Alström syndrome most commonly presents with a cone-rod dystrophy, progressive sensorineural hearing loss, short stature, obesity, cardiomyopathy and various degrees of metabolic disturbances [6, 18, 19, 20, 21]. Most symptoms are typically begin in the first decade of life but there is a severety of the phenotypic spectrum .
Here we describe two siblings who presented with decreased central vision, dyschromatopsia, photophobia, high myopia, and cone-rod dysfunction. Our patients demonstrated mild phenotypes of many of the typical clinical symptoms of AS leading to a delayed diagnosis. For both cases, the initial symptom was mild light sensitivity with onset at two years of age. Based on the fundus appearance and visual ability, the patients were originally given a diagnosis of myopia and optic atrophy. During first decade of the life, the patients had a relatively stable ocular appearance. Based on the history of early onset light sensitivity, high myopia, nystagmus, decreased visual acuity, decreased of color vision, and cone dysfunction much greater than rod dysfunction on ERG, our initial differential diagnosis was achromatopsia versus a cone-rod dystrophy. However, research genetic testing revealed two novel frameshift variants in ALMS1 in both brothers. The first was a single base pair duplication c.9894dupC (p.S3298fs, NM_015120, exon 12) and the second a single base pair deletion c.10769delC (p.T3590fs, NM_015120, exon 16). Upon further systemic review, additional findings consistent with Alstrom syndrome were found including: history of otitis media (Patient 1 and 2), mild developmental delay (Patient 1 and 2), type 2 diabetes mellitus (Patient 1), testosterone deficiency (Patient 1) and mild hearing loss (Patient 2).
Most pathogenic variants in ALMS1 occur downstream from exon 7, with the ‘hot spots’ for disease-causing variants in exons 8, 10, and 16 [2, 3, 14]. Both our variants were not previously described, but, there are two pathogenic mutations located close to these variants [14, 23]. One of these variants, c.10775delC (exon 16), was the most frequently identified in patients of English descent, suggesting a possible founder effect . In addition, we know that majority of the mutations that are nonsense and frameshift variations are predicted to cause premature protein truncation, resulting in the early termination of ALMS1 or a non-functional protein .
Our diagnostic findings: visual fields, ffERG, mfERG, SD-OCT, fundus appearance are consistent with typically clinical findings in a cone-rod dystrophy as usually seen in AS.
There are several interesting clinical findings our patients. Consistent with a mild systemic phenotype,neither of our patients had cardiac, renal or hepatic dysfunction. Nearly 89% of patients with AS have hearing loss with average age of detection of 7.45 years (range 1.5–15), predominantly symmetric, sensorineural, that may progress to a severe degree . Only one of our patients had a history of chronic otitis media with mild hearing loss that did not manifest until the third decade. Nearly 82% patients with AS have type 2 diabetes mellitus with the median age of onset 16 years, but only one sibling had diabetes mellitus type 2 that was not diagnosed until age 29 [1, 3, 7]. Unlike most patients with AS, where the height is normal in early childhood, but stalls in adolescence, our patients have normal stature (50-75th centile) . Obesity generally begins to develop in the first few years of life and without weight control the BMI of most young children is >95th percentile (3). Our patients have weight less than the 90th percentile. Additionally, our patients both presented with high myopia, but previous studies primarily reported hyperopia in AS, ranging from mild to high, and mentioned only two cases of myopia [6, 18, 19, 20, 21, 25, 26, 27, 28]. Our patients have no family history of myopia, indicating that its development may be specific to these novel variants in ALMS1. Finally, our patients have also had the presence of ptosis in both eyes and this feature not described before AS patients.
Currently, there is no known cure for AS other than managing underlying systemic diseases. The supportive treatments are available to manage symptoms and include a diet high in anti-oxidants, correction of refractive error, low-vision aids and wearing sunglasses outside. Although we only report two cases of the rare condition we have provided detailed clinical features and genotype-phenotype correlation in the two novel frameshift variants in ALMS1 that were never described before to our knowledge. The two new variants result in a mild phenotype, delayed onset, presence of high myopia, ptosis, late onset of hearing loss, and mild systemic features. We recommend a thorough systemic evaluation coupled with diagnostic and genetic testing in patients with achromatopsia/cone-rod dystrophy to avoid misdiagnosis.