Shivanand R. Patil

Abnormality of chromosome 11 in patients withfeatures of Beckwith-Wiedemann syndrome

Two unrelated children with features of Beckwith-Wiedemann syndrome have been found to have partial duplication of chromosome 11p. A review of six other reported cases of partial duplication of 11 p revealed features of this syndrome not previously recognized. We suggest that karyotype studies with banding techniques should be done in children with features of Beckwith-Wiedemann syndrome and developmental delay or retardation.

Risk of preeclampsia in second-trimester triploid pregnancies

Objective To determine the magnitude of the risk and the predictive clinical characteristics for development of preeclampsia when triploidy is diagnosed in the second trimester. Methods A retrospective analysis of databases maintained by the cytogenetics laboratories at the University of Iown and University North Carolina was performed to identify all cases of triploidy. We examined the karyotype, maternal serum screening (particularly the hCG level), ultrasound results, and evidence of maternal hypertensive disease. Results Seventeen cases of triploidy were identified between 1987 and 1996. Preeclampsia or hypertension complicated six of these cases with onset between 15 and 22.5 weeks gestation. In these six cases, the serum hCG level was extremely high. Serum results were available in seven cases in which preeclampsia did not develop, and the hCG levels were under 0.09 multiples of the median in five of the seven cases. In all six cases in which preeclampsia or hypertension developed, there was stenographic evidence of placentomegaly. Sonographic findings in 16 17 cases revealed fetal growth restriction, oligohydramnios, fetal anomalies, placentomegaly, or a combination of these. Conclusion In our series of pregnancies complicated by triploidy, the risk of developing preeclampsia or hypertension in the second trimester was 35%. It appears that elevated serum hCG levels and placentomegaly are associated with a higher risk of preeclampsia but low hCG levels are not. This information is important in counseling patients who are hesitant to terminate a pregnancy purely for a fetal abnormality, even if the anomaly is lethal.

Cytogenetic abnormalities in tumors of patients with von hippel-lindau disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that causes the development of benign and malignant tumors in several organ systems. Tumors causing significant morbidity include retinal angioma, cerebellar hemangioblastoma (CH), renal cell carcinoma (RCC), and pheochromocytoma (Pheo). Cytogenetic studies of tumors in VHL patients are rare. Cytogenetic findings in tumors from 12 patients with VHL disease, including four RCCs, three CHs, and five Pheos are presented. Three of the four RCC cases were abnormal. Monosomy 3 or a deletion of 3p was present in all three abnormal cases. Complete or partial trisomy of chromosome 5 was present in two cases. A deletion of 14q, trisomy 7, and a missing Y were each observed in one case. These findings indicate that a deletion of 3p may be a primary cytogenetic change in RCCs associated with VHL disease in addition to playing a role in sporadic RCC. Duplications of 5q and deletions of 14q may be important secondary changes in the progression of the malignant phenotype. No visible cytogenetic abnormalities were observed in the three CHs, or in four of the Pheos. One of the five Pheos was found to exhibit mosaic trisomy 7; its significance is unclear at the present time.

Cytogenetic heteromorphisms: Survey results and reporting practices of Giemsa-band regions that we have pondered for years

CONTEXTnCytogenetic heteromorphisms (normal variants) pose diagnostic dilemmas. Common Giemsa-band heteromorphisms are not described in the literature, although Giemsa-banding is the method most frequently used in cytogenetic laboratories.nnnOBJECTIVEnTo summarize the responses from more than 200 cytogeneticists concerning the definition and reporting of cytogenetic heteromorphisms, to offer these responses as a reference for use in clinical interpretations, and to provide guidance for interpretation of newly defined molecular cytogenetic heteromorphisms.nnnDESIGNnThe Cytogenetics Resource Committee of the College of American Pathologists and the American College of Medical Genetics administered a proficiency testing survey in 1997 to 226 participant cytogenetic laboratories. Supplemental questions asked whether participants considered particular Giemsa-banded chromosomal features to be heteromorphisms and if these would be described in a cytogenetic clinical report.nnnRESULTSnResponses were obtained from 99% of participants; 61% stated they would include selected heteromorphism data in a clinical report. More than 90% considered prominent short arms, large or double satellites, or increased stalk length on acrocentric chromosomes to be heteromorphisms; 24% to 36% stated that they would include these in a clinical report. Heterochromatic regions on chromosomes 1, 9, 16, and Y were considered heteromorphisms by 97% of participants, and 24% indicated they would report these findings. Pericentric inversions of chromosomes 1, 2, 3, 5, 9, 10, 16, and Y were considered heteromorphisms with more than 75% of respondents indicating they would report these findings.nnnCONCLUSIONSnResponses were not unanimous, but a clear consensus is presented describing which Giemsa-band regions were considered heteromorphisms and which would be reported.

Microdeletion of 17q22q23.2 encompassing TBX2 and TBX4 in a patient with congenital microcephaly, thyroid duct cyst, sensorineural hearing loss, and pulmonary hypertension.

Microdeletions of the long arm of chromosome 17 are being reported with increasing frequency. Deletions of 17q22q23.2 may represent a genetically recognizable phenotype although its spectrum of genomic abnormalities, clinical manifestations, and critical regions are not fully delineated. Isolated reports and small case series suggest that deletions of 17q22q23.2 result in haploinsufficiency of dosage sensitive genes NOG, TBX2, and TBX4, which may be responsible for many aspects of the phenotype. Shared clinical features in this group of patients include microcephaly, prenatal onset growth restriction, heart defects, tracheoesophageal fistula, and esophageal atresia (TEF/EA), skeletal anomalies, and moderate to severe global developmental delay. We describe a female patient who presented with severe congenital microcephaly, thyroglossal duct cyst, sensorineural hearing loss, mild tracheomalacia, abnormal auricles, pulmonary hypertension, developmental delay, and postnatal onset growth delay. She had no TEF/EA or heart defects. Using a high density oligonucleotide microarray, we identified a microdeletion at 17q22q23.2, resulting in the heterozygous loss of several genes, including TBX2 and TBX4 but not NOG. The breakpoints did not lie within known segmental duplications. This case helps to further delineate the critical region for TEF/EA, which is likely confined to the chromosomal region proximal to 17q23.1, and suggests that genes in 17q23.1q23.2 may be associated with thyroglossal duct cysts. The role of TBX2 and TBX4 in pulmonary hypertension warrants investigation.

Sister Chromatid Exchange Analysis in Nurses Handling Antineoplastic Drugs

Sister chromatid exchange (SCE) analyses were carried out in hospital nurses to determine whether an increased frequency of SCE may be used as an indicator of occupational exposure to potentially harmful antineoplastic drugs. In our study of 18 oncology nurses who handled these agents for an average of three days per week, we found no increase in mean SCE frequency (9.3 +/- 1.7 SCEs/cell) and no difference in the distribution of individual mean SCE frequencies compared to a group of 18 nurses who did not handle these drugs (9.5 +/- 1.5 SCEs/cell). There was a great deal of individual variation in mean SCE frequency as well as in SCE values in individual cells. No relationship with SCE frequency was found in terms of a subjects age, or the number of days of exposure to the drugs. Since conflicting results have been reported in persons handling antineoplastic drugs, SCE analysis alone is probably not a reliable indicator of exposure to possible mutagenic/carcinogenic effects of these drugs. SCE analysis may be helpful in conjunction with other studies, such as an analysis of urinary mutagens, or in studies of occupational exposure to agents other than antineoplastic drugs which may have a more noticeable effect on SCE frequency.

Apparent Germline Mosaicism for a Novel 19p13.13 Deletion Disrupting NFIX and CACNA1A

We report on a case of apparent germline mosaicism in a family of two sisters carrying a novel 19p13.13 deletion. The 11‐year‐old proposita was referred for evaluation of macrocephaly, moderate intellectual disability (ID), and episodic ataxia. Array comparative genomic hybridization (CGH) detected a 399u2009kb microdeletion with breakpoints within genes NFIX and CACNA1A. A similar deletion was also seen in the elder sibling who presented with macrocephaly, ID, and strabismus. The deletions were confirmed to be de novo after the parental aCGH analysis suggesting that this is an example of germinal mosaicism. This study contributes additional information for the newly identified 19p13 deletion syndrome and clarifies the clinical roles of genes in the involved region. This case of apparent germline mosaicism represents the only known family in the cohort of 1,800 patients analyzed by our group.

A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features

Larger imbalances on chromosome 4p in the form of deletions associated with Wolf–Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype–phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation‐heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low‐set ears, and short neck. Using a high‐density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patients presentation and genomic findings help further delineate clinical significance of re‐arrangements in the 4p16 region without the involvement of WHS critical region.

Association of the X chromosomal region q11→22 and Klinefelter syndrome

A male patient with typical Klinefelter syndrome features was found to have a 47, XXq‐Y chromosome complement. The X chromosome with the deletion was late‐replicating. We suggest that the region q11→22 of the extra X chromosome is important for expression of the Klinefelter phenotype.

Fragile site expression in families with von Hippel-Lindau disease

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder that predisposes to diverse tumors including renal cell carcinoma. Six affected and four unaffected subjects from five families were studied to determine the frequency of fragile site expression. Peripheral lymphocyte cultures from each subject were treated with low folate, 5-fluorodeoxyuridine (FUdR), and FUdR plus caffeine for fragile site induction. A site was considered to be fragile if it was expressed at least two times in half of the affected or unaffected subjects. Of the established sites, four were expressed in the unaffected group (3p14, 6p22, 8q22, and Xp22) and six were expressed in the affected group (3p14, 4q31, 5q31, 7q32, Xp22, and Xq22). Only 3p14 and Xp22 were expressed in both groups. There were four new sites: three (3q26, 6p21, 7p15) in the unaffected group and one (16q24) in the affected group. The 3p14 site was expressed twice as frequently in affected versus unaffected subjects. This finding is of interest because of reports of the involvement of 3p14 in hereditary renal cell carcinoma and in VHL.