Case Report: Identification of two novel ALMS1 variants in a patient with a ciliopathy resembling Alström syndrome

Alström syndrome (AS) is a rare autosomal recessive ciliopathy caused by biallelic pathogenic variants in the ALMS1 gene. The condition is characterized by a spectrum of clinical manifestations, including cone-rod dystrophy, sensorineural hearing loss, metabolic disturbances, and progressive multiorgan involvement. Ciliopathies share considerable clinical overlap, and some cases present with features that resemble AS without meeting all diagnostic criteria. This study aims to identify the pathogenic variants in a Chinese patient with a ciliopathy resembling AS.

We report a 27-year-old Chinese female with a body mass index (BMI) of 28.4 kg/m². The patient initially presented with progressive hearing loss at age 2 years, followed by visual impairment beginning at age 8 years. At age 17 years, she developed progressive alopecia accompanied by scaly, patchy papules. By age 22 years, she was diagnosed with polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus (T2DM). Laboratory investigations revealed dyslipidemia and hyperinsulinemia. Abdominal ultrasonography demonstrated hepatic steatosis and medullary sponge kidney, while pelvic ultrasound indicated polycystic ovarian morphology. Echocardiography revealed ventricular septal thickening. Whole-exome sequencing (WES) identified that our patient was a compound heterozygote for two novel variants in the ALMS1 gene, comprising c.12114 + 1G>T and c.1856_1860dup (p.Ser621Leufs*23). Both variants were classified as likely pathogenic in accordance with the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. Based on the clinical phenotype and molecular findings, a diagnosis of a ciliopathy resembling AS was made, although a definitive diagnosis of AS could not be confirmed due to incomplete ocular phenotyping. Disease management included metformin and pioglitazone for T2DM, continued use of hearing aids, and scheduled regular follow-up evaluations.

This report describes two novel ALMS1 variants, expanding the known mutational spectrum of the gene. Genetic testing plays a supportive role in diagnosis and is valuable for familial screening and counseling, although a definitive diagnosis of AS would require complete ophthalmic phenotyping and functional validation.