Layout 1 Endocrine involvement in Kearns-Sayre syndrome Eur J Transl Myol 35 (2) 13634, 2025 doi: 10.4081/ejtm.2025.13634 Dear Editor, We were interested to read the article by Amergoolov et al. on two patients with Kearns-Sayre Syndrome (KSS) due to single mtDNA deletions who had phenotypic endocrine dis- orders among other features.1 Patient 1, a 20-year-old fe- male, was diagnosed with hypogonadism, diabetes and osteoporosis, and patient 2, a 22-year-old male, was dia- gnosed with impaired glucose tolerance and osteoporosis.1 It was found that the severity of clinical manifestations in- creases with the size of the mtDNA deletion, but that other factors such as heteroplasmy, mtDNA duplications or pleio- plasmia can also determine the severity of the disease.1 The study is impressive, but some points should be discussed. The first point is that the endocrine involvement in KSS is more extensive than described in the article. KSS patients often show developmental delay and short stature early in life.2 Short stature is usually due to reduced secretion of So- matotropic Hormones (STH) from the pituitary gland. Pi- tuitary insufficiency has previously been diagnosed in these patients.3 How high were the STH levels in the two index cases? There are also KSS patients with hypothyroidism,4 hypoparathyroidism,5 hypocorticism (Addison’s disease),3 hypoadrenalism, pancreatic insufficiency and hypogonad- ism.6 Patients with multiple endocrinopathies have also been reported.7 Therefore, it is recommended to perform a complete hormone panel in these patients, including not only pituitary hormones, but also thyroid, parathyroid, pan- creatic, gonadal, renal and adrenal hormone levels. The second point is that neither patient 1 nor patient 2 had an MRI of the brain including the pituitary gland.1 In order to assess whether a pituitary apoplexy, adenoma, empty sella or hypophysitis was present, it would have been im- portant that at least the hypothalamus and pituitary gland were examined with contrast in both patients. KSS can also manifest with leukoencephalopathy or basal ganglia calci- fications,8 which is why it is also important to perform a cerebral MRI in both cases. The third point is that KSS can also manifest with anaemia, leukopenia or thrombocytopenia or even pancytopenia, as in Pearson’s bone marrow syndrome. Was there any ev- idence of involvement of the hematopoietic system in either patient? The fourth point is that KSS can also be associated with renal insufficiency.9 Did either patient suffer from renal dis- ease such as Toni-Debre-Fanconi syndrome, renal insuffi- ciency, nephrolithiasis, nephrotic syndrome, renal cysts, renal tubular acidosis, Bartter-like syndrome, focal segmen- tal glomerulosclerosis, tubulointerstitial nephritis, nephro- calcinosis, and benign or malignant neoplasms, as previously reported.9 The fifth point is that cardiac involvement in KSS includes not only AV block III, but also several other cardiac abnor- malities. These include cardiomyopathy and various supra- ventricular and ventricular arrhythmias.10 Screening for ventricular arrhythmias by Holter monitoring is therefore crucial, as ventricular arrhythmias can determine outcome and are usually amenable to treatment. The sixth point is that heteroplasmy rates have not been re- ported.1 Since the phenotype may depend not only on the deletion size but also on the heteroplasmy rate, it is essential to determine this influencing factor. Although KSS is in- herited via the maternal trait in only four percent of cases, it is important to report whether the mtDNA deletions found were inherited from the mothers or arose de novo. The seventh point is that the conclusions are only partially justified. It is not justified to conclude from two cases that the severity of the disease increases with the size of the deletion and that other factors of mitochondrial genetics may determine the phenotype. Finally, it should be explained what is meant by pleioplas- mia. Do the authors mean mtDNA copy number or do they mean mtDNA polymorphisms that additionally determine the phenotype? Overall, this interesting study has limitations that put the results and their interpretation into perspective. Addressing these limitations could strengthen the conclusions and re- Key Words: mtDNA, deletion, Kearn-Sayre syndrome, mitochondrial disorder, endocrine involvement. Eur J Transl Myol 35 (2) 13634, 2025 doi: 10.4081/ejtm.2025.13634 Polyendocrinopathy and multisystem involvement are common phenotypic features of Kearns-Sayre syndrome Josef Finsterer Neurology Department, Neurology & Neurophysiology Center, Vienna, Austria. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. - 171 - Endocrine involvement in Kearns-Sayre syndrome Eur J Transl Myol 35 (2) 13634, 2025 doi: 10.4081/ejtm.2025.13634 inforce the message of the study. All unanswered questions need to be clarified before readers uncritically accept the conclusions of the study. KSS patients should be system- atically and prospectively screened for polyendocrinopathy and for multisystem involvement in the disease. Better pow- ered, multicenter studies are needed before conclusions can be drawn about the relationship between the severity of KSS and mtDNA genetics. Ethical approval Not applicable. Consent to participation Not applicable. Consent for publication Not applicable. Funding None received. Availability of data and material All data are available from the corresponding author. Conflict of interest The author has no conflict of interest to declare. Corresponding author Josef Finsterer, Neurology Deartment, Neurology & Neu- rophysiology Center, Postfach 20, 1180 Vienna, Austria. Tel. +43-1-5861075 - Fax. +43-1-5861075. ORCID ID: 0000-0003-2839-7305. E-mail: fifigs1@yahoo.de References 1. Amergoolov II, Khruleva YI, Pavlova MG, et al. En- docrine disorders in Kearns-Sayre syndrome with dif- ferent severity of symptoms: two case reports and a literature review. Eur J Transl Myol 2024;34: 12897. 2. Quintos JB, Hodax JK, Gonzales-Ellis BA, et al. Ef- ficacy of growth hormone therapy in Kearns-Sayre syndrome: the KIGS experience. J Pediatr Endocrinol Metab 2016;29:1319-24. 3. Finsterer J, Winklehner M, Stöllberger C, Hummel T. Unusual Phenotype and Disease Trajectory in Kearns- Sayre Syndrome. Case Rep Neurol Med 2020;2020: 7368527. 4. Berio A, Piazzi A. Kearns-Sayre syndrome, compen- sated hypothyroidism and complete atrio-ventricular block. Panminerva Med 2006;48:258. 5. Pellock JM, Behrens M, Lewis L, et al. Kearns-Sayre syndrome and hypoparathyroidism. Ann Neurol 1978;3:455-8. 6. Kitamura E, Yamane K, Takeuchi M, et al. [Kearns- Shy syndrome associated with choreic movement, primary hypogonadism, and brain CT abnormalities]. Nihon Naika Gakkai Zasshi 1985;74:582-9. Japanese. 7. Berio A, Piazzi A. Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome. Pediatr Med Chir 2013;35:137-40. 8. Carboni P, Giacanelli M, Porro G, et al. Kearns-Sayre syndrome. A case of the complete syndrome with encephalic leukodystrophy and calcification of basal ganglia. Ital J Neurol Sci 1981;2:263-8. 9. Finsterer J, Scorza FA. Renal manifestations of pri- mary mitochondrial disorders. Biomed Rep 2017;6: 487-94. 10. Wiseman K, Gor D, Udongwo N, et al. Ventricular arrhythmias in Kearns-Sayre syndrome: A cohort study using the National Inpatient Sample database 2016-2019. Pacing Clin Electrophysiol 2022;45: 1357-63. Disclaimer All claims expressed in this article are solely those of the authors and do not necessarily represent those of their af- filiated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Submitted: 15 January 2025. Accepted: 20 January 2025. Early access: 14 January 2025. - 172 -