Large Muscles

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LARGE OR PROMINENT MUSCLES

Drugs
Endocrinopathy
Focal enlargement
Infections
Lipodystrophy
Macroglossia
Inherited
Hypertrophy
Muscular dystrophy
Myotonia
Storage disorders
Overusage
Partial denervation
Pathology
Short stature

Amyloidosis:
Enlarged tongue

Overusage

Neural
- Myokymia/ Neuromyotonia
  - Isaac's Syndrome
- Schwartz-Jampel
- Dystonia & Athetosis
- Exercise
  - Bodybuilding
  - Pathology: Muscle
- Spasticity with persistent muscle spasms
- Orthostatic tremor
Muscle

Partial Denervation

Focal: Radiculopathy; Nerve lesion
Later-onset Spinal Muscular Atrophies
Polyneuropathy: HMSN I & II

Endocrinopathy

Muscular Dystrophies & Myopathies

Disorders
- Dystrophinopathies: Especially posterior calf
- Limb-Girdle Muscular Dystrophy: 1C; 2D; 2E; 2I; 2L; 2N; ISPD
- Myopathy with abnormal merosin
- Congenital muscular dystrophy
- Hypokalemic periodic paralysis
- Gowers-Laing distal myopathy: Anterior tibial
- McArdle
- Hypertrophy syndromes
  - Muscle: Myostatin
  - Strongman + Myalgia: DCST2
- FHL1: Hyaline body myopathy; Uruguay
Muscle features causing hypertrophy
- Common: Fat infiltration; Connective tissue proliferation
  - Especially calf ± other muscles
- Muscle fiber hypertrophy
- Mass: Neoplasm or Focal myositis

Infections

Cysticercosis
Trichinosis
Schistosomiasis

Drug treatment

β₂ adrenergic agonists: Albuterol; Clenbuterol
Androgenic steroids

Storage & replacement

Glycogen
Amyloid
Fatty replacement of muscle
Gangliosidoses

Focal enlargement

Extremities or Trunk
- Focal partial denervation
  - Radiculopathy (± Complex repetitive discharges or Myokymia)
  - Old polio
- Focal myokymia
- Focal myositis: Acute onset; Pain
- Ruptured tendon or muscle
- Gluteus: FHL1
Face
- Familial hypertrophy of masticatory muscles
- Hemifacial myohyperplasia

Tongue (Macroglossia)

Glycogen storage, type II
Amyloid
Mitochondrial myopathy, infantile, transient
Familial: Autosomal Dominant
Hypothyroid
Duchenne muscular dystrophy
LGMD 2I
Neurofibromatosis
Mucopolysaccharidosis
Sialuria
Beckwith-Wiedemann syndrome
Simpson-Golabi-Behmel overgrowth : Glypican-3
Trisomy 21
Cabezas
Focal tongue dystonia
Transient hypoglycemia of infancy
Glycogen storage disease of heart, Lethal, Congenital
Systemic: Other
- Angioedema
- Lymphoma
- Acromegaly

Extraocular muscles

Thyroid eye disease
Orbital myositis
Neoplasm: Primary, Metastatic, lymphoma
Carotid cavernous fistula
Inflammatory: Infections; Sarcoidosis
Amyloidosis
Acromegaly

Masses

Granulomas (Sarcoid);
Ossification & Calcinosis
Amyloid
Infection (Abscess)
Infarction
Neoplasm
- Malignant
  - Sarcoma
  - Myxoid-laden
  - Liposarcoma
  - Angiosarcoma
  - Neurofibrosarcoma
  - Lymphoma
  - Malignant fibrous histiocytoma
  - Hemangioendothelioma
  - Hemangiopericytoma
- Benign
  - Myxoma
  - Lipoma
  - Seroma
  - Hemangioma

Tongue disorders: Other
Fungiform papillae
HSAN III: IKBKAP
Shape
Triangular: LIMS2
Trombone: AR-CMT2S; IGHMBP2
Weakness or Atrophy
AAA
ALS
Amyloid: TTR; GSN
CMT: 4C, 4D
CODAS (Hemiatrophy)
Contractures + Weakness: KY
FOSMN
Myasthenia gravis: AChR; MuSK
OPMD: PABPN1
SBMA: AR
XII nerve
Weakness
Images

Duchenne Muscular Dystrophy

Hypoglossal nerve lesion

Skeletal Disorders: Short stature, etc.

Lipodystrophy syndromes ¹

Familial or Genetic
Acquired
- Generalized: Lawrence syndrome
- Partial: Barraquer-Simons syndrome
- HIV infection
- Localized
  - Drug-induced
  - Pressure-induced
  - Panniculitis variety
  - Centrifugal variety
  - Idiopathic
Differential diagnosis
- SHORT syndrome
- Werner syndrome
- Neonatal progeroid syndrome (Wiedeman-Rautenstrach syndrome)
- Severe weight loss
- Multiple symmetric lipomatosis
- Cushing's syndrome

MUSCLE & MUSCLE FIBER HYPERTROPHY: Pathology

Muscle exercise or overuse
- Muscle fiber hypertrophy: Type II > I
- Possible switch of type 2B fibers to 2A
- Pathology: Muscle
- Related syndromes
- Exercise in animals: Increased fiber splitting
Androgen treatment ¹¹
- Cross-sectional areas: Type I & II fibers increased (Dose-dependent)
- Myonuclei: Increased number
- No changes in fiber types
Myotonia congenita
- Absent type 2B muscle fibers
Muscular dystrophy
- Fatty replacement of muscle
  - Duchenne & Becker dystrophies
- Muscle fiber hypertrophy
  - FSH & some chronic limb-girdle syndromes
  - Large muscle fibers: Type 1 & 2
  - Muscle size: Normal or small
  - Hypercontracted muscle fibers
    - Duchenne muscular dystrophy: Biopsies from younger patients
- Endomysial connective tissue: Increased
Focal myositis
- Perimysial connective tissue: Increased
Storage disorders, Muscle
- Vacuolar deposits in muscle fibers
- Amyloid in endomysium
Partial denervation: Chronic
- Spinal muscular atrophy
  - Large muscle fibers: Type 1
  - Muscle size: Normal or small
- Grouped atrophy: Other
  - Small fibers: Type 2 fiber predominance

Beckwith-Wiedemann syndrome

● Cyclin-dependent kinase inhibitor 1C

; Chromosome 11p15.4
● Duplication of chromosome 11p15.5; Dominant with incomplete penetrance
● Influenced by genomic imprinting and uniparental disomy

Epidemiology
- Incidence: 1/14,000
Genetics: Imprinted gene
- Paternal copy is repressed: Methylated at implantation
- Expression solely from maternal copy
Clinical
- Macroglossia
- Gigantism; Hemihypertrophy
- Coarse facial features; Prominent mandible
- Ears: Linear ear lobe creases ; Posterior helical indentations
- GI: Omphalocele; Exomphalos; Visceromegaly; Prune belly; Umbilical hernia
- Endocrine: Neonatal hypoglycemia; Adrenocortical cytomegaly
- Neoplasms: Embryonal; 10%
  - Adrenal; Nephroblastoma; Hepatoblastoma; Rhabdomyosarcoma
  - Wilms tumor; Congenital gastric teratoma
  - Hemangiomas
- GU: Renal medullary dysplasia; Overgrowth of external genitalia
- Cardiomyopathy: Occasional
Laboratory
- Hypoglycemia
External link: Gene Reviews

Myhre Syndrome

⁸
● Mothers against decapentaplegic, drosophila, homolog of, 4 (SMAD4)

; Chromosome 18q21.2; Dominant

Nosology: Described by Selma Ann Myhre
Epidemiology: Male > Female
Genetics
- Inheritance: Sporadic
- Mutations
  - Loci: Arg496Cys; Ile500 (Val,Leu,Thr)
  - Missense
  - Location: Mad homology 2 domain
- Allelic disorders
  - Juvenile polyposis/Hereditary hemorrhagic telangiectasia
  - Polyposis, juvenile intestinal
  - Pancreatic cancer, Somatic
SMAD4 protein
- Involved in the TGF-β & BMP signaling pathways
- Tumor suppressor
Clinical features
- Onset age
  - Childhood or Adult
  - Milder disease with adult onset
- Muscle
  - Hypertrophy: Especially males
  - Chronic denervation
- Morphology: Pseudo-muscular build
- CNS
  - Deafness: Conductive & Sensori-neural; Older patients
  - Mental: Retardation; Autism
  - Motor delay
- Heart
  - Congenital defect
  - Aortic hypoplasia & stenosis
  - Restrictive cardiomyopathy
  - Pericardial disease
- Skin
  - Thick
  - Stiff
  - Fibrosis, especially after surgery
- Face: Dysmorphism
  - Palpebral fissures & Mouth: Small & Short
  - Maxillary hypoplasia
  - Prognathism
  - Short philtrum
- Skeletal
  - Short tubular bones: Brachydactyly; Hands & Feet
  - Short stature
  - Joints: Decreased mobility
  - Ribs: 11; Broad
  - Calvarium: Thickened
  - Epiphyses: Cone-shaped
  - Iliac wings: Hypoplastic
  - Femoral necks: Broad
  - Vertebrae: Short & large pedicles
- Endocrine
  - Precocious puberty
  - Cryptorchidism
- Eye: Cataract, congenital
Laboratory
- Muscle biopsy
- EMG: Denervation, chronic ²
  - Action potentials: Long polyphasic

Lipodystrophy: Hereditary

Congenital (Berardinelli-Seip)
CGL1: AGPAT2
CGL2: BSCL2
CGL3: Caveolin-1
CGL4: Cavin
Partial
Barraquer-Simons (Acquired): LMNB2; 19p13
Familial Partial Lipodystrophy (FPLD)
1

2 (Köbberling-Dunnigan): Lamin A/C; 1q22
3: PPARG; 3p25
4

: PLIN1

; 15q26
5

: CIDEC

; 3p35
6

: LIPE (HSL)

; 19q13
7: Caveolin-1
8

: ADRA2A2

: PLAAT3

MDP: POLD1

; 19q13
FPLD: ZMPSTE24

; 1p34
SHORT

: PIK3R1

; 5q13
Myopathy + Lipodystrophy
PTRF; 17q21
PRAAS1: PSMB8; 6p21
Other
Achalsia-Progeria

: BUD13

CDG1a: PMM2
Insulin-resistant diabetes + acanthosis nigricans: INSR; 19p13
Flier's syndrome
Keppen-Lubinsky: KCNJ6; 21q22
Mandibuloacral dysplasia

: LMNA; 1q22
MFN2
Spastic ataxia & Cataracts

Also see
Large muscles
Lipodystrophy Syndromes

Insulin-resistant diabetes mellitus with acanthosis nigricans (Flier's syndrome )
● Insulin receptor (INSR)

; Chromosome 19p13.2; Dominant

Genetics
- Allelic with: Leprechaunism & Rabson-Mendenhall syndrome
Clinical features
- Acral hypertrophy: Ears, nose, chin, finger tips
- Muscle cramps
- Insulin-resistant diabetes mellitus
- Lipodystrophy
- Skeletal: Brachydactyly; Supernumerary teeth; Bitemporal skull narrowing
- GU: Female virilization with clitoromegaly; polycystic ovaries; Sponge kidneys
- Other: Acanthosis nigricans; Exophthalmos; Hypertrichosis

Familial partial lipodystrophy: Köbberling-Dunnigan Syndrome (FPLD2)

⁶
● Lamin A/C

; Chromosome 1q22; Dominant

Genetics
- Lamin A/C mutations
  - Missense
  - Affect globular carboxy-terminus of lamin A/C
  - Arg482
    - Most common mutated amino acid (90%)
    - Arg482Gln, Arg482Trp, Arg482Leu
  - Exon 11
    - Encodes C-terminal domain specific for lamin A isoform
    - Arg582His: Atypical KDS syndrome; Affects lamin A only
    - Other: S573L, S583L & R584H
  - Lys486Asn: Adds potential new glycosylation site
  - Cys591Phe
    - Partial lipodystrophy
    - Insulin resistance
    - Cardiac abnormalities: Aortic valve pathology
    - In vitro nuclei: Enlargement; Lamina invagination; Lamin A aggregation
  - Other: Asp486N; G465D; Arg548
- Mutations in Lamin A/C gene: Other syndromes
Clinical features
- Fat changes
  - Loss of subcutaneous fat
    - Onset: Post-pubertal
    - Location: Limbs; ± Trunk & Gluteal regions; Spares face
  - Fat accumulation: Neck; Shoulders; Face; Genitalia (Labia majora)
  - Normal fat: Between muscles; Abdominal & thoracic cavities; Bone marrow
- Myopathy
  - Muscle hypertrophy
    - More prominent in women
    - Pathology
      - Hypertrophy: Types I & II muscle fibers
      - Internal nuclei: Increased
      - Split fibers: Rare
      - Cytoplasmic bodies: Occasional
      - Inflammatory cell foci: Few, Small, Perivascular
      - Myostatin mRNA: Reduced
      - SMAD molecules: Adherance to nuclear membrane; Reduced within nucleus
      - Lamin A/C staining: Normal
  - Myalgias (70%)
- Neuropathy
  - Multiple entrapment syndromes: Carpal tunnel; Ulnar at elbow
  - Nerve pathology
    - Tomaculae
    - Segmental demyelination
    - Axon loss: Large & Small myelinated
- Acanthosis nigricans
- Diabetes
Laboratory
- Insulin dependent diabetes
  - Insulin resistance
  - Hyperinsulinemia
- Hyperlipoproteinemia: Type IV

Acquired partial lipodystrophy (Barraquer-Simons syndrome)

⁵
● Lamin B2 (LMNB2)

Chromosome 19p13.3; Often sporadic

Epidemiology
- Family history
  - None in most cases
  - Discordance noted in some monozygotic twins
- Female:Male ratio = 4:1
- Some subject with APL do not have LMNB2 mutations
Genetics
- Mutations
  - Heterozygous
  - Mutations: A407T; R215Q; Intron 1-6C-T; c.82G-A
  - May be present (Rarely) in control populations
- Other disorders with nuclear envelope mutations
  - Lamin A/C: Numerous laminopathies
  - Emerin: Emery-Dreifuss muscular dystrophy
  - Lamin B receptor
    - Pelger-Huet anomaly
    - Hydrops-ectopic calcification-moth-eaten skeletal dysplasia
- Complex trait with genetic component
Onset
- Before adulthood: 5 to 20 years
- Gradual
Clinical
- Subcutaneous fat loss
  - Bilateral
  - Head, Neck, arms & thorax
  - Not legs
- Associated conditions:
  - Complement C3 deficiency (11%)
  - Glomerulonephritis (11%)
  - Dermatomyositis (22%)
  - Treated type 2 diabetes (56%)
  - Treated hypertension (56%)
  - Type IV or V dyslipoproteinemia (89%)
  - Hepatomegaly (56%)
  - Hirsutism (43% of women)
  - Polycystic ovarian disease (29% of women)
  - Early vascular disease (at age <50 years) (22%)

Berardinelli-Seip Congenital Lipodystrophy Syndrome
● CGL1

: 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2)

; Chromosome 9q34.3; Recessive
● CGL2

: BSCL2

; Chromosome 11q12.3; Recessive
● CGL3

: Caveolin-1 (CAV1)

; Chromosome 7q31.2; Recessive

Genetics
- Mutations
  - AGPAT2: Most nonsense, splice, or frameshift; Loss of gene function
  - BSCL2
    - Mutations: Most nonsense, splice, or frameshift; Loss of gene function
    - BSCL2 allelic disorders
  - Caveolin-1
    - Mutations: Homozygous nonsense (Glu38X)
    - Allelic disorders
      - Lipodystrophy, familial partial, type 7, Dominant
      - Pulmonary hypertension, primary, 3, Dominant
  - Frequency: AGPAT2 & BSCL2 mutations in 95%
Clinical features
- Generalized lipodystrophy: Subcutaneous & Visceral
- GI: Hepatomegaly; splenomegaly; Portal hypertension
- Skin: Acanthosis nigricans; Hyperpigmentation
- Hair: Hypertrichosis; Curly scalp hair
- Diabetes mellitus: Nonketotic; Insulin-resistant
- GU: Enlarged genitalia; Polycystic ovaries
- Muscle: Hypertrophy
- CNS: Mental retardation; Hypothalamic hamartoma
- Specific features
  - AGPAT2: Bone cysts
  - BSCL2: Intellectual impairment; More severe phenotype
  - Caveolin-1: Absent accelerated linear growth in childhood; Acromegaloid features; Abnormal calcium homeostasis
Laboratory
- Hyperlipidemia: Hypertriglyceridemai
- Plasma leptin: Low; Consistent with absent body fat
- Hyperandrogenism

Mandibular hypoplasia, Deafness and Progeria (MDP) syndrome ⁹
● Polymerase (DNA-directed), Delta 1, Catalytic subunit (POLD1)

; Chromosome 19q13.33; Dominant (Sporadic)

Epidemiology: 4 individuals
Mutation: Ser605del; Inframe deletion
POLD1 protein
- Cooperates with WRN, a DNA helicase, to help maintain genome stability
Clinical
- Adipose tissue
  - Subcutaneous: Very reduced
  - Visceral: Increased
- Skin: Scleroderma; Telangiectasia
- Ligament contractures
- Limb muscles: Reduced mass
- Mandibular hypoplasia
- Males: Hypogonadism & Undescended testes
- Sensorineural deafness
Laboratory
- Insulin resistance

Proteasome-Associated Autoinflammatory Syndrome 1 (PRAAS1)

⁷
● Proteasome subunit, Beta-type, 8 (PSMB8; LMP7)

; Chromosome 6p21.32; Recessive

Nosology
- JMP (Joint contractures; Muscle atrophy; Panniculitis)
- CANDLE (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy & Elevated temperature)
- Nakajo-Nishimura (NNS)
Epidemiology: Japan, Portugal & Mexico families
Genetics
- Mutations: Thr75Met; Lys105Gln; Cys135X; Gly197Val; Gly201Val
- Monogenic autoinflammatory diseases
- Polymorphism associations
  - IDDM
  - Immune myopathy: "Anti-Synthetase syndromes"
- Digenic PRAAS1
  - PRAAS1 mutation, Heterozygous
  - Additional mutations: PSMA3 ; PSMB4
- PRAAS: Other
  - 2 : POMP
  - 3 : PSMB4
    - Also digenic: PSMB4 + PSMB9 mutations
PSMB8 protein
- β5i Proteasome (Immunoproteasome) subunit
- Immunoproteasome-mediated proteolysis: Generates immunogenic epitopes presented by MHC Class I molecules
- Chymotrypsin-like
- Mutation effects: May alter MHC Class I antigen processing
Clinical
- Onset ages: 2 months to Childhood
- Joint Contractures: Hands & Feet
- Muscle
  - Atrophy: Limbs; Arms > Legs
  - Myositis with Sarcoplasmic inclusions ¹²
- Lipodystrophy: Panniculitis-Induced
  - Most prominent early: Face; Arms; Thorax
  - Progression: Abdomen; Lower extremities
- Weakness: Arms & Legs
- Fever: Periodic
- CNS: Variable; Seizures, Basal ganglia calcification
- Skin: Erythematous lesions (Nodular; Pernio-like)
- Hepatosplenomegaly
- Calcinosis
- Fingers & Toes: Elongated; clubbed
- Course: Death in 5th & 6th decade
- Treatment: ? Baricitinib (JAK1/2 inhibition)
Laboratory
- Anemia: Microcytic
- High-density lipoprotein cholesterol: Low
- Hypergammaglobulinemia
- Skin biopsy: Panniculitis
  - Perivascular & Peri-adnexal inflammation
  - Accumulation of ubiquitinated proteins in macrophages
- Body MRI: Loss of subcutaneous fat; Muscle mass reduced, arms
- EMG: Myopathic
- Muscle pathology ¹²
  - Lymphocytes
    - Location: Endomysial; Near non-necrotic muscle fibers
    - Types: CD4 & CD8
  - Muscle fibers
    - MHC-1 upregulation
    - Protein aggregates: TDP-43; p62
    - Rimmed vacuoles: 1 patient
    - Cytoplasmic bodies
  - Vessels: Media hyperplasia
- Serum CK: Normal to 700

Hemifacial Myohyperplasia (HMH; HFMH)

³
● Phosphatidylinositol 3-kinase, catalytic, α (PIK3CA)

; Chromosome 3q26.32; Somatic mutations

General: PIK3CA-related overgrowth syndromes (PROS)
Genetics
- Mutations
  - Missense: Glu545Lys, Glu542Lys, His1047Arg
  - Glu545Lys: Recurrent mutation in overgrowth syndromes
  - Gain of function
- Allelic disorders
  - Breast cancer, somatic
  - Cerebral cavernous malformations 4, somatic
  - CLAPO syndrome, somatic
  - CLOVE syndrome, somatic
  - Colorectal cancer, somatic
  - Cowden syndrome 5
  - Gastric cancer, somatic
  - Hepatocellular carcinoma, somatic
  - Keratosis, seborrheic, somatic
  - Macrodactyly, somatic
  - Megalencephaly-Capillary malformation-Polymicrogyria syndrome, somatic (MCAP)
  - Nevus, epidermal, somatic
  - Nonsmall cell lung cancer, somatic
  - Ovarian cancer, somatic
PIK3CA protein
- 110-kD catalytic α-subunit of PI3K
- Protein product: PIP3
- Role in PTEN effect on cell death
- Cell growth & Proliferation
- Hemimegalencephaly: Caused by somatic mutations in PI3K-AKT3-mTOR pathway
Clinical
- Onset
  - Congenital
  - Occurs early in development: During branchial arch formation
- Muscle hyperplasia
  - 1st branchial arch: Includes muscles of facial expression & orbicularis oculi
  - 2nd branchial arch: Includes muscles of mastication
  - No evidence of hyperplasia of bone or other organ systems on side of the face
- Facial nerve: Paresis, especially marginal mandibular branch; Some patients
- Face structure: On affected side
  - Chin: Dimpling or wrinkling of skin
  - Palpebral fissure: Narrow
  - Nasal & chin deviation: Towards affected side
  - Nasal vestibule: Smaller
  - Auricular displacement: Inferiorly
  - Malar flattening: On affected side
- Possible treatment: Alpelisib (PIK3CA inhibitor)
Laboratory
- Imaging: Face muscles
  - Unilateral enlargement: Muscles of Face expression ± Mastication (Pterygoids; Masseter)
  - Normal muscle signal
  - Facial skeleton: Hypoplasia or Dysplasia; Chin deviation
- Muscle histology: Normal

Muscle Hypertrophy Syndrome (MSLHP)

⁴
● Myostatin (GDF8; MSTN)

; Chromosome 2q32.2; Recessive

Epidemiology: 1 patient described
Genetics
- Splice donor site in intron 1: g.IVS1+5 g→a
- Homozygous
Myostatin protein
- General features
- Absent with mutation
Onset
- Age: Congenital
- Myoclonus: Stimulus sensitive
- Muscle hypertrophy
Clinical
- Muscle
  - Hypertrophy
  - Strength: Increased
- Heart: Normal
- CNS: Myoclonus stopped after 2 months
Heterozygotes: ? Increased strength
Animal disorders
- "Double-muscled" cattle
- Myostatin deficient dog

Muscle Hypertrophy (Strongman) Syndrome, Myalgic ¹³
● DC-STAMP domain-containing protein 2 (DCST2)

; Chromosome 1q22; Dominant

Epidemiology: 1 Saguenay Lac St-Jean, Quebec Canadian family & Others in region
Genetics
- Mutation: Missense; c.T2276C
- Polymorphism (Rs905938): Associated with height
DCST2 protein
- Transmembrane
- Glycoprotein
- Expression
  - Skeletal muscle & ubiquitous
  - Type 1 > 2 muscle fibers
- Sarcoplasmic reticulum
Clinical
- Strength
  - Early: Above average
  - Disease progression: Weakness
    - Eventual LGMD phenotype
    - Psoas
- Muscle: Other
  - Hypertrophy
  - Myalgias: Post activity
  - Cramps
  - Fatigue: With repeated movements
  - Percussion: Pseudomyotonia
- Statin sensitivity
Laboratory
- Serum CK: Normal or Mildly high

Myositis Ossificans

FOP
Traumatic

Localized (Traumatic) myositis ossificans

Epidemiology
- Male = Female
- Incidence: < 1/1,000,000 per year
Clinical
- Onset age: Mean 23 years; Commonly 2nd & 3rd decade
- Prodrome
  - Trauma: Many patients
- Areas affected
  - General: Arm & Thigh
  - Muscles: Quadriceps; Brachialis; Elbow; Lumbar spine
- Swelling in muscle
  - Early: Tender
  - Progression: Rapid over weeks
  - After weeks: Firm & Hard
  - May regress in some patients
- Ossification: After 2 to 4 weeks
- May reduce joint range of motion
- Treatment
  - Initial: Observation
  - Excision
    - Some patients: For joint limitation or pain
    - After maturation: No bone scan uptake; 6 to 12 months
- Recurrence: Rare
Laboratory
- MRI
  - Early: Ill-defined mass with surounding edema
  - Later: Fat signal on T1- & T2-weighted images; No edema
- Pathology
  - Central region: Cellular with macrophages & histiocytes
  - Middle zone: Connective tissue
  - Periphery: Bone

Fibrodysplasia ossificans progressiva (FOP; Münchmeyer syndrome)

¹⁰
● Activin A receptor, type I (ACVR1/ALK2)

; Chromosome 2q23; Dominant or Sporadic

Epidemiology: Prevalence = 1 in 2x10⁶
Genetics
- Mutations: Missense
- Common mutation: R206H in cytoplasmic domain; Activating
ACVR1 protein
- BMP type I receptor
Clinical
- Associated malformations
  - Onset age: congenital
  - Big toes: Hallux valgus, Monophalangic malformations
  - Other
    - Short thumbs
    - 5th finger clinodactyly
    - Cervical vertebrae: Malformed
    - Femoral necks: Short, Broad
    - Teeth: Absent incisors
- Deafness: Conductive
- Scalp: Baldness
- CNS: Mental retardation, mild
- Swellings
  - Onset
    - Age: 1st decade
    - Swellings: Warm & Tender
  - Course
    - Progressive or Regress
- Calcification (Progressive heterotopic endochondral ossification (HEO))
  - Forms qualitatively normal bone
  - Between muscles, Across joints
  - Common locations
    - Early: Dorsal, Axial & Proximal, Cranial
    - Neck & Shoulders
    - Late: Ventral, Appendicular, Caudal, Distal
    - Spared: Diaphragm, Tongue, Extra-ocular, Cardiac, Smooth muscles
  - Precipitants
    - Surgery, Trauma, Injections, Influenza-like illnesses
  - Course
    - Progressive
    - Limited movement of shoulder & spine by 20 years
    - Wheelchair: 30 years
    - Death: Often < 40 years
  - 2° disorders
    - Limb swelling
    - Nerve compression
- Cervical spine
  - Posterior elements: Large
  - Vertebral bodies: Tall, Narrow
  - Facet joints: Fusion between C2 and C7 [8]. The cervical spine
  - Ankylosis: Early in life
- Skeletal: Other
  - Thumbs: Short malformed
  - Clinodactyly
  - Femoral necks: Short, Broad
  - Tibial osteochondromas: Proximal; Medial
  - Jaw: Ankylosis
  - Thoracic insufficiency syndrome (TIS)
    - Pneumonia
    - Heart failure: Right-sided
- Atypical features (FOP-plus)
  - Hips: Synovial osteochondromatosis, intraarticular
  - Degenerative joint disease
  - Growth retardation
  - Eye: Cataracts, Retinal detachment, Childhood glaucoma
  - Craniopharygioma
  - Persistence of primary teeth in adults
  - Cerebellum pathology
  - Cerebral dysfunction: Seizures
  - Polyostotic fibrous dysplasia
  - Primary amenorrhea
  - Aplastic anemia
  - Hypospadias
  - Cerebral cavernous malformations
  - Neuropathic pain: Especially females
Pathology
- Proliferating cells: Glycoprotein rich
- Immune cells: Macrophages, Lymphocytes, Mast cells

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References
1. Am J Med 2000;108:143-152
2. Am J Med Genet 2001;Online July 24
3. Am J Med Genet 2001;103:326-333, J Exp Med 2023;220:e20230926
4. N Engl J Med 2004;350:2682-2688
5. Am J Hum Genet 2006; August
6. Neurology 2007;68:677-683
7. Am J Human Genet 2010; Online December
8. Nature Genet 2011; Online Dec, Eur J Hum Genet 2024 Jul 12
9. Nature Genetics 2013; Online June
10. Orphanet J Rare Dis 2011;6:80
11. Am J Physiol Endocrinol Metab 2002;283:E154-164
12. Neuropathol Appl Neurobiol 2020;46:579-587
13. Neuromuscular Disorders 2014;24:875-876

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