Fact-checked by Grok 2 weeks ago

Pseudohypertrophy

Pseudohypertrophy is a medical condition characterized by the apparent enlargement of muscles or organs due to replacement of normal tissue with non-contractile elements like and fibrous , rather than true cellular . This creates an illusion of increased size and strength, but the affected tissue is typically weakened. The term derives from "pseudo-" (false) and "" (enlargement), and was first described in mid-19th century observations of muscle disorders. It is most commonly associated with muscular dystrophies such as Duchenne and types, where calf muscles often show pseudohypertrophy, as well as endocrine disorders like longstanding untreated manifesting as Kocher-Debre-Semelaigne syndrome. Rarer cases occur in neuropathies, , and even non-muscle organs like the (lipomatous pseudohypertrophy). involves , , and specific testing, with targeting the underlying cause.

Definition and Terminology

Definition

Pseudohypertrophy refers to an apparent enlargement of muscle tissue resulting from the infiltration and replacement of muscle fibers by non-contractile elements, such as fat, fibrous , or accumulation, rather than from the true growth or proliferation of contractile myofibers. This condition leads to a paradoxical presentation where the muscle appears bulky but exhibits reduced strength and functionality due to the diminished proportion of viable muscle tissue. In contrast to true , which arises from enhanced protein synthesis and myofiber enlargement in response to physiological demands like exercise, thereby improving contractile capacity, pseudohypertrophy does not confer any adaptive benefit and is often associated with underlying pathological processes that impair muscle performance. The affected muscles typically feel soft or rubbery upon , distinguishing them from the firm texture of genuinely hypertrophied tissue. Pseudohypertrophy predominantly involves skeletal muscles, with a particular predilection for those in the lower extremities, such as the calf muscles (gastrocnemius and soleus). This phenomenon was first systematically described in the late by Guillaume Benjamin Amand Duchenne de Boulogne in his accounts of progressive muscular dystrophies, where he noted the deceptive swelling of calf muscles in affected individuals.

Etymology

The term "pseudohypertrophy" combines the Greek prefix "pseudo-," derived from ψευδής (pseudḗs), meaning "false" or "lying," with "hypertrophy," which itself stems from ὑπέρ (hupér), meaning "over" or "excessive," and τροφή (trophḗ), meaning "nourishment" or "growth." This etymological structure conveys a concept of deceptive or false excessive growth, distinguishing it from genuine tissue enlargement. The term entered medical literature in the 1870s, with its earliest documented use appearing in 1873 in The Lancet, during discussions of progressive muscle conditions. It was prominently introduced by French neurologist Guillaume Duchenne de Boulogne in his 1868 description of a paralytic disorder, where he coined "paralysie musculaire pseudo-hypertrophique" to characterize the apparent muscle swelling observed in affected patients. In the context of progressive muscle disorders, the term's evolution underscores its contrast with "," which originates from ἀ- (a-, "without") + τροφή (trophḗ, "nourishment"), denoting away due to insufficient growth or maintenance. Pseudohypertrophy thus highlights the illusory that belies underlying degenerative processes, a nuance that emerged as clinicians differentiated superficial enlargement from true pathological in the late .

Other Names

Pseudohypertrophy is also known as false hypertrophy, a term that highlights the apparent enlargement of muscle without corresponding increase in functional strength or true myofiber growth. Another primary synonym is spurious hypertrophy, which underscores the misleading or non-genuine nature of the muscle expansion observed in certain neuromuscular conditions. In clinical contexts, particularly within dystrophies, the term "calf pseudohypertrophy" is commonly used to describe the characteristic enlargement of the gastrocnemius muscles, often presenting as a hallmark sign in . These alternative names arise due to the deceptive appearance of muscle bulk, which results from infiltration by fat and fibrous tissue rather than of contractile elements, leading to paradoxically weak muscles despite their enlarged size. Historically, terms such as "pseudohypertrophic muscular dystrophy" were applied in early 20th-century literature to describe conditions like , but these have become obsolete as pseudohypertrophy is recognized as a non-specific feature across various disorders rather than defining a particular dystrophy subtype. Similarly, "spurious hypertrophy" appeared in older medical texts to denote the same phenomenon of illusory muscle growth.

Pathophysiology

Mechanisms of False Enlargement

Pseudohypertrophy arises primarily from the progressive degeneration of fibers, which are subsequently replaced by non-contractile tissues such as adipose (fat) and fibrous , leading to an apparent increase in muscle volume without corresponding gains in strength or function. This replacement occurs as a compensatory response to ongoing muscle damage, where necrotic fibers are infiltrated and supplanted by fibrofatty elements, resulting in enlarged but weakened muscles. In affected individuals, this process can elevate the non-contractile cross-sectional area of muscles by up to 50-90% compared to healthy controls, as observed through and analyses in conditions like (DMD). In dystrophinopathies, such as DMD and , the core mechanism stems from mutations in the gene, leading to absent or dysfunctional protein. normally stabilizes the (muscle cell membrane) as part of the dystrophin-glycoprotein complex; its deficiency causes membrane fragility and increased permeability, allowing excessive calcium influx into muscle fibers. This calcium dysregulation activates proteolytic enzymes and proteases, triggering cycles of fiber , , and mononuclear cell infiltration, which ultimately promotes the deposition of and to fill the void left by degenerating myofibers. The resulting pseudohypertrophy is particularly evident in calf muscles, where fibrofatty replacement can account for a substantial portion of the observed enlargement. Beyond dystrophin-related disorders, pseudohypertrophy can occur through alternative pathways in certain metabolic myopathies, where abnormal accumulation disrupts muscle and leads to fiber enlargement via storage material deposition. For instance, in glycogen storage diseases like Pompe disease (type II), lysosomal dysfunction causes buildup within muscle cells, contributing to hypertrophy-like changes without true myofiber growth. In endocrine disorders, such as longstanding untreated leading to Kocher-Debre-Semelaigne syndrome (KDSS), thyroid hormone deficiency impairs muscle metabolism and development, resulting in delayed maturation of muscle fibers, increased deposition of and mucopolysaccharides, and infiltration by fat and . This pseudohypertrophy is often generalized or prominent in the lower extremities and is reversible with thyroid . In rare cases involving deposition, such as in light chain (, misfolded protein aggregates infiltrate perivascular and endomysial spaces, mechanically expanding muscle tissue and stimulating satellite cell proliferation, which manifests as pseudohypertrophy. These mechanisms highlight how diverse pathological processes can converge on false muscle enlargement, often linked to muscular dystrophies but extending to other genetic and acquired conditions.

Histological Changes

Histological examination of pseudohypertrophic muscles reveals a characteristic absence of true myofiber , with biopsies instead demonstrating marked variation in muscle fiber size, including small, rounded, or atrophic fibers interspersed with extensive deposits of and fibrous septa. This pseudoenlargement arises from the replacement of functional muscle tissue by non-contractile elements, leading to a heterogeneous appearance under light where viable fibers are often clustered amid areas of fatty and fibrotic infiltration. Specific staining techniques highlight these alterations: staining confirms lipid accumulation within and between muscle fibers, appearing as orange-red droplets that quantify the extent of fatty replacement. delineates by coloring blue against the red of muscle fibers and , revealing increased proliferation that disrupts normal architecture. In cases associated with dystrophinopathies, such as Duchenne or , immunostaining shows reduced or absent expression along the , confirming the underlying protein deficiency. The progression of histological changes typically begins in early stages with evidence of muscle fiber necrosis—characterized by hypereosinophilic fibers with pyknotic nuclei—and regenerative attempts, indicated by basophilic fibers with central nuclei and sarcoplasmic basophilia. As the condition advances, these active processes diminish, giving way to predominant replacement by connective tissue and fat, with fibrosis often exceeding 20% of the tissue area and fat infiltration present in a subset of cases. Ultrastructural analysis via electron microscopy further elucidates these pathologies, disclosing sarcolemmal disruptions such as delta lesions where the plasma membrane is absent or fragmented while the remains intact. Additionally, abnormalities in subsarcolemmal mitochondria, including enlargement and aggregation, are observed, contributing to the degenerative milieu without evidence of compensatory myofiber growth.

Associated Conditions

Muscular Dystrophies

Muscular dystrophies represent the primary group of conditions associated with pseudohypertrophy, characterized by progressive muscle weakness and degeneration due to genetic mutations affecting muscle integrity. In these disorders, pseudohypertrophy arises from the replacement of functional muscle fibers with fat and connective tissue, leading to apparent enlargement despite underlying weakness. The most prominent examples are dystrophinopathies, including Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), along with certain subtypes of limb-girdle muscular dystrophy (LGMD). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the gene on the , resulting in absent or severely deficient protein essential for muscle cell stability. occurs in a high proportion of cases, with enlargement observed in approximately 94% of patients in a from , typically manifesting between ages 3 and 5 as an early hallmark sign. The global of DMD is estimated at 1 in 3,500 to 5,000 male births, making it the most common childhood . This primarily affects the but can extend to other muscles like the deltoids and infraspinatus, contributing to the characteristic clinical of disproportionate lower limb enlargement amid progressive proximal weakness. Becker muscular dystrophy (BMD), a milder allelic variant of DMD, also stems from in-frame mutations in the dystrophin gene, leading to partially functional dystrophin and later-onset symptoms. Pseudohypertrophy in BMD is common, particularly involving the calves and thighs, though it develops later than in DMD, often in adolescence or early adulthood, and is associated with slower disease progression. The prevalence of BMD is lower, approximately 1 in 18,000 to 30,000 males, with pseudohypertrophy contributing to a pseudoathletic appearance in affected individuals despite underlying muscle degeneration. Certain subtypes of limb-girdle (LGMD), such as LGMD2I (now classified as LGMDR9), are linked to mutations in the fukutin-related protein (FKRP) gene, which disrupts of alpha-dystroglycan and impairs muscle membrane stability. In LGMD2I, pseudohypertrophy, often mild and involving the calves, has been reported in affected patients, presenting a phenotypic overlap with dystrophinopathies but with autosomal recessive and variable severity. This subtype accounts for a notable portion of LGMD cases in certain populations, such as , where calf pseudohypertrophy may appear alongside proximal weakness and elevated serum levels.

Rare Genetic Disorders

Myotilinopathies represent a of rare myofibrillar myopathies caused by mutations in the MYOT gene, which encodes the Z-disk protein myotilin essential for stability. These mutations, often missense variants clustered in exon 2 such as Ser55Phe, lead to and muscle fiber disorganization, manifesting clinically as generalized muscle pseudohypertrophy accompanied by stiffness and mild weakness, particularly in the lower extremities. This pseudohypertrophy arises from fatty infiltration and replacement rather than true muscle enlargement, contributing to a Herculean appearance despite underlying myopathic changes. Myotilinopathies have been reported in fewer than 50 families worldwide, underscoring their extreme rarity. Certain distal myopathies, such as Laing distal myopathy (also known as distal myopathy type 1 or MPD1), result from heterozygous mutations in the MYH7 gene encoding the slow/beta cardiac heavy chain, which disrupts myosin filament assembly and . These mutations, frequently affecting the rod domain (e.g., in exons 32–36), cause preferential weakness in distal lower limb muscles, including ankle dorsiflexors and great toe extensors, with calf pseudohypertrophy observed in many affected individuals due to compensatory muscle changes or fat replacement. Additional features may include , , and tendon contractures, with symptom onset often in childhood or early adulthood and slow progression sparing proximal muscles initially. Laing distal myopathy is autosomal dominant and rare, with over 20 distinct MYH7 variants identified across multiple families, though pseudohypertrophy remains a notable but not universal sign. Metabolic myopathies like glycogen storage disease type II (Pompe disease), an autosomal recessive lysosomal storage disorder due to mutations in the GAA gene, can also present with pseudohypertrophy from pathological glycogen accumulation in lysosomes, mimicking true muscle enlargement. In late-onset forms, this manifests as calf muscle hypertrophy with a firm, rubbery texture alongside proximal weakness, elevated creatine kinase levels, and respiratory sparing in some cases, as seen in adolescent presentations. The glycogen buildup leads to lysosomal distension and muscle fiber damage, distinguishing it from dystrophic processes while sharing the false enlargement phenotype. Pompe disease affects approximately 1 in 40,000 individuals overall, with late-onset variants showing variable muscle involvement including pseudohypertrophic features.

Clinical Presentation

Common Symptoms

Pseudohypertrophy, often observed in conditions such as (DMD), is characterized by a progressive decline in muscle strength that contrasts with the apparent enlargement of affected muscles, leading to significant functional impairments. Patients typically experience proximal , particularly in the lower limbs, which manifests as difficulty rising from a seated position, climbing stairs, and running, often resulting in gait abnormalities such as waddling or toe-walking in children. Early fatigue during physical activities is a common complaint, with individuals reporting rapid exhaustion even in routine tasks due to the underlying muscle inefficiency. Occasional muscle , , or , especially in the calves and thighs, may occur, exacerbated by or prolonged standing. In pediatric cases of muscular dystrophies like DMD or (BMD), delayed motor milestones such as late walking or inability to jump are frequently reported, reflecting the insidious onset of weakness. In BMD, symptoms often appear later, in or early adulthood, with slower progression compared to DMD. As the condition advances, particularly in dystrophies like DMD, respiratory difficulties from diaphragmatic weakness and cardiac symptoms such as arrhythmias may emerge, contributing to overall debility. In Kocher-Debre-Semelaigne syndrome (KDSS), associated with untreated , symptoms include delayed developmental milestones, , and generalized weakness alongside pseudohypertrophy, often with myoedema (muscle mounding on percussion). Symptoms typically present between 18 months and 10 years of age and are reversible with thyroid hormone replacement. Symptoms often begin subtly in , preceding noticeable muscle enlargement, and progressively worsen over several years, leading to increasing dependence on assistive devices by in severe cases like DMD.

Physical Signs

Pseudohypertrophy manifests as a visible enlargement of affected muscles, most commonly the calves, which appear enlarged due to the replacement of muscle tissue with fat and fibrous rather than true . This enlargement is typically firm and rubbery to , reflecting the underlying fibrofatty infiltration. In (DMD), the calves are bilaterally and symmetrically involved in the majority of cases, with occasional extension to the muscles. Similar calf pseudohypertrophy occurs in , though less pronounced and with later onset. In KDSS, hypertrophy is often generalized or prominent in lower extremities, accompanied by signs of such as dry skin, constipation, and . During , proximal muscle often elicits Gowers' sign, characterized by the patient using their hands and arms to "walk" up their legs or body to rise from a seated or on the floor, compensating for the inability to activate the pelvic girdle muscles effectively. This sign is a hallmark of DMD and becomes evident as early as ages 2 to 5 years, highlighting the disproportionate weakness in the hip extensors and knee extensors. Gowers' sign may also appear in BMD but later. Deep tendon reflexes in the limbs affected by pseudohypertrophy are typically diminished or absent, particularly in the lower . In DMD, knee reflexes are notably less brisk than ankle reflexes and may be lost by around age 6, while upper limb reflexes like the may remain relatively preserved initially. This correlates with the progressive denervation-like changes in the muscle despite the absence of primary neural involvement. In KDSS, reflexes are usually preserved or hyperactive due to the metabolic . Joint contractures develop early in the course of pseudohypertrophy-associated conditions, secondary to muscle and immobility, affecting the ankles, knees, hips, and elbows. In DMD, shortening contributes to equinus deformity, with contractures appearing within the first decade and exacerbating abnormalities. These fixed deformities result from increased collagen deposition in the , limiting and requiring orthopedic intervention in advanced stages. Contractures are less common or develop later in BMD and KDSS.

Diagnosis

Diagnostic Methods

Diagnosis of pseudohypertrophy begins with a thorough clinical evaluation, including a detailed family history suggestive of X-linked inheritance patterns common in associated dystrophies like Duchenne and types. may reveal characteristic muscle enlargement, prompting further testing, alongside assessment of motor milestones and gait abnormalities. For suspected endocrine causes such as Kocher-Debre-Semelaigne syndrome, including serum (TSH) and free thyroxine (T4) levels are essential to identify . Serum (CK) levels are a key initial screening tool, often elevated 10 to 100 times the upper limit of normal in affected individuals with dystrophies, reflecting ongoing breakdown. Levels typically peak early in childhood and decline with disease progression. (EMG) demonstrates myopathic changes, such as short-duration, low-amplitude potentials and early recruitment patterns, helping to confirm muscle involvement without evidence of neurogenic processes. Imaging modalities like (MRI) reveal fatty infiltration within enlarged muscles, appearing as hyperintense areas on T1-weighted sequences, while shows increased indicative of fibrofatty replacement. remains the gold standard for histopathological confirmation, demonstrating replacement of muscle fibers by fat and , with immunohistochemical staining revealing absent or reduced expression in dystrophinopathies. Genetic testing, including multiplex ligation-dependent probe amplification (MLPA) and sequencing of the DMD gene, identifies causative mutations such as deletions or duplications in over 70% of Duchenne and Becker muscular dystrophy cases, providing a definitive diagnosis. Newborn screening programs for Duchenne muscular dystrophy, implemented in select regions since the 2010s and expanding as of 2025 (including states like Minnesota and Ohio), utilize dried blood spots to detect elevated CK or genetic markers, enabling early identification before symptoms manifest.

Differential Diagnosis

Pseudohypertrophy, characterized by apparent muscle enlargement due to replacement of muscle fibers with or fibrous , must be differentiated from true , where muscle size increases through genuine myofiber growth and is typically associated with preserved or enhanced strength. In athletes, true hypertrophy results from repetitive mechanical loading, leading to firm, functional muscle enlargement without underlying weakness; differentiation is achieved through clinical assessment showing normal muscle power and a muscle revealing hypertrophied fibers without fatty infiltration. Endocrine disorders such as acromegaly, caused by excess growth hormone, can lead to increased muscle mass through hypertrophic changes in muscle fibers (often type I), but are typically accompanied by proximal muscle weakness and systemic features like coarsened facial features and enlarged hands and feet; this is distinguished from pseudohypertrophy by biopsy findings of mixed fiber hypertrophy and atrophy without fibrofatty replacement, alongside elevated insulin-like growth factor 1 (IGF-1) levels. Infiltrative disorders may mimic pseudohypertrophy through non-muscle tissue accumulation within the muscle compartment, leading to enlargement but differing in composition from the fatty deposits typical of dystrophic pseudohypertrophy. involves protein deposition in muscle interstitium, causing pseudohypertrophic appearance with weakness and elevated ; it is ruled out by demonstrating Congo red-positive deposits rather than , often with systemic involvement like or . Tumors, such as intramuscular lipomas or sarcomas, present as focal enlargements that can simulate pseudohypertrophy; imaging modalities like MRI reveal heterogeneous masses or fatty tumors without the diffuse fibrofatty pattern of pseudohypertrophy, and confirms neoplastic cells instead of degenerative changes. Congenital anomalies like Beckwith-Wiedemann syndrome feature , an asymmetric overgrowth affecting one side of the body, including muscles, due to genetic alterations at 11p15.5; this true hypertrophy contrasts with pseudohypertrophy by involving proportional tissue growth without weakness or fatty replacement, and is differentiated through for imprinting defects or paternal . Inflammatory myopathies, such as , can cause muscle swelling from and inflammatory cell infiltration, mimicking the enlargement of pseudohypertrophy but with acute onset and proximal weakness; differentiation relies on elevated serum inflammatory markers (e.g., ), autoantibodies like anti-Jo-1, and a positive response to therapy, alongside muscle showing endomysial rather than fibrofatty degeneration.

Management and Prognosis

Treatment Strategies

Treatment strategies for pseudohypertrophy primarily address the underlying muscular dystrophies, such as (DMD), through supportive and disease-modifying interventions aimed at preserving function and slowing progression. Supportive care forms the foundation of management, including to maintain mobility and prevent further muscle weakening associated with pseudohypertrophic changes. Orthotic devices, such as ankle-foot orthoses, are used to manage contractures that may develop alongside calf pseudohypertrophy in DMD. Corticosteroids, particularly at doses of 0.75 mg/kg/day, are a standard therapy to slow disease progression in DMD by reducing and muscle degeneration, thereby extending ambulation by 2-5 years. Deflazacort, another , offers similar benefits to in stabilizing muscle strength but with potentially fewer side effects like . , a approved by the FDA in 2023 for patients aged 2 years and older, provides comparable efficacy with reduced side effects such as loss and . Givinostat, a approved in 2024, is used as adjunctive therapy in patients aged 6 years and older to delay disease progression. These therapies do not reverse pseudohypertrophy but help mitigate its functional impacts by preserving overall muscle function. Gene therapies and exon- agents target the genetic basis of DMD, which underlies most cases of pseudohypertrophy. , an - approved by the FDA in 2016, is indicated for patients with mutations amenable to 51 , producing truncated to improve muscle function. Subsequent approvals include golodirsen (2019, 53), viltolarsen (2020, 53), and casimersen (2021, 45). Delandistrogene moxeparvovec (), an AAV-based micro-dystrophin approved in 2023, is currently indicated as of 2025 only for patients aged 4 years and with a confirmed DMD , following restrictions due to reports of . Clinical data for show it delays loss of ambulation, with 16.7% of treated patients losing ambulation after three years compared to 46.2% in historical controls. Surgical options are reserved for complications like severe contractures, with tendon release procedures (e.g., lengthening) performed to improve and in ambulatory DMD patients. Such interventions are typically considered when contractures exceed 30 degrees and may prevent worsening but offer limited long-term benefits. of enlarged pseudohypertrophic muscles is rarely pursued due to the predominance of fibrofatty tissue over functional muscle. A multidisciplinary approach is essential, involving coordinated care from neurologists, cardiologists, pulmonologists, and nutritionists to address cardiac monitoring, respiratory support, and nutritional needs in dystrophinopathies. This team-based strategy improves quality of life and adherence to therapies. For non-dystrophic causes of pseudohypertrophy, management targets the underlying condition. In Kocher-Debre-Semelaigne syndrome (KDSS), a rare form associated with longstanding untreated , thyroid replacement with is the primary treatment, often leading to reversal of muscular pseudohypertrophy and improvement in associated symptoms within months. Physiotherapy may aid in addressing muscle stiffness. In rarer cases, such as amyloid infiltration in light-chain , treatment focuses on or stem cell transplantation to address the systemic , with pseudohypertrophy improving if the underlying deposition is controlled.

Prognostic Factors

Pseudohypertrophy, a hallmark of dystrophinopathies such as (DMD) and (BMD), is associated with distinct prognostic trajectories influenced by disease type. In DMD, patients typically become wheelchair-dependent by age 12 due to progressive muscle weakness, with survival often extending into the late 20s or early 30s, primarily limited by cardiorespiratory complications. In contrast, BMD presents a milder course, with most individuals remaining into their 40s or beyond, and average reaching 40-50 years, though cardiac involvement remains a key mortality factor. Modifiable factors significantly impact outcomes in these conditions. Early initiation of glucocorticoid therapy, such as or , prolongs ambulation by 1.4 to 2.5 years and is associated with improved survival over 5-15 years of treatment by delaying pulmonary and cardiac decline. Additionally, the specific type of influences severity; out-of-frame mutations typically cause severe DMD, while in-frame mutations in BMD result in partially functional dystrophin and slower progression. The presence of pseudohypertrophy, characterized by muscle enlargement from and replacement, signals ongoing muscle degeneration that correlates with accelerated progression toward respiratory insufficiency in dystrophinopathies. Respiratory eventually leads to ventilatory failure, a primary cause of morbidity in advanced stages. Recent advances in multidisciplinary care have markedly improved prognosis. Average survival for DMD has risen from approximately 18 years in the pre-1990 era to approximately 30 years as of 2025 for those born after 1990, attributable to widespread use of corticosteroids, , and cardiac management. Emerging gene therapies, such as micro-dystrophin delivery via AAV vectors, show promise for extending lifespan by enhancing muscle function, though long-term human data remain limited, with recent safety concerns noted for some approvals. For KDSS, early thyroid hormone replacement leads to excellent , with full reversibility of pseudohypertrophy and resolution of symptoms if treated promptly, preventing long-term complications like . In rarer conditions like amyloid-related pseudohypertrophy, depends on the response to for the underlying disease.