PIK3CA-Related Overgrowth Spectrum (PROS)

The PIK3CA-related overgrowth spectrum (PROS) comprises a series of clinical syndromes whose main features are a congenital or early childhood occurrence of segmental/focal overgrowth with or without cellular dysplasia. The PIK3CA-related overgrowth spectrum PROS is based on activating somatic mutations in the phosphatidylinositol 3-kinase/AKT/mTOR pathway and leads to heterogeneous phenotypes characterized by segmental overgrowth.

In the past, patients with activating PIK3CA mutations have been clinically diagnosed with:

• Fibroadipose hyperplasia or overgrowth (FAO)
• Hemihyperplasia, multiple lipomatosis (HHML)
• Congenital lipomatous overgrowth, vascular malformations, epidermal nevi, scoliosis/skeletal and spinal syndrome(CLOVE syndrome)
• Macrodactyly, fibroadipose infiltrating lipomatosis and the related megalencephaly syndromes: megalencephaly-capillary malformation(MCAP syndrome)
• Dysplastic megalencephaly (DMEG).

The heterogeneous phenotypes of segmental overgrowth are caused by somatic, activating mutations in the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway.

The predominant areas of overgrowth include the brain, limbs (including fingers and toes), trunk (including abdomen and chest) and face, all usually in asymmetrical distribution. Generalized overgrowth of the brain may be accompanied by secondary overgrowth of specific brain structures, resulting in ventriculomegaly, a markedly thickened corpus callosum, and cerebellar tonsillar ectopia with crowding of the posterior fossa.

Vascular malformations can include capillary, venous and, more rarely, arterial or mixed (capillary-lymphatic-venous or arteriovenous) malformations.

Lymphatic malformations can be located at various sites (internal and/or external) and cause various clinical problems, including swelling, pain and occasionally local bleeding as a result of trauma.

Lipomatous overgrowths may occur ipsilateral or contralateral to a vascular malformation.

The degree of intellectual disability appears to be related primarily to the presence and severity of seizures, cortical dysplasia (e.g. polymicrogyria) and hydrocephalus. Many children have feeding problems, which are often multifactorial. Endocrine problems affect a small number of individuals and most commonly include hypoglycemia (mainly hypoinsulinemic hypoketotic hypoglycemia), hypothyroidism, and growth hormone deficiency.

PROS is diagnosed clinically and by molecular genetics. Detection of a heterozygous mosaic (or more rarely constitutional) activating pathogenic variant in the PIK3CA gene. Sequence analysis is performed on DNA from lesional tissue samples (skin biopsy) or from surgical excision material from overgrown tissue or from non-cultivated tissue (such as skin fibroblasts or other tissues). For the detection of somatic variants, the targeted detection of the entire coding PIK3CA region is recommended, followed by next-generation sequencing with very deep coverage, as it enables the detection of a very small mosaic in the entire gene.

Phosphoinositide 3-kinase inhibitors

Alpelisib (VIJOICE®) 50 mg orally(PI3K inhibitors as adjuvant treatment for various oncologic indications) with food once daily (approximately the same time each day) for patients aged two years to <18 years with PROS. For patients aged six years or older, the dose may be increased to 125 mg once daily after 24 weeks. A starting dose of 250 mg once daily orally with food (around the same time of day) is approved for patients aged ≥18 years. Alpelisib has been specifically approved for the reduction of overgrowth, vascular lesions and other functional complications.

Significant or lipomatous segmental overgrowth may require excision.

Scoliosis and leg length discrepancy may require orthopedic treatment and surgical intervention.

Neurological complications (e.g. obstructive hydrocephalus, increased intracranial pressure, progressive and/or symptomatic cerebellar tonsil ectopia or Chiari malformation and epilepsy in overgrowth/malformations of the brain) may warrant neurosurgical intervention.

Vascular: Depending on the type of vascular malformation, sclerotherapy, laser therapy or oral medication such as sirolimus may be used. Lymphatic malformations can also be treated with oral medication or careful surgical decongestion.

Pain management: For patients with pain, it is recommended to identify the source of the pain and treat the underlying cause.

Endocrinology: In patients with growth hormone deficiency, the hypothalamic-pituitary-adrenal axis should be evaluated; a trial of growth hormone therapy may be considered, with careful monitoring of linear growth and overgrowth. Severe persistent hypoglycemia has been reported and requires investigation and ongoing treatment, which may include administration of cornstarch.

Routine treatment of the following is indicated: cardiac and renal abnormalities, mental retardation and behavioral disturbances, polydactyly and foot deformities, coagulopathy or thrombosis, Wilms tumor, and hypothyroidism.

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