severe chronic neutropenia is a congenital condition defined as an absolute neutrophil count ( anc ) of less than 500/l for at least three months ( 1 , 2 ) . generally ,
underlying hematologic disorders , autoimmune diseases , viral infections , or drugs causing neutropenia should be excluded .
there are three categories according to the onset time or pattern of variation of neutrophil levels : congenital , cyclic , and idiopathic . among them
, severe congenital neutropenia ( scn ) is an inborn disorder with maturation arrest of the early stage of granulopoiesis associated with various genetic abnormalities ( 3 ) .
in addition , cyclic neutropenia ( cn ) is a related disorder characterized by periodic oscillation of the peripheral neutrophil count , with an average 21-day frequency ( 1 , 2 ) . among several associated genetic mutations ,
the variants of the elane sequence comprise approximately 50% of the genetic causes of scn and nearly all of cn ( 4 ) , and it is known to be correlated with more severe neutropenia and serious clinical manifestations in scn ( 5 ) .
we herein introduce a korean girl with typical features of scn and a novel elane gene mutation .
a 9-month - old girl who was born on september 17th , 2009 was transferred to our hospital with prolonged fever and recurrent cervical lymphadenitis on june 25th , 2010 .
her initial laboratory tests revealed severe neutropenia ( anc 90/l ) and increased acute phase reactants ( erythrocyte sedimentation rate 97 mm / hr and c - reactive protein 7.9 mg / dl ) .
she had a past history of admission to the neonatal intensive care unit at another hospital at birth due to omphalitis .
her course of development was normal , and she had no congenital malformation suggestive of specific syndromes associated with neutropenia .
the cervical contrast enhanced computed tomography ( ct ) was performed to exclude abscess formation or deep neck infection that would need incision or aspiration .
bone marrow ( bm ) findings showed early - stage maturation arrest of myelopoiesis ( cellularity 80%-100% , myeloblasts 3.0% , promyelocytes 0.7% , myelocytes 2.2% , metamyelocytes 0.5% , band neutrophils 0.2% , and segmented neutrophils 0.0% ) , with an m : e ratio of 0.43:1 ( fig .
considering her past history and physical examination , scn associated with elane abnormality was suspected .
direct dna sequencing analysis of the elane gene demonstrated a substitution of the 607th base ( g to c ) in exon 5 , resulting in a change of the 203rd codon ( glycine to arginine ) , which is a novel variation of scn ( c.607 g > c ; p.gly203arg ) ( fig .
she had no increase in her anc despite daily administration of subcutaneous 5 - 10 g / kg granulocyte colony stimulating factor ( g - csf ) .
after management with an increased dose ( 15 g / kg / day ) of g - csf for six consecutive days , she recovered and was discharged with a increased anc ( 11,110/l ) ( fig .
however , the anc was again decreased at 990/l when she visited our outpatient clinic one week after cessation of the g - csf injections , and reduced to 130/l after one month .
she has suffered subsequent seven episodes of febrile illnesses until the present ( table 1 ) .
all of them were managed with prompt administration of intravenous empiric broad - spectrum antibiotics , cefepime .
scn is a very rare condition that is diagnosed when the anc is less than 500/l from birth , with myeloid cell differentiation arrest at an early stage in the bm ( 1 , 3 ) .
cn is also a congenital disorder of granulopoiesis characterized by periodic oscillations in the number of circulating neutrophils ( 1 , 2 ) .
patients experience infections when the neutrophil count drops below 500/l and approaches zero . both scn and cn
are related to an elane alteration associated with sporadic or autosomal dominant inheritance ( 6 ) .
scn is a genetically heterozygous disease group with several gene mutations and various modes of inheritance ( 3 , 7 ) .
for example , patients with the hax1 abnormality show developmental delay or epilepsy with autosomal recessive inheritance ( kostmann syndrome ) , while patients with the elane mutation , which arises sporadically or follows autosomal dominant inheritance , have no neurological problems .
her diagnosis was delayed , however , until nine months of age , because her past history of an umbilical cord infection and isolated severe neutropenia was overlooked .
it is important to reconsider patients ' history and laboratory tests in the case of recurrent bacterial infections .
since the patient had no anomalous morphology or neurological problems , we first suspected the elane gene mutation .
if the patients show any malformations , fanconi anemia / schwachman - diamond syndrome ( skeletal abnormality ) , dyskeratosis congenita ( nail dystrophy ) , or diamond - blackfan syndrome ( anomaly of face or hand ) should be considered ( 8) .
mutation of the elane gene ( chromosome 19p13.3 ) encoding human neutrophil elastase ( ne ) is the most common genetic alteration in scn ( 3 ) .
it comprises about 50% of scn and nearly all of cn ( 3 , 4 ) .
there are some cases of korean scn patients , but until today , a genetically confirmed elane gene mutation was the only one in korea ( c.170c > t ; p.ala57val ) ( 9 ) .
neutrophils play a key role in innate immunity and the host 's defense mechanisms by phagocytosing , killing , and digesting bacteria and fungi ( 10 ) .
in particular , azurophilc ( primary ) granules in the neutrophil , which are formed during the promyelocytic stage , contain several important proteins ( myeloperoxidase , cathepsin g , elastase , proteinase 3 , bactericidal / permeability - increasing protein , and defensin ) essential for antibacterial activity . among them , ne attacks gram negative bacteria like klebsiella pneumoniae or escherichia coli ( 11 ) . in neutrophils
in which ne is inactivated , bacteria escape from the phagosome , resulting in increase of bacterial survival ( 12 ) .
although the entire pathophysiology of how the elane mutation develops in neutropenia is unknown , recently it is believed that the mutant ne tends to be misfolded , which leads to apoptosis of myeloid progenitor cells through an ' unfolded protein response ' by the endoplasmic reticulum ( 13 ) .
for those reasons , there are few mature neutrophils , while promyelocytes are normally present ; that is the so - called ' maturation arrest ' in the bm , and thus patients suffer from lifelong infections in scn .
morphologically prominent vacuolations or aberrations of azurophilc granules may appear in the bm ( 7 ) .
infections include bacterial illnesses , such as a urinary tract infection , pneumonia , omphalitis , septicemia , lymphadenitis , otitis media , cellulitis , and fungal disease like oral thrush .
neutrophils contribute to tissue injury and reconstitution as well as play a role in host - defense cells ( 14 ) .
thus , absence of pus at infection sites is the characteristic feature of scn , as demonstrated by the neck ct of the patient in this study ( 7 ) . as a treatment of choice
, the severe chronic neutropenia international registry recommends that the g - csf injection is started at a dose of 5 g / kg / day and continued in upward 2-fold adjustments until the anc reaches over 1,000 - 1,500/l ( 15 ) .
generally , scn patients require a higher dose of g - csf ( median 7.3 - 23.0 g / kg / day , maximum 242.4 g / kg / day ) compared to cyclic or idiopathic neutropenia patients . about 90% of scn patients respond to g - csf treatment , but the remainder have only a temporary or no response to g - csf ( 16 ) .
although the predictors of poor response are not yet demonstrated , most refractory cases have very low initial anc levels . in addition
, the elane gene mutation is known to be associated with more severe neutropenia and serious clinical manifestations in scn ( 5 ) .
although septic mortality is markedly decreased by g - csf treatment , the cumulative incidence of myelodysplastic syndrome ( mds ) or acute myeloid leukemia ( aml ) in scn is about 20% after 10 yr treatment ( 17 ) .
it is controversial whether scn is an obvious precancerous condition , or the g - csf treatment contributes to evolution to mds / aml .
considering that cyclic or idiopathic neutropenia patients do not develop mds / aml in spite of g - csf administration , and refractory scn patients who were exposed to a higher dose of g - csf tend to develop mds / aml , a combination of both theories is also possible . in the case of non - responders ,
stem cell transplantation from an hla - identical sibling is the optimal therapeutic modality ( 8 , 18 ) . in this case , the patient showed only temporary response to subcutaneous 15 g / kg / day of g - csf for six consecutive days .
we have not yet increased the dose of g - csf due to a financial problem associated with standards of korean medical insurance .
to control infections , we selected the 4th generation cephalosporine ( cefepime ) empirically to cover both gram positive and negative bacteria including pseudomonas aeruginosa .
since she has no siblings and is very young , we closely follow her , with the idea of stem cell transplantation in reserve .
 severe congenital neutropenia is a heterozygous group of bone marrow failure syndromes that cause lifelong infections . 
 mutation of the elane gene encoding human neutrophil elastase is the most common genetic alteration . 
 a korean female pediatric patient was admitted because of recurrent cervical lymphadenitis without abscess formation . 
 she had a past history of omphalitis and isolated neutropenia at birth . 
 the peripheral blood showed a markedly decreased absolute neutrophil count , and the bone marrow findings revealed maturation arrest of myeloid precursors at the promyelocyte to myelocyte stage . 
 her direct dna sequencing analysis demonstrated an elane gene mutation ( c.607 g > c ; p.gly203arg ) , but her parents were negative for it . 
 she showed only transient response after subcutaneous 15 g / kg / day of granulocyte colony stimulating factor administration for six consecutive days . during the follow - up observation period 
 , she suffered from subsequent seven febrile illnesses including urinary tract infection , septicemia , and cellulitis . 