title: A female with complete lack of Müllerian fusion, postaxial polydactyly, and tetralogy of fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome?
abstract: We report a 19-year-old, non-Amish Caucasian female patient with primary amenorrhea caused by complete lack of Müllerian fusion with vaginal agenesis or Müllerian aplasia (MA), postaxial polydactyly (PAP), and tetralogy of Fallot. The genital tract anomaly of MA with and without renal or skeletal anomalies comprises Mayer-Rokitansky-Kuster-Hauser syndrome, which has not been reported with tetralogy of Fallot. The phenotypic triad of anomalies most closely resembled McKusick-Kaufman syndrome (MKS; OMIM 236700), a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos (HMC), PAP, and congenital heart malformation that is inherited in an autosomal recessive pattern. While upper reproductive tract anomalies have not been reported with MKS, they have been reported with Bardet-Biedl syndrome (BBS), a syndrome that significantly overlaps with MKS. Both MKS and BBS can be caused by mutations in the MKKS or BBS6 gene on chromosome 20p12 and BBS is also associated with mutations in other genes (BBS1, BBS2, BBS4, and BBS7). To address this heterogenity, we sequenced the causative genes in MKS and BBS but no mutations in these five genes were identified. Fluorescence in situ hybridization (FISH) excluded large deletions of chromosome 20p12 and microsatellite marker studies confirmed biparental inheritance for all of the known BBS loci. The dual midline fusion defects of tetralogy of Fallot and MA suggests that either this patient has a unique syndrome with a distinct genetic etiology or that she has a genetically heterogeneous or variant form of MKS.
authors.affiliation: Genetic Diseases Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
authors.forename: Amalia
authors.initials: A
authors.lastname: Dutra
authors.forename: Dzifa
authors.initials: D
authors.lastname: Kpodzo
authors.forename: Evgenia
authors.initials: E
authors.lastname: Pak
authors.forename: Takaya
authors.initials: T
authors.lastname: Nakane
authors.forename: Joyce
authors.initials: J
authors.lastname: Turner
authors.forename: Margo
authors.initials: M
authors.lastname: Whiteford
authors.forename: Leslie G
authors.initials: LG
authors.lastname: Biesecker
authors.forename: Pamela
authors.initials: P
authors.lastname: Stratton
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology*; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000473:pathology; D002872:Chromosome Deletion; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D056385:Group II Chaperonins; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones / Q000235:genetics; D009095:Mullerian Ducts / Q000002:abnormalities*; D009154:Mutation; D017689:Polydactyly / Q000473:pathology*; D011506:Proteins / Q000235:genetics; D013577:Syndrome; D013771:Tetralogy of Fallot / Q000473:pathology*; D014621:Vagina / Q000002:abnormalities
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C429655:BBS4 protein, human; C464790:Bbs1 protein, human; C473309:Bbs2 protein, human; C473308:Bbs7 protein, human; D003598:Cytoskeletal Proteins; C414726:MKKS protein, human; D008869:Microtubule-Associated Proteins; D018832:Molecular Chaperones; D011506:Proteins; D056385:Group II Chaperonins