Hand-foot-genital syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Hand-foot-genital syndrome is a rare condition that affects the development of the hands and feet, the urinary tract, and the reproductive system. People with this condition have abnormally short thumbs and first (big) toes, small fifth fingers that curve inward (clinodactyly), and short feet. The bones in the wrists and ankles may be fused in people with this condition, or hardening of these bones may be delayed. The other bones in the arms and legs are normal.

Abnormalities of the genitals and urinary tract can vary among affected individuals. Many people with hand-foot-genital syndrome have defects in the ureters, which are tubes that carry urine from each kidney to the bladder, or in the urethra, which carries urine from the bladder to the outside of the body. Recurrent urinary tract infections and an inability to control the flow of urine (urinary incontinence) have been reported. About half of males with this disorder have the urethra opening on the underside of the penis (hypospadias).

People with hand-foot-genital syndrome are usually able to have children (fertile). In some affected females, problems in the early development of the uterus can later increase the risk of pregnancy loss, premature labor, and stillbirth.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the HOXA13 gene cause hand-foot-genital syndrome. The HOXA13 gene provides instructions for producing a protein that plays an important role in development before birth. Specifically, this protein appears to be critical for the formation and development of the limbs (particularly the hands and feet), urinary tract, and reproductive system.

Variants in the HOXA13 gene cause the characteristic features of hand-foot-genital syndrome by disrupting the early development of these structures. Some variants in the HOXA13 gene cause nonfunctional versions of the HOXA13 protein to be produced. Other variants alter the protein's structure and interfere with its normal function within cells. Variants that result in an altered but functional HOXA13 protein may cause more severe signs and symptoms of hand-foot-genital syndrome than variants that lead to a nonfunctional version of this protein.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Hand-foot-genital syndrome is very rare; only a few families with the condition have been reported worldwide.

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.

Abnormality of the uterus · Very frequent (99-80%)

An abnormality of the uterus.

Bicornuate uterus · Very frequent (99-80%)

The presence of a bicornuate uterus.

Proximal placement of thumb · Very frequent (99-80%)

Proximal mislocalization of the thumb.

Short 1st metacarpal · Very frequent (99-80%)

A developmental defect characterized by reduced length of the first metacarpal (long bone) of the hand.

Short distal phalanx of finger · Very frequent (99-80%)

Short distance from the end of the finger to the most distal interphalangeal crease or the distal interphalangeal joint flexion point. That is, hypoplasia of one or more of the distal phalanx of finger.

Short first metatarsal · Very frequent (99-80%)

Short first metatarsal bone.

Short hallux · Very frequent (99-80%)

Underdevelopment (hypoplasia) of the big toe.

Short thumb · Very frequent (99-80%)

Hypoplasia (congenital reduction in size) of the thumb.

Shortening of all middle phalanges of the fingers · Very frequent (99-80%)

Short, hypoplastic middle phalanx of finger, affecting all fingers.

Ureteropelvic junction obstruction · Very frequent (99-80%)

Blockage of urine flow from the renal pelvis to the proximal ureter.

Synostosis of carpal bones · Very frequent (99-80%)

Abnormal dermatoglyphics · Frequent (79-30%)

An abnormality of dermatoglyphs (fingerprints), which are present on fingers, palms, toes, and soles.

Abnormality of the urethra · Frequent (79-30%)

An abnormality of the urethra, i.e., of the tube which connects the urinary bladder to the outside of the body.

Clinodactyly of the 5th finger · Frequent (79-30%)

Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).

Other findings in the same source

From: Orphanet

Additional reported features include Hallux varus (Frequent (79-30%)); Hypoplastic fifth toenail (Frequent (79-30%)); Hypospadias (Frequent (79-30%)); Recurrent urinary tract infections (Frequent (79-30%)); Vesicoureteral reflux (Frequent (79-30%)); Microtia (Occasional (29-5%)); Postaxial hand polydactyly (Occasional (29-5%)); Sacral dimple (Occasional (29-5%)); Spontaneous abortion (Occasional (29-5%)); Strabismus (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 Hand-foot-genital 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 Hand-foot-genital 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.