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Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3(MPPH3)

MedGen UID:
863179
Concept ID:
C4014742
Disease or Syndrome
Synonym: MPPH3
 
Gene (location): CCND2 (12p13.32)
 
Monarch Initiative: MONDO:0014408
OMIM®: 615938

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
This disorder comprises macrocephaly, megalencephaly, ventriculomegaly, polymicrogyria, and polydactyly. Most affected individuals have severely delayed psychomotor development (summary by Mirzaa et al., 2014). For a discussion of genetic heterogeneity of MPPH, see MPPH1 (603387).  http://www.omim.org/entry/615938
From MedlinePlus Genetics
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 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).

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

Clinical features

From HPO
Syndactyly
MedGen UID:
52619
Concept ID:
C0039075
Congenital Abnormality
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".
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.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Megalencephaly
MedGen UID:
65141
Concept ID:
C0221355
Congenital Abnormality
Diffuse enlargement of the entire cerebral hemispheres leading to macrocephaly (with or without overlying cortical dysplasia).
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).
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Thick corpus callosum
MedGen UID:
371993
Concept ID:
C1835194
Finding
Increased vertical dimension of the corpus callosum. This feature can be visualized by sagittal sections on magnetic resonance tomography imaging of the brain.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Ventriculomegaly
MedGen UID:
480553
Concept ID:
C3278923
Finding
An increase in size of the ventricular system of the brain.
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.
Prominent forehead
MedGen UID:
373291
Concept ID:
C1837260
Finding
Forward prominence of the entire forehead, due to protrusion of the frontal bone.

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

Zhao MF, Zhang SL, Xiang Y, Wang Q, Cao GH, Zhang PP, Fan LL, Yu R, Li YL
DNA Cell Biol 2024 Jul;43(7):325-330. Epub 2024 May 3 doi: 10.1089/dna.2023.0391. PMID: 38700464
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

Therapy

Nellist M, Schot R, Hoogeveen-Westerveld M, Neuteboom RF, van der Louw EJ, Lequin MH, Bindels-de Heus K, Sibbles BJ, de Coo R, Brooks A, Mancini GM
Mol Genet Metab 2015 Mar;114(3):467-73. Epub 2014 Dec 5 doi: 10.1016/j.ymgme.2014.11.018. PMID: 25523067

Prognosis

Zhao MF, Zhang SL, Xiang Y, Wang Q, Cao GH, Zhang PP, Fan LL, Yu R, Li YL
DNA Cell Biol 2024 Jul;43(7):325-330. Epub 2024 May 3 doi: 10.1089/dna.2023.0391. PMID: 38700464
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

Zhao MF, Zhang SL, Xiang Y, Wang Q, Cao GH, Zhang PP, Fan LL, Yu R, Li YL
DNA Cell Biol 2024 Jul;43(7):325-330. Epub 2024 May 3 doi: 10.1089/dna.2023.0391. PMID: 38700464
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
Mirzaa G, Parry DA, Fry AE, Giamanco KA, Schwartzentruber J, Vanstone M, Logan CV, Roberts N, Johnson CA, Singh S, Kholmanskikh SS, Adams C, Hodge RD, Hevner RF, Bonthron DT, Braun KPJ, Faivre L, Rivière JB, St-Onge J, Gripp KW, Mancini GM, Pang K, Sweeney E, van Esch H, Verbeek N, Wieczorek D, Steinraths M, Majewski J; FORGE Canada Consortium, Boycot KM, Pilz DT, Ross ME, Dobyns WB, Sheridan EG
Nat Genet 2014 May;46(5):510-515. Epub 2014 Apr 6 doi: 10.1038/ng.2948. PMID: 24705253Free 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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