DiGEORGE ANOMALY (Congenital Thymic Aplasia, Immunodeficiency

With Hypoparathyroidism, Third & Fourth Pouch/Arch Syndrome)

Major Immunologic Features

 Congenital aplasia or hypoplasia of the thymus and parathyroid glands.

 Hypocalcemia.
 Variable degree of T-cell deficiency.
 Immunoglobulin levels and antibody function usually normal.
 Characteristic facial abnormalities.
 Congenital heart disease common.

General Considerations
DiGeorge anomaly is one of the few immunodeficiency disorders with symptoms
immediately following birth. The complete syndrome consists of the following
features: (1) abnormal faces consisting of low-set ears, “fish-shaped―
mouth, hypertelorism, notched ear pinnae, micrognathia, and an antimongoloid
slant of eyes (Figure 22-1); (2) hypoparathyroidism with hypocalcemia; (3)
congenital heart disease; and (4) cellular immunodeficiency. Initial symptoms are
related to associated abnormalities of the parathyroids and heart and may result in
hypocalcemia and congestive heart failure, respectively. If the diagnosis of
DiGeorge anomaly is suspected because of these early clinical findings,
confirmation may be obtained by demonstrating decreased numbers of T cells and
a 22 q11 chromosomal deletion.
Immunologic Pathogenesis
During weeks 6–8 of intrauterine life, the thymus and parathyroid glands
develop from epithelial evaginations of the third and fourth pharyngeal pouches
(Figure 22-2). The thymus begins to migrate caudally during week 12 of
gestation. At the same time, the philtrum of the lip and the ear tubercle become
differentiated along with other aortic arch structures. It is likely that DiGeorge
anomaly is the result of interference with normal embryologic development at
approximately 12 weeks of gestation. In some patients,
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the thymus is not absent but is in an abnormal location or is extremely small,

though the histologic appearance is normal. It is possible that such patients have
“partial― DiGeorge anomaly, in which hypertrophy of the thymus may take
place with subsequent development of normal immunity.

Genetic Pathogenesis
Up to 90% of patients with DiGeorge anomaly have a hemizygous deletion of
22q11, a region termed the DGCR (DiGeorge critical region) that can be readily
detected by fluorescent in situ hybridization (FISH) using probes for this region
and an undeleted chromosome 22 region near this locus. Patients have similar
cardiac defects and the Spritzen (velocardiofacial) syndrome have a similar
deletion. This deleted region includes a DiGeorge candidate gene termed Ufd1
(ubiquitin fusion degradation) that encodes for a transcription factor regulating
cell death in the neural crest, branchial arches, the heart, and the thymus. One or
the other parent of a few patients with the DiGeorge anomaly may also carry the
deletion, and then the disorder is inherited in an autosomal-dominant fashion.
Maternal alcoholism may be a risk factor in some patients with the DiGeorge
anomaly.
Clinical Features
A. Symptoms and Signs:
The most frequent presenting sign in patients with DiGeorge anomaly occurs in
the first 24 hours of life with hypocalcemia
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that is resistant to standard therapy. Various types of congenital heart disease have
been described, including interrupted aortic arch, septal defects, patent ductus
arteriosus, and truncus arteriosus. Renal abnormalities may also be present. Most
patients have the characteristic facial appearance described earlier. Patients who
survive the immediate neonatal period may then develop recurrent or chronic
infection with various viral, bacterial, fungal, or protozoal organisms. Pneumonia,
chronic infection of the mucous membranes with Candida, diarrhea, and failure to
thrive may be present.

Spontaneous improvement of T-cell immunity often occurs, particularly when

initial T cell counts are low but not absent. These patients are considered to have
“partial― DiGeorge anomaly, but the reason for the spontaneous
improvement in T-cell immunity is unknown. Patients should also be suspected of
having DiGeorge anomaly on the basis of hypocalcemia and congenital heart
disease with or without the abnormal facies or T-cell defects. Some of these
patients develop severe T-cell deficiency.
B. Laboratory Findings:
T-cell immunity can be evaluated immediately after birth in a patient suspected of
having DiGeorge anomaly. The lymphocyte count is usually low (<1500/µL)
but may be normal or elevated. A chest x-ray film of the anterior mediastinum
may reveal absence of the thymic shadow, indicating failure of normal
development. Delayed hypersensitivity skin tests to recall antigens are of little
value during early infancy, because sufficient time has not elapsed for
sensitization to occur. T cells are markedly diminished in number, and the
peripheral blood lymphocytes fail to respond to phytohemagglutinin (PHA) or
allogeneic cells.
Immunoglobulin evaluation is not useful because of passive maternal
immunoglobulin. Most DiGeorge patients can produce adequate specific antibody
responses. Sequential studies of both T-cell and B-cell immunity are necessary
because either improvement or deterioration of immunity can occur
spontaneously.
Hypoparathyroidism is diagnosed by low serum calcium, elevated serum
phosphorus, and an absence of parathyroid hormone. Congenital heart disease
may be diagnosed immediately following birth and may be mild or severe. Other
congenital abnormalities include esophageal atresia, bifid uvula, and urinary tract
abnormalities.
Immunologic Diagnosis
T-cell immunity may be markedly depressed, as indicated by lymphocytopenia,
depressed numbers of circulating T cells, and diminished proliferative responses
to PHA and allogeneic cells. Normal T-cell immunity may develop with time,
particularly if the initial CD4 cell count exceeds 400 cells/µL and there is some
proliferative response to mitogens.
Many patients with DiGeorge anomaly have normal B-cell immunity as indicated
by normal levels of immunoglobulins and a normal antibody response following
immunization. Others, however, have low immunoglobulin levels and fail to make
specific antibody following immunization. Live attenuated viral vaccines should
not be used for immunization in these patients. Natural killer (NK) cell activity is
normal.
Differential Diagnosis
Infants with severe congenital heart disease and subsequent congestive heart
failure who develop transient hypocalcemia should be suspected of having
DiGeorge anomaly. When the characteristic facial features are found, suspicion
should be even stronger. Studies of T-cell immunity usually establish a diagnosis,
except in infants with DiGeorge anomaly who have effective T-cell immunity. It
is essential that all infants with congenital heart disease and hypocalcemia be
monitored until they are at least 1 year old.
The hypocalcemia associated with DiGeorge anomaly is usually permanent, in
contrast to that seen in congenital heart disease with congestive heart failure.
Parathyroid hormone levels are low to absent, and the patients are resistant to the
standard treatment for hypocalcemia. Low parathyroid hormone levels may also
be found in transient hypocalcemia in infancy.
Immunologic studies in DiGeorge anomaly and in severe combined
immunodeficiency disease may be identical in the newborn period. Patients with
the fetal alcohol syndrome may have facial and cardiac abnormalities similar to
those in patients with DiGeorge anomaly, as well as recurrent infections
associated with decreased T-cell immunity.
Treatment
Patients with T-cell deficiency should receive Pneumocystis carinii prophylaxis.
General care includes management of hypocalcemia and correction of cardiac
abnormalities. The hypocalcemia is controlled by calcium supplementation orally
in conjunction with vitamin D or parathyroid hormone. Congenital heart disease
frequently results in congestive heart failure and may require immediate surgical
correction. If surgery is performed prior to the availability of a fetal thymus or
bone marrow transplantation, blood transfusion products should be irradiated with
3000 R to prevent a graft-versus-host (GVH) reaction.
Transplantation of fetal thymus, postnatal thymus, and HLA-matched bone
marrow have all been used for permanent reconstitution of T cell immunity. No
attempts at immunologic reconstitution are warranted if T-cell immunity is
normal. Most patients undergo spontaneous resolution of the T-cell
immunodeficiency. Intravenous immunoglobulin therapy should be used if
antibody deficiency exists and to control recurrent infection.
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Complications & Prognosis

Prolonged survival has been reported following successful thymus transplantation
or spontaneous remission of immunodeficiency. Sudden death may occur in
untreated patients or in patients initially found to have normal T-cell immunity.
Congenital heart disease may be severe, and the infant may not survive surgical
correction. Death from GVH disease following blood transfusions has been
observed in patients in whom a diagnosis of DiGeorge anomaly was not
suspected. Most patients who survive long term have minimal heart disease.