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.