Neuroimaging findings in Macrocephaly-Capillary Malformation: A longitudinal study of 17 patients

Boston University, Boston, Massachusetts, United States
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 12/2007; 143A(24):2981-3008. DOI: 10.1002/ajmg.a.32040
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Here, we report the neuroimaging findings and neurological changes in 17 unpublished patients with Macrocephaly-Capillary Malformation (M-CM). This syndrome has been traditionally known as Macrocephaly-Cutis Marmorata Telangiectatica Congenita (M-CMTC), but we explain why M-CM is a more accurate term for this overgrowth syndrome. We analyzed the 17 patients with available brain MRI or CT scans and compared their findings with features identified by a comprehensive review of published cases. White matter irregularities with increased signal on T2-weighted images were commonly observed findings. A distinctive feature in more than half the patients was cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. In four such cases, we confirmed that the tonsillar herniation was an acquired event. Concurrently, with the development of these findings, ventriculomegaly (frequently obstructive) and dilated dural venous sinuses were observed in conjunction with prominent Virchow-Robin spaces in many of those in whom cerebellar tonsil herniation had developed. We postulate that this constellation of unusual features suggests a dynamic process of mechanical compromise in the posterior fossa, perhaps initiated by a rapidly growing cerebellum, which leads to congestion of the venous drainage with subsequently compromised cerebrospinal fluid reabsorption, all of which increases the posterior fossa pressure and leads to acquired tonsillar herniation. We make a distinction between congenital Chiari I malformation and acquired cerebellar tonsil herniation in this syndrome. We also observed numerous examples of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria which primarily involved the perisylvian and insular regions, and cerebral and/or cerebellar asymmetric overgrowth. Other findings included a high frequency of cavum septum pellucidum or vergae, thickened corpus callosum, prominent optic nerve sheaths and a single case of venous sinus thrombosis. One patient was found to have a frontal perifalcine mass resembling a meningioma at age 5 years. This is the second apparent occurrence of this specific tumor in M-CM.

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Available from: John M Graham, Oct 12, 2015
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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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    • "ly or both , perisylvian PMG , variable connective tissue dyspla - sia , hypotonia , and mild to severe intellectual disability . More than 140 cases have been reported in the literature and numerous sets of diagnostic criteria proposed [ Clayton‐Smith et al . , 1997 ; Moore et al . , 1997 ; Franceschini et al . , 2000 ; Lapunzina et al . , 2004 ; Conway et al . , 2007 ; Gonzalez et al . , 2009 ; Martínez‐Glez et al . , 2010 ] . The most consistent features of MCAP appear to be congenital or early postnatal MEG and cutaneous capillary malformations , such as persistent nevus flammeus and / or vivid cutis marmorata [ Mirzaa et al . , 2012 ] . However , wide phenotypic variability has been observed , wh"
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    ABSTRACT: The megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) and megalencephaly-capillary malformation (MCAP) syndromes are highly recognizable and partly overlapping disorders of brain overgrowth (megalencephaly). Both syndromes are characterized by congenital or early postnatal megalencephaly, with a high risk for progressive ventriculomegaly leading to hydrocephalus and cerebellar tonsillar ectopia leading to Chiari malformation, and cortical brain abnormalities, specifically polymicrogyria. MCAP is further characterized by distinct cutaneous capillary malformations, finger or toe syndactyly, postaxial polydactyly, variable connective tissue dysplasia and mild focal or segmental body overgrowth, among other features. MPPH, on the other hand, lacks consistent vascular or somatic manifestations besides postaxial polydactyly in almost half of reported individuals. We identified de novo germline mutations in PIK3R2 and AKT3 in individuals with MPPH, and both postzygotic, mosaic and rare germline mutations in PIK3CA in individuals with MCAP. PIK3R2, AKT3, and PIK3CA are members of the critical phosphatidylinositol-3-kinase (PI3K)-vakt murine thymoma viral oncogene homolog (AKT) pathway that is well implicated in cell growth, proliferation, survival, apoptosis, among other diverse cellular functions. The identified mutations in these three genes have been shown to lead to gain of function and activation of the PI3K-AKT pathway. Germline and postzygotic mutations of PIK3CA and other PI3K-AKT-mTOR pathway genes have also been identified in several other overgrowth syndromes, highlighting the key role of this signaling pathway in normal development and pathophysiology of a large group of congenital anomalies. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 05/2013; 163(2). DOI:10.1002/ajmg.c.31361 · 3.91 Impact Factor
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    • "To objectively assess the severity of CBTE, we measured the distance the cerebellar tonsils extended below the foramen magnum line. We also consolidated all white matter abnormalities including dysmyelination and alterations in the thickness of the white matter, as white matter signal abnormalities [Conway et al., 2007]. "
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    ABSTRACT: 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.
    American Journal of Medical Genetics Part A 02/2012; 158A(2):269-91. DOI:10.1002/ajmg.a.34402 · 2.16 Impact Factor
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