Hypohidrotic Ectodermal Dysplasia with Immune Deficiency

DISEASE CARD

Disease group	Ectodermal Dysplasia
DISEASE NAME	HYPOHIDROTIC ECTODERMAL DYSPLASIA WITH IMMUNE DEFICIENCY HYPOHIDROTIC ECTODERMAL DYSPLASIA WITH IMMUNODEFICIENCY WITH OSTEOPETROSIS AND LYMPHOEDEMA
Synonymous	-
Estimated prevalence	-
OMIM	300291, 300301
Inheritance	x-linked dominant
Gene (s)	IKK-gamma (603273)

Clinical Description

Hypohidrotic ectodermal dysplasia (HED) with immune deficiency has originally been identified in a patient with military tuberculosis and in a patient with recurrent life-threatening infections due to Pseudomonas aeruginosa, Mycobacterium avium and cytomegalovirus^{.1, 2} Patients displayed highly variable features of HED (see Hypohidrotic Ectodermal Dysplasias). Further cases followed, where HED occurred together with recurrent or serious, life-threatening infections due to the pathogens Streptococcus pneumonia, Staphylococcus aureus, gram-negative bacteria (Pseudomonas spp., Haemophilus influenzae) or mycobacteria. Failure to thrive is common in these patients as well as premature death, as infections start in early infancy or first years of life. Laboratory abnormalities are present in most patients and include (severe) hypogammaglobulinaemia with low serum IgG levels as well deficiencies of further immunoglobulin isotypes (IgA, IgM, IgE). Rarely, elevated IgM levels can occur.^{3, 4}

Additional, a few cases of HED with immunodeficiency with osteopetrosis and lymphedema have been reported so far.^5-8

Pathogenesis

HED with immune deficiency is an X-linked dominant disorder caused by a mutation in the IKBKG gene (formerly known as NEMO - NF-kappa β Essential MOdulator). Impaired antibody response to polysaccharides (polysaccharide vaccinations, particularly pneumococcus). This mutation is present in most patients, rarely a defect natural killer cell activity is causative. The pathogenesis of osteopetrosis is not entirely clear, but NF-kβ is an essential molecule in osteoclast development. ^{3, 9, 10}

Diagnosis

The diagnosis is usually made soon after birth as most patients display typical features of HED together with severe hypogammglobulinaemia and serious, recurrent infections. The presence of a hypomorphic mutation in IKBKG will help confirm the diagnosis.

Although immunodeficiency occurs only in males, several mothers show features of incontinentia pigmenti (caused by heterozygous IKBKG gene mutation) or conical teeth.⁹

Treatment

Affected patients will require intensive in-patient management in order to treat serious infections. Intravenous immunoglobulins and prophylactic antibiotics are frequently necessary. Some may require bone marrow transplantations.¹¹ For treatment recommendations of HED clinical features see “Hypohidrotic Ectodermal Dysplasias”

References

^{1. Frix CD, 3rd, Bronson DM. Acute miliary tuberculosis in a child with anhidrotic ectodermal dysplasia. Pediatr Dermatol. 1986;3(6):464-467.}

^{2. Sitton JE, Reimund EL. Extramedullary hematopoiesis of the cranial dura and anhidrotic ectodermal dysplasia. Neuropediatrics. 1992;23(2):108-110.}

^{3. Smahi A, Courtois G, Rabia SH, et al. The NF-kappaB signalling pathway in human diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency syndromes. Hum Mol Genet. 2002;11(20):2371-2375.}

^{4. Fusco F, Pescatore A, Conte MI, et al. EDA-ID and IP, two faces of the same coin: how the same IKBKG/NEMO mutation affecting the NF-κB pathway can cause immunodeficiency and/or inflammation. Int Rev Immunol. 2015;34(6):445-459.}

^{5. Dupuis-Girod S, Corradini N, Hadj-Rabia S, et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics. 2002;109(6):e97.}

^{6. Mansour S, Woffendin H, Mitton S, et al. Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection. Am J Med Genet. 2001;99(2):172-177.}

^{7. Roberts CM, Angus JE, Leach IH, McDermott EM, Walker DA, Ravenscroft JC. A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID). Eur J Pediatr. 2010;169(11):1403-1407}

^{8. Carlberg VM, Lofgren SM, Mann JA, et al. Hypohidrotic ectodermal dysplasia, osteopetrosis, lymphedema, and immunodeficiency in an infant with multiple opportunistic infections. Pediatr Dermatol. 2014;31(6):716-721.}

^{9. Döffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001;27(3):277-285.}

^{10. Orange JS, Brodeur SR, Jain A, et al. Deficient natural killer cell cytotoxicity in patients with IKK-gamma/NEMO mutations. J Clin Invest. 2002;109(11):1501-1509.}

^{11. Abbott JK, Quinones RR, de la Morena MT, Gelfand EW. Successful hematopoietic cell transplantation in patients with unique NF-κB essential modulator (NEMO) mutations. Bone Marrow Transplant. 2014;49(11):1446-1447.}