Multiple endocrinopathies (growth hormone deficiency, autoimmune hypothyroidism and diabetes mellitus) in Kearns-Sayre syndrome

Abstract

Kearns-Sayre syndrome is characterized by onset before 20 years, chronic progressive external opthalmoplegia, pigmentary retinal degeneration, and ataxia (and/or hearth block, and/or high protein content in the cerebrospinal fluid) in the presence of mtDNA rearrangements. Multiple endocrine dysfunction associated with this syndrome was rarely reported. In this paper, the Authors report on a female patient with Kearns-Sayre syndrome with large heteroplasmic mtDNA deletion, absence of cytochrome c oxidase in many muscle fibers, partial GH deficiency, hypothyroidism and subsequently insulin dependent diabetes mellitus (IDDM). Anti-thyroid peroxidase and antithyreoglobulin antibodies were present in high titer in serum while anti-islet cell antibodies were absent. The patient developed thyroiditis with Hashimoto encephalopathy. The presence of GH deficiency, autoimmune thyroiditis with hypothyroidism and IDDM distinguishes this case from others and confirms the association of Kearns-Sayre syndrome with multiple endocrine dysfunction. Hashimoto encephalopathy and anti-thyroideal antibodies suggest that in this patient, predisposed by a genetic factor (a mitochondrial deletion) anti-thyroideal antibodies may have contributed to the hypothyroidism and, by interfering with cerebral mitochondrial function, may have caused the encephalopathy. GH deficiency and IDDM can be attributed to oxidative phosphorylation deficiency but the autoimmunity may also have played a role in the production of glandular insufficiencies. It seems important to search for endocrine autoimmunity in every case of KSS.

Mitochondrial disease and endocrine dysfunction

“…However, numerous case reports have documented hypothyroidism developing in a heterogeneous group of patients, including 15% (6 out of 40) of an adult cohort with late onset chronic progressive external ophthalmoplegia, and was more frequent than diabetes mellitus (5%) in this cohort [119]. Hypothyroidism has been described in patients with mtDNA deletions including Kearns-Sayre syndrome [12,48,55]. In the literature review by Harvey et al in 1992, 7 of 226 cases (3%) with probable Kearns-Sayre syndrome had thyroid disease [48].…”

“…Growth hormone deficiency has been described in multiple case reports and case series with MELAS [10,[49][50][51][52][53], decreased complex II activity [54], mtDNA deletion disorders [12,13,[55][56][57][58], and various mitochondrial diseases without genetic confirmation [59,60]. Growth hormone deficiency and/or short stature has also been documented in nuclear-encoded defects of mitochondrial translation, e.g.…”

“…However, it is difficult to draw firm conclusions on such small numbers. There are also reports of patients with growth hormone deficiency who did not respond to growth hormone treatment [60,65].…”

Unusual Phenotype and Disease Trajectory in Kearns–Sayre Syndrome

“…ough the patient fulfilled the diagnostic criteria for KSS, he additionally presented with a plethora of manifestations, of which some have been reported earlier in KSS. In addition to the features required for diagnosing KSS, the patient presented with the known features of diabetes [4], hypocorticism (hyponatremia) [5], short stature [6], white matter lesions [7], hypoacusis [1], migraine [8], hepatopathy [9], steatosis [10], and cataract [11]. Features so far unreported in KSS include congenital anisocoria, severe caries, liver cysts, pituitary enlargement, desquamation of hands and feet, bone chondroma, aortic ectasia, dermoidal cyst, and polyposis of nasal sinuses.…”

Cerebral Manifestations of Mitochondrial Disorders

“…Hypopituitarism may manifest as short stature, hypothyroidism, hypocorticism, hypogonadism, polydipsia, or arterial hypotonia. Hypopituitarism has been reported in MELAS, 64 KSS, 65 or nsMIDs from mutations in the isoleucyl t-RNA synthetase gene 66 . Pituitary adenoma has been reported in LHON 67 and some nsMIDs 68 .…”