Alström syndrome (ORPHA:64)
A rare multisystemic disorder characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), and progressive hepatic and renal dysfunction.
Epidemiology
Alström syndrome (AS) has a suggested prevalence of 1/1000,000 in Europe and North America. A much higher frequency was reported in some populations with a high level of consanguinity or those that are geographically isolated. More than 950 cases have been identified worldwide.
Clinical description
The clinical features, age of onset, and severity can vary greatly among and within families. Cone-rod retinal dystrophy usually develops within a few weeks after birth, with the first symptoms being nystagmus and extreme photodysphoria or light sensitivity. It is progressive and leads to blindness, usually by the second decade of life. Most patients develop mild-to-moderate slowly progressive bilateral sensorineural hearing loss. There is evidence of multi-organ fibrosis in AS. DCM manifests in approximately 2/3 of patients, either as infants or as adolescents. Patients are at risk of sudden congestive heart failure at any age. Obesity with hyperphagia, insulin resistance and hyperinsulinemia are early and consistent features. Liver dysfunction usually begins in childhood with steatosis (fatty liver). In some cases, cirrhosis, portal hypertension and liver failure can occur. Chronic respiratory illness (bronchitis/pneumonia), pulmonary hypertension, recurrent otitis media, and hypertriglyceridemia are frequent. Slowly progressive nephropathy can lead to end stage renal failure. Patients have distinctive facial characteristics ( thin hair, premature frontal balding, deep-set eyes with a rounded face and thick ears,). Most children have characteristic wide, thick, flat feet, and short stubby fingers and toes with no polydactyly or syndactyly. Hypogonadism in males/hyperandrogenism in females is also reported. Most patients have normal intelligence, although some reports have indicated delayed global development and intellectual disability. As some phenotypes develop slowly over time, non-classical presentations have also been reported.
Etiology
AS is caused by mutations in the ALMS1 gene (2p13.1). Its molecular function is currently unknown, although roles in ciliary function, cell cycle control, and intracellular transport have been suggested.
Diagnostic methods
Diagnosis is made on the basis of the clinical features observed (major/minor), and typically confirmed with genetic testing. Family history is considered a major criteria in the diagnosis of AS.
Differential diagnosis
Differential diagnoses include Bardet-Biedl syndrome, Biemond syndrome type 2, Wolfram syndrome, Cohen syndrome, familial isolated DCM and mitochondrial disorders.
Antenatal diagnosis
Prenatal testing can be offered if the ALMS1 mutations have been previously identified in a family member.
Genetic counseling
AS is transmitted autosomal recessively and genetic counseling is recommended.
Management and treatment
Management should include vigilant monitoring and treatment of the emerging clinical manifestations. Red-orange tinted prescription lenses can reduce photophobia. As blindness occurs in all cases, early educational planning to teach patients Braille, computing skills and adaptive living skills is essential. Bilateral digital hearing aids and cochlear implants can increase hearing capabilities. Heart failure is mainly treated with angiotensinogen-converting enzyme (ACE) inhibitors, beta-blockers, diuretics, and digoxin. Heart transplantation could be also considered. Diabetes can be managed with a low-fat, low sugar diet, exercise, metformin, glitazones, incretin analogues, and SGLT2 inhibitors (beneficial in 2/3 of cases). Beta-blockers, sclerotherapy of the esophageal veins, and banding usually treat portal hypertension. In unsuccessful cases a transjugular intrahepatic portosystemic shunt may be needed. In those with renal disease, ACE inhibitors can be considered. In several cases, renal transplantation has been successful. New medications are in clinical trials, and include PBI-4050 (phase 2 completed), a compound with anti-fibrotic and anti-inflammatory properties, and setmelanotide for the treatment of hyperphagia in rare forms of genetic obesity including AS.
Prognosis
Although the life span of AS patients can be shortened, early diagnosis and intervention can moderate the progression and improve the longevity and quality of life of patients.

                            Last update: 
                            August 2019


                            - Expert reviewer(s): 
                            Dr Pietro MAFFEI