Large Muscles

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LARGE OR PROMINENT MUSCLES

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

Amyloidosis:
Enlarged tongue

Overusage

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

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
- Muscle hypertrophy syndrome (Myostatin)
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
Face
- Familial hypertrophy of masticatory muscles
- Hemifacial myohyperplasia
Duchenne Muscular Dystrophy
Tongue (Macroglossia)
- Glycogen storage, type II
- Amyloid
- Familial: Autosomal Dominant
- Hypothyroid
- Duchenne muscular dystrophy
- LGMD 2I
- Neurofibromatosis
- Mucopolysaccharidosis
- Sialuria
- Beckwith-Wiedemann syndrome
- Simpson-Golabi-Behmel overgrowth : Glypican-3
- Trisomy 21
- Focal tongue dystonia
- Transient hypoglycemia of infancy
- 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
    - Subcutaneous malignant fibrous histiocytoma
    - Hemangioendothelioma
    - Hemangiopericytoma
  - Benign
    - Myxoma
    - Lipoma
    - Seroma
    - Hemangioma

Skeletal Disorders: Short stature, etc.

Lipodystrophy syndromes¹

Familial or Genetic
- Congenital generalized: Berardinelli-Seip Syndrome
- Familial partial
  - Köbberling-Dunnigan Syndrome: Lamin A/C; 1q21
  - Insulin-resistant diabetes mellitus with acanthosis nigricans (Flier's syndrome)
  - Mandibuloacral dysplasia
- Myopathy + Lipodystrophy
  - PTRF; 17q21
  - PSMB8: 6p21
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
- Type 2 muscle fiber hypertrophy
Myotonia congenita
- Absent type 2B muscle fibers
Partial denervation
- Type 2 fiber predominance
- Grouped atrophy
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
Spinal muscular atrophy
- Large muscle fibers: Type 1
- Muscle size: Normal or small
Storage disorders
- Vacuolar deposits in muscle fibers
- Amyloid in endomysium

Beckwith-Wiedemann syndrome

l Cyclin-dependent kinase inhibitor 1C

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

Genetics: Imprinted gene
- Paternal copy is repressed: Methylated at implantation
- Expression solely from maternal copy
Incidence: 1/14,000
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
Laboratory
- Hypoglycemia
External link: Gene clinics

Myhre Syndrome

⁸
l SMAD4

; Chromosome 18q21.2; Dominant

Epidemiology: Male > Female
Genetics
- Mutations
  - Ile500 locus
  - Missense
  - Location: Mad homology 2 domain
- Allelic with
  - Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome
  - Polyposis, juvenile intestinal
SMAD4 protein
- Involved in the TGF-β & BMP signaling pathways
- Tumor suppressor
Clinical features
- Muscle
  - Hypertrophy: Especially males
  - Chronic denervation
- CNS
  - Deafness: Conductive & Sensori-neural; Older patients
  - Mental: Retardation; Autism
- Heart: Congenital defect
- Skin: Thick
- Facial dysmorphism
  - Palpebral fissures & Mouth: Small & Short
  - Maxillary hypoplasia
  - Prognathism
  - Short philtrum
- Skeletal
  - Short tubular bones: 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
Laboratory
- Muscle: Denervation, chronic²
  - EMG: Long polyphasic action potentials
  - Muscle biopsy: Grouped atrophy

Lipodystrophy

Flier
Congenital (Berardinelli-Seip)
CGL1: AGPAT2
CGL2: BSCL2
CGL3: Caveolin-1
CGL4: Cavin
Partial
Barraquer-Simons (Acquired): LMNB2
FPLD1

FPLD2 (Köbberling-Dunnigan): Lamin A/C
FPLD3: PPARG
Myopathy + Lipodystrophy
PTRF; 17q21
PSMB8: 6p21
Large muscles
Syndromes
Spastic ataxia & cataracts

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

l Insulin receptor

; Chromosome 19p13.3; 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
l Lamin A/C

; Chromosome 1q21.2; 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
l 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

l CGL1

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

; Chromosome 9q34; Recessive
l CGL2

: BSCL2

; Chromosome 11q13; Recessive
l CGL3

: Caveolin-1 (CAV1)

; Chromosome 7q31.1; Recessive

Mutations
- AGPAT2: Most nonsense, splice, or frameshift; Loss of gene function
- BSCL2: Most nonsense, splice, or frameshift; Loss of gene function
- Caveolin-1: Homozygous nonsense (Glu38X)
- Frequency: AGPAT2 & BSCL2 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
BSCL2 mutations also occur in
- SPG 17 (Silver syndrome)
- Hereditary distal motor neuropathy, 5B

JMP syndrome

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

; Chromosome 6p21.3; Recessive

Epidemiology: Portugal & Mexico families
Genetics
- Mutation: Thr75Met
- Monogenic autoinflammatory diseases
- Polymorphism associated with IDDM
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: Childhood
- Joint Contractures: Hands & Feet
- Muscle Atrophy: Limbs
- Lipodystrophy: Panniculitis-Induced
  - Most prominent early: Face; Arms; Thorax
  - Progression: Abdomen; Lower extremities
- CNS: Variable; Seizures, Basal ganglia calcification
- Skin: Erythematous lesions
- Hepatosplenomegaly
Laboratory
- Microcytic Anemia
- High-density lipoprotein cholesterol: Low
- Hypergammaglobulinemia
- Skin biopsy: Panniculitis
- Body MRI: Loss of subcutaneous fat; Muscle mass reduced, arms

Hemifacial Myohyperplasia³
l Recessive or Sporadic

Onset: Congenital; Occurs early in development during branchial arch formation
Clinical
- 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
  - Dimpling or wrinkling of skin
  - Narrowed palpebral fissure
  - Nasal & chin deviation towards affected side
  - Smaller nasal vestibule
  - Auricular displacement inferiorly
  - Malar flattening on affected side
Laboratory
- Imaging: Facial muscles
  - Unilateral enlargement: Muscles of facial expression and/or mastication
  - Normal muscle signal
  - Facial skeleton: Hypoplasia or dysplasia
- Muscle histology: Normal

Muscle hypertrophy syndrome

⁴
l Myostatin (GDF 8)

; Chromosome 2q32.1; 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
- HeartNormal
- CNS: Myoclonus stopped after 2 months
Heterozygotes: ? Increased strength
Animal disorders: "Double-muscled" cattle

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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
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

1/4/2013