|Classification and external resources|
Macrocephaly-capillary malformation (M-CM) is a multiple malformation syndrome causing abnormal body and head overgrowth and cutaneous, vascular, neurologic, and limb abnormalities. Though not every patient has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformation (naevus flammeus or port-wine stain type birthmark over much of the body; a capillary malformation of the upper lip or philtrum is seen in many patients with this condition), body asymmetry (also called hemihyperplasia or hemihypertrophy), polydactyly or syndactyly of the hands and feet, lax joints, doughy skin, variable developmental delay and other neurologic problems such as seizures and low muscle tone.
History and Nomenclature
This disorder was recognized as a distinct syndrome in 1997 and named macrocephaly-cutis marmorata telangiectasia congenita or M-CMTC. A new name, macrocephaly-capillary malformation, abbreviated M-CM, was recommended in 2007. This new name was chosen to more accurately describe the skin markings associated with this disorder. In January 2012, a paper proposed new names for the syndrome: megalencephaly-capillary malformation or megalencephaly-capillary malformation-polymicrogyria with an abbreviation of MCAP.
Mosaic mutations in PIK3CA have been found to be the genetic cause of M-CM. Genetic testing for the mutation is currently only available on a research basis. Other overgrowth conditions with distinct phenotypes have also been found to be caused by mosaic mutations in PIK3CA. How different mutations in this gene result in a variety of defined clinical syndromes is still being clarified.  Mutations in PIK3CA have not been found in a non-mosaic state in any of these disorders, so it is unlikely that the conditions could be inherited.
Diagnosis and Characteristics
Diagnosis is usually based on clinical observation. Various sets of criteria have been suggested to identify the disorder in an individual patient, all of which include macrocephaly and a number of the following: somatic overgrowth, cutis marmorata, midline facial birthmark, polydactyly/syndactyly, asymmetry (hemihyperplasia or hemihypertrophy), hypotonia at birth, developmental delay, connective tissue defect and frontal bossing. Currently no consensus exists about which diagnostic criteria are definitive and so evaluation by a medical geneticist or other clinician with familiarity with the syndrome is usually needed to provide diagnostic certainty. It is not clear if there are some features which are mandatory to make the diagnosis, but macrocephaly appears essentially universal though may not be congenital. The distinctive vascular abnormalities of the skin often fade over time, making the diagnosis challenging in older children with this condition.
The brain can be affected in several ways in this syndrome. Some children are born with structural brain anomalies such as cortical dysplasia or polymicrogyria. While developmental delay is nearly universal in this syndrome it is variable in severity, with the majority having mild to moderate delays and a minority having severe cognitive impairment. Some patients are affected with a seizure disorder. White matter abnormalities on magnetic resonance imaging (MRI), suggesting a delay in white matter myelination, is commonly seen in early childhood. Some patients may have asymmetry of the brain, with one side being noticeably larger than the other. One interesting phenomenon that seems very common in this syndrome is the tendency for disproportionate brain growth in the first few years of life, with crossing of percentiles on the head circumference growth charts. A consequence of this disproportionate brain growth appears to be a significantly increased risk of cerebellar tonsillar herniation (descent of the cerebellar tonsils through the foramen magnum of the skull, resembling a Chiari I malformation neuroradiologically) and ventriculomegaly/hydrocephalus. Such cerebellar tonsil herniation may occur in up to 70% of children with M-CM.
The medical literature suggests that there is a risk of cardiac arrhythmias in early childhood. The cause for this is unknown. In addition, a variety of different congenital cardiac malformations have been reported in a small number of patients with this disorder.
Like other syndromes associated with disproportionate growth, there appears to be a slightly increased risk of certain types of childhood malignancies in M-CM (such as Wilms' tumor). However, the precise incidence of these malignancies is unclear.
There is no cure for this condition. Treatment is supportive and varies depending on how symptoms present and their severity. Some degree of developmental delay is expected in almost all cases of M-CM, so evaluation for early intervention or special education programs is appropriate. Rare cases have been reported with no discernible delay in academic or school abilities.
Physical therapy and orthopedic bracing can help young children with gross motor development. Occupational therapy or speech therapy may also assist with developmental delays. Attention from an orthopedic surgeon may be required for leg length discrepancy due to hemihyperplasia.
Children with hemihyperplasia are thought to have an elevated risk for certain types of cancers. Recently published management guidelines recommend regular abdominal ultrasounds up to age eight to detect Wilms' tumor. AFP testing to detect liver cancer is not recommended as there have been no reported cases of hepatoblastoma in M-CM patients.
Congenital abnormalities in the brain and progressive brain overgrowth can result in a variety of neurological problems that may require intervention. These include hydrocephalus, cerebellar tonsillar herniation (Chiari I), seizures and syringomyelia. These complications are not usually congenital, they develop over time often presenting complications in late infancy or early childhood, though they can become problems even later. Baseline brain and spinal cord MRI imaging with repeat scans at regular intervals is often prescribed to monitor the changes that result from progressive brain overgrowth.
Prognosis varies widely depending on severity of symptoms, degree of intellectual impairment, and associated complications. Because the syndrome is rare and so newly identified, there are no long term studies.
- Clayton-Smith J, Kerr B, Brunner H, Tranebjaerg L, Magee A, Hennekam RC et al. (1997). "Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome.". Clin Dysmorphol 6 (4): 291–302. PMID 9354837.
- Moore CA, Toriello HV, Abuelo DN, Bull MJ, Curry CJ, Hall BD et al. (1997). "Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities.". American Journal of Medical Genetics 70 (1): 67–73. doi:10.1002/(SICI)1096-8628(19970502)70:1<67::AID-AJMG13>3.0.CO;2-V. PMID 9129744.
- Toriello HV, Mulliken JB (2007). "Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM).". American Journal of Medical Genetics 143A (24): 3009. doi:10.1002/ajmg.a.31971. PMID 17963258.
- Mirzaa, GM.; Conway, RL.; Gripp, KW.; Lerman-Sagie, T.; Siegel, DH.; deVries, LS.; Lev, D.; Kramer, N. et al. (Feb 2012). "Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis.". American Journal of Medical Genetics 158A (2): 269–91. doi:10.1002/ajmg.a.34402. PMID 22228622.
- Rivière, JB.; Mirzaa, GM.; O'Roak, BJ.; Beddaoui, M.; Alcantara, D.; Conway, RL.; St-Onge, J.; Schwartzentruber, JA. et al. (2012). "De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes.". Nat Genet 44 (8): 934–40. doi:10.1038/ng.2331. PMID 22729224.
- Kurek, KC.; Luks, VL.; Ayturk, UM.; Alomari, AI.; Fishman, SJ.; Spencer, SA.; Mulliken, JB.; Bowen, ME. et al. (Jun 2012). "Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.". American Journal of Human Genetics 90 (6): 1108–15. doi:10.1016/j.ajhg.2012.05.006. PMID 22658544.
- Lee, JH.; Huynh, M.; Silhavy, JL.; Kim, S.; Dixon-Salazar, T.; Heiberg, A.; Scott, E.; Bafna, V. et al. (2012). "De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.". Nat Genet 44 (8): 941–5. doi:10.1038/ng.2329. PMID 22729223.
- Lindhurst, MJ.; Parker, VE.; Payne, F.; Sapp, JC.; Rudge, S.; Harris, J.; Witkowski, AM.; Zhang, Q. et al. (2012). "Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.". Nat Genet 44 (8): 928–33. doi:10.1038/ng.2332. PMID 22729222.
- Franceschini P, Licata D, Di Cara G, Guala A, Franceschini D, Genitori L (2000). "Macrocephaly-Cutis marmorata telangiectatica congenita without cutis marmorata?". American Journal of Medical Genetics 90 (4): 265–9. doi:10.1002/(SICI)1096-8628(20000214)90:4<265::AID-AJMG1>3.0.CO;2-S. PMID 10710221.
- Robertson SP, Gattas M, Rogers M, Adès LC (2000). "Macrocephaly--cutis marmorata telangiectatica congenita: report of five patients and a review of the literature.". Clin Dysmorphol 9 (1): 1–9. PMID 10649789.
- Conway RL, Pressman BD, Dobyns WB, Danielpour M, Lee J, Sanchez-Lara PA et al. (2007). "Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients.". American Journal of Medical Genetics 143A (24): 2981–3008. doi:10.1002/ajmg.a.32040. PMID 18000912.
- Yano S, Watanabe Y (2001). "Association of arrhythmia and sudden death in macrocephaly-cutis marmorata telangiectatica congenita syndrome.". American Journal of Medical Genetics 102 (2): 149–52. doi:10.1002/ajmg.1428. PMID 11477607.
- Kuint, J.; Globus, O.; Ben Simon, GJ.; Greenberger, S. "Macrocephaly-capillary malformation presenting with fetal arrhythmia.". Pediatr Dermatol 29 (3): 384–6. doi:10.1111/j.1525-1470.2011.01677.x. PMID 22329570.
- Erener Ercan, T.; Oztunc, F.; Celkan, T.; Bor, M.; Kizilkilic, O.; Vural, M.; Perk, Y.; Islak, C. et al. (Mar 2012). "Macrocephaly-Capillary Malformation Syndrome in a Newborn With Tetralogy of Fallot and Sagittal Sinus Thrombosis.". J Child Neurol 28 (1): 115–9. doi:10.1177/0883073812439346. PMID 22451530.
- Dueñas-Arias, JE.; Arámbula-Meraz, E.; Frías-Castro, LO.; Ramos-Payán, R.; Quibrera-Matienzo, JA.; Luque-Ortega, F.; Aguilar-Medina, EM. (Sep 2009). "Tetralogy of Fallot associated with macrocephaly-capillary malformation syndrome: a case report and review of the literature.". Journal of Medical Case Reports 3 (1): 9215. doi:10.4076/1752-1947-3-9215. PMC 2827170. PMID 20210980.