H e m a t o lo g y E d u c a t io n - European Hematology Association

ization. In WASP deficiency, lymphoid and myeloid
cells are functionally perturbed in multiple aspects. Rare
human patients were found expressing a constitutively
active variant of WASP, leading to increased actin polymerization
and congenital neutropenia. 19 Increased
WASP activity also causes defective cytokinesis, increasing
the risk of myelodysplasia. 20
Neutrophil granulocytes critically depend on glucose
metabolism. This is highlighted by mutations in
SLC37A4 21 and G6PC3, 22 respectively. SLC37A4
encodes the glucose-6-phosphate transporter (G6PT)
mediating transition of G6P from cytosol to the endoplasmic
reticulum, whereas G6PC3 encodes a ubiquitously
expressed homologue of glucose-6-phosphatase.
Whereas in G6PT, deficiency congenital neutropenia is
associated with metabolic complications (glycogen storage,
hypoglycemia), G6PC3 deficiency causes congenital
neutropenia in conjunction with variable structural
defects or the cardiovascular and urogenital system.
This disease is phenotypically quite variable and may
also present with inner ear deafness or growth failure.
Interestingly, in contrast to glycogen storage disease
type Ia and type Ib, G3PC3 deficiency does not result in
metabolic complications, presumably because glucose
homeostasis is regulated mainly be G6PC1 and G6PT.
A number of other rare genetic defects have been
reported to control differentiation, migration, and viabili-
London, United Kingdom, June 9-12, 2011
ty of neutrophil granulocytes. For example, Hermansky–
Pudlak syndrome type II, caused by defects in AP3B1, is
associated with congenital neutropenia and hypopigmentation.
23 The gene encodes for a subunit of the adaptor
protein 2 complex controlling vesicular trafficking.
Mutations in P14/MAPBPIP, encoding an endosomal protein,
have been discovered in a single pedigree with congenital
neutropenia, combined immunodeficiency, and
hypopigmentation. In contrast to patients with severe
congenital neutropenia, patients with defects in AP3 and
MAPBPIP do not have a myeloid maturation arrest. The
mechanism of neutropenia remains to be resolved.
In American Indians, a rare variant of congenital neutropenia
has been identified that is associated with poikiloderma,
hyperkeratosis, and nail dystrophy. 24 Using a targeted
next generation sequencing approach, Volpi et al. identified
mutations in C16Orf57 as the cause for Clericuziotype
neutropenia. 25 Recently, Clericuzio et al. confirmed
that C16Orf57 is also the mutated gene in Athabascan
patients with poikiloderma and neutropenia. 26 The function
of the mutated protein is still unknown.
Some other monogenetic diseases, such as wartshypogammaglobulinemia,immunodeficiency-myelokathexis
(WHIM) syndrome, Cohen syndrome, Shwachman
Diamond syndrome, cartilage-hair-hypoplasia, or Barth
syndrome may also be associated with congenital neutropenia
(Table 1).
Table 1. Synopsis of disease with congenital neutropenia and related animal models.
Hematology Education: the education programme for the annual congress of the European Hematology Association | 2011; 5(1) | 147 |