Clinical manifestations and pathogenesis of mitochondrial dysfunction in short stature

Mitochondria plays a pivotal role in cellular energy production, and their dysfunction can lead to a spectrum of mitochondrial diseases, affecting various organs with a wide range of clinical symptoms. Among these, short stature is a notable manifestation, yet its pathogenesis related to mitochondrial dysfunction remains underexplored.

A comprehensive literature search was conducted in the PubMed, Medline, and EMBASE databases from inception to November 2024. Patient demographics, genetic confirmation type, clinical features associated with short stature or growth abnormalities, and any interventions or treatments alongside treatment outcomes were extracted.

Our article provides a comprehensive review of the clinical manifestations and delves into the molecular mechanisms of mitochondrial dysfunction that are associated with short stature. A total of 134 genetically confirmed cases with primary mitochondrial disease (PMD) associated with short stature with mtDNA (e.g., m.3243A>G, large-scale deletions) and nDNA mutations (e.g., NDUFB3, SURF1). Median age at short stature detection was 8 years, with 40% presenting earlier. Growth hormone deficiency (GHD) occurred in 15% of cases, showing variable responses to therapy. Pathogenesis involves mitochondrial dysfunction, growth plate impairment, and endocrine disorders. Early diagnosis relies on timely genetic testing. Management of PMD includes tailored dietary strategies, supplementation, and cautious GH therapy due to potential risks. Emerging gene therapy and multidisciplinary care are emphasized to address disease complexity and optimize outcomes.

Previous reviews have described the endocrine aspects of mitochondrial diseases. Although the list of endocrine diseases is comprehensive, it is not specific for short stature. This review focuses on short stature, and it is more specific than previous reviews in terms of etiology, pathogenesis, diagnosis, treatment, and prospects.