Simpson-Golabi-Behmel Syndrome Type 1

Clinical characteristics: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities); and, commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma.

Diagnosis/testing: The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing. The diagnosis is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in GPC3 or an intragenic or whole-gene deletion of GPC3 identified by molecular genetic testing.

Management: Treatment of manifestations: Prompt treatment of neonatal hypoglycemia and airway obstruction resulting from micrognathia and glossoptosis. Treatment of cleft lip and/or cleft palate or macroglossia and related feeding difficulties, obstructive sleep apnea, ophthalmologic issues, hearing loss, heart defects, urogenital abnormalities, skeletal abnormalities, seizures, Wilms tumor, and other types of tumors per standard recommendations by appropriate pediatric specialists. Speech therapy as needed. Neurodevelopmental assessment to determine the need for special education, occupational therapy, and/or physical therapy.

Surveillance: Screening for Wilms tumor and hepatoblastoma with abdominal ultrasound and serum AFP level every three months from time of diagnosis until age four years; renal ultrasound every three months until age seven years; no specific tumor screening protocol has been established for neuroblastoma, gonadoblastoma, or medulloblastoma, but follow up with a cancer predisposition specialist every six months is recommended. Annual (or as indicated) ophthalmologic and audiologic evaluations in childhood; sleep study if there are concerns about sleep dysregulation including sleep apnea; routine monitoring of kidney function if renal anomalies are present; evaluation for scoliosis at least annually or during periods of rapid growth; monitoring of serum glucose level in the neonatal period; monitoring of developmental progress at each visit through adolescence.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the GPC3 pathogenic variant in the family in order to identify as early as possible those who would benefit from preventive measures such as tumor surveillance.

Pregnancy management: Gestational hypertension, diabetes, preeclampsia, fetal distress, and preterm labor have all been reported in mothers of individuals with SGBS1. Fetal macrocephaly and overgrowth may necessitate cesarean delivery or early induction of labor.

Genetic counseling: SGBS1 is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1. Males with SGBS1 will pass the pathogenic variant to all their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for families in which the pathogenic variant has been identified.