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McKusick-Kaufman Syndrome

, MB, BS, PhD.

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Initial Posting: ; Last Update: June 4, 2015.

Estimated reading time: 25 minutes


Clinical characteristics.

McKusick-Kaufman syndrome (MKS) is characterized by the combination of postaxial polydactyly (PAP), congenital heart disease (CHD), and hydrometrocolpos (HMC) in females and genital malformations in males (most commonly hypospadias, cryptorchidism, and chordee). HMC in infants usually presents as a large cystic abdominal mass arising out of the pelvis, caused by dilatation of the vagina and uterus as a result of the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by failure of the distal third of the vagina to develop (vaginal agenesis), a transverse vaginal membrane, or an imperforate hymen. Cardiac malformations that have been described at least once in individuals with MKS include atrioventricularis (AV) communis with a left-sided superior vena cava, atrial septal defect, ventricular septal defect, AV canal, small aorta and hypoplastic left ventricle, tetralogy of Fallot, and patent ductus arteriosus.


Diagnosis of MKS is based on clinical findings. The clinical diagnosis of MKS in a female with HMC and PAP cannot be made until the age of at least five years and requires absence of features of Bardet-Biedl syndrome (BBS). Identification of biallelic pathogenic variants in MKKS (also known as BBS6) is used to help establish the diagnosis of MKS.


Treatment of manifestations: Surgical repair of the obstruction causing HMC and drainage of the accumulated fluid. Treatment for polydactyly and congenital heart defects is standard.

Prevention of secondary complications: Care with anesthesia in the neonatal period as severe HMC can cause diaphragmatic compression.

Surveillance: Monitoring of blood pressure and renal function in those with renal anomalies; ongoing surveillance for manifestations of BBS, including growth and developmental assessments, ophthalmologic examination, and electroretinogram (ERG).

Genetic counseling.

MKS is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if the pathogenic variants have been identified in the family. Although HMC, PAP, and CHD can be detected by prenatal ultrasound examination, the reliability of prenatal ultrasound as a method of prenatal diagnosis is unknown because the degree of PAP in individuals with MKS is variable and HMC may not be apparent until after birth.


Suggestive Findings

Diagnosis of McKusick-Kaufman syndrome (MKS) should be suspected in individuals with the following features:

  • In females
    • Hydrometrocolpos (HMC)
    • Postaxial polydactyly (PAP)
    • Congenital heart disease (CHD)
  • In males
    • Genital malformations (most commonly hypospadias, cryptorchidism, and chordee),
    • Postaxial polydactyly (PAP)
    • Congenital heart disease (CHD)
  • In all. No manifestations of overlapping syndromes, such as Bardet-Biedl syndrome (BBS)

Hydrometrocolpos (HMC) in infants is dilatation of the vagina and uterus caused by the accumulation of cervical secretions from maternal estrogen stimulation. HMC can be caused by:

  • Failure of the distal third of the vagina to develop (vaginal atresia or agenesis)
  • A transverse vaginal membrane
  • Imperforate hymen; however, in the child with this finding reported by El-Messidi & Fleming [2006], the child was too young for it to be determined whether the actual diagnosis was MKS or BBS.

HMC often presents at birth as a large, cystic abdominal mass arising out of the pelvis, which can be sufficiently large to be clinically obvious and is verified using an ultrasound scan. The mass can be large enough to cause intestinal obstruction, urinary outflow obstruction leading to dilatation of the ureter (hydroureter) and kidneys (hydronephrosis), inferior vena caval obstruction, and/or elevation of the diaphragm resulting in breathing difficulties.

Postaxial polydactyly (PAP) is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot.

  • The additional digit can be fully formed or can be a rudimentary skin tag (often called a "minimus").
  • If clinical examination is insufficient, radiographs may be used to determine whether the polydactyly is postaxial or mesoaxial (also known as insertional) (i.e., the presence of an extra digit or digits anywhere between the thumb and fifth finger). Mesoaxial polydactyly is much less common than postaxial polydactyly.

Congenital heart disease (CHD). Cardiac malformations that have been described at least once in individuals with MKS are atrioventricularis (AV) communis with a left-sided superior vena cava, atrial septal defect, ventricular septal defect, AV canal, small aorta and hypoplastic left ventricle, tetralogy of Fallot, and patent ductus arteriosus [Slavotinek & Biesecker 2000]. Because of the limited number of individuals with MKS and cardiac malformations, the relative incidences are unknown.

Note: (1) HMC and PAP in a non-Amish female without evidence of overlapping syndromes (see Differential Diagnosis) are sufficient for a clinical diagnosis of MKS [Slavotinek & Biesecker 2000]. (2) Because HMC and PAP can also be found in female infants with Bardet-Biedl syndrome (BBS), the clinical diagnosis of MKS in a female with HMC and PAP must be delayed until at least age five years and requires absence of features of BBS (e.g., rod-cone dystrophy, developmental delay or intellectual disability, obesity, abnormalities of renal structure or function) [David et al 1999, Slavotinek & Biesecker 2000]. (3) Males with one or more features of MKS should have at least one affected female relative to establish the clinical diagnosis of MKS. (4) Other physical findings in addition to the characteristic phenotypic triad associated with MKS are listed in Table 2. Although these features are nonspecific and have not been used to establish the diagnosis of MKS, the presence of renal anomalies may also prove useful in establishing the diagnosis of MKS.

Establishing the Diagnosis

The diagnosis of MKS is established in a proband with the identification of biallelic pathogenic variants in MKKS, also known as BBS6 (see Table 1).

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of MKKS is performed first followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
  • A multigene panel that includes MKKS and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, genome sequencing, and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel) has not confirmed a diagnosis in an individual with features of MKS. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in McKusick-Kaufman Syndrome (MKS)

Gene 1MethodProportion of Probands with Pathogenic Variants 2 Detectable by Method
MKKSSequence analysis 3Up to 100% 4, 5, 6
Gene-targeted deletion/duplication analysis 7Unknown

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Pathogenic variants in MKKS were detected in the Amish pedigree with MKS, the only family definitely known to have this phenotype. The variant detection frequency for MKKS variants in individuals with MKS is unknown. However, pathogenic variants in MKKS/BBS6 are found in approximately 4.8% of individuals with BBS [Deveault et al 2011].


Individuals with MKS within the Amish population are all homozygous for the pathogenic variants p.His84Tyr or p.Ala242Ser [Stone et al 2000]. Although the frequency of p.Ala242Ser is nearly 1% in the general population, the combination of p.His84Tyr and p.Ala242Ser is rare and the frequency is unknown. Note: (1) Both pathogenic variants (p.His84Tyr and p.Ala242Ser) were present in cis configuration on one chromosome from an apparently normal, "unrelated" Amish individual, implying that carries are unaffected. (2) The phenotypic effects of both pathogenic variants in trans configuration are unknown, as this has not been observed. (3) Haplotype analysis could be considered as a means to distinguish between cis configuration and trans configuration in a symptomatic individual who has both pathogenic variants.


The pathogenic variants identified can be hypomorphic alleles rather than complete loss of function, which more commonly causes the BBS phenotype.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

McKusick-Kaufman syndrome (MKS) (HMC and PAP without age-dependent features of BBS) was first diagnosed in a large Amish family [Stone et al 1998] and although rare, is presumed to be pan ethnic. In the Amish population, variable expressivity has been described: 70% of affected females have HMC, 60% of affected individuals of both sexes have PAP, and 15% of affected individuals of both sexes have CHD [Stone et al 1998, Slavotinek & Biesecker 2000]. Of note, many individuals with HMC and PAP diagnosed as having MKS were reported at an age too young to manifest the age-dependent features of BBS [David et al 1999, Slavotinek & Biesecker 2000]. The true incidence of physical findings associated with the MKS phenotype is therefore unknown.

Table 2 shows the most common associated features in 49 individuals of Amish and non-Amish ethnicity with the MKS phenotype [Slavotinek & Biesecker 2000]; 75% were diagnosed at birth and 98% by age six months.

Table 2.

Phenotypic Features of Individuals with MKS

FindingNumber of Individuals (%)
HMC42/44 (95%)
Vaginal agenesis26/44 (59%)
Urogenital sinus16/44 (36%)
Ectopic urethra8/44 (18%)
No urethral opening6/44 (14%)
No vaginal opening4/44 (9%)
Genitourinary tract fistulae6/44 (14%)
PAP – limbs
Hands only12/42 (29%)
Feet only6/42 (14%)
Hands and feet 111/42 (26%)
Four-limb polydactyly 111/42 (26%)
Other digital
Syndactyly12/49 (24%)
Metacarpal/tarsal anomalies8/49 (16%)
Postaxial minimus6/49 (12%)
Brachydactyly3/49 (6%)
Absent phalanges2/49 (4%)
Interstitial polydactyly0/48 (0%)
Heptadactyly2/48 (4%)
Various (see below)7/49 (14%)
Hydronephrosis31/49 (63%)
Hydroureter12/49 (24%)
Renal cysts2/49 (4%)
Calyceal dilatation7/49 (14%)
Renal atrophy/hypoplasia 22/49 (4%)
Corticomedullary dysplasia 33/46 (6%)
Nonfunctioning kidney2/49 (4%)
Imperforate anus4/49 (8%)
Anal atresia1/49 (2%)
Hirschsprung disease6/49 (12%)
Anteriorly placed anus2/49 (4%)

Four-limb polydactyly involves both hands and both feet; polydactyly of the hands and feet means that both upper and lower limbs are affected, but not every limb.


Renal dysplasia is a histologic diagnosis that describes abnormal differentiation of the renal parenchyma.


Corticomedullary dysplasia is abnormal differentiation of both the cortex and the medulla of the kidney. If focal, renal function may be preserved; if bilateral and extensive, renal failure can result.

Other Findings Associated with MKS

Cardiovascular malformations. Congenital heart defects comprising atrioventricular canal defect, atrial septal defect, ventricular septal defect, complex congenital heart disease with an atrioventricular canal defect, small aorta and hypoplastic left ventricle, Tetralogy of Fallot, and a patent ductus arteriosus have been reported in patients with an MKS phenotype [Slavotinek & Biesecker 2000, Tsai et al 2014].

Prognosis. Studies on life span have not been performed on individuals with MKS, but life span is not known to be reduced.

Development. Developmental delay was present in 3/37 individuals (14%) in one study [Slavotinek & Biesecker 2000]. Normal development has also been described at age five years [Gilli et al 1981], six years [Lurie & Wulfsberg 1994], and 14 years [Hamel & ter Haar 1984].

Growth. Height ranges from the 25th centile to below the third centile.

Gynecologic issues. Fertility has been described; one 16-year-old girl gave birth to a healthy son [Cohen & Javitt 1998].

Three young women required hysterectomy at puberty for complications of endometriosis [Paredes Esteban et al 1996].

Genotype-Phenotype Correlations

No genotype-phenotype correlation has been reported for pathogenic variants in MKKS and either the MKS or the BBS phenotype [Moore et al 2005, Deveault et al 2011].


Non-penetrance has been estimated to occur in at least 9% of affected Amish males and 3% of affected Amish females [Stone et al 1998].

Determination of penetrance in the non-Amish population has not yet been possible due to the rarity of the syndrome.


MKS was first described as HMC and PAP in the Amish population.


More than 90 individuals with the MKS phenotype from different ethnic groups have been reported. The majority were reported at birth or in the neonatal period because of HMC; thus BBS was frequently not excluded. The true prevalence of MKS is unknown and the incidence of MKS has not been estimated in the non-Amish population.

In the Amish, one allele with the sequence variants c.[250C>T;724G>T] (p.[His84Tyr;Ala242Ser]) was found in 100 "control chromosomes" from individuals apparently not closely related to individuals with MKS [Stone et al 2000]. This finding implies a carrier frequency of 1%-3% for MKS in the Amish population [Stone et al 2000], or an incidence of approximately 1:10,000.

Differential Diagnosis

Disorders in which Hydrometrocolpos (HMC) and Postaxial Polydactyly (PAP) Occur

Bardet-Biedl syndrome (BBS) (see Genetically Related Disorders) is characterized by rod-cone dystrophy, truncal obesity, postaxial polydactyly, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. The visual prognosis for children with BBS is poor. Night blindness is usually evident by age seven to eight years; the mean age of legal blindness is 15.5 years. Birth weight is usually normal, but significant weight gain begins within the first year and becomes a lifelong issue for most individuals. A majority of individuals have significant learning difficulties; a minority have severe impairment on IQ testing. Renal disease is a major cause of morbidity and mortality.

Eighteen genes are known to be associated with BBS: BBS1, BBS2, ARL6 (BBS3), BBS4, BBS5, MKKS (BBS6), BBS7, TTC8 (BBS8), BBS9, BBS10, TRIM32 (BBS11), BBS12, MKS1 (BBS13), CEP290 (BBS14), WDPCP (BBS15), SDCCAG8 (BBS16), LZTFL1 (BBS17), and BBIP1 (BBS18).

The phenotypic overlap between MKS and BBS is significant, not gene-specific, and can show intrafamilial variability [Deveault et al 2011]. Individuals diagnosed with HMC and polydactyly in the newborn period have been shown to have pathogenic variants in BBS2, TTC8 (BBS8), BBS10, and BBS12 in addition to MKKS (BBS6) [Schaefer et al 2011].

Ellis-van Creveld syndrome (EVC) (OMIM 225500). The cardinal phenotypic features of EVC are chondrodysplasia with acromelic growth retardation, polydactyly, ectodermal dysplasia with dystrophy of the nails, and congenital heart disease, most commonly an atrial septal defect [Ruiz-Perez et al 2000, Al-Khenaizan et al 2001]. Several individuals reported as having MKS based on the findings of HMC and PAP had clinical features consistent with EVC [Arcellana et al 1996, Yapar et al 1996]. The two genes known to be associated with EVC and the allelic disorder Weyers acrodental dysostosis (OMIM 193530) are EVC1 [Ruiz-Perez et al 2000] and EVC2 [Galdzicka et al 2002, Ruiz-Perez et al 2003]; however, further locus heterogeneity is suggested by the lack of linkage to either the EVC loci or the MKKS locus in one individual with an EVC phenotype and HMC [Digilio et al 2004].

Other. A woman age 19 years with lack of Müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydacytly, and tetralogy of Fallot had normal development, normal weight, and no evidence of retinal dystrophy. No MKKS sequence variants were identified by sequence analysis; thus, it is unknown if the individual has a variant form of MKS or a new syndrome [Slavotinek et al 2004].

Disorders in which PAP Occurs

Pallister-Hall syndrome (PHS). Overlap of MKS with PHS has been described [el Hammar et al 1998, McCann et al 2006, Kos et al 2008]. PHS is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed adrenal insufficiency. The diagnosis of PHS is based on family history and the clinical findings of hypothalamic hamartoma, central and postaxial polydactyly, bifid epiglottis, imperforate anus and renal abnormalities, and family history. PHS is caused by mutation of GLI3. It is inherited in an autosomal dominant manner.

Disorders in which HMC Occurs

Bardet-Biedl syndrome. HMC occurring as part of BBS has been associated with pathogenic variants in several other BBS-related genes besides MKKS (e.g., BBS10 and BBS12 [Billingsley et al 2010]).

VACTERL association. VACTERL is an acronym for an association of physical findings that comprises vertebral anomalies, anal atresia, cardiac malformations, tracheoesophageal fistula, renal abnormalities, and limb anomalies including hexadactyly (OMIM 192350). Clinical similarity between MKS and VACTERL association has been noted on the basis of tracheal abnormalities in individuals with HMC.

Chromosome disorder. Interstitial deletion of chromosome 8q21.11-q24.13 was reported in three young females with HMC who had multiple exostoses that appeared after age three years and craniofacial features consistent with trichorhinophalangeal syndrome type 2 (Langer-Giedion syndrome) [Fryns 1997].

No other cytogenetic abnormalities have been associated with HMC, although two chromosome abnormalities have been associated with vaginal agenesis:

  • De novo translocation [46,XX, t(8;13)(q22.1;q32.1)] in a female with vaginal agenesis and congenital amastia [Amesse et al 1999]
  • Chromosome 13 variant with double satellite stalks on the short arm 46,XX,13pstk+) in a female with vaginal agenesis, posterior displacement of the urethra, small uterus, absent cervix, and bilateral absence of the radii, but no polydactyly [Behera et al 2005]


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with McKusick-Kaufman Syndrome, the following evaluations are recommended:

  • Pelvic ultrasound examination to detect genitourinary malformations (Table 3)
  • Skeletal radiographs to detect osseous polydactyly and syndactyly
  • ECG and echocardiogram, to detect congenital heart defects
  • Renal ultrasound examination and a renal imaging study to detect pelvicalyceal abnormalities, renal hypoplasia, or cystic dysplasia of the kidneys
  • Assessment of height, weight, and head circumference and initiation of a carefully maintained growth chart to document obesity that may indicate Bardet-Biedl syndrome (BBS).
  • Determination of developmental status by standard screening tools to detect developmental delay that may indicate BBS. If delays are identified, a more detailed assessment of developmental and cognitive abilities is indicated.
  • Ophthalmologic examination and electroretinogram to evaluate for manifestations of BBS in children with weight greater than the 90th centile and/or short stature and/or developmental delay or intellectual disability.
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Prompt surgical repair of the obstruction causing hydrometrocolpos and drainage of the accumulated fluid is important.

Standard treatment is indicated for the following:

  • Polydactyly and syndactyly
  • Congenital heart defects
  • Anal anomalies and Hirschsprung disease (surgical treatment)

Prevention of Secondary Complications

Recurrent urinary tract infections and re-stenosis of the vaginal orifice are the most common complications in individuals with MKS following surgical drainage of the HMC [Slavotinek & Biesecker 2000].

Care should be taken with anesthesia in the neonatal period if severe hydrometrocolpos causing diaphragmatic compression is present. Gastric decompression and preoxygenation prior to tracheal intubation were used in the anesthetic management of one neonate with severe hydrometrocolpos compressing the diaphragm [Tekin et al 2003].


The following are appropriate:

  • In individuals with renal abnormalities, monitoring of blood pressure and renal function.
  • In individuals with interim history of severe constipation, rectal biopsy to exclude Hirschsprung disease
  • Continuing surveillance for manifestations that would establish the diagnosis of BBS including the following:
    • Serial growth measurements to track height and weight until at least age five years to document obesity that can occur with BBS
    • Developmental assessments until at least age five years to detect developmental disabilities that can occur with BBS
    • Regular ophthalmologic examination and electroretinogram (ERG) (if appropriate) after age five years to evaluate for visual signs and symptoms of retinitis pigmentosa [A Verloes, personal communication]
    • As diabetes mellitus is a rare complication of BBS, measurement of fasting blood glucose as appropriate
    • Investigations for rarer complications of BBS, including hearing assessment, dental assessment, electroencephalogram, and thyroid function tests as appropriate
  • Consideration of later complications of surgery for HMC, including recurrent urinary tract infections and re-stenosis and infection of the vaginal tract [Lueth & Wood 2014]. Surveillance as appropriate for each individual is recommended.

Agents/Circumstances to Avoid

In the newborn with severe HMC, care with anesthesia in the neonatal period is appropriate, as HMC can cause diaphragmatic compression.

Evaluation of Relatives at Risk

It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
  • If the pathogenic variants in the family are not known:
    • Sisters of females with MKS should have examination of the external genitalia for vaginal membranes or an imperforate vagina and of the hands and feet for polydactyly, and an echocardiogram for the congenital heart defects associated with MKS.
    • Brothers of affected females should have an examination of the external genitalia for hypospadias, cryptorchidism, and chordee and of the hands and feet for polydactyly, and an echocardiogram for cardiac manifestations of MKS.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

McKusick-Kaufman syndrome (MKS) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one MKKS pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
  • De novo pathogenic variants in MKKS have not been observed.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier of an MKKS pathogenic variant is 2/3.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with MKS are obligate heterozygotes (carriers) for a pathogenic variant in MKKS.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an MKKS pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

MKS vs BBS. Genetic counseling should encourage caution regarding premature diagnosis of MKS because of the possibility of complications of BBS appearing at a later age.

Triallelic inheritance. Although triallelic inheritance has not been established for the original Amish MKS pedigree (see Molecular Pathogenesis, Nakane & Biesecker [2005]), several reports have described BBS phenotypes with three mutant alleles with at least one allele involving the MKKS locus [Badano et al 2003, Beales et al 2003, Hichri et al 2005, Hjortshøj et al 2010]. In a study that examined BBS1, BBS2, BBS4, MKKS, BBS10, and BBS12 by DHPLC, 8/49 individuals with BBS (16%) were found to have three sequence variants in two BBS-related genes. The additional sequence variants were interpreted as possibly resulting from triallelic inheritance, heterozygous carrier status for a separate BBS-related gene, or rare polymorphisms [Hjortshøj et al 2010]. In individuals who had three sequence alterations, two pathogenic variants were present in one BBS-related gene and deemed to be pathogenic, whereas the third alteration in the separate BBS-related gene was a single amino acid substitution. Four of the single amino acid substitutions occurred in MKKS (p.Ala242Ser and p.Ile 339Val). The pathogenicity of these MKKS alterations was unclear [Hjortshøj et al 2010], and they were not definitely associated with modification of the BBS phenotype. However, the finding of three mutant alleles has previously been associated with a more severe BBS phenotype than in family members with two mutant alleles [Beales et al 2003]. Triallelic inheritance appears to be less common than autosomal recessive inheritance in BBS and was not observed in one large study, leading the authors to state that BBS should be viewed solely as an autosomal recessive condition [Deveault et al 2011]. Triallelic inheritance has not been observed in association with the MKS phenotype to date.

Note: In triallelic inheritance, the phenotype is dependent on the inheritance of two pathogenic variants at one locus and another pathogenic variant at a separate locus.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the MKKS pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MKS are possible.

Ultrasound examination. The manifestations of MKS (HMC, PAP, and CHD) can be detected by prenatal ultrasound examination. The reliability of prenatal ultrasound as a method of diagnosing MKS is unknown because the degree of PAP in individuals with MKS is variable and HMC may not be apparent until after birth. Cardiac defects may also not be present.

Detection of cystic abdominal masses that were postnatally identified as HMC has been accomplished at 26 weeks' gestation [Gupta et al 2010] and at 33 weeks' gestation [Slavin et al 2010]. Fetal magnetic resonance imaging (MRI) has also been shown to be superior to ultrasound examination for anatomic localization of the mass, and thus for diagnosis, in some cases [Gupta et al 2010].

It is worth noting that two initial prenatal sonograms at ten and 19 weeks' gestation were normal in a female who was later found to have an ill-defined lower abdominal mass and bilateral mild hydronephrosis by sonogram in labor at 42 weeks [Khatwa et al 2005].

Ultrasound guided decompression of hydrometrocolpos in a fetus has also been reported [Chen et al 1996].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

McKusick-Kaufman Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for McKusick-Kaufman Syndrome (View All in OMIM)


Molecular Pathogenesis

The molecular basis for the differences in phenotype between MKS and BBS remains undetermined. It was first postulated that the differences between the MKS and BBS phenotypes were the result of quantitative or qualitative differences in the protein encoded by MKKS [Katsanis et al 2001, Slavotinek & Biesecker 2001]. It is interesting that mice with a targeted mutation to remove exon 3, which contains the start codon of murine Mkks [Fath et al 2005], have a phenotype that more closely resembles BBS than MKS: the mice develop obesity with high leptin levels and photoreceptor degeneration and have lower levels of social dominance than heterozygotes and wild-type controls. In addition, the males show an absence of flagella in the seminiferous tubules at all ages [Fath et al 2005].

Additional work has shown that at least some pathogenic variants in MKKS result in a protein that is more rapidly degraded by the HSC70 interacting protein (CHIP)-dependent, ubiquitin-proteasome pathway than wildtype protein [Hirayama et al 2008]. Among the MKKS pathogenic variants tested, both p.His84Tyr and p.Ala242Ser mutant proteins, as found in MKS, underwent accelerated degradation compared to wildtype proteins, but these pathogenic variants did not result in an increase in insolubility. As some MKKS pathogenic variants proved capable of increasing both the rate of degradation and insolubility, it is plausible that phenotypic severity could be modulated by pathogenic variant severity or that the functional ability of the chaperone-dependent protein degradation system could modify the severity of clinical findings [Hirayama et al 2008].

Triallelic inheritance has not been demonstrated for the MKS phenotype. In a study on the original Amish family with MKS, in which three affected children were homozygous for both the p.His84Tyr and p.Ala242Ser pathogenic variants ([c.250C>T;724G>T (p.His84Tyr;Ala242Ser)]; see Table 4), sequencing of BBS1, BBS2, BBS3, BBS4, BBS5, and BBS7 in the parents failed to identify any pathogenic variants in the coding sequence or splice sites [Nakane & Biesecker 2005]. Involvement of BBS8 in triallelic inheritance for this family was excluded by genotyping [Nakane & Biesecker 2005]. However, this study could not exclude possible triallelic inheritance resulting from a pathogenic variant present in a regulatory region or deep within an intron, a microdeletion of a BBS-related gene not detectable by genotyping, or a pathogenic variant in a BBS-related gene that was not sequenced [Nakane & Biesecker 2005].

Finally, it is interesting to note that 1/22 female Bbs4 homozygous knockout mice was found to have HMC [Eichers et al 2006], whereas HMC was not observed in the Mkks homozygous knockout mouse [Fath et al 2005].

Gene structure. MKKS has six exons. The start codon of the gene is in exon 3. Two alternatively spliced 5' exons (exon 1A and exon 1B) are not translated [Stone et al 2000]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Pathogenic variants have been identified in all of the coding exons of the gene. No known mutation "hot spot" exists. A high frequency of "isolated" sequence alterations have been observed in MKKS [Beales et al 2001, Katsanis et al 2001]. Possible explanations other than the failure of sequencing strategies to detect cryptic pathogenic variants include triallelic inheritance or autosomal recessive inheritance with a modifying locus [Katsanis et al 2001].

Click here for more detailed information on pathogenic variants in MKKS (pdf).

Table 4.

Selected MKKS Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.

Normal gene product. The protein encoded by MKKS is a 570-amino acid protein that has the greatest similarity to the Group II chaperonins (archebacterial chaperonins and eukaryotic T complex-related proteins [Slavotinek & Biesecker 2001]). Chaperonins are members of the chaperone protein family or heat shock proteins and stabilize nonnative or unfolded proteins during heat shock or cellular stress. Group I chaperonins (e.g., GroEL in E. coli) are composed of seven identical subunits of 57 kd arranged in two rings stacked back to back. Each subunit has an apical domain, an intermediate domain, and an equatorial domain. The apical domain has hydrophobic residues that bind to nonnative substrate. After binding of the unfolded protein, a co-chaperonin or capping molecule (GroES), and ATP, the chaperonin complex can undergo a conformational change that allows the nonnative protein to be folded in a protected cellular environment [Shtilerman et al 1999].

Note: Two other BBS-associated genes, BBS10 and BBS12, also encode a protein related to the group II chaperonins [Stoetzel et al 2006, Stoetzel et al 2007].

MKKS/BBS6 encodes a chaperonin-like subunit that facilitates the stabilization of BBS7, enabling the generation of an assembly intermediate, the BBSome core, prior to formation of the BBSome, a group of proteins involved with ciliary trafficking [Barbelanne et al 2015].

Abnormal gene product. The Amish pathogenic variant p.His84Tyr was first predicted to affect ATP hydrolysis in the equatorial domain of the protein encoded by MKKS, and thus to disrupt protein function. Both pathogenic variants have now been shown to result in protein instability and more rapid protein degradation, as described in Molecular Pathogenesis [Hirayama et al 2008].


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Chapter Notes

Revision History

  • 4 June 2015 (me) Comprehensive update posted live
  • 29 June 2010 (me) Comprehensive update posted live
  • 8 October 2009 (cd) Revision: sequence analysis available clinically
  • 20 October 2006 (me) Comprehensive update posted live
  • 2 August 2004 (me) Comprehensive update posted live
  • 10 September 2002 (me) Review posted live
  • 5 March 2002 (as) Original submission
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