McKusick-Kaufman Syndrome

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. PAP is the presence of additional digits on the ulnar side of the hand and the fibular side of the foot. A variety of congenital heart defects have been reported including atrioventricular canal, atrial septal defect, ventricular septal defect, or a complex congenital heart malformation.

Diagnosis/testing.

The clinical diagnosis of MKS can be established in a proband based on clinical diagnostic criteria of HMC and PAP in the absence of clinical or molecular genetic findings suggestive of an alternative diagnosis. The molecular diagnosis can be established in proband with suggestive findings and biallelic pathogenic variants in MKKS identified by molecular genetic testing. However, care must be taken to ensure that the proband does not have Bardet-Biedl syndrome, an allelic condition with considerable clinical overlap and age-dependent features including retinal dystrophy, obesity, and intellectual disability.

Management.

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

Surveillance: Watch for recurrent later complications of surgery for HMC; ongoing surveillance for manifestations of BBS including growth and developmental assessments, ophthalmologic examination, and electroretinogram, renal anomaly complications and development of severe constipation (which raises the possibility of Hirschsprung disease).

Agents/circumstances to avoid: Care with anesthesia in the neonatal period as severe HMC can cause diaphragmatic compression.

Genetic counseling.

MKS is inherited in an autosomal recessive manner. If both parents of an individual with MKS are known to be heterozygous for an MKKS pathogenic variant, each sib of an affected individual has at conception 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. (Note: Genetic counseling should encourage caution regarding premature diagnosis of MKS [i.e., a diagnosis made before age 5 years] because of the possibility of manifestations of Bardet-Biedl syndrome appearing at a later age.) Carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the MKKS 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 of MKS is unknown because these findings are variable and may not be apparent in an individual 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)
• PAP **
• CHD

In all

• Insufficient manifestations of overlapping syndromes, such as Bardet-Biedl syndrome (BBS) for a diagnosis of this syndrome or another condition
• Family history typically consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity and unaffected parents). Absence of a known family history does not preclude the diagnosis.

* Hydrometrocolpos (HMC) in infants is dilatation of the vagina and uterus caused by the accumulation of cervical secretions as a result of 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; in rare cases, HMC and polydactyly may be associated with an imperforate hymen, but many individuals reported with these findings were described at young ages and it is thus not known if 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), obstruction of the inferior vena cava, 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 polydactyly); that is, the presence of an extra digit or digits between the thumb and fifth finger. Mesoaxial polydactyly is much less common than postaxial polydactyly.

Establishing the Diagnosis

The clinical diagnosis of McKusick-Kaufman syndrome (MKS) can be established in a proband based on clinical diagnostic criteria of HMC and postaxial polydactyly in the absence of clinical or molecular genetic findings suggestive of an alternative diagnosis in an individual age five years or older. Evidence of likely autosomal recessive inheritance can be a supporting factor. A molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in MKKS (also known as BBS6) identified by molecular genetic testing (see Table 1).

Molecular Diagnosis

The molecular diagnosis of MKS is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in MKKS identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic MKKS variants of uncertain significance (or identification of one known MKKS pathogenic variant and one MKKS variant of uncertain significance) does not establish or rule out the diagnosis.

Because the phenotype of MKS is indistinguishable from BBS through early childhood, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of MKKS, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel that includes MKKS and other genes of interest, including the genes for BBS (see Differential Diagnosis) is likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. 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. (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.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  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)

Clinical Description

McKusick-Kaufman syndrome (MKS), defined as hydrometrocolpos (HMC) and postaxial polydactyly (PAP) without the development of the age-dependent features of BBS, was first diagnosed in a large Amish family [Stone et al 1998]. Although the MKS phenotype is very rare, it has been presumed to be pan ethnic following descriptions of HMC in association with polydactyly in numerous ancestries. In the Amish population, variable expressivity for MKS 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 congenital heart disease (CHD) [Slavotinek & Biesecker 2000]. Of note, many individuals with HMC and PAP diagnosed as having MKS have been reported at an age too young to manifest the age-dependent features of BBS [Mallmann et al 2019]. The true incidence of physical findings associated with the MKS phenotype alone is therefore unknown.

Table 2 shows the most frequent associated features in 49 individuals of Amish and non-Amish ethnicity who were diagnosed with MKS; 75% were diagnosed at birth and 98% by age six months [Slavotinek & Biesecker 2000]. Of these individuals, 44 were female and five were male. No similar large studies have been realized more recently and the majority of recent case reports have comprised single individuals with HMC reported in the first year of life [Adam et al 2017, Halim et al 2018]. The degree of similarity of the phenotype between the Amish and non-Amish population is unclear and has not been systematically studied; in addition, it is not known if these individuals would have developed manifestations of BBS as they aged.

The incidence of genital findings in males has also been difficult to establish outside the Amish population due to the rarity of the condition, but in 11 males who had affected sisters or other female relatives diagnosed with MKS, polydactyly was present in all cases and only one had genital abnormalities comprising cryptorchidism and hypospadias [Chitayat et al 1987]; however, the incidence of BBS among these individuals is not known.

Table 2.

Phenotypic Features of Individuals with McKusick-Kaufman Syndrome (MKS)

Genotype-Phenotype Correlations

No genotype-phenotype correlations for MKKS have been identified.

Penetrance

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.

Nomenclature

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

Prevalence

More than 100 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.

Stone et al [2000] estimated a heterozygote frequency of 1%-3% for MKS in the Amish population or an incidence of approximately 1:10,000 [Scott et al. 2017].

Other Disorders with Overlapping Clinical Features

Hydrometrocolpos and postaxial polydactyly (PAP)

• Ellis-van Creveld syndrome (EVC). Cardinal phenotypic features of EVC comprise chondrodysplasia with acromelic growth restriction, polydactyly, ectodermal dysplasia with dystrophy of the nails, and congenital heart disease [Ruiz-Perez et al 2000, Ruiz-Perez et al 2003]. Although individuals reported as having HMC and PAP have had clinical features consistent with EVC [Digilio et al 2004], genetic testing should differentiate these conditions. EVC is an autosomal recessive disorder known to be associated with pathogenic variants in EVC or EVC2.
• A woman age 19 years with lack of müllerian fusion, vaginal agenesis, a unicornuate uterus, postaxial polydactyly, brachydactyly, 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].
• Pallister-Hall syndrome (PHS). Overlap of MKS with PHS has been described due to HMC and postaxial polydactyly [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. PHS is caused by pathogenic variants in GLI3 and is inherited in an autosomal dominant manner.

Hydrometrocolpos with preaxial polydactyly. HMC has also been reported in one case in association with preaxial, "mirror" polydactyly [Traisrisilp et al 2021], but genetic testing in this individual did not confirm either MKS or BBS.

HMC can be a feature of several malformation syndromes (see Mallmann et al [2019]) including:

• Mayer-Rokitansky-Küster-Hauser syndrome
• Herlyn-Werner-Wunderlich syndrome
• Intraabdominal teratoma
• 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).
• Trichorhinophalangeal syndrome. HMC is a rare finding in trichorhinophalangeal syndrome II (Langer-Giedion syndrome) [Schinzel et al 2013].

Vaginal agenesis. Rarely, vaginal agenesis can be described with chromosome aberrations (e.g., see Anant et al [2020]).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with McKusick-Kaufman syndrome (MKS), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with McKusick-Kaufman Syndrome (MKS)

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with McKusick-Kaufman Syndrome (MKS)

Surveillance

Table 6.

Recommended Surveillance for Individuals with McKusick-Kaufman Syndrome (MKS)

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 [Tekin et al 2003].

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. Examination of the external genitalia for vaginal membranes or an imperforate vagina, and of the hands and feet for polydactyly; echocardiogram for the congenital heart defects associated with MKS
  • Brothers of affected females. Examination of the external genitalia for hypospadias, cryptorchidism, and chordee; and of the hands and feet for polydactyly; 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 ClinicalTrials.gov 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.

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., presumed to be carriers of one MKKS pathogenic variant based on family history).
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for an MKKS pathogenic variant and to allow reliable recurrence risk assessment. (In rare families, only one parent of a proband with an autosomal recessive disorder is heterozygous and the proband is affected as the result of either (1) one pathogenic variant inherited from the heterozygous parent and a second pathogenic variant that occurred de novo in the proband or (2) uniparental isodisomy and consequent homozygosity for the pathogenic variant transmitted by a heterozygous parent [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents of an individual with MKS are known to be heterozygous for an MKKS pathogenic variant, each sib of an affected individual has at conception 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.
• Intrafamilial clinical variability has been observed in sibs with biallelic pathogenic MKKS variants [Manara et al 2019].
• 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.
• The heterozygote frequency of MKS in the Amish population is estimated to be 1%-3% (see Prevalence), increasing the risk that an affected individual may have a reproductive partner who is heterozygous for the specific MKKS variant allele found in the Amish population (see Molecular Pathogenesis). The offspring of an affected individual and a heterozygous reproductive partner are at 50% risk of being affected and 50% risk of being heterozygous.

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 Detection

Carrier testing for at-risk relatives requires prior identification of the MKKS pathogenic variants in the family.

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 Bardet-Biedl syndrome. Genetic counseling should encourage caution regarding premature diagnosis of MKS (i.e., a diagnosis made before age 5 years) because of the possibility of manifestations of Bardet-Biedl syndrome appearing at a later age.

Family planning

• The optimal time for determination of genetic risk 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

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

Ultrasound examination. The manifestations of MKS, including hydrometrocolpos (HMC), postaxial polydactyly (PAP), and congenital heart disease, can be detected by prenatal ultrasound examination. If present, these findings may not be identified until late second trimester or third trimester, or may not be apparent until after birth. Given the variability in findings of MKS, the reliability of prenatal ultrasound as a method of diagnosing MKS is unknown.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

McKusick-Kaufman syndrome (MKS), like Bardet-Biedl syndrome (BBS) is part of a group of disorders known as ciliopathies. At least 26 different genes are associated with BBS and it has long been recognized that pathogenic variants in MKKS (also known as BBS6) have been associated with both MKS and BBS.

In the Old Order Amish kindred in which MKS was first described, the phenotype was recorded as due to homozygosity for two pathogenic variants, p.His84Tyr and p.Ala242Ser, inherited in cis (i.e., p.[His84Tyr, Ala242Ser]; [His84Tyr, Ala242Ser]). The p.[His84Tyr, Ala242Ser] allele, with both variants, is present in approximately 2% of the Amish population, but is very rare outside of this ancestry. To date, very few individuals outside the Amish population diagnosed clinically with MKS have been found to have biallelic pathogenic variants in MKKS.

The proteins encoded by the genes that cause BBS form two main complexes: the BBSome (a multi-protein complex) and the BBS chaperonin complex [Scott et al 2017]. The BBSome, consisting of eight proteins (BBS1, BBS2, BBS4, BBS5, BBS7, BBS8, BBS9, and BBS18) is involved in ciliary function by transporting ciliary cargo destined for the plasma membrane of the cell, whereas the BBS chaperonin complex, comprising MKKS/BBS6, BBS10, and BBS12, functions as a scaffold for assembly of the BBSome complex [Scott et al 2017]. Other BBS-related genes have also been identified.

Wild type MKKS protein binds SMARCC1 and is actively transported between the cytoplasm and nucleus, whereas the MKKS protein resulting from the MKS-associated allele, MKKS/BBS6 p.[His84Tyr, Ala242Ser] found in the Amish population, binds to SMARCC1, but is defective in its ability to enter the cell nucleus [Scott et al 2017]. Other variants in MKKS associated with BBS were not found to alter nuclear import. The MKKS/BBS6 p.[His84Tyr, Ala242Ser] allele was shown not to impair cilia-related processes and this may explain the milder phenotype associated with MKS compared to BBS [Scott et al 2017].

Mechanism of disease causation. MKS occurs via a loss-of-function mechanism consistent with autosomal recessive conditions.

Table 7.

Notable MKKS Pathogenic Variants

Author Notes

Dr Slavotinek received her medical degree from the University of Adelaide and her PhD from Flinders University in South Australia. She trained in Clinical Genetics in the United Kingdom and subsequently did a Genetics Fellowship at the National Institutes of Health to become Board certified in Clinical Genetics in the USA. She joined the Department of Pediatrics at UCSF in 2002 and is now a Professor of Clinical Pediatrics. Dr Slavotinek is an author on more than 195 peer-reviewed publications in addition to book chapters and reviews. Dr Slavotinek divides her time between practicing in clinical genetics, clinical genomics research, and basic laboratory research.

Web page: brain.ucsf.edu/anne-slavotinek-md-phd

Acknowledgments

The author is grateful to Dr Leslie Biesecker for his role in the discovery of MKKS and for his insights on MKS and BBS.

Revision History

• 3 December 2020 (ha) Comprehensive update posted live
• 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

Literature Cited

• Abu-Safieh L, Al-Anazi S, Al-Abdi L, Hashem M, Alkuraya H, Alamr M, Sirelkhatim MO, Al-Hassnan Z, Alkuraya B, Mohamed JY, Al-Salem A, Alrashed M, Faqeih E, Softah A, Al-Hashem A, Wali S, Rahbeeni Z, Alsayed M, Khan AO, Al-Gazali L, Taschner PE, Al-Hazzaa S, Alkuraya FS. In search of triallelism in Bardet-Biedl syndrome. Eur J Hum Genet. 2012;20:420–7. [PMC free article: PMC3306854] [PubMed: 22353939]

• Adam A, Hellig J, Mahomed N, Lambie L. Recurrent urinary tract infections in a female child with polydactyly and a pelvic mass: consider the McKusick-Kaufman syndrome. Urology. 2017;103:224–6. [PubMed: 28153592]

• Anant M, Raj N, Yadav N, Prasad A, Kumar S, Saxena AK. Two distinctively rare syndromes in a case of primary amenorrhea: 18p deletion and Mayer-Rokitansky-Kuster-Hauser syndromes. J Pediatr Genet. 2020;9:193–7. [PMC free article: PMC7375842] [PubMed: 32714621]

• Chitayat D, Hahm SY, Marion RW, Sachs GS, Goldman D, Hutcheon RG, Weiss R, Cho S, Nitowsky HM. Further delineation of the McKusick-Kaufman hydrometrocolpos-polydactyly syndrome. Am J Dis Child. 1987;141:1133–6. [PubMed: 3631003]

• Cohen E, Javitt MC. Term pregnancy in a patient with McKusick-Kaufman syndrome. AJR Am J Roentgenol. 1998;171:273–4. [PubMed: 9648816]

• Deveault C, Billingsley G, Duncan JL, Bin J, Theal R, Vincent A, Fieggen KJ, Gerth C, Noordeh N, Traboulsi EI, Fishman GA, Chitayat D, Knueppel T, Millán JM, Munier FL, Kennedy D, Jacobson SG, Innes AM, Mitchell GA, Boycott K, Héon E. BBS genotype-phenotype assessment of a multiethnic patient cohort calls for a revision of the disease definition. Hum Mutat. 2011;32:610–9. [PubMed: 21344540]

• Digilio MC, Torrente I, Goodship JA, Marino B, Novelli G, Giannotti A, Dallapiccola B. Ellis-van Creveld Syndrome with hydrometrocolpos is not linked to chromosome arm 4p or 20p. Am J Med Genet A. 2004;126A:319–23. [PubMed: 15054850]

• Goyal S, Singh IR, Vanita V. Novel mutation in MKKS/BBS6 linked with arRP and polydactyly in a family of North Indian origin. Clin Exp Ophthalmol. 2020;48:343–55. [PubMed: 31989739]

• Halim A, Afzal T, Fatima S, Riaz S. A newborn with rare McKusick syndrome. J Coll Physicians Surg Pak. 2018;28:S140–2. [PubMed: 29866251]

• Hjortshøj TD, Grønskov K, Philp AR, Nishimura DY, Riise R, Sheffield VC, Rosenberg T, Brøndum-Nielsen K. Bardet-Biedl syndrome in Denmark-report of 13 novel sequence variations in six genes. Hum Mutat. 2010;31:429–36. [PubMed: 20120035]

• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]

• Hulleman JD, Nguyen A, Ramprasad VL, Murugan S, Gupta R, Mahindrakar A, Angara R, Sankurathri C, Mootha VV. A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome. Mol Vis. 2016;22:73–81. [PMC free article: PMC4734152] [PubMed: 26900326]

• Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]

• Kos S, Roth K, Korinth D, Zeilinger G, Eich G. Hydrometrocolpos, postaxial polydactyly, and hypothalamic hamartoma in a patient with confirmed Pallister-Hall syndrome: a clinical overlap with McKusick-Kaufman syndrome. Pediatr Radiol. 2008;38:902–6. [PubMed: 18478223]

• Mallmann MR, Reutter H, Mack-Detlefsen B, Gottschalk I, Geipel A, Berg C, Boemers TM, Gembruch U. Prenatal diagnosis of hydro(metro)colpos: a series of 20 cases. Fetal Diagn Ther. 2019;45:62–8. [PubMed: 29478043]

• Manara E, Paolacci S, D'Esposito F, Abeshi A, Ziccardi L, Falsini B, Colombo L, Iarossi G, Pilotta A, Boccone L, Guerri G, Monica M, Marta B, Maltese PE, Buzzonetti L, Rossetti L, Bertelli M. Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study. Ital J Pediatr. 2019;45:72. [PMC free article: PMC6567512] [PubMed: 31196119]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]

• Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K, King L, Francomano C, Freisinger P, Spranger S, Marino B, Dallapiccola B, Wright M, Meitinger T, Polymeropoulos MH, Goodship J. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 2000;24:283–6. [PubMed: 10700184]

• Ruiz-Perez VL, Tompson SW, Blair HJ, Espinoza-Valdez C, Lapunzina P, Silva EO, Hamel B, Gibbs JL, Young ID, Wright MJ, Goodship JA. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet. 2003;72:728–32. [PMC free article: PMC1180248] [PubMed: 12571802]

• Schaefer E, Durand M, Stoetzel C, Doray B, Viville B, Hellé S, Danse JM, Hamel C, Bitoun P, Goldenberg A, Finck S, Faivre L, Sigaudy S, Holder M, Vincent MC, Marion V, Bonneau D, Verloes A, Nisand I, Mandel JL, Dollfus H. Molecular diagnosis reveals genetic heterogeneity for the overlapping MKKS and BBS phenotypes. Eur J Med Genet. 2011;54:157–60. [PubMed: 21044901]

• Schinzel A, Riegel M, Baumer A, Superti-Furga A, Moreira LM, Santo LD, Schiper PP, Carvalho JH, Giedion A. Long-term follow-up of four patients with Langer-Giedion syndrome: clinical course and complications. Am J Med Genet A. 2013;161A:2216–25. [PubMed: 23913778]

• Scott CA, Marsden AN, Rebagliati MR, Zhang Q, Chamling X, Searby CC, Baye LM, Sheffield VC, Slusarski DC. Nuclear/cytoplasmic transport defects in BBS6 underlie congenital heart disease through perturbation of a chromatin remodeling protein. PLoS Genet. 2017;13:e1006936. [PMC free article: PMC5550010] [PubMed: 28753627]

• Slavotinek AM, Biesecker LG. Phenotypic overlap of McKusick-Kaufman syndrome with bardet-biedl syndrome: a literature review. Am J Med Genet. 2000;95:208–15. [PubMed: 11102925]

• Slavotinek AM, Dutra A, Kpodzo D, Pak E, Nakane T, Turner J, Whiteford M, Biesecker LG, Stratton P. A female with complete lack of Müllerian fusion, postaxial polydactyly, and tetralogy of Fallot: genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome? Am J Med Genet A. 2004;129A:69–72. [PubMed: 15266619]

• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]

• Stone DL, Agarwala R, Schaffer AA, Weber JL, Vaske D, Oda T, Chandrasekharappa SC, Francomano CA, Biesecker LG. Genetic and physical mapping of the McKusick-Kaufman syndrome. Hum Mol Genet. 1998;7:475–81. [PubMed: 9467007]

• Stone DL, Slavotinek A, Bouffard GG, Banerjee-Basu S, Baxevanis AD, Barr M, Biesecker LG. Mutation of a gene encoding a putative chaperonin causes McKusick-Kaufman syndrome. Nat Genet. 2000;25:79–82. [PubMed: 10802661]

• Tekin I, Ok G, Genc A, Tok D. Anaesthetic management in McKusick-Kaufman syndrome. Paediatr Anaesth. 2003;13:167–70. [PubMed: 12562491]

• Traisrisilp K, Nunthapiwat S, Luewan S, Tongsong T. Fetal hydrometrocolpos with pre-axial mirror polydactyly as a new variant of McKusick-Kaufman syndrome. J Clin Ultrasound. 2021;49:62–5. [PubMed: 32537787]

• Tsai HF, Wu MH, Cheng YC, Chang CH, Chang FM. Prenatal ultrasonography and postnatal follow-up of a case of McKusick-Kaufman syndrome. Taiwan J Obstet Gynecol. 2014;53:241–4. [PubMed: 25017277]