Simpson–Golabi–Behmel syndrome

Overview

Simpson–Golabi–Behmel syndrome (SGBS) is a rare genetic overgrowth disorder that affects multiple organ systems and is characterized by pre- and postnatal overgrowth, distinctive facial features, congenital malformations, and an increased risk of embryonal tumors. It primarily affects males and follows an X-linked recessive inheritance pattern. First described in the 1970s, SGBS is part of a group of syndromes known as overgrowth syndromes, which also includes Beckwith–Wiedemann syndrome. Despite its rarity, early diagnosis is important due to associated risks, particularly the potential for tumor development in childhood.

Causes

SGBS is caused by mutations in the GPC3 gene (glypican 3), which is located on the X chromosome (Xq26). This gene plays a critical role in regulating cell growth and division by modulating signaling pathways such as Wnt and Hedgehog, which are essential for embryonic development. In some cases, mutations in the GPC4 gene have also been implicated.

Because SGBS is inherited in an X-linked recessive manner, it primarily affects males who inherit the mutated gene from their carrier mothers. Female carriers usually do not show symptoms, although some may have mild features. In rare cases, females can be affected if they have skewed X-inactivation or chromosomal abnormalities involving the GPC3 gene.

Symptoms

Simpson–Golabi–Behmel syndrome exhibits a wide range of features, which can vary significantly among affected individuals. Common clinical manifestations include:

Growth Features:

• Macrosomia (large body size at birth)

• Pre- and postnatal overgrowth

• Large hands and feet

Craniofacial Features:

• Coarse facial features

• Macroglossia (enlarged tongue)

• Wide nasal bridge

• Hypertelorism (widely spaced eyes)

• Prominent jaw and lips

Skeletal and Muscular Abnormalities:

• Broad ribs

• Large, prominent sternum

• Polydactyly (extra fingers or toes) in some cases

• Hernias (umbilical or inguinal)

Internal Organ and Developmental Features:

• Congenital heart defects

• Kidney anomalies (e.g., hydronephrosis)

• Gastrointestinal malformations

• Developmental delay or intellectual disability (mild to moderate)

Tumor Risk:

• Increased risk of embryonal tumors such as Wilms tumor, hepatoblastoma, and neuroblastoma

• Tumor surveillance is recommended during early childhood

Diagnosis

Diagnosis of Simpson–Golabi–Behmel syndrome is based on clinical presentation, family history, and genetic testing. Key diagnostic steps include:

• Clinical evaluation: Observation of overgrowth, characteristic facial features, and congenital anomalies

• Family history: Identification of other male relatives with similar symptoms or unexplained infant deaths

• Genetic testing: Molecular testing to identify mutations in the GPC3 gene confirms the diagnosis

• Prenatal imaging: Ultrasound may reveal macrosomia, polyhydramnios, or organ anomalies suggestive of SGBS

In females, carrier testing may be performed if there is a known family mutation or an affected male relative. Differential diagnosis includes other overgrowth syndromes like Beckwith–Wiedemann syndrome and Sotos syndrome.

Treatment

There is no cure for SGBS, and treatment is focused on managing symptoms, supporting development, and monitoring for complications. A multidisciplinary approach is essential and may include:

Monitoring and Surveillance:

• Regular abdominal ultrasounds and serum alpha-fetoprotein (AFP) testing for tumor surveillance (especially Wilms tumor and hepatoblastoma) until at least age 8

• Periodic renal and cardiac evaluations

Supportive and Surgical Management:

• Surgical repair of congenital anomalies (e.g., hernias, heart defects)

• Speech therapy for macroglossia-related speech or feeding difficulties

• Orthopedic evaluation for skeletal abnormalities or polydactyly

Developmental Support:

• Early intervention services (physical, occupational, and speech therapy)

• Individualized educational support for children with learning difficulties

Genetic Counseling:

• For affected families to understand inheritance patterns and reproductive options

• Carrier testing and prenatal diagnosis can be offered for at-risk pregnancies

Prognosis

The prognosis for individuals with Simpson–Golabi–Behmel syndrome varies depending on the severity of symptoms and presence of complications. Many affected individuals can live into adulthood with supportive care, though early childhood may involve significant medical interventions.

Key factors influencing prognosis include:

• The severity of congenital anomalies (e.g., cardiac defects)

• The presence and management of developmental delays

• The early detection and treatment of tumors

With early diagnosis, regular surveillance, and multidisciplinary care, many individuals with SGBS can achieve a good quality of life. Lifelong follow-up is recommended to monitor growth, development, and overall health.