Ovarian Follicle Histology

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Primordial Follicle

  • Comprises:
    • The primary oocyte, which is arrested in meiosis I
    • A single layer of flat granulosa cells; the granulosa cells and oocyte interact to guide follicular maturation
    • A basement membrane (aka, lamina) surrounds the follicle
    • In puberty, follicles are cyclically “recruited” for further development
  • Primordial follicles are found towards the outermost portion of the ovary

Primary follicle

  • Comprises:
    • The growing primary oocyte
    • Newly formed zona pellucida, which is thick a-cellular coat that covers the oocyte; It displays sperm receptors and facilitates the acrosome reaction necessary for fertilization; after fertilization, the zona pellucida prevents additional sperm from joining with the oocyte.
    • Single layer of granulosa cells transition from flat to cuboidal, which reflects their greater cellular activity.

Secondary follicle

  • Comprises
    • Primary oocyte; has achieved meiotic and developmental competence (it is capable of completing meiosis and preparing for implantation).
    • Zona pellucida, and,
    • Multiple layers of cuboid granulosa cell (typically 6-9 layers)
    • Theca cells, which arise from the ovarian interstitium, begin to accumulate around the basement membrane of the secondary follicle.

Tertiary follicle

  • Comprises
    • Secondary oocyte, which is the product of meiosis I (we’ve omitted the polar body)
    • Zona pellucida
    • Granulosa cells separated by the antrum
    • Cumulos oophorus is the collection of granulosa cells that support the secondary oocyte
    • Corona radiata is a subset of the cumulus oophorus that directly surround the zona pellucida.
    • Theca cells have diversified, and now form the theca interna and externa layers.
    • Of the late tertiary follicles, only one, the so-called “dominant follicle,” is ovulated.

Ruptured follicle

  • Transitions physiologically and morphologically to become the corpus luteum, which acts as a temporary endocrine gland.
  • Ovulated secondary oocyte takes the corona radiata with it; in most cases, it is swept into the uterine tube and transported to the uterus for menstruation or implantation.

Subcutaneous Mycoses

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Common fungal traits:

  • Many are dematiaceous, aka, pigmented fungi.
    – It is thought that the melanin in their cells contributes to virulence.
  • Many are dimorphic, which means they exist in both hyphal and yeast forms.
  • Reside in soil, on plants, and decaying vegetation.
  • Trauma to the skin introduces pathogenic fungi to the underlying tissues.
    – Thus, infections tend to occur on the extremities, especially the feet and hands, which are likely to be inoculated during gardening or field work.
  • Chronic, granulomatous lesions in the skin and deeper tissue.
    – Often, histopathologic samples will show Splendore-Heoppliphenomenon, aka, asteroid bodies, which are characterized by eosinophilic materials radiating from the microorganisms.
  • Initial lesion occurs at the site of inoculation, for example, in the skin of the feet
    – Then spreads to deeper tissues, which can include the lymphatics, muscles, and connective tissues.
  • Rarely disseminate to other organs.
  • Long-term antifungals can be used to treat some subcutaneous mycoses.

Lymphocutaneous sporotrichosis
“Rose Gardener’s Disease”
– Many individuals are inoculated via rose thorns.

  • The fungi most often responsible are members of the Sporothrix schenckii complex.
  • Mycosis manifests as linear cutaneous nodules and ulcers that begin at the site of inoculation and travel along the path of the draining lymphatics.
    – In some patients, the lesions will become suppurative; the discharged pus contains fungi that is useful for diagnostic purposes.

Chromoblastomycosis
Chromomycosis

  • Caused by a variety of fungi
    – Fonsecae, Cladosporium, Phialophora, etc.
  • Histopathologic samples show characteristic Medlar bodies (aka, sclerotic bodies or muriform cells).
    – Medlar bodies are cells with transverse septa and thick, pigmented cell walls; some liken them to copper pennies.
    In the sample, we can see some Medlar bodies within a giant cell.
  • Chromoblastomycosis produces slowly developing, chronic lesions that can cause progressive tissue fibrosis.
    – Lesion morphology varies; for example, some patients have warty or “cauliflower-like” nodules, while others develop plaques with central scarring.
  • Mild cases where warty nodules are involved may be cured by excision.
  • However, excision is not practical in patients with extensive lesions, as we see in the example of plaques; thus, long-term antifungals are the preferred treatment in such cases.

Eumycotic Mycetoma
Madura foot or Maduramycosis

  • Caused by Madurella mycetomatis and other fungi.
  • Because mycetoma is also caused by bacteria, it’s important to culture samples from the patient to rule out actinomycetemycetoma, which requires a different intervention.
  • Eumycotic mycetoma is characterized by painless nodules that progress to ulcers; the ulcers discharge fluid and granules.
    – Granules comprise the fungal hyphae
    – The color of the granule is indicative of the microorganism type
    M. mycetomatis granules are dark brownish-black.
  • Eumycotic mycetoma is a chronic and progressive condition,and new sinuses form as older sinuses heal.
  • The draining sinuses produce swelling and tissue deformity;infection can ultimately invade and destroy deeper tissues.
  • Unfortunately, eumycotic mycetoma often responds poorly to antifungal treatments, so amputation is often necessary to prevent further destruction.

Subcutaneous Entomophthoromycosis

Conidiobolus coronatus

  • Conidiobolomycosis most commonly affects adults.
  • Inhalation produces infection in the nasal and paranasal sinuses.
  • Swelling and deformity of the nose and upper lip can be quite dramatic, though relatively painless.

Basidiobolus ranarum

  • Basidiobolomycosis more commonly affects male children.
  • Produces “rubbery” dark lesions on the buttocks, thighs, and shoulders.
    – Gastrointestinal involvement is possible, though rare.

Subcutaneous Phaeohyphomycosis

  • Various species
    – Exophiala, Bipolaris, Curvalaria, etc.
  • Histopathologic samples are characterized by irregular hyphae.
  • Infection produces slow growing cysts, or, sometimes, plaques.

Superficial & Cutaneous Mycoses

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Two key phyla:

Basidiomycota
– Specifically, species of Malassezia, which are yeast that colonize the superficial layers of the skin and hair.

  • Because they do not invade or destroy living tissues, they generally do not trigger an immune response.
  • Infections common in warm, moist environments.

Ascomycota
Dermatophytes are fungal pathogens that can invade the skin and cause dermatophytoses, such as ringworm.
– Dermatophytic species come from three genera:
Trichophyton, Epidermophyton, and Microsporum.
– These molds infect keratin of the skin, hair, and nails; because they cause damage to the tissues, they trigger an immune response.
– These fungi cause mycoses called tineas, aka, ringworm
Are acquired from contact with infected soil, animals, or other humans.

Laboratory diagnosis

  • KOH (potassium hydroxide) testing, in which skin scrapings and KOH are viewed under microscope.
  • Calcofluor white stain is also used to detect fungi in samples.
    – Fluorescent stain with affinity for the chitin in fungal cell walls.

Treatments

When necessary, treatments for superficial and cutaneous mycoses involves topical and/oral antifungals, in addition to good hygiene.

Mycoses

  • Pityriasis versicolor
    Sometimes called tinea versicolor
  • Caused by species of the Malassezia genus.
    – In the microscopic image we can see Malassezia cells and some short hyphae; some authors describe their appearance as looking like “spaghetti and meatballs.”
  • Young adults in warm, moist environments are most likely to develop pityriasis versicolor.
  • Fungi are spread via human to human contact.
  • Lesions appear as either hypo- or hyper-pigmented, and typically appear on the upper body, face, and neck.
  • Tinea nigra is caused by the fungus Hortaea werneckii
  • In the microscopic image, we can see septate hyphae and budding cells.
  • Tinea nigra is most common in children and young adults in tropical and subtropical climates.
  • Manifests as patches of small dark dots, typically on the palms of the hands and soles of the feet.
  • White piedra (piedra means “stone”) is caused by species of Trichosporon, which are yeasts that colonize the hair shaft.
  • Individuals in tropical and subtropical areas are most likely to have white piedra.
  • Manifests as soft white or cream-colored nodules on the hair shafts.
  • Black piedra is caused by the yeast Piedra hortae, which colonizes the hair and scalp of individuals in tropical areas.
  • It produces firm dark nodules in the hair.
  • Tineas
    Commonly referred to as Ringworm.
  • Caused by dermatophytic fungi.
  • The tineas are named for their location on the body, as follows:
    – Tinea capitis develops on the scalp, especially of children, and is associated with alopecia, scaling, and cervical and suboccipital lymphadenopathy.
    – Tinea barbae is ringworm that occurs in areas of facial hair.
    – Tinea corporis is ringworm that appears on the trunk or extremities; it produces red rings with scaly skin and is pruritic (itchy).
    – Tinea cruris, aka, jock itch, is most common in adolescent and young males; it produces a rash on the upper thighs, but typically does not involve the scrotum.
    – Tinea pedis, aka, athlete’s foot, can involve all aspects of the feet:
    Interdigital is the most common, and involves the skin between the toes
    Moccasin tinea pedis is chronic and involves the sides and soles of the feet
    Vesicular tinea pedis is characterized by inflammation with vesicles and lesions
    – Tinea unguium is a fungal infection of the nails (thus, it is a type of onychomycosis).

Rickettsiaceae, Anaplasmataceae, & Coxiellaceae

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Rickettsiaceae, Anaplasmataceae, Coxiellaceae

  • Small, intracellular pathogens
  • Obligate aerobes
  • Gram-negative rods that stain best with Giemsa or Gimenez stains.
  • Some infections caused by these species are self-limiting
    • Doxycycline can be administered to shorten illness duration and prevent complications.

Species overview

Be aware that all of these species were formerly categorized as members of Rickettsiaceae, and that intertextual variation exists.

Rickettsiaceae damages endothelial cells of blood vessels

  • Rickettsia rickettsii causes Rocky Mountain Spotted Fever
  • Rickettsia akari causes rickettsial pox
  • Rickettsia prowazekii and Rickettsia typhi cause different forms of typhus
  • Orientia tsutsugamushi causes scrub typhus.
    to damage to the endothelial cells of blood vessels.

Anaplasmataceae

  • Ehrlichia chaffeensis causes human monocytic ehrlichiosis
  • Ehrlichia ewingii causes human ewingii ehrlichiosis
  • Anaplasma phagocytophilum causes human granulocytic anaplasmosis.

Coxiellaceae

  • Coxiella burnetti causes Q fever.

INFECTIONS, RESERVOIRS, AND VECTORS

Rickettsia rickettsii

  • Rocky Mountain Spotted Fever
    — Fever, headache, myalgias, and, sometimes, confusion (as a result of CNS involvement).
    — Patients commonly develop a macular rash that can progress to petechiae; the rash characteristically begins on the wrists and ankles, then spreads to the palms, soles, and trunk. This pattern of spread is a helpful distinguisher.
    — Gastrointestinal involvement is possible, and can cause abdominal pain, nausea, vomiting, and/or diarrhea.
    — Left untreated, disseminated vasculitis can lead to multi-organ failure.
  • Ticks and rodents are key reservoirs; hard ticks are vectors.

Rickettsia akari

  • Rickettsialpox
    — Typically less severe than Rocky Mountain Spotted Fever.
    — Patients experience fever and papulovesicular rash with eschars. Headaches and myalgia are possible.
    — Rodents are the reservoirs; mites are the vectors.

Rickettsia prowazekii

  • Epidemic typhus
    — Brill-Zinsser disease is the result of latent infection that manifests years, even decades, later.
    — Patients experience fever, headache, chills, myalgia, and a macular rash that spreads from the trunk to the extremities.
    — CNS involvement is possible, and can present as confusion.
    — If left untreated, vasculitis can lead to multi-organ failure.
    — Humans are the main reservoir, and the human body louse is the vector; be aware that flying squirrels and their fleas have also been described as reservoirs and vectors.

Rickettsii typhi

  • Endemic typhus (aka, murine, typhus)
    — Patients experience fever, headache, myalgia, and a maculopapular rash that spreads from the trunk to the extremities.
    — Gastrointestinal involvement is possible, and more common in children.
    — Cases are typically mild, but severe cases can lead to renal dysfunction or respiratory impairment (experienced as cough, dyspnea).
    — Small mammals, particularly cats and rodents, are key reservoirs; their fleas are the vectors.

Orientia tsutsugamushi

  • Scrub fever
    — Fever, intense headahces, mylagias, and a maculopapular rash that starts on the trunk; in some cases, eschars will form, especially at the site of inoculation.
    — Lymphadenopathy and pulmonary and neurologic involvement are common; gastrointestinal involvement may also occur.
    — Reservoirs include mites (chiggers) and rodents; mites are the vector.

Ehrlichia chaffeensis

  • Human monocytic ehrlichiosis
    — Fever, headache, and myalgia; Coughing is common in adults.
    — The rash associated with this infection varies, and is more common in children.
    — Central nervous system involvement is possible.
    — Leukopenia, thrombocytopenia, and elevated transanimases.
    — Deer, dogs, and other mammals are common reservoirs; soft ticks are the vector.

Anaplasma phagocytophilum

  • Granulocytic anaplasmosis
    — Similar symptoms and signs to human monocytic ehrlichiosis
    — Rash is rare.
    — Small mammals are the reservoirs; soft ticks are the vector.

Coxiella burnettii

  • Q fever
    — Fever, headache, and myalgia, but no rash.
    — Chronic Q fever can lead to serious complications, including hepatitis, pneumonia, and subacute endocarditis.
    — Reservoirs include mammals, ticks, and birds; though ticks are a potential vector, most cases of Q fever are the result of the aerosol inhalation or consumption of the bacteria in contaminated milk.

Developmental Bone Anomalies

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Skeletal Dysplasias

  • A heterogenous group of disorders that include disorders of Bone Growth (eg, achondroplasia).

Limb Malformations

  • Of the digit (suffix: -dactly)
  • Of the limbs (suffix: -melia)

BONE GROWTH: REVIEW

Typical long bone in a mature stage of endochondral ossification

  • We see the hyaline cartilaginous model (its template) and periosteal bone collar.
    -In the center, we draw the medullary cavity, which forms as the primary ossification center degenerates and remodels. It’s filled with hematopoetic marrow (which comprises red and white blood cell precursors) from vasculature that invades the cavity.
    -Secondary ossification centers lie in the epiphyses.
    -We include the epiphyseal growth plates and specify the direction of growth.

Epiphyseal growth plate zones

  • The reserve zone is filled with fetal hyaline cartilaginous cells.
  • The proliferative zone is filled with chrondrocytes that proliferate but do NOT hypertrophy.
  • The hypertrophic zone is filled with hypertrophic chondrocytes.
  • We show the zone of vascular invasion.

BONE REMODELING: REVIEW

Osteoprogenitor cells and Osteoblasts

  • We see an osteoprogenitor cell and an osteoblast on a slab of bone matrix (the inorganic component is hydroxyapatite and the organic component is osteoid).
  • Members of the (bone morphogenetic protein) BMP family and Transforming growth factor stimulate these cells to become osteoblasts.
  • Within a lacuna, lies an osteocyte.
  • Vitamin D and Parathyroid hormone (PTH) stimulate osteoblasts to secrete factors that promote osteoclastogenesis – the formation of osteoclasts.
  • Osteoblasts produce M-CSF (macrophage colony stimulating factor), which stimulates proliferation of monocytes, which later fuse into multinucleated PREosteoclasts (we’ll see that these nuclei can be as robust as 30 nuclei in a single osteoclast).
  • RANKL (an osteoprotegerin ligand) binds to the RANK receptor on the multinucleated osteoclast to stimulate differentiation from pre-osteoclast to osteoclast.
  • To regulate osteoclast differentiation, osteoblasts release osteoprotegerin, which binds RANKL and inhibits its binding to the RANK receptor.

Osteoclasts

  • Osteoclasts resorb bone.
  • They are dome-shaped with a ruffled border, and have a site of active bone resorption, the subosteoclast/Howship lacuna.
  • Actin fibers attach the edge of the cell to the bony surface, which forms the sealing (aka clear) zone of the osteoclast.
  • Cytoplasm contains:
    -Numerous nuclei.
    -Acidophilic vesicles, which are key to the osteoclasts ability to degrade bone – these vesicles release hydrogen ions into the subosteoclastic zone that can reduce the pH to as low as ~4.5 to solubilize mineralized bone.
  • The cytoplasm is also rich in mitochondria.

THE SKELETAL DYSPLASIAS

ACHONDROPLASIA

  • This is an ossification anomaly that manifests with short limbs.
  • Patients have short stature, pronounced lordosis, and bowed legs.
  • This is a more severe form of hypochondroplasia.

Systemic complications

  • Obstructive sleep apnea (OSA)
  • Recurrent otitis media

Neurologic manifestations

  • Macrocephaly
  • Spinal stenosis
  • Hydrocephalus

Genetics

  • Autosomal Dominant (80%) of patients have denovo mutations
  • FGRFR3 gene Mutation

Achondrogenesis

  • Think Achondroplasia but as a Lethal Skeletal Dysplasia — prenatally morbid or stillbirth.

MARFAN SYNDROME

  • Patients have abnormally long bones.

Systemic complications

  • Dislocated lens (ectopia lentis)
  • Aortic aneurysm and dissection
  • Mitral valve prolapse
  • Long, narrow face, with crowded teeth
  • Scoliosis or kyphosis

Neurologic manifestations

  • Dural ectasia
  • Spinal stenosis
  • Hydrocephalus

Genetics

  • Autosomal Dominant
  • FBN1 gene
  • Fibrillin-1 protein with mycrofibril abnormalities with decreased elasticity

HEREDITARY MULTIPLE OSTEOCHONDROMAS (AKA HEREDITARY MULTIPLE EXOSTOSES)

  • Bone tumors (osteochondromas) form at the end of long bones and cause shortening of growth.

Systemic complications

  • Transformation from benign tumor to malignancy (sarcoma)

Neurologic manifestations

  • Direct nerve pressure

Genetics

  • EXT1 and EXT2 gene
  • Heparan sulfate is nonfunctional
  • Autosomal Dominant

ENCHONDROMATOSIS (AKA OLLIER’S SYNDROME)

  • Bone tumors form at the ends of long bones, near the growth plates, thus these patients generally have short stature.

Systemic complications

  • Transformation from benign tumor to malignancy (chondrosarcoma)

Genetics

  • Somatic (non-heritable)
  • IDH1 & IDH2 genes for isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2

POLYOSTOTIC FIBROUS DYSPLASIA

  • Fibrous scar tissue develops in bones.

Mccune-Albright Syndrome

A genetic disorder that occurs in females, involves of polyostotic fibrous dysplasia and also multiple endocrinopathies that notably manifest with precocious puberty and café-au-lait spots.

Endocrinopathies in Mccune-Albright Syndrome

  • Precocious Puberty
  • Hyperthyroidism
  • Goiter
  • Acromegaly
  • Cushing’s syndrome (rare)

Dermatologic Manifestations

  • Café-au-lait spots

Genetics

  • GNAS gene for guanine nucleotide-binding protein (G-protein)

FIBROUS DYSPLASIA OSSIFICANS (AKA PROGRESSIVE MYOSITIS OSSIFICANS)

  • Musculoskeletal structures (muscles, tendons, ligaments) are replaced with bone (ossified). * This extra-skeletal ossification causes immobility, manifesting with difficulty even opening one’s mouth to eat or ability to breath.

Genetics

  • AVCR1 gene for BMP type 1 receptor
  • Autosomal Dominant

HEREDITARY HYPOPHOSPHATEMIC RICKETS

  • Patients suffer from a bowing of bones due to chronic hypophosphatemia (in adults, this causes osteomalacia – bone softening).

Pathophysiology

  • Hypophosphatemia

Genetics

  • PHEX gene
  • Most common: X-linked dominant

OSTEOPETROSIS

  • Bones are abnormally dense (thick).

Systemic complications

  • Anemia
  • Hepatosplenomegaly
  • Immunodeficiency

Neurologic manifestations

  • Cranial neuropathies

OSTEOPOIKILOSIS

  • Bones are spotted with round areas of increased bone density.

OSTEOGENESIS IMPERFECTA

  • Bones are abnormally fragile: fractures occur commonly.
  • Mild forms of the disease are associated with blue-appearing sclera.
  • Severe forms are lethal just after birth due to inability to adequately breathe.

Genetics

  • COL1A1 and COL1A2 genes (mostly)
  • Autosomal Dominant (mostly)

EHLERS-DANLOS

  • Causes hypermobile joints.

Systemic complications

  • Hypermobile joints
  • Elastic skin
  • Kyphoscoliosis
  • Respiratory changes from severe scoliotic abnormalities

Genetics

  • Autosomal recessive

CLEIDOCRANIAL DYSPLASIA

  • Manifests with abnormalities in the clavicles and skull [delayed closure of the fontanelles], most notably (hence its name).
  • These bones develop from intramembranous ossification, thus we can remember the disorder as one of pathologic intramembranous ossification.

Bony abnormalities

  • Clavicles
  • Skull
  • Teeth

Genetics

  • RUNX2 gene
  • Autosomal Dominant

Additional notable causes of skeletal dysplasia include:

Neurofibromatosis

Storage Disorders: Gaucher Disease and the Mucopolysaccharidoses.

LIMB AND DIGIT DEVELOPMENT

  • The upper limb bud forms at ~ day 24, followed shortly thereafter by the lower limb bud (at ~ day 28).
  • The limb bud comprises a core of mesenchyme, surrounded by ectoderm.
  • The AER (apical ectodermal ridge) forms a thickening at the distal end of the limb bud.
  • The distal upper limb bud forms a digital plate, distally (for the fingers) and a carpal plate (for the hand). Then, via programmed cell death, digital rays form.

COMMON LIMB DISORDERS: TERMINOLOGY

  • Amelia is absence of a limb.
  • Meromelia is absence of a part of a limb.

DIGIT DISORDERS

  • Syndactyly is webbing (fusion) of digits.
  • Polydactyly is presence of extra digits.
  • Brachydactyly is shortening of digits.

Known Teratogens that cause limb and digit malformations, include

Pharmaceuticals

  • Valproate
  • Phenytoin
  • Warfarin

Toxins

  • Cocaine
  • Alcohol (fetal alcohol syndrome)

Metabolic conditions

  • Hyperglycemia (gestational diabetes)

Infections

  • Varicella Zoster

Genetic Myopathies

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GENETIC MYOPATHIES (INHERITED MUSCLE DISEASES, MUSCULAR DYSTROPHIES)

Muscle histology: Review

  • Epimysium envelopes the muscle.
  • Perimysium divides the muscle into fascicles.
  • Endomysium lies within the muscle fascicle: it comprises a loose areolar connective tissue that maintains the extracellular environment for proper muscle cell functioning.

Muscle fascicle histology: Review

  • The muscle cell is covered in endomysium.
  • The cell has many nuclei.
  • Dot-like myofibrils constitute the muscle cell milieu.

Muscle Cell Physiology: Review/Pathology Introduction

  • Proteins stabilize myofibrils to the muscle cell and can be linked to well-defined related myopathies.
  • Each Myofibril includes a Z-disk, which transects an I Band, flanked by A Bands.
  • Repeating light and dark bands gives muscle fibers a striated appearance.
  • Desmin filaments encircle the Z disks.
  • Desmin-related myopathy (DRM) is an inherited disease which results in disorganized and weak skeletal muscle fibers. DRM can be fatal, as it also affects cardiac and smooth muscles.
  • Plectin links the desmin filaments.
  • Alpha-B-crystallin (a heat shock protein) protects desmin from stress-induced damange. Together: desmin, plectin, and alpha-B-crystallin constitute a Z-disk protection network.
  • Dystrophin-associated glycoprotein complex (DAGC) comprises:
    -Dystroglycan subcomplex, which links dystrophin to laminin, a key external lamina protein (called laminin-2 in skeletal muscle, which has an associated myopathic syndrome).
    -Sarcoglycan subcomplex, which, when defective can cause sarcoglycanopathies – a similar manifestation of weakness as those from dystrophinopathies – and are a common cause of limb-girdle muscular dystrophy.
    –Dystrophin stabilizes the sarcolemma during muscle contraction. When pathologic, it produces the dystrophinopathies (eg, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy).
  • Syntrophins are recruited to the sarcolemma and manage the assembly of other proteins.
  • Dystrobrevins link desmin to dystrophin and syntrophin.

MUSCULAR DYSTROPHIES

DYSTROPHINOPATHIES (DUCHENNE, BECKER):

Overview

  • X-linked, Recessive form of muscular dystrophy that affects boys and occurs from a genetic mutation that prevents the synthesis of dystrophin.
  • Muscle is replaced with fatty and fibrous connective tissue, which presents with pseudohypertrophic muscles: muscles that are enlarged from fat and connect tissue (not muscle).
  • Duchenne Muscular Dystrophy is a severe dystrophinopathy wherein children are non-ambulatory at ~ age 13 – pseudohypertrophy of calf muscles is a notable clinical finding.
  • Becker Muscular Dystrophy is a less severe dystrophinopathy in that patients aren’t non-ambulatory until ~ age 40.
  • As a helpful mnemonic add the treatment adage that the goal of corticosteroids is to: Make Duchenne boys into Becker men.

Duchenne Muscular Dystrophy

  • Most severe form
  • Manifests in childhood with proximal weakness (especially calf hypertrophy)
  • Loss of ambulation ~ age 13

Becker Muscular Dystrophy

  • Less severe form
  • Manifests in early teens
  • Loss of ambulation ~ age 40

Genetic & Diagnostic Characteristics of Duchenne & Becker Muscular Dystrophies

  • Genetics
    -X-Linked, Recessive
    -Dystrophin gene mutation that leads to reduction/absence of dystrophin protein with resultant sarcolemma damage
  • Diagnosis: Elevated CK (~20,000), Dystrophin Gene Deletion
  • Treatment: Corticosteroids

Myotonic Dystrophy, Type 1

  • Characterized by myotonia (eg, inability to release a grip) [relaxes with repetition vs. paramyotonia which worsens with repetition]. Responds to Mexilitine.
  • Weakness of lower extremities, hands, neck, and face
  • Additional systemic features
    -Cataracts
    -Cardiac conduction defects
    -Early Frontal balding

Myotonic Dystrophy, Type 2

  • Myotonia
  • Weakness of neck, shoulders, elbows, and hips.

Genetic & Diagnostic Characteristics of the Myotonic Dystrophies

  • Autosomal Dominant
  • Anticpiation in DM-1 with the DMPK gene [CTG Trinucleotide repeats]
  • EMG findings of myotonic discharges.

Oculopharyngeal Muscular Dystrophy

  • Ptosis and dysphagia
  • Onset > age 40
  • Genetics
    -Autosomal Dominant
    -PABPN1 gene

Fascioscapulohumeral Muscular Dystrophy

  • Asymmetric facial and scapular muscles (scapular winging) and humeral (upper arm) atrophy: difficulty whistling, closing eyes, throwing ball
  • Symptoms appear in adolescence
  • Genetics
    -Autosomal Dominant
    -D4Z4 contraction on chromosome 4q35 (Majority of genetic cause)

Limb-Girdle Muscular Dystrophies

  • Present with proximal weakness at any age, manifesting with waddling gait, scapular winging, possible joint contractures.
  • Cardiomyopathy or respiratory compromise are key potential complications
  • Diagnosis: Elevated CK, genetic testing, and immunohistochemical muscle biopsy staining
  • Genetics
    -Various genetic pathologies involving muscle cell proteins: sarcolemmal, cytosolic, nuclear envelope.
    -Notable forms: -LMNA gene [lamin A/C], CAPN3 gene [calpainopathy], DYSF gene [dysferlinopathy], SGC genes [sarcoglycanopathies]

Emery-Dreifuss Muscular Dystrophy

  • Skeletal & cardiac muscle are affected
  • Early contractures (joint deformities)
  • Upper arm/lower leg wasting
  • Genetics
    -X-linked
    -EMD gene (most commonly), which forms emerin: a nuclear envelope protein.
    -LMNA gene (less commonly), which forms lamin A/C

CONGENITAL MYOPATHIES

Central Core Myopathy

  • Floppy infants
  • Associated skeletal abnormalities: scoliosis, hip dislocation, joint deformities
  • Risk of malignant hyperthermia from anesthetics
  • Pathology: microscopic cores in the center of muscle fibers
  • Genetics
    -Autosomal Dominant
    -RYR1 gene for the Ryanodine Receptor 1, which forms a channel that releases calcium from muscle cells

Nemaline Rod Myopathy

  • Infant onset is most common – Hypotonia and poor respiration
  • Adults – Proximal weakness and skeletal abnormalities (scoliosis and contractures)
  • Abnormal clumps of threaded filaments (hence: “nema” for “thread”) in muscle fibers that can look like rods.
  • Genetics
    -Autosomal recessive.
    -Mutations in sarcommeric proteins.

METABOLIC MYOPATHIES

Pompe Disease (Acid Maltase Deficiency)

  • Infantile-onset (classic vs non-classic): myopathy, hypotonia, hepatomegaly, congenital heart defects
  • Late-onset: Progressive weakness and respiratory failure.
  • Genetics
    -Autosomal recessive.
    -GAA gene for acid alpha-glucosidase (acid maltase), which is key for break-down of glycogen to glucose within lysosomes.

McArdle Disease (Glycogen Storage Disease Type V)

  • Exercise-induced Pain/Cramps/Fatigue, which alleviates with rest (“Second Wind” phenomenon).
  • Severe forms cause rhabdomyolysis with myoglobinuria.
  • Genetics
    -PYCM gene for myophosphorylase, which is specific to muscle. It breaks down glycogen to glucose-1-phosphate.
  • Forearm ischemic exercise test: lactate [no change], ammonia [normal increase].
  • Muscle biopsy: lack of phosphorylase. Subsarcolemmal glycogen deposits.
  • Treatment: Enzyme replacement therapy, Avoidance of maximal exercise, High-protein and low carbohydrate diet.

Carnitine Palmitoyltransferase Deficiency 2

  • Lipid metabolism disorder that prevents the body from using fat for energy during periods of fasting.
  • Carnitine Palmitoyltransferase 2 (CPT2) is involved in inner mitochondrial membrane transport – deficiency comprises mitochondrial fatty oxidation.
  • Three forms of the disorder (from most severe to least): lethal neonatal, infantile hepato-cardio-muscle, and myopathic.
    -Myopathic form causes: myalgias and rhabdomyolysis.
  • Genetics
    -CPT2 gene mutation involving fatty acid oxidation within mitochondria.
    -Long-chain fatty acids must attach to carnitine to enter mitochondria. Once inside, CPT2 removes carnitine for fatty oxidation – without CPT2, fatty acids can’t be used for energy.
  • Treatment: High carbohydrate, Low fat diet.

CHANNELOPATHIES

Myotonia Congenita (Thomsen & Becker Disease)

  • Abnormal muscle excitability that is NON-dystrophic, exacerbated in cold.
  • Muscle stiffness. Myotonia (eg, inability to release a grip) [relaxes with repetition vs. paramyotonia which worsens with repetition]. Responds to Mexilitine.
  • Genetics
    • CLCN1 gene – chloride channelopathy, SCN4A – sodium channelopathy
      -Thomsen – Autosomal Dominant. Becker – Autosomal Recessive.

Familial Periodic Paralysis

  • Flaccid weakness in the setting of hypokalemia or hyperkalemia that can last hours to days.
  • Triggered by intense exercise, large carbohydrate meal, viral infection, or medications.
  • Genetics
    -Autosomal Dominant
    -CACNA1S gene – calcium channelopathy, SCN4A – sodium channelopathy
  • Don’t forget other potential causes of episodic weakness: Myasthenia Gravis, Lambert-Eaton, Thryotoxicosis, and Metabolic Derangement – calcium, phosphorous, magnesium, sodium.

MITOCHONDRIAL MYOPATHIES

  • Maternally-inherited
  • Ragged red fibers / Subsarcolemmal accumulation of abnormal mitochondria

Skull Development & Developmental Anomalies

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Skull Malformations

  • Macrocephaly, Megalencephaly, and Microcephaly.

Craniosynostosis

Premature closure of the cranial sutures.

  • Disorders of a single suture: Trigonocephaly, Plagiocephaly, Scaphocephaly, and Brachycephaly.
  • Disorders that involve multiple suture synostoses.

SKULL MALFORMATIONS

Macrocephaly

  • Cranial enlargement (to > 98% of normal range). Although it can be due to enlargement of any of the 3 brain compartments: brain tissue, CSF, or blood, it’s most commonly due to obstructive hydrocephalus – enlargement of the CSF ventricles. It typically necessitates ventriculostomy or shunting.

Megalencephaly

  • Generalized cranial enlargement of the gray and white matter of the brain due to either anatomic abnormalities (eg, neurocutaneous disorders) or metabolic abnormalities (eg, lysosomal storage disorders or leukodystrophies).
  • Megalencephaly is technically a form of macrocephaly, since, indeed it involves enlargement of the cranium – but, again, the majority of cases of macrocephaly are NOT generalized brain matter enlargement but rather due to hydrocephalus.

Microcephaly

  • A generalized abnormally small cranium (to < 98% of normal range), either due to a primary genetic cause (ie, a chromosomal or metabolic abnormality (eg, phenylketonuria) or an acquired condition (eg, perinatal infection).

NORMAL SKULL ANATOMY AND DEVELOPMENT

Neurocranium

Divides into the…

  • Cranial vault, which provides a roof for the brain.
  • Skull base, which provides a floor for the brain.

Viscerocranium

  • Comprises the facial bones.

SKULL DEVELOPMENT

  • The cranial vault and viscerocranium develop via intramembranous ossification (again, which has no intermediate cartilaginous model).
  • The skull base develops via endochondral ossification, which develops via a cartilaginous matrix.

The cranial vault comprises:

  • Frontal bone, Parietal bone, upper portion of the Occipital bone, and Squamous portion of the Temporal bone – all of these develop via intramembranous ossification.

The key bones of the the skull base:

  • The lower portion of the Occipital bone, the Petrous portion of the Temporal bone, and the Sphenoid bone – all of these bones develop via endochondral ossification.
  • Key viscerocranial bones:
    The Zygomatic bone and Maxilla and Mandible – they develop via intramembranous ossification.
  • The bones of the face derive from embryonic cells from the pharyngeal arches (from neural crest cells (other than the laryngeal cartilages, which derive from mesoderm)).

SKULL SUTURES

  • At birth, the skull has openings (sutures) to accommodate brain growth, because the cranial vault ossifies early via intramembranous ossification. These sutures allow the fetal skull to ossify quickly prior to delivery [via intramembranous ossification] (so the brain doesn’t get squashed) and yet still accommodate skull distortion during birth (called, molding) and permit rapid brain growth during the first two years of life when the brain quadruples in size to 75 percent of its adult volume!
  • Metopic – forms between midline aspects of the left/right aspects of the frontal bone.
  • Coronal – lies between the frontal and parietal bones.
  • Sagittal – lies between the bilateral parietal bones.
  • Lambdoid – lies between the parietal bones and occipital bone.
  • There are three additional minor sutures: frontonasal, temporosquamosal, and frontosphenoidal.

THE FONTANELLES

The large openings that exist in the newborn calvarium.

  • The frontal bone covers the majority of the anterior frontal lobes.
  • The parietal bones cover the remainder and the parietal lobes.
  • The occipital bone covers the occiput.

Anterior fontanelle

  • Forms at the junction of the sagittal, coronal, and metopic sutures at the anterior of the skull – it’s palpable in midline, just behind the forehead; it closes at 1.5 to 2 years of age.

Posterior fontanelle

  • Forms from the intersection of the sagittal and lambdoid sutures; it closes at 3 – 6 months of age.

CRANIOSYNOSTOSES

  • Premature cranial suture closure (synostosis).

Scaphocephaly

  • The most common type of synostosis; accounts for half of the incidences of synostosis each year.
  • There is synostosis of the sagittal suture – the skull is shaped like the narrow hull of a boat (the derivation of its name).
  • In accordance with Virchow’s law, the interruption of brain growth is in perpendicular to the plane of the synostosis – thus the abnormal brain growth is in parallel to the synostosis. The skull elongates (in parallel to the synotic suture) – this results in an elongated, narrow skull.
  • The term dolichocephaly (elongated head) is either used synonymously scaphocephaly or as a broader catch-all for elongated head.

Brachycephaly

  • Results from bicoronal synostosis.
  • The skull cannot develop normally along the sagittal plane and we show, instead, that it manifests with a wide, short skull – again, in accordance with Virchow’s law, the skull develops in parallel to the plane of the synostosis.
  • In unilateral coronal synostosis (as opposed to bilateral), also results in plagiocephaly because, as we can imagine, it results in a twisting/oblique appearance (but here of the frontal calvarium).

Trigonocephaly

  • Secondary to metopic synostosis, which results in a failure of frontal outward development.
  • It manifests with a pointed forehead… the eyebrows may appear “pinched.”
  • To help link the name to the shape, we show that trigonocephaly results in a triangular shaped head, when viewed from above.

Lambdoid synostosis

  • Posterior plagiocephaly (a twisted skull) due to an inability of a side of the occiput to grow outward, thus there is an oblique oblique deformity of the posterior calvarial vault.

DESCRIPTIVE TERMINOLOGY FOR MULTIPLE SUTURE SYNOSTOSES

Cloverleaf Deformity (aka Kleeblattschädel)

  • Multiple sutures fuse prematurely – unfortunately, the brain actually can grow through the anterior fontanelle, can be a finding of certain genetic syndromes as described below…

SYNDROMES:

FGFR2 GENE (FIBROBLAST ABNORMALITY)

Apert Syndrome

  • Multiple suture synostoses w/possible cognitive delays
  • Syndactly vs Polydactly
  • Possible hearing loss, hyperhidrosis, spine fusion, oro-palatal malformations
  • Genetics: Autosomal dominant, FGFR2 gene abnormality, which is important in fibroblast embryonic development of bone.

Crouzon Syndrome

  • Multiple suture synostoses w/o cognitive delays
  • Possible hearing loss and oro-palatal malformations
  • Genetics: Autosomal dominant, FGFR2 gene abnormality, which is important in fibroblast embryonic development of bone.

Pfeiffer Syndrome

  • Multiple suture synostoses w/anywhere from no neurologic complications to significant complications.
  • Syndactly vs Brachydactly
  • Possible Anykylosis (bone fusion at the joints)
  • Genetics: Autosomal dominant, FGFR2 gene abnormality, which is important in fibroblast embryonic development of bone.

RAB23 OR MEGF8 GENE (VESICLE TRANSPORT)

Carpenter syndrome

  • Multiple suture synostoses w/possible cognitive delays
  • Brachydactly vs Polydactly vs Syndactly
  • Cryptorchidism
  • Kyphoscoliosis
  • Genetics: Autosomal recessive, RAB23 or MEGF8 gene mutations, which is important in vesicle transport.

Parathyroid Glands

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Hormonal regulation of extracellular calcium and phosphate concentrations by the parathyroid glands.

Key Principles

Free calcium participates in various cellular processes, including:

  • Skeletal, cardiac, and smooth muscle contraction
  • Nerve conduction
  • Blood clotting
  • Bone and tooth formation
  • Enzyme activation and deactivation

Phosphate is a part of ATP

  • Participates in cellular metabolism
  • Plays a role in enzyme activation and deactivation

Storage and Release:

Calcium and phosphate are stored within hydroxyapatite crystals of bone

  • When bone is resorbed, calcium and phosphate are released into the extracellular fluid
  • Calcium and phosphate levels are regulated by the same hormones:
    • Parathyroid hormone, which is secreted by chief cells of the parathyroid glands
    • Vitamin D (in activated form)

(The physiologic role of calcitonin, a hormone released by the thyroid gland in response to increased calcium concentrations, is as of yet uncertain, and, therefore, omitted in this tutorial.)

PARATHYROID HORMONE PATHWAYS:

In response to lowered extracellular calcium concentration, the parathyroid glands secrete parathyroid hormone (PTH).

Bone:

  • In bone, episodic, transient binding of parathyroid hormone causes an increase in new bone synthesis
  • Prolonged exposure to parathyroid hormone promotes resorption of old bone, and, therefore, the release of calcium and phosphate into extracellular fluid

Clinical consequences of these dichotomous effects:

  • Osteoporosis, which is characterized by loss of bone density, can be treated with intermittent PTH administration
  • Continuous release of PTH in individuals with hyperPARAthyroidism causes excessive bone resorption

Kidneys:

  • Increased calcium reabsorption in the distal convoluted tubule of the nephrons
  • Decreased phosphate reabsorption in the proximal convoluted tubule, which leads to phosphaturia, an increase in phosphate in the urine
    – This action is important because, otherwise, reabsorbed phosphate would complex with the reabsorbed calcium, which would negate its physiologic effects in the body.

PTH STIMULATES RENAL ACTIVATION OF VITAMIN D

Kidney

  • Vitamin D acts increases renal reabsorption of both calcium and phosphate

Small Intestine

  • Vitamin D increases calcium and phosphate reabsorption

Bones

  • Vitamin D works with parathyroid hormone to facilitate skeletal remodeling, which requires both synthesis and resorption of bone.

Clinical correlation:

Vitamin D deficiency in children causes rickets, in which skeletal development is impaired, the bones are weak, and, consequently, growth is often stunted.

System-wide consequences of calcium imbalances:

Hypocalcemic individuals experience hyperreflexia, muscle twitching and cramping, numbness and tingling

  • Trousseau’s sign, characterized by involuntary hand and feet spasms, carpopedal spasms, which can be provoked by the examiner by inflating a blood pressure cuff to cause prolonged brachial artery occlusion.
  • The Chvostek sign, characterized by hyper excitable facial muscle twitching in response to tapping the facial nerve.

Hypercalcemic individuals experience hyporeflexia, muscle weakness, lethargy, and, polyuria.

Bone Remodeling

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BONE REMODELING

HOMEOSTATIC PROCESS OF BONE REMODELING

Key Functions

  • Regulates calcium blood levels
  • Repairs worn-out bone
  • Responds to bone stress

Actions

  • Osteoblasts form bone from calcium in blood and that osteoclasts break down bone and push calcium into blood.
  • LOW blood (plasma) calcium levels stimulate osteoclast activity and inhibit osteoblast activity.
  • HIGH blood (plasma) calcium levels inhibit osteoclast activity and stimulate osteoblast activity.
  • Reabsorbed bone releases calcium into blood and PTH (parathyroid hormone) is a key physiologic mediator for bone homeostasis.

Clinical Correlation: In Osteoporosis, bone resorption exceeds deposition.

THE BIOLOGICAL PROCESS OF BONE REMODELING

OSTEOBLAST GENERATION

Osteoblasts are the primary mediators of bone formation.

Osteoprogenitor cells

  • Spindle-shaped osteoblast precursors.
  • They are funneled into ossification centers for linear bone growth.
  • They line both the periosteum and the endosteum for appositional bone growth.

Osteoblasts

  • Lie along bone matrix. Bone matrix comprises an inorganic component: hydroxyapatite and an organic component: osteoid.
  • Osteoblasts are critical to bone formation, they:
    -Secrete osteoid (the organic (unmineralized) portion of bone – ie, the type 1 collagen fibers and ground substance).
    -Mineralize hydroxyapatite (the hydroxylated calcium and phosphate component of bone) via osteocalcin and osteonectin
    -Mediate osteoclastogenesis (the formation of osteoclasts) via M-CSF (macrophage colony stimulating factor) and RANKL with inhibition by osteoprotogerin.
  • Stimulation of osteoprogenitor cell differentiation:
    -Members of the (bone morphogenetic protein) BMP family
    -Transforming Growth Factor Beta

Thoracic Cage

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Thoracic cage

  • Protects the chest organs (the heart and lungs).

Main Structures:

The sternum (aka, breastbone) lies anteriorly.
12 thoracic vertebrae lie posteriorly.
12 ribs articulate with the thoracic vertebrae.

Sternum

  • Manubrium (superiorly)
  • Body (long and flat, middle portion)
  • Xiphoid process
    • Easily injured during chest compression (for CPR).
  • Sternal angle
    • Where manubrium and body meet
    • Easily palpated to find rib 2
  • Sternal indentations:
    • Jugular notch (aka, suprasternal notch) is on the superior border of the manubrium.
    • Clavicular notches are to the sides of the jugular notch; these are where the clavicles (aka, collarbones), articulate with the sternum.
    • Costal notches articulate with the costal cartilages of the ribs (“costal” refers to the ribs).

Rib Types

  • True ribs
    • Ribs 1-7; articulate with the sternum directly via their costal cartilages.
  • False ribs
    • Ribs 8-12; do not articulate directly with the sternum.
    • Ribs 11 and 12 are “floating ribs,” do not articulate at all with the sternum.

Rib Features

  • Head
    • Articulates with the vertebral body; typically comprises two articular surfaces separated by a bony crest.
  • Neck
    • Extends from the head, and terminates at the tubercle.
  • Tubercle
    • Comprises an articular facet, which is where the rib articulates with the transverse process of the vertebra.
  • Shaft
    • Longest portion of the rib, extends from tubercle to rib end.
  • Angle
    • Bend in rib, just lateral to tubercle.

Rib/vertebra articulation

  • Head and tubercle of rib articulate with body and thoracic process of vertebrae.

Intercostal spaces

  • The spaces between the ribs
  • House muscles and neurovascular structures.
    • Intercostal neurovascular bundle, especially the intercostal artery, must be avoided during insertion of a chest tube.