Vazken M. Der Kaloustian

Positional cloning of the gene for Nijmegen breakage syndrome

Nijmegen breakage syndrome (NBS), also known as ataxia-telangiectasia (AT) variant, is an autosomal recessive disorder characterized by microcephaly, growth retardation, severe combined immunodeficiency and a high incidence of lymphoid cancers. Cells from NBS patients display chromosome instability, hypersensitivity to ionizing radiation and abnormal cell-cycle regulation after irradiation, all of which are characteristics shared with AT. Recently, the NBS locus was mapped at 8q21 by two independent approaches, complementation studies and linkage analysis. Here, we report the positional cloning of the NBS gene, NBS1, from an 800-kb candidate region. The gene comprises 50 kb and encodes a protein of 754 amino acids. The amino-terminal region of the protein shows weak homology to the yeast XRS2, MEK1, CDS1 and SPK1 proteins. The gene is expressed at high levels in the testes, suggesting that it might be involved in meiotic recombination. We detected the same 5-bp deletion in 13 individuals, and conclude that it is likely to be a founder mutation.

Frontometaphyseal dysplasia: mutations in FLNA and phenotypic diversity.

Frontometaphyseal dysplasia is an X‐linked trait primarily characterized by a skeletal dysplasia comprising hyperostosis of the skull and modeling anomalies of the tubular bones. Extraskeletal features include tracheobronchial, cardiac, and urological malformations. A proportion of individuals have missense mutations or small deletions in the X‐linked gene, FLNA. We report here our experience with comprehensive screening of the FLNA gene in a group of 23 unrelated probands (11 familial instances, 12 simplex cases; total affected individuals 32) with FMD. We found missense mutations leading to substitutions in the actin‐binding domain and within filamin repeats 9, 10, 14, 16, 22, and 23 of filamin A in 13/23 (57%) of individuals in this cohort. Some mutations present with a male phenotype that is characterized by a severe skeletal dysplasia, cardiac, and genitourinary malformations that leads to perinatal death. Although no phenotypic feature consistently discriminates between females with FMD who are heterozygous for FLNA mutations and those in whom no FLNA mutation can be identified, there is a difference in the degree of skewing of X‐inactivation between these two groups. This observation suggests that locus heterogeneity may exist for this disorder.

A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder clinically characterized by distal and proximal sensory loss that is caused by the reduction or absence of peripheral sensory nerves. Recently, a novel gene called HSN2 has been found to be the cause of HSAN type II in five families from Newfoundland and Quebec. Screening of this gene in an HSAN type II Lebanese family showed a 1bp deletion mutation found in a homozygous state in all affected individuals. This novel mutation supports the hypothesis that HSN2 is the causative gene for HSAN type II. Ann Neurol 2004;56:572–575

Prolidase deficiency: A multisystemic hereditary disorder

Prolidase deficiency is a rare hereditary disorder with a wide spectrum of clinical manifestations including skin ulcers, eczematous eruptions, characteristic facies, mental retardation, splenomegaly, and susceptibility to infections. We report two new cases of prolidase deficiency. Our patients had the typical manifestations of prolidase deficiency. One also had lupus erythematosus. Prolidase activity was either normal or half-normal in all family members. The skin disease in our patients did not respond to topical glycine/proline ointment or to oral vitamin C.

Possible new variant of Nijmegen breakage syndrome

We report on a child with microcephaly, small facial and body size, and immune deficiency. The phenotype is consistent with Nijmegen breakage syndrome (NBS), with additional clinical manifestations and laboratory findings not reported heretofore. Most investigations, including the results of radiation-resistant DNA synthesis, concurred with the diagnosis of NBS. Cytogenetic analysis documented abnormalities in virtually all cells examined. Along with the high frequency of breaks and rearrangements of chromosomes 7 and 14, we found breakage and monosomies involving numerous other chromosomes. Because of some variation in the clinical presentation and some unusual cytogenetic findings, we suggest that our patient may represent a new variant of Nijmegen breakage syndrome.

New form of hidrotic ectodermal dysplasia in a Lebanese family

We report a sister and brother born to consanguineous parents presenting with severe hypodontia, fine hair, and onychodysplasia. Five other relatives are similarly affected. The comparison with other ectodermal dysplasias is presented and discussed. The possibility of a new autosomal recessive form of ectodermal dysplasia is raised.

Unusual dicentric chromosome 22 associated with a 22q13 deletion

Tina Babineau, Heather L. Wilson, Angelika J. Dawson, Bernard N. Chodirker, Vazken M. Der Kaloustian, Suzanne Demczuk, and Heather E. McDermid* Department of Human Genetics, Montreal Children’s Hospital, Division of Medical Genetics, McGill University, Montreal, Canada Department of Biological Sciences, University of Alberta, Edmonton, Canada Department of Pediatrics and Child Health and Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Canada

Unilateral radio-ulnar synostosis, generalized hypotonia, and developmental delay with a characteristic facial appearance: a further case report.

In 1992, Der Kaloustian et al. described two sibs with generalized hypotonia, developmental delay, unilateral radio-ulnar synostosis (RUS), and a characteristic facial appearance which, they proposed, represented a new syndrome [DerKaloustian et al., 1992].Wenowdescribe a 12-year-old girl with similar clinical manifestations. These three casesmay represent a specificmultiple congenital anomaly/mental retardation syndrome. The proposita was born to non-consanguineous parents of New Zealand European extraction. Her mother was 27-year-old at the time. The pregnancy was uncomplicated, with no known exposure to teratogens. However, there were decreased fetal movements in utero. She was born at term with a birthweight of 3,910 g, an OFC of 36 cm, and a length of 52 cm. Abnormal physical findings noted at birth included a high sloping forehead, retrognathia, and a posterior cleft palate. Her neonatal course was complicated by feeding difficulties and persistent hypotonia. Developmental progress was slow. She first walked independently at 22 months. She did not develop any speech.Droolinghas beenapersistent problemthroughout infancy and early childhood. She has also suffered from recurrent middle ear infections. The posterior cleft palate was repaired at the age of 10 months. On examination at the age of 12 years, her weight was 38 kg (10th centile), her length was 145 cm (10th centile), and her OFC was 53.4 cm (50th centile). She had a dolichocephalic head with an elongated, narrow face, and mild right esotropia (Fig. 1a,b). There was a small patch of alopecia at the site of a parietal whorl. Her ears were slightly low set with flattening of both antihelices (Fig. 2). There were signs of a posterior cleft palate repair with a narrow, high-arched palate. She had a mild pectus excavatum. There was marked rightsided limitation to supination and pronation but full extension at the elbows. She had camptodactyly of the left fifth finger, bilateral fifth finger clinodactyly, mild genu valgum, and a sandal gap between the first and second toes (Figs. 3 and 4). She had a wide-based gait and walked with her right foot externally rotated.

Genetic diseases of the skin: Progress and perspectives

The recent years have witnessed rapid advances in the basic understanding of genetic disorders, especially monogenic conditions. This development is, to a great extent, as a consequence of the remarkable progress in molecular genetic technology and the completion of the Human Genome Mapping Project. Many genes involved in the causation of various diseases were identified and pathogenetic mechanisms were elucidated. By May 2000, the mutations of more than 1,000 genes were recognized to be responsible for hereditary disorders [Antonarakis and McKusick, 2000]. Online Mendelian Inheritance in Man (OMIM) has become an essential reference, consulted by basic scientists and clinicians alike, to keep abreast of developments and significant newly acquired information on specific genes and hereditary conditions. These advances concern most systems, and in particular, the skin and its appendages. By now, more than 160 Mendelian genodermatoses have been identified to be associated with allelic variants of around 140 genes [Irvine and McLean, 2003]. This development is helping to gradually establish ‘‘the morbid cutaneous anatomy of the human genome’’ [McKusick and Amberger, 1993; Bale, 2001]. Knowledge of genotype/phenotype correlations has allowed a better understanding of the basic and intricate role of genes in skin structure and physiology. For example, the molecular diagnosis of newly discovered keratin disorders in humans, and keratin defects experimentally generated in mice, have allowed important insights into the structure of the keratins and the intricate cytoskeleton of the keratinocytes [Bennett and Lamoraux, 2003; Porter and Lane, 2003]. The same is true for the study of pigmentary disorders in mice and men [Bennett and Lamoraux, 2003]. The elucidation of gap-junction and calcium-channel disorders has helped us comprehend cell-to-cell interactions. These and other advances in the knowledge of genes and their mutations have offered us new perspectives in the pathogenesis of hereditary skin diseases. However, the association of the mutation of a gene resulting in a specific phenotype has become more complex, as new information has been acquired. The one gene-one disorder concept is still accepted for many conditions. In others, however, various mutations in the same gene produce dissimilar phenotypes under the label of different diseases. Thus, site-specific mutations within connexin 26 (GJB2) gene may produce Vohwinkel syndrome, nonsyndromic deafness or the keratinichthyosis-deafness (KID) syndrome [Kelsell et al., 1997, 2001; Richard et al., 2002]. Similarly, three different mutations in the XPD gene may result respectively in three clinical conditions as xeroderma pigmentosum (XP), Cockayne syndrome combined with XP, and trichothiodystrophy with photosensitivity [Lehmann, 2001]. It is also noted that a similar phenotype may originate from mutations in different genes. Thus, in striate palmoplantar keratoderma, mutations have been found in desmoplakin, desmoglein1, and keratin 1 [Whittock et al., 2002a,b; Kljuic et al., 2003]. Defects in various structural proteins composed of heterodimers or heterotrimers may have phenotypically similar dominant-negative effects. For example, there are keratin disorders with type I/type II keratin heterodimers, or junctional epidermolysis bullosa (EB) with a mutation in any one of three constituent chains of paminin-5 trimers. Digenic inheritance (the presence of mutations in two distinct genes) is another newetiological concept. It has been associated with severe, non-lethal, junctional epidermolysis bullosa (JEB). The affected individual was a compound heterozygote for premature termination codons in COL17A1, and simultaneously, heterozygous for a premature termination codon in the LAMB3 group [Floeth and Bruckner-Tuderman, 1999]. Advances of molecular research have also resulted in novel nosological Dr. Vazken M. Der Kaloustian is Professor at the Departments of Pediatrics and Human Genetics, McGill University, in Montreal, Canada. His main field of research is clinical genetics and, in particular, genetic diseases of the skin. He has published more than 150 articles and chapters, as well as 3 books. He has been on the editorial boards of books and journals, including the American Journal of Medical Genetics. He has also served as consultant for the World Health Organization and as member of its specialty committees for certain genetic disorders. Dr. Rudolf Happle is Professor Emeritus at the Department of Dermatology, Philipp University of Marburg, Germany. His main field of research is genodermatology, especially cutaneous syndromes and skin disorders with mosaicism, as well as hair diseases, particularly the topical immunotherapy of alopecia areata. He has published more than 400 articles, mostly on genetic skin diseases. He is a member of the editorial board of several journals with international readership, including the American Journal of Medical Genetics. *Correspondence to: Vazken M. Der Kaloustian, M.D., McGill University, Professor of Pediatrics & Human Genetics, Montreal Children’s Hospital, MUHC, 2300 Tupper Street, Montreal, Quebec H3H 1P3, Canada. E-mail: vazken.derkaloustian@mcgill.ca DOI 10.1002/ajmg.c.30028

Skeletal and cardiac malformations with thrombocytopenia: a new syndrome?

We describe a female patient with multiple anomalies suggestive of a new syndrome. Manifestations include: VSD and ASD, mild developmental delay, conductive hearing loss, minor facial anomalies, thrombocytopenia, and radiological findings (including carpal fusion). Some of these manifestations may be present in the Keutel syndrome, IVIC syndrome, and the 10qter deletion syndrome. However, none of these syndromes can explain the spectrum of anomalies seen in our patient.