Mayer-Rokitansky-Küster-Hauser syndrome type 2 (ORPHA:2578)
A form of Mayer-Rokitansky-Küster-Hauser syndrome, characterized by congenital aplasia of the uterus and upper two-thirds of the vagina that is associated with at least one other malformation such as renal, vertebral, or, less commonly, auditory and cardiac defects.
Epidemiology
MRKH syndrome has an estimated worldwide incidence of 1/4500 live female births. The prevalence of MRKH syndrome type 2 is unknown.
Clinical description
MRKH syndrome type 2 is most often diagnosed in adolescence as the first symptom is most commonly a primary amenorrhea in young women presenting with otherwise normal development of secondary sexual characteristics and normal external genitalia. Patients lack the uterus and the upper 2/3 of the vagina. Because of this, difficulties with sexual intercourse have been reported. Pelvic pain can be reported in those with uterine remnants. As the uterus is missing or not functional, women cannot bear children but ovaries are normal and functional. Other associated malformations seen in MRKH type 2 include upper urinary tract malformations (40% of cases), unilateral renal agenesis (23-28%; see this term), ectopia of one or both kidneys (17%; see this term), renal hypoplasia (4%), horseshoe kidney and hydronephrosis. Skeletal abnormalities, mainly of the spine and less frequently in the face and limbs, are also reported. Spinal malformations encountered include scoliosis, isolated vertebral anomalies (asymmetric, fused or wedged vertebrae), isolated Klippel-Feil syndrome and/or Sprengel deformity (see these terms), rib malformation or agenesis, and spina bifida (see this term). Face and limb malformations are mainly brachymesophalangy, ectrodactyly, duplicated thumb, absent radius, atrio-digital dysplasia (Holt-Oram-like syndrome) and facial asymmetry. Hearing impairment, due to middle ear malformations or sensorineural defects, is seen in 10-25% of cases. Heart malformations are very rare but include valvular pulmonary stenosis, Tetralogy of Fallot (see these terms) Holt-Oram or velocardiofacial-like syndromes, aorto-pulmonary window or atrial septal defects.
Etiology
The exact etiology of MRKH syndrome remains largely unknown, even if the spectrum of malformation encountered suggests a developmental defect of the intermediate mesoderm during embryogenesis (by the end of the 4th week of fetal life), leading to an alteration of the blastema of the cervicothoracic somites and the pronephric ducts. Initially, MRKH syndrome was considered to be of sporadic occurrence, suggesting the involvement of non-genetic or environmental factors. However, no link between an environmental cause and MRKH syndrome has ever been established. It is now clear that MRKH syndrome has a genetic origin, through increasing family descriptions and numerous genetic studies already completed. The latter have led to reveal several chromosomal abnormalities associated with the disease, such as small interstitial duplications in 1q21.1 and in Xpter-p22.32, or deletions in 4q34-qter, 8p23.1, 10p14, 16p11.2, 17q12, 22q11.21 and Xq21.31. These genomic rearrangements affect numerous genes. Putative candidate genes have been described, such as HNF1B (17q12), LHX1 (17q12), SHOX (Xp22.33 and Yp11.32), TBX6 ( 16p11.2), and ITIH5 (10p14). The phenotype-genotype correlations however, cannot be established.
Genetic counseling
MRKH syndrome (type 1 or type 2) was thought to be purely sporadic but in familial cases it seems to be inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Genetic counseling can be beneficial in these familial cases.

                            Last update: 
                            January 2015


                            - Expert reviewer(s): 
                            Dr Karine MORCEL