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Chapter 29 Inherited Bone Marrow Failure Syndromes 385

major. In this regard, the therapeutic benefit of oral iron chelators mutations in phenotypically healthy family members were reported.
such as Exjade should be explored fully. For example, two siblings with congenital neutropenia inherited the
same heterozygous ELANE mutation from their hematologically
normal father. In another family, a healthy father of a congenital
INHERITED BONE MARROW FAILURE SYNDROMES neutropenia patient was mosaic for his daughter’s Cys42Arg mutation
WITH PREDOMINANTLY NEUTROPENIA in peripheral blood hematopoietic cells. The mutation was found in
about 50% of his T lymphocytes but only in 10% of his neutrophils.
Kostmann Syndrome and Severe This is congruent with a lack of recurrent infection phenotype in
Congenital Neutropenia the father. The mutation was evident in myeloid precursors but
was selectively lost during myelopoiesis or failed to mature to
neutrophils.
Background The exact mechanism whereby mutant ELANE causes neutrope-
nia is unclear. ELANE encodes neutrophil elastase, a glycoprotein
Kostmann syndrome (KS) and severe congenital neutropenia (SCN) synthesized in the promyelocyte/myelocyte stages and packed in the
refer to inherited types of neutropenia with onset in early childhood azurophilic cytoplasmic granules. It is released in response to infec-
of profound neutropenia (ANC <200/µL), recurrent life-threatening tion and inflammation. There are several proposed mechanisms for
infections, and a maturation arrest of myeloid precursors at the how mutations in ELANE cause neutropenia. The wild-type neutro-
promyelocyte-myelocyte stage of differentiation. Some experts in the phil elastase diffusely localizes throughout the cytoplasm. It has been
field refer to KS as the autosomal recessive type of severe inherited shown that the mutated protein is not reduced, but mistrafficked and
neutropenia and to SCN to all the other inherited neutropenia with is abnormally concentrated in the nucleus and plasma membrane.
similar phenotype. However, because many IBMFSs are inherited in Interestingly, mutations that disrupt the ATG translation initiation
different modes and because SCN and KS are indistinguishable codon or the immediately adjacent Kozak sequence have shown to
phenotypically in the majority of the patients, the option to “split” cause translation from downstream in-frame initiation codons, yield-
the two disorders is debatable. In this chapter, we will refer to them ing a protein that lack the amino-terminally domain sequences that
as Kostmann/severe congenital neutropenia (K/SCN). are important for ER-localizing. A second theory suggests that the
The initial description of syndrome made by Dr. Kostmann in mutant protein leads to accumulation of nonfunctional protein in
1956 included several neutropenic patients in a large intermarried the endoplasmic reticulum, activation of unfolded protein response,
Swedish kinship. An autosomal recessive mode of inheritance in 24 and apoptosis of K/SCN neutrophils. Related to this theory, decreased
cases was deduced by inference because of hematologically normal expression of Bcl-2 was observed in K/SCN myeloid progenitor cells
parents with two or more neutropenic children in several families. along with constitutive mitochondrial release of cytochrome C and
Recently, homozygous germline HAX1 mutations have been identi- excessive cellular apoptosis. Of note, administration of G-CSF
fied in patients with K/SCN, including some from the original pedi- restored Bcl-2 expression and improved survival of myeloid progeni-
gree described by Dr. Kostmann, confirming an autosomal recessive tor cells. Another proposed mechanism is downregulation of lym-
inheritance in these families. Nevertheless, it is now clear that the K/ phoid enhancer-binding factor 1 (LEF-1) in K/SCN. This leads to
SCN group is genetically heterogeneous despite a shared hematologic reduced transcription of LEF1-target genes such as C/EBP-α and
phenotype (see Table 29.1). The first identified K/SCN gene was the impaired granulocytic differentiation.
neutrophil elastase 2 gene (ELA2 or ELANE), which was found HAX1 was reported to be mutated in 40% of patients with K/
mutated on one allele in patients with K/SCN, indicating an auto- SCN in a European study but in only few patients in the CIMFR.
somal dominant inheritance in many cases. HAX1 localizes to the mitochondria. It contains two domains remi-
niscent of a BH1 and BH2 of the BCL-2 family. It promotes normal
potential of the inner mitochondrial membrane and protects myeloid
Epidemiology cells from apoptosis. The direct function of HAX1 in promoting
survival may explain the accelerated apoptosis reported in K/SCN
K/SCNs are rare. The estimated incidence based on data from neutrophils. HAX1-mutant K/SCN cells are also characterized by
CIMFR from 2001–2010 was 4.7 cases per million live births per reduced LEF1 levels as in ELANE-mutant K/SCN cells.
year. There is equal distribution of the disease between genders. There A constitutively activating mutation in the Wiskott-Aldrich
might be different frequency of specific genetic groups in different syndrome protein encoded by the WASP gene was discovered in five
countries. For example, HAX1 mutations in North America was males from a three-generation family. The phenotype was composed
found only in patients who immigrated from certain European of severe neutropenia from birth, bacterial infections, monocyto-
countries. penia, and shifts of lymphocyte subsets. BM morphology showed
a selective maturation arrest at the promyelocyte/myelocyte stage
similar to K/SCN. Mutant WASP leads to constitutive activation
Etiology, Genetics, and Pathophysiology of the WASP protein because of disruption of an autoinhibitory
domain in the wild-type protein. This increased WASP protein
The discovery of heterozygous mutations in the ELANE gene encod- activity produces marked abnormalities of cytoskeletal structure and
ing neutrophil elastase in 22 of 25 sporadic and dominantly inherited dynamics, disruption of mitosis, genomic instability, and apoptosis of
patients with K/SCN was the entry point for understanding the neutrophils.
molecular basis of the disorder in many patients. Among patients Mutations in the proto-oncogene GFI1 also cause K/SCN with
with K/SCN enrolled in the North American cohort, the most severe neutropenia and a maturation arrest at the promyelocyte–
common mutations are in ELANE (about 60%). Mutations in other myelocyte stage. GFI1-deficient mice exhibit severe neutropenia with
genes (e.g., in GFI1 and GCPC3 were rare). The rest of the patients accumulation of abnormal arrested progenitors and increased HSC/P
did not have identified mutations and no mutations in HAX1 were proliferation. GFI1 is a transcriptional repressor of several transcrip-
found. In Europe ELANE mutations are present in 60% of patients, tion programs. The first transcription program is active during the
followed by mutations in HAX1 in 20% to 25% of patients. Mutant progenitor stage. During this stage, GFI1 downregulates the HoxA9-
ELANE also occurs in all cases of classical cyclic neutropenia, but the Pbx1-Meis1 transcription factor complex. Because HOXA9 drives
mutations cluster in exon 4 or 5 on the gene or at the junction of progenitor proliferation, GFI1 deficiency leads to uncontrolled
exon 4 with intron 4. Patients with congenital neutropenia have HOXA2 activation and accumulation of arrested-differentiation
mutations more widely distributed over exons 2, 3, 4, and 5. myeloid progenitors. The second transcription program is activated
Although typical K/SCN patients present early in life with severe during terminal granulopoietic differentiation. During this stage,
neutropenia and life-threatening infections, rare cases with ELANE GFI1 represses genes that promote differentiation of nongranulocytic