The Changing Face of Endogenous Cushing Syndrome: From Growth Failure in Childhood to Cardiometabolic Burden in Adulthood

Technical Summary: The Changing Face of Endogenous Cushing Syndrome

Problem Statement
Endogenous Cushing syndrome (CS) is a rare disorder characterized by chronic exposure to excess endogenous glucocorticoids, leading to significant multisystem morbidity and increased mortality. While the biochemical diagnosis and etiological classification of CS are well-established, the clinical expression of the disease is highly heterogeneous. A critical gap exists in the characterization of age-related phenotypic differences across the full spectrum of endogenous CS etiologies. Existing literature often focuses on either exclusively adult cohorts or highly selected pediatric pituitary series (Cushing disease), limiting the generalizability of findings across the entire disease spectrum. Furthermore, it remains unclear whether observed phenotypic variations are driven by differences in disease etiology or represent fundamentally distinct biological expressions of cortisol excess based on developmental stage. This lack of clarity contributes to diagnostic delays, as clinicians may rely on "classical" adult metabolic stigmata for children or miss the specific auxological clues in pediatric patients.

Methodology
This study employed a retrospective observational design at a high-volume tertiary endocrine referral center (Postgraduate Institute of Medical Education and Research, India). The cohort included 281 consecutive patients with biochemically confirmed endogenous CS evaluated between January 2006 and December 2025. Patients were stratified into two primary groups: pediatric/adolescent (≤ 18 years, n=41) and adult (> 18 years, n=240).

Data were extracted from electronic medical records, covering baseline demographics, clinical symptoms, anthropometrics, biochemical profiles, and etiological classifications. Key methodological features included:

• Auxological Assessment: Calculation of height and BMI Standard Deviation Scores (SDS) using WHO standards, assessment of growth velocity, and evaluation of pubertal status.
• Biochemical Analysis: Measurement of morning/late-night cortisol, urinary free cortisol (UFC), and dexamethasone suppression tests. UFC values were normalized relative to the upper limit of normal (× ULN) to account for assay variations over the study period.
• Cardiometabolic Burden Score: An exploratory composite score (0–5) was constructed based on the presence of hypertension, diabetes mellitus, obesity, hypertriglyceridemia, and proximal myopathy. High burden was defined as ≥3 abnormalities.
• Statistical Analysis: Between-group comparisons utilized t-tests, Mann–Whitney U tests, and chi-square/Fisher's exact tests. Multivariable logistic regression was performed to assess independent associations between age group and clinical outcomes, adjusting for sex, BMI, etiological subtype, morning cortisol, and ACTH dependency.

Key Contributions
The paper provides a comprehensive, real-world comparison of pediatric/adolescent and adult phenotypes across the entire spectrum of endogenous CS etiologies (including Cushing disease, ectopic ACTH, and adrenal causes), rather than isolating specific subtypes. It introduces a structured analysis of auxological discordance (height vs. BMI SDS) as a marker for pediatric presentation and utilizes an exploratory composite score to quantify cumulative cardiometabolic burden. Crucially, the study demonstrates that phenotypic differences persist even when controlling for biochemical severity and etiological distribution.

Results
The analysis revealed distinct, age-dependent phenotypic heterogeneity despite comparable biochemical severity and etiological distribution between groups:

1. Pediatric/Adolescent Phenotype:

   • Auxological Distinctiveness: Patients exhibited a marked "height-BMI discordance." Mean height SDS was reduced (−1.72 ± 1.21), while BMI SDS was elevated (+2.08 ± 0.91).
   • Growth and Puberty: Impaired growth velocity was documented in 83.3% of evaluable patients, and delayed puberty/hypogonadism occurred in 36.0%. Short stature (height SDS < −2) was present in 38.7%.
   • Clinical Presentation: Weight gain was nearly universal (100% vs. 81.0% in adults, P=0.0008). Generalized obesity was significantly more frequent in children (29.3% vs. 10.1%).
   • Metabolic Burden: Rates of diabetes, hypertension, and skeletal complications were significantly lower than in adults.

2. Adult Phenotype:

   • Systemic Metabolic Burden: Adults demonstrated significantly higher rates of diabetes mellitus (63.8% vs. 26.8%), hypertension (76.2% vs. 50.0%), proximal myopathy (63.8% vs. 45.0%), and fracture/osteoporosis (23.4% vs. 7.9%).
   • Biochemical Profile: Adults had higher fasting glucose, HbA1c, and triglyceride levels. While morning ACTH was slightly higher in adults, the proportion of ACTH-dependent disease was similar between groups.
   • Cardiometabolic Score: Adults had a significantly higher median burden score (3 vs. 2) and a higher prevalence of high burden (≥3 complications) compared to children (65.6% vs. 39.5%).

3. Multivariable Analysis:

   • After adjusting for covariates, adult age remained independently associated with diabetes (OR 3.21), hypertension (OR 2.54), and high cardiometabolic burden (OR 2.68).
   • Conversely, pediatric/adolescent age was independently associated with generalized obesity (OR 2.92).
   • Etiological distribution (Cushing disease vs. adrenal vs. ectopic) did not differ significantly between age groups, suggesting the phenotypic differences are driven by age/developmental stage rather than etiology.

Significance and Claims
The authors conclude that endogenous Cushing syndrome exhibits clear age-dependent phenotypic heterogeneity. The study posits that younger patients present predominantly with an auxological phenotype characterized by disproportionate weight gain, impaired linear growth, and pubertal disturbances. In contrast, adults present with a cardiometabolic and myopathic phenotype dominated by diabetes, hypertension, and skeletal fragility.

The significance of these findings lies in their potential to refine diagnostic pathways. The paper argues that recognition of these age-specific patterns can support earlier diagnostic suspicion:

• In pediatric practice, clinicians should prioritize the combination of weight gain and impaired growth velocity over obesity alone as a red flag for hypercortisolism.
• In adult practice, the cumulative burden of metabolic and musculoskeletal complications should be viewed as a primary presentation, even in the absence of classical stigmata.

The authors modestly note that while the study is retrospective and limited by potential documentation bias and assay variations over time, the findings are hypothesis-generating and suggest that age and developmental stage meaningfully influence disease expression independent of biochemical severity or etiology. This distinction is critical for reducing diagnostic delays, which are particularly detrimental to growth and development in pediatric patients.