Contributed by Jacob Smith, MD., Sarangarajan Ranganathan, MDFINAL DIAGNOSIS
Alström Syndrome
DISCUSSION
Alström syndrome is a primary ciliopathy that presents with a wide variety of signs and symptoms. The clinical manifestations begin in infancy and progress variably to include vision and hearing loss, as well as endocrine, cardiac, pulmonary, renal and liver abnormalities [1, 2, 3]. It was first reported in 1959 in a report of three patients. Alström syndrome is an autosomal recessive disorder caused by mutations in the ALMS1 gene with an estimated prevalence of one to nine per one million in the general population [4]. There have been approximately 950 cases reported worldwide [4]. The ALMS1 gene is located on chromosome 2p13, spans 23 exons, and encodes a predicted 461.2-kDa protein of 4169 amino acids [3, 5]. The mRNA expressed by ALMS1 is found in many tissues and differential expression or chimerism may explain the varying clinical presentations [2, 5]. The role of ALMS1 is still not fully understood, but studies have demonstrated that it localizes to centrosomes and to the base of cilia, which suggest roles in ciliogenesis and intracellular trafficking [6, 7, 8]. There are many clinical features of Alström syndrome and the presentation and rate of progression are variable. Early signs of disease are visual disturbances and sensorineural hearing deficits [1, 2, 3]. Intellectual disability is a rare presentation [3]. These children have characteristic facial profiles which include: deep-set eyes, rounded face, thick ears, premature frontal balding, thin hair, hyperostosis frontalis interna, discolored teeth and extra or missing teeth [3]. Lumbar scoliosis and kyphosis are common. No polydactyly or syndactyly have been reported [3]. Later in childhood metabolic disturbances begin and include the following: insulin resistance and hyperinsulinemia, truncal obesity, hypogonadism, hypertriglyceridemia, hypothyroidism, short stature, and low growth hormone [1, 2, 3]. As the disease progresses, multiple organ failure may occur in the heart, liver, lung and/or kidneys [1]. The criteria for diagnosis of Alström syndrome is the presence of two mutated alleles or a single mutated allele in the presence of specific clinical findings [3]. Currently, patients are treated symptomatically as there is no targeted therapy.
In one of the few studies examining the pathologic changes in Alström syndrome, Marshall JD et al obtained post mortem tissue samples from three women and two men aged 27 to 42 years of age. In all five patients, there was evidence of glomerular and interstitial renal fibrosis. Three of the patients had micronodular cirrhosis of the liver with severe portal fibrosis, fatty changes, and nodules of regenerative liver parenchyma. Two patients had mild portal fibrosis. Other organs that demonstrated fibrosis were the pancreas, heart, testis, and ovaries. Overall, this study demonstrated that patients with Alström syndrome have severe fibrosis in multiple organ systems [1].
Pathologic changes previously reported in Alström syndrome were found in our patient. The kidney biopsy revealed glomerulosclerosis in 17% of the glomeruli examined and findings of focal segmental glomerulosclerosis (FSGS) seen in Figure 1. Interstitial fibrosis was present on the Trichrome stain. The liver biopsy revealed macrovesicular steatosis pattern that involved 33-66 percent of the liver core biopsy with delicate periportal sinusoidal fibrosis seen in Figure 2. It is thought that the steatosis represents the initial presentation that may eventually progress to severe fibrosis with about 10% of patients dying of end-stage liver disease [1, 2, 3, 9].
This case highlights a rare entity that requires the involvement of multiple subspecialities for coordinated pediatric care. In conclusion, Alström syndrome is an autosomal recessive primary ciliopathy characterized on biopsy as multiorgan fibrosis.
REFERENCES
Contributed by Jacob Smith, MD., Sarangarajan Ranganathan, MD
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