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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2(MPPH2)

MedGen UID:
863175
Concept ID:
C4014738
Disease or Syndrome
Synonyms: MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2, SOMATIC; MPPH2
 
Gene (location): AKT3 (1q43-44)
 
Monarch Initiative: MONDO:0014407
OMIM®: 615937

Disease characteristics

Excerpted from the GeneReview: MPPH Syndrome
MPPH (megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus) syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria (BPP). At birth the occipital frontal circumference (OFC) ranges from normal to 6 standard deviations (SD) above the mean for age, sex, and gestational age; in older individuals the range is from 3 to 10 SD above the mean. A variable degree of ventriculomegaly is seen in almost all children with MPPH syndrome; nearly 50% of individuals have frank hydrocephalus. Neurologic problems associated with BPP include oromotor dysfunction (100%), epilepsy (50%), and mild-to-severe intellectual disability (100%). Postaxial hexadactyly occurs in 50% of individuals with MPPH syndrome. [from GeneReviews]
Authors:
Ghayda Mirzaa   view full author information

Additional descriptions

From OMIM
MPPH2 is an overgrowth syndrome comprising megalencephaly, hydrocephalus, and polymicrogyria; polydactyly may also be seen. There is considerable phenotypic similarity between this disorder and the megalencephaly-capillary malformation syndrome (MCAP; 602501) (summary by Gripp et al., 2009). For a discussion of genetic heterogeneity of MPPH, see 603387.  http://www.omim.org/entry/615937
From MedlinePlus Genetics
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.

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).

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.  https://medlineplus.gov/genetics/condition/megalencephaly-polymicrogyria-polydactyly-hydrocephalus-syndrome

Clinical features

From HPO
Postaxial hand polydactyly
MedGen UID:
609221
Concept ID:
C0431904
Congenital Abnormality
Supernumerary digits located at the ulnar side of the hand (that is, on the side with the fifth finger).
Hydrocephalus
MedGen UID:
9335
Concept ID:
C0020255
Disease or Syndrome
Hydrocephalus is an active distension of the ventricular system of the brain resulting from inadequate passage of CSF from its point of production within the cerebral ventricles to its point of absorption into the systemic circulation.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Polymicrogyria
MedGen UID:
78605
Concept ID:
C0266464
Congenital Abnormality
Polymicrogyria is a congenital malformation of the cerebral cortex characterized by abnormal cortical layering (lamination) and an excessive number of small gyri (folds).
Hypoplasia of the corpus callosum
MedGen UID:
138005
Concept ID:
C0344482
Congenital Abnormality
Underdevelopment of the corpus callosum.
Hemimegalencephaly
MedGen UID:
140910
Concept ID:
C0431391
Finding
Enlargement of all or parts of one cerebral hemisphere.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Macrocephaly
MedGen UID:
745757
Concept ID:
C2243051
Finding
Occipitofrontal (head) circumference greater than 97th centile compared to appropriate, age matched, sex-matched normal standards. Alternatively, a apparently increased size of the cranium.
Hyperextensible skin
MedGen UID:
66023
Concept ID:
C0241074
Finding
A condition in which the skin can be stretched beyond normal, and then returns to its initial position.
Cutis marmorata
MedGen UID:
78093
Concept ID:
C0263401
Disease or Syndrome
A reticular discoloration of the skin with cyanotic (reddish-blue appearing) areas surrounding pale central areas due to dilation of capillary blood vessels and stagnation of blood within the vessels. Cutis marmorata generally occurs on the legs, arms and trunk and is often more severe in cold weather.

Recent clinical studies

Etiology

Mirzaa GM, Rivière JB, Dobyns WB
Am J Med Genet C Semin Med Genet 2013 May;163C(2):122-30. Epub 2013 Apr 16 doi: 10.1002/ajmg.c.31361. PMID: 23592320

Diagnosis

Su XR, Ma B, Zhang C, Li TG, Han BL, Wu WR, Nie F
Fetal Diagn Ther 2024;51(2):154-158. Epub 2023 Nov 26 doi: 10.1159/000535509. PMID: 38008077
Goergen SK, Alibrahim E, Christie J, Dobrotwir A, Fahey M, Fender L, Frawley K, Manikkam SA, Pinner JR, Sinnott S, Romaniello R, Sandaradura SA, Taylor J, Vasudevan A, Righini A
AJNR Am J Neuroradiol 2021 Aug;42(8):1528-1534. Epub 2021 May 6 doi: 10.3174/ajnr.A7131. PMID: 33958329Free PMC Article
Shi X, Lim Y, Myers AK, Stallings BL, Mccoy A, Zeiger J, Scheck J, Cho G, Marsh ED, Mirzaa GM, Tao T, Golden JA
Ann Neurol 2020 Dec;88(6):1077-1094. Epub 2020 Sep 28 doi: 10.1002/ana.25890. PMID: 32856318Free PMC Article
Terrone G, Voisin N, Abdullah Alfaiz A, Cappuccio G, Vitiello G, Guex N, D'Amico A, James Barkovich A, Brunetti-Pierri N, Del Giudice E, Reymond A
Eur J Hum Genet 2016 Aug;24(9):1359-62. Epub 2016 Feb 10 doi: 10.1038/ejhg.2016.7. PMID: 26860062Free PMC Article
Mirzaa GM, Conway RL, Gripp KW, Lerman-Sagie T, Siegel DH, deVries LS, Lev D, Kramer N, Hopkins E, Graham JM Jr, Dobyns WB
Am J Med Genet A 2012 Feb;158A(2):269-91. Epub 2012 Jan 6 doi: 10.1002/ajmg.a.34402. PMID: 22228622

Prognosis

Goergen SK, Alibrahim E, Christie J, Dobrotwir A, Fahey M, Fender L, Frawley K, Manikkam SA, Pinner JR, Sinnott S, Romaniello R, Sandaradura SA, Taylor J, Vasudevan A, Righini A
AJNR Am J Neuroradiol 2021 Aug;42(8):1528-1534. Epub 2021 May 6 doi: 10.3174/ajnr.A7131. PMID: 33958329Free PMC Article

Clinical prediction guides

Mok KM, Carpenter JL, Herrada P, Greene C, Yazbek S, Erdemir G
Pediatr Neurol 2024 Dec;161:185-187. Epub 2024 Sep 21 doi: 10.1016/j.pediatrneurol.2024.09.016. PMID: 39395260
Su XR, Ma B, Zhang C, Li TG, Han BL, Wu WR, Nie F
Fetal Diagn Ther 2024;51(2):154-158. Epub 2023 Nov 26 doi: 10.1159/000535509. PMID: 38008077
Goergen SK, Alibrahim E, Christie J, Dobrotwir A, Fahey M, Fender L, Frawley K, Manikkam SA, Pinner JR, Sinnott S, Romaniello R, Sandaradura SA, Taylor J, Vasudevan A, Righini A
AJNR Am J Neuroradiol 2021 Aug;42(8):1528-1534. Epub 2021 May 6 doi: 10.3174/ajnr.A7131. PMID: 33958329Free PMC Article
Shi X, Lim Y, Myers AK, Stallings BL, Mccoy A, Zeiger J, Scheck J, Cho G, Marsh ED, Mirzaa GM, Tao T, Golden JA
Ann Neurol 2020 Dec;88(6):1077-1094. Epub 2020 Sep 28 doi: 10.1002/ana.25890. PMID: 32856318Free PMC Article
Rivière JB, Mirzaa GM, O'Roak BJ, Beddaoui M, Alcantara D, Conway RL, St-Onge J, Schwartzentruber JA, Gripp KW, Nikkel SM, Worthylake T, Sullivan CT, Ward TR, Butler HE, Kramer NA, Albrecht B, Armour CM, Armstrong L, Caluseriu O, Cytrynbaum C, Drolet BA, Innes AM, Lauzon JL, Lin AE, Mancini GM, Meschino WS, Reggin JD, Saggar AK, Lerman-Sagie T, Uyanik G, Weksberg R, Zirn B, Beaulieu CL; Finding of Rare Disease Genes (FORGE) Canada Consortium, Majewski J, Bulman DE, O'Driscoll M, Shendure J, Graham JM Jr, Boycott KM, Dobyns WB
Nat Genet 2012 Jun 24;44(8):934-40. doi: 10.1038/ng.2331. PMID: 22729224Free PMC Article

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