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Overgrowth syndromes — clinical and molecular aspects and tumour risk

Abstract

Overgrowth syndromes are a heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as visceromegaly, macrocephaly and a large range of various symptoms. These syndromes are caused by either genetic or epigenetic anomalies affecting factors involved in cell proliferation and/or the regulation of epigenetic markers. Some of these conditions are associated with neurological anomalies, such as cognitive impairment or autism. Overgrowth syndromes are frequently associated with an increased risk of cancer (embryonic tumours during infancy or carcinomas during adulthood), but with a highly variable prevalence. Given this risk, syndrome-specific tumour screening protocols have recently been established for some of these conditions. Certain specific clinical traits make it possible to discriminate between different syndromes and orient molecular explorations to determine which molecular tests to conduct, despite the syndromes having overlapping clinical features. Recent advances in molecular techniques using next-generation sequencing approaches have increased the number of patients with an identified molecular defect (especially patients with segmental overgrowth). This Review discusses the clinical and molecular diagnosis, tumour risk and recommendations for tumour screening for the most prevalent generalized and segmental overgrowth syndromes.

Key points

  • Overgrowth syndromes are a heterogeneous group of disorders with clinical overlap and specific clinical traits that make it possible to distinguish between them.

  • Most overgrowth syndromes are caused by anomalies in factors that are implicated in the control of cell proliferation or in the control of epigenetic markers.

  • Advances in the past decade have enabled the identification of mosaic molecular defects in hyperplastic tissues of patients with segmental overgrowth, particularly in the PI3K–AKT pathway.

  • An increased risk of tumours is usually reported in patients with overgrowth syndromes.

  • Syndrome-specific tumour screening programmes are needed on the basis of international consensus meetings.

  • Strategies for molecular explorations should be based on an accurate clinical description, as the molecular defects can be genetic (mutations), cytogenetic (large rearrangements) or epigenetic.

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Fig. 1: Representation of the 11p15 region in humans.
Fig. 2: Proposed molecular testing strategy for overgrowth syndromes.

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Glossary

Macrosomia

Fetal macrosomia has been defined in several different ways, including birthweight of 4,000–4,500 g (8 lb 13 oz to 9 lb 15 oz) or >90th percentile for gestational age after correcting for neonatal sex and ethnicity. On the basis of these definitions, macrosomia affects 1–10% of all pregnancies. A diagnosis of fetal macrosomia can be made only by measuring birthweight after delivery.

Exomphalos

A midline anterior incomplete closure of the abdominal wall in which there is herniation of the abdominal viscera into the base of the abdominal cord (also known as omphalocele).

Macroglossia

Increased length and width of the tongue.

Lateralized overgrowth

Overgrowth of only one side of the body (also known as hemihypertrophy).

Naevus flammeus

A congenital vascular malformation consisting of superficial and deep dilated capillaries in the skin that result in a reddish to purplish discolouration of the skin.

Visceromegaly

Enlargement of the internal organs in the abdomen, including the liver, spleen, stomach, kidneys or pancreas.

Uniparental disomy

(UPD). The inheritance of two homologous chromosomes from the same parent. These genetic anomalies arise from errors in meiosis and/or mitosis and can occur independently or in combination.

Assisted reproductive technologies

Consist of procedures that involve the in vitro handling of both human oocytes and sperm, or of embryos, with the objective of establishing a pregnancy.

Diastasis recti

A separation of the rectus abdominis muscle into right and left halves (which are normally joined at the midline at the linea alba).

Pectus excavatum

A defect of the chest wall characterized by a depression of the sternum, giving the chest (pectus) a caved-in (excavatum) appearance.

Postaxial polydactyly

A form of polydactyly in which the extra digit or digits are localized on the side of the fifth finger or fifth toe.

Genu varum

A positional abnormality marked by outward bowing of the legs in which the knees stay wide apart when a person stands with the feet and ankles together.

Genu valgum

A positional abnormality in which the legs angle inward, such that the knees are close together and the ankles are far apart.

Microretrognathism

A form of developmental hypoplasia of the mandible in which the mandible is mislocalized posteriorly.

Hemimegalencephaly

Enlargement of all or parts of one cerebral hemisphere.

Polymicrogyria

A congenital abnormality of the cerebral hemisphere characterized by an excessive number of small gyri (convolutions) on the surface of the brain.

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Brioude, F., Toutain, A., Giabicani, E. et al. Overgrowth syndromes — clinical and molecular aspects and tumour risk. Nat Rev Endocrinol 15, 299–311 (2019). https://doi.org/10.1038/s41574-019-0180-z

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