. Also, 1 patient had conductive loss and auditory neuropathy and auditory dyssynchrony. Four of the 6 patients had magnetic resonance imaging features of lesions consistent with intracranial hemangiomas involving auditory structures. All 6 patients had facial hemangiomas in a nearly identical distribution ipsilateral to the ear with the hearing loss, with involvement of the proposed facial segments S1 and S3, the affected ear, the periauricular region, and the midoccipital area of the scalp. CONCLUSIONS: There is an underrecognized risk of hearing loss in patients with PHACE syndrome, although the exact nature of such deficiencies can vary. Patients with PHACE syndrome who have cutaneous hemangiomas involving the ear should be evaluated for intracranial hemangiomas and monitored for hearing loss. Early detection and therapy of intracranial hemangiomas may slow or stop tumor growth, resultant hearing loss, and structural damage.

A novel procedure for genotyping of single nucleotide polymorphisms in trisomy with genomic DNA and the invader assay.

Individuals with trisomy 21 display complex phenotypes with differing degrees of severity. Numerous reliable methods have been established to diagnose the initial trisomy in these patients, but the identification and characterization of the genetic basis of the phenotypic variation in individuals with trisomy remains challenging. To date, methods that can accurately determine genotypes in trisomic DNA samples are expensive, require specialized equipment and complicated analyses. Here we report proof-of-concept results for an Invader(R) assay-based genotyping procedure that can determine SNP genotypes in trisomic genomic DNA samples in a simple and cost-effective manner. The procedure requires only two experimental steps: a real-time measurement of the fluorescent Invader(R) signal and analysis with a specifically designed clustering algorithm. The approach was tested using genomic DNA samples from 23 individuals with trisomy 21, and results were compared to genotypes previously determined with pyrosequencing. Additional assays for 15 SNPs were tested in a set of 21 DNA samples to assess assay performance. Our method successfully identified the correct SNP genotypes for the trisomic genomic DNA samples tested, and thus provides an alternative to determine SNP genotypes in trisomic DNA samples for subsequent association studies in patients with Down syndrome and other trisomies.