WT1 splicing alterations in Wilms' tumors.

Hereditary and sporadic forms of tumors are generally related to germ-line and somatic mutations of the same tumor suppressor gene. Unexpectedly, in Wilms' tumor, somatic mutations of the WT1 gene were found only occasionally in sporadic cases, although constitutional mutations of this gene are clearly associated with predisposition. It has been suggested that abnormal splicing may be another mode of somatic WT1 alteration. However, this idea was based on the analysis of a small series of tumors, precluding accurate evaluation of the frequency of such changes. To investigate WT1 changes at the somatic level in more detail, we analyzed the levels of the four isoform transcripts produced by alternative splicing events in a large series of 50 tumors, normal mature kidneys, and fetal kidneys. We characterized splicing alterations in 63% of sporadic Wilms' tumors. Moreover, taking into account the decreased and increased overall levels of WT1 mRNA, the percentage of sporadic tumors with changes in WT1 expression reached 90%. Whether and how these alterations of expression play a role in the tumorigenic process remain to be evaluated.

Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

Constitutional mutations of the WT1 gene, encoding a zinc-finger transcription factor involved in renal and gonadal development, are found in most patients with Denys-Drash syndrome (DDS), or diffuse mesangial sclerosis (DMS) associated with pseudohermaphroditism and/or Wilms tumor (WT). Most mutations in DDS patients lie in exon 8 or exon 9, encoding zinc finger 2 or zinc finger 3, respectively, with a hot spot (R394W) in exon 9. We analyzed a series of 24 patients, 10 with isolated DMS (IDMS), 10 with DDS, and 4 with urogenital abnormalities and/or WT. We report WT1 heterozygous mutations in 16 patients, 4 of whom presented with IDMS. One male and two female IDMS patients with WT1 mutations underwent normal puberty. Two mutations associated with IDMS are different from those described in DDS patients. No WT1 mutations were detected in the six other IDMS patients, suggesting genetic heterogeneity of this disease. We analyzed genotype/phenotype correlations, on the basis of the constitution of a WT1 mutation database of 84 germ-line mutations, to compare the distribution and type of mutations, according to the different symptoms. This demonstrated (1) the association between mutations in exons 8 and 9 and DMS; (2) among patients with DMS, a higher frequency of exon 8 mutations among 46, XY patients with female phenotype than among 46,XY patients with sexual ambiguity or male phenotype; and (3) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions.

Interstitial deletion of the proximal region of the long arm of chromosome 18, del(18q12) a distinct clinical entity? A report of two new cases.

Two unrelated mentally retarded patients were found to have an interstitial deletion of 18q12. They were a 2-year-old, short, macrocephalic and autistic girl, and a 5-year-old boy. Six other liveborn patients with comparable deletion have been so far identified. The common findings are mild dysmorphic features (telecanthus, epicanthal folds, flaring eyebrows, small mouth with thin upper lip), hypotonia, behavioural disorders, mental retardation with speech delay and lack of major malformation.

X-linked hypohidrotic ectodermal dysplasia and t(X;12) in a female.

A female patient with features of hypohidrotic ectodermal dysplasia (HED) was found to be a carrier of a de novo t(X;12) with a breakpoint in Xq13.1. This is the second instance of an X/autosome translocation, with apparently the same X breakpoint, reported in HED.

Multibranched chromosomes in the ICF syndrome: immunodeficiency, centromeric instability, and facial anomalies.

A new patient with the rare ICF syndrome (immunodeficiency, centromeric heterochromatin instability, and facial anomalies) is reported. The six patients previously reported in the literature are reviewed. The main clinical and cytogenetic characteristics of the syndrome are discussed.

6q1 monosomy: a distinctive syndrome.

A female infant with a de novo del 6q14q16.2 and five other patients with del 6q1 reported in the literature allow the delineation of a characteristic syndrome, the main features of which are: severe mental retardation, a round face with full cheeks, upslanting palpebral fissures, a short neck, umbilical hernia, malpositioned feet with syndactyly II-III, and typical dermatoglyphics with an excess of whorls and clinodactyly of the Vth finger.

[Interstitial deletion in the long arm of chromosome 7]. / Délétion interstitielle du bras long du chromosome 7.

An interstitial deletion of 7q (q31.2-q32.3) is reported. Main features of this boy included facial dysmorphy, psychomotor retardation and absence of language.

Maternal origin of a de novo balanced t(21q21q) identified by ets-2 polymorphism.

Molecular investigations were done in a woman with a de novo balanced t(21q21q) discovered because of the birth of a trisomic 21 baby. Polymorphisms detected with probe ets-2 after Msp I digestion showed that both chromosomes 21 involved in the rearrangement were of maternal origin. The most likely hypothesis is that of a disomic 21 oocyte fertilized by a nullisomic 21 sperm.

Low dose rate ionizing radiation induces increased growth capacities of d-deletion retinoblastoma skin fibroblasts.

Skin fibroblasts from normal children and three children with a 13q deletion retinoblastoma (Rb) were exposed to cumulative low doses of gamma rays. The typical response of normal donors was a reduction in the lifespan of irradiated fibroblasts, the precocity of the decline being inversely related to the dose received. In contrast, the lifespan of one Rb cell line (Rb1) was prolonged; irradiated cells with an increased growth potential showed a higher number of cells at confluency and more cells were entering DNA synthesis phase than in non-irradiated cells. Another Rb cell line (Rb2) demonstrated a normal lifespan following irradiation but foci were observed in irradiated cultures. Cytogenetic analysis revealed no selection of abnormal clones in these cell populations. The third Rb line examined (Rb3) responded like a normal cell line. We suggest that irradiated skin fibroblasts derived from some patients with Rb are in certain cases able to express abnormal growth capacities which may be one of the manifestations of the high susceptibility of the individual's stromal cells to carcinogenic agents.

[Trisomy 7. Internal intersexuality (masculine uterus) and severe abnormality of the anterior chamber of the eye]. / Trisomie 7. Intersexualité interne (homme à utérus) et anomalie grave du segment antérieur de l'ceil.

Full trisomy 7, without evidence of mosaicism, was observed in a newborn male having survived three months. Apart from facial dysmorphism, he had unusual malformations: severe anomalies of the splenomesenteric vascular system, persistence of Müllerian ducts (uterus masculinus), major anomalies of the anterior chamber of eye.

[Stimulation by ionizing radiation of the proliferative potential of fibroblasts from children with del(13q14) retinoblastoma]. / Stimulation par des radiations ionisantes du potentiel prolifératif de fibroblastes d'enfants atteints de del (13q14) rétinoblastome.

Skin fibroblasts from normal children and two children with a 13q14 deletion retinoblastoma (Rb) were submitted to fractionated doses of gamma radiations. Irradiation reduced the population doublings in normal fibroblasts and the decline was inversely related to the dose. An increase in population doublings was obtained with one of the Rb cell lines. Foci appeared in the irradiated culture of the other Rb donor. It is suggested that fibroblasts from patients with Rb are able to express some phenotypical properties of transformed cells, perhaps related to factors rendering them more susceptible to carcinogens.

[Retinoblastoma and interstitial deletion of 13q (author's transl)]. / Rétinoblastome et délétion intercalaire du chromosome 13.

The authors report an observation of retinoblastoma associated with partial monosomy 13q [46, XY, t (2;10) (q21;q24), inv(9), del(13)(q13q213)] and discuss the origin of this exceptional childhood tumor by gene mutation of chromosome rearrangement.

[Increased sister-chromatid exchanges in fibroblasts from a del(13)-retinoblastoma patient (author's transl)]. / Augmentation des échanges de chromatides dans les fibroblastes d'un enfant atteint de del(13)-rétinoblastome.

Sister-chromatid exchanges were studied in fibroblasts from a child with del(13)-retinoblastoma. The skin biopsy was performed before the clinical onset of the tumor. The observed frequency of SCE, 19.65 per cell, was significantly increased as compared to that of a normal control, 14.68 per cell (t = 3.57, p < 0.001).