Moon Facies - Definition and When to Call It

Definition

• Frameworks for Internal Medicine defines it as: "rounded face due to fat deposition" - a clinical manifestation of Cushing's syndrome
• ScienceDirect / Practical Pediatric Endocrinology defines it as: "a rounded red face that is characteristic of Cushing syndrome"
• Cleveland Clinic: fat deposits build up along the sides of the skull, and the face can become so round that the ears are not visible from the front

When Do You Call It Moon Facies?

Main Causes

1. Cushing's syndrome - excess endogenous cortisol (adrenal tumor, pituitary adenoma - Cushing's disease, ectopic ACTH)
2. Exogenous corticosteroids - the most common cause in clinical practice; develops in slightly more than 10% of patients on steroids, but is uncommon below physiologic replacement doses (Rheumatology, 2-Volume Set, 2022)
3. Obesity - can produce a similar appearance but without the other Cushingoid features

Classic Cluster (Cushingoid Appearance)

• Buffalo hump (dorsal fat pad)
• Supraclavicular fat pads
• Central/truncal obesity with thin limbs
• Violaceous abdominal striae
• Skin thinning and easy bruising
• Hypertension
• Hirsutism (in women)

Proximal Myopathy in Cushing's Syndrome - Mechanism Explained

What Does It Look Like Clinically?

• Weakness is proximal (shoulders, hips, thighs) - distal muscles are largely spared
• Legs affected more than arms
• Onset is typically insidious - patients first notice difficulty rising from a chair, climbing stairs, or lifting arms overhead
• Eventually leads to frank muscle wasting
• Crucially: serum CK (creatine kinase) is usually normal - this is a key distinguishing feature from inflammatory myopathies
• Reported in up to 70% of patients with active primary Cushing's syndrome (Firestein & Kelley's Textbook of Rheumatology, 2022)

Why Proximal? The Core Mechanisms

1. Type II Muscle Fiber Atrophy (The Most Important Mechanism)

• Muscle biopsy shows increased vacuolation and glycogen accumulation in type II fibers (Firestein & Kelley's Rheumatology)
• GCs activate the glucocorticoid receptor (GR) inside muscle cells, which then drives the transcription of genes that destroy muscle protein

2. Increased Muscle Protein Catabolism (Breaking Down Muscle)

3. Suppression of Protein Synthesis (Blocking Muscle Building)

• Suppresses PI3K/AKT/mTORC1 signaling - this pathway is the master regulator of muscle protein synthesis. Glucocorticoids suppress it directly via GR activation, and also by inducing SIRT6, which inhibits AKT/mTORC1
• Reduces IGF-1 (Insulin-like Growth Factor-1) locally in muscle - IGF-1 normally promotes satellite cell proliferation and new muscle fiber synthesis
• Upregulates myostatin - a powerful inhibitor of muscle growth; glucocorticoids increase myostatin expression, further blocking regeneration
• Reduces insulin sensitivity in muscle - less glucose uptake means less energy for muscle synthesis

4. Mitochondrial Dysfunction

5. Additional Contributing Factors

• Hypokalemia - Cortisol has mineralocorticoid-like activity, causing potassium wasting through the kidney. Low potassium directly impairs muscle membrane excitability and contraction
• Hypophosphatemia - Can further reduce muscle contractility
• In endogenous Cushing's (ACTH-dependent causes): excess ACTH itself may impair neuromuscular junction transmission by reducing quantal content of the end-plate potential - an additional myopathic mechanism on top of the cortisol effect

Why Does It Persist Even After Treatment?

Summary Diagram of Mechanisms

Excess Cortisol / Glucocorticoids
         |
         ├── Activates GR in muscle
         |        |
         |        ├── Upregulates ubiquitin-proteasome (UPS) → protein degradation
         |        ├── Activates lysosomal cathepsins → protein degradation
         |        ├── Activates calpains → myofilament degradation
         |        ├── Suppresses PI3K/AKT/mTOR → ↓ protein synthesis
         |        ├── Upregulates myostatin → blocks muscle regeneration
         |        └── Reduces IGF-1 → ↓ satellite cell proliferation
         |
         ├── Mitochondrial dysfunction → ↓ energy supply
         ├── Hypokalemia → ↓ membrane excitability
         └── Excess ACTH (endogenous only) → ↓ neuromuscular transmission
                   ↓
         Preferential TYPE II FIBER ATROPHY
         (Type II fibers dominate PROXIMAL muscles)
                   ↓
         PROXIMAL MYOPATHY

Key Articles

1. Gé fard-Gontier et al., Journal of Neurology, 2025 - "Glucocorticoid-induced myopathy: a comprehensive review" - covers pathophysiology (catabolic + anti-anabolic mechanisms), diagnostic challenges, and emerging therapies including IGF-1, branched-chain amino acids, and exercise. PMID: 41148376
2. Permpoon et al., Int J Mol Sci, 2025 - "Glucocorticoid-Mediated Skeletal Muscle Atrophy: Molecular Mechanisms and Potential Therapeutic Targets" - covers GR transactivation, SIRT6/AKT/mTORC1 suppression, the kynurenine/IDO-1 pathway, LSD1 cooperation with GR, and novel drug targets including 11β-HSD1 inhibitors and myostatin blockers. PMID: 40806744
3. Reincke M., Endocrinol Metab, 2021 - "Cushing Syndrome Associated Myopathy: It Is Time for a Change" - specifically focused on Cushing's-associated myopathy, noting its underdiagnosis and calling for updated diagnostic and management approaches. PMID: 33915607

• UPS (ubiquitin-proteasome) upregulates MuRF-1 and Atrogin-1, tagging muscle proteins for destruction
• Lysosomal cathepsins degrade structural muscle proteins
• Calpains (calcium-activated) break down myofilaments

• PI3K/AKT/mTORC1 signaling is suppressed - muscle cannot synthesise new protein
• IGF-1 is reduced - satellite cells cannot regenerate new fibers
• Myostatin is upregulated - a brake on all muscle growth