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Copyright 2006, 2011
NORD is very grateful to Ghayda Mirzaa, MD, Acting Clinical Instructor/Molecular Genetics Fellow, Department of Human Genetics, University of Chicago; Maria C. Garzon, MD, Professor of Clinical Dermatology and Clinical Pediatrics, Columbia University; and William B. Dobyns, MD, Professor of Human Genetics, Neurology and Pediatrics, Department of Human Genetics, University of Chicago, for assistance in the preparation of this report.
Megalencephaly-capillary malformation syndrome (MCAP), formerly known as macrocephaly-capillary malformation, is a rare, complex disorder involving the skin, connective tissue, brain and other organs that is usually present at birth. Affected individuals have a disproportionately large head and 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 "cutis marmorata"). Most children with MCAP have an enlarged brain (or megalencephaly), in addition to other findings on brain MRI associated with neurologic problems.
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 mistakenly 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 "macrocephaly-capillary malformation syndrome" (or M-CM). Recently, the name was modified from this latter term to "megalencephaly-capillary malformation" (or MCAP, in short) because the term "macrocephaly" refers to a large head due various causes, whereas "megalencephaly" 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.
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 macorsomia). In most large infants at birth, however, the somatic overgrowth tends to decrease or normalize with age, and some may experience growth deficiency after birth (postnatally). 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.
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 "Salmon patch") 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 persist to variable degrees in some. 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 locations as well.
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.
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.
The exact cause of macrocephaly-capillary malformation is unknown. Most cases occur randomly, for no apparent reason (spontaneously). While there are reports of family members with large heads (or megalencephaly), no family members (e.g., siblings or parents) with MCAP have been reported in the medical literature. Advanced paternal age has been noted in some cases.
The exact incidence of macrocephaly-capillary malformation is unknown. Since its first description as a distinct entity in 1997, more than 140 cases 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.
Symptoms of the following disorders can be similar to those of MCAP syndrome. Comparisons may be useful for a differential diagnosis.
Cutis marmorata telangiectatica congenita syndrome (CMTC) is a rare type of vascular malformation composed predominantly of capillary and vein-sized vessels within the skin. The skin lesions are characterized by a lace-like vascular pattern that are often pink-purple in color and may involve a limited or more widespread area of the skin surface. As a result, the skin has a purple or blue marbled or "fishnet" appearance resembling cutis marmorata. In some affected individuals, thinning of the skin (atrophy), breakdown (ulceration) or complete absence of the skin in affected areas may also be present. From 27 to 50 percent (see references) of affected individuals have additional associated abnormalities including pink or dark red, irregularly shaped patches of skin (capillary malformation, port wine stain, nevus flammeus); loss of muscle tissue (wasting) on one side of the body (hemiatrophy); elevated fluid pressure within the eye (glaucoma); and/or reduced growth of one leg. (For more information on this disorder, choose "cutis marmorata telangiectasia congenita syndrome" as your search term in the Rare Disease Database.)
Klippel-Trenaunay syndrome, a rare disorder that is present at birth (congenital), is characterized by the presence of a capillary vascular malformation (port wine stain) on the skin of an arm or leg (cutaneous) occurring in association with) excessive growth (hypertrophy) of the soft tissue and bone of that leg and/or arm (limb), and varicose veins (venous malformations). Some affected individuals will also have an underlying lymphatic malformation of the affected limb. In individuals with the disorder, such hypertrophy typically affects one limb or one side of the body (hemihypertrophy). The symptoms and findings associated with the disorder may vary in range and severity from case to case. (For more information on this disorder, choose "Klippel-Trenaunay" as your search term in the Rare Disease Database.)
Megalencephaly polymicrogyria-polydactyly hydrocephalus (MPPH) syndrome is a rare disorder characterized by an abnormally large brain (megalencephaly), extra fingers or toes (polydactyly), the accumulation of excessive cerebrospinal fluid in the skull (hydrocephalus), and polymicrogyria, a condition in which the brain has too many folds or ridges that are also abnormally small. The symptoms of MPPH syndrome show great overlap with macrocephaly-capillary malformation and one report in the medical literature suggested that the two disorders may actually be different expressions of one disease spectrum. The exact relationship between macrocephaly-capillary malformation and MPPH (if any) is not fully understood. The exact cause of MPPH syndrome is unknown.
Additional disorders may have symptoms and physical findings that are similar to macrocephaly-capillary malformation including Sturge-Weber syndrome, Beckwith-Wiedemann syndrome, PTEN hamartoma syndrome, Proteus syndrome, Costello syndrome, Sotos syndrome and CLOVE syndrome. These disorders usually have additional findings that distinguish them from macrocephaly-capillary malformation. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
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. Different diagnostic criteria have been proposed in the medial literature. Recent investigations suggest that diagnosis before birth (antenatal) is reliable.
Clinical Testing and Work-Up
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 month 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 child's treatment.
Treatment will vary depending upon many factors including the presence and severity of specific abnormalities; an individual's 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 child's 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 child's 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:
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For information about clinical trials sponsored by private sources, in the main, contact:
Contact for additional information about megalencephaly-capillary malformation:
Ghayda Mirzaa, MD, FAAP, FACMG
Seattle Children's Research Institute
Center for Integrative Brain Science
1900 Ninth Avenue Mailstop C9S-10
Seattle WA 98101
(206) 884-1276 office
(206) 884-1210 fax
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FROM THE INTERNET
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Report last updated: 2011/12/08 00:00:00 GMT+0