Page 824 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 51

CONGENITAL DISORDERS OF LYMPHOCYTE FUNCTION

Sung-Yun Pai and Luigi D. Notarangelo

Over 200 molecular defects that result in primary immune defi- patients with partial DGS who have good cellular immunity (with
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ciency are known to date. Many of these gene defects have been CD8 count >300 cells/µL); however, these vaccines are contraindi-
identified in recent years with the advent of whole-exome and whole- cated in patients with complete DGS. Use of immunosuppressive
genome sequencing. The study of patients with primary immune drugs is indicated in patients with complete atypical form of the
deficiencies has unraveled fundamental mechanisms that govern disease.
lymphocyte development and function. Importantly, characterization Ultimately, survival in patients with complete DGS requires
of the molecular basis of these diseases has revealed unanticipated immune reconstitution. Bone marrow transplantation from human
heterogeneity of the clinical and immunological phenotype. This leukocyte antigen (HLA)-identical donors may allow engraftment
chapter reviews disorders of thymus organogenesis, severe combined of mature T cells contained in the graft. However, because of the
immune deficiency (SCID), other combined immunodeficiencies, absence of thymic tissue, no newly developed T cells are generated,
disorders with immune dysregulation, and defects of humoral and the patient may remain susceptible to pathogens that are not
immunity. recognized by donor-derived T cells contained in the graft.
By contrast, thymic transplantation represents the treatment
of choice for patients with complete DGS, including the atypical
DEFECTS OF THYMUS ORGANOGENESIS variant. The thymus obtained as discarded tissue from unrelated
infants undergoing heart surgery is sliced and cultured in vitro,
The thymus is the primary organ where T lymphocytes are generated then implanted in the quadriceps muscles of the infant. Using this
and educated. Endoderm-derived thymic stem cells derived from the approach, 36 out of 50 infants with complete DGS treated by Dr.
third pharyngeal pouch differentiate into cortical and medullary epi- Markert at Duke University were reported to survive. In most cases,
thelial cells, which in turn induce the differentiation of hematopoietic naive T cells appear at around 4–7 months of age; these cells are
precursors into T cells. Thus, defects of thymus organogenesis have tolerant to donor thymic cells, display a polyclonal repertoire, and
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important consequences on immune function. have normal proliferative capacity. Although the number of CD3
T cells in transplanted patients often remains lower than normal,
their diversity and function is sufficient to prevent life-threatening
DiGeorge Syndrome infections.
DiGeorge syndrome (DGS) is caused by developmental anomalies
of the third and fourth pharyngeal pouches, and is characterized FOXN1 Deficiency
by thymic hypoplasia, hypoparathyroidism, conotruncal heart
malformation (especially interrupted aortic arch type B or truncus The transcription factor FOXN1 (whose gene is mutated in the nude
arteriosus), and facial dysmorphisms (micrognathia, hypertelorism, mouse) plays a critical role in thymus and eccrine glands develop-
antimongoloid slant of the eyes, cleft palate, and ear malformations). ment. FOXN1 mutations in humans cause athymia, profound T-cell
Hypocalcemic seizures are common. Feeding problems, microcephaly, lymphopenia, alopecia totalis, and nail dystrophy. Similar to DGS,
speech delay, neurobehavioral problems (including bipolar disorders, reconstitution of T-cell immunity can be achieved with thymic
autistic spectrum disorders, and schizophrenia later in life), and transplantation.
scoliosis are frequently observed.
Between 50% and 90% of patients with DGS carry a hemizygous
deletion of chromosome 22q11, which occurs in ~1:3000 newborns, CHARGE Syndrome
most arising de novo. Fluorescent in situ hybridization readily identi-
fies the 22q11del in most cases. More rarely, DGS is associated with This syndrome is characterized by the association of coloboma,
CHARGE syndrome, chromosome 10p deletion, or with mutations heart anomalies, choanal atresia, mental retardation, genital and
of the TBX1 gene, contained within the 22q11 interval. ear anomalies, and immunodeficiency. Most cases are sporadic, and
Most patients have “partial DGS”, manifested by mild T-cell represent de novo mutations of the CHD7 or of the SEMA3E genes;
lymphopenia and immunodeficiency. Such patients may be asymp- less frequently, the disease is inherited as an autosomal dominant
tomatic, may have oral thrush and recurrent infections, or may trait. The immunodeficiency is secondary to defects of thymic devel-
develop autoimmune disease such as juvenile idiopathic arthritis, opment. There is a variable degree of T-cell lymphopenia, which in
immune thrombocytopenic purpura, and Raynaud phenomenon. some cases is very severe, resembling SCID.
Approximately 1% of DGS patients have “complete DGS”, with
absence of circulating T cells. Some DGS patients may develop low
numbers of oligoclonal T lymphocytes that undergo activation in SEVERE COMBINED IMMUNE DEFICIENCY DUE TO
vivo and infiltrate target tissues, causing skin rash, liver dysfunction, EARLY DEFECTS IN T LYMPHOCYTE DEVELOPMENT
and lymphadenopathy. This condition is known as complete atypical
DGS. SCID, the most severe form of congenital immunodeficiency, is
Treatment of DGS includes correction of severe heart defects, and caused by defects that completely abrogate the development of T
supplementation with calcium and vitamin D for hypocalcemia. If a lymphocytes, and in some cases also that of B and/or natural killer
significant immune defect is present, prophylaxis of Pneumocystis jir- (NK) lymphocytes. Advances in the genes responsible, newborn
oveci pneumonia with trimethoprim-sulfamethoxazole (TMP-SMZ) screening, and gene therapy have had a strong impact on diagnosis
is indicated. Live-attenuated vaccines can be safely administered to and therapy of SCID.

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