Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP)

Was ist Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP)?

Megalenzephalie-Kapillarfehlbildung syndrom ist eine multiple Fehlbildungsstörung. Seine Schwere variiert zwischen den einzelnen Personen.

Erstmals in 1997 als eigenständige Erkrankung identifiziert, gibt es seitdem nur 140 gemeldete Fälle, aber möglicherweise trägt eine Unterdiagnose zu dieser Zahl bei.

Bei dieser seltenen Entwicklungsstörung handelt es sich hauptsächlich um Gewebeüberwucherung in verschiedenen Körperteilen. Ein großes Gehirn (Megalozephalie) ist eines der Hauptmerkmale des syndrom.

Syndrom Synonyme:
M-CM Makrozephalie – Kapillarfehlbildung Makrozephalie – Kapillarfehlbildung; Mcm Makrozephalie-Cutis Marmorata Teleangiectatica Congenita; Mcmtc MCAP MCTC Megalenzephalie - Kapillarmissbildung Megalenzephalie - Kapillarmissbildung Syndrom Megalencephaly-cutis Marmorata Telangiectatica Congenita Überwucherung - Polysyndaktylie - Hämangiome Überwucherung-Polysyndaktylie-Hämangiome

Was Genveränderungen verursachen Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP)?

Somatische Mutationen zum Gen PIK3CA. Es wird nicht angenommen, dass es sich um einen vererbbaren Zustand handelt.

Die Vererbung von Mosaiken erfolgt sehr früh in der Entwicklung eines Fötus. Im Wesentlichen handelt es sich um einen Fehler bei der Zellteilung. Der menschliche Körper besteht aus 46 Chromosomen in 23 Paaren. Mosaikismus tritt auf, wenn ein Individuum Zellen mit mehr oder weniger Chromosomen als üblich in seinem Körper hat 46. Dies kann Probleme auslösen, die verschiedene Systeme und Körperteile betreffen.

Was sind die wichtigsten symptome von Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP)?

Das Wichtigste symptome des syndrom gehören Gehirnüberwucherung (Megalenzephalie) einen großen Kopf.

Kapillarfehlbildungen oder Hautläsionen im Gesicht, am Rumpf und an den Gliedmaßen sind eine der wichtigsten symptom. Eine vorstehende Stirn, zusätzliche Finger und Zehen sowie schlaffe Haut und Gelenke gehören ebenfalls dazu symptome des syndrom. Ebenso wie die Körperasymmetrie.

Andere Gesundheitszustände im Zusammenhang mit der syndrom gehören niedriger Muskeltonus, Krampfanfälle und Herzfehler. Symptome kann zwischen einzelnen Personen stark variieren.

Mögliche klinische Merkmale/Merkmale:
Cavum septum pellucidum, Zerebrale Ischämie, Asymmetrisches Wachstum, Arnold-Chiari-Malformation, Aplasie/Hypoplasie des Kleinhirns, Arteriovenöse Malformation, Frontal Bossing, Sporadisch, Somatische Mutation, Ventrikelseptumdefekt, Viszerale Angiomatose, Makrozephalie, Teleangiektasien der Haut, Abnormalität der neuronalen Haut Migration, Nephroblastom, Mikrophthalmie, Megalenzephalie, Meningeom, Arrhythmie, Leukämie, Muskelhypotonie, Progressive Makrozephalie, Intellektuelle Behinderung, Hypermobilität der Gelenke, Gelenkschlaffheit, Weithals, Optikusatrophie, Überwucherung, Zehensyndaktylie, Krampfanfall, Syndaktylie, Großes Ohrläppchen, Fuß Polydaktylie, Handpolydaktylie, Polymikrogyrie, Epikanthus, tiefliegendes Auge, Ventrikulomegalie, Gesichtsasymmetrie, Fingersyndaktylie, glattes Philtrum, Cutis marmorata, abgeschrägte Lidspalten, Fehlbildung des Herzens und der großen Gefäße, eingedrückter Nasenrücken, volle Wangen, Hypermelantelorismus, , Hydrozephalus, Hohe Stirn, Breite Stirn, Hernie, Cogn itive Beeinträchtigung, global

Wie wird jemand getestet? Megalencephaly-Capillary Malformation-Polymicrogyria syndrome (MCAP)?

Die ersten Tests auf Megalencephalie-Kapillar-Missbildung-Polymikrogyrie können mit einem Screening der Gesichtsanalyse über die FDNA Telehealth Telegenetics-Plattform beginnen, mit der die Schlüsselmarker des Syndroms identifiziert und die Notwendigkeit weiterer Tests aufgezeigt werden können. Eine Konsultation mit einem genetischen Berater und dann einem Genetiker wird folgen. 

Basierend auf dieser klinischen Konsultation mit einem Genetiker werden die verschiedenen Optionen für Gentests geteilt und die Zustimmung für weitere Tests eingeholt.

Medizinische Informationen zu Megalenzephalie-Kapillarfehlbildung-Polymikrogyrie Syndrom

Barnicoat et al., (1996) reported two infants with a similar syndrome of overgrowth, haemangiomas, and polydactyly associated with syndactyly. In one female infant birth weight and head circumference were above the 97th centile whereas length was between the 50th and 90th centile. Hypoglycaemia developed on day two but was easy to control and there was no evidence of hyperinsulinaemia. Hypoglycaemia and thrombocytopenia needing treatment were problems in the first few days of life. The facial features were coarse with a relatively large head. The neck was short with redundant skin folds. The nasal bridge was flat. There was a large cavernous haemangioma on the right shoulder. There was syndactyly between fingers 3-4 on both hands and post-axial polydactyly of both feet. Radiographs showed severe demineralisation of the skeleton with Wormian bones in the skull. The long bones were slender. CT brain scan showed mild periventricular leukomalacia and a mild communicating hydrocephalus initially, but intracranial pressure increased and a shunt was needed by three months. The second infant had somewhat similar features. There was no generalised macrosomia but the hands were disproportionately large. The facial features were similar to the first case. There were large capilliary haemangiomata over the palmar and dorsal aspects of both hands and on the back, as well as on both feet and legs. There was a cavernous haemangioma on the left axilla and also one on the left cheek and upper lip displacing the nose to the right. Post-axial polydactyly of the left hand with bilateral 3-4 syndactyly of the fingers with fused nails on one side were noted. There was 2-3 and 4-5 syndactyly of both feet. NMR scanning of the brain showed hydrocephalus and a venous malformation with massive dilation of the sagittal, straight and sigmoid sinuses with thrombosis.
Toriello et al., (1996), Clayton-Smith et al., (1997) and Moore et al., (1997) reported a group of children with a distinctive overgrowth syndrome. This is characterised by macrocephaly, limb asymmetry, and vascular stains. Birth weight is increased. There were cutis marmorata and a characteristic haemangioma of the philtrum of the upper lip. These cutaneous features may fade with age. Carcao et al., (1998) reported a case where MRI scans showed protrusion of the cerebellar tonsils through the foramen magnum, a lumbar syrinx and ""hydrops of the optic nerves"".
Franceschini et al., (2000) reported two convincing cases without cutis marmorata. The patient reported by Hallett et al., (1995) seems to have features of the condition although there was also acanthosis nigricans and gingival fibromatosis. Yano and Watanabe (2001) reported three cases of poor clinical outcomes. In two cases there were intractable cardiac arrhythmias and sudden death. Robertson et al., (2000) reported five further cases and provide a good review. Lapunzina et al., (2004) have done the same. Schwartz et al., (2002) reported a male with some features of the condition (although not entirely convincing) who had a retinoblastoma. It seems likely that the case reported by Megarbane et al., (2003) with polydactyly and intestinal lymphangiectasia falls into this group. A case reported by Stoll (2003) had a t(2;17)(p11;p13) translocation.
Garavelli et al., (2005) looked at the MRI findings of 10 cases and found abnormalities in all (megalencephaly, asymmetry, increased white matter signals). Giuliano et al., (2004) reported seven cases and stress the neurological sequelae (all were delayed, five cases had cerebral asymmetry with hemimegalencephaly in three, hydrocephalus in three and an Arnold-Chiari type I in one).
The neurological features of 17 patients were discussed by Conway et al., (2007). White matter irregularities (increased signal on T2-weighted images) were found in the majority and a distinctive feature was cerebellar tonsilar herniation and progressive crowding of the posterior fossa. This, postulated the authors, suggested a dynamic process, possibly initiated by a rapidly growing cerebellum, congestion of venous drainage and an increase in pressure, that led, in some of their cases, to tonsillar herniation. They also found evidence of an abnormal cortical morphogenesis.
A long-term follow-up of a case reported by Canham and Holder (2008) showed that growth and head circumference ended up just within the normal range, that the vascular skin lesions faded with time. Only the varicosities (in this case mild) remained.
Note however that of the 12 cases reported by Wright et al., (2009), all showed a reticulated or confluent port-wine stain (not cutis marmorata) and seven had centrofacial capillary malformations. There is macrocephaly with ventricular dilatation. Syndactyly between toes 2 and 3 is common and there may be limb asymmetry. Some cases have 3/4 syndactyly of the fingers and occasionally post-axial polydactyly. Congenital heart defects have occasionally occurred (Dinleyici et al., 2005, Gonzalez et al., 2009). There may also be joint laxity and hyperelastic skin. Developmental delay is common. MRI scans may show evidence of delayed myelination. Hydrocephalus usually develops. Apnoe due to cranio-cervical cord compression has also been reported (Franklin et al., 2009). See under Hemihypertrophy-hemimegalencephaly-polydactyly for a condition with similar features. Proteus syndrome has to be considered. Note the three cases reported by Gonzalez et al., (2009) who state that unlike Proteus there may be checker-board pattern to the hypertrophy ie., face, and then the leg opposite to the trunk). They also state that unlike Proteus the hypertrophy occurs irrespective of the vascular stain.
The clinical features and diagnostic criteria are well reviewed by Martinez-Glez et al., (2010).
Polymicrogyria and a thickened corpus callosum are also features (Mirzaa et al., 2012).
The case reported by Papetti et al., (2012) had hemimegalencephaly, polymicrogyria and cerebellar tonsillar herniation.
Discordant monozygotic twins were reported by Lederer et al., (2012). Note the excellent paper by Reviere et al., (2012) who looked at three families with either MPPH or MCAP and thereafter further cases, They found two mutations in AKT3, one in PIK3R2 in 11 unrelated families with MPPH and 15, mostly postzygotic mutations in PIK3CA in 23 individuals with MCAP and one with MPPH. It could be that PTPN11 is also involved (Docker et al., 2015).
McDermott et al., (2016) detected the presence of PIK3CA mutation in hair and in the secondary tooth of the affected individual. Dental crowding as the clinical manifestation of the PIK3CA mutation within the dental tissue has been suggested by Canham and Holder (2008).
Mirzaa et al., (2016) identified PIK3CA mutations in 60 individuals in a cohort of 181 individuals with brain and body overgrowth. Sixteen of 29 PIK3CA mutations were novel. The phenotypes were not simply related to the level and distribution of PIK3CA mutations, but also to the class of mutation. The clinical presentation was as follows: (1) severe focal overgrowth due to low-level but highly activating hotspot mutations, (2) predominantly brain overgrowth and less severe somatic overgrowth due to less-activating mutations, (3) intermediate phenotypes (capillary malformations with overgrowth) with intermediately activating mutations. Levels of mosaicism were on average lower in peripheral blood lymphocytes than saliva, and lower in saliva than in skin fibroblasts. In ten patients germline or apparently germline PIK3CA mutations were identified.
Yeung et al., (2017) described seven molecularly confirmed patients with PIK3CA-Related Overgrowth Spectrum. Clinical presentations included congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis and other skeletal abnormalities, Klippel–Trenaunay syndrome, lymphatic malformations. Two individuals showed atypical phenotypes that cannot be classified into existing disease categories. The age of patients ranged from three to 18 years. Central nervous system was unaffected in all the patients.
Takagi et al., (2017) described a boy with megalencephaly and a de novo heterozygous missense mutation in the AKT3 gene. Clinical characteristics included hypotonia, developmental delay, frontal bossing, flattened nasal bridge and hyperlaxity. Novel features were transient hypoglycemia, and growth hormone deficiency.
Alcantara et al., (2017) described 14 additional patients with AKT3 mutations. Patients with highly asymmetric cortical dysplasia usually had the common p.E17K mutation; patients with constitutional AKT3 mutations showed more variable phenotypes (bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia, diffuse megalencephaly without cortical dysplasia).
Steiner et al., (2018) described six patients with PIK3CA gene mutation-related segmental overgrowth syndromes. All patients had a history of previous surgery and four of them developed abnormal scarring in tissue affected by overgrowth.
A male patient polymicrogyria in association with hypoglycemia was described by Stutterd et al. (2018). Ventriculomegaly and macrocephaly were noted prenatally. At birth, he showed overgrowth, relative macrocephaly with frontal bossing, coarse facies, broad and upturned nasal tip, full upper lip, low-set ears with squared helix, capillary malformations, redundant skin on hands and feet, and mild lateral deviation of fingers. Brain MRI showed megalencephaly and severe hydrocephalus that required ventriculoperitoneal shunt. Asymptomatic preprandial hypoglycemia, and episodes of atrial ectopic tachycardia were also documented.

* This information is courtesy of the L M D.
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