The triple A syndrome or Allgrove syndrome (MIM*231550) is characterized by 
adrenocorticotropic hormone (ACTH) resistant Adrenal insufficiency, Achalasia of 
the cardia and Alacrima. In addition to the main features, patients frequently 
suffer from neurological disturbances. Dermatological abnormalities such as 
palmoplantar hyperkeratosis as well as other signs like short stature, 
microcephaly and osteoporosis point to the multisystemic character of the 
disorder. The molecular defect of the autosomal recessively inherited triple A 
syndrome is not known. We initially performed a systematic genome linkage scan 
in eight triple A families and were able to map the syndrome to a 6 cM interval 
on human chromosome 12q13 near the type II keratin gene cluster. A refinement of 
the triple A critical region was achieved by detailed haplotype analysis in a 
further 37 families from different ethnic backgrounds. There was no indication 
of genetic heterogeneity. The achalasia-alacrima (AA) syndrome which has been 
defined as a distinct clinical entity (MIM 200440) is most likely a variant of 
the triple A syndrome as shown by haplotype analysis in three AA families. We 
constructed a high-resolution BAC/PAC-based transcript map of the region which 
will greatly facilitate the identification of the triple A syndrome gene. The 
considerable intra- and interfamilial variability of the severity of the 
disorder implies a variable expression of an impaired pleiotropically acting 
gene.