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390 Part IV Disorders of Hematopoietic Cell Development

and improvement of warts in combination with imiquimod. Immu- The translocase transports glucose-6-phosphate into the lumen of
noglobulin levels and specific antibody response were not fully the endoplasmic reticulum, where it is hydrolyzed into glucose and
corrected. inorganic phosphate. Absence of translocase results in an inability to
liberate glucose from glucose-6-phosphate. Consequently, patients
with GSD-1b are susceptible to fasting hypoglycemia, lactic acidosis,
G6PC3-Associated SCN (Dursun Syndrome) hepatomegaly, poor linear growth, delayed pubertal development,
and other systemic complications.
This syndrome is an autosomal recessive form of SCN caused by Most patients have neutropenia, which ranges from mild to severe.
biallelic mutant G6PC3. Wild-type G6PC3 encodes glucose-6- A strict correlation between genotype and the degree of neutrope-
phosphatase catalytic subunit 3, which, when mutated, confers an nia has not been established. Some studies reported hypocellular
increased susceptibility of neutrophils to apoptosis. BM samples BM; however, BM testing on nine patients from the City of Hope
morphology varied among the reported patients, but included mild National Medical Center in 2001 before G-CSF therapy revealed
to moderate decrease in mature neutrophils, normal appearing normal to hypercellularity in all patients. Maturation arrest at the
BM or promyelocyte-myelocyte maturation arrest. Neutropenia is myelocyte stage or later is a feature. Neutrophil apoptosis appears to
usually severe, rendering patients susceptible to severe bacterial be a central mechanism leading to granulopoietic failure. Neutrophil
infections. Lymphopenia and thrombocytopenia may occur. Struc- dysfunction with defective chemotaxis and an impaired respiratory
tural heart defects, urogenital abnormalities, venous angiectasia on burst is an additional feature. Patients are consequently susceptible
the trunk and extremities, intellectual disability, inflammatory to recurrent infections and to inflammatory bowel disease. Infections
bowel disease, and a broad range of other physical abnormalities are most commonly involve the skin, perirectal area, ears, and urinary
additional features. One reported patient developed MDS and sub- tract, but septicemia, pneumonia, and meningitis may also occur.
sequently AML. The most frequently isolated organisms include Staphylococcus aureus,
group A streptococci, Streptococcus pneumoniae, Escherichia coli, and
Pseudomonas.
Barth Syndrome G-CSF therapy is extremely effective in almost all GSD-1b
patients. BM cellularity increases, the ANCs increase exuberantly,
Barth syndrome is a rare multisystem metabolic disorder inherited and impaired oxygen radical formation is corrected. AML while on
in an X-linked recessive mode. It is the first human disease in which G-CSF is a rare event. Prospective data on GSD-1b patients receiving
the primary causative factor is an alteration of cardiolipin remodeling. G-CSF therapy from the SCNIR identified 40% with splenomegaly
Cardiolipin is a component of the inner mitochondrial membrane before starting G-CSF, 81% with splenomegaly by the first year of
necessary for proper functioning of the electron transport chain. treatment, and 100% with splenomegaly by 3 years. Hypersplenism
The findings in typical cases are mild to severe neutropenia, can occur but can be overcome by reducing the G-CSF dosage or
dilated or hypertrophic cardiomyopathy, underdeveloped skeletal by splenectomy. Histology of the surgically excised spleens shows
musculature and muscle weakness, exercise intolerance, growth delay, extramedullary hematopoiesis.
cardiolipin abnormalities, and 3-methylglutaconic aciduria. ANCs
are variable, but total agranulocytosis has been reported. BM mor-
phology includes a maturation arrest at the myelocyte stage. On Other Inherited Neutropenias
electron microscopy, mitochondria show concentric, tightly packed
cristae and occasional inclusion bodies in various tissues, including Other inherited neutropenia disorders are associated with specific
granulocyte precursors. Clinically, the cardiomyopathy dominates the mutant genes, but they do not necessarily have the K/SCN BM
clinical picture, but gingivitis, oral problems, and bacterial sepsis phenotype, nor is their pathophysiology necessarily similar (see Table
from neutropenia can be problematic. Most patients do not need 29.8). Immune deficiency appears to be an important component
treatment with G-CSF. Anecdotal reports and the authors’ experience of these syndromes. These miscellaneous forms tend to have distin-
(Y. Dror, unpublished data) suggest that G-CSF is highly effective in guishing physical abnormalities such as partial albinism and are not
correcting the neutropenia and preventing infections. The myriad predisposed to MDS/AML.
clinical problems requires a multidisciplinary approach. Female car-
riers are healthy and hematologically normal, likely because of INHERITED BONE MARROW FAILURE SYNDROMES
extreme skewing of X-inactivation. The initial impression that Barth
syndrome was a lethal infantile disease has been modified; age distri- WITH PREDOMINANTLY THROMBOCYTOPENIA
bution in 54 living patients ranges from 0 to 49 years and peaks
around puberty. Thrombocytopenia With Absent Radii Syndrome
The Barth syndrome gene was mapped to Xq28, which led
to the cloning of the TAZ gene and the various mutations that Background
account for the phenotype. TAZ produces several different mRNAs
with resultant proteins called tafazzins. Mutations in TAZ result Thrombocytopenia absent radii syndrome has two essential features,
in a decrease in tetralinoleoyl species of cardiolipin and an accu- hypomegakaryocytic thrombocytopenia and bilateral radial aplasia
mulation of monolysocardiolipin within cells. A murine model of with thumbs present. It is one of a group of IBMFSs that includes
Barth syndrome has been developed. Knocked-down cellular models FA, DBA, and radioulnar synostosis with radial ray anomalies.
and patient BM cells are characterized by accelerated cell death. The manifestations of the phenotype vary widely, and patients can
However, a recently proposed mechanism for the neutropenia present with abnormalities involving skeletal, skin, gastrointestinal,
involves exposure of cell surface phosphatidylserine because of brain, renal, and cardiac systems. The identification of biallelic
ROS, and consequently increased clearance of neutrophils by tissue mutations in RBM8A in patients with TAR syndrome determined
macrophages. the autosomal recessive inheritance of this disorder. Almost always,
parents of patients with TAR are phenotypically normal. Women
with TAR syndrome can conceive and give birth to hematologically
Glycogen Storage Disease Type 1b and phenotypically normal offspring. Three cases of AML and one
case of acute lymphoid (lymphoidic) leukemia in TAR syndrome
Glycogen storage disease type 1b is caused by a deficiency in patients have been reported. Using a denominator of about 300
glucose-6-phosphate translocase (transporter) because of mutant published cases of TAR, four leukemic episodes (1–2% crude
G6PT1 (SLC37A4). GSD-1b patients experience disturbed glucose rate) suggests a predisposition to the development of hematologic
homeostasis and quantitative or qualitative neutrophil abnormalities. malignancies.