Developmental Disorders of the Lymphatics

An information blog for disorders of the lymphatics. For all articles, please click on "Archives" - Due to spammers, I will no longer allow comments, sorry.

Saturday, December 31, 2005

Kasabach-Merritt Syndrome

Kasabach-Merritt syndrome

141000

HEMANGIOMA-THROMBOCYTOPENIA SYNDROME

Alternative titles; symbols KASABACH-MERRITT SYNDROME; KMS

TEXT

With giant hemangiomas in small children, thrombocytopenia and red cell changes compatible with trauma ('microangiopathic hemolytic anemia') have been observed. The mechanism of the hematologic changes is obscure. No evidence of a simple genetic basis has been discovered. Mulvihill (1982) pointed out to me that hemangioma of the placenta can cause symptomatic thrombocytopenia of the newborn. Experience with the therapy of 6 children with capillary hemangiomas in association with consumptive coagulopathy (Kasabach-Merritt syndrome) was reviewed by Larsen et al. (1987). Sencer et al. (1987) reported the case of a newborn infant with splenic hemangioendothelioma with thrombocytopenia, anemia, and disseminated intravascular coagulation. A splenectomy was indicated despite the known risks of subsequent overwhelming sepsis by encapsulated organisms. Vellodi and Bini (1988) described a severe hyperkalemia resulting in 'malignant ventricular arrhythmias.' They attributed the hyperkalemia to breakdown of erythrocytes. Breakdown of platelets is another possible source.

Enjoiras et al. (1997) concluded that the vascular lesion underlying KMS is not a 'true,' classic, involuting type of hemangioma of infancy. It is a different vascular tumor with a resemblance pathologically to either tufted angioma or kaposiform hemangioendothelioma in association with lymphatic-like vessels.

As indicated, the Kasabach-Merritt syndrome is seen in children with large vascular tumors and is characterized by very low platelet counts and a consumption of coagulation factors causing life-threatening complications. It appears that thrombocytopenia in these patients is caused by intratumoral trapping of platelets. From studies in a mouse model of Kasabach-Merritt syndrome, Verheul et al. (1999) concluded that increased platelet production stimulated by thrombopoietin (THPO; 600044) increased survival and inhibition of tumor growth.

SEE ALSO

Brizel and Raccuglia (1965); David et al. (1983); Propp and Scharfman (1966); Rodriguez-Erdmann et al. (1970)

REFERENCES

1. Brizel, H. E.; Raccuglia, G. :
Giant hemangioma with thrombocytopenia. Radioisotopic demonstration of platelet sequestration. Blood 26: 751-756, 1965.PubMed ID :
5844148

2. David, T. J.; Evans, D. I. K.; Stevens, R. F. :
Haemangioma with thrombocytopenia (Kasabach-Merritt syndrome). Arch. Dis. Child. 58: 1022-1023, 1983.PubMed ID :
6660888

3. Enjoiras, O.; Wassef, M.; Mazoyer, E.; Frieden, I. J.; Rieu, P. N.; Drouet, L.; Taieb, A.; Stalder, J.-F.; Escande, J.-P. :
Infants with Kasabach-Merritt syndrome do not have 'true' hemangiomas. J. Pediat. 130: 631-640, 1997.PubMed ID :
9108863

4. Larsen, E. C.; Zinkham, W. H.; Eggleston, J. C.; Zitelli, B. J. :
Kasabach-Merritt syndrome: therapeutic considerations. Pediatrics 79: 971-980, 1987.PubMed ID :
3108848

5. Mulvihill, J. J. :
Personal Communication. Bethesda, Md., 4/1982.

6. Propp, R. P.; Scharfman, W. B. :
Hemangioma-thrombocytopenia syndrome associated with microangiopathic hemolytic anemia. Blood 28: 623-633, 1966.PubMed ID :
5950934

7. Rodriguez-Erdmann, F.; Murray, J. E.; Moloney, W. C. :
Consumption-coagulopathy in Kasabach-Merritt syndrome. Trans. Assoc. Am. Phys. 83: 168-175, 1970.PubMed ID :
5534090

8. Sencer, S.; Coulter-Knoff, A.; Day, D.; Foker, J.; Thompson, T.; Burke, B. :
Splenic hemangioma with thrombocytopenia in a newborn. Pediatrics 79: 960-966, 1987.PubMed ID :
3588149

9. Vellodi, A.; Bini, R. M. :
Malignant ventricular arrhythmias caused by hyperkalaemia complicating the Kasabach-Merritt syndrome. J. Roy. Soc. Med. 81: 167-168, 1988.

10. Verheul, H. M. W.; Panigrahy, D.; Flynn, E.; Pinedo, H. M.; D'Amato, R. J. :
Treatment of the Kasabach-Merritt syndrome with pegylated recombinant human megakaryocyte growth and development factor in mice: elevated platelet counts, prolonged survival, and tumor growth inhibition. Pediat. Res. 46: 562-565, 1999.PubMed ID :
10541319

CONTRIBUTORS

Victor A. McKusick - updated : 1/10/2000Victor A. McKusick - updated : 6/21/1997

CREATION DATE

Victor A. McKusick : 6/4/1986

EDIT HISTORY

mcapotos : 1/20/2000terry : 1/10/2000terry : 6/24/1997terry : 6/21/1997mimadm : 9/24/1994warfield : 4/8/1994carol : 4/1/1992supermim : 3/16/1992supermim : 3/20/1990ddp : 10/27/1989

Copyright © 1966-2004 Johns Hopkins University

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Kasabach-Merritt syndrome

Hemangioma Thrombocytopenia Syndrome

ImportantIt is possible that the main title of the report Hemangioma Thrombocytopenia Syndrome is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report

Synonyms

Kasabach-Merritt Syndrome
Thrombocytopenia-Hemangioma Syndrome

Disorder Subdivisions

None

General Discussion

Hemangioma-Thrombocytopenia Syndrome (also known as Kasabach-Merritt Syndrome) is a rare disorder characterized by an abnormal blood condition in which the low number of blood platelets causes bleeding (thrombocytopenia). The thrombocytopenia is found in association with a benign tumor consisting of large, blood-filled spaces (cavernous hemangioma). The exact cause of this disorder is not known.

Resources

National Organization for Rare Disorders, Inc.55 Kenosia Ave,PO Box 1968Danbury, CT 06813-1968Tel: (203)744-0100 Fax: (203)798-2291 Tel: (800)999-6673TDD: (203)797-9590 Email: orphan@rarediseases.org

NIH/National Heart, Lung and Blood Institute, 31 Center Drive MSC 2480,Building 31A Rm 4A16,Bethesda, MD 20892-2480 Tel: (301)592-8573 Fax: (301)480-4907 Email: nhlbiinfo@rover.nhlbi.nih.gov

Genetic Alliance, 4301 Connecticut Avenue NW,Suite 404,Washington, DC 20008-2304 USA Tel: 2029665557 Fax: 2029668553 Tel: 8003364363 Email: info@geneticalliance.org

Hemangioma Support System c/o Cynthia Schumerth, 1484 Sand Acres Drive, DePere, WI 54115 Tel: (920)336-9399 Hemangioma Newsline PO Box 0358 Findlay, OH 45839-0358 USATel: 4194251593 Fax: 4194251593 Email: hemangnews@msn.com

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Kasabach-Merritt syndrome: therapeutic considerations.

Kasabach-Merrit Syndrome: A Case Review

Kasabach-Merritt Syndrome

Kasabach-Merritt Syndrome

Kasabach-Merritt Syndrome

Tuesday, December 20, 2005

German Syndrome

231080

Links

GERMAN SYNDROME

TEXT

Lewin and Hughes (1987) presented the cases of a male-female sib pair with 'arthrogryposis,' hypotonia-hypokinesia sequence, and lymphedema. The parents were Ashkenazi Jewish. The authors suggested that the condition in these sibs was the same as that described by German et al. (1975). The boy died at age 2 years of cor pulmonale; the girl was stillborn. This was the first instance of affected sibs. Three of the 4 known families with affected children have been Ashkenazi Jews.

REFERENCES

1. German, J.; Morillo-Cucci, A.; Simpson, J. L.; Chaganti, R. S. K. :
Generalized dysmorphia of a similar type in 2 unrelated babies. Birth Defects Orig. Art. Ser. XI(2): 34-38, 1975.


2. Lewin, S. O.; Hughes, H. E. :
German syndrome in sibs. Am. J. Med. Genet. 26: 385-390, 1987.PubMed ID :
3812590

CREATION DATE

Victor A. McKusick : 2/9/1987

EDIT HISTORY

mimadm : 2/19/1994carol : 7/15/1992supermim : 3/16/1992supermim : 3/20/1990ddp : 10/26/1989marie : 3/25/1988

Copyright © 1966-2004 Johns Hopkins University

Pub Med NIH

Monday, December 19, 2005

Lymphatics at the crossroads of angiogenesis and lymphangiogenesis

Abstract

Scavelli C, Weber E, Agliano M, Cirulli T, Nico B, Vacca A, Ribatti D.

Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bar Medical School, Italy.

The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis. Knowledge of lymphatic development has now been redefined at the molecular level, providing an interesting target for innovative therapies. This review highlights the recent insights and advances into the field of lymphatic vascular research, outlining the most important aspects of the embryo development, structure, specific markers and methods applied for studying lymphangiogenesis. Finally, molecular mechanisms involved in the regulation of lymphangiogenesis are described.

PubMed

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Molecular lymphangiogenesis: new players.

Tammela T, Petrova TV, Alitalo K.

Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Helsinki University Central Hospital, POB 63 (Haartmaninkatu 8), 00014 University of Helsinki, Helsinki, Finland.

The function of the lymphatic vascular system as a conduit for immune cells and excess tissue fluid has been known for over a century, but the molecular players involved in lymphangiogenesis--the formation of lymphatic vessels--have remained unknown until recently. Signals mediated by vascular endothelial growth factor-C, the homeodomain transcription factor PROX1 and the forkhead transcription factor FOXC2 have been implicated in the growth, morphogenesis and hierarchic organization of the lymphatic vascular network. Recent results have also shown the importance of the angiopoietin-Tie and ephrin-Eph signaling systems in lymphangiogenesis, suggesting that these pathways regulate the lymphatic vascular system in a manner similar to, yet distinct from, their regulation of angiogenesis. This review provides an overview of the molecular players involved in lymphangiogenesis, with special emphasis on recently discovered molecular mechanisms

PubMed

Sunday, December 18, 2005

Fabry's Disease

Alternative Titles: Fabry Disease

ANGIOKERATOMA, DIFFUSEANDERSON-FABRY DISEASEHEREDITARY DYSTOPIC LIPIDOSISALPHA-GALACTOSIDASE A DEFICIENCYGLA DEFICIENCYCERAMIDE TRIHEXOSIDASE DEFICIENCYGALACTOSIDASE, ALPHA, INCLUDED; GLA, INCLUDEDALPHA-GALACTOSIDASE A, INCLUDED

Fabry's Disease

What is Fabry's Disease?

Is there any treatment?

What is the prognosis?

What research is being done?

Organizations

What is Fabry's Disease?

Fabry disease is a lipid storage disorder caused by the deficiency of an enzyme involved in the biodegradation of fats. The enzyme is known as ceramidetrihexosidase, also called alpha-galactosidase A. A mutation in the gene that controls this enzyme causes insufficient breakdown of lipids, which then build up in the body and cause a number of symptoms. The gene that is altered in this disorder is on the X-chromosome. If a woman has the mutated gene, her sons have a 50 percent chance of having the condition, and her daughters have a 50 percent chance of being a carrier. Symptoms of the disorder include burning sensations in the hands and feet that get worse with exercise and hot weather, and small, raised, reddish-purple blemishes on the skin. Some boys will also have eye manifestations, especially cloudiness of the cornea. As they grow older, they may have impaired arterial circulation leading to early heart attacks and strokes. The kidneys may become progressively involved, and require kidney transplantation or dialysis. A number of individuals have gastrointestinal difficulties characterized by frequent bowel movements shortly after eating. Some female carriers may also exhibit symptoms of the disorder.

Is there any treatment?

The pain in the hands and feet usually responds to medications such as Tegretol (carbamazepine) and dilantin. Gastrointestinal hyperactivity may be treated with metoclopramide or Lipisorb® (a nutritional supplement). Recent experiments indicate that enzyme replacement is effective therapy for patients with this disorder.

What is the prognosis?

Patients with Fabry disease usually survive into adulthood, but they are at risk for strokes, heart attacks, and kidney damage. It is anticipated that enzyme replacement and eventually gene therapy will eliminate these difficulties.

What research is being done?

NINDS supports research to find ways to treat and prevent lipid storage disorders such as Fabry disease.

Select this link to view a list of all studies currently seeking patients.

Organizations

info@fabry.org
Tel: 660-463-1355 Fax: 660-463-1356

National Tay-Sachs and Allied Diseases Association, 2001 Beacon StreetSuite 204,Brighton, MA 02135 info@ntsad.org Tel: 617-277-4463 800-90-NTSAD (906-8723) Fax: 617-277-0134

National Organization for Rare Disorders (NORD), P.O. Box 1968(55 Kenosia Avenue)Danbury, CT 06813-1968 orphan@rarediseases.org Tel: 203-744-0100 Voice Mail 800-999-NORD (6673)Fax: 203-798-2291

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Fabry disease

What is Fabry disease?

Fabry disease is an inherited disorder caused by a buildup of a particular type of fat (lipid) in the body's cells. This buildup results in pain and potentially life-threatening complications such as progressive kidney damage, heart attack, and stroke. Milder forms of the disorder may appear later in life and only affect the heart.

How common is Fabry disease?

This condition affects an estimated 1 in 40,000 to 117,000 live births. Milder forms of the disorder may be more common.

What genes are related to Fabry disease?

Mutations in the GLA gene cause Fabry disease.

The GLA gene makes an enzyme called alpha-galactosidase A. This enzyme is active in lysosomes, which are structures inside cells that digest and recycle particles that the cell doesn't need. The enzyme normally breaks down a particular molecule called globotriaosylceramide. Mutations in the GLA gene prevent alpha-galactosidase A from breaking down globotriaosylceramide, allowing it to build up in the body's cells. Over time, this buildup damages cells throughout the body, particularly blood vessels in the skin, kidneys, heart, and nervous system.

How do people inherit Fabry disease?

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the gene that causes the disorder is located on the X chromosome (one of the two sex chromosomes). In males, who have only one X chromosome, one altered copy of the gene is sufficient to cause the condition. In females, who have two X chromosomes, a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In some cases, females with one altered copy of the GLA gene may have mild signs and symptoms related to the condition. Other women with one altered copy of the gene experience severe features of the disorder and require treatment.

Where can I find information about Fabry disease?

You may find the following resources about Fabry disease helpful.


NIH Publications - National Institutes of Health Fabry's Disease Information Page (National Institute of Neurological Disorders and Stroke)

MedlinePlus - Health Information Health Topic: Genetic Brain Disorders

Educational resources - Information pages (2 links)

Patient support - For patients and families (4 links)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary

Gene Tests - DNA tests ordered by healthcare professionals

ClinicalTrials.gov - Linking patients to medical research

PubMed - Recent literature

What other names do people use for Fabry disease?

Alpha-galactosidase A deficiency
Anderson-Fabry Disease
Angiokeratoma Corporis Diffusum
Angiokeratoma diffuse
Ceramide trihexosidase deficiency
Fabry's Disease
GLA deficiency
Hereditary dystopic lipidosis

See How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about Fabry disease?

See How can I find a genetics professional in my area? in the Handbook.

Ask the Genetic and Rare Diseases Information Center.

Where can I find general information about genetic conditions?

The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?
What are the different ways in which a genetic condition can be inherited?
If a genetic disorder runs in my family, what are the chances that my children will have the condition?
Why are some genetic conditions more common in particular ethnic groups?

These links provide additional genetics resources that may be useful.

Genetics and health
Resources for Patients and Families
Resources for Health Professionals

What glossary definitions help with understanding Fabry disease?

ceramides ; chromosome ; complication ; deficiency ; enzyme ; gene ; heart attack ; lipid ; lysosome ; molecule ; mutation ; nervous system ; recessive ; sign ; symptom ; X-linked recessive

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.

References (3 links)

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional.

See How can I find a genetics professional in my area? in the Handbook.

National Institutes of Health

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See Also:

Fabry Disease

Saturday, December 17, 2005

Turner Syndrome

Classification: Primary Hereditary Lymphedema with other symptoms

Named after Dr. Henry Turner who was one of the first to describe its features in the 1930's. An internist at the University of Oklahoma, he first identified a common set of traits or physical features in seven of his patients in an article published in 1938. This is a chromosomal condition caused when one of the two x chromosomes normally found in females is missing or incomplete. However, the actual chromosomal deficiency was not identified until 1959.

The condition is diagnosed, or confirmed by a blood test called a kerotype. The test analyzes the chromosomal composition of the individual. Another unique feature of Turner Syndrome is that is occurs only in females.

Characteristics include short stature, lack of ovarian development, webbed neck and/or arms, low hairline at the base of the neck. Other reported signs include cardio-vascular difficulties, kidney and thyroid problems, and scoliosis. Another complication of Turner Syndrome is lymphedema.Because this is a chromosomal based disorder there is no cure. There are treatments however that can lesson the symptoms. These include growth hormone, estrogen replacement therapy.

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Turner Syndrome:

Affects only females because it is sex-linked.* Frequently the lymphatic system, (specifically the valves), is underdeveloped, resulting in childhood lymphoedema. This sometimes resolves by adolescence. Other features of Turner’s Syndrome include short stature, infertility, and sometimes problems with the heart, kidney, or thyroid.(XO instead of XX chromosome; not hereditary]

Ackowledgement


What is Turner syndrome?

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Turner Syndrome Society of the United States

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Turner Society Syndrome Support Society

Turner syndrome [TS] is a chromosome abnormality affecting only females, caused by the complete or partial deletion of the X chromosome. The incidence of TS is approximately 1:2000 live female births.


Confirmation of a diagnosis of TS is by karyotype but a suspected diagnosis can be made by a series of characteristic physical features i.e. web neck, broad chest and widely spaced nipples, low hairline and increased carrying angle of the elbows and other features. Two main clinical features of TS are short stature and non-functioning ovaries. Diagnosis can be made at birth if, for instance, a newborn needs heart surgery because of coarctation of the aorta or because of oedema of the hands and feet. Pre-natal diagnosis is sometimes made by chorionic villous sampling, amniocentesis or ultra sound. However, most girls are diagnosed in early childhood when growth fails or later when the absence of a pubertal growth spurt and development of secondary sexual characteristics become apparent.


Girls with TS may have only a few or several of the features associated with TS, but short stature and infertility are nearly always present. The possibility of growth hormone treatment for short stature and IVF for infertility are options now available to those with TS.

The majority of girls and women with TS are healthy, happy and lead normal lives.

Turner Syndrome[TS]

Turner syndrome is named after an American endocrinologist Dr Henry Turner who, in 1938 described seven women patients with similar physical features including short stature and the absence of female sexual characteristics, increased skin folds in the neck and a wide carrying angle of the arms. Earlier [1930] a German paediatrician, Otto Ullrich, had described the same physical characteristics in female patients. TS is sometimes known as Ullrich-Turner syndrome. It was not until 1959 after the technique for analysing human chromosomes was developed that it was reported that one of the X chromosomes was missing in TS. Later it was shown that the X chromosome can be missing from just some of the body cells or only part of the X chromosome can be missing.

Chromosomes

Chromosome analysis [karyotype] is how a diagnosis of TS is confirmed.

Chromosomes are genetic material inherited 50/50 from both parents. Normally each cell in the body has 23 pairs of chromosomes which make 46 chromosomes in total. One pair of chromosomes are the sex chromosomes and these determine the sex of a baby. In a male there will be an X and a Y chromosome[46XY] and in a female there will be two X chromosomes [46XX]. In TS there is only one X chromosome instead of the usual two [45X or 45XO] the O represents the missing X chromosome. The missing X chromosome, [from either the mother’s egg or the father’s sperm] is an accident and is lost during the cell division that follows conception. 45XO is known as classic TS. Sometimes the X chromosome is missing from only some of the cells [46XX/45XO] and this is known as Turner mosaic. There are a number of other variations in the karyotype for TS, including ring chromosomes. Sometimes a small part of a Y chromosome may be present in TS this is known as mixed gonadal dysgenesis. A geneticist will give a full description of a karyotype and genetic counselling is recommended for all those diagnosed as having TS.

Physical features and clinical characteristics

The term ‘syndrome’ is used to describe a collection or combination of symptoms which result from a single cause, it does not necessarily mean that all are present in the person who has a syndrome.

There are number of physical features and clinical characteristics which may or may not be present in the girl/woman with Turner syndrome. The following is not a comprehensive list but gives some of the possible features of TS.

Lymphoedema of hands and feet [puffy hands and feet]
Broad chest and widely spaced nipples
Droopy eyelids
Low hairline
Low-set ears
Spoon shaped, or small, or hyperconvex nails
Short fourth toe and short fingers
Web neck
High arch palate [which can sometimes lead to feeding problems in babies with TS]
Short stature
Cubitus Valgus[carrying angle of the arms where it is difficult to straighten the elbow]
Otitis media [middle ear infections]
Hearing problems
Myopia [short sightedness]
Pigmented naevi [moles]
Infertility
High blood pressure
Kidney and urinary tract problems
Coarctation [narrowing or constriction of the aorta]
Thyroid problems
Small lower jaw [can lead to orthodontic problems]
Osteoporosis [due to lack of oestrogen, a result of ovarian failure]
Diabetes mellitus
Behavioural problems
Learning difficulties/spatial awareness problems [not mental retardation]


Treatment

There are a number of treatments available to those with TS, and each girl/woman should be treated according to her individual needs.

TS is a ‘cradle to grave’ condition and as such should be treated throughout life in a variety of ways. The girl/woman with TS should be under the care of an endocrinologist [doctor specialising in hormones], initially a paediatric endocrinologist followed by attendance at an Adult TS clinic; there, in addition to an adult endocrinologist, there may be, for example, a gynaecologist/obstetrician present and possibly, hearing and cardiac specialists. A psychologist may also be available to help with problems which may arise from low self esteem and specific learning difficulties.

Those diagnosed in utero or at birth should be under the care of a paediatrician immediately after birth. Girls with TS usually grow at a normal rate until around 3 or 4 years of age when their growth may begin to slow down. In the majority of girls with TS it is possible to increase their final height potential with growth hormone[GH] treatment and this will be discussed with parents by a paediatric endocrinolgist. The success of growth hormone treatment depends on a number of factors such as the age at which GH treatment is started, compliance and when oestrogen is introduced. There is also the possible use of oxandrolone [an anobolic steriod] to promote growth, and again this will be discussed by the specialist. Oestrogen is used to induce secondary sexual characteristics i.e breast development and at an appropriate age is used with progestogen to induce withdrawal bleeds [periods]. Oestrogen is also important for proper mineralisation of bones. Women with TS are able to have an entirely normal sex life. Although girls/women with TS have non- functioning ovaries they have a normal uterus and vagina and it is possible that some women with TS will be able to have a child using a donor egg and IVF treatment. But as in the normal population this is not guaranteed.

Babies with TS born with a heart murmur or narrowing of the aorta [coarctation] will need an expert cardiological assessment and occasionally need surgery to correct the problem.
Girls with TS are more prone than others to middle ear infections, and recurrent infections can lead to deafness if not promptly treated. A consultation with an ear, nose and throat [ENT] specialist would be helpful. All adults with TS need regular hearing checks because a degree of hearing impairment is common.


High blood pressure is quite common in adolescents and adults with TS and should be checked regularly and if necessary treated. There is also a slightly higher risk of diabetes and thyroid gland disorders in women with TS, and this too should be checked.

Osteoporosis can be a problem due to the lack of oestrogen, and HRT [hormone replacement therapy] can possibly help in preventing the early onset of osteoporosis.

Regular health checks are a must for women with TS, and attendance at a specialist adult TS clinic is desirable. These clinics are specifically for women with TS and will usually have specialists from a variety of disciplines present. Ask your GP or contact the TSSS for details of the nearest clinic to where you live. Some hospitals have specialist adolescent clinics to aid the smooth transition from paediatric to adult care.

Occupational therapists, speech therapists, psychologists, educational psychologists, podiatrists, orthodontists, ENT, cardiologists, obstetrician/gynaecologists, endocrinologists, geneticists, dieticians, audiologists, endocrine nurses, ophthalmologists are all specialists in their fields who can possibly help in the care and treatment of those with Turner syndrome. There are also support organisations which can offer practical tips and contact with others with TS.

Turner Syndrome Support

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For Further Information:

Turner Syndrome

Turner Syndrome

Tuesday, December 13, 2005

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

Pub Med

..........

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

Pub Med

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See Also:

ECTODERMAL DYSPLASIA 1, ANHIDROTIC; ED1

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

Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother - Abstract

Anhidrotic ectodermal dysplasia and immunodeficiency: the role of NEMO

Wednesday, December 07, 2005

Dysplasia-Anhidrotic-Immunodeficiency

Dysplasia-Anhidrotic-Immunodeficiency

OL-EDA-ID Syndrome

ECTODERMAL DYSPLASIA, ANHIDROTIC, WITH IMMUNODEFICIENCY, OSTEOPETROSIS, AND LYMPHEDEMA; OLEDAIDGene map locus Xq28

TEXT

A number sign (#) is used with this entry because the phenotype is caused by hypomorphic mutations in NEMO (IKBKG; 300248).

Doffinger et al. (2001) examined 2 unrelated male patients who presented with the novel OL-EDA-ID syndrome. Both were sons of mothers with mild incontinentia pigmenti (308300), and both died of overwhelming multiple infections at 2.5 and 1.5 years of age, respectively. Both had osteopetrosis, lymphedema, and anhidrotic ectodermal dysplasia. Immunologic variables in the second patient showed a poor inflammatory response and increases in the levels of blood inflammatory markers with fever either absent or delayed during infection. Blood monocytes and polymorphonuclear cells were normal in number and morphology. The B- and T-cell counts and responses to vaccine protein antigens were normal. Serum titers of antibodies against S. pneumoniae were low, despite proven infection. Serum titers of isohemagglutinins were low. Serum levels of immunoglobulin isotypes were normal for age, with the exception of low to normal IgG levels. Both patients carried an X420W mutation in IKBKG, or NEMO (300248.0002). Different alleles were present at the flanking polymorphic loci in the 2 patients, indicating 2 independent mutational events. Both patients died of overwhelming infectious disease caused by a variety of microorganisms, including gram-positive cocci, gram-negative bacilli, mycobacteria, and fungi. There were impaired cellular responses to TNF-alpha (191160).

Doffinger et al. (2001) compared the induction of IFN-gamma (147570) by peripheral blood mononuclear cells (PBMC) from one of the patients and a control. The patient's PBMC displayed a lower level of IFN-gamma production upon costimulation with IL12 (see 161560) and various concentrations of IL1-beta (147720) or IL18 (600953) than the control PBMC. There were impaired cellular responses to lipopolysaccharide in this patient. The patient also exhibited dissociated cellular responses to CD154 (CD40LG; 300386), suggesting that some but not all CD40 (109535)-mediated signals are NEMO-dependent in both dentritic cells and B cells.

REFERENCES

H. 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

Pub Med

......

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

Pediatrics/AAPPublications

......

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:
Case Reports
PMID: 11242109 [PubMed - indexed for MEDLINE]


.........

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, UK2 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 B (NF-B) essential modulator, NEMO, or inhibitor of B kinase (IKK-). This protein is essential for activation of the transcription factor NF-B, which plays an important role in human development, skin homoeostasis, and immunity.
Keywords: anhidrotic ectodermal dysplasia; immunodeficiency; NEMO; NF-B
We present an update on the first reported patient with EDA-ID syndrome
1 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-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-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-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

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]
Doffinger R, Smahi A, Bessia C, et al. X-linked anhydrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-B signalling. Nat Genet 2001;27:277–85. [CrossRef][Medline]
IUIS Scientific Group. Primary immunodeficiency diseases. Clin Exp Immunol 1999;118(suppl 1):1–28. [CrossRef]
Priolo M, Lagana C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet 2001;38:579–85. [Abstract/Free Full Text]
Aradhya S, Nelson DL. NF-B signalling and human disease. Curr Opin Genet Develop 2001;11:300–6. [CrossRef][Medline]
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]
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]

British Medical Journals

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

PubMed

Alpha Galactosidase B Deficiency

Shindler Disease

ALPHA-GALACTOSIDASE B; GALB

Alternative titles; symbols

N-ACETYL-ALPHA-D-GALACTOSAMINIDASE; NAGALYSOSOMAL ALPHA-N-ACETYLGALACTOSAMINIDASE DEFICIENCY, INCLUDEDSCHINDLER DISEASE, INCLUDEDNEUROAXONAL DYSTROPHY, SCHINDLER TYPE, INCLUDEDKANZAKI DISEASE, INCLUDEDGene map locus 22q11

TEXT

In a study of man-rodent somatic cell hybrids, de Groot et al. (1978) assayed human N-acetyl-alpha-D-galactosaminidase activity and concluded that alpha-galactosidase B and mitochondrial aconitase (ACO2; 100850), known to be on chromosome 22, are syntenic. They also obtained evidence for direct assignment of alpha-galactosidase B to chromosome 22. Alpha-NAGA was thought to be a more appropriate designation for this enzyme than alpha-galactosidase B by de Groot et al. (1978), who claimed that there was no structural relationship between alpha-gal A (on the X chromosome; GLA; 301500) and so-called alpha-gal B. However, DNA studies (Wang et al., 1990;Wang and Desnick, 1991), described later, led to a different conclusion. In man-rodent cell hybrids, Geurts van Kessel et al. (1979, 1980) studied chronic myeloid leukemia cells to determine the site of the break on 22q relative to markers assigned to chromosomes 22 and 9. Alpha-NAGA remained with the Ph-1 chromosome, whereas ACO2 went with chromosome 9. Thus, the former is probably in band 22q11, whereas the latter is between it and 22qter.

Wang et al. (1990) isolated a full-length 2.2-kb cDNA and a genomic cosmid clone containing the entire NAGA gene. Sequence analysis revealed striking similarities between the NAGA locus and exons 1-6 of alpha-galactosidase A, suggesting that the 2 genes evolved by duplication and divergence from a common ancestral locus. Wang and Desnick (1991) also pointed to remarkable amino acid identity between the NAGA and GLA genes.

In 2 sons of a German couple with remote consanguinity, van Diggelen et al. (1987, 1988) described the clinical and biochemical features of lysosomal alpha-N-acetylgalactosaminidase deficiency. The boys showed neurologic abnormalities starting at age 9 months, followed by progressive psychomotor deterioration. By the age of 2.5 and 4 years, they had 'largely lost their previously acquired motor and language skills.' Growth had been normal. Computerized tomographic scans were normal, and there was no organomegaly, obvious coarsening of the facies, or skeletal dysplasia. A uniquely abnormal pattern of urinary oligosaccharides was demonstrated by thin-layer chromatography. Among the carbohydrate-hydrolyzing lysosomal enzymes, only alpha-NAGA had not previously been associated with a disorder. The levels of this enzyme were very low in cultured fibroblasts, leukocytes and plasma, whereas these levels were normal in a healthy brother. Both parents had low normal or reduced activity. A major neutral oligosaccharide from the urine of 1 patient was identified as the blood group A determinant, a trisaccharide with terminal alpha-N-acetylgalactosamine. The concentration of this product in the urine of the older boy, who was a secretor and had blood group A, was 5 times normal. The younger boy, who had blood group O, did not excrete this trisaccharide. Schindler et al. (1988) described the clinical findings as consisting of severe psychomotor retardation with myoclonic seizures, decorticate posture, optic atrophy, blindness, marked long tract signs, and total loss of contact with the environment. No features of other lysosomal storage diseases were present. Ultrastructural examination of peripheral nerves was unremarkable, whereas the rectal mucosa contained dystrophic autonomic axons with 'tubulovesicular' material. A unique pattern of abnormal urinary oligosaccharides/glycopeptides was found by thin-layer chromatography. Wang et al. (1988) pointed out that the brothers reported by van Diggelen et al. (1987) had a clinical course and neuropathologic findings similar to those in Seitelberger disease, the infantile form of neuroaxonal dystrophy (256600). The characteristic 'spheroids' were observed histologically and ultrastructurally in terminal axons in gray matter. This disorder, which they referred to as Schindler disease, must represent, therefore, a form of infantile axonal dystrophy, the first in which a specific enzymatic defect has been identified. The disorder is autosomal recessive. Schindler et al. (1989) also characterized the disorder as a neuroaxonal dystrophy. They pointed out that although the disorder is caused by deficiency of a lysosomal enzyme, no lysosomal storage could be identified. It has been proposed that the dystrophic axons in infantile neuroaxonal dystrophy result from defective retrograde axonal transport. How deficiency of alpha-N-acetylgalactosaminidase might lead to a similar problem is not clear. Using PCR amplification and sequence analysis of PCR product from type I and type II offspring of consanguineous matings, Wang et al. (1990) demonstrated single basepair mutations in the homozygous state in both type I and type II. (Type I is classic Schindler disease; type II is an adult disorder with angiokeratoma as a prominent feature (104170.0002). Type II might appropriately be called Kanzaki disease (Kanzaki et al., 1989).)

Keulemans et al. (1996) reported the genotypes of 5 more patients with NAGA deficiency. One of them, related to the first reported German family (van Diggelen et al., 1987), had classic Schindler disease and the same homozygous mutation, i.e., glu325to-lys (104170.0001). The only manifestations in another patient, a 5-year-old Dutch girl whose family was clinically described by de Jong et al. (1994), were convulsions during fever and psychomotor retardation starting after the age of 1 year. She had 2 different mutations: glu325-to-lys inherited from her father and ser160-to-cys (104170.0004) inherited from her mother. The same genotype was found in a clinically unaffected 3.5-year-old brother of the proband. Keulemans et al. (1996) suggested that the brother might be a preclinical case of NAGA deficiency detected through screening. A homozygous nonsense mutation, glu193-to-ter, was found in 2 adult Spanish sibs who had angiokeratoma, lymphedema, and vacuolization in dermal cells, but no neurologic signs. These sibs, previously reported by Chabas et al. (1994), were clinically similar to the original patient described by Kanzaki et al. (1989). Although at the metabolic level the patients with NAGA deficiency are similar, extreme differences between the infantile form(s) and the adult form (Kanzaki disease) suggested to Keulemans et al. (1996) that other factors or genes contribute to the clinical heterogeneity.

Bakker et al. (2001) reviewed the 11 known patients with alpha-NAGA deficiency. The patients, who were from 7 families of German, Japanese, Dutch, Spanish, French/Italian/Albanian, and Moroccan descent, showed extreme clinical heterogeneity from no clinical symptoms to infantile neuroaxonal dystrophy. They reiterated the suggestion that alpha-NAGA deficiency is not a single disease entity but that factors other than alpha-NAGA contribute to the phenotype variation. They further speculated that severe infantile patients have a double disease: neuroaxonal dystrophy in addition to alpha-NAGA deficiency, without causal relationship.

ALLELIC VARIANTS(selected examples)

.0001 SCHINDLER DISEASE [NAGA, GLU325LYS]

In the first cases described with Schindler disease (15,16:van Diggelen et al., 1987, 1988), Wang et al. (1990) found a G-to-A transition at nucleotide 973 of the NAGA gene, resulting in substitution of lysine for glutamic acid as residue 325 (E325K).

Bakker et al. (2001) reported homozygosity of the E325K mutation in the 3-year-old son of consanguineous Moroccan parents. He showed congenital bilateral cataract and an abnormal oligosaccharide pattern in urine suggestive of alpha-NAGA deficiency. At the age of 12 months he showed slightly delayed neuromotor development, which became more prominent in the next 2 years. NMR of the brain showed diffuse white matter abnormalities with a secondary, symmetrical demyelinization. The proband and his 7-year-old healthy brother had undetectable alpha-NAGA activity in leukocytes and a profound deficiency in fibroblasts. The parents had alpha-NAGA activity consistent with heterozygosity. Mutation analysis revealed homozygosity of the E325K mutation in the proband and his healthy brother, whereas a third sib and both parents were heterozygous. The family demonstrated the extreme clinical heterogeneity of alpha-NAGA deficiency, as the homozygous brother at the age of 7 years showed no clinical or neurologic symptoms.

.0002 KANZAKI DISEASE [NAGA, ARG329TRP]

In a 46-year-old Japanese woman with disseminated angiokeratoma, Kanzaki et al. (1989) demonstrated numerous cytoplasmic vacuoles in cells of the kidney and skin. Enzyme activities against synthetic and natural substrates were normal in leukocytes and fibroblasts. Her urine contained a large amount of sialylglycoaminoacids, with predominant excretion of an O-glycoside-linked glycoaminoacid. No information was provided on the patient's family. The enzyme studies excluded Fabry disease (301500), fucosidosis (230000), galactosialidosis (256540), and the various mucolipidoses and mucopolysaccharidoses. Desnick (1991) recounted reading an abstract by Kanzaki et al. (1988) in which the presence of angiokeratoma attracted his attention because of his longtime work with Fabry disease; the possibility that this disorder was related to Schindler disease was suggested by the excretion of large amounts of glycopeptides in the urine. A collaboration thereafter led to the demonstration that indeed there is deficiency of alpha-galactosidase B in Kanzaki disease also (Wang et al., 1990). Even though the disorder was much milder, with no neurodegeneration and no neuroaxonal dystrophy, the deficiency of enzymes seemed to be of the same order as in type I Schindler disease. In the laboratory of Desnick (1991), a substitution of tryptophan for arginine-329 was demonstrated as the basic defect (Wang et al., 1994). Again, it is remarkable that a change so close to that in Schindler disease could cause such a different phenotype. This situation is comparable to that of the Hurler and Scheie forms of mucopolysaccharidosis I and to the allelic mild and severe forms of many lysosomal storage diseases. Kanzaki et al. (1991) provided further evidence that there are 2 forms of alpha-N-acetylgalactosaminidase deficiency with sialopeptiduria: a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral lysosomal inclusions, and an adult-onset form with angiokeratoma, extensive lysosomal accumulation of sialoglycopeptides, and the absence of detectable neurologic involvement. Kanzaki et al. (1993) gave an extensive description of the 46-year-old Japanese woman with the adult form of lysosomal alpha-N-acetylgalactosaminidase deficiency. The angiokeratomas first appeared on her lower torso when she was 28 years old and later became diffusely distributed. Her 2 unaffected children had half-normal enzyme levels, consistent with autosomal recessive inheritance. The woman had mild intellectual impairment and peripheral neuroaxonal degeneration. She was the product of a first-cousin marriage and worked in a hospital as a nurse's aide. Endoscopic examination demonstrated telangiectasia on the gastric mucosa. Dilated blood vessels were present on the ocular conjunctiva and dilated vessels with corkscrewlike tortuosity were observed in the fundi.

To identify the mutation causing this phenotypically distinct adult-onset form of NAGA deficiency, Wang et al. (1994) used reverse transcription, amplification, and sequencing of the NAGA transcript. The change was a C-to-T transition at nucleotide 985, resulting in an R329W amino acid substitution. The base substitution was confirmed by hybridization of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Wang et al. (1994) showed that in transiently expressed COS-1 cells, both the E325K (infantile-onset) and R329W (adult-onset) precursors were processed to the mature form; however, the E325K mutant polypeptide was more rapidly degraded than the R329W subunit, thereby providing a basis for the distinctly different infantile- and adult-onset phenotypes.

.0003 KANZAKI DISEASE [NAGA, GLU193TER ]

Keulemans et al. (1996) showed by PCR and sequence analysis that the Spanish brother and sister with manifestations of Kanzaki disease described by Chabas et al. (1994) were homozygous for an E193X mutation in exon 5 leading to complete loss of NAGA protein.

.0004 NAGA DEFICIENCY, MILD FORM [NAGA, SER160CYS ]

Keulemans et al. (1996) reported that a Dutch girl with NAGA deficiency and mild neurologic manifestations was heterozygous for the E325K (104170.0001) mutation and a C-to-G change at nucleotide 11017 (numbering according to Yamauchi et al., 1990) in exon 4, leading to a substitution of serine for cysteine at residue 160. The same genotype was found in the 3-year-old asymptomatic brother of the proband, who was presumed by the authors to be presymptomatic.

SEE ALSO

Wang et al. (1990)

REFERENCES

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