WNT4 Deficiency

WNT4 deficiency is a rare genetic condition affecting females, leading to the underdevelopment or absence of the uterus and vagina. It is caused by mutations in the WNT4 gene. Elevated androgen levels in the blood can trigger the development of male characteristics, such as male-pattern hair growth on the chest and face.

Individuals with this genetic defect develop breasts but do not menstruate. Mayer–Rokitansky–Küster–Hauser syndrome is a related but distinct condition. Some women initially diagnosed with MRKH are later found to have WNT4 deficiency. Most women with MRKH syndrome do not have WNT4 gene mutations. The absence of menstruation may be the first clinical sign of WNT4 deficiency, which can cause significant psychological challenges, and counseling is recommended.

Signs and symptoms

Due to the rarity of WNT4 deficiency, case reports are scarce, making it difficult to compile a comprehensive list of signs and symptoms. More cases need to be identified to better understand the potential spectrum of associated symptoms. However, from identified cases and the mechanism of action, certain symptoms have been characterized to explain WNT4 deficiency.

• Failure to begin menstrual cycles (amenorrhea)

  
  

• Ambiguous genitalia (short vagina, severely underdeveloped/absent uterus) but normal pubertal characteristics like breast development and pubic hair

  
  

• Infertility

  
  

• Difficulty with sexual intercourse

  
  

• Pain during intercourse

  
  

• Abnormally high levels of androgens in the blood (hyperandrogenism)

  
  

• Possible development of acne and male-pattern hair growth, including facial/chest hair (hirsutism)

  
  

• Prone to urinary tract infections and/or kidney stones

Causes

WNT4 deficiency is a very rare disorder affecting females, caused by mutations in the WNT4 gene found on chromosome 1. This gene promotes female sex development and suppresses male sex development, providing instructions for producing a protein responsible for forming the female reproductive system, kidneys, and several hormone-producing glands.

The WNT4 protein regulates the formation of the Müllerian ducts, which develop into the uterus, fallopian tubes, cervix, and upper part of the vagina. It is also crucial for the development of ovaries and oocytes (female egg cells).

This disorder may result from a random spontaneous mutation or be inherited as an autosomal dominant trait. Dominant genetic disorders occur when a single copy of an abnormal gene is enough to express its phenotypic traits. While the abnormal gene can be inherited from either parent, it cannot be inherited from the mother due to infertility. It is unclear if the mutation can be inherited from the father or arises from new mutations in the gene.

WNT4 is a secreted protein encoded by the WNT4 gene on chromosome 1, located at (1p35). The functions of the WNT4 protein are not fully understood, and more research is needed to determine the underlying mechanism causing the symptoms associated with this disease.

WNT4 is known to bind to the frizzled family of receptors, resulting in the transcriptional regulation of target genes.

Frizzled receptors are atypical G protein-coupled receptors involved in the Wnt signaling pathway and others. WNT4 is produced in ovarian somatic cells and up-regulates the Dax1 gene, inhibiting steroidogenic enzymes. It increases follistatin expression, inhibiting anti-testis action and supporting ovarian germ cell survival.

Diagnosis

WNT4 deficiency is congenital, present at birth, but may remain undiagnosed until adolescence when female puberty begins. The onset of the menstrual cycle marks puberty, but primary amenorrhea (lack of menstruation) might prompt a visit to a physician and initiate diagnosis.

Due to its rarity, WNT4 deficiency may be suspected only after extensive clinical evaluation, detailed patient history, and identification of characteristic symptoms, such as an absent or underdeveloped uterus and/or vagina with normal external genitalia.

Specialized imaging techniques like ultrasounds or magnetic resonance imaging (MRI) can visualize internal organs (uterus, ovaries, and kidney) to confirm WNT4 deficiency. Modern science allows molecular genetic analysis to reveal WNT4 gene mutations and confirm the diagnosis. Karyotyping can also be performed to rule out other conditions by examining chromosome integrity in a cell sample.

A female with WNT4 deficiency will have a normal 46, XX karyotype, but abnormalities on those chromosomes may be present.

Related disorders / common misdiagnoses

WNT4 deficiency can be misdiagnosed due to similar symptoms with other disorders. One such disorder is Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome.

Women with WNT4 deficiency are sometimes misdiagnosed with MRKH syndrome due to similar signs and symptoms. The main difference is that in MRKH syndrome, there is no WNT4 gene mutation, despite underdevelopment of the uterus/vagina and amenorrhea, while maintaining normal ovarian function. MRKH syndrome is often the initial diagnosis, but extensive genetic testing and imaging analysis can confirm WNT4 deficiency.

Additionally, complete androgen insensitivity syndrome is a rare disorder where individuals are genetically male (46, XY) but do not respond to androgens. This syndrome presents intersex characteristics, as the person appears female externally but is genetically male with a 46, XY karyotype.

Prevention/treatment

WNT4 is a congenital disease with autosomal dominant inheritance, so prevention is not possible. With an absent uterus, conceiving is not an option, but other conception methods may be available due to functional ovaries. Genetic testing might be recommended to prevent passing the gene, given its autosomal dominant inheritance.

Treatment is still evolving, as few cases have been reported and severity varies. Treatment focuses on specific symptoms for each individual, requiring a team of specialists such as pediatricians (for diagnoses under age 18), internists, gynecologists, nephrologists, endocrinologists, plastic surgeons, urologists, psychiatrists, and others.

• Counseling

  
  

• Genetic Testing

  
  

• Antibiotics to treat recurrent UTIs

  
  

• Non-Surgical techniques like vaginal dilators to increase vaginal depth, easing pain and difficulty during intercourse

  
  

  • Franck's Dilator Method - involves applying the vaginal dilator for up to 6 weeks to several months to stretch and widen the vaginal walls

    
    

• Plastic Surgery

  • Vaginoplasty to create an artificial vagina

Prognosis

Due to the rarity of this disorder, prognosis evidence is limited. However, women diagnosed with WNT4 deficiency may live long lives. The diagnosis leads to infertility, difficulty with intercourse, and recurring kidney stones, which may affect quality of life. Extensive counseling and group therapy might be necessary to adapt to a different lifestyle.

Epidemiology

Concrete epidemiological evidence for WNT4 deficiency is lacking due to its rarity. The most solid evidence is its autosomal dominant inheritance pattern and the mutation on chromosome 1. No evidence shows population favorability, distribution patterns, risk factors, or environmental factors.

Current research/research directions

WNT4 deficiency is an extremely rare genetic disorder, and there is limited research available specifically on the disease. Although there is an understanding of the gene and its function in the body, the scarcity of cases makes it challenging to conduct extensive research on the disorder. However, future research on the WNT4 gene could be valuable for evaluating conditions like polycystic ovary disease/syndrome (PCOS), a common condition affecting many women.

PCOS also exhibits hyperandrogenic traits, and a better understanding of the milder form of WNT4 and its signaling pathways in ovarian tissues could help clarify its role in the hyperandrogenic states observed in PCOS patients.

Research on the WNT4 gene is ongoing in relation to other conditions linked to its properties. Despite the rarity of this disorder, the WNT4 gene plays a significant role in various biological functions. For example, in 2016, researchers investigated how the WNT4 gene influences estrogen receptor signaling and endocrine resistance in invasive lobular carcinoma cell lines.

As a crucial signaling molecule in mammary gland development regulated by a progesterone receptor, the WNT4 pathway has been utilized in breast cancer research to modulate the endocrine response in invasive lobular carcinoma. Additionally, the WNT4 gene is involved in research concerning kidney function. In 2013, DiRocco et al. published a study on WNT4 and beta-catenin signaling in medullary kidney fibroblasts, revealing that WNT4 expression in renal fibrosis is crucial in the proliferation process.