Ectodermale dysplasia, anhidrotic, with immundeficiency D84.9

Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is a recessive X-linked disorder that typically affects only males. Affected individuals experience recurrent severe infections due to immunodeficiency in early infancy or the first few years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial and fungal infections. Laboratory tests usually show dysgammaglobulinemia with low IgG subsets and normal or elevated IgA and IgM levels, suggesting impaired B-cell "class switching," although immunologic abnormalities may be subtle compared with the clinical picture and B- and T-cell counts are typically normal. There is a weak antibody response to polysaccharide vaccines, particularly pneumococcal; the response to other vaccines is variable.

Ectodermal dysplasia and immunodeficiency-1 (EDAID1) is caused by a hemizygous mutation in the IKK-gamma gene(IKBKG or NEMO; 300248) on chromosome Xq28.

The phenotype is highly variable, likely due to various hypomorphic mutations, and can be fatal in childhood. Patients also have features of ectodermal dysplasia, including conical incisors, hypo-/anhidrosis, and thin skin or hair. Severely affected individuals may also have lymphedema, osteopetrosis, and, rarely, hematologic abnormalities.

Clinical management of EDAID1 depends on the severity of the disorder. Many patients respond well to IVIG and prophylactic antibiotics (summary by Orange et al., 2004, Heller et al. 2020).

Some patients may benefit from bone marrow transplantation. Although only males are usually affected by the immunodeficiency, many patients inherit a mutation from a mother that has mild features of IP or conical teeth (Doffinger et al., 2001, Orange et al. 2004; Roberts et al. 2010, Heller et al. 2020).

The International Incontinentia Pigmenti Consortium (2000) reported a male infant with a severe form of EDAID1. In addition to recurrent infections, the boy suffered from osteopetrosis and lymphedema. He was born with multiple capillary angiomas, developed lower limb lymphedema, and suffered from failure to thrive. Furthermore, recurrent infections due to poor immune function. He survived for two and a half years. Death due to tuberculosis infection. Genetic analysis revealed a hemizygous X420W mutation in the IKBKG gene (300248.0002) inherited from his mother, who suffered from incontinentia pigmenti. Doffinger et al (2001) later studied this patient and classified him as "anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema"(OLEDAID), which falls within the phenotypic spectrum of EDAID1.

Doffinger et al (2001) reported another boy of French descent with a similar OLEDAID phenotype, including recurrent infections, anhidrotic ectodermal dysplasia, lymphedema, and osteopetrosis. The number and morphology of monocytes and polymorphonuclear cells in the blood were normal, and the numbers of B and T cells and responses to vaccine protein antigens (tetanus and polio) were normal. However, serum titers of antibodies to pneumococci were low despite evidence of infection. Serum levels of immunoglobulin isotypes were normal for age, except for low to normal IgG levels.

1. Doffinger R et al (2001) X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling. Nature Genet. 27: 277-285.
2. Heller S et al (2020) T cell impairment is predictive for a severe clinical course in NEMO deficiency. J Clin Immun 40: 421-434.
3. Jain A et al . Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohidrotic ectodermal dysplasia. Nature Immun 2: 223-228.
4. Orange JS et al (2002) Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest 109: 1501-1509.
5. Orange JS et al (2004) The presentation and natural history of immunodeficiency caused by nuclear factor kappa-B essential modulator mutation. J Allergy Clin Immun 113: 725-733.
6. Roberts CML et al (2010) A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency. Europ J Pediat 169: 1403-1407.
7. The International Incontinentia Pigmenti Consortium. Genomic rearrangement in NEMO impairs NF-kappa-B activation and is a cause of incontinentia pigmenti. Nature 405: 466-472.