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Last updated: February 02, 2021
Years published: 2006, 2011, 2017, 2021
NORD gratefully acknowledges Ghayda Mirzaa, MD, FAAP, FACMG, Associate Professor of Pediatrics and Human Genetics, Seattle Childrenโs Hospital Research Institute, Center for Integrative Brain Science; Maria C. Garzon, MD, Professor of Clinical Dermatology and Clinical Pediatrics, Columbia University; William B. Dobyns, MD, Professor of Human Genetics, Neurology and Pediatrics, Department of Human Genetics, University of Chicago; and John M Graham, Jr., MD, ScD, Professor Emeritus of Pediatrics, Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, for assistance in the preparation of this report.
Summary
Megalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation, is a complex disorder that involves many organ systems including the skin, blood vessels, connective tissue, brain and others, and that usually manifests at birth. i. Most affected individuals have a disproportionately large head and vascular malformations including capillary malformations on the skin of the midline face, trunk and limbs. These capillary malformations often show a lacy or reticulated pattern (resembling a net or web, and are sometimes termed โcutis marmorataโ). Most children with MCAP have an enlarged brain (or megalencephaly) and other findings on brain MRI scans with associated neurological problems.
Introduction
Multiple terms have been used in the past for this syndrome. The earliest one was macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) because the vascular lesions were believed to be consistent with CMTC. However, careful examination of the skin in these children revealed that the vascular lesions are not CMTC but rather capillary malformations (described below), and so the syndrome was accurately renamed to โmacrocephaly-capillary malformation syndromeโ (or M-CM). Recently, the name was modified from this latter term to โmegalencephaly-capillary malformationโ (or MCAP, in short) because the term โmacrocephalyโ refers to a large head due various causes, whereas โmegalencephalyโ is a more specific and accurate term that refers to the truly enlarged brain present in this syndrome.
The symptoms and severity of MCAP vary greatly from one person to another. Some individuals may develop milder symptoms, while others have more serious complications and it is important to note that affected individuals may not have all of the symptoms discussed below. Families of affected children should talk to their physician and medical team about their specific features, associated symptoms and discuss their medical management and overall prognosis.
Growth abnormalities
The vast majority of infants born with MCAP have an abnormally large head (or megalencephaly) at birth that tends to be progressive, and maybe associated with a large body size at birth (i.e., somatic overgrowth or macrosomia). In most infants with body overgrowth birth, the overgrowth tends to either stay stable, decrease or normalize with age, and some may experience growth deficiency after birth. Infants and children may also display an asymmetric growth pattern, which ranges from one side of the body being clearly larger than the other (frank hemihypertrophy), to more subtle asymmetries of the body.
Vascular abnormalities
As newborns, children with MCAP have distinctive skin lesions that may be scattered over the trunk, limbs, and midline face. These skin findings are most often a specific type of vascular malformation known as capillary malformations. Capillaries are tiny blood vessels that form a fine network throughout the body connecting arteries and veins and are responsible for the exchange of various substances such as oxygen between cells and tissues. When abnormally widened (dilated) or malformed, these distinctive skin lesions appear. The most common location is the midline face (on the forehead, or above the upper lip), in which case the term nevus flammeus (or more commonly โSalmon patchโ) is used. These facial lesions occur in a significant number of healthy children. Therefore their presence alone does not establish the diagnosis of MCAP. And while they may fade as children with MCAP grow older, they can persist to variable degrees. Other commonly seen lesions include cutis marmorata, which are generalized capillary malformations that may range from subtle lesions resembling the common marbled appearance of the skin of Caucasian infants to more recognizable lesions that persist. Finally, some children have infantile hemangiomas that may occur anywhere on the body. These may also persist in some children and, rarely, occur in internal organs (e.g., liver, spleen as well).
Brain abnormalities
Besides megalencephaly, children with MCAP may develop abnormal widening of the sac-like spaces (ventricles) of the brain that contain cerebrospinal fluid (or ventriculomegaly). Excessive accumulation of fluid may lead to hydrocephalus, one of the potentially serious complications of this syndrome. Furthermore, enlargement and herniation of the cerebellar tonsils (or a Chiari malformation) may occur which may also lead to hydrocephalus and brainstem compression. Given these two potentially serious complications of this syndrome, it is recommended that children are regularly monitored for symptoms related to hydrocephalus and cerebellar tonsillar herniation, such as headaches, lethargy, breathing abnormalities, and recurrent vomiting.
Additional structural abnormalities of the brain have been reported in MCAP including cerebellar/cerebral asymmetry, abnormalities in the development of the cerebral cortex (cortical dysplasia), and white matter abnormalities. One particularly common type of cortical malformation in MCAP is polymicrogyria (PMG), which refers to abnormally small and numerous folds of the cortical surface. The corpus callosum (a midline structure that joins the two cerebral hemispheres) is usually twice as thick as normal.
Given all of these brain abnormalities, children with MCAP are at greater risk than the general population of developing associated neurological abnormalities including developmental delay and neurocognitive impairment (ranging from mild to severe), seizures and tone abnormalities.
Digital abnormalities and other physical features of MCAP syndrome
Infants with MCAP commonly have webbing of the digits (or syndactyly) that may involve the 2nd-3rd and 4th fingers or toes. Other physical abnormalities include a prominent forehead (frontal bossing), extra fingers and toes (polydactyly), loose (hyperelastic) skin, and loose joints (joint laxity). Secondary to abnormal growth, affected infants may also experience unequal development of the face and legs (facial and limb asymmetry). In rare cases, congenital heart defects, abnormal heart rhythms (arrhythmias), and genitourinary abnormalities may occur.
Most cases of MCAP are caused by variants in the PIK3CA gene. Most of the identified variants are not inherited, but occur in a fraction of cells as the baby develops (I.e., post-zygotic mutations). While there are reports of family members with large heads (or megalencephaly), recurrence in family members (e.g., siblings or parents) with MCAP have been reported in the medical literature. Advanced paternal age has been noted in some patients but this association is not proven.
The exact incidence of macrocephaly-capillary malformation is unknown. Since its first description as a distinct entity in 1997, more than 200 affected individuals have been reported. Some patients may go unrecognized or misdiagnosed making it difficult to determine the true frequency of MCAP in the general population. Males and females appear to be affected in equal numbers.
A diagnosis of macrocephaly-capillary malformation may be confirmed through a thorough clinical evaluation that includes a detailed history and physical examination looking for MCAP-associated features. Molecular diagnosis requires demonstration of a mosaic activating mutation in PIK3CA, which may require advanced genetic testing to be performed on affected tissues (e.g., skin fibroblasts) or samples other than blood. Different diagnostic criteria have been proposed in the medial literature.
Clinical Testing and Work-Up
Brain Imaging techniques such as magnetic resonance imaging (MRI) is recommended for all children with megalencephaly overall, and features of MCAP syndrome specifically. Furthermore, given the potential complications in MCAP (hydrocephalus and cerebellar tonsillar herniation), frequent MRI monitoring is recommended. While no standard recommendations exist regarding the frequency of imaging, an MRI scan every 6 months until 2-3 years of age may be reasonable. More frequent imaging maybe recommended if there are concerning signs or symptoms (such as very rapidly enlarging head size, rapidly progressive hydrocephalus and/or cerebellar tonsillar ectopia).
Treatment and surveillance of a child affected with MCAP may require the coordinated efforts of a team of specialists including a pediatrician, neurologist, developmental specialists, orthopedic surgeon, ophthalmologist, and, in some cases, neurosurgeon, dermatologist and other healthcare professionals who may need to systematically and comprehensively plan an affected childโs treatment.
Treatment will vary depending upon many factors including the presence and severity of specific abnormalities; an individualโs age and general health; and/or other elements. Decisions concerning the use of particular interventions should be made by physicians and other members of the health care team in careful consultation with the patient, based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks; patient preference; and other appropriate factors.
Hydrocephalus and cerebellar tonsillar ectopia warrant immediate attention and referral to a neurosurgeon. Rapidly progressive hydrocephalus may require neurosurgical shunting, and experience suggests that some patients benefit from a minimally-invasive 4th ventriculostomy. The guidelines for the management of cerebellar tonsillar ectopia are less clear. However surgical management (posterior fossa decompression) should be considered on a case-by-case basis and discussed with the neurologist and neurosurgeon involved in the childโs care. Seizures, if present, should be managed by a neurologist.
The vascular anomalies associated with MCAP, especially if few or small, may fade or disappear without treatment (i.e., undergo spontaneous remission) within the first few years of life. Some patients have undergone laser ablation therapy for lesions depending on their size, location and extent. The appropriate management of these vascular anomalies should therefore be discussed with childโs caring physicians.
Other therapies may include physiotherapy and occupational therapy as appropriate, and special education services.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Contact for additional information about megalencephaly-capillary malformation syndrome:
Ghayda Mirzaa, MD, FAAP, FACMG
Seattle Childrenโs Research Institute
Center for Integrative Brain Science
1900 Ninth Avenue Mailstop C9S-10
Seattle WA 98101
(206) 884-1276 office
(206) 884-1210 fax
[email protected]
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Lapunzina P, Clayton-Smith J. Macrocephaly-Cutis Marmorata Telangiectatica Congenita (Macrocephaly-Capillary Malformation). In: Neurocutaneous Disorders: Phakomatoses and Hamartoneoplastic Syndromes, Ruggieri M, Pascual Castroviejo I, Di Rocco C, editors. Springer-Verlag/Wien, New York, NY; 2008:323-332.
Cohen MMJr, Nori G, Weksberg R. Overgrowth syndromes. 1st ed. Oxford University Press, New York, NY; 2002:169-171.
JOURNAL ARTICLES
Mirzaa G, Timms A, Conti V, et al.: PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. Journal of Clinical Investigation Insight 2016 Jun 16;1(9).
Keppler-Noreuil KM, Sapp JC, Lindhurst MJ, et al.: Clinical delineation and natural history of PI3KCA โrelated overgrowth spectrum. American Journal of Medical Genetics, Part A 2014;164:1713-1733.
Riviere J-B, Mirzaa GM, OโRoak BJ, et al.: De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes, Nature Genetics 2012;44(8):934-40.
Martinez-Glez V, Romanelli V, Mori MA, et al. Macrocephaly-capillary malformation: analysis of 13 patients and review of the diagnostic criteria. Am J Med Genet. 2010;152A:3102-3106.
Gonzalez ME, Burk CJ, Barbouth DS, Connelly EA. Macrocephaly-capillary malformation: a report of three cases and review of the literature. Pediatr Dermatol. 2009;26:342-346.
Wright DR, Friedan IJ, Orlow SJ, et al. The misnomer โmacrocephaly-cutis marmorata telangiectasia congenita syndrome.โ Report of 12 new cases and support for revising the name to macrocephaly-capillary malformation. Arch Dermatol. 2009;145:287-293.
Gonzalez ME, Burk CJ, Barbouth DS, Connelly EA. Macrocephaly-capillary malformation: a report of three cases and review of the literature. Pediatr Dermatol. 2009;26:342-346.
Gripp KW, Hopkins E, Vinkler C, et al. Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly, polymicrogyria-polydactyly hydrocephalus syndromes. Am J Med Genet A. 2009;149:868-876.
Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations. Part II: associated syndromes. J Am Acad Dermatol. 2007;56:541-564.
Conway RL, Pressman BD, Dobyns WB, et al. Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients. Am J Med Genet A. 2007;143A;2981-3008.
Toriello HV, Mulliken JB. Accurately renaming macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) as macrocephaly-capillary malformation (M-CM). Am J Med Genet A. 2007;143A:3009.
Lapunzina P, Gairi A, Delicado A, et al. Macrocephaly-cutis marmorata telangiectatica congenita: report of six new patients and a review. Am J Med Genet A. 2004;130:45-51.
Garzon MC, Schweiger E. Cutis marmorata telangiectatica congenita. Semin Cutan Med Surg. 2004;23:99-106.
Giulino F, David A, Edery P, et al. Macrocephaly-cutis marmorata telangiectatica congenita: seven cases including two with unusual cerebral manifestations. Am J Med Genet A. 2004;126:99-103.
Magarbane A, Haddad J, Lyonnet S, et al. Child with overgrowth, pigmentary streaks, polydactyly, and intestinal lymphangiectasia: macrocephaly-cutis marmorata telangiectatica congenita syndrome or new disorder. Am J Med Genet A. 2003;116:184-87.
Robertson SP, Gattas M, Rogers M, et al. Macrocephaly-cutis marmorata telangiectatica congenita: report of five patients and a review of the literature. Clin Dysmorphol. 2000;9:1-9.
INTERNET
Mirzaa G, Conway R, Graham JM Jr, et al. PIK3CA-Related Segmental Overgrowth. 2013 Aug 15. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK153722/ Accessed Jan 25, 2021.
Garavelli L. Megalencephaly-capillary malformation syndrome. Orphanet. Last Update January 2020. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=60040 Accessed Jan 25, 2021.
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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