What are the other Names for this Condition? (Also known as/Synonyms)

• Megalencephaly and Perisylvian Polymicrogyria with Postaxial Polydactyly and Hydrocephalus
• Megalencephaly-Postaxial Polydactyly-Polymicrogyria-Hydrocephalus Syndrome
• MPPH Syndrome

What is Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome? (Definition/Background Information)

• Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome, or MPPH Syndrome, is a rare genetic disorder that manifests as developmental delays and various birth defects in newborn children (congenital manifestation). It develops when the normal function of any of the three genes, namely the PIK3R2, AKT3, or CCND2 genes, is affected
• By definition, MPPH Syndrome is characterized by abnormally large brain (megalencephaly), extra digit on the outer side of the hand or foot (postaxial polydactyly), excessive folding on the brain (polymicrogyria), and excess fluid buildup in the brain cavities (hydrocephalus), resulting in severe associated signs and symptoms. This disorder may develop from sporadic mutations (majority of cases), or it may be inherited from one’s parents (rarely)
• The syndrome may be diagnosed through specialized genetic testing. Following a diagnosis, Megalencephaly-Postaxial Polydactyly-Polymicrogyria-Hydrocephalus Syndrome may be managed based on the presenting symptoms and extent of involvement of the brain and other body systems. The treatment may involve physician experts from several specialties, and can include the use of vision aids, seizure control, speech and language therapy, physiotherapy, and surgery
• The prognosis is primarily dependent on the severity of the disorder, and it varies from one child to another. Many children with Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome are able to cope well through adequate treatment and supportive care. Some of the signs and symptoms associated with the condition are known to improve with time. However, in case of severe brain involvement, the prognosis may be guarded

Who gets Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome? (Age and Sex Distribution)

• The incidence of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome is unknown, but it is a very rare disorder. Presently, about 60 cases are reported in the medical literature
• In many cases, individuals with mild signs and symptoms may be undiagnosed in their lifetime. Hence, a true incidence of the disorder may be difficult to estimate
• MPPH Syndrome is a congenital disorder, and the presentation of symptoms may occur at or following the birth of the child
• Both males and females are equally affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome? (Predisposing Factors)

In a vast majority of individuals, there are no identified risk factors for Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome.

• In some individuals, a positive family history may be an important risk factor for MPPH Syndrome
• Currently, no environmental and lifestyle (including dietary) factors have been implicated
• The syndrome is not caused by what the expectant mother does or does not do, either prior to or during pregnancy

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome? (Etiology)

Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome is caused by mutation(s) in either of the AKT3, CCND2, or PIK3R2 genes that are located on chromosomes 1, 12, and 19 respectively. AKT3 gene is in chromosome band 1q44, CCND2 gene is in band 12p13.32, and PIK3R2 gene lies in the band 19p13.11.

• Each gene codes for proteins involved in an important cellular chemical signaling pathway, known as the PI3K-AKT-mTOR pathway. Causative mutation(s) in the three genes increase the activity of the respective proteins
• The proper functioning of this pathway is crucial for growth and proliferation of cells in an organized manner, including cells in the brain
• Mutations in these three genes leads to hyperactivation of this pathway, resulting in rapid and abnormal growth in brain cells (which begins in the fetal stages)
• In the majority of cases, the disorder occurs as a result of de novo mutations in the causative genes during the formation of reproductive cells or early in the development of embryos. Most affected individuals, therefore, do not have a family history of the condition. In rare cases, MPPH Syndrome can be inherited in an autosomal dominant manner
• Additionally, the condition can also occur due to germline mosaicism, in which an unaffected parent has mutations in the sperm or egg cells, which the child inherits. Somatic mosaicism may be another cause of this disorder, in which affected individuals carry mutations in some cells and not others

Autosomal dominant inheritance: Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

It is important to note that a child’s development and future is not only influenced by the chromosome material duplicated/deleted and genes involved, but also by other factors such as one’s environment, involvement of other genes, and unique personality.

Additional (general) information on chromosomes, which is helpful in understanding the disorder:

Chromosomes are microscopic thread-like protein structures present in each cell nucleus that carry genetic information in the form of DNA (deoxyribonucleic acid). DNAs are nucleic acids that encodes the genetic information of any organisms; a basic unit of the DNA is termed a gene with a specific set of instructions and a defined function. Each chromosome is “X” shaped with a center, called the centromere, and two short arms (termed p arms) and two long arms (termed q arms).

Humans have 46 chromosomes in the cell nucleus, in 23 pairs, of which one pair is named the sex chromosome. In males, it is designated XY, for chromosome X and chromosome Y; while, in females, it is designated XX, for a pair of chromosome X. The other 22 pairs of chromosomes are numbered chromosome 1 through 22, approximately according to size (with chromosome 1 being the largest; chromosome 21 being the smallest) and are referred to as autosomes or somatic chromosomes. During conception, the embryo inherits one copy of each chromosome from each parent (i.e., mother and father). Any alteration in the chromosome numbers or structure, such as via addition or deletion of chromosomal material, can result in mild to severe genetic abnormalities that may manifest as birth defects, growth delays, and intellectual disabilities.

What are the Signs and Symptoms of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome?

The signs and symptoms of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome may be significantly different from one individual to another. In general, the degree of signs and symptoms are often related to the amount of chromosome material deleted and the number of genes affected and/or its dysfunction.

The commonly noted signs and symptoms of MPPH Syndrome in children include:

• Developmental delays; delays in reaching milestones
• Large-sized head (due to large brain size), including prominent forehead. Other abnormal facial features include widely-spaced eyes and low nose bridge
• Excessive folding in the brain, called polymicrogyria, resulting in function disruption of the brain cortex including:
  • Paralysis of the face, throat, and tongue
  • Difficulty with speech and swallowing
  • Drooling
  • Crossed eyes
  • Abnormalities of the corpus callosum
• Epileptic seizures are commonly noted in children; these include absence seizures, partial seizures, generalized tonic clonic seizures, and infantile spasms
• Congenital hydrocephalus due to increased buildup of cerebrospinal fluid in the brain
• Presence of an extra finger or toe, typically on the outer side (i.e., side farthest from the thumb or big toe), termed postaxial polydactyly
• Poor muscle tone (hypotonia) causing motor delays that can be mild or severe, particularly during infancy. This can cause the following:
  • Feeding problems (sucking and swallowing) leading to small and underweight children
  • Difficulty in holding small items such as a cup or spoon
  • Drawing and writing difficulties
  • Difficulty in climbing stairs and difficulty in sitting without support
  • Standing and walking difficulties
  • Help needed for wearing clothes and undressing
• Intellectual disabilities
• Speech and learning disabilities (slow learning)
• Psychomotor impairment (i.e., slowing down of physical reaction, movements, and speech)
• Vision impairment

How is Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome Diagnosed?

Children can have varying signs and symptoms. Some children with mild signs and symptoms may go undiagnosed in their lifetimes. Given the rarity of the condition, the healthcare provider should have a high index of suspicion to consider Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome in the differential diagnosis. Often, specialized tests are necessary to confirm the disorder.

MPPH Syndrome is diagnosed on the basis of the following information:

• Complete physical examination and thorough medical history evaluation, including family medical history
• Assessment of the presenting signs and symptoms, including evaluation of body systems such as vision, hearing, muscles, heart, kidneys, central nervous system, genitalia, and immune system
• Hearing and vision assessment
• Laboratory tests, as needed, such as electrolyte levels, serum calcium levels, thyroid function test, kidney function test, urine tests, sex hormone studies, etc.
• Radiological studies of the affected regions, as needed
• Brain scans: These may include prenatal ultrasounds and MRI scans, and CT/MRI scans after development of the child
• Neurological examination that involves the central nervous system (brain and spinal cord)
• Behavioral studies
• Prenatal studies including abdominal ultrasonography
• Specialized genetic testing techniques are often required to confirm the diagnosis. This may include:
  • Fluorescence in situ hybridization (FISH) testing
  • Array comparative genomic hybridization (array-CGH)
  • DNA sequencing

Often, karyotyping of the chromosome is not adequate to diagnose the condition, since individuals with this condition can have normal karyotype chromosomal studies.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome?

The complications of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome may include:

• Severe emotional stress for parents and caregivers
• Pregnancy complications
• Delayed milestone achievement that may affect when a child rolls, sit, crawl, or walk
• Ventriculomegaly - increased cerebrospinal fluid in the brain ventricles causing it to increase in size, due to progressive increase in brain size
• Delayed speech development
• Risk of falls and injury due to seizures
• Poor growth due to malnutrition caused by weak suckling
• Severe physical and intellectual disabilities due to severe involvement of the brain
• Overall reduced quality of life

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome Treated?

There is no cure for Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops. It also depends on the severity of the signs and symptoms and the body systems affected. Individuals with mild signs and symptoms may require periodic monitoring without significant medical intervention. Often, a multidisciplinary team of specialists including pediatricians, ophthalmologists, neurologists, internists, surgeons, and other healthcare professionals are involved in managing the condition.

The treatment measures for MPPH Syndrome may involve:

• Seizure control using anticonvulsant medication, vitamin supplements, and ketogenic diet. Seizure control is important to ensure that the child’s learning ability is not significantly affected.
• Special education: Employing learning strategies via music therapy, visual and tactile books, learning through fun and play, and lots of repetition. Writing by holding a pencil may be very difficult; but touchscreen computers and keyboards are known to be easier to use and learn
• Speech and language therapy
• Physiotherapy for weakened muscles, including incorporating daily exercise regimen
• Development of motor skills via daily exercises, swimming, hydrotherapy, and other adapted activities; use of specially-designed toys and daily-used items (such as spoons and cups)
• For feeding difficulties, medications, feed thickeners, bottle-feeding expressed milk, including special diets and nutritional supplements
• Use of suitable glasses and surgical rectification of vision defects, if necessary
• Mild cases of hydrocephalus may be treated using medications, while severe forms of congenital hydrocephalus may necessitate shunt placement or endoscopic third ventriculostomy (ETV) procedure. Shunting procedures may not be helpful in case of ventriculomegaly
• Surgical procedure to treat ventriculomegaly caused by overgrowth of the brain
• Psychotherapy, behavior modification, and establishing discipline techniques, as necessary
• Occupational therapy

Regular medical screening at periodic intervals with tests and physical examinations are necessary and highly recommended.

How can Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome be Prevented?

Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome may not be preventable since many of these genetic disorders are diagnosed at or following the birth of the child. A majority of cases are sporadic occurrences, which means there is no family history of the condition.

In some rare cases, the condition may be familial, meaning they occur within families. In expecting parents with a familial history:

• Genetic (chromosome) testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome? (Outcomes/Resolutions)

The prognosis of Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome is dependent upon the severity of the signs and symptoms and associated complications, if any. It may be assessed on a case-by-case basis, but it is generally difficult to predict the long-term outlook, particularly when severe and progressive involvement of the brain is noted.

• Children with mild conditions are generally able to cope well via appropriate treatment and adaptive behaviors as they get older. Some of the abnormalities are known to resolve or improve with time
• Weak muscle tone (hypotonia) severity may determine motor function delays; it generally improves with physiotherapy and as the child gets older
• Children usually require lifelong medical support and care; it may also take some children a long time (several years) to gain a measure of independence

Additional and Relevant Useful Information for Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/