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Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

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MPPH Syndrome

Synonyms: Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome, Megalencephaly-Postaxial Polydactyly-Polymicrogyria-Hydrocephalus Syndrome

, MD, FAAP, FACMG.

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Estimated reading time: 21 minutes

Summary

Clinical characteristics.

The MPPH 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 those 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.

Diagnosis/testing.

The clinical diagnosis of MPPH syndrome can be established in individuals with the two core features: megalencephaly and BPP. The molecular diagnosis of MPPH syndrome is established in a proband with some of the suggestive clinical and imaging features and the identification of a heterozygous pathogenic variant in one of three genes: AKT3, CCND2, or PIK3R2. While most individuals with MPPH syndrome have a germline pathogenic variant in one of these three genes, some have a somatic mosaic pathogenic variant (most commonly reported in PIK3R2).

Management.

Treatment of manifestations: Hydrocephalus warrants early neurosurgical intervention. Oromotor difficulties, developmental delays, and epilepsy are treated as per usual clinical care standards.

Surveillance: Follow up with a pediatric neurologist, at least every six months until age six years, and yearly thereafter. Brain MRI to detect hydrocephalus and/or cerebellar tonsillar ectopia is provisionally recommended every six months from birth to age two years, and yearly from age two to six years. In older individuals, the frequency should be determined within the context of prior brain imaging findings and clinical findings. Long-term neurologic follow up is warranted for epilepsy. Routine follow up with a developmental pediatrician given the high risk of developmental delays and/or intellectual disability.

Genetic counseling.

MPPH syndrome is inherited in an autosomal dominant manner. Most individuals with MPPH syndrome have the disorder as the result of a de novo AKT3, CCND2, or PIK3R2 pathogenic variant. In one family, vertical transmission of a PIK3R2 pathogenic variant was observed; in two families, parental germline mosaicism for a PIK3R2 pathogenic variant seemed likely (given recurrence of MPPH syndrome in sibs and failure to detect the pathogenic variant in DNA isolated from parental blood samples). Each child of an individual with a germline pathogenic variant has a 50% chance of inheriting the pathogenic variant. Once the AKT3, CCND2, or PIK3R2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk for MPPH syndrome and preimplantation genetic diagnosis are possible.

Diagnosis

Suggestive Findings

MPPH syndrome should be suspected in individuals with the following clinical and imaging findings [Mirzaa et al 2004, Mirzaa et al 2012]. Note: Findings shown in bold are core features.

Clinical findings

  • Macrocephaly or megalencephaly (occipito-frontal circumference ≥2 SD above the mean); onset either prenatally or postnatally
  • Postaxial polydactyly of one or more extremities
  • Hypotonia
  • Early-onset epilepsy
  • Intellectual disability
  • Oromotor dysfunction

Imaging findings

  • Cortical brain malformations, particularly bilateral perisylvian polymicrogyria (BPP)
  • Progressive ventriculomegaly leading to hydrocephalus
  • Cerebellar tonsillar ectopia or Chiari malformations
  • Thick corpus callosum (or mega corpus callosum)

Establishing the Diagnosis

The clinical diagnosis of MPPH syndrome can be established in individuals with the two core features: megalencephaly and polymicrogyria).

The molecular diagnosis of MPPH syndrome is established in a proband with some of the suggestive clinical and imaging features and the identification of a heterozygous pathogenic variant in one of three genes: AKT3, CCND2, or PIK3R2 (Table 1). While most individuals with MPPH syndrome have a germline (i.e., constitutional) pathogenic variant in one of these three genes, some individuals have been reported with a somatic mosaic pathogenic variant in one of these genes (most commonly PIK3R2).

Note that failure to detect either a germline or somatic mosaic pathogenic variant in one of these three genes in a proband does not exclude a clinical diagnosis of MPPH syndrome in individuals with the two core clinical and imaging features.

Molecular genetic testing approaches used to identify germline and somatic pathogenic variants can include a combination of serial single-gene testing, chromosomal microarray analysis (CMA), and use of a multigene panel.

First-Tier Testing

Serial single-gene testing can be considered in order of the likelihood of identifying a germline pathogenic variant (Table 1). Sequence analysis of the gene of interest is performed first.

Second-Tier Testing

For somatic mosaicism. If no germline pathogenic variant is found in any of the three genes, sequence analysis for AKT3 or PIK3R2 with methods to detect somatic mosaicism may be warranted and/or testing for a large duplication of 1q43-q44 that includes AKT3.

  • Sequence analysis of DNA derived from saliva or skin (whether visibly affected or not) may detect a pathogenic variant not detected in DNA isolated from blood.
  • Sensitivity to detect low-level mosaicism of a somatic pathogenic variant is theoretically greatest using massively parallel sequencing (also known as next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues

For duplication of 1q43-q44 that includes AKT3. Because not all gene-targeted deletion/duplication methods are designed to size large CNVs, CMA is the most appropriate for detection of this duplication.

Testing to Consider

A multigene panel that includes AKT3, CCND2, PIK3R2, and other genes of interest (see Differential Diagnosis) may also be considered to detect germline and somatic variants in the MPPH-related genes. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing based tests. (3) Somatic mosaicism for variants in the three MPPH-related genes may not be detected by all commercially available multigene panels due primarily to the inability to test tissues other than blood (e.g., skin or buccal cells) and/or technical limitations in detecting low-level mosaicism; thus, clinicians considering use of a multigene panel need to select a panel specifically optimized to detect mosaicism for the three MPPH-related genes.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in MPPH Syndrome

Gene 1Number of Persons with Molecularly Confirmed MPPH Syndrome Attributed to a Pathogenic Variant in This Gene 2Number of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4CMA 5
AKT312/416/126/12 6
CCND212/4112/12NA
PIK3R217/4117/17 7, 8NA
1.
2.

References for the 41 patients with a molecularly confirmed diagnosis: Mirzaa et al [2012], Poduri et al [2012], Rivière et al [2012], Wang et al [2013], Chung et al [2014], Jamuar et al [2014], Mirzaa et al [2014], Nakamura et al [2014], Tapper et al [2014], Conti et al [2015], Harada et al [2015], Nellist et al [2015], Hemming et al [2016], Terrone et al [2016]. Note that the other 23 individuals with a clinical diagnosis of MPPH syndrome did not undergo the complete molecular and cytogenetic testing required to detect the range of causative germline and somatic pathogenic variants.

3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 1q44 region.

6.

Duplications of 1q43-q44, which include AKT3, are detectable by CMA and cause macrocephaly and intellectual disability [Chung et al 2014, Wang et al 2013, Hemming et al 2016]. Somatic duplication of this locus has been identified in individuals with hemimegalencephaly and focal cortical dysplasia [Poduri et al 2012, Jamuar et al 2014, Conti et al 2015]. Although these large duplications would be detected by gene-targeted deletion/duplication assays, some methods would be unable to size the duplication.

7.

Mosaicism for a PIK3R2 pathogenic variant has been reported in individuals with MPPH syndrome [Mirzaa et al 2015].

8.

Most individuals with a PIK3R2 pathogenic variant have the same recurrent p.Gly373Arg variant. Only three other PIK3R2 pathogenic variants have been reported to date [Nakamura et al 2014, Mirzaa et al 2015, Terrone et al 2016].

Clinical Characteristics

Clinical Description

The MPPH syndrome is a developmental brain disorder characterized by megalencephaly (brain overgrowth) with the cortical malformation bilateral perisylvian polymicrogyria. Males and females are affected similarly.

To date 62 individuals with features of MPPH syndrome have been reported with either a clinical diagnosis (presence of the two core clinical and imaging findings: megalencephaly and polymicrogyria) , and/or a molecularly confirmed diagnosis (Table 1) [Mirzaa et al 2004, Colombani et al 2006, Garavelli et al 2007, Tohyama et al 2007, Pisano et al 2008, Tore et al 2009, Verkerk et al 2010, Osterling et al 2011, Mirzaa et al 2012, Rivière et al 2012, Kariminejad et al 2013, Zamora & Roberts 2013, Mirzaa et al 2014, Nakamura et al 2014, Tapper et al 2014, Demir et al 2015, Mirzaa et al 2015, Nellist et al 2015, Terrone et al 2016].

Neurologic Findings

Megalencephaly (brain overgrowth). Most individuals with MPPH syndrome reported to date have congenital or early postnatal megalencephaly (i.e., rapidly progressive megalencephaly within the first year of life).

Occipital frontal circumference (OFC) at birth ranges from normal to 6 SD above the mean for age, sex, and gestational age.

Later OFCs range from 3 to 10 SD above the mean.

In individuals with MPPH syndrome who develop hydrocephalus, brain overgrowth persists after surgical intervention (e.g., neurosurgical shunting), an observation consistent with true brain overgrowth [Mirzaa et al 2012].

Cortical malformations. To date, all individuals with MPPH syndrome have cortical brain malformations, particularly polymicrogyria (PMG). In almost all instances, the PMG is bilateral perisylvian polymicrogyria (BPP) and is largely symmetric. BPP is associated with neurologic problems that can include oromotor dysfunction, epilepsy, and intellectual disability.

Ventriculomegaly and hydrocephalus. Variable degrees of ventriculomegaly are seen in almost all children with MPPH syndrome. Nearly 50% of reported individuals with MPPH syndrome have frank hydrocephalus requiring neurosurgical placement of a shunt. Based on limited retrospective data, the risk for hydrocephalus and/or cerebellar tonsillar ectopia with low brain stem or high spinal cord compression appears to be highest in the first two years of life [Mirzaa et al 2012].

Oromotor dysfunction, including expressive language or speech delay, difficulties handing oral secretions (with profuse drooling), and dysphagia is seen in most individuals with MPPH syndrome. These features are largely attributed to (and well-known to occur with) bilateral perisylvian polymicrogyria [Mirzaa et al 2015].

Epilepsy. Approximately 50% of individuals with MPPH syndrome have early-onset epilepsy. Epilepsy types range from focal to generalized. Eight children with infantile spasms have been reported. Epilepsy may be refractory to several antiepileptic drugs. One individual with an AKT3 pathogenic variant had severe refractory infantile spasms that responded to a ketogenic diet [Nellist et al 2015].

Tone abnormalities, particularly hypotonia, are present at birth in most infants. Although tone may improve with age, several older individuals have remained severely hypotonic.

Intellectual disability. Almost all reported individuals with MPPH syndrome have intellectual disability that ranges from mild to severe. The degree of intellectual disability is largely determined by the following:

  • Extent and severity of the cortical malformations (i.e., severity and distribution of PMG) (see Phenotype Correlations by Gene)
  • Age of onset and severity of epilepsy. Early-onset epilepsy (particularly in the newborn period), and generalized epilepsy are typically associated with more severe developmental and cognitive issues.

Other Findings

Postaxial polydactyly involving from one to all four extremities has been reported in 50% of children with MPPH syndrome.

Additional clinical features

  • Common
    • Feeding difficulties (occasionally requiring gastrostomy tube placement)
    • Visual problems (including cortical visual impairment and blindness)
  • Seen in <5 individuals each
    • Congenital cardiovascular defects (including ventricular septal defect, atrial septal defect)
    • Thyroid problems (including hypothyroidism, Hashimoto thyroiditis)
    • Renal anomalies (e.g., duplicated renal collecting system)
  • Seen in one individual only

Phenotype Correlations by Gene

AKT3. Features including connective tissue laxity and cutaneous capillary malformations can overlap with the megalencephaly-capillary malformation (MCAP) syndrome (see Differential Diagnosis) [Mirzaa et al 2012, Rivière et al 2012, Nakamura et al 2014, Nellist et al 2015].

CCND2. Polymicrogyria (PMG) appears to be more severe and widespread, typically extending to the frontal and/or occipital lobes. These extensive cortical malformations correlate with increased severity of epilepsy and intellectual disability [Mirzaa et al 2014].

Postaxial polydactyly is more commonly observed than with mutation of either PIK3R2 or AKT3 [Mirzaa et al 2014].

Genotype-Phenotype Correlations

In general no differences in phenotype have been observed between individuals with a molecularly confirmed diagnosis and those with a clinical diagnosis only. The exceptions are several individuals with a molecularly confirmed diagnosis of MPPH syndrome who had bilateral perisylvian polymicrogyria but lacked the core clinical feature of megalencephaly [Mirzaa et al 2015].

Penetrance

Although penetrance for MPPH syndrome is expected to be high, to date it cannot be definitively determined to be 100% due to the identification of low-level mosaic somatic PIK3R2 pathogenic variants in individuals who have only one of the core features (i.e., bilateral perisylvian polymicrogyria) [Mirzaa et al 2015].

Prevalence

MPPH syndrome has been reported to date in 62 individuals from various ethnic backgrounds. Therefore, data regarding prevalence are limited.

Differential Diagnosis

Table 3.

Disorders to Consider in the Differential Diagnosis of MPPH Syndrome

DisorderGeneMOIClinical Features of the Disorder
Also in MPPH syndromeNot in MPPH syndrome
MCAP syndrome (see PIK3CA-Related Segmental Overgrowth)PIK3CADe novo / mosaic 1
  • MEG (congenital or postnatal)
  • BPP
  • Postaxial polydactyly
  • Ventriculomegaly or hydrocephalus
  • Somatic vascular malformations (capillary malformations, often multiple)
  • Somatic overgrowth (focal segmental)
PTEN hamartoma tumor syndromePTENDe novo / AD
  • MEG (congenital or postnatal)
  • Focal segmental cortical malformations (rare)
  • Papillomatous papules
  • Trichilemmomas
  • Vascular malformations (hemangiomas, arteriovenous malformations)
  • Increased cancer predisposition (thyroid, breast, endometrium)
MTOR-related disorders 2MTORDe novo / mosaic
STRADA-related disorders (OMIM 611087)STRADA (LYK5)AR
  • Early lethality
  • Uniformly poor neurodevelopmental outcome

AD = autosomal dominant; AR = autosomal recessive; BPP = bilateral perisylvian polymicrogyria; FCD = focal cortical dysplasia; MCAP = megalencephaly-capillary malformation; MEG = megalencephaly; MOI = mode(s) of inheritance

1.

MCAP is not typically inherited; to date most affected individuals (21/24) had somatic mosaicism for a PIK3CA pathogenic variant, suggesting that the variant occurred post-fertilization in one cell of the multicellular embryo.

2.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with megalencephaly-postaxial polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome, the following evaluations are recommended:

  • Physical examination with particular attention to head size (OFC)
  • In the presence of hydrocephalus and/or cerebellar tonsillar ectopia, full spinal MRI to evaluate for syringomyelia or syrinx formation
  • Assessment by a pediatric neurologist with evaluation of suspected seizures as indicated
  • Assessment of feeding by a feeding specialist, nutritionist, and gastroenterologist for evidence of chewing and swallowing difficulties and dysphagia
  • Developmental assessment
  • Echocardiogram (to evaluate for structural cardiac defects)
  • Renal ultrasound examination (to evaluate for structural renal defects)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Neurosurgical complications (hydrocephalus and cerebellar tonsillar ectopia). Findings warranting neurosurgical referral include rapidly enlarging OFC, obstructive hydrocephalus, symptoms of increased intracranial pressure, and progressive or symptomatic cerebellar tonsillar ectopia (CBTE) or Chiari malformation. Early treatment of hydrocephalus may reduce the risk for progressive CBTE, but data to determine the most appropriate neurosurgical management are lacking.

Feeding difficulties such as chewing and swallowing difficulties and dysphagia require evaluation by a feeding specialist and/or gastroenterologist to promote early identification and prompt intervention which may include dietary modification and/or placement of a gastrostomy (G) tube.

Speech therapy is indicated for difficulties with speech, swallowing, and feeding.

Epilepsy may require long-term antiepileptic treatment.

Developmental delays. Initiation of physical, occupational, and speech therapy is recommended within the first year of life.

Surveillance

Given the limited number of individuals reported with MPPH syndrome, no formal surveillance guidelines exist; however, recommended surveillance includes the following:

  • Follow-up with a pediatric neurologist, at least every six months until age six years, and annually thereafter.
  • Brain MRI to detect hydrocephalus and/or cerebellar tonsillar ectopia; provisionally recommended every six months from birth to age two years, and annually from age two to six years. In older individuals, the frequency should be based on prior results and clinical findings, with particular attention to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
  • Long-term neurologic follow up is recommended for management of epilepsy.
  • Routine follow up with a developmental pediatrician is appropriate, given the high risk for developmental delays and/or intellectual disability.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

MPPH syndrome is expressed in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic (and germline) mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%. While there may be phenotypic variability within the same family, all sibs who inherit a pathogenic variant will have features of MPPH syndrome.
  • If the AKT3, CCND2, or PIK3R2 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (but as-yet unknown) because of the possibility of parental germline mosaicism; further data are necessary to establish the recurrence risk for sibs.

Offspring of a proband

  • Each child of an individual with a germline AKT3, CCND2, or PIK3R2 pathogenic variant has a 50% chance of inheriting the pathogenic variant; while there may be phenotypic variability within the same family, all offspring who inherit a pathogenic variant will have features of MPPH syndrome.
  • The risk for transmission to offspring of an individual with somatic mosaicism for an MPPH-related pathogenic variant (i.e., the pathogenic variant is thought to have occurred post-fertilization in one cell of the multicellular embryo) is expected to be less than 50%.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a germline AKT3, CCND2, or PIK3R2 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo (or, in rare cases, a parent may have germline mosaicism). However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the AKT3, CCND2, or PIK3R2 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for MPPH syndrome are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for MPPH Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

MPPH Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for MPPH Syndrome (View All in OMIM)

123833CYCLIN D2; CCND2
603157PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 2; PIK3R2
603387MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 1; MPPH1
611223AKT SERINE/THREONINE KINASE 3; AKT3
615937MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 2; MPPH2
615938MEGALENCEPHALY-POLYMICROGYRIA-POLYDACTYLY-HYDROCEPHALUS SYNDROME 3; MPPH3

Molecular Genetic Pathogenesis

AKT3, CCND2, and PIK3R2 encode key proteins within the phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR) pathway, a major signaling pathway involved with key cellular functions including protein synthesis, metabolism, cell cycle, survival, growth, and proliferation [Engelman et al 2006, Vanhaesebroeck et al 2012].

Gain-of-function variants in these and other genes within the pathway (including PIK3CA and MTOR) are associated with a spectrum of diffuse and segmental developmental brain disorders including megalencephaly, hemimegalencephaly, polymicrogyria, and focal cortical dysplasia [Mirzaa & Poduri 2014].

AKT3 is a serine/threonine kinase and the principal target of phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIK3R2 encodes the beta regulatory subunit of the PI3K enzymatic complex, a kinase complex that phosphorylates phosphatidylinositol 4,5-bisphosphate, to generate PIP3. Binding of PIP3 to the AKT complex leads to phosphorylation of multiple downstream PI3K-AKT-MTOR targets, including MTOR (mammalian target of rapamycin) itself.

CCND2, a protein that mediates the G1-S transition of the cell cycle, is among the downstream targets of the PI3K-AKT-MTOR pathway [Engelman et al 2006, Mirzaa et al 2014].

AKT3

Gene structure. The V-Akt murine thymoma viral oncogene homolog 3 encodes the serine/threonine kinase, AKT3. AKT3 (NM_005465.4) comprises 13 coding exons.

Pathogenic variants. To date, three AKT3 gain-of-function missense variants have been reported (see Table 4) [Rivière et al 2012, Nakamura et al 2014, Nellist et al 2015]. Data suggest that the mutational spectrum is broader [unpublished data].

Table 4.

AKT3 Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.548T>Ap.Val183AspNM_005465​.4
c.686A>Gp.Asn229Ser
c.1393C>Tp.Arg465Trp

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. AKT3 encodes 479 amino acids of the v-AKT murine thymoma viral oncogene homolog 3 or RAC-gamma serine/threonine protein kinase. AKT3 is a key regulator of PI3K-AKT-MTOR pathway function including metabolism, proliferation, cell survival, growth, and angiogenesis. AKT3 is highly expressed in brain lung and kidney. It is composed of three functional domains (PH, kinase and C-terminal domains).

Abnormal gene product. Gain-of-function pathogenic variants in AKT3 lead to higher levels of phosphorylation of PI3K-AKT-MTOR pathway target proteins [Rivière et al 2012]. Further, in a study of malformations associated with focal cortical epilepsy caused by the p.Glu17Lys AKT3 pathogenic variant, p.Glu17Lys expressing neural progenitors caused a non-cell autonomous migration defect in neighboring cells. Treatments aimed at either blocking downstream AKT signaling or inactivating AKT targets restored migration, suggesting that PI3K-AKT-MTOR pathway inhibitors may be potential treatments for some forms of focal epilepsy [Baek et al 2015].

Cancer and benign tumors. AKT3 is a key modulator of several sporadic tumors (including melanoma, glioma, and ovarian cancer) that occur in the absence of any other findings of MPPH syndrome. Somatic gain-of-function missense variants across all functional domains of AKT3 are seen in a variety of tumors in the Catalogue of Somatic Mutations in Cancer (COSMIC). These somatic variants in AKT3 are not present in the germline; thus, predisposition to these tumors is not heritable.

CCND2

Gene structure. CCND2 encodes the cyclin D2 protein that regulates the G1-S transition of the cell cycle. CCND2 (NM_001759.3) comprises five coding exons.

Pathogenic variants. To date, seven CCND2 missense variants involving four amino acid residues have been reported. All are within exon 5, the terminal exon of the gene.

Table 5.

CCND2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.808A>Tp.Lys270TerNM_001759​.3
c.838A>Gp.Thr280Ala
c.839C>Ap.Thr280Asn
c.842C>Gp.Pro281Arg
c.842C>Tp.Pro281Leu
c.841C>Tp.Pro281Ser
c.851T>Gp.Val284Gly

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CCND2 encodes 289 amino acids of the cyclin D2 protein, which is a regulatory component of the cyclin D2-CDK4 (DC) complex. This complex phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G1-S transition.

Abnormal gene product. CCND2 pathogenic variants cause accumulation of degradation-resistant CCND2. Specifically, the amino acid residue p.Thr280 has been shown to be the site for GSK-3β mediated phosphorylation, which triggers ubiquitin-mediated degradation of CCND2. Therefore, pathogenic variants abolishing this phosphorylation site result in accumulation of degradation-resistant cyclin D2, cell cycle progression, and increased neuronal proliferation [Mirzaa et al 2014].

Cancer and benign tumors. Sporadic tumors (including ovarian and testicular tumors) occurring in the absence of any other findings of MPPH syndrome have shown high level expression of CCND2. These somatic variants are not present in the germline; thus, predisposition to these tumors is not heritable. CCND2 is also overexpressed in astrocytomas and glioblastomas [Parry & Engh 2012, Koyama-Nasu et al 2013].

PIK3R2

Gene structure. The phosphatidylinositol 3-kinase β regulatory subunit (PIK3R2) encodes a lipid kinase within the PI3K enzymatic complex. PIK3R2 (NM_005027.2) comprises 15 coding exons.

Pathogenic variants. To date, 33 of the 35 published incidences of PIK3R2 pathogenic variants are a single recurrent variant (p.Gly373Arg) within the first sequence homology (SH) domain of the protein [Rivière et al 2012, Nakamura et al 2014, Mirzaa et al 2015, Terrone et al 2016].

Table 6.

PIK3R2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1117G>Ap.Gly373ArgNM_005027​.2

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PIK3R2 encodes the regulatory subunit of the PI3K enzymatic complex, a kinase that phosphorylates PtdIns (4,5) P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 recruits PH domain-containing proteins to the membrane, including AKT and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility, and morphology [Engelman et al 2006]. PIK3R2 binds to activated (phosphorylated) protein-tyrosine kinases through its SH2 domain and acts as an adapter, mediating the association of the p110 catalytic unit with the plasma membrane.

Abnormal gene product. The recurrent PIK3R2 pathogenic variant, p.Gly373Arg, causes hyperactivation of PI3K-AKT-MTOR pathway downstream targets [Rivière et al 2012].

Cancer and benign tumors. Somatic gain-of-function pathogenic variants in PIK3R2 occur in sporadic tumors, particularly endometrial cancer in the absence of any other findings of MPPH syndrome. These somatic PIK3R2 variants are not present in the germline; thus, predisposition to these tumors is not heritable.

References

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Chapter Notes

Author Notes

Dr Ghayda Mirzaa is a physician scientist at the Seattle Children's Research Institute. Her research is focused on understanding the developmental basis and genetic causes of a wide range of developmental brain disorders, with a particular focus on brain growth problems including megalencephaly and microcephaly. Dr Mirzaa's research team studies the natural history of MPPH syndrome.

Acknowledgments

We thank our patients and their families and health care providers for their collaboration and contribution to our knowledge about MPPH syndrome.

Revision History

  • 17 November 2016 (bp) Review posted live
  • 31 March 2016 (gm) Original submission
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