Ectodermal Dysplasia, Hypohidrotic, with Immune Deficiency
Alternative titles; symbols
HED-IDECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNE DEFICIENCY, INCLUDEDEDA-ID, INCLUDEDHYPER-IgM IMMUNODEFICIENCY, X-LINKED, WITH ECTODERMAL DYSPLASIA, HYPOHIDROTIC, INCLUDEDXHM-ED, INCLUDED
Gene map locus Xq28
TEXT
A number sign (#) is used with this entry because of evidence that hypohidrotic ectodermal dysplasia with immune deficiency, an X-linked recessive disorder, is caused by mutations in the IKK-gamma gene (IKBKG, or NEMO; 300248).
DESCRIPTION
Hypohidrotic ectodermal dysplasia (HED; 305100), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant (129490) and autosomal recessive (224900) forms exist.
CLINICAL FEATURES
Zonana et al. (2000) studied males from 4 families with HED and immunodeficiency (HED-ID), in which the disorder segregated as an X-linked recessive trait. Affected males manifested dysgammaglobulinemia and, despite therapy, had significant morbidity and mortality from recurrent infections. The proband in 1 of the 4 families with HED-ID studied by Zonana et al. (2000) presented during the first year of life with recurrent infections and had repeated hospitalizations for pneumonia and bacterial infections of both bone and soft tissues.
Immunoglobulin levels were abnormally low, and inability to sweat had been noted since infancy, requiring life-long cooling measures. Dental examination at age 12 years showed absence of 7 teeth from his secondary dentition as well as conical-shaped maxillary lateral incisors. He developed bronchiectasis with pulmonary insufficiency and died at the age of 17 years after bilateral lung transplantation. A younger brother had similar clinical manifestations. Both had normal scalp hair. The clinical features in the other 3 families were very similar, although some of the affected members had sparse head hair.
Doffinger et al. (2001) identified 5 additional kindreds with anhidrotic ectodermal dysplasia and immunodeficiency. Survival ranged from 9 months to 17 years. In all patients, ectodermal dysplasia features were somewhat milder than in those children with anhidrotic ectodermal dysplasia without immunodeficiency. Most children experienced failure to thrive, recurrent digestive tract infections, often with intractable diarrhea and recurrent ulcerations, recurrent respiratory tract infections, often with bronchiectasis, and recurrent skin infections, suggesting that they were generally susceptible to various gram-positive and gram-negative bacteria. The only blood immunologic abnormality detected in all patients tested was a poor antibody response to polysaccharide antigens (anti-AB isohemagglutinins and antibodies against H. influenzae and S. pneumoniae). In most patients, low levels of IgG or IgG2 were detected. Intravenous immunoglobulins and prophylactic antibiotics had occasionally been sufficient to improve clinical status when started early.
MOLECULAR GENETICS
Because mutations in the IKK-gamma gene were shown to cause familial incontinentia pigmenti (IP2; 308300), Zonana et al. (2000) speculated that since IKK-gamma plays a role in T- and B-cell function, the association of a skin disorder with the immune defect in the X-linked HED-ID might be due to a mutation in the NEMO gene. IP2 affects females and, with few exceptions, causes male prenatal lethality. Hypothesizing that 'milder' mutations at the NEMO locus may cause HED-ID, Zonana et al. (2000) studied affected members of 4 families and in all found mutations in exon 10 of the NEMO gene affecting the C terminus of the IKK-gamma protein (see, e.g., 300248.0007).
Mutations in the CD40L gene (300386) lead to deficient CD40L expression on T cells and cause X-linked hyper-IgM immunodeficiency (XHM; 308230). Mutations in the ectodysplasin gene (ED1; 300451) and in the DL gene (604095) lead to ectodermal dysplasia (ED). Some patients, however, have XHM associated with ED (XHM-ED) and have normal CD40L expression on T cells, no CD27 (186711) expression on T cells, and no mutations in the DL or ED1 genes. In 2 patients with XHM-ED, Jain et al. (2001) identified mutations in the NEMO gene. The mutations, cys417 to arg (300248.0009) and asp406 to val (300248.0011), occurred in the putative zinc finger motif of NEMO, a potentially shared intracellular signaling component for DL and CD40L. The 2 unrelated male patients had serum gamma-globulin concentrations of less than 200 mg/dL in infancy. One patient had presented with pneumococcal meningitis at 9 months of age, and both patients suffered from frequent upper respiratory and sinus infections despite intravenous gamma-globulin replacement therapy. In contrast to XHM patients, neither XHM-ED patient had a history of opportunistic infections suggestive of T-cell dysfunction. One patient had conical-shaped molars and incisors. Skin biopsies for both patients confirmed the absence of eccrine sweat glands and a paucity of hair follicles. Unlike some of the patients with ED and immunodeficiency reported by Zonana et al. (2000), both XHM-ED patients had normal bone density and neither had a medical history indicative of Mycobacterium avium complex infection.
REFERENCES
1. Doffinger, R.; Smahi, A.; Bessia, C.; Geissmann, F.; Feinberg, J.; Durandy, A.; Bodemer, C.; Kenwrick, S.; Dupuis-Girod, S.; Blanche, S.; Wood, P.; Rabia, S. H.; and 16 others :
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling. Nature Genet. 27: 277-285, 2001.PubMed ID : 11242109
2. Jain, A.; Ma, C. A.; Liu, S.; Brown, M.; Cohen, J.; Strober, W. :
Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic (sic) ectodermal dysplasia. Nature Immun. 2: 223-228, 2001.PubMed ID : 11224521
3. Zonana, J.; Elder, M. E.; Schneider, L. C.; Orlow, S. J.; Moss, C.; Golabi, M.; Shapira, S. K.; Farndon, P. A.; Wara, D. W.; Emmal, S. A.; Ferguson, B. M. :
A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am. J. Hum. Genet. 67: 1555-1562, 2000.PubMed ID : 11047757
..........
ECTODERMAL DYSPLASIA, HYPOHIDROTIC, WITH IMMUNE DEFICIENCY
Alternative titles; symbols HED-IDECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNE DEFICIENCY, INCLUDEDEDA-ID, INCLUDEDHYPER-IgM IMMUNODEFICIENCY, X-LINKED, WITH ECTODERMAL DYSPLASIA, HYPOHIDROTIC, INCLUDEDXHM-ED, INCLUDED
Gene map locus Xq28
TEXT
A number sign (#) is used with this entry because of evidence that hypohidrotic ectodermal dysplasia with immune deficiency, an X-linked recessive disorder, is caused by mutations in the IKK-gamma gene (IKBKG, or NEMO; 300248).
DESCRIPTION
Hypohidrotic ectodermal dysplasia (HED; 305100), a congenital disorder of teeth, hair, and eccrine sweat glands, is usually inherited as an X-linked recessive trait, although rarer autosomal dominant (129490) and autosomal recessive (224900) forms exist.
Zonana et al. (2000) studied males from 4 families with HED and immunodeficiency (HED-ID), in which the disorder segregated as an X-linked recessive trait. Affected males manifested dysgammaglobulinemia and, despite therapy, had significant morbidity and mortality from recurrent infections. The proband in 1 of the 4 families with HED-ID studied by Zonana et al. (2000) presented during the first year of life with recurrent infections and had repeated hospitalizations for pneumonia and bacterial infections of both bone and soft tissues.
Immunoglobulin levels were abnormally low, and inability to sweat had been noted since infancy, requiring life-long cooling measures. Dental examination at age 12 years showed absence of 7 teeth from his secondary dentition as well as conical-shaped maxillary lateral incisors. He developed bronchiectasis with pulmonary insufficiency and died at the age of 17 years after bilateral lung transplantation. A younger brother had similar clinical manifestations. Both had normal scalp hair. The clinical features in the other 3 families were very similar, although some of the affected members had sparse head hair.
Doffinger et al. (2001) identified 5 additional kindreds with anhidrotic ectodermal dysplasia and immunodeficiency. Survival ranged from 9 months to 17 years. In all patients, ectodermal dysplasia features were somewhat milder than in those children with anhidrotic ectodermal dysplasia without immunodeficiency. Most children experienced failure to thrive, recurrent digestive tract infections, often with intractable diarrhea and recurrent ulcerations, recurrent respiratory tract infections, often with bronchiectasis, and recurrent skin infections, suggesting that they were generally susceptible to various gram-positive and gram-negative bacteria. The only blood immunologic abnormality detected in all patients tested was a poor antibody response to polysaccharide antigens (anti-AB isohemagglutinins and antibodies against H. influenzae and S. pneumoniae). In most patients, low levels of IgG or IgG2 were detected. Intravenous immunoglobulins and prophylactic antibiotics had occasionally been sufficient to improve clinical status when started early.
MOLECULAR GENETICS
Because mutations in the IKK-gamma gene were shown to cause familial incontinentia pigmenti (IP2; 308300), Zonana et al. (2000) speculated that since IKK-gamma plays a role in T- and B-cell function, the association of a skin disorder with the immune defect in the X-linked HED-ID might be due to a mutation in the NEMO gene. IP2 affects females and, with few exceptions, causes male prenatal lethality. Hypothesizing that 'milder' mutations at the NEMO locus may cause HED-ID, Zonana et al. (2000) studied affected members of 4 families and in all found mutations in exon 10 of the NEMO gene affecting the C terminus of the IKK-gamma protein (see, e.g., 300248.0007).
Mutations in the CD40L gene (300386) lead to deficient CD40L expression on T cells and cause X-linked hyper-IgM immunodeficiency (XHM; 308230). Mutations in the ectodysplasin gene (ED1; 300451) and in the DL gene (604095) lead to ectodermal dysplasia (ED). Some patients, however, have XHM associated with ED (XHM-ED) and have normal CD40L expression on T cells, no CD27 (186711) expression on T cells, and no mutations in the DL or ED1 genes. In 2 patients with XHM-ED, Jain et al. (2001) identified mutations in the NEMO gene. The mutations, cys417 to arg (300248.0009) and asp406 to val (300248.0011), occurred in the putative zinc finger motif of NEMO, a potentially shared intracellular signaling component for DL and CD40L. The 2 unrelated male patients had serum gamma-globulin concentrations of less than 200 mg/dL in infancy. One patient had presented with pneumococcal meningitis at 9 months of age, and both patients suffered from frequent upper respiratory and sinus infections despite intravenous gamma-globulin replacement therapy. In contrast to XHM patients, neither XHM-ED patient had a history of opportunistic infections suggestive of T-cell dysfunction. One patient had conical-shaped molars and incisors. Skin biopsies for both patients confirmed the absence of eccrine sweat glands and a paucity of hair follicles. Unlike some of the patients with ED and immunodeficiency reported by Zonana et al. (2000), both XHM-ED patients had normal bone density and neither had a medical history indicative of Mycobacterium avium complex infection.
REFERENCES
1. Doffinger, R.; Smahi, A.; Bessia, C.; Geissmann, F.; Feinberg, J.; Durandy, A.; Bodemer, C.; Kenwrick, S.; Dupuis-Girod, S.; Blanche, S.; Wood, P.; Rabia, S. H.; and 16 others :
X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappa-B signaling. Nature Genet. 27: 277-285, 2001.PubMed ID : 11242109
2. Jain, A.; Ma, C. A.; Liu, S.; Brown, M.; Cohen, J.; Strober, W. :
Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic (sic) ectodermal dysplasia. Nature Immun. 2: 223-228, 2001.PubMed ID : 11224521
3. Zonana, J.; Elder, M. E.; Schneider, L. C.; Orlow, S. J.; Moss, C.; Golabi, M.; Shapira, S. K.; Farndon, P. A.; Wara, D. W.; Emmal, S. A.; Ferguson, B. M. :
A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am. J. Hum. Genet. 67: 1555-1562, 2000.PubMed ID : 11047757
..........
See Also:
ECTODERMAL DYSPLASIA 1, ANHIDROTIC; ED1
Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO
posted by Pat O'Connor @ 1:48 AM
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