Clinical and molecular studies in two families with Fraser syndrome: a new FRAS1 gene mutation, prenatal ultrasound findings and implications for genetic counselling.

Fraser syndrome is a rare autosomal recessive genetic disorder characterized by cryptophthalmus, variable expression of cutaneous syndactyly of fingers and toes, genital ambiguity and renal agenesis/dysgenesis. We present here molecular and clinical findings of four fetuses with FS from two families. Molecular genetic studies in the two families revealed mutations in FRAS1 gene allowing better genetic counselling and subsequent prenatal diagnosis in one of the two families. In family one, a nonsense mutation (c.3730C>T, p.R1244X) previously described in a Polish patient was found. In family two a novel nonsense mutation previously not known was detected (c.370C>T, p.R124X). PGD is planned for family 1.

Two cases of 9p deletion syndrome and a case of partial trisomy 8 and partial monosomy 9p.

Two cases of 9p deletion syndrome anda case of partial trisomy 8 and partial monosomy 9p: We report 3 girls with mental retardation (MR), distinctive malformations of the skull and facial region, including trigonocephaly, small palpebral fissures, and unusually midface hypoplasia, congenital heart defects which are characteristics of monosomy 9p. We performed GTG banding and fluorescence in situ hybridization (FISH) method in all cases. By using cytogenetic methods, three terminal deletions of the short arm of the chromosome 9 were identified and in 2 patients the deletion was de novo, and one patient inherited deletion. FISH analysis showed 46,XX,del(9)(pter-p22).ish del(9)(pter-->p22) in two patients and 46,XX,-9,+der(9)t(8;9)(q24.3;p22)pat.ish der(9)t(8;9)(q24.3;p22)pat (305J7-T7x1,wcp8+,wcp9+) in the third patient. This report compares the symptoms and features of our patients with previously reported patients with a 9p deletion syndrome.

Acute complete splenic infarction in a patient with Hirschsprung's disease and literature review of complete splenic infarction.

Here we report a case of Hirschsprung's disease presenting with acute complete splenic infarction due to thrombus in the splenic vena. MTHFR C677T (methylenetetrahydrofolate) gene homozygote mutation was a risk factor for thrombosis. According to our knowledge, this is the first report for a Hirschsprung's disease patient with acute complete splenic infarct due to isolated splenic vein thrombosis accompanied by MTHFR C677T gene homozygote mutation.

Fusion of a novel gene, RCC17, to the TFE3 gene in t(X;17)(p11.2;q25.3)-bearing papillary renal cell carcinomas.

A subset of childhood and young adult renal cell carcinomas displays a recurrent translocation t(X;17)(p11;q25) as the sole cytogenetic abnormality. In two young girls, we demonstrate that this translocation results in the fusion of a novel gene, designated RCC17, at chromosome 17q25, to the transcription factor TFE3 located on the Xp11 chromosomal region. In both cases, the t(X;17) fuses the NH(2)-terminal region of RCC17 to the COOH-terminal part of TFE3 including the basic helix-loop-helix DNA-binding domain and the leucine zipper dimerization domain. The reciprocal fusion transcript TFE3/RCC17 is also expressed. RCC17 encodes a putative protein of 553 amino acids. It is ubiquitously expressed in normal adult tissues. No significant similarity was found with other fusion partners of TFE3 or with any relevant functional protein domains, precluding informed speculation about the normal function of this gene.

Phenotype-genotype correlation in familial Mediterranean fever: evidence for an association between Met694Val and amyloidosis.

Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by recurrent attacks of inflammation of serosal membranes. Amyloidosis is the most severe complication of the disease. The aim of this study was to investigate the genotype-phenotype correlation and specifically the association between amyloidosis and the four common mutations in exon 10 of the gene causing FMF (MEFV) in a total of 83 FMF families from three ethnic groups: North African Jews, Armenians and Turks. A significant association was found between amyloidosis and the specific mutation at the MEFV gene: Met694Val (RR = 1.41, P = 0.02). Amyloidosis was present in 18 out of 87 homozygous FMF patients (20.7%) and in only two out of the 41 compound heterozygous FMF patients (4.9%). No patients carrying other mutations had amyloidosis. There was no significant association between the various mutations and the type or severity of the FMF symptoms. This finding underscores the importance of performing molecular studies on all suspect FMF patients. In addition to providing accurate diagnosis, these tests allow identification of presymptomatic genetically affected individuals, detection of carriers and assessment of the risk for amyloidosis in later life.

Syndrome of congenital cutis laxa with ligamentous laxity and delayed development: report of a brother and sister from Turkey.

Congenital cutis laxa with ligamentous laxity and delayed development has recently been defined as a distinct entity of autosomal recessive inheritance. Here we report on 2 new cases of this syndrome. With severe manifestations in the male, X-linked dominant inheritance is discussed. Results of ultrastructural studies of skin and biochemical studies are reported.

Therapy-related refractory anemia with ringed sideroblasts in chronic lymphocytic leukemia. involvement of 3q21 region.

Therapy-related myelodysplastic syndrome/acute myelogenous leukemia (t-MDS/AML) is extremely rare in chronic lymphocytic leukemia (CLL) despite extensive use of alkylating agents. We present a case of heavily treated CLL with resultant therapy-related refractory anemia with ringed sideroblasts (RARS). A complex cytogenetic abnormality including involvement of 3q21 was detected and to our knowledge, is the first report of a RARS case with a 3q21 abnormality.

Chromosomal findings in cultured melanocytes from a giant congenital nevus.

A giant congenital pigmented nevus was observed in a newborn male. A melanocyte culture was established from nevus fragments removed at age 6 days. Analysis of 136 metaphases harvested from the primary culture showed 74% normal mitoses, 22% polyploids, and 4% mitoses with chromosome rearrangements involving in particular 1p, 12q, and 19p. In addition, the culture showed a high level of HLA-DR expression. Although histology showed no sign of malignancy, these findings may illustrate one of the first events which might eventually progress toward malignancy.

del(17)(q25) in a patient with hairy cell leukemia: a new clonal chromosome abnormality.

Clonal chromosomal aberrations are reported in about 25% of the patients with hairy cell leukemia (HCL). No consistent cytogenetic abnormality has been described in HCL; most of the chromosomal changes found have been deletions and inversions, with the rare occurrence of translocations. While most of the chromosomal aberrations in HCL are common to the ones found in B cell chronic lymphocytic leukemia and other B cell lymphoproliferative disorders, there are also certain chromosomal changes that are not found in other B cell lymphoproliferative disorders. We present here a 63-year-old male patient with hairy cell leukemia with the clonal del(17)(q25), which has not previously been reported in HCL.

Multiple clonal chromosome aberrations in a case of childhood focal nodular hyperplasia of the liver.

A case of focal nodular hyperplasia is described that was accompanied by intense reactive stromal changes giving rise to a pseudosarcomatous appearance. Cytogenetic study revealed complex karyotypic abnormalities including five partially identifiable clonal aberrations and one marker chromosome. The composite karyotype was interpreted as: 45-46,XY,add(4)(q21-25)[24], add(11)(p14)[24], add (19)(p13)[15], der(20)t(1;20)(q25;p12)[31], add(21) (q22)[13],-22[3], +mar[2][cp31]. In addition, quadriradial or complex figures, telomeric associations tas, unidentified ring chromosomes, chromosome breaks, and markers were seen in some cells. Such cytogenetic findings, although suggestive of malignancy, could most likely be related to a nonneoplastic condition, i.e., the unusual florid reactive changes associated with this focal nodular hyperplasia.

Clinical and cytogenetic studies of two cases of Klinefelter syndrome with hereditary retinoblastoma and rhabdomyosarcoma.

Two children with Klinefelter syndrome (KS), one associated with bilateral hereditary retinoblastoma (RB) and the other with rhabdomyosarcoma (RMS) are reported. Both were boys and chromosomally mosaic for KS. The hereditary retinoblastoma case yielded 46,XY,del(13)(q12q14.2)/47, XXY(c),del(13)(q12q14.2) in PHA-stimulated lymphocytes. The rhabdomyosarcoma case yielded 46,XY/ 47,XXY(c) in peripheral blood cells whereas tumor revealed trisomy 8, trisomy 7, and t(7;13)(q33;q32) in addition to 46,XY/47,XXyc mosaicism.

Variable clinical expression of Holt-Oram syndrome in three generations.

Holt-Oram syndrome is a distinct autosomal dominant entity presenting with upper limb defects and cardiac abnormality. No correlation between the severity of the heart and the limb defects has been established. Here we report variable clinical expression of Holt-Oram syndrome in three generations. The grandfather presented with typical upper limb defects: phocomelia of arms with three digits on each hand, congenital heart defect and narrow shoulders. His son manifested cardiac conduction disturbance with no congenital heart or skeletal defect. The granddaughter showed ventricular septal defect and moderate radial deviations of both hands with no obvious hypoplasia of the extremities. Clinical data of the presented family suggests lack of penetrance with respect to skeletal and structural cardiac abnormalities in the Holt-Oram syndrome.

[A comparative study of the karyotypes of fetuses of spontaneous early abortions obtained by direct method and by long-term culture]. / Etude comparée des caryotypes de produits d'avortements spontanés précoces obtenus par une méthode directe et par culture à long terme.

The direct method of chromosomal preparations on chorionic villi biopsies has been applied to the cytogenetic study of 34 early spontaneous abortion products. These results were compared with those obtained through long term cultures performed simultaneously from the same samples. The success rate obtained through the direct method (86.2%) is superior to that of the long term culture (76.4%). However, the combined use of both techniques further improves the success rate (94.1%) and the reliability of the results. Among the 32 informative cases, 15 chromosomal aberrations (46.8%) have been detected. These data demonstrate the value of the direct method of karyotyping chorionic villi from spontaneous abortion products. However, considering the specific advantages of either method respectively, the authors recommend that both be used simultaneously for optimal diagnostic efficiency.

Impact of Fluorescence in Situ Hybridization in the Detection of Cryptic Fusion Transcript PML/RARA and A Complex t(5;15;17) in a Case of Acute Promyelocytic Leukemia.

Genetic aspects of a 28 year-old female patient with typical morphological and clinical features of acute promyelocytic leukemia is presented. Pml/rara fusion transcript and a complex translocation involving chromosomes 5, 15 and 17 were detected by fluorescence in situ hybridization (FISH) technique which was applied as in adjunct to conventional cytogenetics. The patient deceased soon in spite of the immediate ATRA and cytostatic therapy.

Association of syndactyly, ectodermal dysplasia, and cleft lip and palate: report of two sibs from Turkey.

Two Turkish sibs, products of a second cousin marriage, with tetramelic syndactyly, ectodermal dysplasia, cleft lip and palate, renal anomalies, and mental retardation are reported. Similarities between these two brothers and previously reported cases and their mode of transmission are discussed.

Severe intrauterine growth retardation, aged facial appearance, and congenital heart disease in a newborn with Johanson-Blizzard syndrome.

We report a female newborn with Johanson-Blizzard syndrome associated with extreme intrauterine growth retardation, aged facial appearance, and atrial septal defect. Other features are microcephaly, prominent veins over the scalp, alopecia over the vertex, wide-open fontanelle, high forehead, antimongoloid slant, edematous eyelids, the absence of eyebrows and eyelashes, beaked nose with alae nasi, low-set ears, thin lips, and micrognathia. Investigations revealed deafness and congenital hypothyroidism. We believe that this association of severe intrauterine growth retardation and congenital heart disease represents the components of this syndrome.

Familial trisomy 11p resulting from a balanced paternal translocation: 3 new cases including first trimester diagnosis.

Three related new cases with almost complete trisomy 11p due to paternal balanced translocation 46, XY, t(7; 11) (q36.1; p11.1) are reported. The proband (Case 1) was a malformed stillborn with exomphalos, case 2 was diagnosed in the first trimester by direct chromosome preparations from chorionic villi, and confirmed on fetal products after termination of pregnancy. Case 3, a cousin to cases 1 and 2, was a 29-weeks-old fetus with omphalocele discovered at ultrasound. Literature reports of trisomy 11p are reviewed with regard to those new cases, and the possible relationship of this chromosome imbalance with the Beckwith-Wiedemann Syndrome is discussed.

The acrocallosal syndrome in a Turkish boy.

A 6 month old Turkish boy with the acrocallosal syndrome is reported. The patient, born to consanguineous, healthy parents, presented with macrocephaly, a prominent forehead, hypertelorism, polydactyly of the fingers and toes, severe motor and mental retardation, hypotonia, and absence of the corpus callosum. The mode of inheritance is discussed and our case is compared with previously reported cases of the syndrome.