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The continuing failure to recognise Alström syndrome and further evidence of genetic homogeneity
  1. * Molecular Medicine Unit, Level 6, Clinical Sciences Building, St James's University Hospital, Leeds LS9 7TF, UK
  2. Department of Clinical Genetics, St James's University Hospital, Leeds LS9 7TF, UK

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    Editor—A disorder may be prone to misdiagnosis or underdiagnosis when it is rare, has multiple presentations, a slowly evolving phenotype, or no pathognomonic test. Such would seem to be the case for Alström syndrome.1 We have recently diagnosed this disorder in seven members of six Pakistani families. In none of the affected subjects had the correct diagnosis previously been made. Instead the given diagnoses were Bardet-Biedl syndrome, Leber's amaurosis, a type of retinitis pigmentosa, sporadic dilated cardiomyopathy, an unidentified mitochondrial disorder, and Usher syndrome. This experience is not unusual since in a recent British study of Alström syndrome patients, seven of 22 had initially been incorrectly diagnosed.2

    The clinical features of Alström syndrome are well illustrated in our families.3 Progressive visual impairment presented in the first 6 months of life as photophobia and nystagmus, advancing to a cone-rod dystrophy and registered blindness in the second decade. Truncal obesity and acanthosis nigricans were evident before 5 years, but became more obvious after puberty. Male external genitalia remained small (especially in males with obvious gynaecomastia). All patients were of short stature by the age of 8 but none manifested diabetes mellitus, although this has previously been reported as a common feature.1 Sensorineural deafness presented late in the first decade. Renal failure frequently develops during the third decade, 3 this being the cause of death in three family members suspected to have had Alström syndrome. A dilated cardiomyopathy can also occur at any age and often spontaneously improves. It may present in the first year of life before other disease features and did so in two affected subjects in the families reported here.

    After further pedigree determination, we found that four of the families were related (fig 1) and that the remaining two families were also part of a larger pedigree. Genotyping showed that polymorphic markers D2S292, D2S2113, D2S2110, and D2S2112 were homozygous in all affected subjects. Markers D2S136 and D2S286 delineate the criti-cal region of 10 cM in our families. D2S136 lies 4 cM telomeric to the minimal critical region reported by Macari et al,5 while our centromeric boundary (D2S286) is coincident with that of Collin et al.4 Using MLINK,6 a maximum two point lod score of +4.62 was obtained for the marker D2S2113 at θ=0. Genetic linkage analysis thus confirmed our clinical diagnosis and the recent reports of an Alström syndrome gene location at chromosome 2p13.4 5

    Figure 1

    The simplest genealogical links between affected family members of family 1.    

    Our experience suggests that Alström syndrome should be considered in all cases of early onset dilated cardiomyopathy and cone-rod dystrophy/atypical Leber's amaurosis. Follow up should be undertaken to seek additional features of this autosomal recessive disorder with a 1 in 4 recurrence risk. To date, all published Alström syndrome families have shown linkage to chromosome 2p13, suggesting that the disorder is genetically homogeneous. Now that a locus has been identified, gene cloning and mutation detection can be anticipated which will allow diagnostic testing in any suspected case of Alström syndrome. Functional analysis of the cloned gene may also provide wider insights into the pathogenesis of dilated cardiomyopathy and maturity onset diabetes mellitus.


    This study was supported by the British Heart Foundation. Research in the authors' laboratories is also supported by the West Riding Medical Research Trust, the Medical Research Council, the Wellcome Trust, Action Research, Northern and Yorkshire Regional Health Authority, Yorkshire Cancer Research, and the Birth Defects Foundation.


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