Inheritance of hyperbilirubinemia: evidence for a major autosomal recessive gene.

BACKGROUND AND AIM: To clarify the precise mode of inheritance of Gilbert syndrome, an unconjugated familial hyperbilirubinemia, where impaired bilirubin conjugation is caused by reduced UGT1A1 activity determined by a defective function of the A(TA)6TAA promoter region of the UGT1A1 gene. SUBJECTS AND METHODS: Serum bilirubin levels were measured in a large, homogeneous resident population from North-Eastern Italy, consisting of 1.639 males (age 44.5+/-13.9, range 18-89 years), and 1.420 females (age 45.1+/-15.0, range 18-85). In 112 nuclear families from hyperbilirubinemic probands living in the same area a complex segregation analysis was then performed. In both samples we carefully excluded potentially confounding factors of bilirubin levels (alcohol abuse, excessive cigarette smoking, drug consumption, overt haemolysis and liver disease). RESULTS: Mean serum bilirubin concentrations are higher in males than in females, showing fluctuations through the different age periods in males. Complex segregation results demonstrate that unconjugated hyperbilirubinemia exhibits a precise mode of inheritance in which a major recessive gene with a frequency of 0.45 is responsible for higher serum bilirubin values. CONCLUSIONS: This major recessive gene accounts only for a part of the serum bilirubin concentration, thus implying additional, environmental factors for the clinical appearance of GS.

Inherited and acquired thrombophilia: pregnancy outcome and treatment.

Maternal thrombophilias increases the risk of an adverse pregnancy outcome. An extensive literature review highlights the role of inherited and acquired thrombophilic disorders in spontaneous abortion, both early and late, recurrent or isolate, in intrauterine growth retardation, in placenta abruption, in pre-eclampsia and in venous thromboembolism. We have particularly focused attention on the following factors: antithrombin III (ATIII), proteins C (PC) and S (PS) deficiencies, genetic mutations particularly factor V Leiden (FVL), prothrombin gene G20210A (PTM) and the thermolabile variant of the methylene tetrahydrofolate reductase C677T (MTHFR) gene, lupus anticoagulant (LAC) and anticardiolipin antibodies, VIIIc factor, hyperhomocysteinemia and acquired activated protein C resistance. Appropriate treatment can improve pregnancy outcome without teratogenic effects.

Ionizing radiations in pregnancy and teratogenesis: a review of literature.

The present paper is a review of the data available in the literature concerning the prenatal exposure to radiation evaluating the reported teratogenic effect. We have particularly focused on the fetal effects of maternal ionising radiation exposure, both diagnostic and occupational, particularly in terms of congenital anomalies and birth weight. Ionising radiation represents a possible teratogen for the fetus, but this risk has been found to be dependent on the dosage and the effects correlatable to the gestational age at exposure. Recently, of particularly note is the fact that maternal thyroid exposure to diagnostic radiation has been associated with a slight reduction in the birth weight. Inadvertent exposure from diagnostic procedures in pregnancy doesn't usually increase the natural risk of congenital anomalies but creates a considerable state of maternal anxiety. Diagnostic radiological procedures should be avoided in pregnant women unless the information cannot be obtained by other techniques.

Methimazole embryopathy: delineation of the phenotype.

We report on a further case of congenital anomalies in a child exposed to methimazole during the first trimester of pregnancy (from first to seventh gestational week), and define a specific malformation pattern related to prenatal methimazole exposure and consisting of choanal and esophageal atresia, scalp defects, minor facial anomalies and psychomotor delay.

Inheritance of astigmatism: evidence for a major autosomal dominant locus.

Although astigmatism is a frequent refractive error, its mode of inheritance remains uncertain. Complex segregation analysis was performed, by the POINTER and COMDS programs, with data from a geographically well-defined sample of 125 nuclear families of individuals affected by astigmatism. POINTER could not distinguish between alternative genetic models, and only the hypothesis of no familial transmission could be rejected. After inclusion of the severity parameter, COMDS results defined a genetic model for corneal astigmatism and provided evidence for single-major-locus inheritance. These results suggest that genetic linkage studies could be implemented and that they should be limited to multiplex families with severely affected individuals.

CD4 and CD8 T lymphocyte inheritance. Evidence for major autosomal recessive genes.

The CD4/CD8 ratio has long been used for the follow-up and monitor of many infectious diseases. Following the demonstration in 1983 that the CD4/CD8 ratio in the mouse is under genetic control, it was subsequently shown to be controlled by a major locus in man. To define the mode of inheritance of the CD4/CD8 ratio, we addressed the absolute number of CD4 and CD8 cells in a large unselected control sample and in members of 70 nuclear families. Pedigrees of nuclear families were analyzed by complex segregation analysis. Data was adjusted prior to this analysis to remove the effects of relevant covariates. The non-genetic-transmission and the multifactorial model could be easily rejected for both CD4 and CD8 cells. Among the different inheritance models, involving both a major gene and a multifactorial (MFT) component, a major autosomal recessive gene with a residual MFT effect controlling the high number of CD4 and a major autosomal recessive gene with a residual MFT effect controlling the high number of CD8 cells were the significantly best-fitting ones. Our findings have some practical implications. Among all, the knowledge of the CD4+ cell number and the proportion between CD4+ and CD8+ T cells could be a useful parameter in predicting human immunodeficiency virus infection outcome.

Adverse effects of prenatal methimazole exposure.

BACKGROUND: A specific phenotype of methimazole (MMI) induced malformations has recently been postulated. MMI embryopathy is characterized by minor dysmorphic features, choanal atresia and/or esophageal atresia, growth retardation, and developmental delay. METHODS: We prospectively studied the outcome of pregnancy in 241 women counseled by 10 Teratology Information Services (TIS) of the European Network of Teratology Information Services (ENTIS) because of MMI exposure, and compared them with those of 1,089 pregnant women referred to TIS because of exposure to nonteratogenic drugs (control group). Information was obtained by mail or telephone interview. RESULTS: There was no increase in the general rate of major anomalies or of spontaneous or induced abortions in the MMI-exposed group in comparison with the control group. Two newborns were affected with one of the major malformations that are part of the postulated embryopathy. CONCLUSIONS: The results of this study indicate that choanal as well as esophageal atresia may have a higher incidence than expected in fetuses exposed to MMI between 3 and 7 gestational weeks. Until further data are available, thyrotoxicosis should be treated with propylthiouracil, as it is apparently safer for use during the fertile period.