Leucodystrophy and oculocutaneous albinism in a child with an 11q14 deletion.

We report a patient with an undetermined leucodystrophy associated with type 1A oculocutaneous albinism (OCA). Type 1 OCA results from recessive mutations in the tyrosinase gene (TYR) located in 11q14.3. The patient was found by FISH to carry a deletion of at least the first exon of the TYR gene on one chromosome and a (TG) deletion at codon 244/245 on the second chromosome. The existence of the microdeletion suggested that a gene responsible for leucodystrophy was located in the vicinity of the TYR gene. A combination of a test of hemizygosity and contig mapping studies allowed us to map the gene within a 0.6 cM region flanked by microsatellite markers D11S1780 and D11S931.

A novel immunodeficient mouse model--RAG2 x common cytokine receptor gamma chain double mutants--requiring exogenous cytokine administration for human hematopoietic stem cell engraftment.

Gene transduction into immature human hematopoietic cells collected from umbilical cord blood, bone marrow, or mobilized peripheral blood cells could be useful for the treatment of genetic and acquired disorders of the hematopoietic system. Immunodeficient mouse models have been used frequently as recipients to assay the growth and differentiation of human hematopoietic stem/progenitor cells. Indeed, high levels of human cell engraftment were first reported in human/murine chimeras using NOD/SCID mice, which now are considered as the standard for these types of experiments. However, NOD/SCID mice have some clear disadvantages (including spontaneous tumor formation) that limit their general use. We have developed a new immunodeficient mouse model by combining recombinase activating gene-2 (RAG2) and common cytokine receptor gamma chain (gamma c) mutations. The RAG2-/-/gamma c- double mutant mice are completely alymphoid (T-, B-, NK-), show no spontaneous tumor formation, and exhibit normal hematopoietic parameters. Interestingly, human cord blood cell engraftment in RAG2-/-/gamma c- mice was greatly enhanced by the exogenous administration of human cytokines interleukin-(IL-3) granulocyte-macrophage colony-stimulating factor, (GM-CSF), and erythropoietin in contrast to the NOD/SCID model. This unique feature of the RAG2-/-/gamma c- mouse model should be particularly well suited for assessing the role of different cytokines in human lymphopoiesis and stem/progenitor cell function in vivo.

Confirmation of assignment of a locus for Rubinstein-Taybi syndrome gene to 16p13.3.

A two month-old girl was diagnosed as a case of Rubinstein-Taybi syndrome (RTS) on typical facial dysmorphism, broad and duplicated distal phalanges of thumbs and halluces, growth retardation and psychomotor development delay. Chromosome analysis demonstrated a de novo pericentric inversion of one chromosome 16: 46,XX,inv(16)(p13.3;q13). This association confirms assignment of a locus for RTS gene to 16p13.3, as two others translocations involving the same breakpoint have already been reported.

Submicroscopic deletion of chromosome 16p13.3 in patients with Rubinstein-Taybi syndrome.

The Rubinstein-Taybi syndrome (RTS) is a well-defined entity characterized by growth and mental retardation, broad thumbs and halluces, and typical face. The RTS locus was assigned to 16p13.3, and interstitial submicroscopic deletions of this region (RT1 cosmid, D16S237) were initially identified in 25% of RTS patients. The gene for the human CREB binding protein, the transcriptional coactivator CBP, is included in the RT1 cosmid, and mutations in CBP have recently been identified in nondeleted RTS patients. We investigated 30 French patients with RTS. Among these patients, 3 had the RT1 microdeletion (frequency 10%). There is no obvious phenotypic difference between the patients with and without the RT1 deletion. The RT1 probe appears useful for confirmation of the diagnosis but is of little interest as a screening tool. By pooling data including the previous series and our current series, the cumulative frequency of the 16p13.3 microdeletion is 11.9% (19 in 159). This frequency of approximately 12% deleted patients appears more accurate than the 25% previously reported. Molecular investigations of CBP are in process in our series to clarify the cause of RTS.

Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH.

Autism is a rare neurodevelopmental disorder with a strong genetic component. Co-occurrence of autism and chromosomal abnormalities is useful to localize candidate regions that may include gene(s) implicated in autism determinism. Several candidate chromosomal regions are known, but association of chromosome 22 abnormalities with autism is unusual. We report a child with autistic syndrome and a de novo 22q13.3 cryptic deletion detected by FISH. Previously described cases with 22q13.3 deletions shared characteristic developmental and speech delay, but autism was not specifically reported. This case emphasizes a new candidate region that may bear a gene involved in autism etiopathogenesis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:839-844, 2000.

Chromosome analysis of adenomatous polyps of the colon: possible existence of two differently evolving cytogenetic groups.

A chromosomal study of 42 colonic adenomatous polyps was performed using a technique of direct chromosome analysis derived from the prenatal procedure for diagnosing chromosomal alterations from chorionic villi sampling. Abnormal karyotypes were found in 22 cases. Trisomy 7, the most frequently found alteration, was found in 13 cases, followed by trisomy 13 (nine cases). Monosomy 18 was observed in two cases; in one of these, that of a polyp which had degenerated into an intra-mucosal adenocarcinoma, it was associated with 17p monosomy. Interestingly, these two types of alterations (trisomy 7 versus 18 and 17p monosomy) were not found together in the same lesion. This suggests that there could be two distinct chromosomal behaviors which might be related to the two cytogenetic groups described for colorectal adenocarcinoma. However, the respective frequencies of such cytogenetic groups varied inversely between adenomas and adenocarcinomas, thus suggesting that they evolve differently.

Trisomy 22 with thyroid isthmus agenesis and absent gall bladder.

This manuscript reports a fetus of 24 weeks gestation, detected on echography to have congenital anomalies: intra-uterine growth retardation, facial dysmorphism, ventricular septal defect with aortic displacement and 8-mm nuchal skinfold thickness. Karyotype was performed. Post termination of pregnancy autopsy showed additionnal internal organ anomalies included: absent gall bladder and thyroid isthmus agenesis. To our knowledge, these anomalies have never been described in trisomic 22 fetuses. This case suggests that chromosome 22 could play a role in thyroid development.

Abdominal lymphatic dysplasia and 22q11 microdeletion.

We report the case of a child with 22q11 microdeletion who presented with abdominal lymphatic dysplasia resulting in exsudative enteropathy. This primitive and localized lymphatic malformation is consistent with the vascular theory in the velocardiofacial syndrome.

[Prenatal diagnosis of nuchal edemas and cystic hygromas of the neck. 49 cases]. / Diagnostic prénatal des oedèmes de la nuque et des hygromas kystiques du cou. A propos de 49 cas.

OBJECTIVES: Determine the pathogenesis of fetal nuchal oedema and cystic hygromas of the neck and establish prenatal prognosis factors. METHODS: Retrospective study of 49 cases including 35 early diagnoses (10 to 14 weeks gestation) and 14 late diagnosis (after 15 weeks). Chorial villosity biopsy was performed for fetal karyotype. RESULTS: The global rate of genetic or chromosomic abnormalities in the fetuses was 47%. The fetuses with nuchal associated with other echographic anomalies had a high risk of chromosomic aberrations (80%). Fetuses with nuchal oedema alone during the first trimester had a higher risk of trisomy 21 proportionally with the age of the mother and paradoxically no trisomy 21 was found in women under 30 years of age. When early nuchal oedema regressed spontaneously in an euploid fetus, echographic surveillance can be proposed to detect possible polymalformation syndromes discovered late. Cystic hygromas of the neck were diagnosed from 15 weeks gestation and were always pathologic. CONCLUSION: Interpreting nuchal images in the fetus must take into account the echographic term at discovery and its isolated or associated nature. Further studies are needed to determine indications for chorial villosity biopsy in mothers under 30 with a fetus with isolated nuchal oedema which regresses spontaneously during the first trimester.

[Williams syndrome (microdeletion 7q11.23), model of behavioral phenotype]. / Le syndrome de Williams (microdélétion 7q11.23), modèle de phénotype comportemental.

A specific behavioral phenotype is recognized in some genetic entities, particularly in microdeletion syndromes secondary to cytogenetically undetectable chromosomal deletions. Williams syndrome (WS) is a developmental disorder displaying dysmorphic signs, heart malformations and behavioral phenotype associated, in most cases, with a deletion of chromosome 7q11.23. We described physical and neuro-psychological assessment of nine cases of SW. Molecular studies were performed using Southern blot analyses or FISH, and identified a 7q11.23 deletion in all cases. Behavioral phenotype of WS is characterized by hyperactivity, engaging and jovial personality, hypersensitivity in hearing, and some elements of speech may be enhanced. Moderate mental retardation is frequently present. Previously reported studies have revealed specific cognitive deficits including deficits in language development and in long term memory, and poor visual-motor integration. Two genes, LIMK1 and STX1A, have been supposed to be implicated in determinism of WS behavioral phenotype. A specific behavioral phenotype is also demonstrated in others microdeletion syndromes, focusing attention on some chromosomal regions supposed to contain candidate genes involved in cognitive and behavioral traits.

[Interphase FISH analysis of frozen or fixed tissues for the detection of t(11;14) (q13;q32) in mantle cell lymphoma]. / Analyse par FISH interphasique de tissus congelés ou fixés pour la détection de la t(11;14)(q13;q32) dans les lymphomes du manteau.

Cytogenetic analyses have revealed that mantle cell lymphomas (MCL) are closely associated with the t(11;14)(q13;q32). This translocation juxtaposes the immunoglobulin heavy chain gene (IGH) sequences with the BCL-1 locus, leading to up-regulation of the CCND1 gene and consequently to an overexpression of cyclin D1 protein. We studied 27 MCL with characteristic morphological and immunological (CD5+, CD10-, CD20+, CD23-) features and 2 controls (reactionnal lymphadenitis) to evaluate the feasibility and the interest of FISH analysis on interphase cells from frozen or paraffin-embedded tissues. Sections (CC) and touch preparations (EC) of frozen tissues and sections of paraffin-embedded tissues (CF) were successfully hybridized with the Vysis LSI IgH/CCND1 dual color dual fusion translocation probe. The touch preparations presented a lower cellularity than sections, therefore allowing an easier analysis. Hybridization spots intensities were found stronger in CC and EC than in CF. The percentages of t(11;14) positive cells were similar in CC, EC and CF from a same patient. The percentage of non hybridized cells, analogous in CC and EC, was higher in CF. However, the CF were directly analysed on microscope without the need of any numerical picture treatment. The t(11;14) was detected in all the cases (27/27) and positive cells percentages were always higher than the probe cut-off (5%). The FISH analysis on interphase cells appears a performing and rapid technique to detect t(11;14) in MCL on both frozen and paraffin-embedded tissue, thus extending its practical and diagnostic use.

[ORL and speech aspects in DiGeorge syndrome]. / Aspects ORL et phoniatrique du syndrome de DiGeorge.

The DiGeorge syndrome presents clinically as a combination of a congenital cardiopathy with immune deficiency and predisposition to infections, signs of hypoparathyroidis with severe hypocalcaemia in the neonatal period, and facial dysmorphism. New techniques in molecular cytogenetics (in-situ fluorescent hybridisation--FISH) have provided evidence of microdeletion of chromosome 22q11 in most cases of the DiGeorge syndrome. There is an important overlap between this syndrome, the velo-cardio-facial syndrome, and certain other cono-truncal cardiac anomalies which are linked with the same microdeletion syndrome. Basing their observation on a case of the partial syndrome, the authors emphasise the otological and maxillo-facial aspects, and especially the effects on speech and language. It is essential to carry out repeated audiometric testing to exclude an audiometric cause for the speech and language problems. At the same time, thorough speech and language assessment is necessary to establish the degree of velar insufficiency (rhinolalia). These will guide the speech therapy rehabilitation, and quantify the psycho-affective component. Surgery on the palate may be a possibility, depending on the progress in speech and language improvement.

Mosaic maternal uniparental isodisomy for chromosome 7q21-qter.

Uniparental disomy (UPD) for several human chromosomes is associated with clinical abnormalities. We report the case of a 2-year-old boy with severe intrauterine and post-natal growth retardation (IUGR/PNGR) and highly variable sweat chloride concentrations. The patient was identified as heterozygous for the F508del mutation of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Unexpectedly, the signal corresponding to the maternally inherited F508del allele appeared much more intense than the paternally derived wild allele. Molecular analysis including polymorphic marker studies, microsatellites and single-nucleotide polymorphisms subsequently showed that the boy was a carrier of a de novo mosaic maternal isodisomy of a chromosome 7 segment while there was a biparental inheritance of the rest of the chromosome. This is the first report of a mosaic partial UPD7. The matUPD7 segment at 7q21-qter extends for 72.7 Mb. The karyotype (550 bands) of our patient was normal, and fluorescence in situ hybridization with probes mapping around the CFTR gene allowed us to rule out a partial duplication. The detection of this chromosomal rearrangement confirms the hypothesis that the 7q31-qter segment is a candidate for the localization of human imprinted genes involved in the control of IUGR and PNGR. It also emphasizes the importance of searching for UPD7 in severe, isolated and unexplained IUGR and PNGR.

Refined localisation of the voltage-gated chloride channel, CLCN3, to 4q33.

Mutations in ion channels have been shown to be responsible for a variety of neurological and muscular diseases. The voltage-gated chloride channel CLCN3 was recently mapped to chromosomal region 4q32. We are analysing a young female patient with Wolf-Hirschhorn syndrome and chorea associated with an inversion-deletion of chromosome 4 [46XX,inv(4)del(4)(qter-->q33::p15.32-->q33]. Considering that chorea in this patient might be due to the disruption of a gene at either of the 4p15.32 or 4q33 breakpoints, CLCN3 was considered as a candidate gene. We showed by FISH analysis with a CLCN3 YAC that the gene was not broken by the inv-del event, and was therefore an unlikely candidate. Using high resolution techniques, we refined the localisation of CLCN3 to 4q33.

Risks of transabdominal chorionic villus sampling before the 12th week of amenorrhea.

The authors report on a series of 210 chorion villus sampling diagnoses made with a needle by the transabdominal route. The rate of fetal loss was 4.2 per cent. Placental localization was important: fetal losses were 8 per cent when the placenta was strictly posterior (transamniotic route), whereas it was only 1.6 per cent when it was not posterior. Moreover, all fetal losses occurred (apart from one at 12.5 weeks of amenorrhea) before the 12th week of amenorrhea. The authors suggest that choriocentesis by the transabdominal route should not be performed before the 12th week of amenorrhea, and that the amniotic membrane should not be disturbed before the 13th week of amenorrhea.

First trimester diagnosis of fetal nuchal edema. Report of 29 cases.

During a 4-year period, 29 fetal nuchal edemas were observed, associated with other ultrasound abnormalities in 7 cases (24%). Fetal karyotypes were abnormal in 10 cases: 6 trisomy 21; 3 trisomy 18, and 1 Turner's syndrome. Isolated fetal nuchal edema was associated with aneuploidy in 4 cases: 3 trisomy 21, and 1 trisomy 18. The average age of the women carrying a fetus with nuchal edema associated or not with a trisomy 21 was 38.3 and 30.8 years, respectively. These results are similar to those found in the literature. It would appear that maternal age is a better marker in trisomy 21 screening than isolated fetal nuchal edema.