Hypoglycemia during infancy is a potentially fatal condition that may cause severe long-standing neurological morbidity. The main causes of hypoglycemia include ketotic hypoglycemia, endocrine disorders, such as hyperinsulinism, as well as deficiency of glucagon, cortisol, growth hormone (GH), and epinephrine; enzymatic defects, such as galactosemia, fructose intolerance, glycogen storage disease (GSD), and disorders of gluconeogenesis; disorders of fatty acid oxidation as well as sepsis and intoxication.
We present a 14-month-old female infant with recurrent episodes of severe hypoglycemia and metabolic acidosis who was diagnosed with fructose-1,6-diphosphatase (1,6-FDPase) deficiency. Evaluation of her hypoglycemia also revealed GH deficiency. To the best of our knowledge, the combination of 1,6-FDPase deficiency and GH deficiency has not been described previously.
A 14-month-old female infant was admitted to our emergency room because of diarrhea and vomiting accompanied by apathy and hyperventilation. She is the first child of first-cousin parents of Moslem Arab origin. The pregnancy and delivery were normal. There are no known metabolic disorders in the family. Until the age of 6 months, she maintained normal growth, around the 50th percentile for body weight, body height, and head circumference. Since the age of 6 months, she demonstrated a gradual but substantial decline in body weight, height, and head circumference moving toward the 3rd percentile and was diagnosed as failure to thrive.
Two months before the present admission, she arrived in the emergency room with grunting. She had clinical signs of dehydration and prolonged capillary filling of 3–4 s. Her rectal temperature was 36.3°C. She was tachycardic, with a heart rate of 171 beats per minute, and had Kussmaul breathing. Abdominal examination showed hepatomegaly. Neurological examination was unremarkable. Results of her preliminary blood tests revealed a white blood cell count of 17,600/μL, with 58% neutrophils, hemoglobin level of 11.3 g/dL, and platelet count of 793,000/μL. Serum glucose was remarkably low (30 mg/dL), with normal electrolytes and renal functions. Venous blood gases showed metabolic acidosis with pH 7.07, pCO2 14.1 mm Hg, HCO3 3.9 mEq/L, and elevated lactate level of 80 mg/dL. Liver enzymes were elevated (aspartate aminotransferase 212 U/L, alanine aminotransferase 168 U/L), with normal serum albumin, alkaline phosphatase, lactate dehydrogenase, total bilirubin, and ammonia. Partial thromboplastin time (52 s) and the prothrombin time ratio (INR 1.52) were increased. Uric acid levels were significantly elevated, 15.6 mg/dL; urinary sediment showed marked ketonuria with mild hematuria. The calculated anion gap was 22 mEq/L.
She was treated with intravenous glucose containing fluids and bicarbonate with rapid improvement. Due to her initial severe clinical condition, she was also immediately treated with intravenous ceftriaxone. Stool cultures were positive for Salmonella group C infection. The patient was released after 5 days of hospitalization due to the rapid marked improvement. After the hospitalization, she was followed up in our outpatient clinic, and repeated blood gases and glucose levels were normal and her liver enzymes and INR returned to normal. Assessment of urinary organic acids and serum amino acids were also normal.
At the age of 14 months, she was admitted again because of 1-day symptoms of acute gastroenteritis accompanied by apathy and hyperventilation. Physical examination showed hepatomegaly. Her blood glucose level was 2 mg/dL, and her blood gases were pH 7.1, pCO2 18.4 mm Hg, HCO3 5.5 mEq/L. Because of the recurrent episodes of hypoglycemia and metabolic acidosis, which develop quickly during infections, the counterregulatory hormones were assessed during hypoglycemia, and findings showed a blood insulin level <2 mU/L and cortisol level of 47 μg/dL, which are both appropriate responses. However, the GH response was low (4.1 μg/L). IGF-1 level was undetectable (<25 ng/mL). Repeated GH measurement during another episode of hypoglycemia was also inappropriately low (4.0 μg/L). Thyroid function tests and blood lipids were normal. Lactate levels and serum alanine levels were extremely elevated. Fasting test was performed, and hypoglycemia (glucose level of 38 mg/dL) occurred after only 5 h of fasting. Glucagon injection during the fasting hypoglycemia resulted in a further decrease of blood glucose.
Her clinical course and laboratory results led us to a preliminary diagnosis of a metabolic disorder combined with a GH deficiency. Lymphocytic enzymatic tests demonstrated 1,6-FDPase deficiency (4.1 pmol/min/mg protein; normal range 40–130 pmol/min/mg protein), a key enzyme in gluconeogenesis. Molecular genetic analysis demonstrated frameshift mutation in the FBP1 gene c.960_1insG.
She was treated with frequent meals (every 3 h) and fructose-free diet with vitamin C supplementation. There was no need for continuous artificial feeding to maintain a normal glucose level. In addition, she received GH replacement therapy, with gradual improvement of growth percentiles.
We present an infant with recurrent episodes of severe, rapidly developing hypoglycemia and lactic acidosis. As the hypoglycemia was so pronounced, we focused in our initial workup on potential causes of hypoglycemia (Table 1). The patient had ketotic hypoglycemia; thus, a disorder in fatty acid oxidation and hyperinsulinemia were ruled out (as indeed shown by the adequate undetectable insulin levels during the hypoglycemic episode). A notable finding during the episodes of hypoglycemia was hepatomegaly. Hypoglycemia combined with hepatomegaly is less likely in ketotic hypoglycemia, hypopituitarism, and adrenal insufficiency. In addition, the laboratory results of elevated serum alanine and uric acid levels directed us to the possible diagnosis of two metabolic disorders: GSD and/or enzymatic defect in the gluconeogenesis pathway. The lack of glucose increase in response to glucagon injection and the development of hypoglycemia after fasting time of only 5 h also supported these two diagnostic options.
|Hypoglycemia||Ketonuria||Hepatomegaly||Lipids||Uric acid||Glucose response to glucagon||Serum alanine after prolonged fast|
|Ketotic hypoglycemia||Severe if miss meals||+++||None||Normal||Normal||↑||↑||↓↓|
|FA oxidation disorder||Severe if miss meals||None||None to +||Normal||Moderately elevated||↑||↓↓|
|Hypopituitarism||Moderate if miss meals||++||None||Normal||Normal||↑||↓||↓↓|
|Adrenal insufficiency||Severe if miss meals||++||None||Normal||Normal||↑||↓↓||↓↓|
|1,6-FDPase||Severe if fasting||+++||+++||Elevated||Elevated||↑||None to ↓↓||↑↑|
|Galactosemia||After milk||+||+++||Normal||Normal||↑||None to ↓↓||↓|
|Fructose intolerance||After fructose||+||+++||Normal||Normal||↑||None to ↓↓||↓|
The hormonal assessment during hypoglycemia revealed adequately increased cortisol levels, which ruled out the possibility of adrenal insufficiency. In contrast, GH levels during two episodes of hypoglycemia were inadequately low. This, combined with undetectable IGF-I levels, indicated GH deficiency. It is noteworthy that, usually, GH deficiency is diagnosed following lack of adequate response to two GH provocation tests. The mechanism of GH response in some of these tests (e.g., insulin, glucagon) is induction of hypoglycemia. Provocation tests were unnecessary in the present case study because GH did not respond to two episodes of true hypoglycemia. Magnetic resonance imaging of the brain showed hypoplastic anterior pituitary and ectopic posterior pituitary, suggesting idiopathic congenital GH deficiency. However, GH deficiency could not explain all other concomitant features, such as severe lactic acidosis, hepatomegaly and impaired liver function, and hyperuricemia. Thus, the possibility of a combined defect was suggested. The relatively benign course of the disorder, the absence of other target organ involvement and/or damage, and the normal laboratory results without frequent hypoglycemia between episodes did not support the diagnosis of GSD. This led us to the diagnosis of 1,6-FDPase deficiency as was found by the enzymatic tests.
1,6-FDPase deficiency was first described in 1970 by Baker et al. (1), who found recurrent episodes of hypoglycemia and lactic acidosis in a 5-year-old girl. FDPase is a key enzyme in gluconeogenesis. FDPase deficiency is a rare, autosomal recessive condition, characterized by episodes of hypoglycemia and metabolic acidosis (1, 2). Precipitating factors include febrile illness, vomiting or fasting, even for relatively short periods, and intake of fructose-containing formulas. The main laboratory findings during episodes are hypoglycemia, lactic acidosis, ketosis, and hyperuricemia. Hepatomegaly associated with abnormal liver function tests has been observed. The symptoms resolve dramatically with the administration of glucose and bicarbonate (3). Recently, a few mutations have been identified in the gene coding for 1,6-FDPase (4). During infancy and early childhood, episodes of hypoglycemia could be lethal and require recurrent hospitalizations. After puberty, the frequency of the episodes decreases dramatically, probably due to an increase in hepatic glycogen content and a decreased frequency of infections (5).
To the best of our knowledge, the combination of 1,6-FDPase deficiency and GH deficiency was never described. Interestingly, a relationship between GSD types 1a and 1b (GSD1a and GSD1b, respectively) and GH deficiency was recently described (6). The authors reported that 10% of patients with GSD1a and 42% of patients with GSD1b had short statute. Circulating IGF-I levels were lower in patients with GSD1b. Impaired GH secretion during GH-releasing hormone plus arginine provocation test was found in 40% of patients with GSD1a and 57% of patients with GSD1b. The presence of antipituitary antibodies (APA) was significantly higher in GSD1b compared with GSD1a and controls and was inversely related to the GH response to the GH provocation test. The authors concluded that, in GSD1a, impaired GH secretion was associated with normal range IGF-I levels and thus with normal stature. In contrast, in GSD1b, increased APA probably led to impaired GH secretion, reduced IGF-I, and short stature. Interestingly, GH replacement therapy in GSD type 3 resulted in extreme elevation of blood lipids, which necessitated cessation of treatment (7). In the present case study of combined 1,6-FDPase deficiency and GH deficiency, baseline lipid levels were normal, and GH therapy normalized linear growth without any lipid profile impairment. Moreover, although APA were not determined in the present study, the MRI finding suggests congenital anatomic pituitary defect.
Finally, Nitzan et al. (8) described a case of FDPase deficiency and prolonged prothrombin time. Their hypothesis was that prothrombin time prolongation might be caused by an accumulation of intermediate metabolites of fructose metabolism and gluconeogenesis pathways. We found no other examples of this association, but in some of the reported cases, results of prothrombin time were not cited. Our patient also demonstrated elevated prothrombin time during the episodes, with normal levels in between. Whether this is part of the natural course of the disease, reflecting a more general hepatic dysfunction, needs to be further investigated.
In summary, we report a female infant with recurrent hypoglycemia and severe metabolic acidosis due to the rare combination of 1,6-FDPase deficiency and GH deficiency. Pediatricians should be aware of the possibility of combined causes of severe hypoglycemia in infancy.
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