IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome is characterized by systemic autoimmunity, typically beginning in the first year of life. Presentation is most commonly the clinical triad of watery diarrhea, eczematous dermatitis, and endocrinopathy (most commonly insulin-dependent diabetes mellitus). Most children have other autoimmune phenomena including Coombs-positive anemia, autoimmune thrombocytopenia, autoimmune neutropenia, and tubular nephropathy. Without aggressive immunosuppression or bone marrow transplantation, the majority of affected males die within the first one to two years of life from metabolic derangements or sepsis; a few with a milder phenotype have survived into the second or third decade of life.
Diagnosis is based on clinical features and on the identification of a mutation in FOXP3. FOXP3 is the only gene in which mutations are known to cause IPEX syndrome. Approximately 25% of males with symptoms suggestive of IPEX syndrome have mutations identified in FOXP3.
Treatment of manifestations: Immunosuppressive agents (e.g., cyclosporin A, FK506) alone or in combination with steroids; sirolimus (rapamycin) for persons in whom FK506 therapy is toxic or ineffective; granulocyte colony stimulating factor (G-CSF, filgrastim) for autoimmune neutropenia; nutritional support; standard treatment of diabetes mellitus and autoimmune thyroid disease. Bone marrow transplantation (BMT) can resolve clinical symptoms.
Prevention of primary manifestations: BMT, if performed early in the course of disease.
Prevention of secondary complications: Prophylactic antibiotic therapy for those with autoimmune neutropenia or recurrent infections; aggressive management of dermatitis with topical steroids and anti-inflammatory agents to prevent infection.
Surveillance: Periodic evaluation of complete blood count, glucose tolerance, thyroid function, kidney function, and liver function for evidence of autoimmune disease.
Evaluation of relatives at risk: If the family-specific mutation is known, FOXP3 molecular genetic testing in at-risk males immediately after birth to permit early diagnosis and BMT before significant organ damage occurs; otherwise, monitoring at-risk males for symptoms to enable early diagnosis and treatment.
IPEX syndrome is inherited in an X-linked manner. The risk to sibs of the proband depends on the carrier status of the mother. If the mother of the proband is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation are carriers and will not be affected. Affected males pass the disease-causing mutation to all of their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for pregnancies at risk are possible for families in which the disease-causing mutation has been identified.
The term IPEX is an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked. A clinical triad resulting from widespread autoimmunity suggests a diagnosis of IPEX syndrome:
- Enteropathy that manifests as chronic watery diarrhea. Onset is typically in the first months of life; villous atrophy with a mononuclear cell infiltrate (activated T cells) in the lamina propria is the most common finding in biopsy.
No laboratory findings specifically identify affected individuals. Evidence of immune dysregulation manifested by the following is suggestive of the syndrome:
- Elevated serum concentration of immunoglobulin E (IgE) and in some cases, IgA
- Autoimmune anemia, thrombocytopenia, and/or neutropenia
- Autoantibodies to pancreatic islet antigens, thyroid antigens, small bowel mucosa, and other autoantigens
- Decreased numbers of FOXP3-expressing T cells in peripheral blood determined by flow cytometry
- Serum concentration of IgG and IgM
- Circulating leukocyte counts
- Neutrophil function
- Serum concentration of complement
- In vitro proliferative responses of T lymphocytes to common mitogens (e.g., phytohemagglutinin, cross-linking of CD3) or activation with specific antigen (e.g., tetanus, candida). Peripheral blood mononuclear cells from individuals with IPEX syndrome show an excess production of the Th2 cytokines IL-4, IL-5, IL-10, and IL-13 and decreased production of the Th1 cytokine interferon-γ [Chatila et al 2000, Nieves et al 2004].
Note: Caution must be exercised when interpreting data regarding the immune responses of individuals with IPEX syndrome as many are on immunosuppressants at the time of diagnosis.
Molecular Genetic Testing
Gene. FOXP3 is the only gene in which mutations are known to cause IPEX syndrome.
Evidence for locus heterogeneity. Owen et al  suggest the possibility of an additional autosomal locus. Among the males who lack FOXP3 mutations, approximately half have low FOXP3 mRNA expression levels and low numbers of FOXP3-expressing cells in peripheral blood [Torgerson, unpublished results], suggesting that defects in other genes or gene products, possibly in the same pathway as FOXP3, may cause a similar phenotype.
- Sequence analysis of all exons, exon/intron boundaries, and the first polyadenylation site detects mutations in approximately 25% of males with a clinical phenotype suggestive of IPEX syndrome [Torgerson, unpublished results].
Interpretation of test results.For issues to consider in interpretation of sequence analysis results, click here.
To confirm/establish the diagnosis in a proband
- Assessment of general immune function including blood cell counts and white blood cell differential
- Analysis of T- and B-cell subsets
- Measurement of serum concentration of immunoglobulins including IgE
- Screening for autoimmune liver and renal disease with measurement of serum concentration of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine; urinalysis
- Flow cytometry to evaluate regulatory T cells for expression of both FOXP3 and CD25 (helpful as an initial screen for the disorder)
- Sequence analysis of FOXP3 for definitive diagnosis
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: (1) Carriers are heterozygotes for this X-linked disorder but do not exhibit clinical features of IPEX syndrome. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male or obligate carrier female is not available for testing, sequence analysis of the at-risk female.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with mutations in FOXP3.
No contiguous gene deletion syndromes that include deletion of FOXP3 have been reported.
Males. IPEX syndrome is generally considered to be a syndrome of neonatal enteropathy [Ruemmele et al 2004] and neonatal polyendocrinopathy [Dotta & Vendrame 2002]. The most common presentation of IPEX syndrome is severe watery diarrhea, type 1 insulin-dependent diabetes mellitus, thyroiditis, and dermatitis in males younger than age six months. It is frequently accompanied by other autoimmune phenomena. Males with a somewhat milder disease phenotype can present at older ages but no affected individuals are known to have survived beyond the third decade of life.
The enteropathy of IPEX syndrome, often the first symptom, is present in virtually all affected individuals. Even in those with milder disease, the diarrhea typically begins in the first six to12 months of life. Watery diarrhea, which may at times also have mucus and blood, leads to malabsorption, failure to thrive, and cachexia, often requiring the use of total parenteral nutrition (TPN). Food allergies are common [Torgerson et al 2007].
Endocrinopathy is present in the majority of affected individuals. Type 1 diabetes mellitus, often with onset in the first months of life, is the most common endocrine manifestation. Thyroid disease (most often hypothyroidism) is also common [Wildin et al 2002, Gambineri et al 2003].
The outcome of IPEX syndrome is universally poor. Most children die within the first or second year of life from metabolic derangements, severe malabsorption, or sepsis. Although improvements in immunosuppressive regimens and bone marrow transplantation (BMT) have prolonged survival, even those with the mildest disease have survived only into the second or third decades of life [Powell et al 1982, Kobayashi et al 2001, Levy-Lahad & Wildin 2001, Taddio et al 2007].
Most affected individuals have other autoimmune phenomena including Coombs-positive anemia, immune thrombocytopenia, autoimmune neutropenia, hepatitis, and tubular nephropathy. Lymphadenopathy, splenomegaly, and alopecia have also been reported Powell et al , Ferguson et al .
Severe or invasive infections including sepsis, meningitis, pneumonia, and osteomyelitis affect more than 50% of individuals with IPEX syndrome [Gambineri et al 2008; Torgerson, unpublished results]. The most common pathogens identified were Staphylococcus, Enterococcus, cytomegalovirus, and Candida. Some infections may be secondary to immunosuppressive therapy; however, many occur prior to the initiation of treatment. It is unclear, however, whether individuals with IPEX syndrome truly have an increased susceptibility to infectious pathogens or whether their infections are related to the poor barrier function of the gut and skin.
Female carriers of FOXP3 mutations are generally healthy. However,
- One female carrier had an expression level of FOXP3 mRNA intermediate between the very low level observed in her affected son and the normal level in a control [Bennett et al 2001].
- One carrier female has type I diabetes mellitus.
- X-chromosome inactivation studies performed on one carrier female demonstrated that normal and mutated FOXP3 alleles are equally expressed in peripheral blood mononuclear cells [Tommasini et al 2002]. However, subsequent studies of the FOXP3+ regulatory T cell population demonstrated a selective advantage for cells utilizing the normal X chromosome, resulting in complete skewing of X chromosome usage in this cell subset [Di Nunzio et al 2009].
As a rule, males with mutations that abrogate expression of functional FOXP3 protein (nonsense, frameshift, or splicing mutations) have severe, early-onset IPEX syndrome.
Mutation of the first polyadenylation signal of the gene with an otherwise normal gene sequence leads to low expression levels of normal FOXP3 mRNA and generally results in severe, early-onset disease as well [Bennett et al 2001]. In one of the three kindreds with this type of mutation, two affected males had mild, late-onset disease and lived into the second and third decades of life, suggesting that other modifying factors that affect mRNA stability may be the cause of the observed variability [Powell et al 1982].
A number of affected individuals have missense (point) mutations that result in expression of mutant proteins, some of which appear to be functionally hypomorphic and are associated with a milder clinical phenotype [De Benedetti et al 2006, Lopes et al 2006, Gavin et al 2006, d’Hennezel et al 2009, McMurchy et al 2010].
IPEX syndrome is rare: fewer than 150 affected individuals have been identified worldwide. No accurate estimates of prevalence have been published. It is, however, likely to be underreported judging by the prevalence of other syndromes caused by mutations in similarly-sized genes located nearby on the X chromosome (e.g., Wiskott-Aldrich syndrome).
Other syndromes with neonatal diabetes mellitus
- Transient neonatal diabetes mellitus caused by an imprinting disorder involving chromosome region 6q24
- Dominant pancreatic hypoplasia associated with congenital heart disease [OMIM 600001]
- A presumed recessive disorder or imprinting defect causing an islet cell developmental defect [OMIM 600089]
Other syndromes of polyendocrinopathy
- Schmidt syndrome (APS II/III) [OMIM 269200]
- Autoimmune lymphoproliferative syndrome (ALPS) characterized by hemolytic anemia, thrombocytopenia, and splenomegaly; type 1 diabetes mellitus; and thyroid disease
Other syndromes with immunodeficiency
- CD25 (IL2RA) deficiency [OMIM 606367], identified in three individuals with an IPEX syndrome-like clinical phenotype [Roifman 2000, Caudy et al 2007]. In addition to autoimmunity, however, these individuals also had features of severe cellular immunodeficiency with susceptibility to severe cytomegalovirus infections. Unlike IPEX syndrome, CD25 deficiency has normal IgE. CD25 deficiency is inherited in an autosomal recessive manner.
- STAT5B deficiency [OMIM 245590], identified in ten individuals worldwide with a syndrome of autoimmunity and immune deficiency characterized by low but not absent T and NK cell numbers as well as decreased FOXP3 protein expression [Cohen et al 2006]. In addition to the immunologic problems, affected individuals also have a form of dwarfism related to the fact that growth hormone mediates its effects through STAT5 [Kofoed et al 2003]. STAT5B deficiency is inherited in an autosomal recessive manner.
- Wiskott-Aldrich syndrome, characterized by thrombocytopenia, eczema, and a combined immune deficiency. Inheritance is X-linked.
Other syndromes with protracted diarrhea in infancy [Sherman et al 2004]
- Microvillus inclusion disease
- Tufting enteropathy
- Autoimmune enteropathy
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with IPEX syndrome, the following evaluations are recommended:
- Endocrine. Glucose tolerance test, thyroid function tests, and autoantibodies to pancreatic islet antigens and thyroid antigens
- Hematologic. Complete blood count and differential, Coombs test
- Immunologic. Serum IgG, IgM, IgA, and IgE concentrations; regulatory T cell numbers
- Hepatic. Serum AST, ALT, GGT, and total bilirubin
- Renal. Serum concentration of BUN and creatinine; urinalysis
- Nutrition assessment. Serum electrolyte levels including calcium, magnesium, and zinc; serum albumin and pre-albumin
Treatment of Manifestations
Monitor fluid intake to assure adequate intravascular volume.
Use of nutritional support, including TPN or elemental or low-carbohydrate-containing formula if necessary, can be beneficial [Sherman et al 2004].
Follow the standard treatment protocols for diabetes mellitus and autoimmune thyroid disease.
The most effective treatment for the enteropathy of IPEX syndrome is T cell-directed immune suppression (i.e., cyclosporin A and FK506) either alone or in combination with steroids [Di Rocco & Marta 1996]. Toxicity, tachyphylaxis, and increased susceptibility to infection related to chronic use of these agents reduce their potential for long-term amelioration of symptoms in most individuals.
Sirolimus (rapamycin) has been successfully used in patients for whom FK506 was either ineffective or toxic [Bindl et al 2005, Yong et al 2008]. The ability of sirolimus to suppress effector T cell function while allowing Treg cells to continue to develop and function offers some theoretic advantages for its use [Strauss et al 2007].
In persons with autoimmune neutropenia, granulocyte colony stimulating factor (G-CSF, filgrastim) may be beneficial.
In one person who developed pemphigus nodularis, use of rituximab improved pemphigus and other IPEX syndrome-associated symptoms [McGinness et al 2006]. It has also been effective in controlling autoimmune hemolytic anemia, immune thrombocytopenic purpura, and autoimmune neutropenia in persons with IPEX syndrome [Torgerson, unpublished results].
In persons with severe disease in whom other therapies have failed and symptoms remain severe, cytotoxic drugs or biologic agents that target T cells may be beneficial, as demonstrated by complete remission of symptoms during a bone marrow transplantation conditioning regimen of anti-thymocyte globulin, busulfan, and cyclophosphamide [Baud et al 2001].
Bone marrow transplantation (BMT) offers the only potential cure for IPEX syndrome. Early attempts at BMT using myeloablative conditioning regimens met with only limited success because of transplant-related mortality and other complications related to the underlying disease [Baud et al 2001]. Recent approaches using non-myeloablative conditioning regimens have markedly improved outcomes and survival [Burroughs et al 2007, Lucas et al 2007, Rao et al 2007]. While generally less toxic, these reduced-intensity conditioning regimens still appear to generate long-term, stable engraftment of a regulatory T cell population [Burroughs et al 2010] and, if performed early, can prevent the development of irreversible diabetes mellitus or thyroiditis.
Prevention of Primary Manifestations
BMT is currently the only cure for IPEX syndrome; the degree of symptomatic remission may depend on use of BMT prior to irreversible damage to target organs such as pancreatic islet cells and thyroid.
Prevention of Secondary Complications
Patients with autoimmune neutropenia or recurrent infections resulting from severe eczema may benefit from prophylactic antibiotic therapy to decrease the risk of severe infectious complications.
Aggressive management of dermatitis with topical steroids and anti-inflammatory agents can help to prevent infections from pathogens that enter as a result of the poor barrier function of the skin.
Appropriate surveillance includes periodic evaluation of complete blood count, thyroid function, glucose tolerance, kidney function (measurement of serum concentration of BUN, creatinine), and liver function (measurement of serum concentration of AST, ALT) for evidence of autoimmune disease.
Agents/Circumstances to Avoid
Immune activation, for example by immunizations or severe infections, has been reported to cause worsening or exacerbation of disease symptoms [Powell et al 1982]. This does not indicate an absolute contraindication for vaccination in IPEX syndrome but does suggest that there may be benefit to giving vaccines individually instead of combining several vaccines on a single day.
Evaluation of Relatives at Risk
Molecular genetic testing of at-risk males in a family with a known disease-causing mutation either prenatally or immediately after birth enables early diagnosis and BMT in affected males before significant organ damage occurs.
If the disease-causing mutation is not known, monitoring at-risk males for early-onset diarrhea, diabetes mellitus, thyroid dysfunction, and autoimmune hematologic manifestations can allow early identification of affected males.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
There is no evidence that initiation of immunosuppressive therapy prior to the onset of symptoms prevents the primary manifestations of IPEX syndrome. Bone marrow transplantation prior to the onset of symptoms can, however. prevent disease.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
IPEX syndrome is inherited in an X-linked manner.
Risk to Family Members
Parents of a proband
- The father of an affected male will not have the disease nor will he be a carrier of the disease-causing mutation.
- In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
- The percentage of affected males who have no family history of IPEX syndrome is not known. If an affected male represents a simplex case, the following possibilities regarding his mother's carrier status and carrier risks of extended family members need to be considered:
- The mother is not a carrier and the affected male has a de novo disease-causing mutation.
- The mother is a carrier of a disease-causing mutation.
- Female carriers of IPEX syndrome are asymptomatic.
Sibs of a proband
- The risk to the sibs depends on the carrier status of the mother.
- If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Males who inherit the mutation will be affected; females who inherit the mutation are carriers and will not be affected.
- If the proband presents a simplex case and if his mother's carrier status is unknown, her risk of being a carrier is unknown.
- Germline mosaicism has not been observed.
Offspring of a proband. Males pass the disease-causing mutation to all of their daughters and none of their sons.
Other family members. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).
Carrier testing of at-risk female relatives is possible if the disease-causing mutation in the family has been identified.
X-chromosome inactivation is skewed only in regulatory T cells [Di Nunzio et al 2009] and is random in all other lymphocyte populations [Tommasini et al 2002]; therefore, X-chromosome inactivation studies are of limited use in carrier detection.
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
- The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.
DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.
Prenatal testing is possible for at-risk pregnancies if the FOXP3 mutation has been identified in a family member. The usual procedure is to determine the fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- American Diabetes Association (ADA)ATTN: Center for Information1701 North Beauregard StreetAlexandria VA 22311Phone: 800-342-2383 (toll-free information/support); 703-549-1500Email: AskADA@diabetes.org
- Diabetes UKMacleod House10 ParkwayLondon NW1 7AAUnited KingdomPhone: 020 7424 1000Fax: 020 7424 1001Email: firstname.lastname@example.org
- Immune Deficiency Foundation (IDF)40 West Chesapeake AvenueSuite 308Towson MD 21204Phone: 800-296-4433 (toll-free)Email: email@example.com
- International Patient Organisation for Primary Immunodeficiencies (IPOPI)FirsideMain RoadDownderry Cornwall PL11 3LEUnited KingdomPhone: +44 01503 250 668Fax: +44 01503 250 668Email: firstname.lastname@example.org
- Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center747 Third AvenueNew York NY 10017Phone: 866-463-6474 (toll-free); 212-819-0200Fax: 212-764-4180Email: email@example.com
- European Society for Immunodeficiencies (ESID) RegistryDr. Gerhard KindleUniversity Medical Center Freiburg Centre of Chronic ImmunodeficiencyEngesserstr. 479106 FreiburgGermanyPhone: 49-761-270-34450Email: firstname.lastname@example.org
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
|Gene Symbol||Chromosomal Locus||Protein Name||Locus Specific||HGMD|
|FOXP3||Xp11||Forkhead box protein P3||FOXP3 @ LOVD|
CCHMC - Human Genetics Mutation Database (FOXP3)
Primary Immunodeficiency Disease (PID) Databases (IPEX)
Normal allelic variants. 11 translated exons
Pathologic allelic variants. The majority of disease-causing mutations in FOXP3 are either frameshift mutations that predict a foreshortened protein product or missense mutations within the C-terminal forkhead DNA-binding domain. Some mutations also affect the leucine zipper and a transrepression domain located within the N-terminal proline-rich region of the protein, demonstrating the essential role for these domains in FOXP3 function [Chatila et al 2000, Lopes et al 2006].
Normal gene product. FOXP3 encodes forkhead box protein P3 (FOXP3), a forkhead DNA-binding protein that is expressed primarily in CD4+CD25+ regulatory T cells. The protein consists of 431 amino acids and has important functional domains including:
- A C2H2 zinc finger and leucine zipper (both conserved structural motifs involved in protein-protein interactions) in the central portion
Proteins bearing forkhead DNA-binding motifs comprise a large family of related molecules that play diverse roles in enhancing or suppressing transcription from specific binding sites. Several members of this protein family are involved in patterning and development [Gajiwala & Burley 2000]. FOXP3 is expressed primarily in lymphoid tissues (thymus, spleen, and lymph nodes), particularly in CD4+ CD25+ regulatory T lymphocytes. In mice, it is required for the development and suppressive function of this important regulatory T cell population [Fontenot et al 2003, Hori et al 2003, Khattri et al 2003, Sakaguchi 2003]. In humans, it is not expressed at baseline in CD4+CD25- or CD8+ T cells but is expressed upon T cell activation [Gavin et al 2006, Allan et al 2007]. The significance of this inducible expression in effector T cells is unknown.
Abnormal gene product. The FOXP3 protein is absent in most individuals with IPEX syndrome; some individuals with FOXP3 point mutations express a protein that appears to have decreased function, thereby leading to a milder form of the disease [De Benedetti et al 2006, Gambineri et al 2008].
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- 27 January 2011 (me) Comprehensive update posted live
- 12 December 2007 (me) Comprehensive update posted to live Web site
- 27 April 2006 (cd) Revision: FOXP3 testing available clinically
- 19 October 2004 (me) Review posted to live Web site
- 11 February 2004 (mh) Original submission
Department of Pediatrics and Communicable Diseases
University of Michigan Medical School
Ann Arbor, Michigan
Divisions of Immunology and Rheumatology
University of Washington
Initial Posting: October 19, 2004; Last Update: January 27, 2011.
University of Washington, Seattle, Seattle (WA)
Hannibal MC, Torgerson T. IPEX Syndrome. 2004 Oct 19 [Updated 2011 Jan 27]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2015.