Mirzaa GM, Conway RL, Gripp KW et al.Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet A 158A:269-291

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA. gmirzaa@bsd.uchicago
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 02/2012; 158A(2):269-91. DOI: 10.1002/ajmg.a.34402
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The macrocephaly-capillary malformation syndrome (M-CM), which we here propose to rename the megalencephaly-capillary malformation syndrome (MCAP; alternatively the megalencephaly-capillary malformation-polymicrogyria syndrome), and the more recently described megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) are two megalencephaly (MEG) disorders that involve a unique constellation of physical and neuroimaging anomalies. We compare the features in 42 patients evaluated for physical and neuroimaging characteristics of MCAP and MPPH and propose a more global view of these syndromes based on classes of developmental abnormalities that include primary MEG and growth dysregulation, developmental vascular anomalies (primarily capillary malformations), distal limb anomalies (such as syndactyly and polydactyly), cortical brain malformations (most distinctively polymicrogyria, PMG), and variable connective tissue dysplasia. Based on these classes of developmental abnormalities, we propose that MCAP diagnostic criteria include progressive MEG with either vascular anomalies or syndactyly. In parallel, we propose that MPPH diagnostic criteria include progressive MEG and PMG, absence of the vascular anomalies and syndactyly characteristic of MCAP, and absence of brain heterotopia.

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    • "CLOVES syndrome represents a more severe subset of that spectrum. In addition, previous authors [Lee et al., 2012; Mirzaa et al., 2012; Rivière et al., 2012] have described the megalencephaly syndromes that have overlapping findings with CLOVES, FAO and HHML. Therefore, we propose the phenotypic designation of PIK3CA-Related Overgrowth Spectrum. "
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    ABSTRACT: Somatic mutations in the phosphatidylinositol/AKT/mTOR pathway cause segmental overgrowth disorders. Diagnostic descriptors associated with PIK3CA mutations include fibroadipose overgrowth (FAO), Hemihyperplasia multiple Lipomatosis (HHML), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/skeletal and spinal (CLOVES) syndrome, macrodactyly, and the megalencephaly syndrome, Megalencephaly-Capillary malformation (MCAP) syndrome. We set out to refine the understanding of the clinical spectrum and natural history of these phenotypes, and now describe 35 patients with segmental overgrowth and somatic PIK3CA mutations. The phenotypic data show that these previously described disease entities have considerable overlap, and represent a spectrum. While this spectrum overlaps with Proteus syndrome (sporadic, mosaic, and progressive) it can be distinguished by the absence of cerebriform connective tissue nevi and a distinct natural history. Vascular malformations were found in 15/35 (43%) and epidermal nevi in 4/35 (11%) patients, lower than in Proteus syndrome. Unlike Proteus syndrome, 31/35 (89%) patients with PIK3CA mutations had congenital overgrowth, and in 35/35 patients this was asymmetric and disproportionate. Overgrowth was mild with little postnatal progression in most, while in others it was severe and progressive requiring multiple surgeries. Novel findings include: adipose dysregulation present in all patients, unilateral overgrowth that is predominantly left-sided, overgrowth that affects the lower extremities more than the upper extremities and progresses in a distal to proximal pattern, and in the most severely affected patients is associated with marked paucity of adipose tissue in unaffected areas. While the current data are consistent with some genotype-phenotype correlation, this cannot yet be confirmed. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 04/2014; 164(7). DOI:10.1002/ajmg.a.36552 · 2.16 Impact Factor
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    • "megalencephaly, which is most often congenital and appears to be universally progressive, despite neurosurgical intervention for associated ventriculomegaly or hydrocephalus [Conway et al., 2007; Mirzaa et al., 2012]. True megalencephaly is a specific feature seen in a small group of syndromes, much smaller than the heterogeneous group of disorders with large head size overall. "

    American Journal of Medical Genetics Part A 08/2013; 161(8). DOI:10.1002/ajmg.a.35940 · 2.16 Impact Factor
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    • "CLOVES syndrome represents a more severe subset of that spectrum. In addition, previous authors [Lee et al., 2012; Mirzaa et al., 2012; Rivière et al., 2012] have described the megalencephaly syndromes that have overlapping findings with CLOVES, FAO and HHML. Therefore, we propose the phenotypic designation of PIK3CA-Related Overgrowth Spectrum. "
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    ABSTRACT: PIK3CA-associated segmental overgrowth includes disorders of brain (e.g., MCAP [megalencephaly-capillary malformation] syndrome, hemimegalencephaly); and segmental body overgrowth (e.g., CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome, fibroadipose hyperplasia [FH]). Heterozygous (usually somatic mosaic) mutations of PIK3CA are causative. MCAP syndrome is characterized by the major findings of (1) megalencephaly (MEG) or hemimegalencephaly (HMEG) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability; and (2) cutaneous capillary malformations with focal or generalized somatic overgrowth. Additional findings can include digital anomalies (syndactyly, polydactyly), cortical malformations – most distinctively polymicrogyria (PMG); and variable connective tissue dysplasia. CLOVES (or CLOVE) syndrome and fibroadipose hyperplasia (FH) may be associated with (1) MEG or HMEG; and (2) patchy segmental overgrowth associated with skeletal anomalies, lipomatosis, vascular malformations, and epidermal nevi. PIK3CA-associated segmental overgrowth is confirmed in an individual with a mutation in one PIK3CA allele, typically in affected tissues. Because the vast majority of PIK3CA mutations arise postzygotic (and are thus mosaic), more than one tissue may need to be tested. Failure to detect a PIK3CA mutation does not exclude a clinical diagnosis of the PIK3CA-associated segmental overgrowth disorders in individuals with suggestive features. Treatment of manifestations: Significant or lipomatous segmental overgrowth may require debulking; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (e.g., obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Routine treatment of the following, when present, is indicated: cardiac and renal abnormalities; intellectual disabilities and behavior problems; motor difficulties; speech, swallowing, and feeding difficulties. Surveillance: MCAP syndrome: Follow up no less than every six months until age six years and at least yearly thereafter to monitor for neurosurgical complications, breathing or sleep disorders, seizures and orthopedic complications. Provisionally recommended imaging in early childhood includes brain MRI every six months for the first two years, then yearly until age eight years for neurologic complications (e.g., hydrocephalus, cerebellar tonsillar ectopia). Consider screening for Wilms tumor following the protocol suggested for Beckwith-Wiedemann syndrome (BWS) (by ultrasound examination every 3 months until age 8 years); however, tumor risk in PIK3CA-related segmental overgrowth is undetermined and appears to be lower than in BWS. CLOVES syndrome and FH: Monitoring for severe scoliosis, infiltrative lipomatous overgrowth, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems, central phlebectasias, and thromboembolism. PIK3CA-associated segmental overgrowth is not typically inherited. Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for mutations in PIK3CA, suggesting that the mutation occurred post-fertilization in one cell of the multicellular embryo. Two of 24 affected individuals had a de novo germline mutation in PIK3CA. All reported individuals with CLOVES and FH had somatic mosaicism for mutations in PIK3CA. No confirmed instances of vertical transmission or sib recurrence have been reported. Because family members are not known to have an increased risk, prenatal diagnosis is usually not indicated for family members.
    GeneReviews™, Edited by Roberta A Pagon, Margaret P Adam, Thomas D Bird, Cynthia R Dolan, Chin-To Fong, Karen Stephens, 01/2013; University of Washington, Seattle.
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