Bolze et al. (2010) studied a large consanguineous Pakistani pedigree in which a brother and 2 sisters and a female cousin suffered from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction involving modestly elevated transaminases without ... Bolze et al. (2010) studied a large consanguineous Pakistani pedigree in which a brother and 2 sisters and a female cousin suffered from recurrent, stereotypical episodes of fever, encephalopathy, and mild liver dysfunction involving modestly elevated transaminases without cholestasis, metabolic derangement, or synthetic defects, sometimes accompanied by generalized seizures that were difficult to control. Episodes lasted several days, sometimes requiring intensive care. Cranial imaging in 3 patients suggested cerebral atrophy, despite recovery in 2 of them. For some of the episodes, it was possible to identify a viral trigger, including varicella zoster virus, measles-mumps-rubella (MMR) attenuated vaccine, parainfluenza virus, and Epstein-Barr virus (EBV). One of the sisters died at 4 years of age during such an episode, and the other sister and brother died of fatal invasive pneumococcal disease at ages 4 months and 14 months, respectively. Their affected cousin was alive at 2.75 years of age. Howell-Jolly bodies were detected in 2 patients despite the presence of a spleen, indicating functional hyposplenism. Two of the 4 patients had congenital cardiovascular malformations: pulmonary atresia and a ventricular septal defect in 1 sister, and a left-sided superior vena cava that drained into the left atrium in the cousin. In the previous generation, another 5 family members had died in childhood, 2 with 'epilepsy' and 2 from infection (pneumonia and measles, respectively), suggesting that there may have been up to 9 family members with this disorder over 2 generations. Laboratory findings in affected individuals were similar to those seen in autoimmune lymphoproliferative syndrome (ALPS; 601859), including high-circulating CD4(-)CD8(-)TCR-alpha-beta(+) T-cell (DNT) counts, and elevated IL10 (124092) and FASL (TNFSF6; 134638) levels, but the Pakistani patients did not exhibit the clinical features of ALPS.
In 2 sisters and their cousin from a large consanguineous Pakistani pedigree, who had recurrent infections associated with encephalopathy, hepatic dysfunction, and cardiovascular malformations, Bolze et al. (2010) identified homozygosity for a missense mutation in the the FADD ... In 2 sisters and their cousin from a large consanguineous Pakistani pedigree, who had recurrent infections associated with encephalopathy, hepatic dysfunction, and cardiovascular malformations, Bolze et al. (2010) identified homozygosity for a missense mutation in the the FADD gene (602457.0001). The mutation segregated with disease in the kindred and was not found in 282 Pakistani controls. Based on the patients' laboratory findings as well as in vitro and in vivo studies of FADD deficiency, Bolze et al. (2010) concluded that the observed bacterial infections result partly from functional hyposplenism, and the viral infections from impaired interferon immunity.