Overgrowth syndrome

Overview

Overgrowth syndrome refers to a group of rare genetic conditions characterized by excessive physical growth, either generalized or localized along with other developmental abnormalities. These syndromes typically involve increased growth velocity in height, weight, or head circumference and are often apparent from infancy or early childhood. Many overgrowth syndromes are associated with a risk of developmental delay, intellectual disability, distinctive facial features, and an increased predisposition to certain tumors or cancers.

Overgrowth syndromes are genetically heterogeneous, meaning they can result from mutations in different genes. Some well-known types include Beckwith-Wiedemann syndrome, Sotos syndrome, Proteus syndrome, Weaver syndrome, and Simpson-Golabi-Behmel syndrome. Early recognition and diagnosis are crucial for monitoring complications and providing individualized care.

Causes

Overgrowth syndromes are caused by genetic mutations that affect cellular growth and proliferation. These mutations often disrupt signaling pathways involved in growth regulation, including epigenetic modifications, growth factor receptors, and transcription factors.

Examples of Genetic Causes

• Beckwith-Wiedemann Syndrome (BWS): Caused by alterations on chromosome 11p15, affecting genes such as IGF2 and CDKN1C

• Sotos Syndrome: Caused by mutations in the NSD1 gene on chromosome 5q35

• Weaver Syndrome: Associated with mutations in the EZH2 gene

• Proteus Syndrome: Caused by mosaic mutations in the AKT1 gene

• Simpson-Golabi-Behmel Syndrome (SGBS): Linked to mutations in the GPC3 gene on the X chromosome

Inheritance Patterns

• Most overgrowth syndromes are sporadic (non-inherited), caused by de novo mutations

• Some, such as SGBS, follow an X-linked recessive pattern

• Others may be autosomal dominant but with variable expressivity and incomplete penetrance

Symptoms

The clinical features of overgrowth syndromes vary depending on the specific condition, but most share common characteristics of increased growth, developmental anomalies, and tumor predisposition.

General Features

• Increased birth weight and/or length

• Accelerated postnatal growth (height and/or head circumference)

• Macrocephaly (abnormally large head)

• Asymmetry of limbs or body parts (hemihyperplasia)

• Characteristic facial features (syndrome-specific)

• Developmental delay or intellectual disability

• Musculoskeletal anomalies (e.g., scoliosis, joint laxity)

Other Syndrome-Specific Features

• Beckwith-Wiedemann Syndrome: Abdominal wall defects, enlarged tongue (macroglossia), neonatal hypoglycemia, increased tumor risk (e.g., Wilms tumor)

• Sotos Syndrome: Tall stature, learning disability, triangular face, hypotonia, advanced bone age

• Proteus Syndrome: Progressive overgrowth of bones, skin, and other tissues; asymmetric and disfiguring

• Weaver Syndrome: Broad forehead, camptodactyly (bent fingers), hoarse voice, advanced bone age

• Simpson-Golabi-Behmel Syndrome: Coarse facial features, organomegaly, supernumerary nipples, cardiac and renal anomalies

Diagnosis

Diagnosis of overgrowth syndromes involves clinical evaluation, growth monitoring, genetic testing, and imaging studies. Early identification allows for timely surveillance for complications and appropriate developmental support.

Clinical Assessment

• Detailed family and prenatal history

• Physical examination including measurement of height, weight, head circumference, and assessment of asymmetry or dysmorphic features

Imaging Studies

• Abdominal ultrasound: For screening tumors (especially in BWS)

• Skeletal survey: To assess bone age, deformities, and asymmetry

Genetic Testing

• Targeted gene sequencing or deletion/duplication testing based on clinical suspicion

• Chromosomal microarray for detecting copy number variations

• Epigenetic testing (e.g., methylation studies in BWS)

• Whole exome sequencing in undiagnosed or complex cases

Diagnostic Criteria

• Each syndrome may have defined clinical diagnostic criteria based on hallmark features (e.g., BWS consensus diagnostic score)

Treatment

Treatment for overgrowth syndromes is symptom-specific and multidisciplinary. There is no cure for the genetic conditions themselves, but many of the associated features and complications can be effectively managed.

Medical Management

• Surveillance for tumors: Regular abdominal ultrasounds and serum AFP levels (especially in BWS)

• Endocrinology support: For monitoring growth and metabolic issues

• Speech, occupational, and physical therapy: For developmental delays and hypotonia

Surgical Interventions

• Correction of facial or skeletal anomalies (e.g., macroglossia, scoliosis)

• Removal of tumors if detected early

• Orthopedic surgeries for limb length discrepancies or joint issues

Developmental and Educational Support

• Individualized education programs (IEPs)

• Specialized learning support services

Prognosis

The prognosis for individuals with overgrowth syndrome varies depending on the specific type and severity of the condition. Many children with overgrowth syndromes grow into adulthood with manageable challenges, particularly when the condition is diagnosed early and followed with appropriate interventions.

Some forms, such as BWS and Sotos syndrome, have good long-term outcomes with tumor surveillance and developmental support. Others, like Proteus syndrome, can be progressive and cause significant physical disability or complications. The risk of tumors also varies between syndromes and requires lifelong monitoring in some cases.

With multidisciplinary care, including genetic counseling, developmental therapies, and medical surveillance, most individuals can achieve improved quality of life and functional independence.