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Last updated: 3/3/2025
Years published: 2012, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, and Daniel Konrad, MD, PhD, Division of Diabetology and Endocrinology, University Children’s Hospital, Zurich, Switzerland, for assistance in the preparation of this report.
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WNT4 deficiency is a rare genetic disorder that affects females and is characterized by the underdevelopment or absence of the uterus and, in some cases, the vagina. This condition leads to higher levels of androgens—male sex hormones—causing symptoms such as male-pattern hair growth (hirsutism). Females with WNT4 deficiency develop normal secondary sexual characteristics during puberty (e.g., breast development and pubic hair), but do not have a menstrual cycle (primary amenorrhea). The first clinical sign of WNT4 deficiency is not starting a menstrual cycle.
The disorder is caused by changes (variants) in the WNT4 gene, which plays a crucial role in female sexual development. The WNT4 gene suppresses male sex differentiation pathways and promotes the formation of Müllerian duct structures, including the uterus and fallopian tubes, which are need for female sexual development.
WNT4 deficiency may cause significant psychological challenges and counseling is recommended.
Treatment may include surgical correction of the vagina anomalies and management of the specific symptoms.
The number and types of symptoms associated with WNT4 deficiency is not completely understood because there are a small number of people described with this condition. Common features include:
WNT4 deficiency is caused by changes (disease-causing variants) in the WNT4 gene. The WNT4 gene creates (encodes) a protein that is important in stopping male sexual development and supporting female sexual development. Changes in the WNT4 gene create a non-working protein. This negatively impacts the development of the structures that come from the mullerian duct as well as the kidneys (nephrogenesis). The WNT4 protein product is also involved in controlling the production of androgens in the ovaries (ovarian steroidogenesis). The exact functions of the protein product of the WNT4 gene are not fully understood. More research is needed to understand the exact underlying mechanisms that ultimately cause the symptoms associated with WNT4 deficiency.
Gene variants that cause WNT4 deficiency disease can occur randomly as a spontaneous event (i.e., new variant) or it can be inherited in an autosomal dominant pattern.
Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
WNT4 deficiency is an extremely rare disorder that affects females. The exact incidence of the disorder is unknown, and it has only been identified in several females worldwide. Researchers believe that WNT4 deficiency may often go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. WNT4 deficiency is present at birth (congenital) but can go unidentified until adolescence.
Doctors may consider a diagnosis of WTN4 deficiency in a female who has not started her menstrual cycle when puberty begins (primary amenorrhea). A female can be diagnosed with WNT4 deficiency after a thorough clinical evaluation, a detailed patient history and the identification of characteristic symptoms like having an absent or underdevelopment uterus and/or vagina while having normal external genitalia. Molecular genetic testing that shows a disease-causing variant of the WNT4 gene confirms a diagnosis of WNT4 deficiency.
Specialized imaging techniques including ultrasonography and magnetic resonance imaging (MRI) may be used to help in a diagnosis of WNT4 deficiency. An ultrasound records echoes of high-frequency sound waves to produce a detailed image of deep structures within the body. An ultrasound can show the uterus and vagina. It can also be used to check the kidneys. An ultrasound is a simple, noninvasive procedure that does not use radiation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of specific organs and bodily tissues. It is also noninvasive and is generally more sensitive than an ultrasound. An MRI can also be used to check the kidneys and skeleton.
Hysteroscopy is minimally invasive and provides reliable information about the vagina, cervical canal and uterine cavity. It does not evaluate the external contours or the thickness of the uterine wall but allows a doctor to examine the inside of the uterus.
Karyotyping may be performed to rule out other conditions. Karyotyping is used to examine the chromosomes in a sample of cells. Females with WNT4 deficiency have a normal 46, XX karyotype.
Because of the common relationship between Müllerian, renal and urinary anomalies, when a clinician finds one type of these anomalies they should investigate to see if the others are also there.
Treatment
The treatment of WNT4 deficiency is based on treating the specific symptoms that someone has. Treatment may require the coordinated efforts of a team of specialists. Depending on the affected individual’s age at diagnosis, pediatricians or internists, gynecologists, kidney specialists (nephrologists), endocrinologists, orthopedic surgeons, plastic surgeons, physical therapists, psychiatrists and other health care professionals may need to work together to make sure that someone has a well-rounded approach to treatment.
Females with WNT4 deficiency are encouraged to seek counseling after a diagnosis and before treatment because the diagnosis can cause anxiety and extreme psychological distress. Psychological support and counseling both professionally and through support groups is recommended for affected females and their families.
Treatment will usually include appropriate management of the physical findings associated with WNT4 deficiency and psychological support for the emotional issues that often accompany the diagnosis.
In females with Mullerian aplasia, nonsurgical techniques including the use of vaginal dilators, may increase the depth of the vagina to a normal length. This type of treatment can ease the pain and difficulty that may be associated with sexual intercourse. Nonsurgical techniques are considered the first-line approach. Vaginal dilators are specially designed plastic tubes that are used to help enlarge or create a vagina. The most common method is known as Franck’s dilator method. With this method, a physician (and later the affected female) applies a vaginal dilator, which progressively stretches and widens the vagina. This daily procedure may be continued for up to six weeks to several months.
In some people, plastic surgery may be needed to create an artificial vagina (vaginoplasty). There are a variety of different surgical techniques that may be used and there is no consensus as to which technique is best. Females who get surgery to create an artificial vagina will most likely need to use vaginal dilators after the surgery to enhance the chance of success.
Because females with WNT4 deficiency do not have a working uterus, they cannot bear children (infertile). Since affected females have working ovaries, alternative reproductive methods for having children such as in vitro fertilization may be possible. However, because WNT4 deficiency is inherited in an autosomal dominant pattern, the risk of passing on the disorder to children is 50 percent.
Females with WNT4 deficiency who only have one kidney instead of two (unilateral renal agenesis) may have a higher risk for urinary tract infections and/or kidney stones (renal calculi). Physicians should carefully monitor affected females for infection and prescribe antibiotics as necessary.
Genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
The long-term outlook (prognosis) for females with WNT4 deficiency depends on the severity of symptoms and the presence of associated conditions such as renal abnormalities. With appropriate medical care, psychological support and management of symptoms, most individuals can lead healthy lives. However, infertility and the psychological impact of the condition may require ongoing support and counseling. Advances in medical research, particularly in reproductive medicine and genetic therapies, may offer improved options for affected individuals in the future.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Bouazzi L, Sproll P, Eid W, Biason-Lauber A. The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach. Sci Rep. 2019;9(1):17033. Published 2019 Nov 19. doi:10.1038/s41598-019-53370-4
Passos IMPE, Britto RL. Diagnosis and treatment of müllerian malformations. Taiwan J Obstet Gynecol. 2020;59(2):183-188. doi:10.1016/j.tjog.2020.01.003
Sultan C, Biason-Lauber A, Philibert P. Mayer-Rokitansky-Kuster-Hauser syndrome: recent clinical and genetic findings. Gynecol Endocrinol. 2009;25(1):8-11. doi:10.1080/09513590802288291
A. Biason-Lauber, D. Konrad; WNT4 and Sex Development. Sex Dev 1 November 2008; 2 (4-5): 210- 218. https://doi.org/10.1159/000152037
Philibert P, Biason-Lauber A, Rouzier R, et al. Identification and functional analysis of a new WNT4 gene mutation among 28 adolescent girls with primary amenorrhea and müllerian duct abnormalities: a French collaborative study. J Clin Endocrinol Metab. 2008;93(3):895-900. doi:10.1210/jc.2007-2023
Biason-Lauber A, De Filippo G, Konrad D, Scarano G, Nazzaro A, Schoenle EJ. WNT4 deficiency–a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. Hum Reprod. 2007;22(1):224-229. doi:10.1093/humrep/del360
Clément-Ziza M, Khen N, Gonzales J, et al. Exclusion of WNT4 as a major gene in Rokitansky-Küster-Hauser anomaly. Am J Med Genet A. 2005;137(1):98-99. doi:10.1002/ajmg.a.30833
Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman. N Engl J Med. 2004;351(8):792-798. doi:10.1056/NEJMoa040533
Vainio S, Heikkilä M, Kispert A, Chin N, McMahon AP. Female development in mammals is regulated by Wnt-4 signalling. Nature. 1999;397(6718):405-409. doi:10.1038/17068
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:158330; Last Update: 07/17/2017. Available at: https://www.ncbi.nlm.nih.gov/omim/158330 Accessed February 10, 2025.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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