T. W. J. Hustinx

A NEW CHROMOSOMAL INSTABILITY DISORDER: THE NIJMEGEN BREAKAGE SYNDROME

ABSTRACT. Weemaes, C. M. R., Hustinx, T. W. J., Scheres, J. M. J. C, van Minister, P. J. J., Bakkeren, J. A. J. M. and Taalman, R. D. F. M. (Departments of Paediatrics and Human Genetics, University of Nijmegen, Nijmegen, The Netherlands.) Acta Paediatr Scand, 70:557,.–A 10‐year‐old boy with microcephaly, stunted growth, mental retardation, cafe‐au‐lait spots and immunodeficiency is described. An older brother of the patient had the same clinical symptoms and a more severe immunodeficiency. Cytogenetic studies in the proband revealed a typical form of chromosome instability with multiple rearrangements of chromosomes 7 and 14. Such abnormalities were also present, though in very low frequencies, in the father and three of the phenotypically normal sibs. The similarity of the symptoms in the two sibs, the close consanguinity of their parents and the results of the cytogenetic studies in the family favour the hypothesis that the disorder is an inherited one. The clinical features and the chromosome aberrations as present in the proband are usually found in chromosomal breakage syndromes, but it was possible to exclude each of the classical chromosomal breakage syndromes on clinical and/or cytogenetic grounds.

The most common fragile site in man is 3p14

SummaryIn man a common fragile site is known to occur at 3p14. We studied the expression of this fragility in a group of 70 normal healthy subjects. Chromosome breaks, chromatid breaks and gaps at 3p14 could be observed in every examined individual, and in a total of 7000 metaphases they were seen in a mean of 4% of cells. Fluorescence studies in ten persons with chromosome No. 3 polymorphism showed that in all cases both Nos. 3 were about equally liable to breakage. A considerable variation in the fra 3p14 expression was found between individuals as well as in repeated cultures from the same person. Neither sex nor age influences could be detected. Cultures with a high percentage of lesions at 3p14 tended to have also a high number of lesions at other sites. Methotrexate and fluorodeoxyuridine markedly enhanced the expression of fra 3p14 and other fragilities. It is concluded that the chromosomal region at 3p14 represents mans most common fragile site, the expression of which seems to be influenced by environmental and heritable factors.

A presumptive tetrasomy for the short arm of chromosome 9

SummaryFor the identification of an extra chromosome in a female child a number of recently developed staining techniques were used.The extra element found in 86% of the patients peripheral lymphocytes resembles an isochromosome for the short arm of chromosome No. 9, in which case a tetrasomy for this arm would exist. The clinical findings in our patient were compared with those in patients reported to have extra chromosome 9 material.

Congenital adrenal hypoplasia, progressive muscular dystrophy, and severe mental retardation, in association with glycerol kinase deficiency, in male sibs.

2Department of Pediatrics, Groot Ziekengasthuis, s Hertogenbosch, The Netherlands

Karyotype Instability With Multiple 7/14 and 7/7 Rearrangements

SummaryChromosomes were studied in a mentally retarded boy with microcephaly, growth retardation, facial erythema, café-au-lait spots, and IgA deficiency. In the lymphocytes there was a remarkable tendency to exchange parts of the chromosomes Nos. 7 and 14, the translocations almost exclusively taking place in bands 7p13, 7q32 and 14q11. Seven different types of rearrangements between Nos. 7 and 14, and some other chromosomal aberrations were found. No abnormalities could be detected in the bone marrow. The patient somewhat resembles those affected with ataxia-telangiectasia or with Blooms syndrome, but on clinical and cytogenetic grounds these disorders could be excluded.7/14 Translocations similar to those found in our patients lymphocytes have been reported to occur very rarely in the lymphocyte cultures of individuals with apparently normal chromosome constitution. A relationship between these phenomena may exist.

Complex glycerol kinase deficiency syndrome explained as X-chromosomal deletion.

Sirs, Recently, several of us described a family in which three boys suffered from an apparently X-linked syndrome consisting of progressive muscular dystrophy similar to the Duchenne type, adrenal hypoplasia (AH) and glycerol kinase (GK) deficiency (Reiner et al. 1983). Because DMD, AH and GK deficiency are separate X-linked entities, we considered that this disorder might be caused by a small deletion including the three respective gene loci. In the meantime, several cases with GK deficiency have been described that are clinically very similar to our cases (v. Petrykowski et al. 1982, Bartley et al. 1982, Ginns et al. 1984). This has opened up the possibility that all symptoms in these cases are pleiotropic effects of, and thus causally related to, GK deficiency. According to this hypothesis, the marked clinical heterogeneity of the GK syndrome (Ginns et al. 1984) might be attributable to allelic variation. Alternatively, heterogeneity could be explained by some cases being caused by point mutations and others by deletions, or by deletions of varying size. In an attempt to decide between these interpretations we have re-examined two affected boys of our family by probing their DNA with cloned sequences from the short arm of the X-chromosome. One of these, the recently isolated 754 probe from the middle of Xp (M. H. Hofker* el al. 1985 [in press]) consistently failed to yield hybridization signals in PstI, BglII

Connatal Pelizaeus-Merzbacher Disease with congenital stridor in two maternal cousins

SummaryTwo maternal cousins are described with the connatal form of Pelizaeus-Merzbacher Disease (PMD) and congenital stridor. Study of brain biopsy material confirms the diagnosis of PMD. The neuropathological findings are suggestive for the transitional form of this disease. Quantitative morphology gives support to the hypothesis that PMD is a disturbance in maturation of neurons and in myelin formation rather than an active degenerative process. The hereditary transmission is most consistent with a sex-linked recessive pattern. Different X-linked signs seem combined in the presented cases.

Trisomy for the short arm of chromosome No. 10

The clinical and cytogenetic data are presented of a child with multiple congenital malformations, including cystic kidneys. A trisomy for at least the larger part of the short arm of chromosome No. 10 in association with a translocation between chromosomes Nos. 10 and 14 was found in peripheral blood lymphocytes and skin fibroblasts. Both the mother and a younger sib were balanced carriers of the translocation.

Chromosome 7 in ataxia-telangiectasia

ATAXIA-TELANGIECTASIA, or the Louis-Bar syndrome, is a recessive autosomal disorder clinically characterized by progressive cerebel lar ataxia, oculocutaneous telangiectasia, immunodef ic iency, and a predisposi t ion to the deve lopment o f neoplasia. Most often pat ients die f rom pu lmona ry insufficiency or cancer in the first two decades of life. A T is one of the classical ch romosome breakage syndromes; the cells of the pat ients usually display an increased f requency of spontaneous chromosome breaks and rear rangements . C h r o m o s o m e 14 abnor malities are especially f requent and very often there is a t andem 14q/14q translocation, a so-called Dq + marker c h r o m o s o m e ; , Recent ly we have detected ano the r chromosomal abnormal i ty which might be especially associated with AT: in three subsequent ly studied patients we did not find D q + markers but typical ch romosome 7 abnormal i t ies .

Immune responses in four patients with Bloom syndrome.

Abstract Immunological examinations of four patients with Bloom syndrome, belonging to two families, revealed some disturbances of the immune function. All patients had decreased levels of at least one class of immunoglobulins. The disturbances of the lymphocyte stimulation tests demonstrated a remarkable similarity in the siblings: decreased stimulation in vitro by phytohemagglutinin (PHA) and pokeweed mitogen (PWM), low responses on stimulation by specific antigens, and diminished responder capacity in mixed lymphocyte reaction (MLR) in both patients of family I: normal stimulation in vitro by PHA and PWM, high responses on stimulation by specific antigens, and diminished responder capacity in MLR in both patients of family II. This remarkable difference in expression of the defect between both families could be the expression of a genetic heterogeneity.