Lucien Koulischer

Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in parathyroids, enteropancreatic endocrine tissues, anterior pituitary, and other tissues. The gene for MEN1 has recently been cloned and shown to code for a 610‐amino acid protein of enigmatic function which probably acts as a tumor suppressor. Several mutations causing the MEN1 phenotype have been recently identified. In order to determine the spectrum of MEN1 gene mutations in a sample of 25 Belgian patients, we have systematically screened the 10 exons and adjacent sequences of the MEN1 gene by means of an automatic sequencing protocol. Twelve different mutations were identified including nonsense, frameshift, splicing, and missense mutations. Two of these mutations (D172Y and 357del4) occurred more than once. A missense mutation was also found in a kindred with familial hyperparathyroidism. We observed no significant correlation between the nature or position of mutation and the clinical status. We have also detected 6 intragenic polymorphisms and DNA sequence variants and have analyzed their frequencies in our population. Hum Mutat 13:54–60, 1999.

Chromosomes and human infertility. I. Mitotic and meiotic chromosome studies in 202 consecutive male patients.

Mitotic and meiotic chromoqome studies in 202 consecutive infertile male patients are reported. From our results and those available from the literature, the following conclusions can be drawn. 1. Mitotic chromosome analysis definitely must be included in the laboratory investigations of male infertility; meiotic studies are recommended, especially in patients with a normal somatic karyo‐type and unexplained low sperm counts.

Clinical overlap of Beckwith-Wiedemann, Perlman and Simpson-Golabi-Behmel syndromes: a diagnostic pitfall.

We report on a child who died in the neonatal period. Major external anomalies included foetal overgrowth, macroglossia, and ambiguous genitalia (micropenis and perineoscrotal hypospadias with cryptorchidism). Necropsy showed a large right diaphragmatic hernia, visceromegaly, multicystic kidney dysplasia, Langerhans islet hyperplasia, nephroblastomatosis, multiple adrenal adenomas, and dysplastic testicles. The child illustrates the difficulties of the differential diagnosis of overgrowth syndromes in the neonatal period, and the phenotypic overlap of Beckwith‐Wiedemann, Denys‐Drash, Simpson‐Golabi‐Behmel, Perlman and possibly Meacham‐Winn syndromes. Simpson‐Golabi‐Behmel syndrome was felt to be the most likely diagnosis. If this opinion is correct, genital ambiguity, hydramnios and nephroblastomatosis should be added to the clinical spectrum of Simpson‐Golabi‐Behmel syndrome. Differential diagnosis between the above‐mentioned syndromes is of major importance for accurate genetic counseling, considering the differences in recurrence risk. The present case underlines the need for longterm survey of patients suspected of having Simpson‐Golabi‐Behmel syndrome, who could be at risk for embryonic tumours.

Cytogenetic study of bovine oocytes matured in vitro

Described in the present paper is a cytogenetic study of bovine oocytes matured in vitro. The cumulus-oocyte complexes (COC), punctured from ovaries recovered in a local slaughterhouse, were classified into 3 groups according to follicular diameter 1 to 4mm, 5 to 8mm and 9 to 13 mm. Metaphases available for observation were classified as metaphase I, haploid and diploid metaphase II. High levels of haploid metaphases II (90.6, 86.9 and 94.4 %) among the 3 groups of follicular sizes indicated successful meiotic resumption during in vitro maturation and suggested that cytoplasmic maturation may be responsible for low developmental rate after IVM, IVF and in vitro development (IVD).

Genetic Analysis of Rwandan Patients With Cystic Fibrosis-Like Symptoms: Identification of Novel Cystic Fibrosis Transmembrane Conductance Regulator and Epithelial Sodium Channel Gene Variants.

BACKGROUND The defect in chloride and sodium transport in cystic fibrosis (CF) patients is a consequence of CF transmembrane conductance regulator (CFTR) loss of function and an abnormal interaction between CFTR and the epithelial sodium channel (ENaC). A few patients were described with CF-like symptoms, a single CFTR mutation, and an ENaC mutation. METHODS To study African patients with CF-like symptoms and to relate the disease to gene mutations of both CFTR and ENaC genes, we collected clinical data and DNA samples from 60 African patients with a CF phenotype. The CFTR gene was first analyzed in all patients by denaturing high-performance liquid chromatography followed by direct sequencing; whereas, the sodium channel non-voltage-gated 1 alpha (SCNN1A), sodium channel non-voltage-gated 1 beta (SCNN1B), and sodium channel non-voltage-gated 1 gamma (SCNN1G) subunits of the ENaC gene were analyzed by sequencing in the five patients who carried only one CF mutation. The frequency of all identified ENaC variants was established in a control group of 200 healthy individuals and in the 55 CF-like patients without any CFTR mutation. RESULTS Three CFTR mutants, including one previously undescribed missense mutation (p.A204T), and a 5T/7T variant were identified in five patients. ENaC gene sequencing in these five patients detected the following eight ENaC variants: c.72T>C and p.V573I in SCNN1A; p.V348M, p.G442V, c.1473 + 28C>T, and p.T577T in SCNN1B; and p.S212S and c.1176 + 30G>C in SCNN1G. In the 55 CF-like patients without any CFTR mutation, we identified five of these eight ENaC variants, including the frequent p.G442V polymorphism, but we did not detect the presence of the p.V348M, p.T577T, and c.1176 + 30G>C ENaC variants. Moreover, these last three ENaC variants, p.V348M, p.T577T, and c.1176 + 30G>C, were not found in the control group. CONCLUSION Our data suggest that CF-like syndrome in Africa could be associated with CFTR and ENaC mutations.

Private Multiple Congenital Anomaly Syndromes May Result from Unbalanced Subtle Translocations: T(2q;4p) Explains the Lambotte Syndrome

In 1990, Lambotte syndrome was reported as an apparently autosomal recessive multiple congenital anomaly/mental retardation (MCA/MR) syndrome observed in 4 of 12 sibs from a probably consanguineous mating [Verloes et al., Am J Med Genet 1990; 37:119-123]. Major manifestations included intrauterine growth retardation (IUGR), microcephaly, large soft pinnae, hypertelorism, beaked nose, and extremely severe neurologic impairment, with holoprosencephaly in one instance. After the observation of a further affected child born of one unaffected sister, in situ hybridization analysis and chromosome painting techniques demonstrated a subtle t(2;4)(q37.1; p16.2) translocation in the mother, suggesting a combination of 2q/4p trisomy/monosomy in all of the affected children of the family. Many private sporadic or recurrent MCA/MR syndromes maybe due to similar symmetric translocations, undetectable by conventional banding techniques.

Nosology of lysosomal glycogen storage diseases without in vitro acid maltase deficiency. Delineation of a neonatal form

We describe a boy with an early lethal hypertrophic vacuolar cardiomyopathy of neonatal onset. Abnormal intra- and extralysosomal glycogen storage disease was demonstrated in heart and skeletal muscles. Glycogen content was twice the normal in muscles and over 3-fold the normal in the heart. In this organ, over 50% of the intracellular space was occupied by glycogen and possibly oligosaccharides, as demonstrated by the quantitative morphometric analysis of electron micrographs. The activity of acid alpha-glucosidase was increased in the heart, skeletal muscles, and liver, but was normal in leukocytes. A review of the 11 previously published pedigrees of lysosomal glycogen storage disease with normal in vitro alpha-glucosidase activity allows the delineation of three clinical entities: juvenile and neonatal pseudo-Pompe diseases and partial Pompe disease. Partial Pompe disease, due to the tissue-specific absence of acid alpha-glucosidase, was observed in a single patient. The most common form is the late-onset pseudo-Pompe disease, which is characterized by severe cardiomyopathy and mild myopathy appearing in the second or third decade, prominent arrhythmia with Wolf-Parkinson-White syndrome, and sometimes mental retardation. Patients reported as suffering from Antopol disease probably belong to this group. Dominant inheritance (autosomal or X linked) is likely in most families. The present report appears to be the first one to describe a rapidly fatal neonatal form of lysosomal glycogenosis without acid maltase deficiency. The mode of inheritance of this form is not known. Differential diagosis includes Pompe disease (similar histology) and cardiac phosphorylase b kinase deficiency (similar clinical course). The delineation of neonatal pseudo-Pompe disease makes enzymatic confirmation mandatory in each case suspected of Pompe disease.

The Marshall-smith syndrome

The Marshall-Smith syndrome is characterized by accelerated skeletal maturation, failure to thrive and dysmorphic features. This report describes the 17th published case of this rare disorder.

Brachymorphism-onychodysplasia-dysphalangism syndrome.

Three unrelated children are reported with intrauterine proportionate growth retardation and facial dysmorphism (broad nose, flat malar area, large mouth, pointed chin), microcephaly, hypo/aplasia of the terminal fifth digits, and (sub)normal intelligence. Radiological findings include hypo/aplasia or fusion of the distal phalanges of the fifth finger and toe, brachymesophalangism V, and nail dysplasia or aplasia. One child had cystic adenomatoid disease of the lung. The pattern of anomalies presented by these children closely resembles a syndrome incompletely delineated in 1971 by Senior in six children, which has often been considered to be a mild form of Coffin-Siris syndrome. We suggest that this is an independent entity (BOD syndrome). The aetiology is still unknown. Differential diagnosis and nosological difficulties are discussed.

A new form of skeletal dysplasia with amelogenesis imperfecta and platyspondyly

We report two patients, born of consanguineous parents, affected by a disorder resulting in mild growth retardation. Hallmarks are amelogenesis imperfecta (absence of the enamel cap) associated with brachyolmia‐like anomalies: platyspondyly with short pedicles, narrow intervertebral and interpedicular distances, rectangular‐shaped vertebrae with posterior scalloping and herniation of the nuclei, and broad femoral necks. Inheritance appears to be autosomal recessive.