Overgrowth Syndromes-Evaluation, Diagnosis, and Management

Abstract

Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth syndromes generally present with inherent health concerns and, in some instances, an increased risk of tumor predisposition that necessitate prompt diagnosis and appropriate referral. In this review, we introduce some of the more common overgrowth syndromes, along with their molecular mechanisms, diagnostics, and medical complications for improved recognition and management of patients affected with these disorders.

Keywords: Beckwith-Wiedemann; PIK3CA; Proteus Syndrome; Pten; Simpson-Golabi-Behmel; Sotos; Weaver; overgrowth.

Figure 1

Two infants diagnosed with Beckwith–Wiedemann syndrome. The first infant (left and middle), presented with two episodes of symptomatic hypoglycemia, first occurring shortly after birth, and the second one at 7 months of age. Note the right-sided hemihyperplasia involving the right upper and lower extremities (1–1.5 cm difference in humeral and tibial circumferences, a 6% difference). Facial asymmetry was appreciated at 7 months, but can be readily seen in the middle, taken at 19 months of age. Extremity or facial asymmetry should raise suspicion for this syndrome. The patient in the right demonstrates the syndrome's most prominent feature, macroglossia. Methylation studies showed that the IC1 was hypermethylated: the paternal IC1 center is typically methylated, and maternal allele is not. Both patients undergo Beckwith–Wiedemann spectrum (BWSp)-specific cancer surveillance as depicted in Table 2.

Figure 2

Chromosomal arrangement of the 11p15.5 locus. Maternal allele on top (in pink) and paternal allele below (blue) are represented. IC1, imprinting center 1, attracts the non-methylated form CTCF (transcription repressors of the CCCTC-binding family), which activates transcription of H19, a non-coding RNA, which represses growth. When the imprinting center is methylated, as normally occurring on the paternal allele, H19 is not transcribed, and the downstream enhancer elements can act on IGF2, which similar to IGF-1, promotes growth, particularly in the perinatal phase. Imprinting center 2 represses the expression of the potassium channel gene, KCNQ1, via transcription of its antisense (KCNQ1OT1) and the nearby CDKN1C, a growth-repressing cycline. Therefore, when IC2 is methylated, as seen on the maternal allele, CDKN1C is expressed, and growth is attenuated. On the paternal allele, IC2 is not methylated, and CDKN1C along with KCNQ1 are repressed, allowing growth. Either via expression of IGF2 or silencing of CDKN1C, the paternal allele promotes growth. Hypermethylation of IC1 on the maternal allele resulting in IGF2 overexpression is the mechanism seen in the patient in Figure 1 (right). This causes the maternal allele to function similar to the paternal allele, resulting in overgrowth with macroglossia. Loss of methylation of the maternal IC2 resulting in CDKN1C repression will also result in BWSp. Note: IC2 is depicted in this figure in juxtaposition to the KCNQ1 gene for simplification; its true position is within the KCNQ1 gene.

Figure 3

A patient diagnosed with phosphatase and tensin homolog (PTEN)-hamartoma tumor syndrome. She was brought to medical attention shortly after birth for concerns of macrocephaly and hypotonia. Her brain MRI was normal. At 14 months, her fronto-occipital circumference (FOC) was 52.6 cm (+5.38 SD) and 56.4 cm (+5.06 SD) at 35 months. She has been receiving physical therapy since age 6 months due to hypotonia and also speech therapy for expressive language delays. FOC > 3 SD even as isolated finding is suspicious of PTEN-hamartoma tumor syndrome. Due to the increased risk for malignancy (see text and Table 2), she will undergo childhood cancer screening (thyroid carcinoma) and later adult cancer screening (breast, thyroid, endometrial, and colon). Developmental delays are common in this syndrome.

Figure 4

The cellular response to growth factor (GF) via its receptor. Upon dimerization of the receptor, IRS1 (insulin receptor substrate 1) is phosphorylated and activates (via its SH2 domain) downstream effectors, particularly PI3K (phosphatidylinositol 3-kinase). The latter, in turn, phosphorylates the second messenger PIP2 (phosphatidylinositol 4,5-bisphosphate), resulting in the activation of AKT (protein kinase B), which activates the mTORC1 (mammalian target of rapamycin complex 1). This pathway promotes cellular proliferation (via AKT) and also promotes angiogenesis and protein synthesis via the mTORC1 effector. Overactivation of the catalytic unit of PI3K, called PIK3CA, or AKT1 may result in uncontrolled activation of this pathway and signal-independent (over) growth. The former is seen in PIK3CA-related overgrowth spectrum (PROS) and the latter in Proteus syndrome, both are segmental overgrowth syndromes. A similar picture can be seen with biallelic deactivation of PTEN which is a growth repressor, as it dephosphorylates PIP₃ back to its inactive form PIP₂. This condition is seen in PTEN hamartoma tumor syndrome (PHTS). Not shown in the figure, but similar to PHTS, other growth repressors are the TSC1/2 complexes (tuber sclerosis complex), which inhibit mTORC1, but themselves are inhibited by AKT. The pathogenesis of variants in TSC1/2 is different, resulting in discrete tuberous growth of the cutaneous and CNS tissues, and predispose to variety of cancers. Of note, the PI3K/AKT/mTOR pathway is one pathway in which the growth factor activates.