Achondroplastic dwarfism

CASE: A 24-year-old female presents to your office at 12-week's gestation for

routine prenatal counseling, she is 120 cm (47") tall with disproportionately short
upper and lower extremities, Physical examination is also significant for
depression of the nose root and a bulging forehead. She was adopted and has no
knowledge of family history Inherited abnormalities of which of the following cells
is most likely responsible for this patient's constitutional features?

The patient described above has a constellation of physical constellation that

suggest achondroplastic dwarfism-disproportionately short stature (short upper
and lower extremities compared to the axial skeleton) and some cranial
abnormalities. The most common defect in achondroplasia is the mutation of the
Fibroblast growth factor-receptor-3 at the epiphyseal growth plate, Long bones
have a wide epiphysis at each end and narrower, tubular diaphysis in the middle.
Young bone has several layers; in order, from middle to end, they are diaphysis,
metaphysis, epiphyseal cartilage, and epiphysis. Expansion of the epiphyseal
cartilage, also called the "growth plate," is responsible for linear growth. This
growth is regulated by a number of factors, including hormones and cytokines.
The major factors are growth hormone. IGF-I, insulin, thyroid hormone, sex
steroids, and fibroblast growth factor.
If fibroblast growth factor receptor-3 has an activating mutation, growth is
inhibited at the epiphyseal growth plate, ultimately resulting in short, thick,
tubular long bones in the appendicular (limb) skeleton. Axial (spine) length is
usually normal.

Osteoblasts are bone-forming cells, which lay down the bone matrix, which is
later calcified. Osteoclasts are bone-resorbing cells. Inhibition of osteoblasts and
activation of osteoclasts could be responsible for weak bones, but not short
stature.
Fibroblast growth factor regulates the growth of the epiphyseal growth plate and
acts on other cell types, including osteoblasts and endothelial cells.
Stimulation of osteoblasts and endothelial cells leads to formation of bone matrix
and blood vessels, respectively. In achondroplasia, bone vascularity is preserved
because endothelial cells are not mediated by fibroblast growth factor receptor 3.

Hypothalamic and pituitary lesions cause short stature by decreasing the growth
hormone I insulin like growth factor-1(IGF-I) pathway. Short stature in growth
hormone I IGF-I deficiency is proportional; that is, the axial and appendicular
skeleton are proportionate.

Educational Objective:
The most common defect in achondroplasia is an activating mutation of the
fibroblast growth factor receptor-3 at the epiphyseal growth plate which inhibits
growth at the epiphyseal growth plate. The result is short, thick tubular long
bones in the appendicular (limb) skeleton and normal axial (spine) length.
Short stature in growth hormone I IGF-I deficiency is proportional; that is, the
axial and appendicular skeleton are proportionate.

Rickets
Classic features suggestive of vitamin D deficiency: bony prominence at the
costochondral junctions, sometimes called a "rosary chest," and bowed legs.
After formation in the skin or absorption from the gastrointestinal tract, vitamin D
is inactive and requires a hydroxylation step in both the liver and in the kidneys to
form the active I, 25-dihydroxy vitamin D. The major function of activated vitamin
D is increased calcium and phosphorus absorption from the gastrointestinal tract.
Vitamin D is also important in osteoid mineralization.
Vitamin D deficiencies can be from poor sunlight exposure, an inadequate diet, or
defective absorption of vitamin D.
Rickets is a disorder that develops in childhood, Defective mineralization of the
matrix occurs in growing bones, causing weight-bearing bones to bow laterally
(genu varus), bony prominence at the costochondral junction (rachitic rosary),
indentations in the lower ribs (Harrison's sulci), softening of the skull
(craniotabes), hypocalcemia, hypophosphatemia, hypertonia, and growth
retardation.
Histologically, vitamin D deficiency is characterized by an increase in
unmineralized osteoid and widening between osteoid seams. The latter can be
measured by bone histomorphometry and by double tetracycline labeling.

Hyperparathyroidism increases osteoclastic activation resulting in increased bone

resorption; however, the bone resorption in hyperparathyroidism mainly involves
cortical bones. Increased resorption of cortical bones results in subperiosteal
thinning, a characteristic feature of hyperparathyroidism.

Paget's disease is seen in elderly patients and involves only focal points of the
skeleton. The disease process starts as marked, local osteoclastic activation,
followed by increased osteoblastic activity. The net result is the focal formaton of
abnormal bone. New collagen is laid down in a haphazard manner, compared to
the linear manner found in normal bones. The end product is a mosaic of lamellar
bone; irregular sections of lamellar bone are linked by areas of previous bone
resorption, known as "cement lines. "

Histologically, osteopetrosis is characterized by the persistence of primary,

unmineralized spongiosa in the medullary canals. In normal individuals, the
primary spongiosa is normally replaced by the bone marrow.

Educational Objective:
The histological hallmark of rickets is an increase in unmineralized osteoid matrix
and widened osteoid seams. Clinically, there are many notable features, including
bowed legs, a rachitic rosary, Harrison's sulci, craniotabes, and growth
retardation.
 Osteoporosis
Osteoporosis is defined as bone density 2.5 standard deviations below the mean
bone mineral density for young adult women based on bone density
measurement using dual x-ray absorptiometry.
Osteoporosis is predominantly a disease of postmenopausal, white females.
White females have lower bone mass compared to black females. After
menopause, declining estrogen levels accelerate the loss of bone mass mainly
through a decrease in osteoblastic activity and an increase in osteoclastic activity.
The two major types of bone present in an adult skeleton are trabecular and
cortical.
Trabecular bones are also called spongy, or cancellous bones. Trabecular bone
composes only 15% of the total skeleton, by weight, but trabecular bone is
metabolically more active because of its large surface area.
Cortical bones (long bones) contribute by serving as mechanical support and sites
of muscle attachment. Most of the appendicular skeleton (the limbs) is cortical
bone.
Osteoporosis primarily involves trabecular, or spongy, bone. The most prominent
changes in osteoporosis occur in dorsolumbar vertebral bodies, as vertebrae are
predominantly Trabecular. The neck of the femur consists of 50% of trabecular
and 50% of cortical bone, Osteoporotic fractures are most common at vertebral
bodies and second most common at the neck of the femur.

Trabecular thinning with fewer interconnections, this finding is seen with

osteoporosis. In osteoporosis, total bone mass is decreased, along with disruption
of normal bone architecture.

In primary osteoporosis (ie, osteoporosis that is not due to an underlying medical

disorder), serum calcium, phosphorus, and parathyroid hormone (PTH) levels are
typically, in the normal range.
Pathologic fracture, defined as a fracture due to a force significantly less than that
required to fracture a normal bone. A pathologic fracture suggests the presence of
underlying bone pathology, often due to metastatic malignancy or intrinsic bone
disease.
Chronic or recurrent glucocorticoid use, as in patients with rheumatoid arthritis
(RA), is associated with osteoporosis. Glucocorticoids promote osteoporosis by
increasing osteoclast differentiation and activity, decreasing osteoblast activity and
synthesis of bone matrix, inhibiting the intestinal action of vitamin D in promoting
calcium absorption, and increasing parathyroid hormone levels, Patients taking
prednisone daily for 6 months can develop osteoporotic bone changes, and of
patients on prolonged systemic glucocorticoids may develop
pathologic vertebral body fractures. Osteoporosis can also occur due to systemic
absorption of topical glucocorticoids, such as inhaled glucocorticoids used in the
treatment of asthma.