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Ectodermal Dysplasia. Hypoehidrotic, with Immune Deficiency

Hypohidrotic Ectodermal Dysplasia, Osteopetrosis, Lymphedema, and Immunodeficiency

Dysplasia-Anhidrotic-Immunodeficiency

OL-EDA-ID Syndrome

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Clinical and Discussion

Classified as a syndrome of lymphatic dysplasia, this condition also is included in the family of Ectodermal dysplasia syndromes.  One of the complications of this particular form  involved is lymphedema.

Ectodermal Dysplasia (ED) is not a single disorder, but a group of closely related conditions of which more than 150 different syndromes have been identified. The Ectodermal Dysplasias (EDs) are genetic disorders affecting the development or function of the teeth, hair, nails and sweat glands. Depending on the particular syndrome ED can also affect the skin, the lens or retina of the eye, parts of the inner ear, the development of fingers and toes, the nerves and other parts of the body. Each syndrome usually involves a different combination of symptoms, which can range from mild to severe. (1)

Three clinically similar but genetically distinct forms of HED exist. The X-linked recessive (EDA gene) and autosomal recessive forms (EDAR and EDARADD genes) are indistinguishable; the autosomal dominant form (EDAR and EDARADD genes) is milder in expression. In X-linked HED, sequence analysis of the EDA coding region, available on a clinical basis, detects mutations in about 95% of males and a lower percentage of carrier females. Sequence analysis of the EDAR coding region is available on a clinical basis. Molecular genetic testing of the EDARADD gene is available on a research basis only. (2)

Genetic: Gene map locus Xq28; X-linked recessive; hypomorphic mutations in NEMO

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).

Synonyms: OLEDAID Syndrome; HED-ID; ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNE DEFICIENCY, INCLUDED; EDA-ID, INCLUDED HYPER-IgM IMMUNODEFICIENCY, X-LINKED, WITH ECTODERMAL DYSPLASIA, HYPOHIDROTIC, INCLUDED XHM-ED, INCLUDED

Symptoms and Signs:

Other symptoms may include failure to thrive, sparse scalp hair, conical front teeth or peg teeth, dysgammaglobulinemia.

*Note that Ectodermal dysplasia, hypohidrotic, with immune deficiency symptoms usually refers to various symptoms known to a patient, but the phrase Ectodermal dysplasia, hypohidrotic, with immune deficiency signs may refer to those signs only noticable by a doctor.

Diagnosis:

Pre-natal diagnosis is available for some families with X-linked hypohidrotic ectodermal dysplasia, through the use of DNA probes.Diagnosis may also be achieved through the clinical symptoms.

Differential Diagnosis:

Numerous types of ectodermal dysplasia exist. Hypodontia with a vague history of heat intolerance or slight sparseness of the hair is a particularly common and troublesome differential diagnosis [Aswegan et al 1997, Ho et al 1998].

The presence of onychodysplasia (inherent abnormalities of nail development) and other developmental abnormalities favor diagnoses other than hypohydrotic ectodermal dysplasia (HED).

Other types of HED that need to be considered are the autosomal dominant tooth and nail types, including the following:

Treatment:

There is no "cure" and treatment would focus on the signs, symptoms and complications.  There may be surgeries required for dental problems; treatment for lymphedema is required; a program of preventative care is essential due to the immunodificiency.

Prognosis:

Initially guarded based on severity of complications such a immunodeficiency. Normal life span can be achieved. However for this to occur,  treatment of the complications or symptoms such as lymphedema is imperative and the patient will, because of the immunodeficiency, be susceptible to infections. 

Pat O'Connor

May 27, 2008

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Hypohidrotic Ectodermal Dysplasia, Osteopetrosis, Lymphedema, and Immunodeficiency in an Infant with Multiple Opportunistic Infections.

Feb 2013
Carlberg VM, Lofgren SM, Mann JA, Austin JP, Nolt D, Shereck EB, Davila-Saldana B, Zonana J, Krol AL.

Source

Department of Dermatology, Oregon Health and Science University, Portland, Oregon; School of Medicine, Oregon Health and Science University, Portland, Oregon.

Abstract

Osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-HED-ID) is a rare X-linked disorder with only three reported prior cases in the English-language literature. We describe a case of OL-HED-ID in a male infant who initially presented with congenital lymphedema, leukocytosis, and thrombocytopenia of unknown etiology at 7 days of age. He subsequently developed gram-negative sepsis and multiple opportunistic infections including high-level cytomegalovirus viremia and Pneumocystis jiroveci pneumonia. The infant was noted to have mildly xerotic skin, fine sparse hair, and periorbital wrinkling, all features suggestive of ectodermal dysplasia. Skeletal imaging showed findings consistent with osteopetrosis, and immunologic investigation revealed hypogammaglobulinemia and mixed T- and B-cell dysfunction. Genetic testing revealed a novel mutation in the nuclear factor kappa beta (NF-KB) essential modulator (NEMO) gene, confirming the diagnosis of OL-HED-ID. Mutations in the NEMO gene have been reported in association with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID), OL-HED-ID, and incontinentia pigmenti. In this case, we report a novel mutation in the NEMO gene associated with OL-HED-ID. This article highlights the dermatologic manifestations of a rare disorder, OL-HED-ID, and underscores the importance of early recognition and prompt intervention to prevent life-threatening infections.

PubMed

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#300291

ECTODERMAL DYSPLASIA, HYPOHIDROTIC, WITH IMMUNE DEFICIENCY

Alternative titles; symbols

HED-ID
ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNE DEFICIENCY, INCLUDED
EDA-ID, INCLUDED
HYPER-IgM IMMUNODEFICIENCY, X-LINKED, WITH ECTODERMAL DYSPLASIA, HYPOHIDROTIC, INCLUDED
XHM-ED, INCLUDEDGene 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 (EDA; 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 EDA 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. 

In affected members and obligate carriers of a family with ectodermal dysplasia and immune deficiency, originally reported by Lie et al. (1978), Orstavik et al. (2006) identified a splice site mutation in the IKBKG gene (300248.0016). The family had 3 stillborn males, 3 affected males who were small for gestational age and died within 8 months, and 1 male who died at age 5 years. The latter had cone-shaped teeth, oligodontia, serious bacterial infections, and inflammatory bowel disease. Isolated subtle tooth anomalies were found in 3 carriers examined, of whom 2 had random X inactivation and 1 had extreme skewing. Orstavik et al. (2006) stated that this was the first report of random X inactivation in carriers of EDA-ID. 

In a female infant with ectodermal dysplasia and immune deficiency, Martinez-Pomar et al. (2005) identified a mutation in the IKBKG gene (300248.0017). The X-inactivation status of peripheral blood cells from the patient was evaluated at 24, 30, 38, and 48 months of age and was found to have progressed from random at 24 and 30 months to skewed at 38 and 48 months of age, at which point her immunodeficiency had disappeared. Martinez-Pomar et al. (2005) stated that this was the first time that selection against the mutated X chromosome in X-linked disease had been documented in vivo. 

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 ectodermal dysplasia. Nature Immun. 2: 223-228, 2001.
PubMed ID : 11224521
3. Lie, S. O.; Froland, S.; Brandtzaeg, P.; Vandvik, B.; Steen-Johnsen, J. :
Transient B cell immaturity with intractable diarrhoea: a possible new immunodeficiency syndrome. J. Inherit. Metab. Dis. 1: 137-143, 1978.
PubMed ID : 117248
4. Martinez-Pomar, N.; Munoz-Saa, I.; Heine-Suner, D.; Martin, A.; Smahi, A.; Matamoros, N. :
A new mutation in exon 7 of NEMO gene: late skewed X-chromosome inactivation in an incontinentia pigmenti female patient with immunodeficiency. Hum. Genet. 118: 458-465, 2005.
PubMed ID : 16228229
5. Orstavik, K. H.; Kristiansen, M.; Knudsen, G. P.; Storhaug, K.; Vege, A.; Eiklid, K.; Abrahamsen, T. G.; Smahi, A.; Steen-Johnsen, J. :
Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation. Am. J. Med. Genet. 140A: 31-39, 2006.
6. 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

CONTRIBUTORS

Marla J. F. O'Neill - updated : 2/15/2006
Marla J. F. O'Neill - updated : 1/25/2006
Paul J. Converse - updated : 3/6/2001
Ada Hamosh - updated : 3/1/2001

CREATION DATE

Victor A. McKusick : 12/20/2000

EDIT HISTORY

OMIM

http://omim.org/entry/300291

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Abstracts and Studies

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A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID).

Eur J Pediatr. 2010 May 21

Catherine M. L. RobertsContact Information, Janet E. Angus1, Ian H. Leach2, Elizabeth M. McDermott3, David A. Walker4 and Jane C. Ravenscroft1

berts CM, 

Department of Dermatology, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK, catherine.roberts@nuh.nhs.uk.

(1) Department of Dermatology, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK
(2) Department of Histopathology, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK
(3) Department of Immunology, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK
(4) Department of Paediatrics, Nottingham University Hospitals, Derby Road, Nottingham, NG7 2UH, UK

Received: 21 March 2010  Accepted: 20 April 2010  Published online: 21 May 2010

Keywords  NEMO - OL-HED-ID - Immunodeficiency

Abstract

Genetic conditions are increasingly recognised as a cause of multisystem diseases in children. We report a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis and lymphoedema, associated with a novel mutation in the NF-kappabeta essential modulator (NEMO) gene. He is the longest surviving of three reported boys with these clinical features. Hypohidrotic ectodermal dysplasia, a congenital disorder of teeth, hair and eccrine sweat glands is most commonly inherited as an X-linked recessive trait. Associated immunodeficiency (HED-ID) may give rise to serious infections in early life. Mutations in the NEMO gene give rise to a heterogeneous group of disorders, including the X-linked dominant disorder incontinentia pigmenti. This is characterised by typical skin changes leading to linear pigmentary change and variable associated features; in males, prenatal death usually occurs. Our patient, like one if the previous cases and all of their mothers, demonstrates features of incontinentia pigmenti.

SpringerLink

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A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency.

Hum Mutat. 2008 Apr

Lopez-Granados E, Keenan JE, Kinney MC, Leo H, Jain N, Ma CA, Quinones R, Gelfand EW, Jain A.

Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland.

Alterations in nuclear factor kappa B (NF-kappaB) essential modulator (NEMO; HUGO-approved symbol IKBKG) underlie most cases of ectodermal dysplasia with immune deficiency (EDI), a human disorder characterized by anhidrosis with diminished immunity. EDI has also been associated with a single heterozygous mutation at position Ser32 of the NF-kappaB inhibitor IkappaBalpha, one of two phosphorylation sites that are essential for targeting IkappaBalpha for proteasomal degradation and hence for activation of NF-kappaB. We report a novel heterozygous nonsense mutation in the IKBA (HUGO-approved symbol, NFKBIA) gene of a 1-year-old male child with EDI that introduces a premature termination codon at position Glu14. An in-frame methionine downstream of the nonsense mutation allows for reinitiation of translation. The resulting N-terminally truncated protein lacks both serine phosphorylation sites and inhibits NF-kappaB signaling by functioning as a dominant negative on NF-kappaB activity in lymphocytes and monocytes. These findings support the scanning model for translation initiation in eukaryotes and confirm the critical role of the NF-kappaB in the human immune response. Hum Mutat 29(6), 861-868, 2008. Published 2008

Wiley InterScience

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Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations.

Hum Mutat. 2008 May

Fusco F, Pescatore A, Bal E, Ghoul A, Paciolla M, Lioi MB, D'Urso M, Rabia SH, Bodemer C, Bonnefont JP, Munnich A, Miano MG, Smahi A, Ursini MV.

Institute of Genetics and Biophysics Adriano Buzzati-Traverso (IGB-CNR), Naples, Italy.

Mutations in the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG), also called nuclear factor-kappaB (NF-kB) essential modulator (NEMO), gene are the most common single cause of incontinentia pigmenti (IP) in females and anhydrotic ectodermal dysplasia with immunodeficiency (EDA-ID) in males. The IKBKG gene, located in the Xq28 chromosomal region, encodes for the regulatory subunit of the inhibitor of kappaB (IkB) kinase (IKK) complex required for the activation of the NF-kB pathway. Therefore, the remarkably heterogeneous and often severe clinical presentation reported in IP is due to the pleiotropic role of this signaling transcription pathway. A recurrent exon 4_10 genomic rearrangement in the IKBKG gene accounts for 60 to 80% of IP-causing mutations. Besides the IKBKG rearrangement found in IP females (which is lethal in males), a total of 69 different small mutations (missense, frameshift, nonsense, and splice-site mutations) have been reported, including 13 novel ones in this work. The updated distribution of all the IP- and EDA-ID-causing mutations along the IKBKG gene highlights a secondary hotspot mutation in exon 10, which contains only 11% of the protein. Furthermore, familial inheritance analysis revealed an unexpectedly high incidence of sporadic cases (>65%). The sum of the observations can aid both in determining the molecular basis of IP and EDA-ID allelic diseases, and in genetic counseling in affected families.

Wiley InterScience

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X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling.

Doffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, Bodemer C, Kenwrick S, Dupuis-Girod S, Blanche S, Wood P, Rabia SH, Headon DJ, Overbeek PA, Le Deist F, Holland SM, Belani K, Kumararatne DS, Fischer A, Shapiro R, Conley ME, Reimund E, Kalhoff H, Abinun M, Munnich A, Israel A, Courtois G, Casanova JL.

Laboratoire de Genetique Humaine des Maladies Infectieuses, Faculte de Medecine Necker-Enfants Malades, Paris, France.

The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.

Publication Types:

PMID: 11242109 [PubMed - indexed for MEDLINE]

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Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO

E D Carrol1, A R Gennery1, T J Flood1, G P Spickett2 and M Abinun1

1 Department of Paediatric Immunology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
2 Regional Immunology Department, Newcastle upon Tyne Hospitals NHS Trust

Correspondence to:
Dr M Abinun, Department of Paediatric Immunology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE4 6BE, UK;
mario.abinun@ncl.ac.uk

Accepted for publication 10 October 2002

ABSTRACT

Anhidrotic (hypohidrotic) ectodermal dysplasia associated with immunodeficiency (EDA-ID; OMIM 300291) is a newly recognised primary immunodeficiency caused by mutations in NEMO, the gene encoding nuclear factor {kappa}B (NF-{kappa}B) essential modulator, NEMO, or inhibitor of {kappa}B kinase (IKK-{gamma}). This protein is essential for activation of the transcription factor NF-{kappa}B, which plays an important role in human development, skin homoeostasis, and immunity.

Keywords: anhidrotic ectodermal dysplasia; immunodeficiency; NEMO; NF-{kappa}B

We present an update on the first reported patient with EDA-ID syndrome1 subsequently shown to be caused by NEMO mutation,2 and our current understanding of this rare primary immunodeficiency.

Immunodeficiency is an important feature of many rare congenital and hereditary conditions involving multiple organs and systems3 (for example, IPEX—immunodeficiency, polyendocrinopathy, enteropathy, X linked; ICF—immunodeficiency, chromosomal instability, facial anomalies; Netherton syndrome, Schimke immuno-osseous dysplasia, etc). For many of these conditions underlying gene mutations have been recently identified, leading to our better understanding of functions of the immune system. From the practical point of view, recognising that immunodeficiency is part of the broader syndrome is important as the majority of care of these rare and complex patients is supervised locally by general paediatricians. Understanding of the interrelation of the problems these patients face allows previously unrecognised complications to be actively sought and treated.


CASE REPORT

We previously described a 4 year old white boy with clinical features of X linked anhidrotic ectodermal dysplasia who suffered from recurrent life threatening infections caused by Streptococcus pneumoniae. We found that he had associated specific antibody deficiency (SPAD), in particular antipolysaccharide antibody deficiency.1 He initially responded well to intravenous immunoglobulin (IVIg) replacement, but as one of the possible explanations for his SPAD was a maturational delay of the immune system, this was stopped after two years and his specific antibody production was reassessed. The original diagnosis was confirmed, as well as low IgG2 subclass level and very low specific antibody response to tetanus toxoid. He was recommenced on IVIg replacement, and at follow up at age 11 years he has remained free of major infections with no evidence of bronchiectasis on high resolution chest computerised tomography (CT) scanning. However, his serum IgA remains very high and that of IgM is declining, suggestive of ongoing immune dysregulation

DISCUSSION

The classification of ectodermal dysplasias has been recently reviewed, and over 150 distinct phenotypes identified based on presentation of abnormal teeth, skin, nails, sweat glands, and hair.4 After our first report, more than 20 patients have been described with features of immunodeficiency associated with X linked anhidrotic ectodermal dysplasia not caused by mutations in ED1 gene causing the common X linked form. These unrelated patients, including ours, were shown to have mutations in NEMO, the gene coding for a molecule with important functions in the NF-{kappa}B signalling pathway.2,5

The EDA-ID syndrome is clinically heterogeneous; the main features are somewhat milder than those of "classical" anhidrotic ectodermal dysplasia (hypo- or anodontia with conical shaped maxillary incisors, dry skin with hypo- or anhidrosis and hypo- or atrichosis). However, some children manifest a more severe phenotype with osteopetrosis and lymphoedema (OL-EDA-ID; OMIM 300301).6 The immunodeficiency, of which the impaired antibody response to polysaccharide antigens is the most consistent laboratory feature, is severe with significant morbidity and mortality. From early childhood, affected boys suffer from unusually severe, life threatening, and recurrent bacterial infections of lower respiratory tract, skin and soft tissues, bones, and gastrointestinal tract, meningitis, and septicaemia, leading to bronchiectasis, chronic lung disease, intractable diarrhoea, and failure to thrive. The commonly implicated pathogens are Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas species, Haemophilus influenzae, and mycobacteria. A number of reported children have died with disseminated mycobacterial infections. Replacement IVIg, antibiotic treatment and prophylaxis, and avoiding live vaccines, especially BCG, are the current management guidelines; bone marrow transplantation has been attempted in one patient.6

EDA-ID is inherited as an X linked recessive trait; the female relatives of affected boys may have variable clinical features such as dry and/or hyperpigmented skin, hypodontia, conical teeth, and sometimes increased serum IgA. Indeed, our patient’s mother has conical teeth. Interestingly, a female patient with features of EDA-ID and a heterozygous hypomorphic NEMO mutation has recently been reported.7

Functional NEMO is essential for activation of the transcription factor NF-{kappa}B, which is involved in inducing immune and inflammatory responses; it is important for normal T and B cell development, as well as osteoclast function, skin epidermal cell growth, and maintenance of the vessel architecture. Its targets include genes that produce antiapoptotic factors, cell adhesion molecules, cytokines, and chemokines.5 The "loss of function" NEMO mutation causes incontinentia pigmenti (IP), where the consecutive lack of NF-{kappa}B activation results in extreme susceptibility to apoptosis, leading to embryonic death in males, and explains the extremely skewed X inactivation seen in females. Finding of hypomorphic NEMO mutations in patients with allelic syndromes of EDA-ID and OL-EDA-ID suggests that the milder phenotype in affected males and both random and skewed X inactivation seen in female carriers are the result of only partial loss of NEMO function.2,5

Both the phenotype-genotype correlation of patients with EDA-ID and the importance of hypomorphic NEMO mutations in disturbed pathways of primarily innate and possibly acquired immunity are currently being investigated.

ACKNOWLEDGEMENTS

We are grateful to Professor J-L Casanova for collaboration, support, and encouragement.

REFERENCES

  1. Abinun M, Spickett G, Appleton AL, et al. Anhidrotic ectodermal dysplasia associated with specific antibody deficiency. Eur J Pediatr 1996;155:146–7. [CrossRef][Medline]
  2. Doffinger R, Smahi A, Bessia C, et al. X-linked anhydrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-{kappa}B signalling. Nat Genet 2001;27:277–85. [CrossRef][Medline]
  3. IUIS Scientific Group. Primary immunodeficiency diseases. Clin Exp Immunol 1999;118(suppl 1):1–28. [CrossRef]
  4. Priolo M, Lagana C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet 2001;38:579–85. [Abstract/Free Full Text]
  5. Aradhya S, Nelson DL. NF-{kappa}B signalling and human disease. Curr Opin Genet Develop 2001;11:300–6. [CrossRef][Medline]
  6. 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:e97. [Abstract/Free Full Text]
  7. Kosaki K, Shimasaki N, Fukushima H, et al. Female patient showing hypohidrotic ectodermal dysplasia and immnodeficiency (HED-ID). Am J Hum Genet 2001;69:664–5. [CrossRef][Medline]

http://adc.bmjjournals.com/cgi/content/full/88/4/340

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A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency

http://www.pubmedcentral.com/articlerender.fcgi?artid=198529

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Osteopetrosis, Lymphedema, Anhidrotic Ectodermal Dysplasia, and Immunodeficiency in a Boy and Incontinentia Pigmenti in His Mother

http://pediatrics.aappublications.org/cgi/content/full/109/6/e97

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Molecular aspects of hypohidrotic ectodermal dysplasia. Sep 2009

http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.32855/abstract?systemMessage=Wiley+Online+Library+will+be+unavailable+17+Dec+from+10-13+GMT+

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External Links:

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Ectodermal dysplasia - Medline Plus

Ectodermal Dysplasia - eMedicine

Ectodermal dysplasia, hypohidrotic, with immune deficiency

http://www.rightdiagnosis.com/e/ectodermal_dysplasia_hypohidrotic_with_immune_deficiency/intro.htm

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References:

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Ectodermal Dysplasia Society (1)

National Institutes of health Gene Reviews (2)

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Support Groups:

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Ectodermal Dysplasia Society (1) United Kingdom

National Foundation for Ectodermal Dysplasias United States

Lymphedema People for secondary complication of Lymphedema

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Classification and External Resources:

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ICD-10

Q82.4 Ectodermal dysplasia (anhidrotic)
Excludes: Ellis-van Creveld syndrome ( Q77.6 )

ICD-9

2008 ICD-9-CM Diagnosis 757.31

Congenital ectodermal dysplasia

  • A group of hereditary disorders involving tissues and structures derived from the embryonic ectoderm. They are characterized by the presence of abnormalities at birth and involvement of both the epidermis and skin appendages. They are generally nonprogressive and diffuse. Various forms exist, including anhidrotic and hidrotic dysplasias, FOCAL DERMAL HYPOPLASIA, and aplasia cutis congenita.
  • 757.31 is a specific code that can be used to specify a diagnosis
  • 757.31 contains 13 index entries
  • View the ICD-9-CM Volume 1 757.* hierarchy

Index entries containing 757.31:

Basan's (hidrotic) ectodermal dysplasia 757.31
Bason's (hidrotic) ectodermal dysplasia 757.31
Clouston's (hidrotic) ectodermal dysplasia 757.31
Dysplasia - see also Anomaly

  • ectodermal (anhidrotic) (Bason) (Clouston's) (congenital) (Feinmesser) (hereditary) (hidrotic) (Marshall) (Robinson's) 757.31

  • hypohidrotic ectodermal 757.31

Ectodermal dysplasia, congenital 757.31
Feinmesser's (hidrotic) ectodermal dysplasia 757.31
Hypohidrotic ectodermal dysplasia 757.31
Marshall's (hidrotic) ectodermal dysplasia 757.31
Robinson's (hidrotic) ectodermal dysplasia 757.31
Siemens' syndrome

  • ectodermal dysplasia 757.31

Syndrome - see also Disease

  • Clouston's (hidrotic ectodermal dysplasia) 757.31

  • Siemens'

    • ectodermal dysplasia 757.31

Disease Database 30597

OMIM: 300291

MeSH: D004476

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Join us as we work for lymphedema patients everywehere:

Advocates for Lymphedema

Dedicated to be an advocacy group for lymphedema patients. Working towards education, legal reform, changing insurance practices, promoting research, reaching for a cure.

http://health.groups.yahoo.com/group/AdvocatesforLymphedema/

Subscribe: AdvocatesforLymphedema-subscribe@yahoogroups.com

Pat O'Connor

Lymphedema People / Advocates for Lymphedema

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For information about Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema\

For Information about Lymphedema Complications

http://www.lymphedemapeople.com/wiki/doku.php?id=complications_of_lymphedema

For Lymphedema Personal Stories

http://www.lymphedemapeople.com/phpBB2/viewforum.php?f=3

For information about How to Treat a Lymphedema Wound

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound

For information about Lymphedema Treatment 

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment

For information about Exercises for Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema

For information on Infections Associated with Lymphedema

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema

For information on Lymphedema in Children

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children

Lymphedema Glossary

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing

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Lymphedema People - Support Groups

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Children with Lymphedema

The time has come for families, parents, caregivers to have a support group of their own. Support group for parents, families and caregivers of chilren with lymphedema. Sharing information on coping, diagnosis, treatment and prognosis. Sponsored by Lymphedema People.

http://health.groups.yahoo.com/group/childrenwithlymphedema/

Subscribe: childrenwithlymphedema-subscribe@yahoogroups.com

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Lipedema Lipodema Lipoedema

No matter how you spell it, this is another very little understood and totally frustrating conditions out there. This will be a support group for those suffering with lipedema/lipodema. A place for information, sharing experiences, exploring treatment options and coping.

Come join, be a part of the family!

http://health.groups.yahoo.com/group/lipedema_lipodema_lipoedema/?yguid=209645515

Subscribe: lipedema_lipodema_lipoedema-subscribe@yahoogroups.com

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MEN WITH LYMPHEDEMA

If you are a man with lymphedema; a man with a loved one with lymphedema who you are trying to help and understand come join us and discover what it is to be the master instead of the sufferer of lymphedema.

http://health.groups.yahoo.com/group/menwithlymphedema/

Subscribe: menwithlymphedema-subscribe@yahoogroups.com

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All About Lymphangiectasia

Support group for parents, patients, children who suffer from all forms of lymphangiectasia. This condition is caused by dilation of the lymphatics. It can affect the intestinal tract, lungs and other critical body areas.

http://health.groups.yahoo.com/group/allaboutlymphangiectasia/

Subscribe: allaboutlymphangiectasia-subscribe@yahoogroups.com

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Lymphatic Disorders Support Group @ Yahoo Groups

While we have a number of support groups for lymphedema... there is nothing out there for other lymphatic disorders. Because we have one of the most comprehensive information sites on all lymphatic disorders, I thought perhaps, it is time that one be offered.

DISCRIPTION

Information and support for rare and unusual disorders affecting the lymph system. Includes lymphangiomas, lymphatic malformations, telangiectasia, hennekam's syndrome, distichiasis, Figueroa
syndrome, ptosis syndrome, plus many more. Extensive database of information available through sister site Lymphedema People.

http://health.groups.yahoo.com/group/lymphaticdisorders/

Subscribe: lymphaticdisorders-subscribe@yahoogroups.com

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Lymphedema People New Wiki Pages

Have you seen our new “Wiki” pages yet?  Listed below are just a sample of the more than 140 pages now listed in our Wiki section. We are also working on hundred more.  Come and take a stroll! 

Lymphedema Glossary 

http://www.lymphedemapeople.com/wiki/doku.php?id=glossary:listing 

Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema 

Arm Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=arm_lymphedema 

Leg Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=leg_lymphedema 

Acute Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=acute_lymphedema 

The Lymphedema Diet 

http://www.lymphedemapeople.com/wiki/doku.php?id=the_lymphedema_diet 

Exercises for Lymphedema  

http://www.lymphedemapeople.com/wiki/doku.php?id=exercises_for_lymphedema 

Diuretics are not for Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=diuretics_are_not_for_lymphedema 

Lymphedema People Online Support Groups 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_people_online_support_groups 

Lipedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=lipedema 

Treatment 

http://www.lymphedemapeople.com/wiki/doku.php?id=treatment 

Lymphedema and Pain Management 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pain_management 

Manual Lymphatic Drainage (MLD) and Complex Decongestive Therapy (CDT)

http://www.lymphedemapeople.com/wiki/doku.php?id=manual_lymphatic_drainage_mld_complex_decongestive_therapy_cdt 

Infections Associated with Lymphedema 

http://www.lymphedemapeople.com/wiki/doku.php?id=infections_associated_with_lymphedema 

How to Treat a Lymphedema Wound 

http://www.lymphedemapeople.com/wiki/doku.php?id=how_to_treat_a_lymphedema_wound 

Fungal Infections Associated with Lymphe dema 

http://www.lymphedemapeople.com/wiki/doku.php?id=fungal_infections_associated_with_lymphedema 

Lymphedema in Children 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_in_children 

Lymphoscintigraphy 

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphoscintigraphy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Extraperitoneal para-aortic lymph node dissection (EPLND) 

http://www.lymphedemapeople.com/wiki/doku.php?id=extraperitoneal_para-aortic_lymph_node_dissection_eplnd 

Axillary node biopsy 

http://www.lymphedemapeople.com/wiki/doku.php?id=axillary_node_biopsy

Sentinel Node Biopsy 

http://www.lymphedemapeople.com/wiki/doku.php?id=sentinel_node_biopsy

Small Needle Biopsy - Fine Needle Aspiration 

http://www.lymphedemapeople.com/wiki/doku.php?id=small_needle_biopsy 

Magnetic Resonance Imaging 

http://www.lymphedemapeople.com/wiki/doku.php?id=magnetic_resonance_imaging 

Lymphedema Gene FOXC2

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_foxc2

 Lymphedema Gene VEGFC

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_vegfc

 Lymphedema Gene SOX18

 http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_gene_sox18

 Lymphedema and Pregnancy

http://www.lymphedemapeople.com/wiki/doku.php?id=lymphedema_and_pregnancy

Home page: Lymphedema People

http://www.lymphedemapeople.com

Page Updated: Dec. 15, 2011