{07029} healing fracture, histology
{08994} healing fracture, histology

Healing fracture WebPath Tutorial

Healing fracture WebPath Tutorial

* Future pathologists: Here's a rough guide to the x-ray dating of children's fractures.
Two days: Soft tissue edema is usually gone

Four days: Periosteal new born formation beginning

Ten days: Fracture line no longer visible; soft callus present

Fourteen days: Hard callus present

Twenty-one days: Callus is all hard

Ninety days: Bone has remodelled

* Orthopedic nails and screws placed into bone become separated from the bone itself by organized connective tissue continuous with the periosteum. * Allogenic stem cells to enhance bone healing: Impressive animal study, no immunosuppression required J. Bone. Surg. 85: 1927, 2003.

OSTEOGENESIS IMPERFECTA ("brittle bone diseases", * fragilitas ossium; Clin. Ortho. 401: 6, 2002; Lancet 363: 1377, 2004)

A family of diseases having in common defective synthesis of type I collagen.

* The molecular biology has been extensively worked out (Clin. Orth. 343: 23, 1997. Here are the subtypes:

Type I... Make too little pro-α1(1). Normal statue, lax joints, hard of hearing (another mutation: J. Clin. Invest. 85: 282, 1990).

Type II... Pro-α1(1) is too short, etc. The collagen is made but poorly secreted. Bones break in utero or during birth, killing the child (yet another mutation: J. Clin. Invest. 83: 574, 1989)

Type III... Triple helix doesn't form well. Short, many fractures, progressive kyphosis, hard of hearing, bad cases are lethal in childhood

Type IV... Pro-α2(2) is too short, etc. Short stature, somewhat fragile bones

And if you look hard, you find many "forme fruste" people whose bones are just a bit more fragile (J. Clin. Invest. 97: 1035, 1996).

Most are autosomal dominant; type II are either autosomal recessive or new autosomal dominant mutations. (Explain.) In most cases, the teeth are deformed. Except for type IV, all feature distinctive blue sclerae. (The "blue" color results from the translucence of the collagen. Don't rely on this, and don't go calling every relatively dark sclera "blue").

Bisphosphonate for osteogenesis imperfecta: After some early flops, new reports of success. NEJM 339: 947, 1998; Pediatrics 111: 573 & 601, 2003, Lancet 363: 1427, 2004, others; it is now standard.

Bone marrow transplantation: Nat Med. 5: 309, 1999. Gene therapy and somatic cell therapy are under investigation (Clin. Orth. 379-S: S126, 2000).

{12402} osteogenesis imperfecta {15795} osteogenesis imperfecta, blue sclera {18255} osteogenesis imperfecta type II {15801} osteogenesis imperfecta type II {18256} osteogenesis imperfecta, x-ray {15813} osteogenesis imperfecta, sutures not present

Unbreakable increased public awareness of osteogenesis imperfecta

* Other alleles at collagen loci:
Stickler's syndrome: Gawky people with some degree of nerve deafness; COL2A1 (the major type II collagen gene) or another collagen locus: J. Med. Genet. 36: 353, 1999

Achondrogenesis II: Lethal mutation in COL2A1

* Osteogenesis imperfecta must be ruled out in children with fractures attributed to abuse. This isn't difficult. I used to be asked about "temporary brittle bone disease" and after examining the evicence, decided that I don't believe in it. Update: The physician who "discovered" this is now in court for making stuff up (Br. Med. J. 328: 187, 2004).

OSTEOPETROSIS ("marble bones", "Albers-Schonberg disease"; Am. Fam. Phy. 57: 1293, 1998)

This family of diseases features progressive obliteration of the marrow cavity by bone. This is bad because (1) the bones become very brittle, and (2) the patient is likely to die of neutropenia or anemia.

Most of these diseases are autosomal dominant (usually mild) or autosomal recessive (usually severe). The genetics of both have not been fully worked out (J. Clin. Endoc. Metab. 84: 1047, 1999).

The most common recessive gene is a defect in an ATPase that is only expressed in osteoclasts (Am. J. Path. 162: 57, 2003).

Other patients lack carbonic anhydrase II, and the osteoclasts die of too much acid (Hum. Genet. 99: 634, 1997; Blood 97: 1947, 2001). Yet another features a faulty chloride channel, preventing the cytoplasm from becoming sufficiently acidic to dissolve bone in the first place (Am. J. Path. 164: 1537, 2004)

In the severe, autosomal-recessive variant, the skull becomes so deformed from the disease itself and the extramedullary hematopoiesis that the foramina for the optic and other cranial nerves are compromised. Radiologists note a striking resemblance between skull x-rays of these kids and the "Alien" from the Sigourney Weaver space thrillers (Radiology 183: 129, 1992).

As you would expect, the problem seems to be with the osteoclasts. If you get a chance to examine these, they are likely to appear bizarre. Marrow transplantation cures the underlying lesion: Blood 97: 1947, 2001.

"Osteopetrosis tarda" is a forme fruste, usually a subclinical x-ray finding in older folks (Am. Fam. Phys. 57: 1293, 1998), and there is talk of retroviruses causing sporadic cases by destroying osteoclasts.

Osteopetrosis Skull x-ray

ACHONDROPLASIA

An autosomal dominant condition (often a new mutation) in which there is impaired formation of the long bones by the familiar endochondral process. The limb bones are short, with abnormally wide ends. The patient has a head and trunk of normal size, and disproportionately short but well-muscled arms and legs. The face usually has a large forehead, prominent supraorbital ridges, and deepset root of the nose (looks like a very mild Apert's). Sexuality is generally normal, and intelligence is distributed as for the general population, with many well above-average (Am. J. Med. Genet. 41: 208, 1991).

The achondroplasia locus is the receptor for fibroblast growth factor 3.

* The mutation is usually the same, a substitution: Nat. Gen. 13: 233, 1996. Other, worse alleles here give thanatophoric dwarfism, with excessively short ribs and suffocation shortly after birth (update Am. J. Path. 161: 1325, 2002). Rat model Nature Genetics 12: 390, 1996. Some short people have a forme fruste ("hypochondroplasia") with mutated FGF3 (J. Ped. 133: 5, 1998). Sun Hudson, the baby in the 2005 Texas "life support" case, suffered from thanatophoric dwarfism.

* Advanced paternal age is one of the known risk factors for new mutations. Apparently this mutation, and maybe the similar Apert's mutation (see below) give a growth advantage to the sperm clone (Science 301: 606 & 643, 2003).

{25610} achondroplasia {25688} achondroplasia {49474} "achondroplasia" (looks like a thanatophoric dwarf to me, failure of rib development)

Little People of America Good resources

Achondroplastic dwarf KU Collection

Several of history's best-loved entertainers were achondroplastic dwarves (legendary gladiators, the Egyptian good-luck spirit Bes, Pharaoh Pepi's Nubian dancer, Tom Thumb and his wife, the great Renaissance fiction-writer Morgante. The "Munchkins" from the movie version of "The Wizard of Oz" were apparently a mix of pituitary and achondroplastic dwarves. Some people say that Aesop was a black achondroplastic dwarf). The traditional teaching is that dachshund dogs are achondroplastics; we now know that the FGF3 genes seem to be normal, and the gene(s) for the short legs of dachshunds, basset hounds, and bulldogs remains unknown (Can. J. Vet. Res. 64: 243, 2000).

In fact, achondroplasia has a mystique, and has even been considered a desirable trait. See Clin. Genet. 37: 279, 1990. Everyone's heard of the "Little People"'s organizations, and there is much friendly rivalry between achondroplastic and pituitary dwarves as to "which is better", etc., etc.

There are several other dwarfism syndromes that result from defective bone growth. Those that compromise the lengthening of the ribs are fatal shortly after birth (why?)

* Apert's (deformed face, syndactyly) is mutated fibroblast growth factor receptor 2 (Nat. Genet. 13: 48, 1996); documentary "Mary Ann" about an Apert's baby who was so ugly that everybody assumed she was retarded, too, and they put her in a home for retarded kids; she wasn't retarded. Apert's is usually a new mutation, and almost always on Dad's chromosome (Nat. Genet. 13: 9, 1996); this is another of the few genetic diseases that gets more common with advanced paternal age. A milder allele causes Crouzon syndrome; the same advanced paternal age effect has been noted (Am. J. Hum. Genet. 66: 768, 2000).

One of the "pseudoachondroplasia" diseases results from a mutated cartilage matrix protein, which is improperly processed and causes apoptosis of the growth cartilage (Am. J. Path. 163: 101, 2003).

* A "midget" is a normally-proportioned miniature adult; a "dwarf" is short because of disproportion.

{53757} Apert's
{53760} Apert's

* PYCNODYSOSTOSIS

There seems to be a consensus today that artist Henri de Toulouse-Lautrec's dwarfism and deformities were caused by pycnodysostosis. Here is the evidence: He had fragile bones and sustained fractures as a young teen from minor trauma. His facial features were considered bizarre ("cute") from his babyhood. He had an extremely small chin, which he concealed by a beard. His fontanelle never closed. He protected his head by almost always wearing a hat. His fingers were very short, especially at the tips. His parents were first cousins. All this fits with pycnodysostosis and probably nothing else. Making the call: JAMA 191: 111, 1965; more recently Nat. Genet. 10: 128, 1995. This is an autosomal recessive illness caused (at least sometimes) by defective cathepsin K, found only in osteoclasts (J. Clin. Endo. Metab. 85: 425, 2000). Pathology J. Clin. Endo. Metab. 89: 1538, 2004.

* OTHER GENETIC SYNDROMES

There are a host of genetic syndromes involving bone, from families where several members share a minor skeletal anomaly to the horrible fibrodysplasia ossificans progressiva (formerly "bad myositis ossificans"), a dominant-but-variably-expressed mutation (stay tuned; the locus remains elusive) that causes overproduction of bone morphogenetic protein 4 in which wound healing is accompanied by exuberant endochondral bone production.

Camurati-Engelmann disease, or "progressive diaphyseal dysplasia", features bone laid down under the periosteum; the gene is TGF-β1 (Nat. Genet. 26: 273, 2000; J. Biol. Chem. 278: 7718, 2003).

Fibrodysplasia ossificans progressiva 25 year old man From NEJM

Fibrodysplasia ossificans progressiva Six year old girl From Kaplan JBJSA 75A

PYOGENIC OSTEOMYELITIS

Common bacteria can reach the bone via the blood, during surgical or other trauma, or from surrounding tissues (don't forget infected teeth, or the gangrenous feet of diabetics).

Osteomyelitis is especially serious, since the rise in pressure caused by the suppuration (like in a ripe pimple, of course) is often enough to cause infarction of spongy bone and marrow, sequestering the infection and turning it into a chronic infection refractory to all but the most aggressive treatment.

The usual bug is staph, though most of the common bacteria can produce osteomyelitis. In sicklers, salmonella is the usual culprit, and drug abusers who mix their works with tap water are prone to pseudomonas. In 50% or so of cases, you'll grow nothing, probably because somebody gave an antibiotic already.

The anatomic pathology of pyogenic osteomyelitis has many variants. Rupture through the cortex can produce periostitis or (in a growing child) subperiosteal abscess surrounding the entire shaft. Dead bone becomes a sequestrum (and acts like any other foreign body), while new living bone that grows around the dead bone is called the involucrum. Rupture through the skin produces refractory sinuses, where squamous skin cancer is likely to arise because of the ongoing destruction-and-regeneration of the squamous epithelium. A walled-off area full of bacteria is a Brodie's abscess, which can keep the infection going, and perhaps spreading via the bloodstream, for many years. In the chronic infection, the infiltrate is a mix of neutrohpils, lymphocytes, plasma cells, and lipid-laden macrophages; sometimes the plasma cells or macrophage are by far the most abundant. Healed osteomyelitis is often very radio-dense.

Remember that osteomyelitis is likely to complicate bedsores and foot gangrene. Osteomyelitis often becomes a clinician and patient's nightmare. You're already familiar with amyloidosis A, one of the many feared outcomes.

* When there is an open wound that is being managed, pathologists are now being asked to examine a bone biopsy to see whether osteomyelitis is present. This guides antibiotic therapy (Am. J. Med. Sci. 321: 367, 2001). Autopsy series of osteomyelitis in sacral decubiti: Arch. Path. Lab. Med. 127: 1599, 2003.

{05293} osteomyelitis, x-ray (see it? areas of dead bone often end up mottled-radiodense)
{39505} osteomyelitis, x-ray
{40090} osteomyelitis, draining sinus

Osteomyelitis Pittsburgh Pathology Cases

Healing osteomyelitis WebPath Tutorial

Osteomyelitis Pittsburgh Illustrated Case

* SAPHO syndrome is a rare (and/or underdiagnosed?) illness in which abscesses appear unpredictably in the skeleton. The acronym stands for synovitis, acne, pustulosis, hyperostosis (bone bumps especially on the joints, especially those of the chest), and osteitis. The cause is completely obscure, but it's being recognized more nowadays, and being treated effectively with anti-inflammatories and retinoic acid derivatives.

Syphilis
Skull showing old gummas
AFIP

TUBERCULOUS OSTEOMYELITIS

This used to be common everywhere and is still common in the poor nations. While the onset is more insidious than pyogenic osteomyelitis, the infection is extremely destructive and hard to treat.

Pott's disease is the dread tuberculosis of the spine, and TB is the common cause of the infamous psoas abscess.

* Literature buffs: Elizabeth Barrett Browning ("Sonnets from the Portuguese", etc.) was completely disabled by severe chronic pain from Pott's disease for over a decade. When she was given free access to morphine, she became a productive writer and much happier person. Despite ideology, there may be a lesson here.