Effect of age, gender and calciotropic hormones on the relationship between vitamin D receptor gene polymorphisms and bone mineral density.

BACKGROUND/OBJECTIVES: Hypovitaminosis D is a major public health problem worldwide and unexpectedly more so in sunny countries. Vitamin D receptor (VDR) gene is associated with inter-individual variance in bone mineral density (BMD). Studies assessing the effect of VDR gene polymorphisms on BMD yielded conflicting results. The aim of this study was to assess the relationship between VDR polymorphisms and BMD in the Lebanese, across age groups and genders and to assess the effect of PTH and lean mass and vitamin D levels on such relationship. SUBJECTS/METHODS: In total, 203 subjects aged 65-85 years and 336 children aged 10-17 years. Polymorphisms in the VDR gene were assessed with the restriction enzymes BsmI, TaqI and ApaI. Bone mineral content, BMD and lean mass were measured using Dual-Energy X-ray Absorptiometry (DXA). The dominant hand strength was measured in children. RESULTS: Heterozygote genotype was the most frequent in both age groups. There was no difference in the frequency distribution of genotypes between the young and the elderly. No relationship between VDR genotypes and lean mass was found in either age group. Heterozygote boys had the lowest parathormone (PTH) and heterozygote elderly women had the highest BMD at the spine and forearm. CONCLUSIONS: In the Lebanese, the relationship between VDR polymorphisms and BMD differs by age. Survival does not seem to differ by VDR genotype. However, further studies are needed to assess the effect of VDR gene polymorphisms on mortality per se and time to mortality, not evaluated in this study.

Leydig cell hypoplasia due to inactivation of luteinizing hormone receptor by a novel homozygous nonsense truncation mutation in the seventh transmembrane domain.

Inactivating mutations in the LH receptor are the predominant cause for male pseudohermaphroditism in subjects with Leydig cell hypoplasia (LCH). The severity of the mutations, correlates with residual receptor activities. Here, we detail the clinical presentation of one subject with complete male pseudohermaphroditism and LCH. We identify within the proband and her similarly afflicted sibling a homozygous T to G transversion at nucleotide 1836 in exon 11 of the LH/CGR gene. This causes conversion of a tyrosine codon into a stop codon at codon 612 in the seventh transmembrane domain, resulting in a truncated receptor that lacks a cytoplasmic tail. In vitro, in contrast to cells expressing a normal LHR, cells transfected with the mutant cDNA exhibit neither surface binding of radiolabeled hCG nor cAMP generation. In vitro expression under the control of the LHR signal peptide of either a wild type or mutant LHR-GFP fusion protein shows no differences in receptor cellular localization. In conclusion, the in vitro studies suggest that residues in the seventh transmembrane domain and cytoplasmic tail are important for receptor binding and activation without playing a major role in receptor cellular trafficking.

Ring chromosome 18q and jumping translocation 18p in an adult male with hypergonadotrophic hypogonadism.

Constitutional jumping translocations (JT) are rare, especially in phenotypically normal individuals. We report on an adult male with partial hypogonadism as the sole phenotypic abnormality with an unusual chromosome abnormality. In this patient, centric fission of chromosome 18 lead to formation of a ring 18q chromosome, while 18p formed a JT through centromere-telomere fusion with chromosome 8q (66%) or 20q (13%). In 21% of cells, the 18p fragment was missing. Fluorescent in situ hybridization revealed the presence of interstitial telomeres at the junction site of the fusion and unequal distribution of the alphoid sequences through the centric fission, leaving a small, yet functional centromere within the ring. We discuss the phenotype of the patient in light of this unusual karyotype.

A new patient with pure trisomy 4p resulting from isochromosome formation and whole arm translocation.

Short arm isochromosome formation with translocation of the entire long arm of the same chromosome is an unusual constitutional abnormality that has been observed, to our knowledge, in 18 cases. Only one of these previously reported cases involved chromosome 4, resulting in pure trisomy 4p. Pure trisomy 4p has been reported in a number of cases, the majority of them due to familial chromosome rearrangements, and is associated with a distinct pattern of abnormal findings. We report here a second case of a de novo chromosome 4 whole arm translocation with short-arm isochromosome formation, which we have delineated further by FISH studies.

Homologous telomere association of 19q in a female with premature ovarian failure.

Premature ovarian failure (POF) may be due to a variety of genetic mechanisms. We report here, for the first time, telomere association of the long arms of chromosome 19, identified at low frequency (1%) in the peripheral blood cultures of a 30-year-old female with POF. Repeat cultures identified, in addition, the presence of 16q and 22q associations at a lower frequency (0.5%). These consistent observations are suggestive of a non-random event. Their association with POF may just be coincidental or may hypothetically explain it by an abnormal mechanism of chromosome separation, a constitutional telomere anomaly or an unidentified chromosome instability disorder.

Attitudes towards prenatal diagnosis and termination of pregnancy among health professionals in Lebanon.

OBJECTIVES: To assess the attitudes of health professionals in Lebanon towards prenatal diagnosis and termination of pregnancy, for a series of genetic, non-genetic and non-medical conditions. METHODS: A total of 158 questionnaires were sent to geneticists, family doctors, pediatricians and obstetricians/gynecologists, that included information on sociodemographic variables and sets of questions and case scenarios, to which participants were asked to reply anonymously. RESULTS: Responses from the 75 participants revealed that the type of specialty did not significantly influence their attitude. However, acceptance of termination of pregnancy was influenced by gender, age, marital status, religion and its importance in their daily life. In general, acceptance of termination of pregnancy in the case of mild or severe clinical conditions was comparable to that reported from European countries, but more favorable in the case of sex chromosome abnormalities. Acceptance of prenatal diagnosis for non-clinical conditions was, however, lower than that reported in Western nations. CONCLUSION: The study provides a good basis for further studies with a larger number of respondents representing various geographical regions of the country.

Effect of oral iron chelation therapy with deferiprone (L1) on the psychosocial status of thalassaemia patients.

Beta-thalassemia requires life-long treatment, including regular blood transfusion and daily iron chelation by desferrioxamine, which places considerable burden on the social and psychological life of patients. It is expected that oral chelation therapy, which is easier to administer, would improve their psychosocial status. In this sutdy, interviews were conducted with a series of 44 patients recently placed on oral chelation therapy to evaluate their reactions to the new treatment. Eighty-six per cent of patients complied better with the oral chelation therapy. Fifty per cent of patients mentioned that relief from the desferrioxamine pump was the major improvement, while 47% felt psychologically better. Fifty per cent of patients noted improvements in their relationships, while 63% noted increased social activities. Evaluation of a larger sample of patients over a longer period of time is needed in order to confirm the favourable results obtained in this study.

Chromosome 10p11.2-p12.2 duplication: report of a patient and review of the literature.

We report on a young male with mental retardation, slightly upslanting palpebral fissures, strabismus, high-arched palate, retrognathia, and flat feet. Cytogenetic analysis in addition to fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH) showed the presence of a chromosome 10p11.2-->p12.2 duplication. Karyotypes of the parents were normal. Comparison of the clinical findings observed in the present patient with those observed in other reported cases with duplication 10p suggest that the presence of high arched/cleft palate and retrognathia may be related to the 10p11.2-->p12.2 duplication. Also, no critical region for the trisomy 10p syndrome has been delimited.

Constitutional chromosome abnormalities among patients referred for blood karyotype analysis: a 5-year study at the AUBMC.

We report results on 2010 cases of blood referred for constitutional karyotype analysis. Referrals were grouped into 16 different categories, of which reproductive failure represented the highest percentage (33%), followed by structural congenital abnormalities (14.17%), developmental delay (11.34%), Down syndrome (9.65%), and abnormal sexual development (8.16%), while other categories represented smaller percentages. The total rate of abnormality was 16%, and the highest abnormality rates were among the clinically-recognizable chromosomal syndromes, while lower percentages were detected among less specific referrals. However, abnormality rates were generally different from the typical reported rates, probably due to the inclusion of cases not requiring chromosome analysis or the failure to recognize specific chromosomal syndromes. Other identified problems included lack of proper phenotypic description and difficulty in obtaining familial follow-up for proper diagnosis and genetic counseling.

Beta-thalassaemia intermedia in Lebanon.

Approximately one third of thalassaemia patients on record in Lebanon have thalassaemia intermedia. We have analysed three factors in a panel of 73 patients with this less severe form of the disease in our population: mild beta-globin gene mutations, deletions in the alpha-globin gene and the presence of a polymorphism for the enzyme Xmn I in the Ggamma-promoter region. The results show that the most important contributing factor is the beta-genotype: 68% of patients have a mild beta+ mutation (IVSI-6, cd29, -88 or -87), while 26% of patients are positive for the Xmn I polymorphism associated with increased production of HbF, which showed strong linkage to particular mutations (IVSII-1, cd8 and cd30). However, the genotype phenotype correlation is difficult, because many patients were initially misdiagnosed as thalassaemia major and were started early on regular blood transfusions, which was stopped later on. This illustrates well the importance of an early accurate diagnosis of thalassaemia intermedia for appropriate clinical management.

Beta-thalassemia mutations and haplotype analysis in Lebanon.

The molecular basis of beta-thalassemia in Lebanon reflects the heterogeneity of the Lebanese population. Eighteen different mutations were identified among a total of 277 chromosomes. There is evidence of clustering of some mutations in particular geographic regions or among specific religious groups. Haplotype analysis, using seven restriction sites was performed on a total of 110 samples and 11 different haplotypes were identified. The five most common mutations were each found on two different haplotypes, and most linkages were as previously reported in other Mediterranean populations, with a few exceptions, also showing some clustering.

Karyotype of amniotic fluid cells at the AUB-MC results on 2000 cases.

We report results on 2000 cases of amniotic fluid referred for karyotype analysis. Referrals were advanced maternal age in 64% of cases and abnormal ultrasound in 12% of cases. The frequency of chromosome aneuploidy was 2.4% in the first category and that of chromosome abnormalities 8% in the second. The incidence of marker chromosomes was 0.25%, that of mosaicism 0.3%, and maternal cell contamination was observed in 0.6% of cases. The overall culture failure rate was 0.9%. Our results are mostly in accordance with figures from larger surveys, published in the literature and differences might be due to the smaller number of samples in this series and variation in referral and/or sampling protocols.

Acceptance of prenatal diagnosis for genetic disorders in Lebanon.

Acceptance of prenatal diagnosis and termination of pregnancy in the case of an affected fetus may vary from one country to another, depending on the health system, religious belief, cultural and educational backgrounds of the population. Following a previous study on couples at risk for a haemoglobin disorder in Lebanon, we have here interviewed 90 couples at risk for a variety of genetic disorders, in order to assess their acceptance of prenatal diagnosis and the variables that might influence their choice. Overall, 54 per cent of couples said they would request diagnosis in their next pregnancy, while 26 per cent were opposed to such a procedure. In 87. 5 per cent of cases, the reason for refusal was because of religious conviction against termination of pregnancy. Refusal of prenatal diagnosis was also related to a lower socio-economic background and poorer education. Only 12 per cent of couples were properly aware of their genetic risk. Therefore, for prevention of genetic disorders, the emphasis in countries such as Lebanon has probably to be placed on public awareness about genetic risks, the risks of consanguinity, availability of services, while taking into consideration the personal beliefs of the individuals.

A familial case of recurrent hydatidiform molar pregnancies with biparental genomic contribution.

Hydatidiform mole is a benign trophoblastic neoplasia characterized by an abnormal development of the embryo and proliferation of placental villi. Using microsatellite markers amplified by the polymerase chain reaction, we have performed a genetic study on eight independent molar tissues occurring in two sisters. Karyotype and genotype data demonstrate a diploid and biparental constitution in seven of the analyzed moles suggesting a common mechanism underlying the etiology of the various molar pregnancies in this family. The data reported here suggest that complete and partial hydatidiform moles are not always separate entities and that women with familial recurrent hydatidiform moles are homozygous for an autosomal recessive mutation.

Karyotype analysis in chronic myelogenous leukemia. A three-year experience at the American University of Beirut Medical Center (AUBMC).

We report the results of karyotype analysis on cases referred to our laboratory for chronic myelogenous leukemia (CML) over a period of three years. A total of 68 patient were referred and a karyotype was successfully obtained in all cases except one. Thirty-one percent of cases were found to have a normal karyotype, 58.5% were Philadelphia (Ph1) positive while 10.5% of cases had chromosome abnormalities other than Ph1. Among the Ph1 positive cases, 92% had the standard translocation (9;22), 7.7% had a variant translocation and 12.8% had additional chromosome abnormalities. Our results are compared to those generally reported in the literature and the comparisons are discussed.

Familial complex chromosome rearrangement giving rise to balanced and unbalanced recombination products.

We report on a family ascertained through a 14-month-old girl with a terminal deletion of chromosome 8p23.1. Analysis of the karyotype of other relatives showed that the mother is the carrier of a balanced complex 4-break chromosome rearrangement, which she and her brother inherited from their father following recombination. This complex chromosome rearrangement (CCR) was confirmed by fluorescence in-situ hybridization (FISH) using libraries for chromosomes 1, 8, and 9, and telomeric probes for the long arm of chromosome 9. The karyotype of the maternal grandfather was 46,XY,t(1;8) (p31;q21.1),t(8;9) (p23.1;q34). The karyotype of his daughter is 46,XX,rec(8)t(1;8) (p31;q21.1)t(8;9)(p23.1;q34)pat. The karyotype of the proposita is 46,XX,rec(8)t(8;9) (p23.1;q34)mat, and that of her abnormal elder sister is 46,XX,t(1;8)(p31;q21.1)rec(8) t(8;9) (p23.1;q34)mat,der(9)t(8;9) (p23.1;q34) mat. Unbalanced segregation and/or recombination during maternal meiosis gave rise to the two abnormal sisters, one effectively with 8p trisomy and the other with monosomy for that same 8p segment. To our knowledge, this is the first case of a familial CCR giving rise to unbalanced recombination products.

[Retrospective study of nine Lebanese families with fragile X syndrome and review of the literature]. / Etude retrospective de 9 familles libanaises atteintes du syndrome de l'X fragile et revue de la litterature.

The Fragile X syndrome is the most common inherited form of mental retardation. Despite its incidence, which is estimated at 1/4000 boys, only 9 families have been documented so far in Lebanon, of which 3 have been partially investigated. This syndrome therefore seems to be largely ignored by physicians. Although no treatment is yet available for the Fragile X syndrome, the diagnosis of the disorder in a child is essential in order to provide the family with genetic counselling. The most critical point is still to convince the family of the need for such an evaluation and relieve the parents of any feeling of guilt.

A cytogenetic register of down syndrome in Lebanon.

OBJECTIVES: To provide data on the cytogenetics and epidemiology of Down syndrome in our community. METHODS: All cases of Down syndrome diagnosed cytogenetically were entered over a period of 5 years together with data regarding age at referral, parental ages and parity. RESULTS: A total of 280 cases were entered. In postnatal cases, the mean maternal age was 32.19 years and 41.5% of mothers were over 35 years. Only 47.3% of Down syndrome children were diagnosed at less than 1 month of age. The male to female sex ratio of 1.66 is significantly more elevated than that reported in larger registers. CONCLUSIONS: Because of problems inherent to Lebanon, this register does not have a high level of ascertainment, however it appears that the emphasis in a potential prevention programme should be placed on education, information and family planning.

The spectrum of beta-thalassaemia mutations in the Lebanon.

We screened 110 DNA samples from carriers of beta-thalassaemia, using the ARMS-PCR technique with primers for common Mediterranean mutations. Unidentified samples were subjected to a heteroduplex analysis with Universal Heteroduplex Generators covering the beta-globin gene, followed by DNA sequencing. In total, 16 different mutations were detected, the most frequent being IVSI-110 (40%), followed by other common Mediterranean mutations (IVSI-1, IVSII-1, IVSI-6). Other mutations detected were of Lebanese, Turkish, Iranian, Kurdish, Bulgarian and Asian Indian origin. The most heterogeneous religious group seems to be the Sunni Muslims, with 13 mutations, while only 2 mutations were detected among the Christian Maronites. Results from this study are compared with those from other Mediterranean and neighbouring countries.