Pallister-Hall Syndrome

Pallister-Hall syndrome is an autosomal dominant malformation syndrome caused by truncating variants in the middle third of GLI3, with hypothalamic hamartoma, polydactyly, and bifid epiglottis, and often imperforate anus and renal anomalies. Neonatal hypopituitarism, particularly adrenal insufficiency, is the main early life threatening risk.

Pathophysiology. GLI3 is a zinc finger transcription factor in the sonic hedgehog signalling system. Truncation in the middle third produces a transcriptional repressor that acts in a dominant negative fashion, unlike variants in other parts of GLI3 that cause Greig cephalopolysyndactyly or isolated polydactyly.

Expression varies widely, from mild to lethal presentations.

Most cases are de novo, but affected parents transmit with a 50% risk.

• Hypothalamic hamartoma with variable endocrine deficiency (growth hormone, ACTH, TSH, gonadotropins)
• Gelastic (laughing) seizures and other seizure types from the hamartoma
• Central or postaxial polydactyly of hands and feet, syndactyly, and short fingers
• Bifid epiglottis and laryngeal cleft, with airway obstruction
• Imperforate anus and anorectal anomalies
• Renal anomalies (dysplasia, agenesis, hydronephrosis)
• Genital anomalies and cryptorchidism
• Congenital heart disease and lung segmentation anomalies
• Nail dysplasia and dysmorphic ears
• Behavioural and developmental problems, in those with a large hamartoma

• GLI3 sequencing with deletion and duplication analysis, with variants in the middle third consistent with the syndrome.
• Brain MRI for hypothalamic hamartoma and pituitary assessment.
• Endocrine testing: morning cortisol and ACTH, short synacthen test if cortisol is low or borderline, free thyroxine and TSH, IGF-1, and gonadotropins. Early testing in the newborn is needed.
• Airway endoscopy for bifid epiglottis and laryngeal cleft.
• Renal ultrasound, echocardiography and limb radiography.
• EEG if seizures.

Differential diagnosis.

• Greig cephalopolysyndactyly syndrome (GLI3 variants outside the middle third)
• Oral-facial-digital syndromes
• Bardet-Biedl syndrome and McKusick-Kaufman syndrome
• Smith-Lemli-Opitz syndrome

• Adrenal insufficiency: hydrocortisone replacement 8 to 10 mg/m2 daily in three divided doses, and fludrocortisone 0.05 to 0.2 mg daily if mineralocorticoid deficiency is shown. During illness double or triple the dose, and in crisis give hydrocortisone 50 to 100 mg/m2 (maximum 100 mg) intravenously or intramuscularly, with intravenous fluids and glucose.
• Other hormone replacement: levothyroxine 10 to 15 microgram/kg daily in neonates (adults 1.6 microgram/kg daily) for central hypothyroidism, adjusted to free thyroxine. Growth hormone 0.033 mg/kg daily (specialist, limited evidence) when deficiency is shown. Sex steroids for hypogonadism at the usual pubertal age.
• Hypothalamic hamartoma seizures: carbamazepine 5 mg/kg twice daily increasing to 10 mg/kg twice daily (maximum 1.2 g daily in adults) or oxcarbazepine, and surgical disconnection, stereotactic laser ablation or radiosurgery for drug resistant seizures. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Airway: surgical repair of a laryngeal cleft or epiglottic abnormality.
• Anorectal malformation: colorectal surgery and bowel management; use macrogol 0.4 to 0.8 g/kg daily for constipation.
• Renal and urological care: monitor kidney function and treat obstruction or infection.
• Hand and foot surgery for polydactyly and syndactyly at 12 to 24 months.
• Genetic counselling: a 50% recurrence risk when a parent carries the variant; low risk when de novo.

Special groups.

• Newborns with a hypothalamic hamartoma: test the adrenal axis in the first days, because unrecognised adrenal insufficiency can cause fatal collapse.

Monitoring. Cortisol, thyroid function and growth every 3 months in infancy, then every 6 to 12 months. Seizures, kidney function and development at each visit.

Referral and escalation. Refer to clinical genetics, paediatric endocrinology, neurology and surgery. Emergency for hypoglycaemia, hypotension, hyponatraemia or airway obstruction.