Triple A syndrome (alacrima, achalasia, adrenal failure, progressive 
neurodegenerative disease) is caused by mutations in the AAAS gene which encodes 
the protein alacrima achalasia adrenal insufficiency neurologic disorder 
(ALADIN). Our investigation suggests that low bone mineral density (BMD) for 
age/osteoporosis could be a common but overlooked symptom of unexplained 
etiology in this rare multisystemic disease.
INTRODUCTION: The purpose of this study is to evaluate incidence and etiology of 
BMD for age/osteoporosis, a possibly overlooked symptom in triple A syndrome.
METHODS: Dual-energy X-ray absorptiometry (DXA) of the femoral neck, total hip, 
lumbar spine, and radius, bone turnover markers, minerals, total alkaline 
phosphatase (ALP), 25-hydroxy vitamin D (25-OHD), 1,25-dihydroxy vitamin D 
(1,25-OH2D), intact parathyroid hormone (PTH), and adrenal androgens 
(dehydroepiandrosterone sulfate (DHEAS) and androstenedione) were measured in 
five male and four female patients.
RESULTS: At time of diagnosis, low BMD for age was suspected on X-ray in seven 
of nine patients aged 2-11 years (not performed in two patients); normal levels 
of minerals and ALP were found in nine patients and low levels of adrenal 
androgens in eight patients (not measured in one patient). Reevaluation 
5-35 years after introduction of 12 mg/m(2)/day hydrocortisone showed low BMD 
for age in two children, osteopenia in one, and osteoporosis in six adults. 
Normal levels of minerals, ALP, PTH, 1,25-OH2D, procollagen type 1, crosslaps, 
and osteocalcin were found in all patients. Low levels of adrenal androgens were 
found in all and 25OHD deficiency in six patients. Body mass index was <25 % for 
age and sex in eight of nine patients.
CONCLUSION: Low BMD for age/osteoporosis in our patients probably is not a 
result of glucocorticoid therapy but could be the consequence of low level of 
adrenal androgens, neurological impairment causing physical inactivity, 
inadequate sun exposure, and protein malnutrition secondary to achalasia. 
Considering ubiquitous ALADIN expression, low BMD/osteoporosis may be a primary 
phenotypic feature of the disease. Besides optimizing glucocorticoid dose, 
physical activity, adequate sun exposure, appropriate nutrition, and vitamin D 
supplementation, therapy with DHEA should be considered.