The Questions of Developmental Biology

Mutations in FGFR1 can cause Pfeiffer syndrome, characterized by limb defects and
premature fusion of the cranial sutures (craniosynostosis), resulting in abnormal skull and facial
shape. Different mutations in FGFR2 can give rise to various abnormalities of the limbs and face
(Park et al. 1995; Wilkie et al. 1995).
Insulin-like Growth Factors
The epiphyseal growth plate cells are very responsive to hormones, and their proliferation
is stimulated by growth hormone and insulin-like growth factors. Nilsson and colleagues (1986)
showed that growth hormone stimulates the production of insulin-like growth factor I (IGF-I) in
the epiphyseal chondrocytes, and that these chondrocytes respond to it by proliferating. When
they added growth hormone to the tibial growth plates of young mice who could not manufacture
their own growth hormone (because their pituitaries had been removed), it stimulated the
formation of IGF-I in the chondrocytes of the proliferative zone (see Figure 14.16). The
combination of growth hormone and IGF-I appears to provide an extremely strong mitotic signal.
It appears that IGF-I is essential for the normal growth spurt at puberty. The pygmies of the Ituri
Forest of Zaire have normal growth hormone and IGF-I levels until puberty. However, at puberty,
their IGF-I levels fall to about one-third that of other adolescents (Merimee et al. 1987).
Estrogen Receptors
The pubertal growth spurt and the subsequent cessation of growth are induced by sex
hormones (Kaplan and Grumbach 1990). At the end of puberty, high levels of estrogen or
testosterone cause the remaining epiphyseal plate cartilage to undergo hypertrophy. These
cartilage cells grow, die, and are replaced by bone. Without any further cartilage formation,
growth of these bones ceases, a process known as growth plate closure.
In conditions of precocious puberty, there is an initial growth spurt (making the
individual taller than his or her peers), followed by the cessation of epiphyseal cell division
(allowing that person's peers to catch up and surpass his or her height). In males, it was not
thought that estrogen played any role in these events. However, in 1994, Smith and colleagues
published the case history of a man whose growth was still linear despite his undergoing a normal
puberty. His epiphyseal plates had not matured, and he still had proliferating chondrocytes at 28
years of age. His "bone age" the amount of ephiphyseal cartilage he retained was roughly half
his chronological age. This person was found to lack any functional estrogen receptor. At present,
at least three human males have been reported who either cannot make estrogens or who lack the
estrogen receptor. All three are close to 7 feet tall and are still growing (Sharpe 1997). Therefore,
estrogen plays a role in epiphyseal maturation in males as well as in females.
Thyroid hormone and parathyroid-related hormone are also important in regulating the
maturation and hypertrophy program of the epiphyseal growth plate (Ballock and Reddi 1994).
Thus, children with hypothyroidism are prone to developing growth plate disorders.
Extracellular Matrix Proteins
The extracellular matrix of the cartilage is also critical for the proper differentiation and
organization of growth plate chondrocytes. Mutations that affect type XI collagen or the sulfation
of cartilage proteoglycans can cause severe skeletal abnormalities. Mice with deficiencies of type
XI collagen die at birth with abnormalities of limb, mandible, rib, and tracheal cartilage (Li et al.
1995). Failure to add sulfate groups to cartilage proteoglycans causes diastrophic dysplasia, a
human dwarfism characterized by severe curvature of the spine, clubfoot, and deformed earlobes
(Hästbacka et al. 1994).