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.

This Law amends Law No. 239 of 24 March 1970 on the termination of pregnancy. It introduces the following new Section 5a: \"Notwithstanding the provisions of Section 5, the National Board of Health may authorize the termination of a pregnancy if, as a result of amniocentesis or an ultrasonic examination, serological tests, or another reliable examination, it is established that the embryo is affected by a serious disease or physical disability, provided that the 24th week of pregnancy has not expired.\"

This document contains provisions of a 1987 Texas Law relating to third trimester abortions. The law provides the following as the only justifications for performing an abortion on a woman pregnant with a viable unborn child during the third trimester of pregnancy: the abortion is necessary to prevent the death or substantial risk of serious impairment to the physical or mental health of the woman, or reliable diagnostic procedures have revealed that the fetus has a severe and irreversible abnormality. If such an abortion is performed, notification and medical indications justifying the actions must be sent to the Texas Department of Health within 30 days.

This law provides that termination of pregnancy is permitted with the consent of the woman, in a hospital, and with medical assistance a) during the first twelve weeks of gestation; and b) anytime during the pregnancy 1) if continuation of the pregnancy would involve the risk of the death of the woman or serious and permanent injury to her health both physical and mental; 2) in order to prevent the probable transmission to the fetus of a serious hereditary or contagious illness; or 3) in order to prevent the newly-born suffering from serious physical defects or mental disturbances.

This document contains provisions of the 1984 Penal Code of Montserrat relating to sexual offenses, abortion, offenses relating to marriage, homicide and other offenses against the person, and neglect endangering life or health. Part 8 of the Code holds that a man found guilty of raping a woman is liable to life imprisonment. Rape is deemed to involve unlawful (extramarital) sexual intercourse with a woman without her consent (this is determined if the rape involved force, threats, administration of drugs, or false representation). The Code also defines offenses in cases of incest, child abuse, prostitution, abduction, controlling the actions and finances of a prostitute, and having unlawful sexual intercourse with a mentally defective woman. Part 9 of the Code outlaws abortion unless it is conducted in an approved establishment after two medical practitioners have determined that continuing the pregnancy would risk the life or physical/mental health of the pregnant woman or if a substantial risk exists that the child would have serious abnormalities. Part 10 outlaws bigamy, and part 12 holds that infanticide performed by a mother suffering postpartum imbalances can be prosecuted as manslaughter. This part also outlaws concealment of the body of a newborn, whether that child died before, at, or after birth, and aggravated assault on any child not more than 14 years old. Part 12 makes it an offense to subject any child to neglect endangering its life or health.

The plaintiffs were a husband, who had undergone a vasectomy in order not to pass on a hereditary disease, and his wife. After the wife gave birth to a child born with hereditary defects, they brought a wrongful birth suit on their behalf and a wrongful life suit on the behalf of their child. The Court allowed them to recover on their behalf, but not on their child\'s behalf. It held that it is impossible to consider life, even if restricted by handicaps, to constitute damage.