# McKusick–Kaufman syndrome

McKusick–Kaufman syndrome (MKS) is a rare genetic condition caused by mutations in the MKKS gene, which affects 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 looks similar to Bardet–Biedl syndrome (BBS). While MKS mainly causes extra fingers or toes (postaxial polydactyly), fluid buildup in the vagina (hydrometrocolpos), and sometimes heart defects, BBS has more serious 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. It 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. Outside of the Amish population, how often MKS occurs is still unknown.

## Presentation

Clinically, McKusick–Kaufman syndrome is characterized by a combination of three features: postaxial polydactyly, heart defects, and genital abnormalities:
* Vaginal atresia with hydrometrocolpos
* Double vagina and/or uterus.
* Hypospadias, chordee (a downward-curving penis), and undescended testes (cryptorchidism).
* ureter stenosis or ureteric atresia

## Genetics

MKS is characterized by mutations in the MKKS gene on chromosome 20p12.2-p12.1 which is inherited in an autosomal recessive dominance pattern. Both parents of the affected must be heterozygous carriers of the pathogenic variant. Heterozygous carriers for MKS show no symptoms of the disorder, nor can 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.
MKKS is a 6-exon member of the chaperonin family of proteins that prevent protein misfolding. This gene plays an important role in forming cilia, which are tiny hair-like structures on cells that help with movement and signalling. When this gene is mutated, the cilia do not work properly, leading to the symptoms of MKA. Early diagnosis is important to prevent complications and prive the right treatment for each child.

## Diagnosis

The diagnosis of MKS 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.
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.

## Treatment

Treatments are available for accompanying symptoms of MKS, including addressing polydactyly and congenital heart defects.