Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome is a rare disorder that primarily affects the development of the brain. Affected individuals are born with an unusually large brain and head size (megalencephaly). The head and brain continue to grow rapidly during the first 2 years of life. MPPH syndrome is also associated with a brain abnormality called bilateral perisylvian polymicrogyria (BPP). The surface of the brain normally has many ridges or folds, called gyri. In people with BPP, an area of the brain called the perisylvian region develops too many gyri, and the folds are irregular and unusually small. Other brain abnormalities, including a buildup of fluid in the brain (hydrocephalus), have also been reported in people with MPPH syndrome.

The problems with brain development cause a variety of neurological signs and symptoms. People with MPPH syndrome have delayed development and intellectual disability that ranges from mild to severe. About half of affected individuals develop recurrent seizures (epilepsy) beginning early in childhood. People with MPPH syndrome also have difficulty coordinating movements of the mouth and tongue (known as oromotor dysfunction), which leads to drooling, difficulty swallowing (dysphagia), and a delay in the production of speech (expressive language).

About half of people with MPPH syndrome have an extra finger or toe on one or more of their hands or feet (polydactyly). The polydactyly is described as postaxial because it occurs on the same side of the hand or foot as the pinky finger or little toe.

The brain abnormalities characteristic of MPPH syndrome are also found in a closely related condition called megalencephaly-capillary malformation syndrome (MCAP). However, MCAP includes abnormalities of small blood vessels in the skin (capillary malformations) and several other features that are not usually part of MPPH syndrome.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

MPPH syndrome can be caused by mutations in the AKT3, CCND2, or PIK3R2 gene. The proteins produced from all three genes are involved in a chemical signaling pathway called the PI3K-AKT-mTOR pathway. This signaling influences many critical cell functions, including the creation (synthesis) of new proteins, cell growth and division (proliferation), and the survival of cells. The PI3K-AKT-mTOR pathway is essential for the normal development of many parts of the body, including the brain.

Mutations in the AKT3, CCND2, or PIK3R2 gene increase the activity of their respective proteins or prevent the proteins from being broken down when they should. As a result, chemical signaling through the PI3K-AKT-mTOR pathway is enhanced, which increases cell growth and division. In the brain, the increased number of cells leads to rapid and abnormal brain growth starting before birth. The rapid growth disrupts the structure and function of the developing brain. It is less clear how increased PI3K-AKT-mTOR signaling contributes to polydactyly, although the extra digits are probably related to abnormal cell proliferation in the developing hands and feet. CCND2 and PIK3R2 gene mutations are more likely to cause polydactyly than are AKT3 gene mutations.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

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

Almost all cases of this condition result from new (de novo) gene mutations that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

In a small number of cases, people with MPPH syndrome have inherited the altered gene from an unaffected parent who has a mutation only in their sperm or egg cells. This phenomenon is called germline mosaicism.

Rarely, the condition can also result from somatic mosaicism, in which some of an affected person's cells have a gene mutation and others do not. The genetic changes, which are called somatic mutations, arise randomly in one cell during embryonic development. As cells continue to divide, only cells arising from the first abnormal cell will have the mutation.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

MPPH syndrome appears to be a rare disease. About 60 affected individuals have been described in the medical literature.

Which doctor should you see?

The suggested department for discussing Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

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.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Megalencephaly-polymicrogyria-polydactyly-hydrocephalus 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.