Annemarie Sommer

Cornelia de Lange syndrome: clinical review, diagnostic and scoring systems, and anticipatory guidance.

Cornelia de Lange syndrome (CdLS), also known as Brachmann‐de Lange syndrome, is a well‐described multiple malformation syndrome typically involving proportionate small stature, developmental delay, specific facial features, major malformations (particularly the cardiac, gastrointestinal and musculoskeletal systems), and behavioral abnormalities. There is a broad spectrum of clinical involvement, with increasing recognition of a much milder phenotype than previously recognized. Significant progress has been made in recent years in the clinical and molecular delineation of CdLS, necessitating a revision of the diagnostic criteria, more inclusive of the milder cases. In addition, a scoring system of severity has been found to correlate with specific brain changes. Thus, a clinical overview and recommendations for anticipatory guidance are timely in aiding caretakers and professionals to individualize care decisions and maximize developmental potential for individuals with CdLS. These guidelines are derived from consensus based on collective experience of over 500 patients with CdLS, observations of the natural history in children, adolescents, and adults, a review of the literature, and contacts with national support organizations in North America and Europe.

Mutations in PYCR1 cause cutis laxa with progeroid features.

Autosomal recessive cutis laxa (ARCL) describes a group of syndromal disorders that are often associated with a progeroid appearance, lax and wrinkled skin, osteopenia and mental retardation. Homozygosity mapping in several kindreds with ARCL identified a candidate region on chromosome 17q25. By high-throughput sequencing of the entire candidate region, we detected disease-causing mutations in the gene PYCR1. We found that the gene product, an enzyme involved in proline metabolism, localizes to mitochondria. Altered mitochondrial morphology, membrane potential and increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals. Knockdown of the orthologous genes in Xenopus and zebrafish led to epidermal hypoplasia and blistering that was accompanied by a massive increase of apoptosis. Our findings link mutations in PYCR1 to altered mitochondrial function and progeroid changes in connective tissues.

Apnea and sudden unexpected death in infants with achondroplasia

Thirteen infants with achondroplasia and sudden unexpected death or unexplained apnea were discovered through nonsystematic retrospective case collection. Most were initially thought to have died from sudden infant death syndrome. However, historical and pathologic findings suggest that many of these infants had apnea and sudden unexpected death secondary to acute or chronic compression of the lower brainstem or cervical spinal cord. Infants with achondroplasia evidently are at considerably increased risk for such deaths between 1 month and 1 year of age. Appropriate intervention, given these previously unrecognized risks, may include cervical restraint, polysomnographic evaluation, and apnea monitoring.

GTF2I hemizygosity implicated in mental retardation in Williams syndrome: Genotype–phenotype analysis of five families with deletions in the Williams syndrome region

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.

Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly

Recently, Butler et al. [2005; J Med Genet 42:318–321] reported the presence of heterozygous germline mutations in the PTEN tumor suppressor gene in three children with autism and macrocephaly. Here, we report the presence of PTEN mutations in two additional unrelated children with macrocephaly and autism. Our findings extend those of Butler et al. and suggest that PTEN gene sequencing should be included in the genetic evaluation of this subset of autistic individuals.

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.

Missense mutation in the paired domain of PAX3 causes craniofacial-deafness-hand syndrome.

Craniofacial‐deafness‐hand syndrome (MIM 122880) is inherited as an autosomal dominant mutation characterized by the absence or hypoplasia of the nasal bones, profound sensorineural deafness, a small and short nose with slitlike nares, hypertelorism, short palpebral fissures, and limited movement at the wrist and ulnar deviations of the fingers. In a family of three affected individuals with this syndrome, a mother and two children, a missense mutation (Asn47Lys) in the paired domain of PAX3 was initially detected by SSCP analysis. PCR amplification using an oligonucleotide with a terminal 3′‐residue match for the C‐to‐G transversion in codon 47 showed the presence of this mutation in the DNA from all affected members. The DNA from unaffected members were refractory to PCR amplification with the mutation‐specific oligonucleotide but did amplify a control primer pair in the same PCR reaction tube. A previously described missense mutation in this same codon (Asn47His) is associated with Waardenburg syndrome type 3 (Hoth et al., 1993). Substitution of a basic amino acid for asparagine at residue 47, conserved in all known murine Pax and human PAX genes, appears to have a more drastic effect on the phenotype than missense, frameshift and deletion mutations of PAX3 that cause Waardenburg syndrome type 1.

Cardiovascular Abnormalities in the Beckwith-Wiedemann Syndrome

Twelve of 13 patients with Beckwith-Wiedemann syndrome were found to have cardiovascular abnormalities: congenital heart disease in 7 of the 12 and isolated cardiomegaly in the others. No specific type of cardiac abnormality predominated.

Further delineation of Weaver syndrome

Seven new cases of Weaver syndrome are described, including the first reported case in an adult. Overgrowth is usually but not always present. The combination of characteristic facies and developmental delay, with the peculiar radiographic findings of accelerated dysharmonic osseous maturation and splaying of the distal long bones, is diagnostic of Weaver syndrome.

Trisomy 4p: five new observations and overview.

Five new cases of trisomy of the short arm of chromosome No. 4 are presented. In two brothers the abnormality arose from segregation of the 4p chromosome present in the mother who is a carrier of a centric fission of one No. 4 chromosome. In the other three patients, the chromosome imbalance originated from segregation of a balanced maternal 3p/4q or 4/22 translocation.