Page 450 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 29 Inherited Bone Marrow Failure Syndromes 371

thrombopoietin receptor is nonfunctional. Nevertheless, thrombo- and micrognathia. This is a rare disorder, and incidence rates for
poietin agonists that bind to the transmembrane domain might prove complications are difficult to establish; however, there appears to be
efficacious, similar to the in vitro effect of LGD-4665 on cells carry- a predilection to develop cancer as well as hematopoietic disorders in
ing the F104S MPL mutation. LGD-4665 binds to the transmem- children with Dubowitz syndrome. Patients have developed acute
brane domain of the MPL receptor. Initial application of such a leukemia, neuroblastoma, and lymphoma. Approximately 10% of
strategy should be assessed as part of clinical trials because of a patients also develop hematologic abnormalities varying from hypo-
potential risk of developing hematologic malignancies. plastic anemia to moderate pancytopenia and full-blown aplastic
CAMT can be cured by HSCT. Most of the recent published cases anemia. A homozygous splice-site mutation in the NSUN2 gene has
have had successful outcomes. Matched sibling donor sources are been identified in one family. The gene encodes a conserved RNA
ideal even if the donor is a carrier with one mutant allele. Reduced- methyltransferase. Patient cells lack expression of the protein.
intensity conditioning regimens for CAMT have been successfully
used in both related and unrelated donor setting. Such an approach
was successful even in a case with monosomy 7 from the CIMFR Seckel Syndrome
who received BM from an unrelated donor. HSCT using T cell–
+
depleted BM with relatively high CD34 cell numbers and enhanced Sometimes called bird-headed dwarfism, patients with this autosomal
T cell–specific immunosuppression in the transplant cytoreductive recessive developmental disorder have marked intrauterine and
regimens that have also been successful. postnatal growth failure, mental deficiency, severe microcephaly, a
hypoplastic face with a receding forehead and chin, a prominent
curved nose, and low-set or malformed ears. Some patients may show
Future Directions increased chromosomal breakage in lymphocyte cultures with DEB
or MMC and mimic FA. About 25% of patients develop aplastic
Novel therapy that can activate the mutated thrombopoietin receptor anemia or malignancies. There are possibly five genes linked to Seckel
may be suitable for some patients with CAMT. Alternatively, drugs syndrome, all in different cytogenetic locations. There are several
that stimulate downstream targets of the receptor might be effective. genes that have been linked to Seckel syndrome: mutant ATR has
The cellular consequences of specific gene mutations need to be been associated with Seckel Type 1, RBBP8 with Type 2, CENPJ with
further studied because this might help to develop novel strategies in Type 4, CEP152 with Type 5, CEP63 with Type 6, and ATRIP with
patients who do not respond to such therapies. CAMT is also a Type 8. The abnormal gene for Seckel 3 has been mapped to 14q21-
candidate disease for gene therapy because restoration of wild-type q22. Genotyping will distinguish FA from Seckel syndrome.
MPL would provide in vivo selection of corrected HSCs.

Reticular Dysgenesis
Other Inherited Syndromes With
Associated Pancytopenia Reticular dysgenesis is a combined immunodeficiency and BM failure
disorder. It is characterized by severe lymphopenia and agranulocy-
Bone marrow failure and cancer predisposition can occur as part of tosis. Anemia, thrombocytopenia and aplastic anemia may be evident.
several specific other inherited syndromes and in familial settings that Immunologically, the disorder is a variant of severe combined immune
do not exactly correspond with the entities already described. deficiency in which cellular and humoral immunity are absent. A
striking feature is absent lymph nodes and tonsils and an absent
thymic shadow on radiographs. Because of profoundly compromised
Down Syndrome immunity, the syndrome presents early with severe infection at birth
or shortly thereafter. BM specimens are hypocellular with markedly
Down syndrome, or constitutional trisomy 21 (+21), has a unique reduced myeloid and lymphoid elements. Clonogenic assays of
association with aberrant hematologic abnormalities. Four related hematopoietic progenitors consistently show reduced to absent
events can occur. In the neonatal period, a transient myeloproliferative colony growth, indicating that the disorder has its origins at the HSC
disorder with large numbers of circulating blast cells has been observed level. The mode of inheritance is autosomal recessive caused by bial-
in approximately 10% of these infants. The blasts show somatic lelic mutations in mitochondrial AK2. The only curative therapy is
GATA1 mutations and apparently are clonal but, remarkably, disap- HSCT.
pear spontaneously over several weeks in most cases.
Second, in 20% to 30% of these transient cases, true acute mega-
karyoblastic leukemia (AMKL), also with GATA1 mutations, appears Schimke Immunoosseous Dysplasia
later and requires treatment. Acute lymphoblastic and myeloblastic
leukemias are also seen in Down syndrome, but AMKL is the most Schimke immunoosseous dysplasia is an autosomal recessive disorder
common form of myeloblastic leukemia and is estimated to be 500 caused by mutations in the chromatin remodeling gene SMARCAL1
times greater in children with trisomy 21 than in other children. in 50% to 60% of patients. Patients manifest spondyloepiphyseal
Third, the onset of AMKL is frequently preceded by an interval dysplasia with exaggerated lumbar lordosis and a protruding
of MDS characterized by thrombocytopenia; abnormal megakaryo- abdomen. They have pigmentary skin changes and abnormally dis-
cytopoiesis; megakaryoblasts in the BM; and an abnormal karyotype, colored and configured teeth. Renal dysfunction can be problematic
commonly trisomy 8 or monosomy 7. with proteinuria and nephrotic syndrome. Approximately 50% of
Fourth, a few patients have been reported with aplastic anemia. patients have hypothyroidism and 50% have cerebral ischemia; 50%
Of six trisomy 21 with aplastic anemia cases that we identified in the have anemia, 50% have neutropenia, 30% have thrombocytopenia,
literature, three died of BM failure, two responded to androgen and 10% have aplastic anemia. Lymphopenia and altered cellular
therapy, and one underwent HSCT. immunity are present in 80% of patients. Hematopoietic stem cell
transplantation has been applied in five cases with severe BM failure/
immunodeficiency; one of them survived.
Dubowitz Syndrome

This is an autosomal recessive disorder characterized by a peculiar Noonan Syndrome
facies, infantile eczema, small stature, and mild microcephaly. The
face is small with a shallow supraorbital ridge, a nasal bridge at the Noonan syndrome (NS) is a developmental disorder characterized by
same level as the forehead, short palpebral fissures, variable ptosis, the Noonan facies (hypertelorism, ptosis, short neck, low-set ears),