Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, also referred to as Müllerian agenesis, is the second most common cause of primary amenorrhea. It is characterized by congenital absence of the uterus, cervix, and the upper part of the vagina in otherwise phenotypically normal 46,XX females. MRKH syndrome has an incidence of about 1 in 4,500-5,000 newborn females and it is generally divided into two subtypes: MRKH type 1, in which only the upper vagina, cervix and the uterus are affected, and MRKH type 2, which is associated with additional malformations generally affecting the renal and skeletal systems, and also includes MURCS (MÜllerian Renal Cervical Somite) characterized by cervico-thoracic defects. MRKH syndrome is mainly sporadic; however, familial cases have been described indicating that, at least in a subset of patients, MRKH may be an inherited disorder. The syndrome appears to demonstrate an autosomal dominant inheritance pattern, with incomplete penetrance and variable expressivity. The etiology of MRKH syndrome is still largely unknown, probably because of its intrinsic heterogeneity. Several candidate causative genes have been investigated, but to date only WNT4 has been associated with MRKH with hyperandrogenism. This review summarizes and discusses the clinical features and details progress to date in understanding the genetics of MRKH syndrome.

Phenotype of five cases of prenatally diagnosed campomelic dysplasia harboring novel mutations of the SOX9 gene.

OBJECTIVES: Campomelic dysplasia is a rare congenital skeletal disorder characterized by bowing of the long bones and a variety of other skeletal and extraskeletal defects, many of which can now be identified prenatally using advanced ultrasound equipment. The disorder is caused by mutations in SRY-box 9 (SOX9), a gene that is abundantly expressed in chondrocytes as well as in other tissues. However, the correlation between genotype and phenotype is still unclear. We report five cases of prenatally detected campomelic dysplasia in which the diagnosis was confirmed by molecular analysis. METHODS: Ultrasound examinations were performed between 12 and 32 weeks. Standard fetal biometric measurements were obtained. Fetal sex was determined sonographically and confirmed by chromosomal analysis. Genomic DNA was obtained in four cases before termination of pregnancy from chorionic villi or amniocytes and in one case postnatally from peripheral blood. RESULTS: Skeletal dysplasia, most often limb shortening and bowed femora, was observed in one case in the first trimester, in three cases in the second trimester and in one case, presenting late for antenatal care, in the third trimester. Four of the pregnancies were terminated and one was carried to term. Postmortem/postnatal physical and radiographic examinations confirmed the presence of anomalies characteristic of campomelic dysplasia. A de novo mutation in the SOX9 gene was detected in all four cases that underwent termination. The father of the proband in the case that went to term was a carrier of a somatic mosaic mutation without clinical or radiographic signs of campomelic dysplasia. CONCLUSIONS: It is likely that the integrated expertise of ultrasonographers, obstetricians, pediatricians and clinical geneticists will markedly improve the likelihood of accurate prenatal clinical diagnoses of campomelic dysplasia. This will, in turn, encourage more specific molecular testing and facilitate comprehensive genetic counseling.

Unmasking of a Recessive SCARF2 Mutation by a 22q11.12 de novo Deletion in a Patient with Van den Ende-Gupta Syndrome.

Van den Ende-Gupta syndrome (VDEGS) is a congenital condition characterized by craniofacial and skeletal manifestations, specifically blepharophimosis, malar and maxillary hypoplasia, distinctive nose, arachnocamptodactyly, and long slender bones of the hands and feet. To date, only 24 patients have been described. It is generally thought that the syndrome is transmitted by an autosomal recessive mode of inheritance, although evidence for genetic heterogeneity has recently been presented. We report on a girl followed from birth up to 3 years of life with a set of peculiar minor anomalies, arachnocamptodactyly of hands and feet, characteristic of VDEGS in association with a 22q11.12 deletion. Recently, the VDEGS gene was mapped to the DiGeorge syndrome region on 22q11.2, and homozygous mutations in the SCARF2 gene were identified. We now report the first patient with VDEGS due to compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 splice site mutation.

Fetal and placental chromosomal mosaicism revealed by QF-PCR in severe IUGR pregnancies.

A number of genetic and environmental factors are taken into account as responsible for intrauterine growth restriction (IUGR); nevertheless, the relevance of genetic alteration in IUGR aetiology remains to be determined. The aim of this study was to investigate using a combined cytogenetic-molecular approach, improved by a new application of QF-PCR method, the presence of mosaic chromosomal changes in fetal/placental samples from 12 pregnancies with unexplained severe IUGR. This multiple approach allowed us to reveal and quantify subtle chromosomal mosaicisms with less than 5% of trisomic cells even in cases in which cytogenetic and FISH analyses failed to reveal them. These are three pregnancies with a mosaic trisomy for chromosomes 7, 2 and 14; the former case presented matUPD7 and was previously described in this journal (Placenta 22 (2001) 813) in association with pre- and postnatal growth restriction. It is intriguing that chromosomes 7, 2 and 14 are known or suspected to harbour imprinted genes, so that an unbalanced gene dosage in a subset of cells during embryonic development could lead to an early impairment of placental function. Our findings indicate that extensive molecular and cytogenetic studies of IUGR fetal and placental tissues are necessary to reveal at least part of the heterogeneous genetic lesions implicated in IUGR phenotypes.