Heterozygous loss of X-linked genes like CASK and MeCP2 (Rett syndrome) causes developmental delay in girls, while in boys, loss of the only allele of these genes leads to epileptic encephalopathy. The mechanism for these disorders remains unknown. CASK-linked cerebellar hypoplasia is presumed to result from defects in Tbr1-reelin-mediated neuronal migration.
Here we report clinical and histopathological analyses of a deceased 2-month-old boy with a CASK-null mutation. We next generated a mouse line where CASK is completely deleted (hemizygous and homozygous) from postmigratory neurons in the cerebellum.
The CASK-null human brain was smaller in size but exhibited normal lamination without defective neuronal differentiation, migration or axonal guidance. The hypoplastic cerebellum instead displayed astrogliosis and microgliosis, which are markers for neuronal loss. We therefore hypothesise that CASK loss-induced cerebellar hypoplasia is the result of early neurodegeneration. Data from the murine model confirmed that in CASK loss, a small cerebellum results from postdevelopmental degeneration of cerebellar granule neurons. Furthermore, at least in the cerebellum, functional loss from CASK deletion is secondary to degeneration of granule cells and not due to an acute molecular functional loss of CASK. Intriguingly, female mice with heterozygous deletion of CASK in the cerebellum do not display neurodegeneration.
We suggest that X-linked neurodevelopmental disorders like CASK mutation and Rett syndrome are pathologically neurodegenerative; random X-chromosome inactivation in heterozygous mutant girls, however, results in 50% of cells expressing the functional gene, resulting in a non-progressive pathology, whereas complete loss of the only allele in boys leads to unconstrained degeneration and encephalopathy.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterised by the development of multiple schwannomas, especially on vestibular nerves, and meningiomas. The UK NF2 Genetic Severity Score (GSS) is useful to predict the progression of the disease from germline NF2 pathogenic variants, which allows the clinical follow-up and the genetic counselling offered to affected families to be optimised.
METHODS: 52 Spanish patients were classified using the GSS, and patients\' clinical severity was measured and compared between GSS groups. The GSS was reviewed with the addition of phenotype quantification, genetic variant classification and functional assays of Merlin and its downstream pathways. Principal component analysis and regression models were used to evaluate the differences between severity and the effect of NF2 germline variants.
RESULTS: The GSS was validated in the Spanish NF2 cohort. However, for 25% of mosaic patients and patients harbouring variants associated with mild and moderate phenotypes, it did not perform as well for predicting clinical outcomes as it did for pathogenic variants associated with severe phenotypes. We studied the possibility of modifying the mutation classification in the GSS by adding the impact of pathogenic variants on the function of Merlin in 27 cases. This revision helped to reduce variability within NF2 mutation classes and moderately enhanced the correlation between patient phenotype and the different prognosis parameters analysed (R2=0.38 vs R2=0.32, p>0001).
CONCLUSIONS: We validated the UK NF2 GSS in a Spanish NF2 cohort, despite the significant phenotypic variability identified within it. The revision of the GSS, named Functional Genetic Severity Score, could add value for the classification of mosaic patients and patients showing mild and moderate phenotypes once it has been validated in other cohorts.

Schimke immuno-osseous dysplasia (SIOD) is a rare multisystemic disorder with a variable clinical expressivity caused by biallelic variants in SMARCAL1. A phenotype-genotype correlation has been attempted and variable expressivity of biallelic SMARCAL1 variants may be associated with environmental and genetic disturbances of gene expression. We describe two siblings born from consanguineous parents with a diagnosis of SIOD revealed by whole exome sequencing (WES). Results: A homozygous missense variant in the SMARCAL1 gene (c.1682G>A; p.Arg561His) was identified in both patients. Despite carrying the same variant, the two patients showed substantial renal and immunological phenotypic differences. We describe features not previously associated with SIOD-both patients had congenital anomalies of the kidneys and of the urinary tract and one of them succumbed to a classical type congenital mesoblastic nephroma. We performed an extensive characterization of the immunophenotype showing combined immunodeficiency characterized by a profound lymphopenia, lack of thymic output, defective IL-7Rα expression, and disturbed B plasma cells differentiation and immunoglobulin production in addition to an altered NK-cell phenotype and function. Conclusions: Overall, our results contribute to extending the phenotypic spectrum of features associated with SMARCAL1 mutations and to better characterizing the underlying immunologic disorder with critical implications for therapeutic and management strategies.

A significant bias in sex ratio has been documented for several congenital cardiac malformations. Transposition of the great arteries has been associated with a such a bias but no explanation has been proposed for this bias. We evaluated 95 isolated livebirths with transposition of the great arteries cases referred to the Sicilian Registry of Congenital Malformations from 1991 to 1998. We found a statistically significant male bias of 2.8 and this was significantly associated with both maternal and paternal occupational exposure to agricultural chemicals for male infants with transposition, but not for female infants. This study raises new questions about the possible role played by environmental chemicals in relationship to birth defects and to sex ratio imbalance.

Neonatal cholestasis is prolonged elevation of conjugated serum bilirubin (more than 20% of total bilirubin) beyond first 14 days of life. After extensive evaluation a diagnosis of either biliary atresia or neonatal hepatitis is made in 70-80% of cases. Neonatal hepatitis and biliary atresia form a pathophysiologic process directed at various levels of the hepatobiliary tract. Inflammation in the bile duct epithelium may result in the sclerosis and obliteration of the bile ducts and manifest as biliary atresia. Primary hepatocellular inflammation is more likely to result in neonatal hepatitis. Half of the cases of neonatal hepatitis resolve without sequelae, while most of the biliary atresia cases require surgical intervention for repair or, ultimately, liver transplant.

Increasingly large numbers of babies in sub-Saharan African are born with congenital human immunodeficiency virus (HIV). Attention is directed to the risk of vertical transmission, breast feeding and transmission of HIV infection, the risk of progression of HIV-related disease during pregnancy, contraception and HIV infection, counseling, congenital HIV infection, and management. In Africa, heterosexual sex is the primary route of spread of HIV, meaning the virus affects both sexes equally. Further, most HIV-seropositive women are in the sexually active and reproductive age group. The effect of HIV on the immature fetal immune system can be such that the infant does not make antibodies to HIV. Consequently, an infected infant can have negative HIV antibody tests. Viral antigen tests now are helpful in the diagnosis of congenital HIV infection but are costly and not widely available. This difficulty in serological diagnosis means that the frequency of transmission from HIV-infected mothers in their infants remains unknown. There have been 5 reports of apparent spread of HIV through breast feeding, yet it seems unlikely that breastfeeding plays a significant role in the spread of HIV infection. The claim that pregnancy triggers progression of disease in HIV positive women is based on only a series of case reports of Acquired Immune Deficiency Syndrome (AIDS) in pregnancy and an apparently high incidence of AIDS in women who had previously delivered an affected infant. The personal experience of HIV-infected women in sub-Saharan Africa, followed for an average of 2 years after delivery, suggests that pregnancy does not commonly accelerate progression of HIV-related disease, since most remain asymptomatic. Those infected with HIV need good contraceptive advice, and whatever contraceptive a woman chooses, it also should be recommended that condoms are used too whenever there is a risk of sexual spread of HIV infection. Women need current information about their condition, but counseling requires more than factual information. Affected women need and deserve advice and support from their doctor or health worker. Most infants with congenital HIV infection present before age 1. In many cases HIV infection is diagnosed in the 2nd year of life. HIV-infected children present with a wide variety of problems the most common of which are pneumonia and failure to thrive. Mothers need to be reassured that problems arising from HIV infection, such as rashes, dehydration, and chest infections can be treated even though there is no cure as yet for their child\'s underlying weakness.

The complex relationship between alcohol use and pregnancy involves socioeconomic, biomedical, psychological, and ethical factors. In recent years alcohol abuse on the part of women of childbearing age has been increasing steadily. Currently, a significant segment of the American population is at risk for an alcoholic pregnancy. Discussion includes a review of the literature concerning alcohol and pregnancy and covers the following: the symptomatology of fetal alcohol syndrome; prospective and epidemiologic human studies; animal models; etiology of fetal alcohol syndrome (FAS); maternal aspects of alcoholism and pregnancy and associated risk factors; paternal drinking and the theory of germ cell damage; use of ethanol in obstetrics; prevention of FAS; and questions to be answered in the future. The Fetal Alcohol Study Group of the Research Society of Alcoholism has promulgated a list of minimal criteria that must be met before a diagnosis of fetal alcohol syndrome (FAS) can be made. These criteria include prenatal and postnatal growth retardation and at least 2 of the following characteristic facial features: microcephaly, microopthalmia, and/or short palpebral fissures; and midfacial hypoplasia (defined as absent or rudimentary philtrum, thin vermilion border of upper lip, hypoplastic maxilla). The label \"possible FAS\" also is recommended if the criteria are not met, but congenital damage due to alcohol still is suspected. Virtually all infants with FAS have very low birth weights for their gestational age, usually at or below the third percentile. Body length and head circumference also are reduced to a similar degree. Mental retardation is the most debilitating and tragic aspect of this syndrome. Hyperactivity, hyperresponsiveness, hyperacusis, hypotonia, and tremulousness also are commonly described in FAS infants. Numerous studies involving large numbers of pregnant women have provided important data concerning the epidemiology and symptomatology of maternal alcohol use. All of these studies have been based on self reported use of alcohol, and the relationship of these reports to actual intake probably varies. Available prospective studies permit the estimation of the incidence of FAS in general and clarify to some extent the magnitude of risks an alcoholic woman has for giving birth to a defective child. Animal studies are very important in the study of alcohol and pregnancy because they provide an opportunity to control for variables that are seldom accounted for in human beings. One can control dosage and timing of ethanol administration, nutritional factors via pair feeding, and environment, and one can consider individual variation through cross strain comparisons.

This discussion of oral contraceptives (OCs) presents information on the following: types of steroidal contraception OCs, injectable contraceptive agents, implants, intravaginal rings, IUD bearing steroids, male pills, intracervical devices, contraceptive bracelets, and intranasal administration of hormones); guidelines for adolescent usage (why adolescents use OCs, common medical concerns, assessment, prescribing, educating for user effectiveness, and the length of time that the adolescent can use OCs); the marketing of OCs; attitudes toward OCs; the effect of OCs on insulin requirements in diabetes; mortality among OC users; assessing new knowledge of mortality trends and OCs; beneficial and adverse effects; sexual and psychological response to OCs; chromosomal abnormalities and OCs; ectopic pregnancies and the progestogen only pill; liver tumors and OCs; cancer and OCs; eye conditions and OCs; and postpill amenorrhea and infertility. Most adolescents choose OCs as their initial contraceptive method because it is probably the only method of which they have much knowledge. Most adolescents lack the needed level of sexual maturity and sexual sophistication to pause to insert a diaphrage or to use a condom. Another attraction of OCs is reliability. At this time 12 major companies based in 8 countries (excluding China) produce and market OCs. Basically either of 2 estrogens, ethinyl estradiol and mestranol, are used in combination with about 6 different progestogens. Attitudes vary greatly and range from total acceptance to total rejection. Despite some negative views about OC, 32.2% of Australian women in childbearing years are using OCs indicating a high degree of acceptance. The new data available indicate strongly that the hazards of using OCs are somewhat greater than previously suspected. In 1977 the Royal College of General Practitioners reported a death rate from circulatory disease which was in OC users 4.7 times that of women who had never used OCs. The deaths were concentrated among the older women, among cigarette smokers, and those with a long duration of OC use, i.e., over 5 years. Available evidence suggests that OCs do affect a number of transmitter amines in the brain and this might be responsible for the depressed mood in some patients. Critical review of the literature leaves one skeptical concerning claims of either positive or negative influences on the libido.

Controversy still surrounds the use of the injectable contraceptive, Depo-Provera, in 3rd world countries, when it has yet to be approved in the US, Canada, Japan, and other developed nations. Some medical professionals maintain Depo is both safe and effective and could curb rapid population growth worldwide. With no conclusive decision made, some countries have approved Depo while others have not yet decided. Originally approved for a variety of uses, Depo is approved in the US only as a treatment for advanced endometrial cancer; however, it is now available in 65 countries and is used as a contraceptive in the Philippines. Depo and its companion Norigest are both progestonogenic injectables and were developed in the late 1950s. Injectables inhibit ovulation and thicken cervical mucus, thereby preventing fertilization. The reservoir usually lasts from 3-6 months, and its action cannot be reversed until the body has completely absorbed the drug. Injectables are highly effective; most accidental pregnancies occur shortly after the 1st injection before the drug has taken effect or at the end of an interval when its effect is wearing off. Overall the rate of fertility return corresponds to the rates for the pill and the IUD. Injectables have the advantage of preventing side effects brought on by estrogens; thus they would be beneficial to women desiring to use contraception but who cannot manage pill side effects. They do not interfere with lactation and have the lowest failure rate of the reversible methods. Important to developing countries is that injectables require no effort on the part of the user. Injectables do disrupt the menstrual pattern and Depo use often results in weight gain. Little is known about the longterm risks of Depo; however, in 1973 the US Food and Drug Administration withdrew approval of Depo for pregnancy-related uses because of links to birth defects. Other recent studies have uncovered other possible effects including uncertainty about whether injectables affect the composition of breastmilk or whether they raise blood glucose levels. Ethics have entered into the controversy with the \"contraceptive double standard\" where Depo has been exported to 3rd world nations when it has been ruled unsafe for American women. Campaigns have been organized against the distribution and use of injectables in the developed nations and a few in the 3rd world have begun to organize. While the Philippines has approved Depo, it is not yet considered an official method of the National Population Program. Policymakers await a more thorough analysis of factors for and against the promotion of the drug.

Several studies are discussed which concern the risk of congenital defects after oral contraceptive (OC) failure. Janerich, who studied the tie between oral contraception and the possibility of birth defects, concludes that there is a \"tolerable risk\" in OCs causing birth defects. There appears to be no more risk in having birth defects as a result of OCs than any other type of agent. Brent, who has studied the effects of other types of risks such as spontaneous abortion, a major malformation, and an early or late onset of genetic disease, concludes that the risk posed by the use of OC is not significantly larger. Scharden has expressed concern that sex hormones, especially Clomiphene, a drug used to induce ovulation, is teratogenic, and causes harmful side effects in offspring. These and other studies have found that: 1) the risk of defects from hormone ingestion is small; 2) women who use OC may ovulate more than one egg and may therefore have twins, a situation in which there is an increased risk of defects; and 3) the uterine lining may atrophy from OC effects and the child may not have the same kind of support from the endometrium as in the case of a mother who did not take OCs. The consensus of expert opinion is that: 1) abortion is not a necessary decision if OCs are used by mothers; 2) drugs should be stopped once a woman finds she is pregnant; and 3) clinical decisions regarding the birth of a child under conditions of early use of OC should be up to individual patients who are informed of the risk of birth defects.