Mckusick-Kaufman Syndrome

A number sign (#) is used with this entry because of evidence that the McKusick-Kaufman syndrome (MKKS) is caused by homozygous or compound heterozygous mutation in the MKKS gene (604896) on chromosome 20p12.

Mutation in the MKKS gene also causes Bardet-Biedl syndrome-6 (BBS6; 605231).

Description

McKusick-Kaufman syndrome is an autosomal recessive disorder characterized by genitourinary malformations, especially hydrometrocolpos, polydactyly, and, more rarely, heart or gastrointestinal malformations (summary by Schaefer et al., 2011).

Clinical Features

Hydrometrocolpos develops in the female fetus as a result of transverse vaginal membrane and excessive cervical secretions in response to maternal hormone. McKusick et al. (1964) presented evidence that at least one form is inherited as an autosomal recessive. Birth of another affected female in a third sibship closely related to 1 of the 2 reported in 1964 further strengthened the conclusion (McKusick et al., 1968). The observation of 3 more affected sibships among the Amish and further studies of the earlier 3 sibships corroborated the validity of this syndrome (McKusick, 1978).

Kaufman et al. (1972) suggested that postaxial polydactyly and/or congenital heart disease may sometimes accompany hydrometrocolpos. In the kindred of McKusick et al. (1964), one of the girls with hydrometrocolpos had postaxial polydactyly and another girl in the same sibship had polydactyly and congenital heart disease without hydrometrocolpos. Others have reported hydrometrocolpos and polydactyly in isolated cases (e.g., Pare and Elhilali, 1972).

Dungy et al. (1971) found hydrometrocolpos secondary to vaginal atresia and bilateral postaxial hexadactyly in an offspring of first-cousin parents. A comparable disorder, imperforate vagina, is autosomal recessive in the mouse (Gowen and Heidenthal, 1942; Chase, 1944). If the membrane which closes the vagina is removed surgically, the mouse is fully viable and fertile. If untreated, the malformation leads to death about the time of puberty.

Goecke et al. (1981) made the important observation that glanular hypospadias and prominent scrotal raphe are manifestations in the male. Postaxial polydactyly is an expression of the syndrome in males. The polydactyly may be limited to one limb.

Vince and Martin (1989) described 3 affected sibs (2 females and 1 male) in a presumably nonconsanguineous Melanesian family. All 3 had anomalies of the urogenital and cardiovascular systems as well as polydactyly. The brother showed micropenis, glanular hypospadias, and bilaterally undescended testes.

In Beirut, Suidan and Azoury (1979) observed 12 cases of transverse vaginal septum. They suggested that a high frequency might be related to a high frequency of consanguinity in the population they served. All their patients presented in adulthood; the 2 youngest were 16. Only 1 had a complete vaginal septum. McKusick (1980) noted that incomplete vaginal septum as a forme fruste had not been observed in the Amish families.

Knowles et al. (1981) observed choanal atresia, pituitary dysplasia, and vertebral anomalies in a patient with this syndrome.

Rosen and Bocian (1989) presented evidence that in this disorder nonimmune hydrops fetalis can be a cause of the edema that is mistakenly attributed to inferior vena cava compression and lymphatic obstruction by a large pelvic mass.

Davenport et al. (1989) described a male infant with polydactyly, consisting of partial duplication of the third metacarpal and a postaxial accessory digit on both hands and postaxial accessory digits on the feet, as well as penoscrotal hypospadias with chordee. There was no evidence of congenital heart disease. Hirschsprung disease (142623) was established by rectal biopsy. A previous pregnancy had resulted in the intrauterine death of a female fetus with typical features of the Kaufman-McKusick syndrome.

Schaap et al. (1992) described a patient. Pul et al. (1994) described a female infant, the offspring of a first-cousin marriage, who, in addition to the other features of the Kaufman-McKusick syndrome, had esophageal atresia and distal tracheoesophageal fistula.

Slavotinek et al. (2004) reported a 19-year-old, non-Amish Caucasian female patient with a triad of anomalies: primary amenorrhea caused by complete lack of mullerian fusion with vaginal agenesis or mullerian aplasia, postaxial polydactyly, and tetralogy of Fallot. The genital tract anomaly of mullerian aplasia with or without renal or skeletal anomalies comprises Mayer-Rokitansky-Kuster-Hauser syndrome (277000), which had never been reported with tetralogy of Fallot. The phenotypic triad of anomalies was thought to resemble most closely McKusick-Kaufman syndrome. The dual midline fusion defects of tetralogy of Fallot and mullerian aplasia suggested that either this patient had a unique syndrome with a distinct genetic etiology or that she had a genetically heterogeneous or variant form of McKusick-Kaufman syndrome. No mutation was found in the MKKS/BBS6 gene on 20p12, nor in other genes associated with Bardet-Biedl syndrome, BBS1 (209901), BBS2 (606151), BBS4 (600374), and BBS7 (607590). Fluorescence in situ hybridization excluded large deletions of 20p12, and microsatellite marker studies confirmed biparental inheritance for all known BBS loci.

Mapping

Studying Amish individuals with what they called the hydrometrocolpos syndrome (HMCS) originally reported by McKusick et al. (1964), Stone et al. (1997, 1998) used homozygosity mapping to locate the gene for this disorder to 20p12, bounded by markers D20S894 and D20S175. The linkage data showed that 3 individuals (2 females and 1 male) were homozygous for the disease-carrying haplotype but had no apparent manifestations of the disorder. One was the mother of an affected sibship and the other 2 were sibs of affected persons. It is possible that the homozygous, apparently unaffected, sibs had a minor cardiac defect or, in the case of the female, an undiagnosed uterine anomaly. The mapping region included the jagged-1 gene (JAG1; 601920), which is mutant in Alagille syndrome-1 (118450). Stone et al. (1998) sequenced the JAG1 gene in 2 unrelated individuals with McKusick-Kaufman syndrome and found no disease-causing mutations. Stone et al. (1998) stated that the peak 2-point lod score was 3.33, and the peak 3-point lod score was 5.21.

Diagnosis

Differential Diagnosis

David et al. (1999) reported 9 patients who, because of the presence of vaginal atresia and postaxial polydactyly, were diagnosed in infancy with McKusick-Kaufman syndrome; these patients later developed obesity and retinal dystrophy and were diagnosed with Bardet-Biedl syndrome. David et al. (1999) suggested that the phenotypic overlap between McKusick-Kaufman syndrome and Bardet-Biedl syndrome is a diagnostic pitfall, and that all children in whom a diagnosis of McKusick-Kaufman syndrome is made in infancy should be reevaluated for retinitis pigmentosa and other signs of Bardet-Biedl in later childhood.

Hydrometrocolpos and postaxial polydactyly are common to both McKusick-Kaufman syndrome and Bardet-Biedl syndrome. Slavotinek and Biesecker (2000) reviewed reported cases of both syndromes presenting with hydrometrocolpos and postaxial polydactyly early in life, to determine if there are clinical features that allow discrimination between the 2 syndromes, as the primary features of retinitis pigmentosa, obesity, and learning disability in Bardet-Biedl syndrome are age-dependent. They did not find any phenotypic features that allowed reliable differentiation between the 2 syndromes in the neonatal period. However, uterine, ovarian, and fallopian tube anomalies were more common in BBS patients. Slavotinek and Biesecker (2000) concluded that sporadic cases of hydrometrocolpos and postaxial polydactyly in female patients cannot be diagnosed with MKKS until at least age 5 years and that monitoring for the complications of BBS should be performed in these patients.

Schaefer et al. (2011) suggested that MKKS may be an extremely rare presentation of BBS (absence of retinal degeneration, obesity, and cognitive impairment) linked to rare specific allelic variants of the MKKS gene (possibly hypomorphic alleles) or a condition implying one or more other genes (as modifiers or major genes).

Unsinn et al. (1995) described a patient who had hydrocolpos and postaxial polydactyly as well as hypothalamic hamartoblastoma, raising the possibility that the Pallister-Hall syndrome (PHS; 146510) and the McKusick-Kaufman syndrome are one entity. The Pallister-Hall syndrome is characterized by specific facial anomalies, postaxial polydactyly, imperforate anus, and brain anomalies, including a diencephalic hamartoblastoma. McKusick (1995) stated that in his judgment these were not the same entity. Lurie (1995) also questioned that the Kaufman-McKusick syndrome and the Pallister-Hall syndrome can be considered one entity. Lurie and Wulfsberg (1994) found in a survey of 43 reported familial cases neither preaxial nor central forms of polydactyly. Lurie (1995) stated that he also did not remember vaginourethral fistula as occurring in these patients.

Prenatal Diagnosis

Farrell et al. (1986) described prenatal diagnosis of MKKS by ultrasonography and recurrence of abdominal distention due to peritoneal cysts. They suggested that retrograde flow of secretions from the uterus may be a factor in the abdominal distention of hydrometrocolpos.

Molecular Genetics

Stone et al. (2000) analyzed the approximately 450-kb candidate region on chromosome 20p12 by sample sequencing, which revealed the presence of several known genes and EST clusters. Candidate transcripts were evaluated by Northern blot analysis of adult and fetal tissues. One transcript with widespread expression was selected for analysis in a patient from the Amish pedigree and a sporadic, non-Amish case. The Old Order Amish patient was found to be homozygous for 2 missense substitutions in cis (604896.0001) and the non-Amish patient was a compound heterozygote for a frameshift mutation predicting premature protein truncation (604896.0004) and a distinct missense mutation (604896.0003). The MKKS predicted protein showed amino acid similarity to the chaperonin family of proteins, suggesting a role for protein processing in limb, cardiac, and reproductive system development.

Animal Model

Fath et al. (2005) developed an Mkks -/- mouse model in which affected animals demonstrated retinal degeneration, failure of spermatozoa flagella formation, elevated blood pressure, olfactory deficits, and social dominance, but no polydactyly nor vaginal abnormalities. The phenotype of the Mkks -/- mice closely resembled the phenotype of other mouse models of Bardet-Biedl syndrome (Bbs2 -/- and Bbs4 -/-). Fath et al. (2005) suggested that the complete absence of the MKKS gene leads to BBS while the MKKS phenotype is likely to be due to specific mutations.