Grange syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Grange syndrome is a rare condition that primarily affects blood vessels. It is characterized by narrowing (stenosis) or blockage (occlusion) of arteries that supply blood to various organs and tissues. The arteries that are affected can include:

In about half of individuals with Grange syndrome, stenosis or occlusion of the cerebral arteries prevents blood flow to the brain (ischemic stroke). About 20 percent of people with Grange syndrome will have bleeding in the brain (hemorrhagic stroke). In many affected individuals, stenosis or occlusion of the carotid arteries can also lead to strokes.

People with Grange syndrome typically have stenosis or occlusion of the renal arteries that results in chronic high blood pressure (hypertension).

Occlusion or stenosis of the abdominal arteries can cause gastrointestinal problems, such as pain, diarrhea, or constipation, in individuals with Grange syndrome.

People with Grange syndrome can experience chest pain and shortness of breath caused by occlusion or stenosis of the coronary arteries.

Depending on the severity of the blood vessel problems in affected individuals, the signs and symptoms of Grange syndrome can appear anytime from early childhood to mid-adulthood.

Most people with Grange syndrome also have bone abnormalities, such as short fingers and toes (brachydactyly), fused fingers or toes (syndactyly), bones that are prone to breakage, a mild curvature of the spine (scoliosis), or flat feet (pes planus).

Many affected individuals also have heart defects that are present from birth (congenital cardiac anomalies). Women with Grange syndrome may have difficulty carrying a pregnancy to term.

Learning disabilities can occur in people with Grange syndrome. It is unclear whether the learning disabilities are an independent feature of Grange syndrome or if they occur because of the blood flow issues in the brain.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Genetic changes that cause disease are called pathogenic variants. Grange syndrome is caused by pathogenic variants in the YY1AP1 gene. The protein produced from the YY1AP1 gene is part of a group of proteins (a complex) that helps regulate several critical functions within cells. These include gene activity (expression), cell maturation (differentiation), and cell growth and division (proliferation). Researchers believe that this protein complex plays a particularly important role in the development of bones and of smooth muscle cells, which line the walls of blood vessels.

Pathogenic variants in the YY1AP1 gene cause cells to make a version of the protein that does not function properly. This abnormal protein likely disrupts the function of the protein complex, which leads to reduced differentiation of smooth muscle cells. As a result, blood vessel walls do not develop normally, leading to stenosis and occlusion. Similarly, impaired differentiation of bone cells likely contributes to the bone abnormalities seen in people with Grange syndrome.

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 to cause 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

Grange syndrome is a rare condition; it has been reported to affect at least 32 individuals from 16 families.

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.

Arterial stenosis · Very frequent (99-80%)

Narrowing or constriction of the inner surface (lumen) of an artery.

Increased susceptibility to fractures · Very frequent (99-80%)

An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture.

Intellectual disability, borderline · Very frequent (99-80%)

Borderline intellectual disability is defined as an intelligence quotient (IQ) in the range of 70-85.

Specific learning disability · Very frequent (99-80%)

Impairment of certain skills such as reading or writing, coordination, self-control, or attention that interfere with the ability to learn. The impairment is not related to a global deficiency of intelligence.

Aortic regurgitation · Frequent (79-30%)

An insufficiency of the aortic valve, leading to regurgitation (backward flow) of blood from the aorta into the left ventricle.

Hypertension · Frequent (79-30%)

The presence of chronic increased pressure in the systemic arterial system.

Short palm · Frequent (79-30%)

Short palm.

Syndactyly · Frequent (79-30%)

Webbing or fusion of the fingers or toes, involving soft parts only or including bone structure. Bony fusions are referred to as "bony" syndactyly if the fusion occurs in a radio-ulnar axis. Fusions of bones of the fingers or toes in a proximo-distal axis are referred to as "symphalangism".

Other findings in the same source

From: Orphanet

Additional reported features include Patent ductus arteriosus (Occasional (29-5%)); Ventricular septal defect (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 Grange 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 Grange 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.