Maternal Obesity and Offspring Long-Term Infectious Morbidity

Obesity is a leading cause of morbidity world-wide. Maternal obesity is associated with adverse perinatal outcomes. Furthermore, Obesity has been associated with increased susceptibility to infections. The purpose of this study was to evaluate long-term pediatric infectious morbidity of children born to obese mothers. This population-based cohort analysis compared deliveries of obese (maternal pre-pregnancy BMI ≥ 30 kg/m2) and non-obese patients at a single tertiary medical center. Hospitalizations of the offspring up to the age of 18 years involving infectious morbidities were evaluated according to a predefined set of ICD-9 codes. A Kaplan–Meier survival curve was used to compare cumulative hospitalization incidence between the groups and Cox proportional hazards model was used to control for possible confounders. 249,840 deliveries were included. Of them, 3399 were children of obese mothers. Hospitalizations involving infectious morbidity were significantly more common in children born to obese mothers compared with non-obese patients (12.5% vs. 11.0%, p < 0.01). The Kaplan–Meier survival curve demonstrated a significantly higher cumulative incidence of infectious-related hospitalizations in the obese group (log rank p = 0.03). Using the Cox regression model, maternal obesity was found to be an independent risk factor for long-term infectious morbidity of the offspring (adjusted HR = 1.125, 95% CI 1.021–1.238, p = 0.017)

Lethal Congenital Contractural Syndrome Type 2 (LCCS2) Is Caused by a Mutation in ERBB3 (Her3), a Modulator of the Phosphatidylinositol-3-Kinase/Akt Pathway

Lethal congenital contractural syndrome type 2 (LCCS2) is an autosomal recessive neurogenic form of arthrogryposis that is associated with atrophy of the anterior horn of the spinal cord. We previously mapped LCCS2 to 6.4 Mb on chromosome 12q13 and have now narrowed the locus to 4.6 Mb. We show that the disease is caused by aberrant splicing of ERBB3, which leads to a predicted truncated protein. ERBB3 (Her3), an activator of the phosphatidylinositol-3-kinase/Akt pathway—regulating cell survival and vesicle trafficking—is essential for the generation of precursors of Schwann cells that normally accompany peripheral axons of motor neurons. Gain-of-function mutations in members of the epidermal growth-factor tyrosine kinase–receptor family have been associated with predilection to cancer. This is the first report of a human phenotype resulting from loss of function of a member of this group

Lethal Contractural Syndrome Type 3 (LCCS3) Is Caused by a Mutation in PIP5K1C, Which Encodes PIPKIγ of the Phophatidylinsitol Pathway

Lethal congenital contractural syndrome (LCCS) is a severe form of arthrogryposis. To date, two autosomal recessive forms of the disease (LCCS and LCCS2) have been described and mapped to chromosomes 9q34 and 12q13, respectively. We now describe a third LCCS phenotype (LCCS3)—similar to LCCS2 yet without neurogenic bladder. Using 10K single-nucleotide–polymorphism arrays, we mapped the disease-associated gene to 8.8 Mb on chromosome 19p13. Further analysis using microsatallite markers narrowed the locus to a 3.4-Mb region harboring 120 genes. Of these genes, 30 candidates were sequenced, which identified a single homozygous mutation in PIP5K1C. PIP5K1C encodes phosphatidylinositol-4-phosphate 5-kinase, type I, gamma (PIPKIγ), an enzyme that phophorylates phosphatidylinositol 4-phosphate to generate phosphatidylinositol-4,5-bisphosphate (PIP2). We demonstrate that the mutation causes substitution of aspartic acid with asparagine at amino acid 253 (D253N), abrogating the kinase activity of PIPKIγ. Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of PIP2, a molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital arthrogryposis