GLI3-Related Pallister-Hall Syndrome

Clinical characteristics: GLI3-related Pallister-Hall syndrome (GLI3-PHS) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild GLI3-PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with GLI3-PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency.

Diagnosis/testing: The diagnosis of GLI3-PHS can be established in a proband with both hypothalamic hamartoma and mesoaxial polydactyly. Identification of a heterozygous pathogenic variant in GLI3 confirms the diagnosis.

Management: Treatment of manifestations: Urgent treatment for endocrine abnormalities, especially cortisol deficiency; symptomatic treatment of seizures; elective repair of polydactyly. Management of epiglottic abnormalities depending on the abnormality and the extent of respiratory compromise; bifid epiglottis, the most common abnormality, typically does not need treatment. Treatment of behavioral issues per psychologist &/or psychiatrist; seizures may begin or worsen with use of stimulants for attention-deficit disorder; developmental intervention and/or special education for developmental delays; standard treatment of anal atresia or stenosis.

Surveillance: Annually during childhood: assess growth, monitor for signs of precocious puberty, and assess developmental progress, educational needs, and behavioral issues.

Agents/circumstances to avoid: Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement. Some stimulants used for attention-deficit/hyperactivity disorder may exacerbate seizures.

Genetic counseling: GLI3-PHS is inherited in an autosomal dominant manner. Individuals with GLI3-PHS may have an affected parent or may have the disorder as the result of a de novo pathogenic variant. About 25% of individuals have a de novo pathogenic variant. Persons with a de novo pathogenic variant are generally more severely affected than those with a family history of GLI3-PHS. The risk to offspring of an affected individual is 50%. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known. The reliability of ultrasound examination for prenatal diagnosis is unknown.