Manuela Priolo

Ectodermal dysplasias: a new clinical-genetic classification

The ectodermal dysplasias (EDs) are a large and complex nosological group of diseases, first described by Thurnam in 1848. In the last 10 years more than 170 different pathological clinical conditions have been recognised and defined as EDs, all sharing in common anomalies of the hair, teeth, nails, and sweat glands. Many are associated with anomalies in other organs and systems and, in some conditions, with mental retardation. The anomalies affecting the epidermis and epidermal appendages are extremely variable and clinical overlap is present among the majority of EDs. Most EDs are defined by particular clinical signs (for example, eyelid adhesion in AEC syndrome, ectrodactyly in EEC). To date, few causative genes have been identified for these diseases. We recently reviewed genes known to be responsible for EDs in light of their molecular and biological function and proposed a new approach to EDs, integrating both molecular-genetic data and corresponding clinical findings. Based on our previous report, we now propose a clinical-genetic classification of EDs, expand it to other entities in which no causative genes have been identified based on the phenotype, and speculate on possible candidate genes suggested by associated “non-ectodermal” features.

Ectodermal dysplasias: not only ‘skin’ deep

The ectodermal dysplasias (EDs) are a large and complex nosologic group of diseases; more than 170 different pathologic clinical conditions have been identified. Despite the great number of EDs described so far, few causative genes have been identified. We review EDs in the light of the most recent molecular findings and propose a new classification of EDs integrating both molecular‐genetic data and corresponding clinical findings of related diseases.

Infantile Spasms Is Associated with Deletion of the MAGI2 Gene on Chromosome 7q11.23-q21.11

Infantile spasms (IS) is the most severe and common form of epilepsy occurring in the first year of life. At least half of IS cases are idiopathic in origin, with others presumed to arise because of brain insult or malformation. Here, we identify a locus for IS by high-resolution mapping of 7q11.23-q21.1 interstitial deletions in patients. The breakpoints delineate a 500 kb interval within the MAGI2 gene (1.4 Mb in size) that is hemizygously disrupted in 15 of 16 participants with IS or childhood epilepsy, but remains intact in 11 of 12 participants with no seizure history. MAGI2 encodes the synaptic scaffolding protein membrane-associated guanylate kinase inverted-2 that interacts with Stargazin, a protein also associated with epilepsy in the stargazer mouse.

Double Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease

The financial support of Telethon–Italy (grant E791) is gratefully acknowledged. This work was also funded by the Italian Telethon Foundation, the Italian Ministry of Health, and the European Community (contract MH4-CT97-2107).

Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

BackgroundKabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause.MethodsGenomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools.ResultsWe identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site.ConclusionsThis study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management.

MS-MLPA is a specific and sensitive technique for detecting all chromosome 11p15.5 imprinting defects of BWS and SRS in a single-tube experiment

Human chromosome 11p15.5 harbours a large cluster of imprinted genes. Different epigenetic defects at this locus have been associated with both Beckwith–Wiedemann syndrome (BWS) and Silver–Russell syndrome (SRS). Multiple techniques (Southern blotting, COBRA and microsatellite analysis) have been used so far to detect various DNA methylation abnormalities, uniparental disomies and copy number variations, which are characteristics of these two diseases. We have now evaluated a methylation-specific multiplex-ligation-dependent probe amplification assay (MS-MLPA) for the molecular diagnosis of BWS and SRS. Seventy-three samples derived from BWS- and SRS-affected individuals and 20 controls were analysed by conventional tests and MS-MLPA in blind. All cases that were found positive with conventional methods were also identified by MS-MLPA. These included cases with paternal UPD11, hyper- or hypo-methylation at the Imprinting Centre 1 or Imprinting Centre 2 and rare 11p15.5 duplications. In summary, this MS-MLPA assay can detect both copy number variations and methylation defects of the 11p15.5 critical region within one single experiment and represents an easy, low cost and reliable system for the molecular diagnostics of BWS and SRS.

Letters to the EditorDouble Heterozygosity for a RET Substitution Interfering with Splicing and an EDNRB Missense Mutation in Hirschsprung Disease

The financial support of Telethon–Italy (grant E791) is gratefully acknowledged. This work was also funded by the Italian Telethon Foundation, the Italian Ministry of Health, and the European Community (contract MH4-CT97-2107).

Ectodermal abnormalities in Kabuki syndrome.

We describe a girl with Niikawa-Kuroki (Kabuki) syndrome (NKS) with conical incisors, hypodontia, hypoplastic nails, and brittle hair. Abnormal teeth are common in NKS and support a hypothesis of autosomal dominant inheritance of the syndrome [Halal et al., 1989; Silengo et al., 1996]. Hair abnormalities have never been investigated in NKS. The ectodermal involvement in NKS could represent an important clue for the understanding of the pathogenesis of this syndrome.

Molecular characterisation of a supernumerary ring chromosome in a patient with VATER association

Editor—Supernumerary marker chromosomes are rare with an incidence of 0.3-1.5/1000 newborns. Most carriers have a normal phenotype but in 15% of non-satellited marker cases mental retardation and minor anomalies have been reported.1 The origin of several supernumerary ring marker chromosomes has been identified by fluorescence in situ hybridisation (FISH).2 The VATER association is characterised by non-random occurrence of Vertebral anomalies, Anal atresia, Tracheo-oesophageal fistula with Esophageal atresia, Radial limb dysplasia, and Renal defects.3 The acronym VACTERL is used in cases with additional Cardiac and Limb malformations.4 VACTERL with hydrocephalus is thought to be an autosomal recessive disorder distinct from the VATER association.5 Other defects that occur less frequently have been also described.6 A defect in blastogenesis was suggested as a possible aetiology of this malformation spectrum. Martinez-Frias et al 7proposed that combinations of anomalies of blastogenetic origin, such as VATER/VACTERL, should be considered and called “polytopic field defects” instead of the generic term “association”. The knowledge that maternal intake of some teratogens, such as oestroprogestins8 or methimazole,9 may be associated with VATER/VACTERL in the newborn, probably affecting blastogenesis, and familial occurrence of VASTER/VACTERL10 11 suggest heterogeneity in the pathogenesis of the association, although it appears that the underlying causative event takes place at a very early stage of embryonic development. Only one chromosome abnormality has been described in VATER association, a patient with an interstitial 6q deletion,12while an additional case of VATER with 9qh+ has been reported.13 We report here an additional patient with malformations characteristic of VATER association and mosaicism for a small supernumerary ring chromosome derived from the pericentromeric region of chromosome 12. The proband was the term product of an uneventful pregnancy, requiring elective caesarean section because of uterine inertia. Birth weight …

Exclusion of the Sonic Hedgehog gene as responsible for Currarino syndrome and anorectal malformations with sacral hypodevelopment

Anorectal malformations (ARMs) are common congenital anomalies that account for 1:4 digestive malformations. ARM patients show different degrees of sacral hypodevelopment while the hemisacrum is characteristic of the Currarino syndrome (CS). Cases of CS present an association of ARM, hemisacrum and presacral mass. A gene responsible for CS has recently been mapped in 7q36. Among the genes localized in this critical region, sonic hedgehog (SHH) was thought to represent a candidate gene for CS as well as for ARM with different levels of sacral hypodevelopment according to its role in the differentiation of midline mesoderm. By linkage analysis we confirmed the critical region in one large family with recurrence of CS. In addition, the screening of SHH in 7 CS and in 15 sporadic ARM patients with sacral hypodevelopment allowed us to exclude its role in the pathogenesis of these disorders.