Overgrowth syndromes are rare genetic conditions characterized by excessive growth that begins before birth and continues into childhood. This heightened growth can impact nearly any part of the body, including bones, muscles, blood vessels, organs, skin, and fat. The manifestation can be localized, affecting only a specific area, or generalized, impacting the child’s entire body. Each case is unique, with varying severity and affected bodily systems.
Understanding Overgrowth Syndromes
Overgrowth in these syndromes refers to an increase in cell proliferation and tissue enlargement, leading to greater-than-average size for age and sex. Children with these disorders are often larger at birth, exhibiting macrosomia (increased birth weight) and macrocephaly (an abnormally large head). The excessive growth can be observed prenatally through ultrasounds, often noting the fetus is large for gestational age.
Overgrowth can present as generalized, where the entire body grows disproportionately large, or as segmental, affecting only one or more body parts. Segmental overgrowth might involve a single limb, an organ, or a specific region of the body, such as one side of the body being larger than the other, a condition known as hemihyperplasia.
Genetic Origins
Overgrowth syndromes are rooted in genetic mutations or abnormalities. These often involve single gene defects, where a change in a single gene disrupts normal growth regulation. For example, Sotos syndrome is linked to mutations in the NSD1 gene. These genetic alterations can affect pathways that control cell growth and division, such as the PI3K-AKT-mTOR pathway.
The origin of these genetic changes can differ; some cases are inherited from a parent, indicating a familial history. However, many cases arise from de novo mutations, which are new genetic changes that occur in the individual and are not present in either parent’s genes. For example, more than 95% of Sotos syndrome cases are due to de novo mutations. These new mutations can occur spontaneously during the formation of reproductive cells or early embryonic development.
Common Features and Health Implications
The excessive growth associated with overgrowth syndromes can lead to a wide array of physical manifestations and health challenges. Physical deformities are common, including asymmetry. Organomegaly (enlarged organs) is another frequent finding, with conditions like an enlarged tongue (macroglossia), kidney abnormalities, or enlarged abdominal organs. These physical differences can sometimes improve over time, such as macroglossia and hemihyperplasia in Beckwith-Wiedemann syndrome.
Developmental delays are a concern, with varying degrees of intellectual disabilities or motor delays. While some individuals may have normal intelligence, others might experience mild to severe intellectual disability or delays in motor development. For instance, Sotos syndrome is frequently associated with intellectual disability and developmental delay.
A significant concern with many overgrowth syndromes is an increased predisposition to certain childhood cancers. Tumors, particularly embryonic types, can develop, with Wilms tumor (a kidney cancer) and hepatoblastoma (a liver cancer) being among the most common. The risk of these tumors varies by syndrome; for example, Beckwith-Wiedemann syndrome carries an increased risk of Wilms tumor and hepatoblastoma. Additionally, other congenital defects, such as heart or kidney anomalies, or abdominal wall defects like omphalocele, may be present at birth.
Diagnosis and Support
The identification of overgrowth syndromes often begins with indications observed before or shortly after birth. Prenatal ultrasounds may reveal a fetus that is unusually large for its gestational age, which, after ruling out other common causes like maternal diabetes, can raise suspicion for an overgrowth syndrome. Postnatal signs, such as rapid growth, macrosomia, macrocephaly, or distinct physical features, prompt further evaluation. The precise set of symptoms varies between syndromes, which can complicate initial clinical differentiation.
Confirming a diagnosis typically involves genetic testing, which analyzes an individual’s DNA for specific mutations or abnormalities. This testing can be performed using blood or saliva samples and usually takes several weeks for results. While clinical diagnosis based on observable features remains relevant, advancements in molecular genetics have allowed for the identification of the specific genetic underpinnings of many syndromes.
Management of overgrowth syndromes requires a multidisciplinary approach, involving a team of medical specialists. This team may include geneticists, who confirm the diagnosis and provide counseling; oncologists, for cancer surveillance and treatment if tumors develop; developmental pediatricians, to address developmental delays; and orthopedists, for skeletal issues. Early intervention and regular screenings are important, especially for cancers, which may involve regular abdominal ultrasounds and blood tests to detect tumors at an early stage. Supportive therapies, such as physical or speech therapy, are also frequently implemented to address specific developmental or physical challenges.