most common defect causing this disorder is a
deficiency of 21-hydroxylase, an adrenal enzyme
that is involved in the biosynthesis of cortisol and
aldosterone. The production of cortisol would be
impaired as a result of such a defect were it not for
the fact that the plasma concentrations of cortisol are
homeostatically regulated. By maintaining a high
plasma concentration of corticotropin, and thereby
producing a generalized increase in adrenal biosyn-
thetic function, the body is able to overcome mild to
moderate forms of 21-hydroxylase deficiency.
Severe forms of 21-hydroxylase deficiency, on the
other hand, cannot be overcome; they present in the
newborn period with life-threatening salt wasting
due to aldosterone deficiency.
The combination of 21-hydroxylase deficiency
coupled with the corticotropin-driven hyperfunction
of adrenal biosynthesis results in increased plasma
concentrations of many intermediate substances in
the steroid biosynthetic pathway. The most pro-
nounced elevations are in 17-hydroxyprogesterone,
the substrate for 21-hydroxylase in the pathway to
cortisol. In moderate and severe forms of 21-hy-
droxylase deficiency, the plasma concentration of
17-hydroxyprogesterone is markedly increased in the
basal state. In mild forms, the basal plasma concen-
trations of 17-hydroxyprogesterone are less distinctly
elevated and the diagnosis necessitates the use of a
corticotropin stimulation test (Azziz
et al.
1994).
There are also increased plasma concentrations
of the alternative end products, androstenedione and
testosterone, that arise from the peripheral biotrans-
formation of 17-hydroxyprogesterone. It is the
increased concentrations of these androgens that
cause the clinical findings of virilization in newborn
females with severe forms of the deficiency and
oligomenorrhea and hirsutism in females with mild
and moderate forms of the deficiency.
Genetic disorders of plasma proteins
The plasma proteins serve various specialized
functions in the extracellular fluids. A genetic disor-
der involving one of these proteins usually presents
as an impairment in the function served by the
protein. The coagulation proteins provide excellent
examples of the derangement of function that results
from genetic disorders of a plasma protein. If there
is a functional deficiency of a procoagulant protein,
such as factor VIII, the patient will suffer from a
bleeding diathesis. If the patient has a functional
deficiency of an anticoagulant protein, such as
antithrombin III, he or she will have a clotting
tendency. The usual diagnostic approach to a
suspected plasma protein deficiency consists of the
Genetic Disease
10-8
Table 10.5
Substance Accumulation in Genetic Disorders of Metabolism
Defect
Substance
Accumulation
Example
Intracellular Systemic
Anabolic tissue
1.
↓
uptake
precursor
x
familial hypercholesterolemia
2.
↓
metabolism precursor
x
x
galactosemia
3.
↓
metabolism intermediates
with reflux
x
x
alkaptonuria
without reflux
x
glycogen storage disease
4.
↓
metabolism end products
with reflux
x
x
mucopolysaccharidosis
without reflux
x
lysosomal storage disease
Catabolic tissue
5.
↓
uptake
end products
x
dysbetalipoproteinemia
6.
↓
metabolism end product
x
x
Gilbert’s hereditary jaundice
7.
↓
input into
catabolites
x
x
Dubin-Johnson hereditary jaundice
excretory path
Excretory tissue
8.
↓
excretion
catabolites
x
x
renal tubular acidosis
