Susumu Yokoya1, Tomonobu Hasegawa2, Keiichi Ozono3, Hiroyuki Tanaka4, Susumu Kanzaki5, Toshiaki Tanaka6, Kazuo Chihara7, Nan Jia8, Christopher J Child9, Katsuichiro Ihara10, Jumpei Funai11, Noriyuki Iwamoto10, Yoshiki Seino12. 1. Department of Medical Subspecialties, National Center for Child Health and Development, Tokyo, Japan. 2. Department of Pediatrics, School of Medicine, Keio University, Tokyo, Japan. 3. Department of Pediatrics, Graduate School of Medicine, Osaka University, Osaka, Japan. 4. Department of Pediatrics, Okayama Saiseikai General Hospital, Okayama, Japan. 5. Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan. 6. Tanaka Growth Clinic, Tokyo, Japan. 7. Hyogo Prefectural Kakogawa Medical Center, Kakogawa, Japan. 8. Lilly Research Laboratories, Eli Lilly and Company, Indiana, USA. 9. Lilly Research Laboratories, Eli Lilly and Company, Windlesham, UK. 10. Medical Science, Eli Lilly Japan K.K., Kobe, Japan. 11. Scientific Communications, Eli Lilly Japan K.K., Kobe, Japan. 12. JCHO Osaka Hospital, Osaka, Japan.
We would like to thank Dr. Finsterer for his comments and questions (1) regarding the possibility that the short stature in patients from our
study (2) could also be a phenotypic manifestation of
mitochondrial disorders (MIDs).The GeNeSIS postmarketing research programme collected data from the routine clinical care of
growth hormone-treated pediatric patients with growth disorders. Growth disorder diagnoses
provided by investigators were reviewed and prioritized for impact on short stature using a
predefined scheme. Based on this scheme, any diagnosis of an MID would have been noted for the
affected patient and they were not excluded from the study. Although there was a possibility
that some of the Japanese patients with growth hormone deficiency (GHD) included in our study
had unreported MIDs, two Japanese patients from the same investigative site were definitively
diagnoses for MID:• Male (baseline age 13.8 years): This was the
patient reported in our manuscript with the adverse event of insulin-dependent diabetes
mellitus due to underlying mitochondrial encephalopathy, lactic acidosis, and stroke-like
episodes (MELAS). The diagnosis of short stature provided by the physician was congenital GHD
due to mitochondrial tRNA mutation.• Male (baseline age 15.0 years): No diabetes or
indeed MELAS was reported for this patient, although a “cerebral stroke” was reported.
However, this patient also had a short stature diagnosis of congenital GHD due to
mitochondrial tRNA mutation.In the Japanese cohort of patients with GHD, other than these two patients with MID
diagnoses, there were no reports of specific phenotypic features of MID including hearing
impairment, muscle weakness, lactic acidosis, Fanconi syndrome, aminoaciduria, and cerebral
imaging showing focal or diffuse atrophy, leukoencephalopathy, lesions in thalamic, basal
ganglia, brain stem or cerebellar; there was 1 reported event of cardiac failure in a patient
with idiopathic GHD.In relation to Dr Finsterer’s comments regarding neoplastic disease and MIDs, the two
patients diagnosed with MIDs were not included in the four patients with recurrent
craniopharyngioma, and there were no any specific symptoms to suggest MID in these
patients.We again thank Dr. Finsterer for his interest in our paper, but given the observational
nature of the GeNeSIS programme and rareness of cases of MIDs in enrolled patients, we cannot
offer further insights into the frequency of MIDs and impact on GH treatment outcomes.Sincerely,The Authors