Case presentation
A 12-year-old African American girl was diagnosed with severe congenital
neutropenia (SCN) at the age of 2-years. She presented with recurrent
infections since early infancy, absolute neutrophil count (ANC)
< 0.5 103/mm3 and
promyelocyte arrest in bone marrow. She had chronic mucopurulent
rhinosinusitis, recurrent/chronic otitis media and an extensive history
of multiple bouts of superficial skin abscesses and deep cellulitis
requiring multiple hospitalizations. She had bilateral cervical and
submandibular lymphadenopathy, gingival hypertrophy, and chronic
stomatitis, “cauliflower ear” deformity. Her growth and development
was normal for her chronological age. Genetic testing was negative,
including normal karyotype, myelodysplastic syndrome (MDS) panel,
elastase-2 gene, and HAX-1 gene mutations. Her immunoglobulin
levels and lymphocyte subset analyses were normal. She was commenced on
G-CSF which required dose increment to 20 microgram/kg/day due to
apparent G-CSF resistance. Multiple blood smears showed Pelger-Huet
anomaly, monocytosis and intermittent circulating blasts. She had
several surveillance bone marrow evaluations, cytogenetics and
Fluorescence in situ hybridization (FISH) studies to rule out
MDS/leukemia. Bone marrow evaluations since age 6 years showed
dysmegakaryopoiesis along with promyelocyte arrest and mild increase in
reticulin fibrosis.
At age 11-years, she had sixteen hospitalizations with pseudomonas
sepsis, Escherichia coli sepsis, candida infection and rotavirus
gastroenteritis. She had sacral abscess, multiple vaginal and perianal
ulcerations, rectal abscess, upper and lower GI bleeding requiring
multiple red cell transfusions. One of her hospitalizations was
complicated by acute kidney injury and hypertension. Renal biopsy
confirmed diagnosis of post-infectious glomerulonephritis potentially
from a skin infection and was treated with steroids.
Since she had suboptimal and inconsistent response to G-CSF treatment
throughout this period, the option of haploidentical HSCT from her
relative was considered as she lacked full matched donor. To improve her
ANC, thrombopoietin receptor agonist (TPO-RA) Romiplostim was started at
5 microgram/kg/week due to its promising action on HSCs in patients with
severe aplastic anemia(SAA).5,7 Romiplostim was chosen
due to its parenteral mode of administration ensuring absorption. Upon
addition of Romiplostim along with G-CSF (10 mcg/kg/day), her ANC
recovered in 8- weeks (Figure 1) with improvement in her gingival
hypertrophy and oral lesions (Figure 2). An attempt to reduce her G-CSF
dose to 5 mcg/kg/day quickly plummeted her ANC requiring increment in
dosing. She remained on this combination regimen with G-CSF at 10
mcg/kg/day and Romiplostim at 5 mcg/kg/week for 6-months. Her bone
marrow showed mild to moderate reticulin fibrosis. She relocated and
Romiplostim was discontinued. She underwent myeloablative
haplo-identical HSCT from her half-sibling 3-months after
discontinuation of Romiplostim. Pretransplant bone marrow testing showed
reduction in her reticulin fibrosis. She is 1-year since her HSCT and
had full engraftment.
Due to complexity of her clinical course, exome sequencing was performed
using genomic DNA8 which revealed two heterozygous
pathogenic variants in geneNM_001098426.1 [c.1081del
(p.Gln361Argfs*15)and c.217C>T (p.Arg73*)] explaining the
etiology of her SCN.