Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome

A number sign (#) is used with this entry because some cases of megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) have been found to have somatic mutations in the PIK3CA gene (171834) on chromosome 3q26.

Description

Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) is characterized by a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies consisting of syndactyly with or without postaxial polydactyly, connective tissue dysplasia involving the skin, subcutaneous tissue, and joints, and cortical brain malformations, most distinctively polymicrogyria (summary by Mirzaa et al., 2012). This disorder is also known as the macrocephaly-capillary malformation (MCM) syndrome (Conway et al., 2007). Mirzaa et al. (2012) suggested use of the term MCAP rather than MCM to reflect the very large brain size, rather than simply large head size, that characterizes this syndrome, and the importance and high frequency of perisylvian polymicrogyria.

Clinical Features

Moore et al. (1997) described 13 unrelated children with abnormalities of somatic growth, face, brain, and connective tissue including vasculature. They proposed that these children had a distinct disorder, megalencephaly-cutis marmorata telangiectatica congenita (MCMTC), with the features of cutis marmorata, nevus flammeus, cavernous hemangiomas, asymmetric growth pattern, central nervous system malformations, and neurologic abnormalities. See 219250 for a discussion of cutis marmorata telangiectatica congenita (CMTC) without report of the other major findings.

Clayton-Smith et al. (1997) described 9 additional patients and recognized the macrocephaly-CMTC syndrome as a distinct entity.

Carcao et al. (1998) described a child, with nonconsanguineous parents of Guyanese ancestry, with cherry red macules, megalencephaly with hemifacial and segmental overgrowth, macrosomia, cutis marmorata telangiectatica congenita of the trunk, and visceral and subcutaneous cavernous hemangiomas. The megalencephaly was accompanied by MRI findings of CNS dysgenesis with protrusion of the cerebellar tonsils through the foramen magnum (Chiari type I; 118420), lumbar syrinx, and hydrops of the optic nerves. The findings in the patient suggest that a visceral hemangioma and cherry red macules in the eye may be findings of MCMTC. The cases reported by Moore et al. (1997) and Carcao et al. (1998) supported the concept of CNS and vascular dysgenesis in MCMTC.

Vogels et al. (1998) reviewed 4 children with the same association of macrocephaly-body asymmetry-cutis marmorata telangiectatica and cutaneous hemangiomas observed over a period of 20 years. They commented on a distinct craniofacial appearance with macrocephaly and full lips.

Yano and Watanabe (2001) described 3 cases with features of macrocephaly-cutis marmorata telangiectatica congenita with poor clinical outcomes. All cases showed severe growth failure resulting in a weight below the second percentile before a year of age, 2 cases died suddenly of unknown cause at 33 and 19 months, and a third developed atrial flutter, leading to hypotensive shock during a viral illness at age 13 months. The authors suggested that a distinct clinical subtype of MCMTC may exist, and recommended that patients with this condition presenting with severe failure to thrive be closely monitored for arrhythmia and life-threatening episodes.

Lapunzina et al. (2004) reported 6 additional patients with MCMTC and reviewed 69 previously reported patients. Based on their findings, they listed the very frequent (observed in more than 75%), frequent (25 to 75%), and less frequent (less than 25%) components of the syndrome. Mode of inheritance was not clear from this analysis. There was a slight preponderance of males (male:female ratio, 41:33). No affected parents or sibs were observed. Increased paternal age was noted in several cases and parental consanguinity in some.

Giuliano et al. (2004) described 7 patients with MCMTC, including 2 with unusual cerebral manifestations and severe outcomes. One had a complex congenital heart defect and died in the neonatal period; brain MRI revealed generalized cortical dysplasia. The other had an ischemic stroke at age 14; cerebral arteriography showed an abnormal vascular pattern.

Garavelli et al. (2005) reported 10 patients with MCMTC, all of whom had some structural cerebral abnormalities on MRI, including asymmetric hemimegalencephaly, Chiari type I malformation (70%), enlargement of the lateral ventricles, and an abnormally increased signal of periventricular white matter.

Conway et al. (2007) reported a longitudinal analysis of neuroimaging findings in 17 patients with macrocephaly-capillary malformation. More than half the patients had cerebellar tonsillar herniation associated with rapid brain growth and progressive crowding of the posterior fossa during infancy. Concurrent findings included ventriculomegaly and dilated dural venous sinuses, reflecting a dynamic process of mechanical compromise in the posterior fossa. The malformation was considered to be distinct from Chiari malformation type I as it appeared to be acquired in at least 4 patients. There was also evidence of abnormal cortical morphogenesis, including focal cortical dysplasia, polymicrogyria, 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.

Canham and Holder (2008) described a 14-year-old girl with mild MCMTC who was noted to have 'mottled skin' in infancy that had faded by the time of presentation at 3.5 years of age, at which examination she was noted to have macrocephaly, capillary hemangioma over the upper eyelids, nasal bridge, upper lip, and philtrum, and a faint pigmented area over the lower back. In early childhood, she had been diagnosed with a semantic pragmatic language disorder, although she subsequently entered mainstream school without a statement of special educational needs. At 14 years of age, she developed marked varicose veins around her left knee and was found to have incompetence of the long saphenous vein on Duplex scan, with no evidence of other structural anomalies. Her facial hemangioma had almost entirely resolved. Growth had ceased at menarche 3 years earlier, and although her height and head circumference were above the 99.6th centile, the authors noted that those parameters would likely be within the normal range in adulthood. Her secondary dentition had come in earlier than usual, and her teeth were very large, such that several had to be removed. Canham and Holder (2008) concluded that it is possible to have this condition and function within the normal range or with only minor problems, particularly for children with no structural brain anomaly.

Gripp et al. (2009) presented 3 unrelated patients with a phenotype consistent with MCM. In the first patient, brain MRI showed striking megalencephaly and polymicrogyria, along with very large ventricles and cerebellar tonsillar herniation filling the cisterna magna. She had a nevus flammeus extending over the forehead, nose, and philtrum, as well as a capillary malformation resembling cutis marmorata over the trunk and extremities. She had mild coarse dysmorphic features, such as low nasal bridge, wide lips, and low-set ears. Other features included ventricular septal defect and a vascular ring formed by a right aortic arch and aberrant left subclavian artery, as well as vesicoureteral reflux. The second child had megalencephaly with mild ventriculomegaly and diffuse bilateral polymicrogyria. Other features included postaxial polysyndactyly of 1 foot, frontal bossing, depressed nasal bridge, hypertelorism, low-set ears, and mild hemihyperplasia of the right face. Skin findings included a large hemangioma over the left elbow, a facial nevus flammeus that extended from the upper lip to the forehead, and generalized cutis marmorata. The third child had increasing macrocephaly from birth. Brain MRI at 6 weeks showed showed large brain size, extensive asymmetric bilateral polymicrogyria, and mildly enlarged lateral ventricles. Repeat brain MRI at 5 months demonstrated progressive ventricular enlargement and cerebellar tonsillar herniation filling the cisterna magna and crowding the back of the brainstem and upper cervical spinal cord. There was frontal bossing, mildly deep-set eyes, and thickened soft tissue of the cheeks, philtrum and lips. Although there was no syndactyly, polydactyly, or visible capillary malformation, he had mild cutis marmorata, and abdominal ultrasound reportedly showed a vascular anomaly beneath the umbilicus. All children were born premature at 30, 34, and 38 weeks' gestation, respectively. All were less than 12 months of age at the time of the report, and all showed hypotonia with delayed development. None of the parents were related, and there was no family history in any case. Gripp et al. (2009) noted that 2 of the patients had an initial diagnosis of megalencephaly, polymicrogyria-polydactyly hydrocephalus syndrome (MPPH; 603387), a similar syndrome with overlapping features. Gripp et al. (2009) suggested that the 2 disorders may be related or on the same phenotypic spectrum; they proposed the term MPPH-CM to refer to this phenotypic spectrum.

Diagnosis

Franceschini et al. (2000) reported 2 patients with features consistent with a diagnosis of MCMTC, only one of whom had typical cutis marmorata when examined at age 4 months. Based on these cases and their review of the literature, the authors suggested that macrocephaly and at least 2 of the main reported findings (i.e., overgrowth, cutis marmorata, angiomata, polydactyly/syndactyly, asymmetry) are necessary for the diagnosis of MCMTC. They also noted the increased risk for development of nonobstructive hydrocephalus in this syndrome.

Martinez-Glez et al. (2010) reported 13 Spanish patients with MCM and proposed diagnostic criteria. Among their patients, the most frequent features were neuroimaging alterations (100%), macrocephaly (92%), overgrowth (92%), capillary malformations (85%), developmental delay (85%), and asymmetry (62%). Less common features included capillary malformation of the nose, lip and/or philtrum (54%), hydrocephalus (46%), hypotonia (46%), joint laxity (38%), tonsillar herniation/Chiari I (31%), syndactyly of the toes (31%), hemimegalencephaly (31%), polymicrogyria (31%), and frontal bossing (25%). The proposed diagnostic criteria included 3 of 4 major criteria and 2 of 7 minor criteria. Major criteria included macrocephaly, capillary malformation, overgrowth/asymmetry, and neuroimaging alterations. Minor criteria included developmental delay, midline facial capillary malformation, neonatal hypotonia, syndactyly/polydactyly, frontal bossing, connective tissue abnormalities, and hydrocephalus. Genomewide SNP array analysis did not identify any altered gene or region common to all patients.

Mirzaa et al. (2012) reviewed the phenotypic features of 42 patients with a megalencephalic syndrome in an attempt to clarify and simplify the categorization and diagnosis of these disorders. Statistical analysis of particular features yielded 2 main groups: 21 patients with a vascular malformation consistent with MCAP and 19 with no vascular malformation consistent with MPPH; 2 patients were in an overlap group. Vascular malformations were significantly associated with syndactyly and somatic overgrowth at birth, and lack of vascular malformations was associated with polydactyly. The various features were assigned to 5 major classes of developmental abnormalities. Both MCAP and MPPH had (1) megalencephaly and variable somatic overgrowth (particularly in MCAP); (2) distal limb malformations, syndactyly being more associated with MCAP and polydactyly with MPPH; and (3) similar cortical brain malformations (mainly polymicrogyria). In addition, MCAP included (4) developmental vascular abnormalities and (5) occasional connective tissue dysplasia, such as hyperelasticity or thick skin. MPPH lacks vascular malformations, connective tissue dysplasia, and heterotopia. Based on these findings, Mirzaa et al. (2012) proposed diagnostic criteria for the MCAP and MPPH syndromes, and postulated that the 2 disorders represent different, although overlapping, syndromes that may be caused by different genes involved in the same biologic pathway.

Cytogenetics

Stoll (2003) reported a patient with MCMTC who carried a de novo translocation t(2;17)(p11;p13). At birth the patient had widespread erythematous violaceous reticulate cutaneous marking, nevus flammeus of the philtrum, syndactyly of third and fourth fingers of the right hand, prominent forehead, upslanting palpebral fissures, flat nasal bridge, and hypotonia. Transfontanellar ultrasound showed mild ventriculomegaly. Motor development was delayed. At 18 months of age CT scan showed cerebral asymmetry and dilated cerebral ventricles; a ventriculoperitoneal shunt was inserted. Right upper and lower limbs were larger than those on the left. Knees, ankles, and small joints of the hands were hypermobile. The patient died suddenly at 8 years of age.

Molecular Genetics

Riviere et al. (2012) conducted exome sequencing in an individual with MCAP and his parents and performed an analysis of de novo mutations in this trio by including the raw variants that did not meet their initial hard-filtering criteria. Using this approach, they identified a missense change in the PIK3CA gene (G914R; 171834.0011), which encodes the p110-catalytic subunit of class IA PI3K. This mutation was supported by 20 of 177 reads (11%) in the exome sequencing data and was confirmed to be de novo and mosaic by Sanger sequencing and a custom restriction enzyme assay. Riviere et al. (2012) then sequenced the coding exons of PIK3CA in 29 individuals with megalencephaly with no mutations in the AKT3 (611223) or PIK3R2 (603157) genes and identified 14 additional PIK3CA mutations, with mutant allele frequencies ranging from 10 to 50%. Standard variant calling in exomes from 7 additional subjects with MCAP identified a mutation of the PIK3CA gene (C378Y; 171834.0012) that was supported by 68 of 250 reads (27%) in another individual. This mutation showed variable levels of mosaicism depending on the tissue tested. Manual inspection of the Sequence Alignment/Map (SAM) files of the remaining 6 subjects with MCAP of unknown cause using the Integrative Genomics Viewer revealed other candidate mosaic mutations in the PIK3CA gene in all of the 6 affected individuals, with mutations represented by 2 to 15% of the total reads. Sanger sequencing, a custom restriction enzyme assay, or both, confirmed all 6 mutations. Riviere et al. (2012) next performed targeted ultra-deep sequencing (coverage of more than 10,000 reads) of 5 mutation sites in 15 mutation-negative affected individuals, as well as in known mutation carriers and control individuals. This experiment confirmed all previously identified mutations and detected 2 additional low-level mosaic mutations missed by Sanger sequencing. Both were confirmed by a second deep-sequencing experiment and showed mutant allele frequencies ranging from 1 to 8%. Riviere et al. (2012) identified a total of 24 affected individuals with PIK3CA mutations, and all but 3 (LR06-220, LR11-153, and LR11-230) showed evidence of postzygotic mosaicism. In 13 individuals with MCAP, no mutation was found in the PIK3CA gene, the PTEN gene (601728), or 4 other genes encoding subunits of class IA PI3K.

Lee et al. (2012) performed whole-exome sequencing on brain and peripheral blood DNA from 5 HME cases and identified 3 missense mutations: one in the PIK3CA gene (E545K; 171834.0003), one in the AKT3 gene (E17K; 611223.0003), and one in the MTOR gene (C1483Y; see 616638). The individual with the MTOR gene mutation also carried a diagnosis of hypomelanosis of Ito (300337). Lee et al. (2012) then used a modified single base-extension protocol followed by mass spectrometry analysis to detect somatic mutations at a frequency as low as 3% in genetically heterogeneous samples. Reanalysis of the same DNA samples used for whole-exome sequencing again showed the absence of the mutant allele in blood but its presence in the brain, with similar mutation burden as that detected with Illumina sequencing. These somatic mutations were detected at a frequency of 36.6%, 40.4%, and 8.1% in each brain sample. Using the same technology, Lee et al. (2012) screened for these mutations in 15 other HME cases and identified 3 additional cases carrying the PIK3CA E545K variant, each with a mutation burden of about 30%. One of these individuals had hypertrophic regions in the right hand and foot.

Nomenclature

Toriello and Mulliken (2007) suggested that the name MCMTC should be changed to MCM, for 'macrocephaly-capillary malformation.' The authors argued that the vascular lesions in this disorder are neither cutis marmorata nor cutis marmorata telangiectatica congenita, but are rather a type of capillary malformation in a patchy reticular pattern. Mirzaa et al. (2012) suggested use of the term MCAP rather than MCM to reflect the very large brain size, rather than simply large head size, that characterizes this syndrome, and the importance and high frequency of perisylvian polymicrogyria.