ReportHereditary renal adysplasia , pulmonary hypoplasia and Mayer-Rokitansky-Küster-Hauser ( MRKH ) syndrome : a case report

Background: Hereditary renal adysplasia is an autosomal dominant trait with incomplete penetrance and variable expression that is usually associated with malformative combinations (including Müllerian anomalies) affecting different mesodermal organs such as the heart, lung, and urogenital system. Case report: A case showing pulmonary hypoplasia, hip dysplasia, hereditary renal adysplasia, and Mayer-RokitanskyKuster-Hauser syndrome in adulthood is reported here. The i.v. pyelography showed right renal agenesis with a normal left kidney and ureter. Ultrasound and Magnetic Resonance Imaging also showed right renal agenesis with multicystic embryonary remnants in the right hemipelvis probably corresponding to a dysgenetic kidney. An uretrocystoscopy showed absence of ectopic ureter and of the right hemitrigone. She was scheduled for a diagnostic laparoscopy and creation of a neovagina according to the McIndoe technique with a prosthesis and skin graft. Laparoscopy confirmed the absence of the uterus. On both sides, an elongated, solid, rudimentary uterine horn could be observed. Both ovaries were also elongated, located high in both abdominal flanks and somewhat dysgenetics. A conventional cytogenetic study revealed a normal female karyotype 46, XX at a level of 550 GTG bands. A CGH analysis was performed using a 244K oligoarray CGH detecting 11 copy number variants described as normal variants in the databases. The 17q12 and 22q11.21 microdeletions described in other MRKH patients were not present in this case. Four years after operation her evolution is normal, without symptoms and the neovagina is adequately functional. The geneticists have studied her family history and the pedigree of the family is shown. Conclusions: We suggest that primary damage to the mesoderm (paraaxil, intermediate, and lateral) caused by mutations in a yet unidentified gene is responsible for: 1) skeletal dysplasia, 2) inappropriate interactions between the bronchial mesoderm and endodermal lung bud as well as between the blastema metanephric and ureteric bud, and eventually 3) Müllerian anomalies (peritoneal mesothelium) at the same level. These anomalies would be transmitted as an autosomal dominant trait with incomplete penetrance and variable expressivity. Introduction According to previous studies [1], unilateral renal agenesis (RA) is embryologically associated with genital and sometimes extragenital malformations. The associated genital malformations are due either to agenesis or hypoplasia of all derivatives of the ipsilateral urogenital ridge (frequently with unicornuate uterus on the opposite side) or to distal mesonephric anomalies [2]. But involution or secondary renal atrophy without uterine malformation is an alternative embryologic sequence resulting in unilateral RA without Müllerian anomalies. Malformative combinations (including Müllerian anomalies) can sometimes affect different organs derived from the mesoderm, such as the heart, lung, and urogenital system [3]. The MayerRokitansky-Küster-Hauser (MRKH) syndrome is a malformation of the female genitals (occurring in one in 4000 female live births) as a results of interrupted embryonic development of the Müllerian ducts [4]. Strübbe et al. [5] divided their MRKH syndrome patients into two groups: typical (isolated form of congenital agenesis of the vagina and uterus), and atypical form, suggesting to call this last * Correspondence: acien@umh.es 1 Service of Obstetrics and Gynecology, University Hospital of San Juan; Department of Gynecology, "Miguel Hernández" University, Campus of San Juan, Alicante, Spain Full list of author information is available at the end of the article BioMed Central © 2010 Acién et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Acién et al. Orphanet Journal of Rare Diseases 2010, 5:6 http://www.ojrd.com/content/5/1/6 Page 2 of 6 type the GRES (genital, renal, ear, skeletal) syndrome. More recently, Oppelt et al. [4] have also classified their 53 cases of MRKH syndrome in three recognized subtypes: typical, atypical and MURCS (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia) association. And of the 521 cases included in the revision they do of the literature, 64% were typical, 24% atypical and 12% MURCS. Malformations of the renal system were the most frequent type of accompanying malformation, with 23 different malformations in 19 patients, followed by 19 different skeletal changes in 15 patients of the Oppelt et al's cases. They do not mention cases with pulmonary hypoplasia. In this communication, we report the case of a patient presenting right hip dysplasia, congenital right pulmonary hypoplasia (PH), and hereditary renal adysplasia with multicystic embryonary remnants in the right hemipelvis (dysgenetic kidney, mesoderm dysplasia) in addition to the Müllerian anomaly known as Rokitansky or MRKH syndrome. Case Report A 17-year-old woman with primary amenorrhea was sent to us with a diagnosis of Rokitansky syndrome. The patient was born via normal delivery at a weight of 2400 g when her mother was 17. She was admitted to the hospital at an age of 8 days due to vomiting and moderate dystrophy; she was then diagnosed with primary right PH. She was later readmitted several times for pulmonary insufficiency. Two months later, a diagnosis of congenital right pulmonary hypoplasia with hypoplasia of the right lung artery was confirmed. In an ultrasound examination performed 7 months later, the right kidney was not observed. From more recent (at an age of 15 years) X-ray images taken of the pelvis in the Emergency Unit, the patient was also diagnosed with right hip dysplasia; this condition was initially defined as old secondary osteonecrosis of the right femoral head. The patient reported three years of genital and mammary development as well as cyclic pelvic pain for 4-5 days every month despite the primary amenorrhea. She weighed 42 kg and was 153 cm tall. The physical examination revealed normal external genital development and normal breasts. There was complete vaginal atresia. In the combined rectal examination, the pelvis was noted to be free. A transrectal ultrasound did not confirm the presence of a uterus. In this ultrasound examination, there was difficulty visualizing the ovaries; on the right side, however, vascular dilatations or multicystic embryonary remnants could be observed. The abdominal ultrasound did not show the presence of a right kidney. General and hormonal analyses were normal (FSH 3.9 mUI/mL, LH 6.2 mUI/mL, PRL 7.9 ng/mL, E2 35 pg/mL, P 0.3 ng/mL), and chest X-rays and i.v. pyelography showed right pulmonary hypoplasia, dysplasia of the right hip, and right renal agenesis with a normal left kidney and ureter (see Figure 1). Later, a conventional cytogenetic study revealed a normal female karyotype 46, XX at a level of 550 GTG bands. A CGH analysis was performed using a 244K oligoarray CGH (Agilent Technologies, Santa Clara, CA, USA), detecting 11 copy number variants (CNV) described as normal variants in the databases. Some CNVs (17q12 and 22q11.21 microdeletions) described in other MRKH patients were not present in this case. The geneticists have been studying her family history and Figure 2 shows the pedigree of the family, compatible with an autosomal dominant pattern of inheritance. Eight months later, a new transrectal ultrasound was performed. Again, there was no evidence to suggest any functioning rudimentary uterine horn. The right ovary appeared to be normal, and there were the same vascular dilatations or multicystic remnants previously seen on the right side. The left ovary was also difficult to identify properly. The patient, who visited the clinic with her parents, wished operation and to have a neovagina created. She was therefore scheduled for a diagnostic laparoscopy and creation of a neovagina according to the McIndoe technique with a prosthesis and skin graft. Laparoscopy confirmed the absence of uterus. There was a varicocele and/or retroperitoneal multicystic formations on the right side of the small pelvis. On both sides, an elongated, solid, rudimentary uterine horn could be observed. At its superior end, there were ovaries that Figure 1 A. Antero-posterior X-ray of the thorax showing right pulmonary hypoplasia. Ascent of the diaphragm (>) and displacement of the heart to the right. B. I.V. pyelography showing right renal agenesis (or dysplasia) (>). The right hip dysplasia is also shown (>>). C. Transrectal ultrasound image of the supposed right ureterocele. D. Laparoscopic images of both ovaries (RO, right ovary; LO, left ovary). Acién et al. Orphanet Journal of Rare Diseases 2010, 5:6 http://www.ojrd.com/content/5/1/6 Page 3 of 6 were elongated, somewhat dysgenetic (more on the right side), and located very high in both abdominal flanks (Figure 1D). Rudimentary tubes could also be observed. Although the uterine rudimentary tract was slightly thicker on the left side, there did not appear to be even minimal endometrial cavitation of the solid uterine rudimentary horn. Sectioning and dissection from the introitum to the inside below the urethra was performed via a transperineal procedure, thus forming a wide vaginal neocavity reaching the Douglas pouch. Interestingly, the dissection of the neovaginal cavity tended more toward the left fundus than the right, as if there were more atresia on the right side of the supposed location of the vagina. A prosthesis with a skin graft taken from the right buttock was applied, with Interceed® placed between the skin and the prosthesis (Figure 3). The drawing of the genital tract of the patient generated in the surgery theater is shown in Figure 2B. After 10 days, the prosthes