Macrocephaly capillary malformation syndrome

Macrocephaly capillary malformation syndrome also known as megalencephaly-capillary malformation syndrome (MCAP), macrocephaly cutis marmorata telangiectatica congenita, megalencephaly-capillary malformation-polymicrogyria syndrome or megalencephaly cutis marmorata telangiectatica congenita, is a rare complex disorder characterized by overgrowth of several tissues in the body such as the skin, connective tissue, brain and other organs that is usually present at birth. Macrocephaly capillary malformation syndrome’s primary features are a large brain (megalencephaly) and abnormalities of small blood vessels in the skin called capillaries (capillary malformations).

In individuals with macrocephaly capillary malformation syndrome, megalencephaly leads to an unusually large head size (macrocephaly), which is typically evident at birth. After birth, the brain and head continue to grow at a fast rate for the first few years of life; then, the growth slows to a normal rate, although the head remains larger than average. Additional brain abnormalities are common in people with macrocephaly capillary malformation syndrome; these can include excess fluid within the brain (hydrocephalus) and abnormalities in the brain’s structure, such as those known as Chiari malformation and polymicrogyria. Abnormal brain development leads to intellectual disability in most affected individuals and can also cause seizures or weak muscle tone (hypotonia). In particular, polymicrogyria is associated with speech delays and difficulty chewing and swallowing.

The capillary malformations characteristic of macrocephaly capillary malformation syndrome are composed of enlarged capillaries that increase blood flow near the surface of the skin. These malformations usually look like pink or red spots on the skin. In most affected individuals, capillary malformations occur on the midline face, particularly the forehead, the nose, the upper lip, and the area between the nose and upper lip (the philtrum), 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 macrocephaly capillary malformation syndrome. And while they may fade as children with macrocephaly capillary malformation syndrome grow older, they can persist to variable degrees.

In other people with macrocephaly capillary malformation syndrome, the capillary malformations appear as patches spread over the body or as a reddish net-like pattern on the skin called cutis marmorata. 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.

In some people with macrocephaly capillary malformation syndrome, excessive growth affects not only the brain but other individual parts of the body, which is known as segmental overgrowth. This can lead to one arm or leg that is bigger or longer than the other or a few oversized fingers or toes. Some affected individuals have fusion of the skin between two or more fingers or toes (cutaneous syndactyly).

Additional features of macrocephaly capillary malformation syndrome can include flexible joints and skin that stretches easily. Some affected individuals are said to have doughy skin because the tissue under the skin is unusually thick and soft.

The gene called PIK3CA involved in macrocephaly capillary malformation syndrome is also associated with several types of cancer. Only a small number of individuals with macrocephaly capillary malformation syndrome have developed tumors (in particular, a childhood form of kidney cancer known as Wilms tumor and noncancerous tumors in the nervous system known as meningiomas).

The prevalence of macrocephaly capillary malformation syndrome is unknown. At least 150 affected individuals have been reported in the medical literature ¹. Because the condition is often thought to be misdiagnosed or underdiagnosed, it may be more common than reported.

Macrocephaly capillary malformation syndrome appears to affect boys and girls equally and it is seen among all ethnicities. Macrocephaly capillary malformation syndrome occurs sporadically in families who have no other affected family members. While there have been under 300 reported cases of macrocephaly capillary malformation syndrome, there are likely many more affected individuals who have been misdiagnosed, are unrecognized or have not been published in the medical literature.

Macrocephaly capillary malformation syndrome causes

Macrocephaly capillary malformation syndrome is caused by mutations in the PIK3CA gene, which provides instructions for making the p110 alpha (p110α) protein. This protein is one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K), which plays a role in chemical signaling within cells. PI3K signaling is important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, and cell survival. These functions make PI3K important for the development of tissues throughout the body, including the brain and blood vessels.

PIK3CA gene mutations involved in macrocephaly capillary malformation syndrome alter the p110α protein. The altered subunit makes PI3K abnormally active, which allows cells to grow and divide continuously. Increased cell proliferation leads to the overgrowth of the brain, blood vessels, and other organs and tissues characteristic of macrocephaly capillary malformation syndrome.

Macrocephaly capillary malformation syndrome is one of several overgrowth syndromes, including Klippel-Trenaunay syndrome, that are caused by mutations in the PIK3CA gene. Together, these conditions are known as the PIK3CA-related overgrowth spectrum (PROS).

Macrocephaly capillary malformation syndrome inheritance pattern

Macrocephaly capillary malformation syndrome is not inherited from a parent and does not run in families. In people with macrocephaly capillary malformation syndrome, a PIK3CA gene mutation arises randomly in one cell during the early stages of development before birth. As cells continue to divide, some cells will have the mutation and other cells will not. This mixture of cells with and without a genetic mutation is known as mosaicism.

While there are reports of family members with large heads (macrocephaly), no family members (e.g., siblings or parents) with macrocephaly capillary malformation syndrome have been reported in the medical literature. Advanced paternal age has been noted in some patients ².

Macrocephaly capillary malformation syndrome symptoms

The symptoms and severity of macrocephaly capillary malformation syndrome vary greatly from one person to another. Macrocephaly capillary malformation syndrome symptoms are usually recognizable at birth. 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.

Megalencephaly is a major clinical feature (occipitofrontal circumference greater than or equal to 3 SD above the mean), which sometimes progresses to hydrocephaly, malformations of cortical development with polymicrogyria and cerebellar tonsillar herniation (Chiari malformation) ³. Cutaneous capillary anomalies are often scattered over the limbs, palms, soles and trunk, are frequently pink/red and are aggravated by crying and emotions. Facial dysmorphism is observed with frontal bossing, full cheeks, prominent lips and nevus flammeus of the nose and/or philtrum and upper lip.

There is a delay in speech and motor skills. Patients may present neurological symptoms, mainly neonatal hypotonia, and, less frequently, seizures. Additional clinical manifestations include prenatal overgrowth, limb asymmetry, joint laxity, soft skin and thick, ”doughy” subcutaneous tissue, postaxial polydactyly and/or syndactyly of toes 2-3 or fingers 3-4. Some patients develop neoplasias (risk of tumor development estimated at 2-3%). There is a slight increased risk for congenital heart defects and/or cardiac rhythm abnormalities.

Adult occipitofrontal circumferences range from +2 to +10 standard deviations (SDs) above the mean.

Growth abnormalities

Overgrowth is an important characteristic of macrocephaly capillary malformation. The vast majority of infants born with macrocephaly capillary malformation syndrome have an abnormally large head (or macrocephaly) at birth that tends to be progressive, and maybe associated with a large body size at birth (i.e. somatic overgrowth or macrosomia). Besides brain overgrowth, it manifests as prenatal macrosomia and hemihyperplasia. In most large infants at birth (prenatal macrosomia), however, the somatic overgrowth tends to decrease or fall back into the normal range over the first two years and continue to grow at a normal rate thereafter, 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.

Sometimes childrens’ growth falls below the normal curves. When this is due to feeding issues, modified diets or use of a g-tube may be recommended. Some children show signs of endocrine problems such as hypoglycemia or delayed bone age. These children should be evaluated by a pediatric endocrinologist. Some children with macrocephaly capillary malformation have been found to have a growth hormone deficiency.

Clinical trials looking at the risks and benefits of growth hormone therapy in patients with macrocephaly capillary malformation have not been done to date, nor are there any case reports describing the effects and outcomes of growth hormone therapy in any patients with macrocephaly capillary malformation. Not all patients with macrocephaly capillary malformation and a documented growth hormone deficiency have been prescribed growth hormone. Providers should keep in mind when considering growth hormone that there may be an increased tumor predisposition in the syndrome.

Hemihyperplasia or asymmetry is a common characteristic and an important clue to an macrocephaly capillary malformation diagnosis. The degree of asymmetry varies between affected individuals and typically remains proportionate throughout life. This means that the larger limb will remain larger, but will not continue to grow any faster than the rest of the body as children with macrocephaly capillary malformation get older.

Hemihyperplasia is not specific to macrocephaly capillary malformation – it may be seen in other overgrowth syndromes or as an isolated occurrence.

Brain abnormalities

Brain overgrowth and abnormalities are a primary characteristic and cause of complications in macrocephaly capillary malformation. Abnormally large head size is called macrocephaly. The main cause for a large head in macrocephaly capillary malformation is megalencephaly or large brain, although an additional problem such as hydrocephalus can make the head even larger.

Besides megalencephaly, children with macrocephaly capillary malformation syndrome may develop abnormal widening of the sac-like spaces (ventricles) of the brain that contain cerebrospinal fluid (ventriculomegaly). Ventriculomegaly or enlarged lateral ventricles, is commonly seen in macrocephaly capillary malformation and is a term sometimes used interchangeably with hydrocephalus. Ventriculomegaly can be a result of the overall enlargement of the brain in macrocephaly capillary malformation. When the enlargement is due to poor circulation of cerebrospinal fluid, and cerebrospinal fluid (CSF) accumulates causing increased pressure in the brain, hydrocephalus is present (one of the potentially serious complications of this syndrome). Furthermore, enlargement and cerebellar tonsillar herniation (Chiari malformation) may occur which may also lead to hydrocephalus and brainstem compression. As with the rest of the brain, the cerebellum tends to grow disproportionately faster in children with macrocephaly capillary malformation. The rate of brain growth is too fast for the skull to keep up and reshape iteslf. The cerebellum rests in a cavity at the back of the skull called the posterior fossa. The posterior fossa is a restricted space surrounded by bone and a flap of fibrous tissue at the top. As the cerebellum grows, it fills this confined space. When the cerebellum gets too big, the cerebellar tonsils protrude and herniate down through the foramen magnum leading to cerebellar tonsillar herniation. Therefore, cerebellar tonsillar herniation is typically acquired over time in macrocephaly capillary malformation as the brain grows and is why it may not be present in a newborn or in early infancy.

Cerebellar tonsilar herniation, regardless of the underlying cause, can lead to compression or pressure on the brainstem. The herniation can also cause reduced CSF flow through the foramen magnum leading to increased pressure within the brain. Not everyone will have symptoms, but important signs of brainstem compression include:

• seizures
• apnea
• difficulty controlling eye movements
• lethargy
• irritability
• headaches
• neck pain
• balance problems
• muscle weakness
• numbness
• tingling in arms or legs
• dizziness
• vision problems
• difficulty swallowing
• ringing or buzzing in the ears
• hearing loss
• vomiting
• insomnia
• changes in fine motor skills
• depression

Infants may have difficulty swallowing, irritability when fed, excessive drooling, a weak cry, gagging or vomiting, arm weakness, stiff neck, breathing problems and developmental delays. If a child has any of these or other concerning symptoms, it is important to seek medical care right away. If the signs are not recognized early and treated immediately, children can suffer severe complications including sudden death.

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.

Sometimes one side of the brain is larger than the other and malformed, a condition called hemimegalencephaly. If one side is larger but not malformed compared to the smaller side, this would be referred to as asymmetry. The terms hemimegalencephaly and brain asymmetry are often used interchangeably, but some feel this is not precise.

Additional structural abnormalities of the brain have been reported in macrocephaly capillary malformation syndrome 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 macrocephaly capillary malformation syndrome is polymicrogyria, 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 macrocephaly capillary malformation syndrome 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.

Other common neurological findings in macrocephaly capillary malformation include:

• Focal cortical dysplasia
• Polymicrogyria This finding is generally associated with abnormal brain functioning and can co-exist with cognitive disability and seizures.
• Abnormalities of the white matter which may represent delayed or abnormal myelination. Sometimes these changes can resemble a leukodystrophy. While these findings do not necessarily cause functional problems in macrocephaly capillary malformation, such white matter changes may suggest a process of abnormal brain maturation or even brain deterioriation in other disorders.
• Thick corpus callosum In macrocephaly capillary malformation, this structure appears larger than usual. It is unknown if this finding contributes to abnormal neurological functioning.
• Cavum septum pellucidum (CSP): While this is a relatively common finding in macrocephaly capillary malformation, cavum septum pellucidum does not appear to contribute to any neurological problems.
• Cavum septum vergae: Like cavum septum pellucidum (CSP), this finding does not appear to contribute to abnormal neurological functioning.
• Extra axial fluid collections By themselves, these do not necessarily cause any specific neurological problems.
• Thick optic nerve sheaths It is unclear why this occurs nor if it leads to any specific problems in macrocephaly capillary malformation. It appears to be a benign finding.

Most children with macrocephaly capillary malformation have hypotonia. Hypotonia can be caused by problems within the brain or muscle and is seen as part of many different conditions that affect muscle control. Hypotonia in macrocephaly capillary malformation is thought to be due to problems within the brain and is another factor that contributes to developmental delay in affected children. The hypotonia in macrocephaly capillary malformation often improves with age, however, underlying neurological problems can cause this to be an ongoing issue even in older children.

Skin abnormalities

As newborns, children with macrocephaly capillary malformation syndrome have distinctive skin lesions or birthmarks 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. One is a diffuse, vivid and purplish-red discoloration with poorly defined margins in an irregular or patchy distribution throughout the body. This presents in affected newborns and most often resembles a vivid type of cutis marmorata. This very distinctive skin finding is referred to as a capillary malformation. As isolated findings, capillary malformations are very common in normal newborn children. Lay terms used for such facial lesions include “stork’s bite” when it occurs on the nape of the neck or “angel kisses” when seen on the forehead or eyelid. They may be referred to by physicians or in the medical literature as “nevus flammeus” or “angiomata.” These findings may darken with crying or position changes.

In children with macrocephaly capillary malformation, this type of capillary malformation is often more dramatic and pronounced. As the child ages, the involved region fades to a pinkish-red, and with time the malformations can become even less apparent or be noticeable only when the child is cold or has a fever. Sometimes one side or part of the body may be more affected by these capillary malformations than another. In some children, there is a clear and abrupt demarcation of capillary malformations at the body’s midline. This is evidence that the genetic change that causes macrocephaly capillary malformation in the individual is mosaic (meaning the genetic change exists in some cells in the body but not others).

The capillary malformations in macrocephaly capillary malformation are sometimes incorrectly referred to as a port wine stain. While a port wine stain is a type of capillary malformation, it gets darker over time while the capillary malformations seen in macrocephaly capillary malformation fade with time. This skin finding in individuals with macrocephaly capillary malformation can be an alarming phyisical manifestation of the syndrome, but it in fact does not generally cause any discomfort or medical problems. A few children with a clinical diagnosis of macrocephaly capillary malformation have been reported who have no observed capillary malformations, suggesting that the vascular appearance of the skin can disappear completely with time in some individuals. It is not known if those reported cases ever had any vascular changes or if it was just a subtle finding at birth that faded with time.

The other notable newborn skin finding in macrocephaly capillary malformation includes a dark red birthmark frequently seen on the midline of the face, philtrum and/or upper lip. This birthmark is considered a midline capillary malformation. It can be mistaken as either a port wine stain or even a hemangioma (a kind of vascular tumor), but these terms would be incorrect as it remains flat and fades over time. When observed, these midline capillary malformations often prompt physicians to consider the diagnosis of macrocephaly capillary malformation. Other areas of the face that may have these anomalies in macrocephaly capillary malformation include the lower lip, eyelids, and forehead. For the most part, these facial capillary malformations seem to be only a cosmetic issue despite their alarming appearance and pose no additional health risks. While laser therapy to help reduce their visibility can be considered, the extent and location of the lesions along with the fact that they typically fade over time are all important factors for parents to consider when contemplating this treatment.

Early in its discovery, the skin changes of macrocephaly capillary malformation were felt to represent or closely resemble a condition called CMTC (cutis marmorata telangiectatica congenita) and information on cutis marmorata telangiectatica congenita is often encountered on internet searches for macrocephaly capillary malformation. In 2007, the name was changed from cutis marmorata telangiectatica congenita to macrocephaly capillary malformation to more accurately reflect the vascular abnormalities of the disorder. Cutis marmorata telangiectatica congenita is a rare condition that mainly affects the blood vessels of the skin. It is usually seen at birth or soon after and causes a purple marbling of the skin that looks like cutis marmorata but is much more pronounced. This marbling can be limited to only a certain part of the body or can be distributed over large areas (photo). While individuals with cutis marmorata telangiectatica congenita can have delays in development, they do not have the unique neurological problems or abnormalities of brain development seen in macrocephaly capillary malformation. In addition, whereas macrocephaly capillary malformation may have associated overgrowth of affected body parts (hemihyperplasia), cutis marmorata telangiectatica congenita more typically involves undergrowth (hypoplasia) of limbs or body parts affected by the vascular anomaly. While the vivid and diffuse vascular anomalies of macrocephaly capillary malformation may resemble cutis marmorata telangiectatica congenita, these conditions appear to be separate and distinct entities that have obvious differences and there is no evidence that there is a genetic or clinical association between the two conditions beyond the somewhat similar skin findings.

In summary, the vascular and skin findings in macrocephaly capillary malformation are complex and still quite poorly understood. An accurate description of an individual’s skin findings and vascular anomalies is important in providing appropriate diagnostic clues that will reduce the risk of a misdiagnosis. See more below regarding the vascular findings in macrocephaly capillary malformation.

Vascular abnormalities

The abnormal vascular malformations that manifest in the skin of individuals with macrocephaly capillary malformation can also be present deep within the body. Evidence suggests there is an increased risk of malformations of large vessels, such as the arteries or veins that bring blood to and away from the heart. This may correlate with the increased risk of congenital heart defects in this syndrome, since the development of these structures in fetal life is related.

Based on case reports, there appears to be an increased risk of strokes or thromboembolic events in individuals with macrocephaly capillary malformation, although this appears to be in the minority of cases. The literature suggests that these thrombotic events may affect blood vessels either in the brain or in other parts of the body. The exact reason for the increased risk of strokes in macrocephaly capillary malformation is unclear; it may relate to the abnormally formed blood vessels. Because strokes can cause serious or even life-threatening symptoms, it is important to address any symptoms of concern immediately. Signs and symptoms of a stroke affecting the brain include numbness in the face, arm or leg, confusion or difficulty speaking, unexplained dizziness, blurred vision, loss of balance, difficulty swallowing, headaches or even unconsciousness (similar to many of the symptoms described in brainstem compression). A logical approach to this concern could include prescribing a daily baby aspirin as a preventive therapy (as is done in patients who have risk of thromboembolic strokes for other reasons), however, there is no available information to suggest if this should be done on a routine basis for individuals with macrocephaly capillary malformation.

Digital abnormalities and other physical features of macrocephaly capillary malformation syndrome

Infants with macrocephaly capillary malformation syndrome commonly have webbing of the digits (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.

Connective tissue abnormalities

Children with macrocephaly capillary malformation can have connective tissue abnormalities affecting the skin and joints. Connective tissue is a scaffolding-type material that binds and supports the body. It helps make up tendons, joints, ligaments, bones and cartilage. There appears to be a connective tissue defect in macrocephaly capillary malformation. The skin often feels soft, doughy and may appear loose, as if it is too large for the body. Joints may be mildly loose or lax. Joint dislocations have been described at birth. The connective tissue aspects of macrocephaly capillary malformation are poorly understood and will hopefully be clarified over time.

Connective tissue abnormalities in macrocephaly capillary malformation likely contribute to an increased risk of hip dislocations at birth. Surgical intervention is sometimes necessary. While many of these orthopedic and connective tissue problems can contribute to developmental delays, it does not appear that there is long-term damage to the joints, although the information available about this is very limited.

Facial features

A number of unique facial features have been described in individuals with macrocephaly capillary malformation. Although it is difficult to articulate the subtle similarities among affected individuals, it is clear when looking at photos that children with macrocephaly capillary malformation look more like each other than members of their own families. The facial features of macrocephaly capillary malformation are not necessarily specific to the diagnosis, though a clinician with experience in the diagnosis may recognize a specific pattern of the facial features in macrocephaly capillary malformation more readily than another provider.

While the individual facial features can be highly variable, frontal bossing appears to be the most frequent and consistent finding among affected individuals. Other commonly reported characteristics include:

• Facial asymmetry
• Midline facial capillary malformations
• Full lips
• Everted lower lip
• Full cheeks
• Low-set ears
• Thick gums
• Large mouth
• Low or depressed nasal bridge
• Anteverted nostrils
• Overfolded superior helices (the outer fold of the ear)
• Thick, fleshy nose
• Large, fleshy ears or earlobes
• Long philtrum
• Deep-set eyes
• Hypertelorism (wide-spaced eyes)

Heart problems

A small percentage of children with macrocephaly capillary malformation are at risk for dysrhythmia and possible sudden death. The cause of this risk is not understood. It is unclear if this may be due to brain stem compression from brain overgrowth (see brain section) which affects the vagal nerve, or abnormally formed heart tissue. This risk seems greatest in younger children with macrocephaly capillary malformation and there appears to be less risk as they mature. Also, there appears to be an increased risk of congenital heart defects. Some reported abnormalities have included septal defects, Tetralogy of Fallot and coarctation of the aorta. The incidence of structural heart defects in macrocephaly capillary malformation is not known but it appears to be relatively uncommon, perhaps seen in 5-10% of affected individuals. Because the exact nature of the heart issues in macrocephaly capillary malformation remain unclear, a consultation with a pediatric cardiologist may be considered along with an electrocardiogram (EKG). A physician may also consider performing an echocardiogram specifically to look for structural defects, especially if a murmur is present.

Lungs problem

While the lungs themselves appear to be healthy in macrocephaly capillary malformation, there may be obstructive airway issues in this diagnosis. Collapse of the airway and/or voicebox due to inadequate support of the supporting cartilage within the airway is called tracheomalacia and laryngomalacia, respectively. These problems lead to partial airway collapse during breathing or postural changes that can cause a blockage of the airway.

This may sound like wheezing or stridor during normal breathing or sleep. Why this occurs in macrocephaly capillary malformation is not clear. It may be due to muscular hypotonia, the connective tissue problems of the condition, or a combination of factors. These problems are often seen in unaffected children as well. In otherwise normal children, typically the supportive cartilage in the airway grows with age, and the obstructive problems resolve on their own over time. However, the natural history of the pulmonary problems in macrocephaly capillary malformation are not well characterized.

To diagnose a problem with the airway, a pulmonary specialist may opt to do a scope to visualize the structure or dynamic function of the airway. For a child having respiratory or lung issues, a chest x-ray may also be ordered. It is important to be aware of possible underlying respiratory issues prior to any surgical intervention to prevent potential complications during sedation. There otherwise do not appear to be any other major lung concerns other than the potential for apnea in the case of brainstem compression.

Learning disabilities, delays and cognitive impairment

In addition to structural brain abnormalities, functional problems are seen in nearly all individuals with macrocephaly capillary malformation. Developmental disabilities are common and can range from mild, moderate to occasionally severe impairment. It appears that children with disorders of brain formation such as polymicrogyria and cortical dysplasia have more severe impairment; however, long-term studies have not been done to clarify this association.

Motor delays are common and influenced by multiple factors including loose joints, limb asymmetry, and a large head and body size. In typical cases, children learn to walk and talk, but at a later age than expected. Most children require special therapies including physical, occupational and speech. It is important for individuals with macrocephaly capillary malformation and their families to work closely with the resources in their area to ensure appropriate services are received.

It is anticipated that children with macrocephaly capillary malformation will have life-long disabilities. However, it is important to remember that ultimately each child will have his or her own developmental destiny. Children with macrocephaly capillary malformation should be afforded every opportunity to excel within their own limitations. Because there have been so few reported adult cases, it cannot be accurately predicted how delayed or functional children with macrocephaly capillary malformation will be as they mature.

In general, children with macrocephaly capillary malformation are social, happy and playful. They enjoy being part of their families and have meaningful interactions with parents, family and friends.

Based on available information, macrocephaly capillary malformation does not appear to be a condition associated with regression or decline in a person’s mental functioning. Children should be expected to make slow and steady progress developmentally; however, it should also be expected that they will be behind their peers to some degree. Autism is not a typical feature, but has been observed in some cases.

Macrocephaly capillary malformation syndrome cancer risks

Children with Beckwith-Wiedemann syndrome, another overgrowth syndrome associated with hemihyperplasia, have an increased risk for certain types of liver cancer (hepatoblastoma) and kidney cancer (Wilms tumor). While macrocephaly capillary malformation is an overgrowth condition, it is currently unclear if there is truly an increased risk of these cancers. In published reports, there have been two cases of individuals with macrocephaly capillary malformation who were later found to have a Wilms tumor. There have been no reported cases of hepatoblastoma.

The gene mutation that is now thought to cause macrocephaly capillary malformation, PIK3CA, is found mutated in cancer. Additionally, PIK3CA has recently been implicated in CLOVES syndrome, where a Wilms tumor risk has been more clearly demonstrated.

Researchers have recently made the recommendation to screen for Wilms tumor following the guidelines for Beckwith-Wiedemann syndrome: renal ultrasounds every 3 months to age 8 years. The AFP blood test indicated for Beckwith-Wiedemann syndrome to detect hepatoblastoma (liver cancer) is not recommended for macrocephaly capillary malformation patients at this time.

The medical literature for macrocephaly capillary malformation reports one case of leukemia and two of meningiomas (brain tumors).

Macrocephaly capillary malformation syndrome diagnosis

A diagnosis of macrocephaly capillary malformation syndrome is currently made based solely on clinical observations. Though not every affected individual has all features, commonly found signs include macrocephaly, congenital macrosomia, extensive cutaneous capillary malformations, body asymmetry, extra or fused fingers or toes, lax joints, doughy skin, variable developmental delays and other neurologic problems such as seizures and low muscle tone.

Four different diagnostic criteria have been proposed to diagnose macrocephaly capillary malformation and are described below. The first two criteria were developed prior to the name change to macrocephaly capillary malformation and refer to cutis marmorata or cutis marmorata telangiectatica congenita as key features of the condition.

Even with use of clinical diagnostic criteria, an individual’s entire clinical picture must be considered. Providers with personal expertise in evaluating those with macrocephaly capillary malformation and who have familiarity with the variability of the clinical diagnosis are poised to have greater success in making an accurate diagnosis.

Robertson criteria

The first author to propose diagnostic criteria for macrocephaly capillary malformation was Robertson et al. in 2000. This criteria suggested that a diagnosis of macrocephaly capillary malformation could be made in an individual if they had congenital macrocephaly AND cutis marmorata telangiectatica congenita with at least FOUR of the following features:

• Newborn hypotonia
• Developmental delay
• Connective tissue defect (joint laxity, soft skin)
• Frontal bossing
• Midline facial nevus flammeus (capillary malformation)
• Toe syndactyly
• Segmental overgrowth (hemihyperplasia)
• Hydrocephalus

Franceschini criteria

Shortly after the Robertson criteria were published, Franceschini et al. reported two cases of macrocephaly capillary malformation in whom the characteristic vascular changes of the skin faded over time. This was the first paper to clearly make this observation. Franceschini felt that the presence or absence of cutis marmorata telangiectatica congenita/capillary malformation was not necessarily required to make a confident diagnosis since in some affected individuals, this finding was age-dependent and might resolve with time. Therefore, Franceeschini’s criteria stipulated that a diagnosis of macrocephaly capillary malformation should be considered in an individual who has macrocephaly AND at least TWO of the following features:

• Overgrowth
• Cutis marmorata telangiectatica congenita
• Angiomata
• Polydactyly/syndactyly
• Facial and limb asymmetry

Wright criteria

The third criteria presented by Wright et al. in 2009 presented a modification of the two aforementioned criteria and basically combined aspects of both into a new proposed method of diagnosing macrocephaly capillary malformation. These authors retained the combination of macrocephaly AND capillary malformation(s) occurring anywhere on the body as mandatory features with the required presence of a specific number of minor features similar to those proposed by Robertson. However, Wright’s criteria are less restrictive than those of Robertson and they state an individual must have at least TWO of the following in addition to the previously mentioned mandatory features:

• Growth asymmetry
• Developmental delay
• Midline facial capillary malformation
• Neonatal hypotonia
• Syndacytyly/polydactyly
• Frontal bossing
• Joint hypermobility/hyperelastic skin
• Hydrocephalus

Martinez-Glez criteria

A fourth diagnostic criteria was proposed in 2010 by Martinez-Glez et al. and suggests the presence of at least 3 major and two minor criteria. This criteria takes into account the fact that abnormalities on neuroimaging are extremely common in macrocephaly capillary malformation and represent a recognizable pattern of abnormalities:

Major (at least 3)

• Macrocephaly
• Capillary malformation(s)
• Overgrowth/asymmetry
• Neuroimaging alterations
• Ventriculomegaly
• Cavum septum pellucidum or cavum septum vergae
• Frontal bossing
• Cerebellar tonsillar herniation
• Cerebral and or cerebellar asymmetry

Minor (at least 2)

• Developmental delay
• Midline capillary malformation
• Neonatal hypotonia
• Syndactyly/polydactyly
• Connective tissue abnormalities
• Frontal bossing
• Hydrocephalus

Unlike the three prior proposed criteria, the paper published by Martinez-Glez et al. is unique in that the authors attempted to test their criteria against previously reported cases to demonstrate its ability to make an accurate clinical diagnosis of macrocephaly capillary malformation. The authors were able to diagnose 94% of 136 previously reported cases of macrocephaly capillary malformation using their criteria. This suggests that to date, it may be the best set of clinical criteria available to aid in the diagnosis of macrocephaly capillary malformation.

Macrocephaly capillary malformation syndrome treatment

Treatment and surveillance of a child affected with macrocephaly capillary malformation syndrome 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.

Newly published management guidelines ⁴ call for a baseline brain and spine MRI at time of diagnosis, then every 6 months from 0-2 years and every year from 2-6 years with more frequent imaging if particular concerns arise. By age six, the rapid increase in head circumference has slowed and the concerns with the growth of the cerebellum decrease. Imaging beyond age 6 years should depend on previous findings and clinical course.

Management Guidelines summarized ⁴:

• Clinic evaluations no less than every 6 months for the first ~6 years of life, and at least yearly thereafter. Special attention should be paid to a possible elevated risk of cancer and neurological symptoms. Follow up testing should be administered for any positive symptoms reported or exam findings.
• Baseline brain and spinal cord MRI imaging at the time of diagnosis. Repeat brain MRI every 6 months from 0-2 years and every year from 2-6 years. The need for imaging in older patients depends on prior findings and clinical course.
• Kidney cancer (Wilms tumor) screening following the guidelines for Beckwith-Wiedemann syndrome: renal ultrasounds every 3 months to age 8 years. The AFP blood test indicated for
• Beckwith-Wiedemann syndrome to detect hepatoblastoma (liver cancer) is not recommended at this time — there have been no reported cases in macrocephaly capillary malformation syndrome.
• Baseline echocardiogram and electrocardiogram with a pediatric cardiologist to evaluate for cardiovascular malformations and rhythm abnormalities.
• Baseline thrombophilia evaluation.

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.

Placing a ventriculperitoneal (VP) shunt does not completely correct the macrocephaly in affected individuals because the primary cause of macrocephaly in macrocephaly capillary malformation is brain overgrowth. It may reduce the degree of macrocephaly and may over time slow the rate in which the head enlarges in some, but not all affected individuals. Some have also treated hydrocephalus successfully with an endoscopic third ventriculostomy. This procedure eliminates the need for placement of foreign objects such as the tubing required in ventriculperitoneal shunting, thus theoretically reducing complications after surgery. However, there is no clear consensus on the best surgical treatment for hydrocephalus in macrocephaly capillary malformation. macrocephaly capillary malformation patients with both endoscopic third ventriculostomy and ventriculperitoneal shunt have required revisions.

The vascular anomalies associated with macrocephaly capillary malformation syndrome, 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.

When extreme brain overgrowth and cerebellar tonsillar herniation cause symptoms of brainstem compression, some macrocephaly capillary malformation patients have been successfully treated with a procedure called a posterior fossa decompression. This procedure surgically enlarges the opening at the base of the skull, allowing the cerebellum to grow in a space that can now accommodate its size. The goal of this procedure is to resolve or prevent symptoms due to brainstem compression.

The presence of cerebellar tonsillar herniation increases the risk of syringomyelia, a condition where a cyst, called a syrinx, forms on the spinal cord. A syrinx can be detected via spinal MRI. This condition requires monitoring and sometimes surgical management.

Many individuals who have cerebellar tonsillar herniation, an overgrown cerebellum, and enlarged ventricles will require neurosurgery at some point. The timing and type of intervention is a delicate matter and is best determined on a case-by-case basis. Neurosurgical options are dependent upon a number of factors including the severity of the brain abnormalities, the opinions of physicians directly involved in that person’s care as well as symptoms.

Orthopedic issues in macrocephaly capillary malformation are related to limb asymmetry and loose joints. Some may benefit from physical therapy or even leg or ankle braces if there is significant weakness or looseness in the ankles. A shoe lift can also help to alleviate problems if one leg is longer than the other. In some cases, a surgical procedure called an epiphysealysis has been performed to stop the growth plates from growing in the larger leg.

Other therapies may include physiotherapy and occupational therapy as appropriate, and special education services.

Macrocephaly capillary malformation syndrome prognosis

Prognosis depends on the severity of symptoms. Early death, due to complex cardiac heart disease and arrhythmia, has been reported in rare occasions.

References

1. Megalencephaly-capillary malformation syndrome. https://ghr.nlm.nih.gov/condition/megalencephaly-capillary-malformation-syndrome
2. Megalencephaly-Capillary Malformation. https://rarediseases.org/rare-diseases/megalencephaly-capillary-malformation
3. Megalencephaly-capillary malformation syndrome. https://rarediseases.info.nih.gov/diseases/6950/megalencephaly-capillary-malformation-syndrome
4. Rivière JB, Mirzaa GM, O’Roak BJ, et al. De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet. 2012;44(8):934-940. Published 2012 Jun 24. doi:10.1038/ng.2331 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408813