medwireNews: Adrenal insufficiency (AI) is a common clinical feature in children and young adults with single large-scale mitochondrial DNA deletions (SLSMDs), especially in those with Pearson syndrome (PS), Italian researchers have found.
“[T]his study expanded and define[d] the phenotypic spectrum of adrenocortical abnormalities in SLSMDs, providing also a new diagnostic tool to investigate and early treat adrenocortical axis dysfunctions”, they write in the European Journal of Endocrinology.
Barbara Siri (Ospedale Pediatrico Bambino Gesù, Rome, Italy) and co-authors examined adrenocortical function in 18 patients with SLSMDs and 92 healthy individuals. During follow-up, 44% of children with SLSMDs died from disease-related complications.
The six children with PS were aged a median of 4.1 years and had experienced haematological symptoms by age 10 months. Three patients died by age 5 years following a severe haematological presentation and multiple endocrine abnormalities, including diabetes, growth failure and hypoparathyroidism. A further three patients had a milder PS phenotype before progression to Kearns-Sayre syndrome (KSS) with neurological and endocrine disorders, including diabetes, osteoporosis and hypoparathyroidism.
The 12 children with KSS (median age 17.2 years) were diagnosed at a median 7 years of age following growth failure, ptosis and progressive external ophthalmoplegia. These children also experienced endocrine disorders, such as diabetes, mitochondrial diabetes, hypoparathyroidism and osteopenia or osteoporosis, as well as a range of neuromuscular symptoms associated with sensory neural hearing loss, retinopathy, cardiac rhythm abnormalities and proximal tubulopathy.
Adrenocortical axis function was assessed in 16 children, aged a median of 3.5 years in the PS cohort and 6.3 years in the KSS cohort, with follow-up at 1.3 and 4.5 years, respectively.
At initial assessment, 66% of the six PS patients and 40% of the 10 KSS patients had elevated levels of plasma adrenocorticotrophic hormone (ACTH) and the median ACTH level remained significantly higher in both cohorts at follow-up compared with the healthy individuals (109.0 and 53.3 pg/mL vs 19.9 pg/mL, respectively).
In addition, children with SLSMDs had a trend towards lower peak cortisol after low-dose than after high-dose ACTH stimulation tests, whereas healthy children had comparable peak cortisol after both. And both absolute cortisol and cortisol after high- and low-dose stimulation were significantly lower in the SLSMDs cohort than controls, especially in children with PS.
Longitudinal evaluation indicated that 39% of the SLSMDs cohort had impaired adrenocortical function at baseline, including 66% of the PS and 25% of the KSS cohorts, with dysfunction progressing in all but one and two children in these groups, respectively.
Eight children had AI, including five patients who did so in response to stressful situations, namely general anaesthesia, pacemaker implantation, heart failure, recurrent infections and COVID-19. Glucocorticoid replacement therapy (GRT) was “systematically supplemented during acute stressful conditions with any recurrence of symptoms”, the investigators note.
Assessment of mineralocorticoid function showed elevated renin but normal aldosterone in two children with PS and two with KSS and no evidence of mineralocorticoid deficiency; three of these patients were treated with hydrocortisone and fludrocortisone after concurrent diagnosis of primary AI.
Siri and co-authors now recommend that all children with SLSMDs should undergo adrenal and mineralocorticoid assessment including ACTH and basal cortisol level measurements at 6–12-month intervals with ACTH stimulation tests where indicated.
“If normal responses to both [high-dose] and [low-dose ACTH tests] are observed, a Subclinical [primary] AI type I is detected and, based on our clinical experience on mitochondrial patients, a strict follow-up every 4-6 months and a supplementation of GRT during acute stressful procedures should be considered”, the team advises.
“In the case of pathological response to [high-dose tests], a diagnosis of [primary] AI is straightforward and GRT needs to be promptly started”, the authors continue.
“If low ACTH and normal to low basal cortisol levels are detected, a [low-dose test] should be performed; in case of pathological [low-dose test], secondary AI is suspected and [other] hypothalamic-hypopituitary associated dysfunctions should be also investigated.”
By Lynda Williams
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