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Endocrine Manifestations of Kearns–Sayre Syndrome: A Systematic Review of Case Reports

This systematic review of 26 case reports highlights that endocrine dysfunction in Kearns–Sayre syndrome is a common, heterogeneous, and often progressive feature involving multiple glands, frequently preceding classical neurological symptoms and necessitating early multidisciplinary screening to improve patient outcomes.

Original authors: Mahdia Babak, Savera khan, Muhammad Haris, Tolulope Joseph Ogunniy

Published 2026-06-28

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Mahdia Babak, Savera khan, Muhammad Haris, Tolulope Joseph Ogunniy

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

The Big Picture: A Power Plant Failure

Imagine your body is a massive city. Every building in this city (your muscles, heart, eyes, and glands) needs electricity to run. In a healthy body, this electricity comes from tiny power plants inside your cells called mitochondria.

Kearns–Sayre Syndrome (KSS) is like a city-wide power outage caused by a massive crack in the blueprint of these power plants. Specifically, a large chunk of the "instruction manual" (mitochondrial DNA) is missing. Without the right instructions, the power plants can't generate enough energy.

This paper is a systematic review, which means the authors acted like detectives. They gathered 26 different "case files" (stories of individual patients) from around the world to solve a specific mystery: How does this power failure affect the body's hormone factories?

The Mystery: The Hormone Factories Go Dark

The body has many "hormone factories" (endocrine glands) that produce chemicals to keep things running smoothly, like sugar levels, growth, and calcium balance.

The authors found that when the power plants fail, these hormone factories are often the first to go dark. The paper highlights that:

It's not just one factory: Usually, it's not just one gland that fails. It's often a chain reaction where multiple factories shut down at once.
The most common victims: The Pancreas (which controls blood sugar/diabetes) and the Parathyroid (which controls calcium) were the most frequently reported casualties.
The "Silent" Start: In many cases, the hormone problems started before the classic signs of KSS (like eye muscle weakness or heart block) appeared. It's like the smoke alarm going off before the fire is even visible. This often led to diagnostic delays, where doctors treated the symptoms (like diabetes) without realizing the root cause was the mitochondrial power failure.

The Detective Work: How They Found the Clues

The paper tracks how doctors have gotten better at solving this mystery over time:

Old School: In the past, doctors relied on guessing based on symptoms or taking a tiny piece of muscle to look under a microscope.
Modern Era: Now, they use genetic testing to find the missing "blueprint" (the DNA deletion).
The "Heteroplasmy" Factor: The authors explain a concept called heteroplasmy. Imagine a city where some buildings have working power plants and others don't. If a patient has a high percentage of "broken" power plants (high heteroplasmy), their symptoms are usually much more severe and widespread.

The Treatment Challenge: Fixing the Symptoms, Not the Cause

The paper is very clear about the limits of current medicine. Think of it this way:

The Problem: The power plants are broken.
The Current Fix: Doctors can bring in a generator (hormone replacement therapy) to keep the lights on in the hormone factories.
- If the pancreas stops making insulin, they give insulin shots.
- If the thyroid stops working, they give thyroid pills.
The Catch: The generator doesn't fix the broken power plant. The paper notes that while these treatments help manage the numbers (like blood sugar or calcium), they do not stop the disease from getting worse. The underlying energy failure continues to damage the heart, eyes, and brain.
Specific Failures: The paper notes that giving Growth Hormone to children with KSS often doesn't help them grow taller, because the "construction crew" (the cells) is too tired to build, even if they have the materials.

The Main Takeaways

It's a Multisystem Disaster: KSS isn't just an eye or heart disease; it's a whole-body energy crisis that frequently knocks out the hormone system.
Watch the Hormones First: Because hormone problems can appear before the classic eye or heart symptoms, the authors suggest doctors should screen for endocrine issues early if they suspect KSS. This could stop the "diagnostic delay."
No Magic Bullet: Currently, there is no cure. Treatment is about "supportive care"—keeping the city running with generators while the power plants remain broken.
The Evidence is Scattered: The authors had to look at 26 separate stories because KSS is so rare. They couldn't find big studies with hundreds of people; they had to piece together the puzzle from individual case reports.

In Summary

This paper is a collection of stories showing that when the body's internal power grid fails (KSS), the hormone factories are often the first to go dark. While doctors can patch up the leaks with hormone replacements, they cannot fix the broken power grid itself. The best strategy is to be a vigilant detective: if you see a patient with unexplained hormone issues and a hint of eye or heart trouble, check for this rare mitochondrial power failure early to avoid missing the diagnosis.

Technical Summary: Endocrine Manifestations of Kearns–Sayre Syndrome

Problem Statement
Kearns–Sayre Syndrome (KSS) is a rare mitochondrial disorder characterized by progressive external ophthalmoplegia, pigmentary retinopathy, and multisystem involvement. While endocrine dysfunction is a recognized component of the KSS phenotype, its frequency, specific patterns, and management challenges remain incompletely synthesized. Existing epidemiological data often derive from heterogeneous cohorts of mitochondrial diseases rather than KSS-specific populations, limiting the ability to define syndrome-specific prevalence. Furthermore, the natural history of endocrine complications, the variability in diagnostic approaches, and the efficacy of therapeutic interventions are poorly defined. This lack of systematic evaluation hinders the optimization of patient care, particularly given that endocrine abnormalities may precede classical neurological features, leading to significant diagnostic delays.

Methodology
This study is a systematic review conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review was registered with PROSPERO (CRD420241077564).

Search Strategy: A comprehensive search was performed across PubMed, Embase, Scopus, Web of Science, CINAHL, PsycINFO, ASSIA, and Cochrane CENTRAL from inception to September 30, 2025.
Inclusion Criteria: The review included case reports and case series published in English that reported endocrine dysfunction in patients with a confirmed diagnosis of KSS (clinical or genetic). No date restrictions were applied.
Exclusion Criteria: Observational studies, experimental studies, reviews, conference abstracts, letters, editorials, unpublished studies, and animal studies were excluded.
Data Extraction and Quality Assessment: Two independent reviewers screened titles, abstracts, and full texts. Data were extracted regarding patient demographics, diagnostic methods, types of endocrine abnormalities, clinical manifestations, and management strategies. Methodological quality was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal checklist for case reports and case series.
Synthesis: Numerical data were analyzed descriptively, while clinical findings, severity, and management challenges were synthesized qualitatively.

Key Results
The search yielded 769 articles, of which 26 studies (25 case reports and 1 case series) comprising 32 patients met the inclusion criteria.

Demographics: Patients ranged in age from infancy to 48 years at diagnosis, with the majority of cases occurring during adolescence. The cohort included 18 females and 14 males. Studies originated from Europe, Asia, and North America, with publication dates spanning 1978 to 2025.
Endocrine Spectrum: Endocrine involvement was frequently multiglandular. The most common abnormalities were:
- Pancreatic: Diabetes mellitus (61.5% of cases), typically insulin-dependent and often presenting with negative autoimmune markers.
- Parathyroid: Hypoparathyroidism (61.5%), often accompanied by hypocalcemia and hyperphosphatemia.
- Pituitary: Growth hormone deficiency and hypogonadism (26.9%).
- Thyroid: Hypothyroidism (15.4%).
- Adrenal: Adrenal insufficiency (3.8%).
- Polyendocrinopathy: Several cases exhibited combined dysfunction across multiple axes (pituitary, adrenal, gonadal, thyroid, and pancreatic).
Clinical Presentation: Endocrine manifestations often preceded classical neurological features (ophthalmoplegia, retinopathy) by years. Clinical sequelae included poor glycemic control, diabetic ketoacidosis, hypocalcemic tetany, growth failure, delayed puberty, and osteoporosis.
Genotype-Phenotype Correlation: Diagnostic confirmation evolved from clinical criteria and muscle biopsy to molecular identification of mitochondrial DNA (mtDNA) deletions. Higher levels of heteroplasmy were associated with more severe multisystem disease and broader endocrine involvement.
Management Outcomes: Treatment was primarily supportive and replacement-based.
- Diabetes: Insulin therapy was the cornerstone, though glycemic control could fluctuate due to progressive $\beta$ -cell failure.
- Hypoparathyroidism: Managed with vitamin D analogues and calcium, though persistent electrolyte disturbances were noted.
- Growth Hormone: Replacement therapy showed inconsistent benefits, with limited improvement in linear growth, suggesting intrinsic mitochondrial impairment of growth pathways.
- Challenges: Major barriers included diagnostic delay (due to atypical presentations or isolated endocrine symptoms), treatment resistance (e.g., lack of response to growth hormone), adherence issues, and the absence of standardized management guidelines.

Significance and Claims
The authors claim that this systematic review provides the first comprehensive synthesis of endocrine manifestations in KSS based on published case literature. The study highlights that endocrine dysfunction is a common, heterogeneous, and frequently progressive component of KSS, often involving multiple glands.

Key contributions of the paper include:

Diagnostic Awareness: The review underscores that endocrine abnormalities can be the initial presentation of KSS, often preceding the classic triad of symptoms. This suggests that early screening and ongoing multidisciplinary surveillance are essential to reduce diagnostic delays.
Clinical Patterns: It establishes a clear pattern of frequent co-occurrence between diabetes mellitus and hypoparathyroidism, as well as the prevalence of polyendocrine failure.
Management Realities: The paper clarifies that while hormone replacement can improve biochemical control, it does not halt the progression of the underlying mitochondrial disease. It highlights the limitations of current therapies, particularly the poor response to growth hormone in the context of mitochondrial dysfunction.
Genotype-Phenotype Insights: The review reinforces the correlation between mtDNA deletion burden (heteroplasmy) and the severity of multisystem disease, including endocrine involvement.

The authors conclude that while current management remains supportive, the recognition of endocrine dysfunction as a core feature of KSS is critical for optimizing patient outcomes through anticipatory care and coordinated multidisciplinary monitoring. They note limitations inherent to the evidence base, which relies almost entirely on case reports and small series, preventing definitive conclusions on prevalence or causal inferences.