Clinical Presentation of a Child With a Novel ALMS1 Variant Associated With Alström Syndrome and Favorable Response...

Alström syndrome (AS) is a rare autosomal-recessive ciliopathy caused by biallelic variants in ALMS1, with an incidence of 1 in 10,000 to 1 in 1,000,000 live births. We report a female diagnosed at age 5 with a previously unreported homozygous nonsense variant in ALMS1: c.4740C>G (p.Tyr1580Ter), located in exon 8, a known hotspot for pathogenic variants. The variant aligns with the loss-of-function mechanism seen in most ALMS1-related AS cases and is found within a 15 Mb run of homozygosity, consistent with her history of parental consanguinity. Her clinical picture included progressive hearing loss, dyslipidemia, and worsening hyperglycemia despite lifestyle interventions. Due to accelerated weight gain and declining glycemic control, dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), was initiated. Over 48 weeks, BMI decreased from 190% to 160% of the 95th percentile, with a 0.95 z-score reduction, 1.2% HbA1c decrease into the normal range. This case expands our understanding of the ALMS1 mutational spectrum and provides the first longitudinal report of GLP-1 RA benefit in AS, supporting its consideration as adjunctive therapy and highlighting the need for further study.