ESPE Abstracts

Introduction: Co-existence of congenital hypopituitarism and congenital hyperinsulinemia is extremely rare. We present a case of congenital hypopituitarism and hyperinsulinemic hypoglycemia with a novel FOXA2 mutation.

Case: A 22-month-old girl was referred to pediatric endocrinology due to short stature. She was the first child of healthy, non-consanguineous parents with no relevant family history. Delivery was by cesarean section at 40 weeks gestation. Birth weight and length were 3600 grams (76^th percentile) and 48 cm (26^th percentile), respectively. At the age of two days, she had an episode of hypoglycemia requiring hospitalisation for 10 days. Her family reported stalled development from the age of nine months and she had a further three episodes of hypoglycemia, but no endocrinological evaluation was performed. Her father had growth hormone deficiency at 10-years- old requiring growth hormone treatment until 16-years-old. On initial examination, height was 75 cm (-2.76SD) and weight was 8.6 kg (-2.15SD), while mid parental height was 158 cm (-0.87SD). She had no dysmorphic features. Complete blood count, liver and kidney function tests were normal. She had a low free-thyroxine (0.57ng/dL) but thyroid stimulating hormone was normal (2.09 μl/ml). Plasma glucose was 36 mg/dL. Hypoketotic hypoglycemia was confirmed by repeated measurements. Plasma insulin was 2.96 u/ml, C-peptide was 1.15 ng/ml during hypoglycemia. Glucagon stimulation test resulted in a rise in plasma glucose to 102 mg/dL. Both cortisol (6.99 mcg/dL) and growth hormone (0.16 ng/ml) response to hypoglycemia was blunted. Ammonia, lactate, b-hydroxybutyrate and non-esterified free fatty acid levels were normal or suppressed. After hospitalization, glucose infusion and diazoxide was started. She had cortisol response (21 mcg/dL) to low dose adrenocorticotropin stimulation test. Levothyroxine (25mcg-day) was started. When euthyroid, growth hormone stimulation test was performed with L-dopa, but there was no appreciable response (0.28 ng/ml). Magnetic resonance imaging of the pituitary gland demonstrated an ectopic posterior pituitary. Growth hormone replacement was started. Normoglycemia was achieved with diazoxide (15 mg-kg-day) and growth hormone replacement (25 mcg-kg-day). Genetic screening for ABCC8, GCK, GLUD1, HADH, INS, KCNJ11, SLC16A1 and FOXA2 was performed.Sequencing revealed a novel, heterozygous FOXA2 variant (NM_021784.5 c.304delG [p.A102Rfs*11] [p.Ala102ArgfsTer11]) of likely pathogenicity (ACMG guideline). Functional analysis and parents’ genetic studies are still ongoing.

Conclusion: FOXA2 has an important role for both pituitary and pancreatic development. Although the functional analysis is not yet complete, we hypothesize that the detected FOXA2 mutation is related to the phenotype of this patient.