Alstrom syndrome natural history, complications and prognosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1], Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

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Natural History

A wide range of clinical variability is observed among individuals with Alström syndrome, including among siblings. The first clinical presentation of Alström syndrome is usually nystagmus caused by cone-rod dystrophy and resulting in childhood blindness. Disease characteristics that are later in onset include truncal obesity that manifests during the first year of life, progressive sensorineural hearing loss, infantile-onset dilated cardiomyopathy or later-onset restrictive cardiomyopathy, insulin-resistant type 2 diabetes mellitus, and hepatic, pulmonary, and renal dysfunction.

Manifestation	Range of Age Onset	Incidence
Cone-rod dystrophy	Birth - 15 mos	100%
Obesity	Birth - 5 years	98%
Developmental delay	Birth-adolescence	25%-30%
Dilated cardiomyopathy	2 wks - 4 mos	42%
Progressive sensorineural hearing loss	2-25 yrs	88%
Restrictive cardiomyopathy	Juvenile - late 30s	18%
Insulin resistance / type 2 diabetes mellitus	4-30 yrs / 8-40 yrs	92% / 68%
Short stature	Puberty - adult	98%
Hepatic disease	8-30 yrs	23%-92%
Hypogonadotropic hypogonadism	10+ yrs	78% of males
Urologic disease	Adolescence - adult	48%
Renal disease	Adolescence - adult	Variably progressive with age

• Vision problems are progressive and ultimately result in blindness. Rod function is preserved initially but deteriorates as the individual ages, with visual acuity of 6/60 or less by age ten years, increasing constriction of visual fields, and no light perception by age 20 years. In some rare cases, some vision (e.g., the ability to read large print) is retained into the third decade.
• Hyperphagia and excessive weight gain (some studies show weight gain greater than expected for intake) begin during their first year, resulting in childhood truncal obesity. In some individuals body weight tends to normalize, decreasing into the high-normal to normal range after adolescence.
• Hearing loss may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. A high incidence of glue ear (long-standing sticky fluid in the middle ear) can lead to an additional conductive hearing loss.
• More than 60% of individuals with Alström syndrome develop congestive heart failure as a result of cardiomyopathy at some stage of their lives. Onset, progression, and clinical outcome of the cardiomyopathy vary, even within families. More than 40% of affected infants have a transient but severe dilated cardiomyopathy with onset between age three weeks and four months. Most of these children survive and make an apparently full recovery in infancy. At a later age about 10%-15% of this group have spontaneous recurrence of a progressive restrictive cardiomyopathy. The proportion of those with Alström syndrome who develop infantile-onset cardiomyopathy may be underestimated because some infants who succumb may have undiagnosed Alström syndrome. About 20% of individuals with Alström syndrome have later-onset progressive restrictive cardiomyopathy identified between the teens to late 30s. Cardiac magnetic resonance imaging suggests that myocardial fibrosis may be present in clinically affected and asymptomatic individuals.
• In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age.
• Growth rates for young children are normal, but accelerated skeletal maturity (2-3 years advanced bone age) and low-serum growth hormone concentrations result in adult stature that is typically less than the 25th centile. In about 98% of individuals over age 16 years height is below the fifth centile.
• Renal disease is common, slowly progressive, and highly variable, and may be unrelated to diabetes; it manifests as tubulo-interstitial disease resulting from interstitial fibrosis. Initial signs of mildly elevated serum concentrations of creatinine and blood urea nitrogen (BUN) may be followed by polyuria and polydipsia resulting from a concentrating defect. Onset can be in mid-childhood through adulthood. End-stage renal disease (ESRD) can occur as early as the mid- to late teens.
• Progression to cirrhosis and hepatic failure can occur in the second to third decades, and the complications of portal hypertension, ascites, splenomegaly, hepatic encephalopathy, and esophageal varices are also seen.
• Recurrent chest infections are common at all ages. Most frequently there is a combination of restrictive lung disease due to kyphoscoliosis and sometimes pulmonary fibrosis, which has been confirmed in post mortem tissue and may be detected in life with high-resolution chest CT scan. This may progress (with the added effects of cardiomyopathy) to pulmonary hypertension. The resulting susceptibility to severe hypoxia postoperatively or during episodes of pneumonia has been reported.

Complications

• Blindness
• Hearing loss
• Congestive heart failure
• Cirrhosis
• Pancreatitis
• ESRD
• Hypothyroidism
• Pulmonary fibrosis
• Portal hypertension
• Type 2 diabetes mellitus
• Stunted growth

References

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