SNOMEDCT: 720345008; ORPHA: 169095; DO: 0060769;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q11.2 | T-cell immunodeficiency, congenital alopecia, and nail dystrophy | 601705 | Autosomal recessive | 3 | FOXN1 | 600838 |
A number sign (#) is used with this entry because of evidence that T-cell immunodeficiency, congenital alopecia, and nail dystrophy (TIDAND) is caused by homozygous mutation in the FOXN1 gene (600838) on chromosome 17q11.
Biallelic mutation in the FOXN1 gene can also cause T-cell immunodeficiency with thymic aplasia (TIDTA; 242700), which shows overlapping features.
Heterozygous mutation in the FOXN1 gene can cause autosomal dominant infantile T-cell lymphopenia with or without nail dystrophy (TLIND; 618806), a less severe disorder with overlapping features.
T-cell immunodeficiency, congenital alopecia, and nail dystrophy (TIDAND) is an autosomal recessive primary immunodeficiency characterized by congenital thymic aplasia and severe T-cell immunodeficiency apparent at birth or soon thereafter. Affected individuals tend to have recurrent infections, oral candidiasis, and failure to thrive. Immunologic investigations show decreased numbers of T cells with poor proliferative response to phytohemagglutinin (PHA) and variable hypogammaglobulinemia. The phenotype is consistent with a T-/B+/NK+ form of severe combined immunodeficiency (SCID; see, e.g., 102700). Patients with FOXN1 mutations do not respond well to hematopoietic stem cell transplantation, as it is not curative; thymic transplantation offers a potential cure (Chou et al., 2014).
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. The other sister underwent bone marrow transplantation (BMT) from her unaffected brother. 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) provided follow-up of this family. The living sister was alive and free of infection 4 years after the transplantation, although alopecia and nail dystrophy were still present. 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) noted that the 2 sisters originated from a geographically isolated small community in southern Italy.
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 founder R255X mutation (600838.0001) in the FOXN1 gene. Posttermination examination at 15 weeks' gestation showed that the fetus lacked a thymus and that 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.
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.
Markert et al. (2011) reported 2 unrelated children with TIDAND. Both had congenital athymia, alopecia, and nail dystrophy. The first patient, born of consanguineous Portuguese parents, developed slowly progressive BCG adenitis and mild erythroderma in the first months of life and then presented with respiratory failure associated with resistant Mycobacteria bovis infection. Immunologic workup showed T-cell lymphopenia with low naive T cells and increased double-negative CD4-/CD8- T cells, consistent with thymic dysfunction. The T cells were oligoclonal and initially showed poor proliferative response to PHA. The second patient, born of possibly related French/North African parents, presented at 3 months of age with a severe respiratory infection and was found to be positive for herpes HHV6. Immune workup showed absence of T cells and no proliferative response to PHA. The children also had Ig deficiencies and were treated with Ig supplementation. Both patients were treated successfully with allogeneic thymus transplantation, resulting in functional T- and B-cell reconstitution with naive and functional T cells, diverse TCR repertoires, normal postvaccine antibody responses, and significant clinical improvement. However, 1 patient developed autoimmune thyroid disease 1.6 years after transplantation. The authors noted phenotypic overlap to DiGeorge syndrome (DGS; 188400), in which patients have thymic aplasia or hypoplasia.
Chou et al. (2014) reported an infant, born of consanguineous Lebanese parents, with TIDAND. She presented at 1 month of age with a diffuse eczematous rash, erythroderma, alopecia, and severe diarrhea. Laboratory studies showed CD3+ T-cell lymphopenia with most cells having a CD45RO+ memory phenotype and decreased numbers of CD45RA+ recent thymic emigrants. Total B and NK cell numbers were normal, but B cell memory cells were severely decreased. Lymphocyte proliferation to anti-CD3 and PHA was absent, but response to PMA and ionomycin was normal. Prior to the genetic diagnosis, she was treated with hematopoietic stem cell transplantation at age 5 months, but she died from complications.
Radha Rama Devi et al. (2017) reported a 1-month-old girl, born of consanguineous Indian parents, with TIDAND. She presented soon after birth with congenital alopecia, lack of eyebrows and eyelashes, dystrophic nails, recurrent diarrhea with failure to thrive, and oral candidiasis. Immunologic workup showed total absence of T cells and hypogammaglobulinemia. An older sib with a similar phenotype had died at 7 months of age. Exome sequencing identified homozygosity for the Italian founder mutation in the FOXN1 gene (R255X; 600838.0001). The unaffected parents, who were noted not to have ectodermal or immunologic abnormalities, were heterozygous carriers. Functional studies of the variant were not performed. The patient was treated 3 times with hematopoietic stem cells without clinical improvement; she died in infancy.
The transmission pattern of TIDAND in the families reported by Markert et al. (2011) was consistent with autosomal recessive inheritance.
Patients with FOXN1 mutations may not respond well to hematopoietic stem cell transplantation, and it is not curative. Thymic transplantation offers a potential cure (Chou et al., 2014).
In 2 unrelated children with TIDAND, Markert et al. (2011) reported successful treatment with allogenic thymus transplantation. After transplantation, both developed functional T- and B-cell reconstitution with naive and functional T cells, diverse TCR repertoires, normal postvaccine antibody responses, and significant clinical improvement. However, 1 patient developed autoimmune thyroid disease 1.6 years after transplantation. The authors noted phenotypic overlap to DiGeorge syndrome (DGS; 188400), in which patients have thymic aplasia or hypoplasia.
In the 2 sisters with TIDAND described by Pignata et al. (1996), Frank et al. (1999) identified a homozygous nonsense mutation (R255X; 600838.0001) in the FOXN1 gene. Frank et al. (1999) identified this phenotype as a human homolog of the 'nude' mouse.
In 2 unrelated patients with TIDAND, Markert et al. (2011) identified homozygous mutations in the FOXN1 gene. A patient born of consanguineous Portuguese parents was homozygous for the Italian founder mutation (R255X), whereas a patient born of possibly distantly related parents of North African/French descent was homozygous for a missense variant (R320W; 600838.0002). Functional studies of the variants were not performed, but both variants were predicted to abolish FOXN1 activity.
In a girl, born of consanguineous Lebanese parents, with TIDAND, Chou et al. (2014) identified a homozygous frameshift mutation in the FOXN1 gene (600838.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of the variant in patient cells were not performed.
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.
The mouse and rat 'nude' phenotype (see Flanagan, 1966) consists of disruption of normal hair growth and thymus development, causing nude mice and rats to be immunodeficient. The mouse 'nude' locus was localized to mouse chromosome 11 within a less than 1-Mb critical region. Nehls et al. (1994) showed that Foxn1 gene, which is in this critical region, was disrupted on nude mouse and rat mutant alleles.
Adriani, M., Martinez-Mir, A., Fusco, F., Busiello, R., Frank, J., Telese, S., Matrecano, E., Ursini, M. V., Christiano, A. M., Pignata, C. Ancestral founder mutation of the nude (FOXN1) gene in congenital severe combined immunodeficiency associated with alopecia in southern Italy population. Ann. Hum. Genet. 68: 265-268, 2004. [PubMed: 15180707] [Full Text: https://doi.org/10.1046/j.1529-8817.2004.00091.x]
Amorosi, S., D'Armiento, M., Calcagno, G., Russo, I., Adriani, M., Christiano, A. M., Weiner, L., Brissette, J. L., Pignata, C. FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus. Clin. Genet. 73: 380-384, 2008. [PubMed: 18339010] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.00977.x]
Chou, J., Massaad, M. J., Waim, R. H., Bainter, W., Dbaibo, G., Geha, R. S. A novel mutation in FOXN1 resulting in SCID: a case report and literature review. (Letter) Clin. Immun. 155: 30-32, 2014. [PubMed: 25173801] [Full Text: https://doi.org/10.1016/j.clim.2014.08.005]
Flanagan, S. P. 'Nude,' a new hairless gene with pleiotropic effects in the mouse. Genet. Res. 8: 295-309, 1966. [PubMed: 5980117] [Full Text: https://doi.org/10.1017/s0016672300010168]
Frank, J., Pignata, C., Panteleyev, A. A., Prowse, D. M., Baden, H., Weiner, L., Gaetaniello, L., Ahmad, W., Pozzi, N., Caerhalmi-Friedman, P. B., Aita, V. M., Uyttendaele, H., Gordon, D., Ott, J., Brissette, J. L., Christiano, A. M. Exposing the human nude phenotype. Nature 398: 473-474, 1999. [PubMed: 10206641] [Full Text: https://doi.org/10.1038/18997]
Markert, M. L., Marques, J. G., Neven, B., Devlin, B. H., McCarthy, E. A., Chinn, I. K., Albuquerque, A. S., Silva, S. L., Pignata, C., de Saint Basile, G., Victorino, R. M., Picard, C., Debre, M., Manlaoui, N., Fischer, A., Sousa, A. E. First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases. Blood 117: 688-696, 2011. [PubMed: 20978268] [Full Text: https://doi.org/10.1182/blood-2010-06-292490]
Nehls, M., Pfeifer, D., Schorpp, M., Hedrich, H., Boehm, T. New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372: 103-107, 1994. [PubMed: 7969402] [Full Text: https://doi.org/10.1038/372103a0]
Pignata, C., Fiore, M., Guzzetta, V., Castaldo, A., Sebastio, G., Porta, F., Guarino, A. Congenital alopecia and nail dystrophy associated with severe functional T-cell immunodeficiency in two sibs. Am. J. Med. Genet. 65: 167-170, 1996. [PubMed: 8911612] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19961016)65:2<167::AID-AJMG17>3.0.CO;2-O]
Radha Rama Devi, A., Panday, N. N., Naushad, S. M. FOXN1 Italian founder mutation in Indian family: implications in prenatal diagnosis. Gene 627: 222-225, 2017. [PubMed: 28636882] [Full Text: https://doi.org/10.1016/j.gene.2017.06.033]
Vigliano, I., Gorrese, M., Fusco, A., Vitiello, L., Amorosi, S., Panico, L., Ursini, M. V., Calcagno, G., Racioppi, L., Del Vecchio, L., Pignata, C. FOXN1 mutation abrogates prenatal T-cell development in humans. J. Med. Genet. 48: 413-416, 2011. [PubMed: 21507891] [Full Text: https://doi.org/10.1136/jmg.2011.089532]