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Isolated ACTH deficiency — Isolated corticotropin (ACTH) deficiency is a rare disorder [8]. The defect is probably at the pituitary level because there is no ACTH secretory response to corticotropin-releasing hormone (CRH) or vasopressin, as there usually is in hypothalamic disorders [9-11]. Occasional patients may have hypothyroxinemia and hyperprolactinemia that are corrected with glucocorticoid replacement [12,13].

Autoimmune — The following observations suggest that most cases are caused by an autoimmune process:

●Frequent association with other autoimmune endocrine disorders [13]

●The presence of lymphocytic hypophysitis with selective corticotroph absence in some patients [14]

●The presence of antipituitary antibodies in the serum of 10 of 21 patients in one report [15] and the presence of anticorticotroph antibodies in the serum of at least one patient [16]

A novel syndrome, referred to as triple H syndrome, of isolated ACTH deficiency and alopecia areata has been described in two women and one man [17,18]. One woman also had vitiligo and anterograde memory loss, and a magnetic resonance imaging (MRI) scan revealed hippocampal atrophy [17]. A skin biopsy from the male patient showed lymphocytic invasion surrounding the hair follicles [18]. The authors postulated an autoimmune target molecule shared among the hypothalamus (or pituitary corticotrophs), hair follicles, and hippocampus.

Genetic causes — Three extremely rare genetic conditions can cause isolated ACTH deficiency.

Mutations in the POMC gene — A syndrome of early-onset obesity and secondary adrenal insufficiency has been described in seven patients with homozygous or compound heterozygous loss-of-function mutations in the proopiomelanocortin (POMC) gene [19,20]. Their heterozygote relatives were unaffected, indicating a recessive mode of inheritance.

This syndrome has been reproduced in homozygous, POMC gene knockout mice [21]. Daily intraperitoneal injection of alpha-MSH resulted in decreased food consumption, loss of weight, and darkening of coat color that reversed when the alpha-MSH was stopped. These results suggest that obesity in humans with POMC gene defects and possibly other causes of obesity may be treated with agonists specific for the brain melanocortin-4 receptor.

Several POMC mutations and polymorphisms have also been detected in 96 extremely obese children and adolescents; 60 healthy, underweight subjects; and 46 patients with anorexia nervosa, none of which was regularly associated with a particular phenotype [22].

Cleavage enzyme defect — Another cause of isolated ACTH deficiency is a congenital defect leading to impaired function of prohormone convertase 1 (PC1), which cleaves ACTH from POMC [23].

TPIT gene mutations — TPIT is a transcription factor necessary for differentiation of the corticotroph cell and POMC production; TPIT gene mutations may be the most common genetic cause of neonatal isolated ACTH deficiency (IAD). In one report of 27 neonates with IAD, homozygous or compound, heterozygous mutations in the coding region of the TPIT gene were found in 17 of 27 neonates [24]. All parents of the neonates with TPIT mutations were unaffected carriers, confirming a recessive mode of inheritance. Although IAD due to TPIT mutations is a rare disorder, prenatal diagnosis for families at risk would be beneficial as neonatal IAD from any cause, if not diagnosed and treated early, can result in death.

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