Alström syndrome is an autosomal recessive disorder characterized by obesity, sensorineural deafness, and cone-rod dystrophy appearing during the first decade of life.1 Detailed light and ultrastructural histopathology reveals a total absence of rods and cones, intraretinal melanin pigment, retinal pigment epithelium atrophy, and focal chorioretinal fusion.2 Diffuse areas of chorioretinal atrophy and large clumps of pigment develop later in the disease process.3
Male patients usually display hypergonadotrophic hypogonadism but are normally virilized. Chronic nephritis and diabetes caused by insulin resistance occur later, usually in the second or third decade of life. Late-appearing manifestations include hepatic failure, dilated cardiomyopathy, and renal failure.
There are many similarities between Alström syndrome and Leber's congenital amaurosis especially in the early stages of disease when systemic findings are not apparent. Correct diagnosis may be elusive in infancy because accurate determination of vision, hearing, and mental capacity is difficult. Other findings such as diabetes mellitus and renal impairment in Alström syndrome patients usually do not develop until adolescence.4
The pigmentary retinal degeneration of Alström syndrome also may be confused with Bardet-Biedl syndrome.5 Retinal pigmentary degeneration, hypogonadism, and obesity are present in both syndromes. Severe visual loss occurs at a younger age in patients with Alström syndrome. There is a higher incidence of neurogenic deafness and diabetes mellitus in patients with Alström syndrome, but a lower incidence of mental retardation and digital anomalies than in Bardet-Biedl syndrome. Other unusual pigmentary retinopathies that must be distinguished from Alström syndrome include renal retinal dysplasia, Laurence-Moon syndrome, and Ushers syndrome.3,6-9
The following cases in siblings emphasize the importance of serial systemic workup for subclinical diabetes and hepatic dysfunction. The early detection of systemic manifestations helps characterize the disease, thereby narrowing the differential diagnosis and facilitating early genetic counseling.
The two cases reported are siblings who were the full-term products of two normal pregnancies. Two older siblings died soon after birth, one of sepsis and one of an unknown cause. Both parents appeared healthy with a family history positive only for diabetes mellitus in one of the paternal grandparents.
A 12-year-old girl developed searching nystagmus, poor ocular fixation, and poor response to environmental stimuli in early childhood. Visual acuity in each eye had been no light perception bilaterally for the past 5 years. Posterior subcapsular cataracts were present in both eyes. Both fundi revealed waxy, pale discs with attenuated retinal vessels. There was a diffuse pepper-and-salt appearance in the posterior pole and granular depigmentation of the midperipheral retina (Figure 1). Nerve fiber bundle defects were seen in the superior temporal and inferior temporal arcades. Fluorescein angiography revealed diffuse to confluent window defects throughout the posterior and midperipheral retina (Figure 2). The electro retinogram (ERG) showed no photopic or scotopic response. The patient's secondary sexual characteristic development corresponded to Tanner stage I. Her intellectual abilities and general conditions were normal until progressive hearing loss developed. Acanthosis nigricans had recendy developed in the posterior aspect of her neck.
Figure 1 : Fundi of the sister's right (A) and left (B) eyes showed waxy and pale discs, attenuated retinal vessels, and diffuse salt-andpepper appearance In the posterior pole and midperiphery with granular retinal depigmentation.
Figure 2: Fluorescein angiograms of the sister's right eye revealed blocked fluorescein over the macular area with diffuse peppery to confluent hyperfluorescein window defects in the posterior pole and midperipheral retina.
Poor visual acuity and searching nystagmus were first noted in infancy in the 10-year-old brother of case 1 . His visual acuity was 2/200 in both eyes without color sense. The anterior segment was clear bilaterally. The fundi showed waxy, pale discs, attenuated retinal vessels, and retinal pigment degeneration (Figure 3). Nerve fiber bundle defects were evident. No ERG waveform could be detected. Psychomotor and intellectual development were normal. There was no gynecomastia and no external genital development, consistent with Tanner stage I. He was admitted at the same time as his sister due to recently developed hearing impairment and weight gain.
Each family member underwent detailed laboratory examinations (Table 1). Plasma aspartate aminotransferase and alanine aminotransferase concentrations were elevated in both siblings. Elevated fasting plasma triglyceride, glucose and low level of high-density lipoprotein cholesterol levels in the sister were consistent with the diagnosis of diabetes mellitus complicated by dyslipidemia. The baseline levels of plasma leptin concentrations in both siblings and the father were higher than in the normal population with respect to ideal body mass index. Leptin is a plasma protein synthesized in adipose tissue. The higher baseline serum leptin levels correlated well with insulin resistance and obesity. The oral glucose tolerance test showed normal response of plasma glucose for all family members, but a remarkable elevation of corresponding insulin concentrations was noted in both siblings. Insulin suppression testing revealed insulin resistance in the mother and both siblings.
Figure 3: Fundi of the brother's right (A) and left (B) eyes showed prominent waxy and pale discs, markedly attenuated retinal vasculature, and retinal pigment degeneration.
GENERAL CHARACTERISTICS AND BASELINE LABORATORY DATA
The presence of retinal pigmentary degeneration causing early-onset night blindness, progressive hearing loss, obesity, noninsulin-dependent diabetes mellitus, acanthosis nigricans, hypogonadism, and the absence of Polydactyly or mental retardation confirmed die diagnosis of Alström syndrome in these two siblings. The sister had diabetes mellitus with extreme insulin resistance. Although diabetes mellitus was not found in any other family members, the brother had extreme insulin resistance and the mother showed mild insulin resistance. The brother is highly likely to develop diabetes mellitus.
Hepatic dysfunction is less common in Alström syndrome.10-12 Only two such cases have been reported in Asian countries.13,14 The elevated levels of liver enzymes found in these siblings may lead to hepatic cirrhosis in the future. Infantile cardiomyopathy was reported in 18 of 22 Alström syndrome patients, and 5 of those suffered cardiac deaths.4 Despite normal electrocardiogram findings, this risk factor should be evaluated carefully in the follow up of each of our patients. Although renal function was normal at the time of presentation, it is important to bear in mind that renal disease is a constant, but age-related feature. Twelve of the 15 reported cases had laboratory evidence of renal dysfunction, and 3 eventually died of renal failure.3
The manifestation of ocular involvement in patients with Alström syndrome2,3,10,15-17 includes severe visual loss, searching nystagmus, posterior subcapsular cataracts, pigmentary degeneration of the retina without bone spicule formation, optic disc pallor, narrow retinal arteries, asteroid hyalosis, and optic disc drusen (Table 2). The presence of diabetes mellitus may account for the high prevalence of posterior subcapsular cataract in Alström syndrome.
OCULAR MANIFESTATIONS IN PATIENTS WITH ALSTRÖM SYNDROME
Pigmentary degenerations of early childhood are present in a large number of inherited syndromes. In such patients, other systemic manifestations may be difficult to evaluate or may not become apparent until later in life. Therefore, the use of laboratory testing, looking specifically for subclinical hepatic, renal, and endocrine malfunction, is essential to establish a correct diagnosis early in life when effective genetic counseling can be performed and clinical expectations can be discussed with the parents.
1 . Alström CH, Hallgren B, Nilsson LB, Äsander H. Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness: a specific syndrome (not hitherto described) distinct from the Laurence-Moon-Bardet-Biedl syndrome: a clinical, endocrinological and genetic examination based on a large pedigree. Acta Psychiatr Neurol Scand. 1959;34(suppl 129):1-35.
2. Sebag J, Albert DM, Craft JL. The Alström syndrome: ophthalmic histopathology and retinal ultrastructure. Br J Ophthalmol. 1984;68:494-501.
3. Millay RH, Weleber RG, Heckenlively JR. Ophthalmologic and systemic manifestations of Alström's disease. Am J Ophthalmol. 1986;102:482-490.
4. Russell-Eggitt IM, Clayton PT, Coffey R, Kriss A, Taylor DSI, Taylor JFN. Alström syndrome: report of 22 cases and literature review. Ophthalmology. 1998;105:1274-1280.
5. Dyev DS, Wilson ME, Small KW, Pai GS. Alström syndrome: a case misdiagnosed as Bardet-Biedl syndrome. J Pediatric Ophthalmol Strabismus. 1994;31 :272-274.
6. Goldstein JL, Fialkow PJ. The Alström syndrome: report of three cases with further delineation of the clinical, pathophysiological, and genetic aspects of the disorder. Medicine. 1973;52:53-71.
7. Tremblay F, La Roche RG, Shea SE, Ludman MD. Longitudinal study of the early clectroretinographic changes in Alström's syndrome. Am J OphthalmoL 1993; 11 5:657-665.
8. Alter CA, Moshang T Jr. Growth hormone deficiency in two siblings wirh Alström syndrome. Am J Dis Child 1993;147:97-99.
9. Charles SJ, Moore AT, Yates JRW, Green T, Clark P. Alström syndrome: further evidence of autosomal recessive inheritance and endocrinological dysfunction. J Med Genet 1990:27:590-592.
10. Awazu M, Tanaka T, Sato S, Anzo M, Higuchi M, Yamazaki K, Matsuo N. Hepatic dysfunction in two sibs with Alström syndrome: case report and review of the literature. Am J Med Genet. 1997:69:13-16.
11. Connolly MB, Jan JE, Couch RM, Wong LTK, Dimmick JE, Rigg JM. Hepatic dysfunction in Alström disease. Am J Med Genet. 1991;40:421-424.
12. Marshall JD, Ludman MD, Shea SE, Salisbury SR, Willi SM, LaRochc RG, Nishina PM. Genealogy, natural history, and phenotype of Alström syndrome in a large Acadian kindred and three additional families. Am J Med Genet. 1997;73: 150-161.
13. Ikeda Y, Morita Y, Matsuo Y, Akanuma Y, Itakura H, Yamaji T, Kossaka K. A case of Alström syndrome associated with situs inversus totalis and characteristic liver cirrhosis. J Jpn Soc Intern Med. 1974;63:41-49.
14. Horiuchi N, Sasaki A, Suzuki T, Endo Y, Kiyonaga G. A case of Alström syndrome witi cirrhosis of the liver. J Jpn Diab Soc. 1976;19:353-359.
15. Boor R, Herwig J, Schrezenmeir J, Pona BF, Schönberger W. Familial insulin resistant diabetes associated with acanthosis nigricans, polycystic ovaries, hypogonadism, pigmentary retinopathy, labyrinthine deafness, and mental retardation. Am J Med Genet. 1993;45:649-653.
16. Aynaci FM, Okten A, Mocan H, Gedik Y, Sarpkaya Ao. A case of Alström syndrome associated with diabetes insipidus. Clin Genet. 1995;48:164-166.
17. Michaud JL, Heon E, Guilbert F, et al. Natural history of Alström syndrome in early childhood: onset with dilated cardiomyopathy. J Pediatr. 1996;128:225-229.
GENERAL CHARACTERISTICS AND BASELINE LABORATORY DATA
OCULAR MANIFESTATIONS IN PATIENTS WITH ALSTRÖM SYNDROME