McKusick–Kaufman syndrome (MKS) is a rare genetic condition caused by mutations in the MKKS gene, which affect how cells develop and function. It is named after Dr. Robert L. Kaufman and Victor McKusick, who studied the condition and helped identify key features. MKS can be difficult to recognize in infancy because it resembles Bardet–Biedl syndrome (BBS). While MKS mainly causes extra fingers or toes (postaxial polydactyly), fluid buildup in the vagina (hydrometrocolpos), and heart defects, BBS has more severe symptoms such as vision loss and obesity that usually appear later in life. MKS is most common in the Old Order Amish population, where it affects about 1 in 10,000 people. The syndrome was first discovered in this group through a genetic method called positional cloning, which helped scientists identify the MKKS gene as the cause of this condition. Its prevalence outside the Amish population remains unknown.
Presentation
Clinically, McKusick–Kaufman syndrome is characterized by a combination of three features: postaxial polydactyly, congenital heart disease, and genital abnormalities: Genital abnormalities may include: In females:
Vaginal atresia with hydrometrocolpos Urogenital sinus Double vagina and/or uterus Genitourinary tract fistula Ureter stenosis or ureteric atresia In males:
Hypospadias Chordee Cryptorchidism Ureter stenosis or ureteric atresia Postaxial polydactyly and heart defects occur around 35 to 42 days in utero, while genital abnormalities such as uterovaginal plate perforation occurs around the 12th week of development.
Genetics MKS is characterized by mutations in the MKKS gene on chromosome 20p12.2-p12.1 which is inherited in an autosomal recessive pattern. Both parents of an affected individual must be heterozygous carriers of the pathogenic variant. Heterozygous carriers for MKS show no symptoms of the disorder, nor do they develop the disorder. Each child of these carriers has a 1/4 chance of being affected by MKS, a 1/2 chance of being carriers themselves, and a 1/4 chance of being unaffected and a non carrier. Determining penetrance for MKS is challenging without molecular genetic analysis, as subtle malformations may be difficult to detect, and the rarity of the syndrome adds to the complexity. Non-penetrance is estimated to occur in at least 9% of Amish males and 3% of Amish females, while penetrance in the non-Amish population remains undetermined. According to studies, this low penetrance in the Amish population could be a result of genetic modifiers that influence the clinical presentation and severity. MKKS is a six-exon gene that encodes the MKKS protein which has homology with members of the chaperonin family that prevents protein misfolding. This protein has the highest homology with a subunit of a chaperonin complex in the Thermoplasma acidophilum organism, which is structurally similar to a eukaryotic chaperin complex that supports folding of cytoskeletal proteins. The MKKS protein plays an important role in forming cilia, which are tiny hair-like structures on cells that help with movement and signalling. As such, this protein is ubiquitously expressed in development and adulthood. Mutations in MKKS result in a loss of function phenotype; the cilia do not work properly, leading to the symptoms of MKS. In mice, flagella formation failure, retinal degeneration, and deficits in olfaction have been observed. Two notable MKKS variants that lead to MKS are p.His84Tyr and p.Ala242Ser which were first identified in the Amish population. The allele carrying both homozygous missense mutations (p.[His84Tyr, Ala242Ser]), is found in about 2% of the Amish population, but is rare in other ancestry groups. The MKSS variants are a group of mutations that also contribute to the BSS and thus display the genetic overlap between MKKS and BSS. These have provided sights to the genetic underpinning of those disorders. Today, over 40 mutations across the gene are associated with MKS or BBS, including nonsense, missense, insertion, and deletion mutations. Studies of families with MKKS mutations most commonly show a phenotype involving truncation of the normal MKKS protein. However, not all variants have been linked to a pathogenic phenotype. There are advancements in genetic testing, that have improved the diagnostic accuracy, such as multigene panels, which provide a better understanding of these mutations and their roles in MKS and other related ciliopathies.
Diagnosis The diagnosis of MKS in a proband is based on clinical findings and can be confirmed through genetic testing. Molecular confirmation requires the identification of biallelic pathogenic or likely pathogenic variants in MKKS. Given the considerable similarity in clinical features between MKS and Bardet-Biedl syndrome, ruling out BBS is essential for an accurate diagnosis. In the neonatal period, it is difficult to distinguish between MKS and BBS because the age-dependent features of BBS, such as retinal dystrophy, learning disability, obesity, and renal failure, have not yet developed. The clinical diagnosis of MKS is typically confirmed by age five, when the individual does not meet the criteria for BBS or exhibit features that suggest a different diagnosis. Early diagnosis is important to prevent complications and ensure the appropriate treatment for each child. If pathogenic variants in the MKKS gene are identified within a family, carrier screening for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing may be considered. However, the reliability of prenatal ultrasound for diagnosing MKS is uncertain, as the features associated with the syndrome can vary and may not be evident until after birth. Molecular testing for MKS usually involves multigene panels or comprehensive genomic testing. Single-gene testing for MKKS alone is not recommended, as Bardet-Biedl syndrome can result from variants in multiple genes, including MKKS. Using a multigene panel that includes MKKS and genes associated with BBS improves diagnostic accuracy and reduces the likelihood of identifying variants of uncertain significance. In cases where other diagnoses are being considered, broader approaches like exome or genome sequencing may be used.
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