In all patients with SCID, the thymus is severely hypoplastic, with a lack
of corticomedullary distinction and thymocytes. Hassall corpuscles are
either abortive or absent. Symptoms pointing to the diagnosis include
recurrent and/or opportunistic infections with candida (oral candidiasis),
respiratory syncytial virus, adenovirus, parainfluenza virus,
cytomegalovirus, or pneumonia secondary to Pneumocystis carinii. Bacterial pneumonia,
Gram-negative sepsis, and persistent diarrhea with failure to thrive are
common and often the cause of death. Behavioral and neurologic problems
(with severity proportional to dATP levels) are common in ADAD patients and
may include hyperactivity/attention deficit disorders, aggressivity,
sensorineural hearing loss, seizures, spasticity, athetosis, head lag,
tremor, nystagmus, and decreased cognitive function and IQ. Renal problems
have been reported in a number of patients and include proteinuria and
transient proximal renal tubular acidosis. The kidneys often are enlarged,
and histologic examination reveals mesangial sclerosis with thickening of
the subendothelial layer of capillary walls, particularly in the
juxtamesangial region. Some degree of (most likely progressive)
glomerulosclerosis may be seen. Adenosine, which is elevated in ADAD, has
significant effects on arteriolar resistance and renin secretion. Fibrosis
of the adrenal cortex (especially in the subcapsular region) and the
pituitary gland is a common finding. Adrenal insufficiency with a high risk
of hypoglycemia, hyponatremia, and hypokalemia has been reported.
Hypocalcemia is common. Osseous anomalies are characterized by prominent
costochondral junctions, and microscopic examination shows chondroosseous
dysplasia with disordered chondrocyte columns, hypertrophic chondrocytes in
resting cartilage, ballooned lacunae, and abrupt transition of cartilage to
bone. The skin often is edematous and appears hyperpigmented. Pulmonary
alveolar proteinosis has been found in a few patients. Transfusion of normal
erythrocytes leads to a temporary decrease in the serum adenosine
concentration and an increase in lymphocyte count; however, retransfusions
are required every few weeks to maintain ADA activity above a certain level.
Covalent binding of modified bovine intestinal ADA to polyethylene glycol
(polyethylene glycol-modified adenosine deaminase [PEG-ADA]) has been used
successfully to partially correct the enzyme defect and thereby allow immune
function to recover to a degree at least sufficient to prevent opportunistic
infections. The risks and side effects are lower than with bone marrow
transplantation; however, the costs reportedly are excessive. Gene therapy
with viral vectors has been used with some success in a number of patients.
Hemosiderosis with marked iron depositions in hepatocytes, Kupffer cells,
and spleen is seen after chronic transfusions. The most prominent ADAD
patient probably was the “Bubble Boy,” a boy who lived in a germ-proof
plastic enclosure to prevent infections until he died at age 12 years.