The overgrowth syndromes are rare disorders that feature general or segmental macrosomia. These conditions may be caused by inherited or de novo germline pathogenic/likely pathogenic (P/LP) variants, which affect every cell in the individual’s body, or mosaic somatic P/LP variants, which arise during early embryonic development and only affect a portion of the individual’s cells. There is no standard definition for overgrowth, but in general these conditions should be considered when a child’s head size and/or height are greater than 2 standard deviations above the mean, when birth weight is greater than 4,500 grams, or when dysmorphic features are present that are typical of a known syndrome (Kamien et al., 2018). Many of these conditions are associated with an increased risk for tumor development; therefore, early identification of a diagnosis is important for guiding surveillance strategies. Wilms tumor, hepatoblastoma, and neuroblastoma are common tumor types seen in patients with overgrowth syndromes (Brioude et al., 2019).

In infancy, a large head size or large body size are relatively common clinical presentations. High birth weight is a frequent complication of uncontrolled maternal diabetes, which is also associated with an increased risk for congenital abnormalities (Kamien et al., 2018). Most often macrocephaly is benign and isolated, or related to familial macrocephaly, in which some close family members are similarly affected. Neither isolated nor familial macrocephaly require any further intervention. However, macrocephaly is sometimes the first sign of an overgrowth syndrome. Underlying conditions should be considered and investigated when other symptoms are present such as developmental delay/intellectual disability, syndromic features, or evidence of raised intracranial pressure (ICP) (Seal, 2013).

Germline conditions are typically associated with generalized and symmetric overgrowth. Facial dysmorphism, variable degrees of intellectual disability, and increased risk for neoplasm are also characteristic of these conditions. Some examples (and the associated genes) include: Sotos syndrome (NSD1), Marshall-Smith syndrome (NFIX), Weaver syndrome (EZH2), Perlman syndrome (DIS3L2), Bannayan-Riley-Ruvalcaba (PTEN), and Simpson–Golabi–Behmel syndrome (GPC3, GPC4, and OFD1) (Edmonson and Kalish, 2015). These conditions often include additional phenotypic features such as skeletal anomalies, polydactyly, congenital heart defects, and/or diaphragmatic hernia. Molecular testing can be useful for diagnosis, and in most cases can be targeted based on clinical suspicion of a particular form of overgrowth syndrome. Accurate diagnosis is important for genetic counseling about reproductive risks as well as cancer surveillance and prognosis (Kamien et al., 2018).

Somatic overgrowth syndromes are typically distinguished by asymmetric overgrowth isolated to certain parts of the body. Clinical findings show significant phenotypic overlap, making it difficult to distinguish between syndromes in the spectrum by clinical features alone. Features range from small isolated skin lesions to extensive asymmetric extremity overgrowth, macrocephaly, lymphedema, vascular malformations, and tumor susceptibility (Nathan et al., 2017). Some of these conditions occur as a result of somatic activating somatic P/LP variants in the phosphatidylinositol-3-kinase (PI3K)/AKT/mTOR signaling pathway, as well as negative regulating somatic P/LP variants in the PTEN, TSC1, and TSC2 genes. In addition, there are multiple levels of feedback inhibition that interact with the PI3K/AKT/mTOR signaling pathway, including significant involvement of the RAS/MAPK pathway, making these conditions potentially amenable to somatic treatments aimed at this pathway (Keppler-Noreuil et al., 2016; McCuaig, 2017). Indeed, mTOR inhibitor therapy has been shown to be an efficacious and safe treatment for complex overgrowth conditions (Adams et al., 2016). Some examples of somatic overgrowth disorders (and the genes involved) include: 11p15-related overgrowth (isolated hemihypertrophy or Beckwith-Weidemann), Proteus syndrome (AKT1), Megalencephaly-polymicrogyria- polydactyly-hydrocephalus syndrome (AKT3), Sturge Weber or isolated port wine stains (GNAQ and GNA11), Focal cortical dysplasia (MTOR), and PIK3CA-Related Overgrowth Spectrum (PIK3CA). Molecular testing for somatic overgrowth syndromes is complicated by tissue mosaicism. Genetic testing of multiple tissues, especially affected tissue, is generally indicated as part of the diagnostic workup. Failure to identify a P/LP variant does not exclude a diagnosis. Confirmation of diagnosis when possible may be helpful in guiding cancer, ocular and renal surveillance (Suri, 2016; Kalish et al., 2017).

Some specific overgrowth syndromes are described in more detail below:

Sotos Syndrome

Sotos syndrome is characterized by the cardinal features of typical facial appearance, overgrowth (height and/or head circumference ≥2 SD above the mean), and learning disability ranging from mild to severe. It is important to note that the final adult height may normalize, but macrocephaly is usually a consistent finding at all ages. Some affected children attend mainstream schools and are likely to be independent as adults, but others require lifelong care and support. Sotos syndrome includes behavioral issues, congenital cardiac anomalies, neonatal jaundice, renal anomalies, scoliosis, and seizures (Tatton-Brown et al., 2004). Management typically consists of symptomatic treatment and surveillance, particularly if cardiac and/or renal abnormalities (Tatton-Brown et al., 2004).

The diagnosis of Sotos syndrome is established by a combination of clinical findings and molecular genetic testing. NSD1 is the only gene in which P/LP variants are known to cause Sotos syndrome. About 80%-90% of individuals with Sotos syndrome have a demonstrable NSD1 abnormality and more than 95% of individuals have a de novo pathogenic variant (Tatton-Brown et al., 2004).

Marshall-Smith Syndrome/Malan Syndrome

NFIX P/LP variants are suspected to cause a Sotos-like syndrome or a Marshall-Smith syndrome. It has been proposed that this group of characteristics be referred to as Malan syndrome. P/LP variants in NFIX are described as causing postnatal overgrowth and macrocephaly. The facial features seen in some cases (prominent forehead, high anterior hairline, downslanting palpebral fissures, and prominent chin) are also seen in individuals with Sotos syndrome due to NSD1 alterations (Klaassens et al., 2015). One-third of patients have feeding difficulties in the neonatal period and/or hypotonia. The majority have some degree of developmental delay/learning disability and eye findings are commonly seen, including strabismus, nystagmus, and optic disc pallor/hypoplasia. Additionally, some individuals have pectus excavatum and/or scoliosis (Klaassens et al., 2015), but the full spectrum of effects of P/LP variants in NFIX is still being recognized. Whole NFIX gene deletions, often identified through chromosomal microarray analysis, have been identified in approximately 25% of individuals with Malan syndrome (Priolo, 2024).

PIK3CA-Related Overgrowth Spectrum (PROS)

The PIK3CA gene is important for many cell activities including growth, division, migration, and survival. It is also involved in the regulation of several hormones. The PI3K protein is frequently activated in human cancers; often as a result of specific P/LP variants in the PIK3CA gene that promote tumor survival and metastasis (Samuels et al., 2004; Engelman et al., 2008). Heterozygous somatic P/LP variants in PIK3CA have also been associated with many congenital phenotypes, together referred to as the PIK3CA-Related Overgrowth Spectrum. Identification of a PIK3CA P/LP variant in any tissue from an individual with borderline clinical findings establishes the diagnosis of PIK3CA-associated segmental overgrowth (Kurek et al., 2012; Lindhurst et al., 2012).

Expert consensus diagnostic and genetic testing criteria for PIK3CA-related conditions were published in 2015, and expert consensus management guidelines were outlined in 2021 (Keppler-Noreuil et al., 2015; Douzgou et al., 2021). In general, testing is appropriate for any individual with a combination of vascular malformations and asymmetric or segmental overgrowth which was of congenital onset in early childhood. Additional features may include scoliosis, patterning defects, congenital epidermal nevus, soft doughy skin, or joint hypermobility (Keppler-Noreuil et al., 2015). Among these conditions, both benign and malignant neoplasms have been observed, including Wilms tumor, leukemia, and meningioma. Confirmation of a diagnosis may result in increased surveillance (i.e. abdominal ultrasound and AFP level every 3 months until age 8 years) due to possible Wilms tumor risk. Multiple PI3K inhibitors have been developed in recent years as targeted anti-cancer treatments for tumors with activating PIK3CA P/LP variants (Klein et al., 2023).

Specific phenotypes associated with the PIK3CA-Related Overgrowth Spectrum have names that generally describe their characteristic phenotypes. These include Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome (aka MCAPS), Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi and Spinal/skeletal anomalies (aka CLOVES), and Fibroadipose Overgrowth/Hemihyperplasia-Multiple Lipomatosis (FAO/HHML). In some cases, the specific genotype can predict the associate phenotype (Maguolo et al., 2018).

Hemimegalencephaly/Focal Cortical Dysplasia

Hemimegalencephaly (HME) is characterized by enlargement of one cerebral hemisphere. Common features include epilepsy, cognitive and developmental disabilities, contralateral hemiparesis, and hemianopsia. Most individuals have isolated HME, however, HME can be associated with other neurocutaneous syndromes or conditions. The epilepsy is typically progressive and intractable, and most often treated surgically by radical hemispherectomy. HME occurs sporadically and is mosaic in somatic tissues (Mirzaa et al., 2013).

In a study to investigate the genetic cause of HMP, exome sequencing was performed on brain and blood samples from 20 patients affected with hemimegalencephaly. This identified P/LP variants in 30% of the patients in either the PIK3CA, AKT3, or MTOR genes (Lee et al., 2012). In another study of brain tissue from 33 patients with hemimegalencephaly and/or focal cortical dysplasia, mosaic P/LP variants in PIK3CA were identified in 3 patients (one also present in buccal tissue) and a P/LP variant in AKT3 was identified in another (Jansen et al., 2015). In the same study, a germline PTEN P/LP variant was identified in a child with no clinical features of a PTEN-hamartoma disorder. In another study, MTOR P/LP variants were identified in 10 patients with megalencephaly, HME or focal cortical dysplasia (FCD) and in 4 patients, brain malformation occurred with cutaneous pigmentary mosaicism (Mirzaa et al., 2016).