Catechol-O-methyltransferase and breast cancer risk

Recent studies suggest that a polymorphism in catechol-O- methyltransferase (COMT) is associated with increased risk of breast cancer. Methylation by COMT is the principal pathway for inactivation of catechol estrogens, which are hypothesized to participate in estrogen-induced carcinogenesis. We examined the association of COMT genotype and breast cancer risk in a population-based, case-control study of invasive breast cancer in North Carolina. The study population consisted of 654 cases and 642 controls, with approximately equal numbers of African-American and white women and women under the age of 50 and aged 50 or over. Contrary to previous reports, we did not observe an association between one or more copies of the low activity COMT allele (COMT-L) and breast cancer risk. Multivariate relative risks (RRs) were 0.8 (95% confidence interval: 0.6-1.1) for COMT-HL and 0.8 (0.6-1.1) for COMT-LL, compared with the COMT-HH genotype. RRs for COMT did not differ among African-American and white women and we did not observe strong modification of RR estimates by menopausal status, body mass index, physical activity or other covariates. Our results suggest that COMT genotype is not related to breast cancer risk.      

MRI characterization of cerebral dysgenesis in maternal PKU

MPKU pregnancies, with or without dietary treatment to reduce maternal plasma phenylalanine (phe), show variable, increased non-physiologic levels, as the putative cause of fetal teratogenicity. Cerebral dysgenesis with clinical neonatal microcephaly and congenital heart disease indicates altered organ morphogenesis. Although there is not an established precise relationship between maternal phelevels and outcome, dietary restriction before or early in gestation is universally advised. Both human experience and animal research have suggested differential organ responses to high and low phe levels. Structural micrencephaly may be due to reduced brain volume or abnormal regional brain development. Infants in MPKU are also at risk to develop PKU. Micrencephaly was evident by MRI in 8 of 21 infants born to 12 MPKU mothers; 2 infants of one mother developed PKU. All levels of gestational plasma phe were associated with otherwise structurally normal infant micrencephalic brains appropriate for age in myelination. CHD occurred in one micrencephalic infant of a classic MPKU treated in the first trimester. Maternal, cord and neonatal plasma phenylalanine at delivery did not correlate with teratogenic effects. Only untreated 'classic' MPKU fetal effects appear predictable.     

Laryngo-onycho-cutaneous syndrome: an inherited epithelial defect

Three children with an unusual but clearly defined combination of clinical findings that appear to have been inherited in an autosomal recessive manner are described. All had developed laryngeal abnormalities, chronic skin ulceration, nail dystrophy, and conjunctival disease in infancy. In every case, dental enamel was hypoplastic and both skin and mucosal surfaces demonstrated increased susceptibility to trauma. Progression of disease occurred, to life threatening respiratory obstruction in two cases and to effective blindness and fatal respiratory obstruction in the third child. All of these children came from the Pakistani ethnic group. No medical treatment has halted progression of this disease but laser therapy has been partially successful in alleviating laryngeal manifestations. Ultrastructural and immunohistological examination of unaffected skin was undertaken in each child. No abnormality was found in the child with the mildest clinical disease. Both of the other children showed abnormal hemidesmosomes on ultrastructural examination. The most severely affected child also had abnormally weak immunoreactivity with antibodies G71 and GB3 directed against basal cell alpha 6 beta 4 integrin and the basement membrane glycoprotein nicein respectively. These abnormal findings are also seen in skin from patients with junctional epidermolysis bullosa. These three children have the laryngo-onycho-cutaneous syndrome, which may not be rare in their ethnic group. The available clinical and pathological evidence is consistent with this syndrome being caused by an inherited defect affecting the lamina lucida of the skin basement membrane zone. The laryngo-onycho-cutaneous syndrome may therefore represent a new and distinctive type of junctional epidermolysis bullosa.     

Resolution of a proximal humeral defect in type-1 Gaucher disease by enzyme replacement therapy

Although rarely they are a normal variant in children, significant defects in the medial aspect of the proximal humeral metaphysis occur in patients with Gaucher disease due to cortical infiltration and erosion of the periosteum by Gaucher cells. Such changes may lead to pathological fractures in Gaucher patients. These crescentic erosions resolved in a 19-year-old patient with type-1 Gaucher disease following enzyme replacement therapy.     

Comparison of high resolution cytogenetics, fluorescence in situ hybridisation, and DNA studies to validate the diagnosis of Prader-Willi and Angelman's syndromes

Eighty seven referrals with Prader-Willi syndrome and 49 with Angelman's syndrome were studied. High resolution cytogenetics was performed on all probands. Molecular studies, performed on the proband and both parents in each case, utilised multiple probes from within and distal to the 15(q11-13) region in order to establish the presence of DNA deletion or uniparental disomy. In addition, FISH, with probes at D15S11 and GABR beta 3 from the Prader-Willi syndrome/Angelman's syndrome region, was performed on a subset of 25 of these patients. In the referral group with Prader-Willi syndrome, 62 patients had a normal karyotype and 25 were deleted on high resolution cytogenetics. Twenty nine were found to be deleted with DNA techniques. In the Angelman's syndrome group, 37 had a normal karyotype and 12 were deleted on high resolution cytogenetics while 26 were deleted on molecular studies. The diagnosis was reassessed in 35 referrals with Prader-Willi syndrome and 11 with Angelman's syndrome following a non-deleted, non-disomic result. Of individuals who were neither deleted nor disomic on DNA studies, a false positive rate of 11.4% (4/35) for Prader-Willi syndrome and 16.7% (2/12) for Angelman's syndrome was found for a cytogenetically detected deletion. The false negative rate for deletion detected on high resolution cytogenetics was 19.5% (12/62) for Prader-Willi syndrome and 35% (13/37) for Angelman's syndrome. Thus high resolution cytogenetics was shown to be unreliable for deletion detection and should not be used alone to diagnose either syndrome. There were no discrepancies with FISH in 25 cases when FISH was compared with the DNA results, indicating that FISH can be used reliably for deletion detection in both syndromes.     

Operation for gastro-oesophageal reflux associated with severe mental retardation

One hundred and seventy six children with severe mental retardation underwent a fundoplication for considerable gastro-oesophageal reflux. There were six 'early' (3%) deaths and five 'late' deaths. Major complications developed in 17 (10%) children whereas 86 (49%) had 'minor' complications. A revision operation was required in 27 patients. Overall 142 (81%) children achieved a good result. In spite of the high complication rate and the need for a secondary operation in 15% of the patients, the quality of life for these children and their parents and carers is greatly improved by antireflux surgery.     

Isolated vitamin E deficiency and progressive ataxia

A case of progressive spinocerebellar syndrome due to isolated vitamin E deficiency is reported. Measurement of the vitamin E concentration in serum should be included when investigating all children with unexplained, progressive ataxia, even in the absence of malabsorption. Replacement treatment in patients with a vitamin E deficiency can arrest or improve the associated neurological disorder.