McKusick-Kaufman syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

McKusick-Kaufman syndrome is a condition that affects the development of the hands, feet, heart, and reproductive system. It is characterized by a combination of three features: extra fingers and/or toes (polydactyly), congenital heart defects, and genital abnormalities. The most common genital abnormality is hydrometrocolpos, an accumulation of fluid in the vagina and uterus.

In people with McKusick-Kaufman syndrome, the extra digits are typically on the same side of the hand or foot as the pinky or little toe (postaxial polydactyly). The congenital heart defects in individuals with McKusick-Kaufman syndrome can include an atrial septal defect or a ventricular septal defect, which are openings in the wall (septum) that separates the upper or lower chambers of the heart.

A genital abnormality called hydrometrocolpos is common in individuals with McKusick-Kaufman syndrome. Hydrometrocolpos can occur if part of the vagina fails to develop (vaginal agenesis) or if a membrane blocks the opening of the vagina. The blockage allows fluid to build up in the vagina and uterus, stretching these organs and leading to a fluid-filled mass. Other genital abnormalities associated with McKusick-Kaufman syndrome can include a urethral opening on the underside of the penis (hypospadias), a downward-curving penis (chordee), and undescended testes (cryptorchidism).

The signs and symptoms of McKusick-Kaufman syndrome overlap significantly with those of another genetic disorder, Bardet-Biedl syndrome. However, Bardet-Biedl syndrome has several features that are not typically seen in people with McKusick-Kaufman syndrome. These include a gradual loss of vision, developmental disabilities, kidney abnormalities, and obesity. Because some of these features are not apparent at birth, the two conditions can be difficult to tell apart in infancy and early childhood.

Both McKusick-Kaufman syndrome and Bardet-Biedl syndrome belong to a group of conditions called ciliopathies. Ciliopathies are inherited disorders that affect the structure or function of cilia, the microscopic, finger-like projections found on the surface of cells. Cilia are involved in signaling pathways that transmit information between cells.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Some variants (also called mutations) in the MKKS gene have been found to cause McKusick-Kaufman syndrome. The MKKS gene is also called the BBS6 gene. This gene provides instructions for making a protein that plays an important role in early development, specifically in the formation of the limbs, heart, and reproductive system. The protein's structure suggests that it may belong to a family of proteins called chaperonins. Proteins must be folded into the correct shape to function properly, and chaperonins help them do that.

The MKKS protein is thought to play a role in cell division and cell transport. Specifically, the MKKS protein is thought to transport molecules between the cytoplasm and the nucleus of the cell. The MKKS protein also combines with other proteins to form a complex within the cell. This complex is used to assemble the molecules involved in transporting materials that support the function of cilia.

Though it is not clear exactly how variants in the MKKS gene lead to the specific signs and symptoms of McKusick-Kaufman syndrome, two particular variants in the MKKS gene appear to impair the protein's ability to transport a molecule involved in regulating gene activity. This change likely affects the activity of certain genes that are critical during early development.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant that causes the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

More than 100 individuals with McKusick-Kaufman syndrome have been reported in the literature. This condition was first described in the Old Order Amish population, where it affects an estimated 1 in 10,000 people.

The incidence of McKusick-Kaufman syndrome in non-Amish populations is unknown.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Hydrometrocolpos · Very frequent (99-80%)

Hydrometrocolpos is an accumulation of uterine and vaginal secretions as well as menstrual blood in the uterus and vagina.

Cryptorchidism · Frequent (79-30%)

Testis in inguinal canal. That is, absence of one or both testes from the scrotum owing to failure of the testis or testes to descend through the inguinal canal to the scrotum.

Glandular hypospadias · Frequent (79-30%)

A type of hypospadias in which the urethral meatus is located at the head of the penis, but not all the way at the tip.

Hydronephrosis · Frequent (79-30%)

Severe distention of the kidney with dilation of the renal pelvis and calices.

Postaxial hand polydactyly · Frequent (79-30%)

Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).

Urogenital sinus anomaly · Frequent (79-30%)

A rare birth defect in women where the urethra and vagina both open into a common channel.

Abnormal metacarpal morphology · Occasional (29-5%)

Any abnormal shape or structure of the metacarpal bones.

Aganglionic megacolon · Occasional (29-5%)

An abnormality resulting from a lack of intestinal ganglion cells (i.e., an aganglionic section of bowel) that results in bowel obstruction with enlargement of the colon.

Other findings in the same source

From: Orphanet

Additional reported features include Anal atresia (Occasional (29-5%)); Atrial septal defect (Occasional (29-5%)); Brachydactyly (Occasional (29-5%)); Cleft palate (Occasional (29-5%)); Ectopic anus (Occasional (29-5%)); Failure to thrive (Occasional (29-5%)); Finger syndactyly (Occasional (29-5%)); Global developmental delay (Occasional (29-5%)); High palate (Occasional (29-5%)); Hypoplastic left heart (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing McKusick-Kaufman syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for McKusick-Kaufman syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.