It is thought to be activated by phosphorylation, translocate to the nucleus [34C36], bind DNA through its forkhead domain (Fig
It is thought to be activated by phosphorylation, translocate to the nucleus [34C36], bind DNA through its forkhead domain (Fig.?1) [12, 37, 38], and promote the transcription of genes that control the development of epithelial cells [3]. [9C11]. The molecular cause was identified in 1994 to be due to an autosomal recessive deletional mutation in the genelater renamed [7, 12]. Thirty years after its first description in Rabbit polyclonal to A4GALT mice, the human counterpart of the nude phenotype was reported in two sisters presenting with early-onset severe immunodeficiency associated with congenital alopecia and nail dystrophy [1, 2]. FOXN1 is required for the development of epithelial cells in the thymus, the skin, hair and nails [7, 13C19]. As the developmental defect of TECs results in a lack of regular T-cell development and selection, FOXN1 deficiency has been classified as a rare form of severe combined immunodeficiency (SCID) with absent or low T-cells (i.e. a T-/lowB+NK+ SCID). SCID syndromes are an aetiologically heterogeneous group of genetic disorders, defined by defects in T-cell development and function and a variable impact on the development of B- and NK-cells [20]. Consequently patients are unable to produce protective immune responses and present in early infancy with life-threatening infections [20]. Nude SCID is an example of a SCID syndrome that is not due to mutation of a gene expressed in hematopoietic cells but rather constitutes an abnormality of the thymic stromal cell compartment, namely TECs, essential for normal T-cell development [21]. As with other SCIDs, early diagnosis and management is critical in order to prevent accumulation of end-organ damage due to severe infections [22]. Review Disease name/synonyms Nude SCID [2, 23] is also known as FOXN1 deficiency [23], alymphoid cystic thymic dysgenesis (ORPHA169095) [24], severe T-cell immunodeficiency, congenital alopecia, nail dystrophy syndrome (MIM601705) [1] and Winged helix deficiency [2]. Epidemiology Nude SCID is very rare with an estimated incidence of 1/1,000,000. Only nine cases have been reported in the literature to date. Six patients originated from Acerno in southern Italy; all had the same homozygous founder mutation (R255X) carried by 6.52% of the villages inhabitants [25]. An identical mutation was later identified in a Portuguese child born to consanguineous parents [23]. Two additional mutations have been identified in single patients of mixed French/African (R320W) and consanguineous Lebanese origin (S188fs) [23, 26]. Clinical description The human nude SCID phenotype is characterised by the clinical triad of athymia and resultant SCID, congenital AU and nail dystrophy (Table?1) [1, 23, 25C27]. Table 1 Table of reported cases of FOXN1 deficiency alopecia universalis, Omenn Syndrome, failure to thrive, T-cells, B-cells, NK-cells, female, male, sibling, + present, ? absent, months old, years, increased count, decreased count, ? normal count, cluster of differentiation, chest x-ray, antibody, Human leucocyte antigen, bone marrow transplant, T-cell receptor, Bacillus CalmetteCGurin, Human herpes virus 6, T-cell receptor excision circles, Immunoglobulin, Haematopoietic stem cell transplant Sirtinol All reported patients presented in the first months of life with Sirtinol severe, recurrent, life-threatening infections [1, 23, 25] reflecting their severely impaired T-cell-mediated immune response to viral, fungal and opportunistic infections as well as live vaccines [1, 23, 28, 29]. Although B-cells are typically present in normal numbers, antibody production is compromised in the absence of T-cell help [1, 23, 29] rendering patients susceptible to infections with encapsulated bacteria [1, 23, 29, 30]. Patients with nude SCID may have features Sirtinol of Omenn Syndrome (OS) [1, 23, 26], an inflammatory condition caused by expansions auto-reactive T-cells in the setting of SCID and characterised by erythroderma, hepatosplenomegaly, lymphadenopathy, diarrhoea and Sirtinol failure-to-thrive [31]. A detailed description of the immunological phenotype can be found in Tables?1 and ?and22 and in the section on diagnosis. Table 2 Table of suggested diagnostic tests and investigations with expected findings sequencingmutations- Homozygous mutationReferences, polymerase chain reaction, increased, decreased, ? normal, cluster of differentiation, immunoglobulin, T-cell receptor excision circles, Human leucocyte antigen, Phytohaemagglutinin, phorbol myristate acetate, magnetic resonance imaging Dermatological features include congenital alopecia affecting the scalp, eyebrows and eyelashes, and nail dystrophy. The latter most frequently features proximal arciform leukonychia and koilonychia, although canaliform dystrophy and Beaus lines have been noted [32]. Nail dystrophy has also been found in heterozygous carriers of mutations [32]. CNS defects possess only been explained in two fetuses from a single kindred in the highly consanguineous town of Acerno. One displayed anencephaly and spina bifida [13], the other experienced milder abnormalities including an enlarged interhemispheric fissure and absence of the cavum septi pellucidi and corpus callosum [14]. Aetiology Following a fist description of nude SCID [1], linkage analysis and sequencing of the gene in the two index instances, exposed a homozygous nonsense mutation leading to a premature quit codon at amino acid 255 (R255X) [2]. Two additional autosomal recessive mutations (R320W and S188fs) have since been explained [23, 26]. The forkhead package N1 (FOXN1) protein is definitely a transcription element expressed in.