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Alstrom Syndrome

ALSS

Alstrom syndrome is a rare genetic disorder with an autosomal recessive pattern of inheritance. It is characterized by progressive multiorgan dysfunction, visual and hearing impairment, obesity, and cardiomyopathy, all of which lead to a reduction in the lifespan of affected individuals.


Presentation

Alstrom syndrome (ALMS), a rare autosomal recessive condition due to mutations in the ALMS1 gene located on the second chromosome, is characterized by progressive multisystem dysfunction in homozygous individuals while heterozygous individuals are asymptomatic [1] [2] [3] [4]. The clinical presentation is variable in onset as well as severity even in individuals belonging to the same family [5].
Symptoms related to different organ systems appear in childhood and progress with age.

  • Neurological: Affected individuals have normal intelligence with delayed motor and intellectual milestones, balance changes [14] [15], speech problems and cerebellar anomalies [16].

Although growth spurt is normal in early childhood, it plateaus off and individuals with ALMS usually have a short stature, round face, thick ears, frontal alopecia, abnormal and discolored dentition, scoliosis, flat feet and short, fat fingers and toes.

Mortality in young ALMS patients is due to dilated cardiomyopathy while in older patients is mainly due to renal failure [5] [17].

Short Stature
  • It may be associated with acanthosis nigricans, hypergonadotropic hypogonadism, hepatic dysfunction, hepatic steatosis, hyperlipidaemia, dilated cardiomyopathy and short stature.[ncbi.nlm.nih.gov]
  • To investigate if there is an endocrinologic explanation for the short stature in patients with Alström syndrome. Patient reports. The Children's Hospital of Philadelphia, Pa.[ncbi.nlm.nih.gov]
  • However, further tests, including GH dynamics, are needed to determine whether, or to what degree disturbances in the GH/IGF axis contribute to the relatively short stature.[ncbi.nlm.nih.gov]
  • Alström syndrome is a rare autosomal recessive genetic disorder characterized by cone-rod dystrophy, hearing loss, childhood truncal obesity, insulin resistance and hyperinsulinemia, type 2 diabetes, hypertriglyceridemia, short stature in adulthood, cardiomyopathy[ncbi.nlm.nih.gov]
  • Alström syndrome is a rare, autosomal recessive disorder characterized by a wide spectrum of clinical features including early-onset retinal degeneration leading to blindness, sensorineural hearing loss, short stature, obesity, type 2 diabetes, hyperlipidemia[ncbi.nlm.nih.gov]
Recurrent Respiratory Infections
  • Alström syndrome (AS) is a rare, multi-system condition characterized by retinal degeneration, sensorineural hearing loss, obesity, insulin-resistant diabetes, hypertriglyceridemia, cardiomyopathy, hepatorenal disease, and recurrent respiratory infections[ncbi.nlm.nih.gov]
Heart Failure
  • Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure.[ncbi.nlm.nih.gov]
  • Minor criteria Obesity and/or insulin resistance and/or Type 2 Diabetes History of dilated cardiomyopathy with congestive heart failure.[medcaretips.com]
  • Multiple organ systems later can be affected, resulting in blindness , hearing impairment, type 2 diabetes, heart failure , liver disease , urological dysfunction, pulmonary fibrosis , and renal failure.[medicinenet.com]
  • Multiple organ systems later can be affected, resulting in blindness, hearing impairment, type 2 diabetes, heart failure, liver disease, urological dysfunction, pulmonary fibrosis, and renal failure.[medicinenet.com]
Discolored Enamel
  • In both cases, gingivitis was present and also light yellow-brown discolored enamel bands were observed on the anterior teeth. This staining may have resulted from discoloration of the preexisting slight band-like enamel hypoplasia.[ncbi.nlm.nih.gov]
  • In both cases, gingivitis was present and also light yellowbrown discolored enamel bands were observed on the anterior teeth. This staining may have resulted from discoloration of the preexisting slight band-like enamel hypoplasia.[jlc.jst.go.jp]
Hearing Impairment
  • The patient had underlying cone-rod dystrophy of the retinas, nystagmus, obesity, progressive sensorineural hearing impairment, diabetes mellitus, and hypertriglyceridemia, compatible with the clinical diagnosis of Alström syndrome.[ncbi.nlm.nih.gov]
  • Alström syndrome (AS) is a very rare autosomal recessively inherited disorder that can lead to infantile-onset dilated cardiomyopathy, blindness, hearing impairment, obesity, diabetes, hepatic and renal dysfunction.[ncbi.nlm.nih.gov]
  • Alström Syndrome is an extremely rare, autosomal recessive genetic disorder characterized by a group of signs and symptoms including infantile onset dilated cardiomyopathy, blindness, hearing impairment/loss, and obesity; with diabetes, and hepatic and[ncbi.nlm.nih.gov]
  • Alström syndrome (AS; OMIM 203800) is an autosomal recessive disorder characterized by cone-rod dystrophy, dilated cardiomyopathy, sensorineural hearing impairment, developmental delay, and most case had both childhood-onset obesity and hyperinsulinemia[ncbi.nlm.nih.gov]
  • Alstrom syndrome is an extremely rare, autosomal recessive genetic disorder characterized by a group of signs and symptoms including infantile onset dilated cardiomyopathy, blindness, hearing impairment/loss, obesity, diabetes, hepatic and renal dysfunction[ncbi.nlm.nih.gov]
Alopecia
  • We report a case of a 20 -year-old caucasian male with hearing and visual loss, short stature, insulin resistant diabetes, dilated cardiomyopathy, hepatic and renal dysfunction, hypertension, and alopecia.[ncbi.nlm.nih.gov]
  • Systemic findings showed hepatic dysfunction, hyperlipidemia, hypogonadism, short stature, and wide feet in both brothers, whereas hearing loss, renal failure, abnormal digits, history of developmental delay, scoliosis, hypertension, and alopecia were[ncbi.nlm.nih.gov]
  • Although growth spurt is normal in early childhood, it plateaus off and individuals with ALMS usually have a short stature, round face, thick ears, frontal alopecia, abnormal and discolored dentition, scoliosis, flat feet and short, fat fingers and toes[symptoma.com]
  • On examination, she was found to have alopecia, hirsutism, acanthosis, and large sweaty hands. Investigations revealed transaminitis (sixfold high enzymes), high blood sugars, and high serum triglyceride level.[ijem.in]
  • […] growth hormone, which may result in short stature in adulthood; high blood pressure (hypertension), abnormally decreased activity of the thyroid gland and underproduction of thyroid hormones (hypothyroidism), advanced bone age; patchy areas of hair loss (alopecia[rarediseases.org]
Advanced Bone Age
  • The advanced bone age and normal early growth may be due to hyperinsulinism.[ncbi.nlm.nih.gov]
  • One additional manifestation not described widely in the literature, advanced bone age, was observed in all subjects tested.[ncbi.nlm.nih.gov]
  • Minor Criteria Obesity and/or insulin resistance and/or Type 2 Diabetes History of dilated cardiomyopathy with congestive heart failure Hearing loss Hepatic dysfunction Renal failure Advanced bone age 15 years – adulthood 2 major and 2 minor criteria[medcaretips.com]
  • bone ages in puberty, and a markedly reduced final height were observed.[jmg.bmj.com]
Myelopathy
  • Here, we present a patient with AS who presented with cervical myelopathy due to extensive flowing ossification of the anterior and posterior longitudinal ligaments of the cervical spine resulting in cervical spinal cord compression.[ncbi.nlm.nih.gov]
Tonic-Clonic Seizure
  • Patient 2 is a 15-year-old boy who presented at birth with epilepsy and psychomotor developmental delay and generalized tonic-clonic seizures with severe cognitive impairment, features not documented previously in this syndrome.[ncbi.nlm.nih.gov]
Kidney Failure
  • Description Alstrom Syndrome is a very rare genetic condition which leads to progressive blindness and deafness and can also lead to heart and kidney failure, diabetes, liver dysfunction and associated problems.[sightlinedirectory.org.uk]
  • The treatment for renal (kidney) failure depends on how well the kidneys are working, but dialysis and kidney transplants are available should they fail completely.[diabetes.org.uk]
Anorchia
  • Unilateral anorchia with hypergonadotropic hypogonadism is another unique feature of our case.[ncbi.nlm.nih.gov]

Workup

The diagnosis of ALMS is based on the typical clinical presentation, although, occasionally variable phenotypic expression can delay the diagnosis [2] [3]. Cone electroretinography reveals weak cone activity in infancy with severely diminished responses and cone dystrophy on full-field electroretinography by 3 years of age. Optical coherence tomography (OCT) imaging has been used to demonstrate macular thinning and developmental arrest [18]. Laboratory tests help to detect elevated blood sugar levels with hypertriglyceridemia, elevated hepatic transaminases, abnormal renal function tests, albuminuria, low levels of testosterone, elevated gonadotropins, low levels of growth hormone, abnormal levels of insulin-like growth factors [19] [20], elevated leptin levels [20], and secondary or subclinical hypothyroidism.

Molecular genetic analysis is used to confirm the diagnosis [21] [22] [23].

Pericardial Effusion
  • Three of 11 patients (27%) overall and two of 4 of the patients with low EF (50%) had pericardial effusions. CONCLUSIONS: The Alström CMP in this cohort of patients was typically dilated and nonsegmental with predominantly biventricular involvement.[ncbi.nlm.nih.gov]
Albuminuria
  • Laboratory tests help to detect elevated blood sugar levels with hypertriglyceridemia, elevated hepatic transaminases, abnormal renal function tests, albuminuria, low levels of testosterone, elevated gonadotropins, low levels of growth hormone, abnormal[symptoma.com]
Lymphocytic Infiltrate
  • Liver biopsy showed fatty liver, lymphocytic infiltration, and piecemeal necrosis. The second sib had had elevated gamma-glutamyltransferase levels since she was 10 years old.[ncbi.nlm.nih.gov]

Treatment

  • He developed impaired glucose tolerance at 6 years of age and treatment with metformin was initiated. After 8 months of treatment with metformin he developed DM2. The dose of metformin was increased, and rosiglitazone added.[ncbi.nlm.nih.gov]
  • Although there is no specific treatment for this condition, there are treatments to manage many of the symptoms.[diseaseinfosearch.org]
  • The only current treatment options include management of the symptoms. Following 24 weeks of treatment with PBI-450, data for 9 is now available showing the drug can reduce kidney damage.[raredr.com]
  • Topical carbonic anhydrase inhibitors may have a role in the treatment of macular edema in syndromic retinal dystrophies such as Alström syndrome.[ncbi.nlm.nih.gov]
  • After 1 year of rhGH treatment, body fat mass, fat infiltration in the liver, and serum lipid profiles had all decreased.[ncbi.nlm.nih.gov]

Prognosis

  • The prognosis regarding survival is correlated with the severity of renal failure.[ncbi.nlm.nih.gov]
  • Very high incidences of additional disease phenotypes that may severely affect prognosis and survival include endocrine abnormalities, dilated cardiomyopathy, pulmonary fibrosis and restrictive lung disease, and progressive hepatic and renal failure.[ncbi.nlm.nih.gov]
  • Diagnosis - Alström syndrome Prognosis - Alström syndrome A prognosis for Alström syndrome is complicated because it widely varies. Any person that has the syndrome have different set of disorders.[checkorphan.org]
  • Prognosis The prognosis will depend on the progression of glucose intolerance, cardiomyopathy, renal dysfunction and liver impairment. Total blindness and deafness are likely to develop.[patient.info]

Etiology

  • Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal.[ncbi.nlm.nih.gov]
  • 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.[orpha.net]
  • Patient 2 was diagnosed with sensorineural hearing loss of unknown genetic etiology, as was his older brother. Cochlear function at age 6 was tested, and was abnormal.[bjorl.org]

Epidemiology

  • […] patients during infancy or adolescence. [ 2 ] Renal failure, pulmonary, hepatic, and urological dysfunction are often observed, and systemic fibrosis develops with age. [ 2 ] The gene map locus for the affected mutated gene (ALMS1) is 2p12-13. [ 3 ] Epidemiology[patient.info]
  • Summary Epidemiology Prevalence is unknown. Approximately 950 cases have been identified worldwide. Clinical description The clinical features, age of onset, and severity can vary greatly among and within families.[orpha.net]
Sex distribution
Age distribution

Pathophysiology

  • Alström syndrome is being studied as a model which would potentially shed light on the pathophysiology of diabetes mellitus.[ncbi.nlm.nih.gov]
  • Morphological retinal changes demonstrated by SD-OCT may help in understanding the pathophysiology of the disease and defining strategies for treatment such as gene therapy.[ncbi.nlm.nih.gov]
  • Report of three cases with further delineation of the clinical, pathophysiological, and genetic aspects of the disorder. Medicine (Baltimore) 52: 53–71.[preventiongenetics.com]
  • 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.[healio.com]
  • […] hypogonadism, 2 6 androgenetic alopecia, 2 3 growth retardation, 2 8 scoliosis, 3 6 hyperostosis frontalis interna, 3 6 acanthosis nigricans, 3 6 9 cataract, 9 and dilated cardiomyopathy. 10 11 In an Acadian kindred, a putative gene involved in the pathophysiology[jmg.bmj.com]

Prevention

  • Finding in this case suggests that hyperinsulinemia is a secondary event in Alström syndrome, and early-commenced treatment prevents hyperinsulinemia.[ncbi.nlm.nih.gov]
  • This offers hope of secondary prevention because type 2 diabetes can be delayed or reversed by lifestyle interventions.[ncbi.nlm.nih.gov]
  • […] them from getting worse Alström Syndrome is an inherited disorder, and hence, no preventive measures have been reported.[dovemed.com]
  • Metformin treatment alone at the stage of impaired glucose tolerance did not prevent progression to DM2.[ncbi.nlm.nih.gov]
  • Prevention - Alström syndrome Prevention for Alström Syndrome is considered to be harder compared to other diseases/syndromes because it is an inherited condition.[checkorphan.org]

References

Article

  1. Alström CH, Hallgren B, Nilsson LB, Åsander H. Retinal degeneration combined with obesity, diabetes mellitus and neurogenous deafness. A specific syndrome (not hitherto described) distinct from Laurence-Moon-Biedl syndrome. A clinical endocrinological and genetic examination based on a large pedigree. Acta Psychiatr. Neurol. Scand. Suppl. 1959;129:1–35.
  2. Marshall JD, Paisey RB, Carey CM, MacDermott S. In: Gene Reviews [Internet], Seattle (WA): University of Washington, Seattle; 1993-2003. Pagon RA, Bird TC, Dolan CR, Stephens K, editors. 2010.
  3. Marshall JD, Beck S, Maffei P, Naggert JK. Alström Syndrome. Eur. J. Hum. Genet. 2007;15:1193–1202.
  4. Marshall JD, Ludman MD, Shea SE, et al. Genealogy, natural history, and phenotypic features of Alström syndrome in a large Acadian kindred and three unrelated families. Am. J. Med. Genet. 1997;73:150–161.
  5. Marshall JD, Bronson RT, Collin GB, et al. New Alström Syndrome phenotypes based on the evaluation of 182 cases. Arch. Intern. Med. 2005;165:675–683.
  6. Russell-Eggitt IM, Clayton PT, Coffey R, et al. Alström syndrome. Report of 22 cases and literature review. Ophthalmol. 1998;105:1274–1280.
  7. Welsh LW. Alström syndrome: Progressive deafness and blindness. Ann. Otol. Rhinol. Laryngol. 2007;116:281–285.
  8. Paisey RB, Carey CM, Parkinson MJ, et al. Alström syndrome-the case for secondary prevention. Diabet. Res. Clin. Pract. 2000;50 (Suppl. 1): S202.
  9. Paisey RB, Carey CM, Bower L, et al. Hypertriglyceridaemia in Alstrom's syndrome: causes and associations in 37 cases. Clin. Endocrinol. 2004;60:228–231.
  10. Wu WC, Chen SC, Dia CY, et al. Alström syndrome with acute pancreatitis: A case report. Kaohsiung J. Med. Sci. 2003;19:358–361.
  11. Kocova M, Sukarova-Angelovska E, Kacarska R, et al. The unique combination of dermatological and ocular phenotypes in Alstrom syndrome; severe presentation, early onset and two novel ALMS1 mutations. Br. J. Dermatol. 2011; 164 (4): 878-880.
  12. Morgan J, Sadler MA, Siegel S. US, CT, and MR imaging of hepatic masses in Alström syndrome: a case report. Clin. Imaging. 2008;32:393–395.
  13. Charles SJ, Moore AT, Yates JRW, Green T, Clark P. Alstrom's syndrome: further evidence of autosomal recessive inheritance and endocrinological dysfunction. J. Med. Genet. 1990;27:590–592.
  14. Marshall JD, Maffei P, Collin GB,Naggert JK. Alstrom Syndrom: genetics and clinical overview. Curr Genomics. 2011;12(3): 225-235.
  15. Möller C. Vestibular testing in children. In: Newton W, editor. Pediatric Audiological Medicine. Wiley- Blackwell; 2009.
  16. Yilmaz C, Çaksen H, Yilmaz N, et al. Alstrom Syndrome associated with cerebral involvement: An unusual presentation. Eur. J. Gen. Med. 2006;3:32–34.
  17. Minton JA, Owen KR, Ricketts CJ, et al. Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome. The Journal of clinical endocrinology and metabolism. 2006;91:3110–3116.
  18. Vingolo EM, Salvatore S, Grenga PL, et al. High-resolution spectral domain optical coherence tomography images of Alström syndrome. J. Pediatr. Ophthalmol. Strabis. 2010;47:e1–3.
  19. Maffei P, Munno V, Marshall JD, et al. GH and IGF-I Axis in Alström Syndrome. J. Endocrinol. Invest. 2000;23(Suppl. 6):29.
  20. Maffei P, Boschetti M, Marshall JD, et al. Characterization of the IGF system in 15 patients with Alström syndrome. Clin. Endocrinol. 2007;66:269–275.
  21. Collin GB, Marshall JD, Ikeda A, et al. Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome. Nat. Genet. 2002;31:74–78.
  22. Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat. Genet. 2002;31:79–83.
  23. Marshall JD, Hinman EG, Collin GB, et al. Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Hum. Mutat. 2007;28:1114–1123.

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Last updated: 2019-07-11 21:40