Glycogen storage disease (GSD) type I is a rare autosomal recessive disorder manifesting primarily in the liver. Its biochemical features are the result of the inability to catalyze the last reaction of gluconeogenesis and glycogenolysis. This results in profound fasting hypoglycemia, hyperuricemia, hyperlactacidemia, hypertriglyceridemia, and hypercholesterolemia. Patients with GSD also share the hallmark clinical signs of hepatomegaly, poor growth, impaired platelet function, and adiposity. Subtypes of GSD I are the result of various dysfunctions of the glucose-6-phosphatase enzyme complex. Type Ia is caused by glucose-6-phosphatase enzymatic deficiency, whereas type Ib is the result of defects in the glucose-6-phosphate translocase membrane protein (1,2).
The defective protein in GSD type Ib and its clinical manifestation of neutropenia may be linked by the dependence of the neutrophil on this translocase for proper function and maturation. Indeed, more than 90% of these patients have an absolute neutrophil count (ANC) of less than 1,500/mm 3 and have myeloid hyperplasia (3). Studies have shown that patients with GSD type Ib have neutrophils defective in chemotaxis, bactericidal activity, respiratory burst, calcium mobilization, and calcium stores (4,5). Approximately 80% of GSD Ib patients later have recurrent bacterial infections in the form of pneumonia, otitis media, generalized pyoderma, urinary tract infection, conjunctivitis, cellulitis, peridonitis, and abscesses. Usual causative organisms are Staphylococcus aureus, Escherichia coli, group A Streptococcus, Pseudomonas organisms, and Streptococcus pneumoniae(6).
Granulocyte-colony stimulating factor (GCSF) is the standard of care for neutropenia and infectious complications of GSD type Ib patients and has been shown in multiple studies to be effective (7–9). Studies, and our experience, show that some patients with GSD type Ib have poor surgical wound healing despite daily treatment with GCSF (5,6). This problem becomes especially relevant when the need to avoid profound hypoglycemia by continuous, nocturnal, enteral drip feeds results in the need for a gastrostomy tube. A gastrostomy tube simplifies drip feedings without repetitive nasogastric tube placement, which can cause severe epistaxis in a patient with impaired platelet function. After gastrostomy tube placement, normal healing of the surgical wound is required. Moreover, use of a gastrostomy tube may result in constant exposure to damaging gastric secretions at the stoma site, which can lead to chronic breakdown problems.
We present a GSD type Ib patient who had repetitive healing problems at his gastrostomy site. It was our hypothesis that topical and small, slow, continuously infused granulocyte–macrophage colony stimulating factor (GMCSF) could aid in local healing without the known side effects of repeated, full daily GMCSF doses administered subcutaneously.
Our patient was born at full-term gestation via normal vaginal delivery and initially experienced mild neonatal hypoglycemia. The child was switched to feedings every 2 hours and tolerated a regular feeding schedule after approximately 3 weeks of age. At 2 months of age, draining otitis media developed, which was complicated with pineal cyst and periauricular lymphadenitis. The patient later had two subsequent bouts of otitis media in the next 2 months.
At 5 months of age, our patient was diagnosed with GSD type Ib after seeking treatment for hypoglycemia, seizures, and marked hepatosplenomegaly. The patient was also noted to be neutropenic, with initial ANCs ranging from 190 to 550 cells/mm 3 . Liver biopsy was performed, and a diagnosis of GSD type Ib was made. The patient was started on frequent day and nasogastric nighttime drip cornstarch feeds, with resolution of his seizures and hypoglycemic episodes. Daily subcutaneous doses of GCSF at a dose of 8 μg/kg increased the patient's ANC to more than 2,000 in 3 days and maintained ANC at 1,950 to 4,000 cells/mm 3 .
At 8 months of age, the patient underwent surgical placement of a gastrostomy tube to alleviate the need for repeatedly placing a nasogastric tube, which twice previously had been complicated by profuse epistaxis. In repeated outpatient visits, the parents of the child reported drainage and erythema at the gastrostomy tube site. At 23 months of age, right groin ecthyma gangrenosum developed that, when cultured, culture grew Pseudomonas aeruginosa, necessitating a 2-week course of intravenous antibiotic coupled with surgical debridement. The patient continued to have gastrostomy tube drainage complaints, and at 41 months of age, with a 3-week history of worsening drainage and frank pus from the gastrostomy tube site, he required hospital admission for surgical revision of local fascia dehiscence. Even after this surgical intervention, his gastrostomy tube site had continual drainage and erythema that required readmission at 45 months of age for gastrostomy tube site care.
By 50 months of age, with continued poor healing at the gastrostomy tube site, the patient was again admitted for tube removal. Gastrostomy tube complications developed despite daily subcutaneous administration of 180 μg GCSF and documented ANCs of 1,460 to 8,660 cells/mm 3 as an outpatient. He was administered topical GMCSF 10 μg (5 μg/ml) mixed with 3 mL of silvadence cream and applied to the gastrostomy tube site three times daily. Six days after starting topical GMCSF treatment, the wound site showed a dramatic closure, decrease in erythema, and skin healing, allowing us to proceed with surgical closure. Surgical closure was accomplished, and a subcutaneous infusion catheter was placed for pump installation of GMCSF at 5 μg/h (2.5 μg/mL). The pump infused for 48 hours after surgery. The infusion catheter was then removed, and topical GMCSF was reinstituted for 1 more week. Photographs of the gastrostomy site were taken daily (Fig. 1). The patient was discharged home with nasogastric tube feeds and a well-healing gastrostomy tube site on treatment day 10. He was observed as an outpatient, and wound checks at 1 and 2 months after discharge showed the surgical site to be well healed.
Our patient experienced the complications of poor wound healing and chronic breakdown at his gastrostomy tube site despite daily administration of accepted standard doses of GCSF subcutaneously and documented ANC counts of more than 1,400 cells/mm 3 . At this point, we needed another agent or treatment method to promote wound healing and thereby allow surgical closure, which was the parents' wish. A recent report showed improvement in the healing of patients with chronic myeloid leukemia and hydroxyurea-related leg ulcers with topically applied GMCSF (10). In addition to stimulating many cells involved in wound healing, GMCSF attracts inflammatory and endothelial cells and inhibits their migration from the site. It also induces keratinocyte proliferation and growth while recruiting Langerhans cells into the dermis (11,12).
Granulocyte–macrophage colony-stimulating factor stimulates proliferation and maturation of neutrophils, eosinophils, monocytes, and macrophages, whereas GCSF works primarily on the neutrophil component with an even larger increase in neutrophil levels on an equal-mass basis. Both factors enhance neutrophil function as measured in oxidative metabolism, migration inhibition, degranulation, cytokine secretion, recruitment, phagocytosis, and cytotoxicity (11,12). As with other diseases associated with leukopenia or poorly functioning leukocytes, GMCSF and GCSF have been tried in GSD type Ib with improvement of ANC counts and subsequent infections (13). After some initial trials of both factors, it was found that GMCSF was as effective as GCSF but had a more severe side effect profile that included pronounced eosinophilia and local injection site reactions (9,13). Some patients even went on to experience Sweet syndrome, characterized by fever, leukocytosis, neutrophilia, and multiple, sharply demarcated, and painful erythematous cutaneous plaques (13,14). In light of these adverse effects, GCSF injections became the standard treatment for the neutropenia and infectious complications of patients with GSD type Ib.
Our patient had dramatic improvement of his wound site erythema solely with topical GMCSF and effective surgical closure with subcutaneously infused GMCSF shown in Figure 1, which depict the gastrostomy tube site at 24-hour intervals. Our patient did not experience any increase in absolute eosinophil count; pretreatment levels ranged between 120 and 485 cells/mm 3 , and, during treatment, levels ranged between 115 and 505 cells/mm 3 . He also did not have any of the local inflammatory and painful reactions usually seen with full daily subcutaneous doses of GMCSF. To our knowledge, this is the first report of topical use of this agent in a patient with GSD type Ib. More studies are obviously needed, but the use of the GMCSF on a topical basis may have future applicability in poorly healing gastrostomy tube sites in our immunocompromised as well as immunocompetent patients.
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