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Disease Profile

Megalencephaly-capillary malformation syndrome

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Neonatal

ICD-10

Q87.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

M-CM; Megalocephaly cutis marmorata telangiectatica congenita; Macrocephaly cutis marmorata telangiectatica congenita;

Categories

Blood Diseases; Congenital and Genetic Diseases; Rare Cancers;

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 60040

Definition
A rare developmental defect during embryogenesis that is characterized by growth dysregulation with overgrowth of the brain and multiple somatic tissues, with capillary skin malformations, megalencephaly (MEG) or hemimegalencephaly (HMEG), cortical brain abnormalities (in particular polymicrogyria), typical facial dysmorphisms, abnormalities of somatic growth with asymmetry of the body and brain, developmental delay and digital anomalies.

Epidemiology
Over 200 patients have been reported without sex predominance.

Clinical description
Symptoms are usually recognizable at birth. Their severity varies widely among patients. Megalencephaly is a major clinical feature (MEG: occipitofrontal circumference [OFC] greater than or equal to 3 SD above the mean), which sometimes progresses to hydrocephaly, malformations of cortical development with polymicrogyria and Chiari malformation. Cutaneous capillary anomalies are often scattered over the limbs, palms, soles and trunk, are frequently pink/red and are aggravated by crying and emotions. Facial dysmorphism is observed with frontal bossing, full cheeks, prominent lips and nevus flammeus of the nose and/or philtrum and upper lip. There is a delay in speech and motor skills. Patients may present neurological symptoms, mainly neonatal hypotonia, and, less frequently, seizures. Additional clinical manifestations include prenatal overgrowth, limb asymmetry, joint laxity, soft skin and thick, ''doughy'' subcutaneous tissue, postaxial polydactyly and/or syndactyly of toes 2-3 or fingers 3-4. Some patients develop neoplasias (risk of tumor development estimated at 2-3%). There is a slight increased risk for congenital heart defects and/or cardiac rhythm abnormalities. Adult OFCs range from +2 to +10 SDs above the mean.

Etiology
Somatic mutations of the PIK3CA gene (3q26), with evidence of postzygotic mosaicism, were found in several patients. Two individuals had a de novo germline pathogenic variant in PIK3CA. The gene PIK3CA encodes the alpha catalytic subunit of phosphatidylinositol-4,5-bisphosphate 3-kinase. PIK3CA mutations are found in several benign overgrowth syndromes, collectively known as PIK3CA-related overgrowth spectrum (PROS). The mutational spectrum in children with the disorder is broader than other PIK3CA-related overgrowth disorders.

Diagnostic methods
The disorder can be diagnosed based on clinical findings in individuals with classic features of MEG or HMEG (major finding 1) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability and characteristic capillary malformations (major finding 2) with focal or generalized somatic overgrowth.. Mosaic mutations of the PIK3CA gene were mainly identified with the advent of massively parallel or next-generation sequencing (NGS) methods. that facilitate detection of low-frequency variation. The level of mosaicism is often lowest in blood‐derived DNA, and higher in saliva and fibroblast‐derived DNA: multiple tissue samples should be tested, prioritizing samples other than blood.

Differential diagnosis
Differential diagnoses include Hemimegalencephaly (HMEG), Megalencephaly polymicrogyria post-axial polydactyly hydrocephalus (MPPH), Klippel-Trénaunay syndrome (KTS), Beckwith-Wiedemann syndrome (BWS), PTEN-related overgrowth disorders.

Antenatal diagnosis
Findings of prenatal ultrasound include marked fetal overgrowth and progressive macrocephaly in the absence of maternal hyperglycemia or fetal hyperinsulinemia, ventriculomegaly, hydrocephalus, frontal bossing, polydactyly, limb asymmetry, polyhydramnios, hydrops fetalis and pleural effusions.

Genetic counseling
The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population. However, low-level germline mosaicism may theoretically be present in a parent of a very rare child with a germline PIK3CA pathogenic variant.

Management and treatment
Management requires a multidisciplinary approach (involving pediatrician, neurologist, ophthalmologist, cardiologist, orthopedist, physiatrist, ENT, and dermatologist). Neurologic complications (obstructive hydrocephalus, increased intracranial pressure, cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Regular surveillance is recommended (brain MRI in the first 8 years of life, kidney ultrasound for Wilms tumor screening in the first 8 years of life). However, tumor risk in the disorder appears to be lower than in BWS.

Prognosis
Prognosis depends on the severity of symptoms. Early death, due to complex cardiac heart disease and arrhythmia, has been reported in rare occasions.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Arteriovenous malformation
0100026
Asymmetric growth
Uneven or disproportionate growth of one body part compared to another
0100555
Facial asymmetry
Asymmetry of face
Crooked face
Unsymmetrical face

[ more ]

0000324
Finger syndactyly
0006101
Foot polydactyly
Duplication of bones of the toes
0001829
Hand polydactyly
Extra finger
0001161
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
Nevus flammeus
port-wine stain
0001052
Telangiectasia of the skin
0100585
Toe syndactyly
Fused toes
Webbed toes

[ more ]

0001770
Visceral angiomatosis
0100761
Wide mouth
Broad mouth
Large mouth

[ more ]

0000154
30%-79% of people have these symptoms
Aplasia/Hypoplasia of the cerebellum
Absent/small cerebellum
Absent/underdeveloped cerebellum

[ more ]

0007360
Cutis marmorata
0000965
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Frontal bossing
0002007
Full cheeks
Apple cheeks
Big cheeks
Increased size of cheeks
Large cheeks

[ more ]

0000293
Global developmental delay
0001263
High forehead
0000348
Hydrocephalus
Too much cerebrospinal fluid in the brain
0000238
Hypermelanotic macule
Hyperpigmented spots
0001034
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Joint hyperflexibility
Joints move beyond expected range of motion
0005692
Muscular hypotonia
Low or weak muscle tone
0001252
Ventriculomegaly
0002119
5%-29% of people have these symptoms
Arnold-Chiari malformation
0002308
Arrhythmia
Abnormal heart rate
Heart rhythm disorders
Irregular heart beat
Irregular heartbeat

[ more ]

0011675
Cerebral ischemia
Disruption of blood oxygen supply to brain
0002637
Deeply set eye
Deep set eye
Deep-set eyes
Sunken eye

[ more ]

0000490
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Optic atrophy
0000648
Polymicrogyria
More grooves in brain
0002126
Percent of people who have these symptoms is not available through HPO
Broad forehead
Increased width of the forehead
Wide forehead

[ more ]

0000337
Cavum septum pellucidum
0002389
Downslanted palpebral fissures
Downward slanting of the opening between the eyelids
0000494
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Hernia
0100790
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Joint laxity
Joint instability
Lax joints
Loose-jointedness
Loosejointedness

[ more ]

0001388
Large earlobe
Fleshy earlobe
Fleshy earlobes
Prominent ear lobes
prominent ear lobules

[ more ]

0009748
Leukemia
0001909
Megalencephaly
0001355
Meningioma
0002858
Microphthalmia
Abnormally small eyeball
0000568
Nephroblastoma
0002667
Overgrowth
General overgrowth
0001548
Polydactyly
More than five fingers or toes on hands or feet
0010442
Progressive macrocephaly
Progressively abnormally enlarging cranium
Progressively abnormally enlarging skull

[ more ]

0004481
Seizure
0001250
Smooth philtrum
0000319
Somatic mutation
0001428
Sporadic
No previous family history
0003745
Syndactyly
Webbed fingers or toes
0001159
Ventricular septal defect
Hole in heart wall separating two lower heart chambers
0001629

Organizations

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

    Learn more

    These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

    Where to Start

    • Genetics Home Reference (GHR) contains information on Megalencephaly-capillary malformation syndrome. This website is maintained by the National Library of Medicine.
    • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

      In-Depth Information

      • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
      • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
      • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
      • PubMed is a searchable database of medical literature and lists journal articles that discuss Megalencephaly-capillary malformation syndrome. Click on the link to view a sample search on this topic.