PubMed · 16149516
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Yoshihiko Yamada, Hisahiko Sekihara. 2005. [11-Deoxycortisol].. https://pubmed.ncbi.nlm.nih.gov/16149516/
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Triple A syndrome is a rare autosomal recessive disorder characterized by alacrima, achalasia, and adrenal insufficiency. Sjögren's syndrome (SS) is a chronic inflammatory disorder manifested primarily by diminished lacrimal and salivary gland secretions, resulting in symptoms of dry eyes and dry mouth, the so-called "sicca complex". However, a variety of other manifestations also can occur, which can be termed "nonexocrine manifestations". One of the frequent nonexocrine manifestations is dysphagia. In this paper, we present an unusual form of Triple A disease mimicking Sjögren's syndrome, which leads to a challenging diagnosis.
A 12.5-year-old girl with diabetes mellitus type 1 presented with stunted growth and an increase in body weight. Also, her blood-sugar levels were difficult to manage. An adrenocorticotropin-(ACTH)-independent form of Cushing's syndrome was diagnosed. During the dexamethasone-suppression test, a paradoxical increase in urinary-free cortisol excretion was observed, which is a clear indication of primary pigmented nodular adrenocortical disease (PPNAD). The treatment for patients with PPNAD is bilateral adrenalectomy and hormone substitution. PPNAD may be part of the Carney complex, an autosomal dominant multiple neoplasia syndrome. Screening of family members is mandatory. Further investigation for mutations in the gene encoding the regulatory subunit 1A of the protein kinase A (PRKAR1A) may be helpful.
The human PRKAR1A gene encodes the regulatory subunit 1-alpha (RIalpha) of the cAMP-dependent protein kinase A (PKA) holoenzyme. Regulation of the catalytic activity of PKA is the only well-studied function of RIalpha. Inactivating PRKAR1A mutations cause primary pigmented nodular adrenocortical disease (PPNAD) or Carney complex (CNC), an inherited syndrome associated with abnormal skin pigmentation and multiple neoplasias, including PPNAD. Histochemistry of tissues from CNC patients is indicative of autophagic deficiency and this led us to investigate the relationship between RIalpha and mammalian autophagy. We found that fluorescently tagged RIalpha associates with late endosomes and autophagosomes in cultured cells. The number of autophagosomes in prkar1a-/- mouse embryonic fibroblasts (MEFs) was reduced compared with wild-type MEFs. RIalpha co-immunoprecipitated with mTOR kinase, a major regulator of autophagy. Phosphorylated-mTOR levels and mTOR activity were dramatically increased in prkar1a-/- mouse cells, and in HEK 293 cells with RIalpha levels reduced by siRNA. Finally, phosphorylated-mTOR levels and mTOR activity were increased in CNC cells and in PPNAD tissues. These data suggest that RIalpha deficiency decreases autophagy by the activation of mTOR, providing a molecular basis to autophagic deficiency in PPNAD.