Resolution of Inflammatory Colitis With Pegfilgrastim Treatment in a Case of Severe Congenital Neutropenia Due to Glucose 6 Phosphatase Catalytic Subunit-3 Deficiency Zu ¨hre Kaya, MD,* O ¨ du ¨l Eg ˘ritas¸, MD,w Meryem Albayrak, MD,* Pınar Uyar Go ¨c¸u ¨n, MD,z U ¨ lker Koc¸ak, MD,* Buket Dalgıc¸, MD,w and Tu ¨rkiz Gu ¨rsel, MD* Summary: Glucose 6 phosphatase catalytic subunit-3 (G6PC3) deficiency is a heterogenous disorder characterized by severe con- genital neutropenia and a variety of extrahematopoietic manifes- tations. Inflammatory bowel disease like colitis is an uncommon complication of G6PC3 deficiency, described only in adolescent and adults. Herein, we describe inflammatory colitis in a 10-year- old girl with severe congenital neutropenia due to G6PC3 defi- ciency while she was on a high-dose filgrastim. Switching from filgrastim to (pegylated filgrastim) Pegfilgrastim led to rapid reso- lution of colitis, weight gain, and decreased infections. Pegfil- grastim seems to be a better remedy for treatment of G6PC3 deficiency complicated with inflammatory bowel disease. Key Words: G6PC3 deficiency, inflammatory colitis, pegfilgrastim (J Pediatr Hematol Oncol 2014;36:e316–e318) G lucose 6 phosphatase catalytic subunit-3 (G6PC3) deficiency is a recently described form of severe con- genital neutropenia (SCN), characterized by recurrent bacterial infections. 1 It is caused by mutations in glucose 6 phosphatase (G6P) gene, leading to defective glucose metabolism by the G6Pase-b (also known as G6PC3) and G6PT (G6P-transporter) complex within the neutrophil. Mutations in G6PT result in glycogen storage disease type Ib (GSD-Ib), whereas deficiencies in G6Pase-b result in SCN. 2,3 In addition to neutropenia, these patients with G6PC3 deficiency may have various congenital abnormalities including prominent skin veins often developing in adult life, various structural defects involving heart, skeleton, and urogenital systems, growth retardation, and endocrine dis- turbances. 4–9 The age of onset and spectrum of clinical manifestations are highly variable among previously reported patients. 4,5,10 Inflammatory colitis resembling ulcerative colitis or the Crohn disease occur frequently in GSD-Ib, but it has rarely been reported in SCN due to G6PC3 mutation. 10–14 In this study, we describe a case of a 12-year-old girl with G6PC3 mutation complicated with severe IBD, unresponsive to filgrastim but treated success- fully with pegylated filgrastim (pegfilgrastim). CASE REPORT Case 1 The proband, born to consanguineous parents was first seen at the age of 4 months with the complaints of fever, gingival ulcers, perianal redness, diarrhea, and pulmonary infections persisting since birth. Physical examination showed gingivostomatitis and extensive perianal excoriation. No superficial venous pattern or congenital abnormality was observed. Her echocardiography showed patent foramen ovale and a minimal tricuspid insufficiency. Abdominal ultrasound was normal. Laboratory investigations revealed an absolute neutrophil count (ANC) of 0.08  10 9 /L, nor- mal hemoglobin level, and normal platelet counts. Bone marrow examination was normal. Diagnosis of SCN was made, based on low ANC < 0.5 10 9 /L on 3 consecutive blood counts within the last 2 months. The levels of serum immunoglobulin (Ig) G, Ig A, and Ig M were normal. Seroconversion to hepatitis B vaccine given at birth was observed. Autoantibodies and Coombs tests were negative. Conventional filgrastim was started at a dose of 10 mcg/kg every other day, and the dose was escalated up to 15mcg/kg tar- geting to ANC > 1.5 10 9 /L, but ANC remained below 1.0  10 9 /L for most of the times on the follow-up visits. Genetic analyses for ELA-2 and HAX-1 showed no known mutations. She carried a novel homozygous mutation c.623 T > G in exon 5 predicting p.Leu208Arg substitution in the G6PC3 gene. She had been hos- pitalized 10 to 15 times per year because of recurrent fever, gingi- vitis, and gastroenteritis. She remained malnourished until the age of 10 years, when she was hospitalized for protracted abdominal pain, diarrhea, and weight loss over the last 6 months. Microscopic examination of stool showed abundant leukocytes but bacterial cultures were negative. Stool a-1 antitripsin (a 1 -AT) was positive despite regular filgrastim administration. Repeated abdominal ultrasound was normal. Colonoscopic examination revealed pan- colitis, involving entire colonic mucosa, which was hyperemic, edematous, and fragile and covered by ulcerative lesions with white exudates (Fig. 1A). The histopathologic examination of the biopsy from colonic mucosa demonstrated mixed type inflammation including neutrophils leukocytes, ulceration, and granulation tissue. Neither granulomatous inflammation nor cryptic distortion was seen (Fig. 2A). Increasing the dose of filgrastim to 20mcg/kg raised ANC > 1.5 10 9 /L, but abdominal pain, episodes of diarrhea, and low ANC continued during the next 6 months of follow-up period. Therefore, filgrastim stopped and pegfilgrastim was started at a dose of 100mcg/kg per week. Over the next 3 months, her clinical con- dition was rapidly improved with amelioration of abdominal pain and diarrhea, weight gain, and decreased in the number of febrile episodes in association with sustained ANC over 1.5  10 9 /L. Her height was 122cm (<3%) and weight 15kg (<3%) before treat- ment. Repeated colonoscopy and biopsy after 10 months of pegy- lated filgrastim showed marked improvement of colitis (Figs. 1B, 2B). Her height and weight progressively increased reaching 128cm and 21kg, respectively. She is 12 years old now and free of any infections and need for hospitalization. Case 2 A sister of the proband was first seen at the age of 12 months for frequent fever, gingivitis, diarrhea, and poor weight gain since Received for publication May 27, 2013; accepted October 31, 2013. From the *The Pediatric Hematology Unit of the Department of Pediatrics, Division of Pediatric Hematology; wThe Pediatric Gas- troenterology Unit of the Department of Pediatrics, the Depart- ment of Pathology; and zMedical School of Gazi University, Ankara, Turkey. The authors declare no conflict of interest. Reprints: Zu¨hre Kaya, MD, Division of Pediatric Hematology, Department of Pediatrics, Gazi University Medical School, Bes ¸evler, Ankara, 06500 Turkey (e-mail: zuhrekaya@gazi.edu.tr). Copyright r 2013 by Lippincott Williams & Wilkins CLINICAL AND LABORATORY OBSERVATIONS e316 | www.jpho-online.com J Pediatr Hematol Oncol  Volume 36, Number 5, July 2014