ISSN 2472-1972 Response to Letter to the Editor: “Endocrine Disorders in Primary Mitochondrial Disease” 1 2,3,4 Iman Al-Gadi and Shana McCormack 1 2 Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois 60612; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104; Children’s Hospital of Philadelphia Mitochondrial Medicine Frontiers Program, Philadelphia, Pennsylvania 19104; and Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104 Copyright © 2018 Endocrine Society This article has been published under the terms of the Creative Commons Attribution Non- Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc- nd/4.0/). We recently published an observational, cross-sectional study designed to provide estimates of the prevalence of endocrine disorders in the North American Mitochondrial Disease Consortium (NAMDC) cohort . In their letter, Finsterer and Zarrouk-Mahjoub  highlight multiple potential opportunities for leveraging this cohort to enrich further our un- derstanding of the etiology, burden, and management of endocrine disorders in the setting of mitochondrial disease. However, although the NAMDC registry provides a wealth of in- formative and well-curated patient data, it does not currently collect information with sufficient granularity to answer some of the important questions Finsterer and Zarrouk- Mahjoub raise . For example, specific queries regarding endocrine neoplasms, the type of adrenal insufficiency or thyroid disorder, familial clustering of endocrine disorders, and im- portantly, response to therapies were not included. The NAMDC registry does systematically collect data about specific endocrine conditions that were expected to be more prevalent. Clinicians also had the opportunity to note the presence of additional conditions; polycystic ovarian syndrome and irregular menses are examples of these. In our paper, we presented data on conditions with systematically collected information separately from those noted via free text to account for potential biases introduced by these methodological differences . Finsterer and Zarrouk-Mahjoub  also raise a question about the methods by which clinical syndromes related to mitochondrial disease were defined. Definitions of clinical syndromes were made according to standardized, consensus-based diagnostic criteria de- veloped by NAMDC mitochondrial disease clinical experts. A category of multisystemic syndrome was assigned to those individuals with phenotypes not characteristic of a well- defined syndrome; individuals with multisystemic syndrome account for 8% of the cohort. Details on mitochondrial disease clinical syndromes included our cohort can be found in Supplemental Table 3 of our paper . We also agree that there is an interesting association between mitochondrial DNA (mtDNA) deletions and/or duplications and endocrinopathies in our cohort, and we refer the reader to Supplemental Table 2 of our paper  for additional detail. Patients with large-scale rearrangements (i.e., deletions and/or duplications) accounted for 1.7% of our cohort. Individuals with multiple mtDNA point mutations accounted for 3% of the total cohort, whereas individuals with single mtDNA point mutations made up 51% of the cohort. Although beyond the scope of our study , some case reports have Abbreviations: mtDNA, mitochondrial DNA; NAMDC, North American Mitochondrial Disease Consortium. Received 4 May 2018 Accepted 8 May 2018 June 2018 | Vol. 2, Iss. 6 First Published Online 14 May 2018 doi: 10.1210/js.2018-00134 | Journal of the Endocrine Society | 572–573 Downloaded from https://academic.oup.com/jes/article-abstract/2/6/572/4995290 by Ed 'DeepDyve' Gillespie user on 21 June 2018 doi: 10.1210/js.2018-00134 | Journal of the Endocrine Society | 573 suggested that the nature of the mtDNA change may influence the degree of multisystem involvement. For example, pleioplasmic mtDNA rearrangements may be distributed more widely across tissues and thus may explain the simultaneous occurrence of multiple endo- crine disorders in the same individual . With regard to the preponderance of mtDNA molecular genetic diagnoses in the NAMDC registry, we speculate that many of these individuals may have been diagnosed prior to the current availability of advanced molecular diagnostic techniques that permit ready identi- fication of pathologic nuclear DNA defects. It will be interesting to appreciate how the genetic epidemiology of mitochondrial disorders changes over time as these diagnostic techniques are more widely adopted. In summary, much remains to be learned about the etiology and management of endocrine disorders in mitochondrial diseases. The NAMDC registry provides a critical resource to support future prospective studies and, importantly, for the development of evidence-based screening guidelines for endocrine disorders in this high-risk population. Acknowledgments Correspondence: Shana McCormack, MD, 3401 Civic Center Boulevard, Suite 11NW, Philadelphia, Pennsylvania 19104. E-mail: email@example.com. Disclosure Summary: The authors have nothing to disclose. References and Notes 1. Al-Gadi IS, Haas RH, Falk MJ, Goldstein A, McCormack SE. Endocrine disorders in primary mito- chondrial disease. J Endocr Soc. 2018;2(4):361–373. 2. Finsterer J, Zarrouk-Mahjoub S. Letter to the editor: endocrine compromise in mitochondrial disorders. J Endocr Soc. 2018;2(6):570–571. 3. Wilichowski E, Gruters ¨ A, Kruse K, Rating D, Beetz R, Korenke GC, Ernst BP, Christen HJ, Hanefeld F. Hypoparathyroidism and deafness associated with pleioplasmic large scale rearrangements of the mitochondrial DNA: a clinical and molecular genetic study of four children with Kearns-Sayre syndrome. Pediatr Res. 1997;41(2):193–200. Downloaded from https://academic.oup.com/jes/article-abstract/2/6/572/4995290 by Ed 'DeepDyve' Gillespie user on 21 June 2018
Journal of the Endocrine Society – Oxford University Press
Published: May 14, 2018
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