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372 Part IV Disorders of Hematopoietic Cell Development

short stature, congenital heart disease, and multiple skeletal and
hematologic abnormalities. The literature describes several NS Unclassified Inherited Forms of Bone
patients who developed amegakaryocytic thrombocytopenia and Marrow Failure
another who developed pancytopenia and a hypocellular BM. NS is
an autosomal dominant disorder with genetic heterogeneity. So far, Bone marrow failure can cluster in families, but many of these cases
heterozygous germline mutations in one of 14 genes (PTPN11, cannot be readily classified into discrete diagnostic entities such as
SOS1, KRAS, NRAS, RAF1, BRAF, SHOC2, MEK1, CBL, RASA2, FA, SDS, or DC. In other cases, the patients manifest chronic BM
RIT1, MAP2K1, SOS2, and LZTR1) underlie the disorder in 75% shortly after birth or have physical malformations and most likely
of cases. These genes encode for proteins in the RAS-mitogen–acti- also have IBMFSs. The phenotype of these unclassified cases can
vated protein kinases signal transduction pathway. A variant of be complex with varying combinations of cytopenias, macrocytosis,
neurofibromatosis type 1(NF1) caused by germline mutations in the elevated levels of HbF, hypocellular BM, immunologic deficiency,
NF1 gene shares a phenotypic overlap disorder with NS, the so-called physical malformations, and predisposition to leukemia. The BM
neurofibromatosis–Noonan syndrome. Remarkably, children with NS failure might be the result of mutations in novel IBMFS genes or
have an increased risk of juvenile myelomonocytic leukemia (JMML); atypical presentations of classified syndromes. Complex interplay of
however, in contrast to classical JMML, NS-associated myeloprolif- mutations in multiple genes, modifying genes, epigenetic processes,
erative disorder has an aggressive course, and typically remits spon- acquired factors, and chance effects that may be specific to each
taneously within several months. The thrombocytopenia may persist affected cases cannot be excluded. Published examples of unclas-
after the myeloproliferative process improves. Of note, some of the sified IBMFSs have been reviewed and divided into inheritance
mutated genes that cause NS (e.g., PTPN11, KRAS, and NRAS) are patterns, and then subdivided into cases with and without physical
also found as somatic mutations in BM cells from children with anomalies.
JMML. Using the Canada-wide database of the CIMFR, a unique study
was launched on IBMFS cases that were deemed unclassifiable at
study entry. Of 162 enrolled patients, 39 were registered as having
Cartilage-Hair Hypoplasia an unclassified disorder. Although the hematologic phenotypes were
similar to the classified syndromes in the registry (single- or multilin-
Cartilage-hair hypoplasia (CHH) is an autosomal recessive syndrome eage cytopenia, severe aplastic anemia, MDS, AML, and cancer), the
characterized by metaphyseal dysostosis; short-limbed dwarfism; and patients presented at an older age (median, 9 months versus median
fine, sparse hair. Additional skeletal findings include scoliosis, lordo- 1 month for classified), and the variation in clinical presentations was
sis, chest deformity, and varus lower limbs. Aganglionic megacolon substantial. Grouping patients according to physical abnormalities
and other gastrointestinal abnormalities have been reported. Most and hematologic phenotype was not always sufficient to character-
cases in the literature are Finnish or Amish. Mutations in the noncod- ize or diagnose a condition because affected members from several
ing RNA gene RMRP are seen in more than 80% of cases. Macrocytic families fit into different phenotypic groupings. It was difficult to
anemia of varying severity is seen in the majority of patients. Most formulate a sensible and cost-effective diagnostic workup based on
patients have mild and self-limited anemia, but some are severe and the family histories and hematologic and physical findings. Compared
persistent, resembling DBA, and require RBC transfusions. Severe with workups of classifiable syndromes, clastogenic chromosomal
immunodeficiency can occur, often with the severe anemia. HSCT fragility testing and extensive genotyping efforts of the unclassified
has been used successfully to reconstitute the immune system. Neu- cases required use of several-fold higher specific diagnostic tests at a
tropenia has been reported in 25% of CHH cases and lymphopenia cost that was 4.5 times higher per evaluated patient. Despite these
in 65%. Lymphomas and basal cell carcinoma also occur at an efforts and the huge, recent explosion of gene discovery, only 20%
increased frequency. of unclassified patients were diagnosed with a specific syndrome,
underscoring ongoing diagnostic limitations for these disorders.
Pearson Syndrome Treatment of Unclassified Familial Forms of Bone
Marrow Failure
Pearson syndrome is an inherited failure of BM and, in 30% of cases, Because these disorders are rare, broad conclusions about manage-
impaired exocrine pancreatic function caused by acinar cell atrophy ment are difficult to formulate. For full-blown aplastic anemia with
and fibrosis. Patients with Pearson syndrome have a maternally a hypocellular, fatty BM or for MDS/AML, curative therapy with
inherited diagnostic deletion of mtDNA that encodes enzymes that HSCT remains the first choice if a suitable donor is identified. In the
are critical to oxidative phosphorylation. The genetic deletion results familial cases, potential related stem cell donors must be thoroughly
in a syndrome of refractory anemia with ringed sideroblasts and assessed clinically, hematologically, and by diagnostic laboratory
prominent vacuolization of BM erythroid and myeloid precursors. testing to ensure that latent or masked BM dysfunction is not present.
Physical malformations are rarely observed. Severe anemia requir- If a matched sibling donor is not available, an unrelated donor search
ing transfusions is present within the first year of life, sometimes should be initiated, and in the interim, principles of medical manage-
at birth. Pancytopenia may occur alone or in association with ment with androgens and supportive care similar to other IBMFSs
hepatic failure and a renal tubulopathy leading to lactic acidosis. can be used.
The projected median survival time is 4 years. Anemia is managed
with RBC and platelet transfusional support. Erythropoietin has INHERITED BONE MARROW FAILURE SYNDROMES
been used for the anemia of renal failure. G-CSF is indicated for
severe neutropenia. HSCT has been used in two cases with Pearson WITH PREDOMINANTLY ANEMIA
syndrome; both patients engrafted and achieved normal blood
counts. One of the children survived at 3 years follow-up post- Diamond-Blackfan Anemia
HSCT. The second patient developed acute myeloid leukemia 12
months post-HSCT and died. Interestingly, HSCT was associated Background
not only with improved hematopoiesis, but also with resolution of
lactacidemia and acidosis. Although HSCT was traditionally not DBA, previously called congenital hypoplastic anemia, is an inher-
recommended for the hematopoietic complications of Pearson ited form of pure RBC aplasia. The syndrome is heterogeneous
syndrome because of their tendency to improve spontaneously with respect to genetic causes, clinical and laboratory findings, in
in most cases, further studies are necessary to decipher HSCT vitro data, and therapeutic outcome. DBA is the first disease to
role in this disease. The need for pancreatic enzyme replacement be identified as a ribosomopathy. It is also the best example of the
is unclear. ribosomopathies because except for GATA1, all currently known