Case Report: Pallister-Hall syndrome diagnosed in adulthood during evaluation of recurrent hypoglycemia

Pallister-Hall syndrome (PHS) is a rare autosomal dominant disorder caused by pathogenic variants in GLI3 gene. It is characterized by variable combinations of hypothalamic hamartoma, polydactyly, bifid epiglottis, renal and genitourinary abnormalities, imperforate anus, and pituitary dysfunction. Most cases are recognized during infancy or childhood; adult presentation is uncommon and hypoglycemia is not an established manifestation of PHS.

A 26-year-old man with obesity and well-controlled hypertension was referred for evaluation of recurrent fasting and postprandial hypoglycemia associated with intermittent brief loss of consciousness. Physical examination revealed class III obesity, acanthosis nigricans, hand polydactyly, and a history of surgically removed extra toe in childhood. Family history was remarkable for polydactyly affecting the mother and multiple maternal relatives. Biochemical evaluation demonstrated recurrent hypoglycemia with inappropriately unsuppressed insulin and C-peptide concentrations, compatible with endogenous hyperinsulinemic hypoglycemia, during both prolonged fasting and mixed-meal testing. Abdominal magnetic resonance imaging showed no pancreatic lesion but an atrophic right kidney and hepatic steatosis. Whole-exome sequencing identified a heterozygous GLI3 deletion with frameshift variant (NM_000168.6:c.2059del, p.(Glu687LysfsTer6)), confirming the diagnosis of PHS. Subsequent investigations demonstrated a hypothalamic hamartoma and partially bifid epiglottis, further confirming the diagnosis of PHS. The patient was referred for multidisciplinary management and genetic counseling.

This case highlights an unusual late presentation of PHS with recurrent hypoglycemia, severe obesity, and episodic loss of consciousness and demonstrates the multi-systemic involvement in PHS. It emphasizes the importance of careful phenotypic assessment and the value of genetic testing in establishing a unifying diagnosis in complex presentations.