NORD gratefully acknowledges Daniel Konrad, MD, PhD, Division of Diabetology and Endocrinology, University Children's Hospital, Zurich, Switzerland, for assistance in the preparation of this report.
The case reports of individuals with WNT4 deficiency in the medical literature are limited, making it difficult to determine an accurate picture of the disorder. More cases must be indentified in order to achieve a better understanding of WNT4 deficiency and the potential spectrum of associated symptoms.
WNT4 deficiency is characterized by mullerian aplasia, which is the failure of structures derived from the mullerian ducts to develop properly. The mullerian duct is a structure within a growing embryo that ultimately develops into the uterus, fallopian tubes, cervix and the upper portion of the vagina. Affected females have an absent or underdeveloped (rudimentary) uterus. In some cases, the vagina may be absent or underdeveloped as well. The external genitalia are unaffected. The ovaries are functional, although they may produce abnormal amounts of androgens.
In most cases, the initial symptom of WNT4 deficiency is the failure to begin menstrual cycles (primary amenorrhea). Despite amenorrhea, affected females do experience normal secondary sexual development including breast development, the growth of hair under the arms and in the pubic area, and an increase in body fat around the hips and other areas. Because of the absence of the uterus, all affected females are unable to bear children (infertile). Some affected females may experience difficulty while attempting sexual intercourse due to the shortness of the vagina. Some women may also experience pain during intercourse.
Females with WNT4 deficiency may also have abnormally high levels of androgens in the blood. Consequently, affected females may develop acne and a male pattern of hair growth (hirsutism) including hair on the face and/or chest.
In some cases, affected individuals may have kidney (renal) abnormalities such as absence of one kidney (unilateral kidney agenesis). This condition may cause affected individuals to have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi).
WNT4 deficiency is caused by mutations in the WNT4 gene. This genetic mutation can occur randomly as a spontaneous event (i.e., new mutation) or it can be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that the WNT4 gene is located on the short arm (p) of chromosome 1 (1p35). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p35” refers to band 35 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The WNT4 gene creates (encodes) a protein that is vital to suppressing male sex differentiation and promoting female sexual development. Mutations in the WNT4 gene can cause a complete loss of function of this protein, which is believed to be critical to the development of structures derived 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 necessary to determine the exact, underlying mechanisms that ultimately cause the symptoms associated with WNT4 deficiency.
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 women worldwide. Researchers believe that cases of WNT4 deficiency may often go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population. WNT4 deficiency is present at birth (congenital), but can go unidentified until adolescence.
In some cases, females with WTN4 deficiency come to the attention of physicians due to the failure of menstrual cycles to begin during puberty (primary amenorrhea). A diagnosis of WNT4 deficiency may be suspected based upon a thorough clinical evaluation, a detailed patient history and the identification of characteristic symptoms such as an absent or underdevelopment uterus and/or vagina occurring in association with normal external genitalia. Molecular genetic analysis can reveal characteristic mutations of the WNT4 gene and confirm a diagnosis of WNT4 deficiency.
Specialized imaging techniques including ultrasonography and magnetic resonance imaging (MRI) may be used to aid 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 depict the uterus and vagina. It can also be used to evaluate the kidneys. An ultrasound is a simple, noninvasive procedure that lacks radiation. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. It is also noninvasive and is generally more sensitive than an ultrasound. In addition to evaluating the uterus and vagina, an MRI can simultaneously be used to evaluate the kidney and skeleton.
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.
The treatment of WNT4 deficiency is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Depending upon 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 ensure a comprehensive approach to treatment.
Women 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 women with mullerian aplasia, nonsurgical techniques, including the use of vaginal dilators, may increase the depth of the vagina to a normal length. Such 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 then woman herself) 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 cases, plastic surgery may be necessary 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 undergo 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 functional uterus, they cannot bear children (infertile). Since affected women have functional ovaries alternative reproductive methods for having children such as in vitro fertilization may be possible. However, because WNT4 deficiency is an inherited as an autosomal dominant trait, the risk of passing on the disorder to children is 50 percent. Any decision to conceive should be undertaken after careful consultation with their physicians, genetic counselors and appropriate medical personnel.
Females with WNT4 deficiency who exhibit absence of one kidney (unilateral renal agenesis) may have an increased susceptibility to urinary tract infections and/or kidney stones (renal calculi). Physicians should carefully monitor affected females for infection and prescribe antibiotics as necessary.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Sultan C, Biason-Lauber A, Philibert P. Mayer-Rokitansky-Kuster-Hauser syndrome: recent clinical and genetic findings. Gynecol Endocrinol. 2009;25:8-11.
Biason-Lauber A, Konrad D. WNT4 and sex development. Sex Dev. 2008;2:210-218.
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 mullerian duct abnormalities: a collaborative study. J Clin Endocrinol Metab. 2008;93:895-900.
Biason-Lauber A, De Filippo G, Konrad D, et al. WNT4 deficiency-a clinical phenotype distinct from the classic Mayer-Rokitansky-Kuster-Hauser syndrome: a case report. Hum Reprod. 2007;22:224-229.
Clement-Ziza M, Khen N, Gonzales J, et al. Exclusion of WNT4 as a major gene in Rokitansky-Kuster-Hauser anomaly. Am J Med Genet A. 2005;137:98-99.
Biason-Lauber A, Konrad D, Navratil F, Schoenle EJ. A WNT4 mutation associated with mullerian-duct regression and virilization in a 46,XX woman. N Engl J Med. 2004;351:792-798.
Vainio S, Heikkila M, Kispert A, Chin N, McMahon AP. Female development in mammals in regulated by Wnt-4 signaling. Nature. 1999;397:405-409.
Genetics Home Reference. WNT4 Mullerian Aplasia and Ovarian Dysfunction. February 200(. Available at: http://www.ncbi.nlm.nih.gov/omim/158330 Accessed On: January 6, 2011.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:158330; Last Update:12/21/2009. Available at: http://www.ncbi.nlm.nih.gov/omim/158330 Accessed on: January 6, 2011.
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