Pignata et al. (1996) reported 2 sisters with an association of congenital alopecia, severe T-cell immunodeficiency, and ridging and pitting of all nails. A decrease of mature T lymphocytes was mainly due to a low number of helper ... Pignata et al. (1996) reported 2 sisters with an association of congenital alopecia, severe T-cell immunodeficiency, and ridging and pitting of all nails. A decrease of mature T lymphocytes was mainly due to a low number of helper T cells, whereas the number of suppressor/cytotoxic T cells was relatively normal. Mitogen stimulation did not produce an adequate proliferative response. Since a normal proliferative response was seen following phorbol myristate acetate and ionomycin stimulation of T cells, the authors suggested that in these girls there was a block in the signal transmission upstream to protein kinase C. One sister died at the age of 1 year. Another girl underwent bone marrow transplantation (BMT) at 5 months and was alive 1 year after BMT. Pignata et al. (1996) suggested this association is a new syndrome presumably with autosomal recessive inheritance. Although alopecia has been reported in several patients with Omenn syndrome (603554), the sisters reported by Pignata et al. (1996) had alopecia at birth, before clinical evidence of erythrodermia, and the alopecia persisted after BMT. Frank et al. (1999) noted that the 2 sisters originated from a geographically isolated small community in southern Italy. Vigliano et al. (2011) reported studies of a human fetus with the homozygous R255X mutation from the high-risk southern Italian village. There was total blockage of CD4+ T-cell maturation and severe impairment of CD8+ cells, although a few nonfunctional CD8+ cells lacking CD3 were found. Some diversity of the T-cell receptor generation occurred, but it was impaired compared to controls, and there were low levels of alpha/beta TCRs. No thymic tissue was found in the fetus. There were no abnormalities in the development of B cells or natural killer cells. The findings indicated that FOXN1 is crucial for in utero T-cell development in humans. The identification of a limited number of CD8+ cells suggested an extrathymic origin for these cells, implying FOXN1-independent lymphopoiesis.
In the 2 sisters described by Pignata et al. (1996), Frank et al. (1999) identified homozygosity for a mutation (R255X; 600838.0001) in FOXN1 gene. The sister who had received a bone marrow transplant from her brother was alive ... In the 2 sisters described by Pignata et al. (1996), Frank et al. (1999) identified homozygosity for a mutation (R255X; 600838.0001) in FOXN1 gene. The sister who had received a bone marrow transplant from her brother was alive and free of infection 4 years after the transplant (Frank et al., 1999). Detection of the haplotype specific for the wildtype FOXN1 allele as well as the mutant allele was indicative of chimerism and provided evidence of long-term engraftment and expansion of the bone marrow graft. Frank et al. (1999) identified this phenotype as a human homolog of the 'nude' mouse. During a genetic screening of the village population from which the patients reported by Frank et al. (1999) originated, Amorosi et al. (2008) identified a female fetus who was homozygous for the R255X mutation. Post-termination examination at 15 weeks' gestation showed that the fetus lacked a thymus and the skin was grossly abnormal, being tighter than usual and showing basal hyperplasia and dysmaturity, suggesting impaired differentiation. The phenotype was identical to that of the Nude/SCID phenotype of mice. In addition, the fetus had multiple neural tube defects, including anencephaly and spina bifida.
Adriani et al. (2004) reported 4 additional children from the same Italian community reported by Pignata et al. (1996) and Frank et al. (1999) who were affected with congenital alopecia and died from severe infections in early childhood. ... Adriani et al. (2004) reported 4 additional children from the same Italian community reported by Pignata et al. (1996) and Frank et al. (1999) who were affected with congenital alopecia and died from severe infections in early childhood. Screening for the R255X mutation in 843 inhabitants representing 30% of the village population resulted in identification of 55 (6.52%) heterozygous carriers. A genealogic study revealed that these individuals belonged to 39 families that were linked in an extended 7-generation pedigree comprising 483 individuals. Archival research identified a single ancestral couple born at the beginning of the 19th century, and haplotype analysis was consistent with a single ancestral origin for the mutation.