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PIK3CA-Related Segmental Overgrowth

, MD, FAAP, FACMG, , MD, , MD, ScD, and , MD.

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Estimated reading time: 37 minutes

Summary

Clinical characteristics.

PIK3CA-associated segmental overgrowth includes disorders of brain (e.g., MCAP [megalencephaly-capillary malformation] syndrome, hemimegalencephaly); and segmental body overgrowth (e.g., CLOVES [congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies] syndrome, fibroadipose hyperplasia [FH]). Heterozygous (usually somatic mosaic) pathogenic variants of PIK3CA are causative.

MCAP syndrome is characterized by the major findings of (1) megalencephaly (MEG) or hemimegalencephaly (HMEG) associated with neurologic findings of hypotonia, seizures, and mild to severe intellectual disability; and (2) cutaneous capillary malformations with focal or generalized somatic overgrowth. Additional findings can include digital anomalies (syndactyly, polydactyly), cortical malformations – most distinctively polymicrogyria (PMG); and variable connective tissue dysplasia.

CLOVES (or CLOVE) syndrome and fibroadipose hyperplasia (FH) may be associated with (1) MEG or HMEG; and (2) patchy segmental overgrowth associated with skeletal anomalies, lipomatosis, vascular malformations, and epidermal nevi.

Diagnosis/testing.

PIK3CA-associated segmental overgrowth is confirmed in an individual with a pathogenic variant on one PIK3CA allele, typically in affected tissues. Because the vast majority of PIK3CA pathogenic variants arise postzygotic (and are thus mosaic), more than one tissue may need to be tested. Failure to detect a PIK3CA pathogenic variant does not exclude a clinical diagnosis of the PIK3CA-associated segmental overgrowth disorders in individuals with suggestive features.

Management.

Treatment of manifestations: Significant or lipomatous segmental overgrowth may require debulking; scoliosis and leg-length discrepancy may require orthopedic care and surgical intervention. Neurologic complications (e.g., obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsillar ectopia or Chiari malformation; epilepsy in those with HMEG) may warrant neurosurgical intervention. Routine treatment of the following, when present, is indicated: cardiac and renal abnormalities; intellectual disabilities and behavior problems; motor difficulties; speech, swallowing, and feeding difficulties.

Surveillance:

  • MCAP syndrome: Follow up no less than every six months until age six years and at least yearly thereafter to monitor for neurosurgical complications, breathing or sleep disorders, seizures and orthopedic complications. Provisionally recommended imaging in early childhood includes brain MRI every six months for the first two years, then yearly until age eight years for neurologic complications (e.g., hydrocephalus, cerebellar tonsillar ectopia). Consider screening for Wilms tumor following the protocol suggested for Beckwith-Wiedemann syndrome (BWS) (by ultrasound examination every 3 months until age 8 years); however, tumor risk in PIK3CA-related segmental overgrowth is undetermined and appears to be lower than in BWS.
  • CLOVES syndrome and FH: Monitoring for severe scoliosis, infiltrative lipomatous overgrowth, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems, central phlebectasias, and thromboembolism.

Genetic counseling.

PIK3CA-associated segmental overgrowth is not typically inherited. Most affected individuals with MCAP reported to date (21/24) had somatic mosaicism for pathogenic variants in PIK3CA, suggesting that mutation occurred post-fertilization in one cell of the multicellular embryo. Two of 24 affected individuals had a de novo germline pathogenic variant in PIK3CA. All reported individuals with CLOVES and FH had somatic mosaicism for pathogenic variants in PIK3CA. No confirmed instances of vertical transmission or sib recurrence have been reported. Because family members are not known to have an increased risk, prenatal diagnosis is usually not indicated for family members.

GeneReview Scope

PIK3CA-Related Segmental Overgrowth: Included Phenotypes 1
  • CLOVES syndrome
  • Megalencephaly-capillary malformation syndrome (MCAP syndrome)
  • Fibroadipose hyperplasia
  • Hemimegalencephaly

For synonyms and outdated names see Nomenclature.

1.

For other genetic causes of these phenotypes see Differential Diagnosis.

Diagnosis

PIK3CA-associated segmental overgrowth includes brain (e.g., megalencephaly-capillary [MCAP] malformation syndrome, hemimegalencephaly) and segmental body overgrowth (e.g., CLOVES syndrome, fibroadipose hyperplasia [FH]) caused by heterozygous (usually somatic mosaic) PIK3CA pathogenic variants.

Suggestive Findings

PIK3CA-associated segmental overgrowth is suspected in an individual with clinical features of the following syndromes. Of note, some individuals with low-level mosaicism for PIK3CA somatic pathogenic variants may have phenotypes that do not meet clinical diagnostic criteria.

Megalencephaly-capillary malformation (MCAP) syndrome (Table 1) (Figure 1 and Figure 2) is characterized by the major findings (1) megalencephaly (MEG) (Figure 3) or hemimegalencephaly (HMEG) associated with abnormalities of muscle tone, seizures, and mild to severe intellectual disability, and (2) cutaneous capillary malformations with focal or generalized somatic overgrowth. Additional findings can include digital anomalies consisting of syndactyly and polydactyly; cortical malformations, most distinctively polymicrogyria (PMG) (Figure 3); and variable connective tissue dysplasia [Franceschini et al 2000, Robertson et al 2000, Giuliano et al 2004, Lapunzina et al 2004, Wright et al 2009, Martínez-Glez et al 2010, Mirzaa et al 2012].

Figure 1. . Features of MCAP syndrome.

Figure 1.

Features of MCAP syndrome. Photographs of an individual with MCAP syndrome demonstrating the apparent macrocephaly with prominent forehead (D); extensive capillary malformations (A-F1); bilateral 2-3-4 toe syndactyly (G,H); 3-4 finger syndactyly (F1,F2); (more...)

Figure 2. . Features of MCAP syndrome.

Figure 2.

Features of MCAP syndrome. A boy age 40 months with MCAP syndrome (left) and his unaffected twin sister (right). Note left-sided hemihypertrophy, typical facial features, bilateral 2-3 toe syndactyly, and connective tissue dysplasia with loose redundant (more...)

Figure 3. . Characteristic brain MRI of MCAP syndrome in three individuals (A-D, E-H, and I-L).

Figure 3.

Characteristic brain MRI of MCAP syndrome in three individuals (A-D, E-H, and I-L). Note: Megalencephaly with a prominent forehead (A, E, I); cerebellar tonsillar ectopia with a large cerebellum and crowded posterior fossa (A, E, I); ventriculomegaly (more...)

Hemimegalencephaly (HMEG) is characterized by partial or complete enlargement and dysplasia of a cerebral hemisphere, often with variable contralateral involvement. Complex abnormalities (typically noted on brain imaging) include cortical dysgenesis, abnormally increased white matter, and dilated and dysmorphic lateral ventricles [Barkovich & Chuang 1990, Flores-Sarnat 2002, Flores-Sarnat et al 2003].

Table 1.

Findings in MCAP Syndrome

Finding
MajorSupportiveSecondary
Early segmental
overgrowth
(brain > somatic
tissues)
Progressive megalencephaly (MEG) or hemimegalencephaly (HMEG) 1Ventriculomegaly or hydrocephalus
Cerebellar tonsillar ectopia or Chiari malformation
Abnormally thick (mega-) corpus callosum
Congenital somatic overgrowth (generalized/focal)
Somatic or cranial asymmetry
Hypotonia
Developmental delay
Distinctive facial features:
  • Frontal bossing
  • Dolichocephaly
Developmental
vascular
disorders
(abnormal
vasculogenesis)
Cutaneous capillary malformations: 1
  • Midline face (esp. persistent nevus flammeus)
  • Body: widespread (or rarely vivid cutis marmorata)
Venous aneurysms/prominent venous pattern
Aberrant vasculature/vascular rings
Digital anomaliesSyndactyly (2-3, 3-4, 2-3-4):
  • Toes: 2-3 > others
  • Fingers: 3-4 > others
Postaxial polydactyly
Polysyndactyly
Sandal-gap toes
Cortical brain
malformations
Polymicrogyria (PMG)Seizures
Developmental delay
Connective tissue
dysplasia
Skin hyperelasticity
Joint hypermobility
Thick, soft, (or “doughy”) subcutaneous tissue
Hypotonia
Gross developmental delay
1.

MCAP syndrome can be diagnosed based on clinical findings in individuals with classic features of MEG or HMEG (major finding 1) and characteristic capillary malformations (major finding 2).

CLOVES (or CLOVE) syndrome and fibroadipose hyperplasia (Table 2) may be associated with MEG or HMEG, and thus overlap with MCAP syndrome [Gucev et al 2008]. Findings include patchy segmental overgrowth associated with skeletal anomalies, lipomatosis, vascular malformations, and epidermal nevi. Given the clinical and molecular genetic overlap between CLOVES syndrome and fibroadipose hyperplasia, these two conditions may constitute a single large spectrum of somatic overgrowth.

CLOVES syndrome is characterized by congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies. CLOVES syndrome differs from MCAP syndrome by more striking growth dysregulation with complex congenital overgrowth of lipomatous tissues (typically manifest as a truncal lipomatous mass) and combined lymphatic and vascular malformations (Figure 4A). Skeletal anomalies include scoliosis, wide hands and feet, macrodactyly (Figure 4B), and prominent sandal-gap toes [Sapp et al 2007, Alomari 2009a].

Figure 4.

Figure 4.

Features of CLOVES syndrome in a child with (A) a large lipomatous truncal mass that extends into the surrounding tissues and an overlying capillary malformation and (B) macrodactyly of the left foot

Fibroadipose hyperplasia, a severe overgrowth syndrome recently described in ten individuals with mosaic PIK3CA pathogenic variants [Lindhurst et al 2012], is characterized by progressive segmental overgrowth of visceral, subcutaneous, muscular, fibroadipose, and skeletal tissues, and may involve the trunk or extremities. Other variable features include lipomatous infiltration of muscle, progressive adipose dysregulation and regional lipohypoplasia, vascular malformations, testicular abnormalities, and polydactyly.

Table 2.

Classic Features of CLOVES Syndrome and Fibroadipose Hyperplasia (FH)

FeatureCLOVES SyndromeFibroadipose Hyperplasia (FH) 1
OvergrowthLipomatous overgrowth (typically truncal, complex, congenital, progressive)
Spinal-paraspinal extension
Limb & digital overgrowth
Bony overgrowth, leg-length discrepancy
Visceral, subcutaneous, muscular fibroadipose, & skeletal tissues (congenital, progressive; may involve trunk or extremities)
Lipomatous infiltration of muscle (in 6/10)
Disproportionate linear overgrowth (in 10/10)
Cutaneous &
vascular
malformations
Low-flow (capillary, venous, lymphatic; typically overlying truncal overgrowth)
High-flow (arteriovenous; esp. spinal-paraspinal)
Venous thrombosis/embolism
Epidermal nevi (single/multiple)
Vascular malformation (in 2/10)
Epidermal nevi (in 2/10)
Musculoskeletal
/ acral
abnormalities
Scoliosis
Chondromalacia patellae
Dislocated knees
Macrodactyly, wide hands/feet
Sandal gap toes
Symmetric overgrowth feet
Plantar-palmar overgrowth
Progressive skeletal overgrowth (preserved architecture)
Polydactyly
Visceral
abnormalities
Renal agenesis/hypoplasia
Splenic lesions
Testicular or epididymal cysts and hydrocele (in 3/10)
Non-spleen/thymus visceral overgrowth (in 1/10)
Neurologic
abnormalities
Neural tube defect
Tethered cord
Megalencephaly/hemimegalencephaly
Chiari malformation
Polymicrogyria
OtherRegional lipohypoplasia, progressive adipose dysregulation
1.

Features variably identified in ten affected individuals

Establishing the Diagnosis

PIK3CA-associated segmental overgrowth is confirmed in an individual with a pathogenic variant on one PIK3CA allele who meets clinical criteria. In an individual with ambiguous or mild clinical findings [Kurek et al 2012, Lindhurst et al 2012, Rivière et al 2012] (Table 3), identification of a PIK3CA pathogenic variant establishes the diagnosis of PIK3CA-associated segmental overgrowth.

Because the vast majority of reported PIK3CA pathogenic variants are postzygotic (and thus mosaic), more than one tissue may need to be tested.

  • Experience suggests that sequence analysis of DNA derived from saliva or skin (whether visibly affected or not) has a higher detection rate than of peripheral blood-derived DNA.
  • In highly focal disorders such as HMEG, CLOVES, and fibroadipose hyperplasia, pathogenic variants are only detectable in affected tissues. Therefore, absence of a pathogenic variant in a DNA sample is insufficient to exclude the diagnosis [Kurek et al 2012, Lee et al 2012, Lindhurst et al 2012].
  • Failure to detect a PIK3CA pathogenic variant does not exclude a clinical diagnosis of PIK3CA-associated segmental overgrowth disorders in individuals with suggestive features, given that low-level mosaicism is observed in many individuals. Furthermore, locus heterogeneity is a possibility (see Differential Diagnosis).
  • Sensitivity to detect low-level mosaicism of a PIK3CA pathogenic variant is theoretically greatest using massively parallel sequencing (also known as next-generation sequencing) in tissues other than blood, and in particular will be of high yield when analyzing affected tissues in disorders other than MCAP syndrome.

Table 3.

Summary of Molecular Genetic Testing Used in PIK3CA-associated Segmental Overgrowth

Gene 1Test MethodVariants Detected 2Pathogenic Variant Detection Frequency by Test Method 3
PIK3CASequence analysis 4Sequence variants 5Dependent on phenotype, tissue analyzed, and method 6, 7, 8
1.
2.

See Molecular Genetics for information on allelic variants.

3.

The ability of the test method used to detect a variant that is present in the indicated gene

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Most identified PIK3CA pathogenic variants to date are missense, with only a single in-frame 3-bp deletion identified in MCAP syndrome [Rivière et al 2012]. No nonsense or splice site variants, large deletions, or duplications involving PIK3CA have been identified to date.

6.

For MCAP syndrome: 21/24 individuals had somatic mosaicism for a PIK3CA pathogenic variant; 2/24 had a de novo PIK3CA germline variant; and 1/24 had inconclusive results with only one sample available for testing [Rivière et al 2012]. The level of mosaicism varied by the tissue being tested and ranged from 1% to 48%. In individuals in whom three or more tissues were analyzed, blood was the tissue in which the lowest level of mosaicism was observed [Rivière et al 2012]. The level of mosaicism was below 25% in 15 of 18 (83%) samples of blood-derived DNA and in 11 of 22 (45%) samples of saliva- or skin-derived DNA. Detection of these pathogenic variants was facilitated by massively parallel sequencing and would likely have been missed by standard Sanger sequence analysis.

7.

For CLOVES, FH, HMEG: Pathogenic variants were identified in affected tissues (including brain in hemimegalencephaly) with mutated allele frequencies ranging from 1% to 49% overall. The pathogenic variants were not identified in DNA derived from blood (or, in some studies, from either blood or saliva) [Kurek et al 2012, Lee et al 2012, Lindhurst et al 2012].

8.

For HMEG: The same PIK3CA pathogenic variant (c.1633G>A) was identified in four brain samples of affected individuals.

Clinical Characteristics

Clinical Description

PIK3CA-associated segmental overgrowth includes disorders of brain overgrowth (the megalencephaly-capillary (MCAP) malformation syndrome and hemimegalencephaly) and lipomatous body overgrowth (CLOVES syndrome, and fibroadipose hyperplasia [FH]) caused by heterozygous (usually somatic mosaic) PIK3CA pathogenic variants.

Megalencephaly-Capillary Malformation (MCAP) Syndrome

The MCAP syndrome involves striking growth dysregulation manifesting as overgrowth of the brain and multiple somatic tissues. The features vary widely in number and severity among affected individuals.

Those with classic features have congenital or early postnatal megalencephaly (MEG; occipitofrontal circumference [OFC] ≥3 SD above the mean); segmental or generalized somatic overgrowth; single or generalized capillary malformations (most commonly a midline facial capillary malformation, or cutis marmorata); and generalized hypotonia.

Megalencephaly (MEG). In some instances, MEG (with or without ventriculomegaly) is detected prenatally on ultrasound examination [Clayton-Smith et al 1997, Vogels et al 1998,Robertson et al 2000, Nyberg et al 2005, Coste et al 2012]. More than 90% of affected children have congenital MEG that is universally progressive [Clayton-Smith et al 1997, Vogels et al 1998, Robertson et al 2000, Nyberg et al 2005, Coste et al 2012]. A few affected children have normal head size at birth but develop progressive MEG within the first year of life [Moore et al 1997, Conway et al 2007b, Mirzaa et al 2012].

In a review of 21 children with MCAP syndrome and other published and unpublished cases [Mirzaa et al 2012; Author, unpublished data], birth occipitofrontal circumference (OFC) typically ranges from +2 to +7 standard deviations (SDs) above the mean for gestational age. Most children cross OFC percentiles during the first year of life and, although head growth may level off in early childhood, it typically remains at +3 SD or more above the mean.

In children who have undergone neurosurgical shunting for obstructive ventriculomegaly or hydrocephalus, head growth noticeably continues at an accelerated pace, indicating the primary nature of MEG in this syndrome [Moore et al 1997, Conway et al 2007a, Conway et al 2007b, Mirzaa et al 2012].

Adult OFCs range from +2 to as large as +10 SDs above the mean.

The process of generalized brain overgrowth may be accompanied by secondary overgrowth of specific brain structures such as the ventricles, corpus callosum, and cerebellum resulting in ventriculomegaly, a markedly thick corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa, respectively [Conway et al 2007b, Mirzaa et al 2012].

Neurosurgical complications. Given the significant MEG, most individuals with MCAP syndrome undergo brain imaging shortly after birth or within the first year of life leading to early identification of key neuroimaging features discussed below [Vogels et al 1998, Nyberg et al 2005, Conway et al 2007a, Conway et al 2007b, Martínez-Lage et al 2010, Mirzaa et al 2012]. (See Figure 4.)

  • Ventriculomegaly and hydrocephalus. Most affected children have evidence of ventricular dilatation or ventriculomegaly on early brain imaging. In a large review of the neuroimaging findings in MCAP syndrome, 37 out of 65 (56%) children had ventriculomegaly ranging from mild to frank hydrocephalus, with or without cerebellar tonsillar ectopia [Conway et al 2007b]. While it is unclear whether or not ventriculomegaly is obstructive in all these individuals, more than half of affected children undergo ventricular shunting, usually within the first year of life.
  • Cerebellar tonsillar ectopia (CBTE). A large cerebellum, combined with a small posterior fossa leading to cerebellar tonsillar ectopia, or a Chiari malformation, and syringomyelia are potentially common complications in MCAP syndrome. Fifteen of 65 reported cases have evidence of CBTE with or without herniation [Conway et al 2007b]. The degree of ectopia is best objectively assessed by measuring the distance of the cerebellar tonsils below the foramen magnum. Unlike ventriculomegaly, CBTE is rarely congenital in MCAP syndrome.
    The symptoms of a Chiari malformation in children are often difficult to assess and include neck pain or headache, motor weakness, sensory changes, vision problems, swallowing difficulties, or behavioral changes. Infants may have difficulty swallowing, irritability, excessive drooling, or breathing problems, especially central apnea. In two individuals spontaneous “resolution” of CBTE” on follow-up imaging was attributed to disproportionately accelerated skull overgrowth [Mirzaa et al 2012].

Cortical brain malformation and polymicrogyria (PMG). While few reports of PMG with MCAP syndrome appeared in the early literature, it is now clear that it may be present in more than 50% of affected children [Conway et al 2007b; Gripp et al 2009; Mirzaa et al 2012; Authors, unpublished data]. The most common type of PMG in MCAP syndrome is bilateral perisylvian PMG, although other types including bilateral frontal and focal PMG occur. PMG broadly, and bilateral perisylvian PMG in particular, increase the risk for: epilepsy; oral motor weakness leading to feeding, swallowing and expressive language difficulties; developmental delay; and tone abnormalities.

Younger children with PMG (specifically of the frontal region) have hypotonia, are not spastic, and may have pseudobulbar problems, whereas older children often have spasticity and pseudobulbar problems [Mirzaa et al 2012].

Intellectual disability. Most individuals with MCAP syndrome have some degree of intellectual disability, although the degree is broad and ranges from mild learning disability to severe disability. Most have mild-moderate delays yet continue to make steady developmental progress, albeit at a slower rate than average. A few (<10%) have severe handicaps. The range of expected milestone acquisition has not yet been clarified in MCAP.

The degree of intellectual disability appears to be mostly related to the presence and severity of seizures, cortical dysplasia (e.g., PMG), and hydrocephalus. Gross motor delays are probably caused by multiple factors in the individual patient and include MEG, cortical brain malformations, hypotonia, limb asymmetry or overgrowth, and connective tissue dysplasia.

Autistic features and other behavioral abnormalities. A subset of children (6/21) with MCAP syndrome have autism or autistic features [Mirzaa et al 2012], suggesting that autism may be part of the neurocognitive profile of a minority of individuals with this MEG syndrome, similar to PTEN-related disorders [McBride et al 2010]. Other behavioral abnormalities seen in one or a few children include attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive tendencies, and anxiety-related issues.

Seizures. Approximately 30% of individuals with MCAP syndrome have seizures. In some children, seizures are mild and consist of a few episodes that do not warrant long-term antiepileptic drug therapy. In others, seizures may be severe, correlating strongly with the presence of severe and more diffuse cortical dysgenesis, particularly PMG [Lapunzina et al 2004, Conway et al 2007b, Mirzaa et al 2012].

Children with MCAP syndrome and hemimegalencephaly usually have more severe seizures of earlier onset and poor neurocognitive outcome [Barkovich et al 2005, Conway et al 2007b, Mirzaa et al 2012, Rivière et al 2012].

Tone abnormalities. Hypotonia, and particularly neonatal hypotonia, is a frequent finding in MCAP syndrome. This may be primarily central (secondary to MEG and associated brain abnormalities) and partially peripheral (secondary to mild connective tissue dysplasia resulting in lax joints).

Vascular malformations. The majority of children with MCAP syndrome have a capillary type of vascular malformation. Most common are capillary malformations in the mid-facial region (forehead, upper lip and philtrum; such as a persistent nevus flammeus) and generalized or extensive capillary malformations, resembling cutis marmorata. While these lesions may fade as the child grows older, they often persist to some degree and appearance may vary with changes in temperature or temperament [Toriello & Mulliken 2007, Wright et al 2009].

Other vascular abnormalities seen less frequently include infantile hemangiomas (cutaneous, subcutaneous, visceral) that may or may not involute later on in life, dilated and prominent cutaneous and intracranial venous networks, aberrant vasculature in various locations (such as periorbital and cardiac vessels), venous malformations, and vascular rings. Some children undergo laser therapy of cutaneous lesions with no observed recurrences [Clayton-Smith et al 1997; Yano & Watanabe 2001; Akcar et al 2004; Conway et al 2007b; Gripp et al 2009; Wright et al 2009; Mirzaa et al 2012; Authors, unpublished data].

Notably, some individuals with MCAP syndrome have experienced venous thrombosis, and one individual had a large tufted angioma of the shoulder complicated by Kasabach-Merritt syndrome in infancy [Wright et al 2009].

Somatic overgrowth and asymmetry. Most children with MCAP syndrome are large (or macrosomic) at birth [Clayton-Smith et al 1997, Moore et al 1997, Lapunzina et al 2004]. Data suggest that height and weight normalize in most children; however, postnatal growth delay due to growth hormone deficiency of unknown cause has been reported in a few children [Conway et al 2007a].

Some individuals manifest focal or segmental overgrowth of a limb or a few digits, resulting in somatic asymmetry. This focal overgrowth is milder than that in CLOVES syndrome. Furthermore, it is congenital and not relentlessly progressive, unlike that in Proteus syndrome [Biesecker et al 1999]. Focal or unilateral skeletal overgrowth resulting in leg-length discrepancy is common in MCAP syndrome.

Digital anomalies. The most common digital anomaly in MCAP syndrome is cutaneous syndactyly, particularly of toes 2-3 or fingers 3-4. Postaxial polydactyly is also common and some individuals have both (i.e., polysyndactyly). Other less common digital anomalies include sandal-gap (increased gap between) toes, broad thumbs and toes, and hypoplastic and deep-set nails.

Connective tissue dysplasia. Individuals with MCAP syndrome manifest varying degrees of connective tissue dysplasia. The most prominent feature of this is soft and redundant (often described as “doughy”) subcutaneous tissue. Variable degrees of skin hyperelasticity, joint hypermobility, and ligamentous laxity may also be evident on close examination. These changes are often more severe when coexistent with extensive capillary malformations. Combined with generalized hypotonia and the brain abnormalities, they contribute to early gross motor delays.

In a few cases, connective tissue involvement leads to congenital dislocation of the joints, including the hips or knees.

Facial features. The most striking facial feature in individuals with MCAP syndrome is frontal bossing secondary to significant MEG. The face maybe rounded due to overgrowth or increased subcutaneous tissue, or asymmetric due to focal somatic overgrowth. Coarsening of the facial features with prominent lips is common; characteristic ear abnormalities are seen less often [Gripp et al 2009]. No other dysmorphic facial features are consistently observed [Lapunzina et al 2004, Martínez-Glez et al 2010].

Cardiovascular abnormalities. A few children with MCAP syndrome have isolated structural heart disease, such as a single ventricular septal defect (VSD) or atrial septal defect (ASD), of unknown pathogenesis.

More importantly, complex cardiovascular abnormalities involving structural and vascular lesions have been seen in a few affected individuals, including combined ASD with dilated left atrium and mitral valve regurgitation [Yano & Watanabe 2001]; ASD with a giant atrial septal aneurysm [Akcar et al 2004, Dinleyici et al 2004]; ASD, VSD, right-sided aortic arch with an aberrant subclavian artery [Gripp et al 2009, Mirzaa et al 2012]; two muscular VSDs and a vascular ring [Mirzaa et al 2012]; and tetralogy of Fallot [Ercan et al 2013].

Arrhythmias in the fetus or newborn have been reported, overlapping with those above, including atrial flutter in three individuals [Yano & Watanabe 2001, Conway et al 2007b] and supraventricular tachycardia in two [Conway et al 2007b, Kuint et al 2012, Mirzaa et al 2012]. Cardiorespiratory arrest has occurred in some secondary to these heart abnormalities.

Furthermore, four children with complex congenital heart disease and/or cardiac rhythm abnormalities experienced sudden cardiorespiratory arrest (ages 17 days – 19 months) presumably secondary to these cardiac abnormalities [Clayton-Smith et al 1997, Yano & Watanabe 2001, Akcar et al 2004, Conway et al 2007a, Kuint et al 2012, Ercan et al 2013].

Gastrointestinal problems. Individuals with MCAP syndrome occasionally have feeding and swallowing difficulties due to a number of factors, including the underlying brain abnormalities, particularly PMG, poor tone, and gastroesophageal reflux disease (GERD). Furthermore, two individuals with MCAP syndrome and intestinal lymphangiectasias have been reported, suggesting the association of MCAP with lymphatic abnormalities [Thong et al 1999, Mégarbané et al 2003].

Tumors. Many benign and a few malignant tumors have been reported in MCAP syndrome. Malignant tumors seen in individuals with MCAP syndrome include the following:

Overall, the risk for malignancy in MCAP syndrome appears to be lower than in Beckwith-Wiedemann syndrome, as there are reports of malignancy in only three of approximately 150 (2%) individuals. Note: By adding meningiomas, the risk increases marginally to 5/150 (3.3%) [DeBaun & Tucker 1998].

The most common benign tumors in MCAP are vascular, described variably as (cavernous) hemangiomas, angiomata, angiomyolipomas, and vascular masses [Clayton-Smith et al 1997, Moore et al 1997, Martínez-Glez et al 2010]. While most common in skin or subcutaneous tissue, hemangiomas have been described in viscera and skull. Several individuals with MCAP also have lipomas that typically remain stable in size, and at least one individual had multiple lipomas [Wright et al 2009, Mirzaa et al 2012].

See Molecular Genetics, Cancer and Benign Tumors for additional information.

CLOVES Syndrome

CLOVES syndrome (congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies) is a severe overgrowth disorder characterized by focal and congenital lipomatous overgrowth, various vascular and lymphatic malformations, epidermal nevi, acral and musculoskeletal abnormalities, and renal anomalies, among other minor features.

Somatic overgrowth. Newborns typically have complex lipomatous overgrowth of the thoracic and abdominal wall, often with overlying vascular malformations. Variable contiguous extension to the groin, retroperitoneum, mediastinum, and gluteal area may occur. This overgrowth varies in extent and can be unilateral or bilateral at onset. In some cases, the lipomatous overgrowth or mass is identified prenatally on ultrasound examination. Overlying vascular malformations can be capillary, lymphatic, venous, or arteriovenous [Sapp et al 2007, Alomari 2009a].

Other manifestations of overgrowth include symmetric overgrowth with splaying of the feet, macrodactyly, and plantar or palmar overgrowth which results in wrinkling of the overlying palmar or plantar skin distinct from the classic cutaneous connective tissue nevi (CCTN) in Proteus syndrome.

Vascular malformations and epidermal nevi. Both low-flow (capillary, venous, and lymphatic) and high-flow (arteriovenous) malformations occur.

Lymphatic malformations and vesicles within the classic truncal lipomatous overgrowth may occur, and can be complicated by recurrent infections.

High-flow lesions (arteriovenous malformations) within and around the lipomatous mass and in the paraspinal regions are common. These lesions can be associated with severe sequelae (see Clinical Description, Neurologic and spinal complications) [Alomari et al 2011].

Venous malformations (phlebectasia), typically of the thoracic or central veins and prominent superficial veins have been reported. Deep vein thrombosis and pulmonary embolism are potentially fatal complications [Alomari et al 2010].

Epidermal nevi are common, particularly when overlying lipomatous overgrowth [Sapp et al 2007, Alomari 2009a].

Musculoskeletal and acral malformations. Skeletal anomalies can be markedly deforming. The most common is progressive scoliosis ranging from mild to severe [Alomari 2009a, Alomari 2009b].

Additional abnormalities include abnormal vertebral bodies, chondromalacia patellae, knee dislocation, wide hands and feet, wide sandal gap, macrodactyly, and talipes equinovarus. Marked bony overgrowth can result in significant leg length discrepancy necessitating surgery. Hip dysplasia requiring surgical intervention has been reported [Sapp et al 2007, Alomari 2009a, Klein et al 2012].

Abnormalities seen occasionally include pectus excavatum and postaxial polydactyly [Sapp et al 2007, Alomari 2009a, Klein et al 2012].

Neurologic and spinal complications. Direct extension of the lipomatous overgrowth into the paraspinal and intraspinal spaces is associated with high risks for compression of the cord, thecal sac, and nerve roots.

Some individuals have debilitating spinal myopathy due to the fast-flow spinal-paraspinal vascular lesions [Alomari et al 2011]. Additionally, tethered cord, vertebral anomalies, neural tube defects, and spasticity are common.

Individuals with CLOVES syndrome have variable degrees of intellectual disability [Sapp et al 2007, Alomari 2009a]. Their brain malformations overlap with those in MCAP syndrome: macrocephaly with polymicrogyria and seizures resulting in death at age nine weeks [Sapp et al 2007]; hemimegalencephaly with agenesis of the corpus callosum [Gucev et al 2008]; and Chiari malformations [Alomari et al 2011].

Renal and other visceral complications. Renal agenesis/hypoplasia, as well as renal calculi and hematuria have been seen in individuals with CLOVES syndrome. Other visceral anomalies include splenic lesions and extensive deep retroperitoneal, pelvic fatty and lymphatic malformation [Sapp et al 2007, Alomari 2009a, Alomari 2011].

Tumors. Tumors reported in CLOVES syndrome include chorangioma, extradural spinal tumor, hemangioma, and multiple angiomatosis (one each) [Sapp et al 2007].

Fibroadipose Hyperplasia (FH)

Fibroadipose hyperplasia is a severe progressive segmental overgrowth syndrome reported in ten individuals [Lindhurst et al 2012]. This disorder overlaps clinically and molecularly with CLOVES syndrome.

Segmental overgrowth. FH is characterized by severe segmental overgrowth of subcutaneous, muscular, and visceral fibroadipose tissue with skeletal overgrowth resulting in asymmetry. The extent of overgrowth varied among individuals, but was extensive in some and progressed into adulthood. Eight of ten individuals underwent multiple debulking or orthopedic procedures.

Seven of eight individuals on whom records were available had congenital asymmetric overgrowth. Four had skeletal overgrowth with preserved architecture. Bone age, when assessed, was normal.

Notably, four individuals had marked lipoatrophy in areas not affected by overgrowth without evidence of hypoglycemia or insulin resistance.

Other abnormalities include the following (summarized in Table 2):

  • Cutaneous capillary vascular malformations (2 individuals)
  • Testicular or epididymal abnormalities (3 individuals)
  • Epidermal nevi (2 individuals)
  • Polydactyly (1 individual)

All ten individuals with FH had normal intellect.

Genotype-Phenotype Correlations

Analysis of PIK3CA pathogenic variants in neoplastic tissues of individuals without PIK3CA-associated segmental overgrowth has identified four mutational hot spots (see Molecular Genetics and Table 4).

Interestingly, preliminary genotype-phenotype analysis of individuals with PIK3CA-associated segmental overgrowth suggests that MCAP syndrome is primarily associated with PIK3CA pathogenic variants not commonly identified in tumors, whereas hemimegalencephaly, CLOVES syndrome, and fibroadipose hyperplasia are associated with PIK3CA pathogenic variants at the cancer-related mutational hot spots (see Molecular Genetics, Table 4, and Table 5).

Penetrance

Degree of incomplete penetrance cannot be assessed in a mosaic genetic disorder.

Nomenclature

Megalencephaly-capillary malformation (MCAP) syndrome has been renamed several times as understanding of its distinguishing features (particularly the cutaneous vascular anomalies) evolved.

  • Originally termed the macrocephaly-cutis marmorata telangiectatica congenita (M-CMTC) syndrome [Moore et al 1997], the name was later shortened to “macrocephaly-cutis marmorata” (M-CM) syndrome [Cohen 2003].
  • When it was recognized that the terms used for the characteristic cutaneous vascular anomalies were misnomers, the term “macrocephaly-capillary malformation” syndrome was adopted [Toriello & Mulliken 2007, Wright et al 2009].
  • The name was further refined to “megalencephaly-capillary malformation” (MCAP) syndrome, emphasizing that this is true megalencephaly rather than “macrocephaly,” a less specific term denoting a large head due to numerous causes [Mirzaa et al 2012].

Prevalence

Prevalence of PIK3CA-associated overgrowth is difficult to estimate due to variation in ascertainment and the broad phenotypic spectrum. Many individuals have atypical or mild phenotypes leading to misidentification.

PIK3CA-associated overgrowth has been reported in individuals of various ethnic backgrounds.

More than 150 individuals have been reported with MCAP syndrome. Some previously reported as Proteus syndrome or KTS undoubtedly had this disorder; therefore, MCAP syndrome is believed to be a common overgrowth syndrome.

Differential Diagnosis

A number of overgrowth and megalencephaly disorders overlap with the PIK3CA-associated segmental overgrowth syndromes, including the following.

Hemimegalencephaly (HMEG) is characterized by enlargement and dysplasia of all or part of a cerebral hemisphere. In addition to CLOVES syndrome (discussed in this GeneReview), it can be isolated but has also been reported in association with disorders of focal somatic overgrowth and/or vascular malformations such as Klippel Trenauany syndrome, hypomelanosis of Ito, Proteus syndrome, linear nevus sebaceous syndrome, tuberous sclerosis complex, and nevoid basal cell carcinoma [Abdelhalim et al 2003, Sharma et al 2009, Pavlidis et al 2012]. Besides PIK3CA, mosaic pathogenic variants in other genes of the PI3K-AKT pathway (see Molecular Genetic Pathogenesis), including AKT3 and MTOR, have been identified in brain tissue from individuals with HMEG [Lee et al 2012, Poduri et al 2012].

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome was first described in 2004 and has since been reported in 29 individuals [Mirzaa et al 2004, Colombani et al 2006, Garavelli et al 2007, Tohyama et al 2007, Pisano et al 2008, Tore et al 2009, Osterling et al 2011, Kariminejad et al 2013]. This disorder is characterized by significant, and most often congenital, megalencephaly (MEG), bilateral perisylvian polymicrogyria (PMG), postaxial polydactyly, and an increased risk for hydrocephalus. While its four core features, and primarily the neuroimaging manifestations, overlap with MCAP syndrome [Gripp et al 2009], MPPH syndrome can be primarily distinguished by the absence of vascular malformations, focal somatic overgrowth, and connective tissue dysplasia [Verkerk et al 2010]. De novo germline pathogenic variants in PIK3R2 and AKT3, two other core components of the PI3K-AKT pathway, have been identified in MPPH syndrome [Rivière et al 2012].

Klippel-Trenaunay syndrome (KTS) is characterized by disproportionate growth disturbance combined with cutaneous capillary, lymphatic, and venous malformations. KTS typically involves the lower extremities but may affect the upper extremities and may be bilateral. The findings are typically focal and usually spare the craniofacial region, distinguishing it from the more generalized overgrowth observed in PI3KCA-related segmental overgrowth syndromes [Oduber et al 2011].

Bannayan-Riley-Ruvalcaba syndrome (BRRS), the most severe end of the PTEN-related overgrowth spectrum, is characterized by macrocephaly, developmental delay, lipomatosis, intestinal hamartomatous polyposis, and pigmented macules of the penis. While capillary malformations have been seen in BRRS, they are typically isolated and not similar to the capillary malformations in MCAP syndrome. Furthermore, BRRS lacks the significant overgrowth (particularly the truncal lipomatous overgrowth), acral deformities, and other characteristic features of CLOVES syndrome and fibroadipose hyperplasia. BRRS is caused by germline pathogenic variants in PTEN. Most individuals with BRRS have normal intelligence.

Proteus syndrome, a severe overgrowth syndrome, is associated with disproportionate and asymmetric postnatal somatic overgrowth including skeletal overgrowth, cerebriform connective tissue nevi (CCTN), epidermal nevi, dysregulated adipose tissue, and vascular malformations. Proteus syndrome can be primarily distinguished from CLOVES syndrome and fibroadipose hyperplasia by the postnatal onset of overgrowth. Furthermore, Proteus syndrome lacks the characteristic truncal fatty-vascular mass, spinal paraspinal fast-flow lesions and the acral abnormalities characteristic of CLOVES syndrome [Biesecker et al 1999]. Severely deforming and progressive skeletal overgrowth and poor prognosis occur in both disorders. Mosaic pathogenic variants in AKT1 were identified in affected tissues of individuals with Proteus syndrome [Lindhurst et al 2011].

Hemihyperplasia-multiple lipomatosis (HHML) syndrome, a distinct milder form of overgrowth, is characterized by moderate somatic asymmetry and overgrowth with subcutaneous lipomas and occasional vascular malformations, but lacks deep vascular malformations, epidermal nevi, cerebriform connective tissue nevi (CCTN), and hyperostosis. HHML syndrome may overlap with CLOVES syndrome given that overgrowth can be progressive and spinal complications and scoliosis have been reported [Lindhurst et al 2012].

SOLAMEN syndrome is characterized by atypical features of Cowden syndrome including segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevi. It is also associated with tumors such as ovarian cystadenoma, multiple breast tumors, and thyroid adenomas. Fibrocystic breast disease, gingival papules, and multinodular goiter have also been reported. SOLAMEN syndrome results from biallelic inactivation of PTEN (type 2 mosaicism), restricted to the atypical lesions [Caux et al 2007]. (See PTEN Hamartoma Tumor Syndrome.)

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual with PIK3CA-associated segmental overgrowth, the following evaluations are recommended:

  • A thorough history to identify key features of PIK3CA-associated segmental overgrowth
  • A physical examination including a thorough skin, cardiac, abdominal, and musculoskeletal evaluation, as well as a detailed neurologic assessment
  • Investigations to detect abnormalities before they result in significant morbidity/mortality:
    • Baseline brain and spinal cord imaging, especially in children with hemimegalencephaly (HMEG) and MCAP syndrome for early detection of cortical dysplasia, ventriculomegaly, and cerebellar tonsillar ectopia.
    • A cardiovascular assessment including a baseline echocardiogram and electrocardiogram to evaluate for cardiovascular malformations and rhythm abnormalities
    • A baseline renal ultrasound to evaluate for structural renal abnormalities
    • Surgical and orthopedic referrals for individuals suspected of having CLOVES syndrome or fibroadipose hyperplasia, and individuals with MCAP syndrome with focal somatic overgrowth or leg-length discrepancy

Treatment of Manifestations

Patients with PIK3CA-associated segmental overgrowth benefit from a coordinated and multidisciplinary clinical approach tailored to the individual’s specific needs and manifestations.

Referral to the appropriate specialist(s) is recommended for the following findings:

  • Significant or lipomatous segmental overgrowth: referral to a surgeon and/or thoracic surgeon (when lipomatous overgrowth involves the trunk)
  • Leg-length discrepancy secondary to segmental somatic overgrowth
  • Cardiac abnormalities (i.e., structural cardiovascular disease and arrhythmias)
  • Renal abnormalities
  • Intellectual disability and/or difficulties with learning, behavior, or speech, or motor difficulties
  • Speech, swallowing, and feeding difficulties

Neurologic and neurosurgical manifestations

  • MCAP syndrome. Findings warranting neurosurgical referral include rapidly enlarging OFC, obstructive hydrocephalus, symptoms of raised intracranial pressure, and progressive or symptomatic cerebellar tonsillar ectopia (CBTE) or Chiari malformation. Early treatment of hydrocephalus may reduce the risk for progressive CBTE, but data are lacking to determine the most appropriate neurosurgical management. In recent years, favorable outcomes have been observed with ventriculostomy of the third ventricle (rather than insertion of a ventriculo-peritoneal shunt), suggesting that the neurosurgical management of hydrocephalus in MCAP syndrome is evolving.
  • HMEG. Individuals are at risk for severe early-onset epilepsy, focal neurologic signs such as hemiparesis, and severe intellectual disability. Epilepsy and intellectual disability may be improved by hemispherectomy [Di Rocco et al 2006, Kwan et al 2008].
  • Individuals with HMEG and MCAP syndrome with polymicrogyria (PMG) are at increased risk for epilepsy; thus, long-term neurologic follow up is warranted, and many require long-term antiepileptic treatment [Mirzaa et al 2012].

Somatic overgrowth, vascular, lymphatic and musculoskeletal manifestations. CLOVES syndrome and fibroadipose hyperplasia (FH) are associated with severe focal overgrowth, vascular malformations, and orthopedic complications with significant morbidities. Prompt diagnosis (by MR/CT and angiography) is warranted. Most individuals undergo (often several) debulking or orthopedic procedures with significant ensuing complications (see Surveillance).

The following are the main treatment considerations in CLOVES syndrome:

  • The characteristic truncal lipomatous mass infiltrates surrounding tissues and often requires surgical excision. Severe scoliosis, large truncal mass, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems of the feet and hands, and central phlebectasia/thromboembolism are examples of significant morbidities that need active or prophylactic medical intervention.
  • Paraspinal and intraspinal extension have significant risk for compression of the cord, thecal sac, and nerve roots, with resultant major neurologic deficits, warranting prompt diagnosis and multidisciplinary care [Alomari 2009a].
  • Given the risk for thromboembolism in CLOVES syndrome, appropriate prophylactic measures including anticoagulation and caval filtration, particularly in the perioperative period, are recommended. Central and thoracic phlebectasia in individuals with CLOVES syndrome should be considered an indication for placement of a superior vena cava (SVC) filter.

FH is associated with severe progressive overgrowth of fibrous and adipose tissues. While the severity and natural history varied among reported individuals, thorough surgical and orthopedic evaluations are warranted. Most individuals (8/10) underwent extensive debulking or orthopedic procedures.

Surveillance

MCAP syndrome. Provisional surveillance guidelines include regular follow up, no less than every six months until age six years, and at least yearly thereafter. At each visit, the following are recommended with appropriate testing for any positive finding:

  • A medical history with attention to:
    • Childhood cancer
    • Breathing or sleep problems
    • Seizures or other undefined spells, headaches, or new or worsening neurologic symptoms
  • A detailed neurologic evaluation
  • Brain MRI. Based on limited retrospective data available, the risk for hydrocephalus, cerebellar tonsillar ectopia, or both with low brain stem or high spinal cord compression, appears to be highest in the first two years. Brain MRI is provisionally recommended every six months from birth to age two years, and annually from age two to six years. In older individuals, the frequency should be based on prior results and clinical findings, with particular attention to apnea or other abnormal patterns of respiration, headaches, changes in gait, or other neurologic problems.
  • Renal ultrasound. Until additional data are available, screening for Wilms tumor following guidelines developed for Beckwith-Wiedemann syndrome may be considered (i.e., renal ultrasound examination every 3 months until age 8 years).

CLOVES syndrome

  • Given the associated morbidities including severe scoliosis, infiltrative lipomatous overgrowth, paraspinal high-flow lesions with spinal cord ischemia, lymphatic malformations, cutaneous vesicles, orthopedic problems, central phlebectasias and thromboembolism, individuals with CLOVES syndrome require surveillance tailored to their specific needs with particular attention to surgical care [Sapp et al 2007, Alomari 2011, Alomari et al 2011].
  • Commonly occurring postoperative complications of surgical excision of the truncal lipomatous mass include recurrence, hypervascularity, and infiltrative growth. Therefore, diligent surgical care and monitoring are recommended.

Fibroadipose hyperplasia. Data regarding the natural history of fibroadipose hyperplasia are limited. However, given the extensive degree of somatic overgrowth in most individuals, the same surveillance guidelines for CLOVES are tentatively recommended for individuals with FH [Lindhurst et al 2012].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

PIK3CA-associated segmental overgrowth is not known to be inherited. No confirmed vertical transmission or sib recurrence has been reported.

The molecular data show that 21 of 24 affected individuals had somatic mosaicism for pathogenic variants in PIK3CA [Rivière et al 2012], suggesting that mutation occurred post-fertilization in one cell of the multicellular embryo. Two individuals with MCAP syndrome had a de novo germline pathogenic variant in PIK3CA [Rivière et al 2012]. The third had only one tissue tested with inconclusive results.

Risk to Family Members

Parents of a proband. No parent of a child with PIK3CA-associated segmental overgrowth has had any significant, distinctive manifestations of the disorder nor would such a finding be expected, given the somatic mutational mechanism of these disorders.

Sibs of a proband. The risk to sibs of a proband with somatic mosaicism for a pathogenic variant in PIK3CA would be expected to be the same as in the general population.

Offspring of a proband

  • Reproductive outcome data on adults with PIK3CA-associated segmental overgrowth are limited; there are no instances of vertical transmission of these disorders. While adults with MCAP syndrome, CLOVES syndrome, and fibroadipose hyperplasia have been reported, the developmental outcome of individuals with hemimegalencephaly (HMEG) is poor.
  • All but three affected individuals with MCAP syndrome had somatic mosaicism for a pathogenic variant in PIK3CA, suggesting that mutation occurred post-fertilization in one cell of the multicellular embryo. Therefore the risk for transmission to offspring is expected to be less than 50%.
  • Two individuals with MCAP syndrome had a de novo germline pathogenic variant in PIK3CA [Rivière et al 2012]; therefore, offspring of these individuals have a 50% risk of inheriting the PIK3CA pathogenic variant.

Other family members of a proband. The risk to other family members is the same as that of the general population.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mosaic pathogenic variant. This is a relatively new area for clinical genetics as only a small (albeit growing) number of disorders is known to be caused by this genetic mechanism.

Counseling for recurrence risk in PIK3CA-associated segmental overgrowth should emphasize that, while no pregnancy is at zero risk, all evidence suggests that the risk for recurrence is not increased, compared to the general population. The rare families with MCAP syndrome caused by a de novo germline PIK3CA pathogenic variant should be counseled regarding the theoretic risk for parental germline mosaicism, which is estimated at less than 1%.

Family planning

  • The optimal time for determination of genetic risk is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Because PIK3CA-associated segmental overgrowth is not inherited, family members are not known to be at increased risk of being affected and prenatal diagnosis is usually not indicated for family members. However, low-level germline mosaicism may theoretically be present in a parent of a child with a germline PIK3CA pathogenic variant. Prenatal diagnosis, either through a clinical laboratory or a laboratory offering custom prenatal testing, may be an option for such rare families.

In addition, prenatal testing may be an option for pregnancies identified by ultrasound examination to be at risk for these syndromes.

  • Findings on ultrasound examination that suggest MCAP syndrome include marked fetal overgrowth and progressive macrocephaly with no indication of maternal hyperglycemia or fetal hyperinsulinism. Other reported fetal ultrasound findings include ventriculomegaly, pleural effusions, polyhydramnios, hydrops, limb asymmetry, and frontal bossing [Nyberg et al 2005]. A fetal MRI in an affected fetus with megalencephaly and ventriculomegaly revealed diffuse bilateral polymicrogyria and polysyndactyly of one foot [Gripp et al 2009].
  • Findings on prenatal ultrasound examination in CLOVES syndrome include prenatal overgrowth, lipomatous truncal masses, and vascular or lymphatic malformations [Sapp et al 2007, Alomari 2009a, Alomari et al 2011].

Preimplantation genetic diagnosis (PGD). Because the PIK3CA-associated segmental overgrowth syndromes are not inherited, family members are not known to have an increased risk of being affected. The authors recognize no potential role for PGD in these syndromes.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • M-CM Network
    PO Box 97
    Chatham NY 12037
    Phone: 518-392-2150
    Email: hello@m-cm.net
  • M-CM Network Contact Registry
    The M-CM Network contact registry will be used to inform individuals with M-CM and their guardians about: opportunities to participate in research, opportunities to contribute data, and discoveries about M-CM that may impact care decisions.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

PIK3CA-Related Segmental Overgrowth: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for PIK3CA-Related Segmental Overgrowth (View All in OMIM)

171834PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, ALPHA; PIK3CA
602501MEGALENCEPHALY-CAPILLARY MALFORMATION-POLYMICROGYRIA SYNDROME; MCAP
612918CONGENITAL LIPOMATOUS OVERGROWTH, VASCULAR MALFORMATIONS, AND EPIDERMAL NEVI

Molecular Genetic Pathogenesis

The PI3Ks are members of a unique and highly conserved family of intracellular lipid kinases that phosphorylate the 3’-hydroxyl group of phosphatidylinositol and phosphoinositides, a reaction that leads to the activation of many complex and intricate intracellular signaling pathways including the PI3K-AKT-mTOR network. Class IA PI3Ks are activated by growth factor receptor tyrosine kinases (RTKs) and are composed of heterodimers of p110 catalytic and p85 regulatory subunits, each of which has several isoforms encoded by three genes; PIK3R1, PIK3R2, and PIK3R3 encode the p85α, p55α, p50α, p85β, and p55γ isoforms of the p85 regulatory subunit, while PIK3CA, PIK3CB, and PIK3CD encode the highly homologous p110 catalytic subunit isoforms p110α, p110β, and p110δ, respectively [Fruman et al 1998, Cantley 2002, Engelman et al 2006].

Somatic pathogenic gain-of-function variants PIK3CA are frequently found in individuals without PIK3CA-related overgrowth in diverse cancers including colon, breast, brain, liver, stomach, and lung. See Cancer and Benign Tumors.

Gene structure. The PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha gene) encodes the p110α catalytic subunit of class IA PI3K. PIK3CA (NM_006218.2) comprises 21 coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. A number of benign variants have been identified [Quaye et al 2009]. A pseudogene with greater than 95% homology spanning exons 9 to 13 of PIK3CA on chromosome 22 exists [Müller et al 2007].

Pathogenic variants. Eighteen pathogenic variants have been reported in MCAP syndrome, hemimegalencephaly (HMEG), and CLOVES syndrome and fibroadipose hyperplasia [Kurek et al 2012, Lee et al 2012, Lindhurst et al 2012, Rivière et al 2012]. See Table 3 and Table 4.

  • MCAP syndrome. The PIK3CA variant spectrum in MCAP syndrome is wide. PIK3CA pathogenic variants were detected in 24 individuals with MCAP syndrome using both standard and massively parallel sequencing methods [Rivière et al 2012]. It is currently unknown whether MCAP syndrome is genetically heterogeneous or the individuals with MCAP syndrome of unknown cause are in fact heterozygous for low-level mosaic PIK3CA pathogenic variants undetected in the tissue(s) tested.
  • CLOVES syndrome and fibroadipose hyperplasia. Mosaic PIK3CA pathogenic variants from affected (or lesional) tissues were identified in six individuals with CLOVES syndrome and ten individuals with fibroadipose hyperplasia [Kurek et al 2012, Lindhurst et al 2012]. See Table 4.

Table 4.

Select PIK3CA Variants Causing PIK3CA-Related Overgrowth Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeOvergrowth Phenotype (N)Reference
Sequences
c.1258T>Cp.Cys420ArgCLOVES (2)NM_006218​.2
NP_006209​.2
c.1625G>Ap.Glu542LysCLOVES (2)
c.1633G>Ap.Glu545LysHMEG (4) 1, MCAP-plus (1) 2
c.3140A>Gp.His1047ArgCLOVES-FH (9), KTS (3)
c.3140A>Tp.His1047LeuCLOVES-FH (2)
OthersOthersMCAP (23)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

p.Glu545Lys was identified in all four PIK3CA-positive brain tissue samples from individuals with HMEG [Lee et al 2012].

2.

See Cancer and Benign Tumors for a description of this phenotype.

Many of the pathogenic missense variants in PIK3CA have been found in human cancers. See Cancer and Benign Tumors.

Normal gene product. PIK3CA encodes 1068 amino acids of the p110α catalytic subunit of class IA PI3K. Similar to most genes encoding PI3Ks, PIK3CA is widely expressed. p110α is characterized by five functional domains: p85-regulatory subunit-binding domain (p85-BD), Ras-binding domain (Ras-BD), C2 domain, helical domain, and kinase catalytic domain [Chalhoub & Baker 2009].

Abnormal gene product. In cell lines from individuals with PIK3CA-associated overgrowth, stimulation of cells resulted in increased basal hyperphosphorylation of AKT and its downstream targets (e.g., p70S6 kinases), suggesting that PIK3CA pathogenic variants in PIK3CA-associated overgrowth result in enhanced basal activity and activation of downstream signaling of the PI3K-AKT pathway [Kurek et al 2012, Lindhurst et al 2012, Rivière et al 2012].

Cancer and Benign Tumors

Somatic pathogenic gain-of-function variants in PIK3CA are frequently found in diverse cancer types including ovary, breast, lung, brain, stomach, and up to 15%-20% of colorectal cancers. The helical and kinase domains are particular hot spots for somatic pathogenic variants in cancer [Janku et al 2011, Janku et al 2012]. All cancer-associated PIK3CA variants for which functional data are available were shown to result in increased PI3K activity and/or signaling [Shayesteh et al 1999, Liu et al 2011]. Detectable amplification of the gene has also been shown in 58% of ovarian tumors using fluorescence in situ hybridization [Shayesteh et al 1999, Zhang et al 2003].

Among the approximately 160 PIK3CA pathogenic variants listed in the Catalogue of Somatic Mutations in Cancer (COSMIC), common variants in four amino acids (p.Glu542Lys, p.Glu545Lys in exon 9, and p.His1047Arg and p.His1047Leu in exon 20) account for 80% of tumor-associated PIK3CA variants and show the highest oncogenic activity [Samuels et al 2004, Samuels & Ericson 2006, Janku et al 2012]. See Table 5.

Table 5.

Common Cancer-Related PIK3CA Variants Reported in COSMIC Database

DNA Nucleotide ChangePredicted Protein Change# of Cancer Specimens with the Pathogenic Variant
c.1625G>Ap.Glu542Lys633
c.1633G>Ap.Glu545Lys977
c.3140A>Gp.His1047Arg1680
c.3140A>Tp.His1047Leu201

The same four PIK3CA missense variants may be found in individuals with PIK3CA-associated overgrowth and in unaffected individuals with PIK3CA-related cancer (Table 4 and Table 5). Preliminary analysis (see Genotype-Phenotype Correlations) of individuals with PIK3CA-associated segmental overgrowth suggests that MCAP syndrome is primarily associated with somatic mosaicism for PIK3CA pathogenic variants not commonly identified in tumors, whereas hemimegalencephaly and CLOVES syndrome are associated with somatic mosaicism for PIK3CA pathogenic variants at the cancer-related mutational hot spots (see Molecular Genetics, Table 4, and Table 5).

  • HMEG. p.Glu545Lys was identified in brain tissues of all four individuals with HMEG [Lee et al 2012].
  • MCAP syndrome. While 13 of the 15 reported PIK3CA pathogenic variants in MCAP syndrome are reported in COSMIC, only one (p.Glu545Lys) was at a site commonly mutated in PIK3CA-related cancers. This was identified in a child with atypical MCAP syndrome features that overlapped with CLOVES syndrome and hemimegalencephaly, including severe asymmetric brain overgrowth, bilateral cortical dysplasia, severe focal overgrowth of the digits, and epidermal nevi (designated as MCAP-plus in Table 4) [Rivière et al 2012].
  • CLOVES syndrome and fibroadipose hyperplasia. 14 individuals with these phenotypes have PIK3CA pathogenic variants involving three of the four cancer mutational hot spots [Kurek et al 2012, Lindhurst et al 2012].

References

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Chapter Notes

Author Notes

Drs Ghayda Mirzaa and William B Dobyns study the developmental basis of a broad range of developmental brain disorders, with a particular focus on megalencephaly syndromes. They are studying the natural history of PI3KCA-associated megalencephaly syndromes and related phenotypes.

Acknowledgments

We would like to thank the patients, their families, and our collaborators for their valuable contribution to our knowledge about these disorders.

Revision History

  • 15 August 2013 (me) Review posted live
  • 11 March 2013 (gm) Original submission
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