Non-insulinoma persistent hyperinsulinaemic hypoglycaemia caused by an activating glucokinase mutation: hypoglycaemia unawareness and attacks.

OBJECTIVE: Adult-onset non-insulinoma persistent hyperinsulinaemic hypoglycaemia (NI-PHH) and the variant NI-pancreatogenous hypoglycaemia syndrome (NIPHS) are genetically unexplained diseases, without reports of hypoglycaemia unawareness or familial inheritance. DESIGN AND PATIENTS: In a prospective 8-year follow-up, a boy (i) with NI-PHH since age 14 years, his mother (ii), the mother's brother (iii) and his daughter (iv) were studied. RESULTS: Patient (i) was characterized by especially postprandial hypoglycaemia down to 1.6 mmol/l and pronounced variability in diazoxide need with obesity; (ii) had asymptomatic blood glucose down to 2.9 mmol/l, but a severe hypoglycaemic postprandial attack after a slimming diet; (iii) had moderate hypoglycaemic symptoms since childhood and need of frequent eating; and (iv) was asymptomatic until a hypoglycaemic accident in the age of 24. After a slimming diet, symptomatic fasting, but especially postprandial hypoglycaemia occurred (blood glucose 1.9 mmol/l after 19 h fasting; 1.6 mmol/l 3.5 h after OGTT). By CT-scan/endoscopic ultrasound in three of the individuals, insulinoma could not be detected. In all four individuals, an activating glucokinase (GCK) mutation A456V was found. No mutations were found in the ABCC8 or KCNJ11 genes. The patients responded to treatment with diazoxide or octreotide long acting release. CONCLUSION: This is the first report to highlight a genetic cause to adult-onset NI-PHH/NIPHS. The activating GCK mutation was dominantly inherited, but only after year-long follow-up and investigations, other family members were diagnosed symptomatic. Hypoglycaemia unawareness seems to be a prominent feature, but hypoglycaemic attacks occur after slimming, especially postprandially. PHH-GCK was medical responsive.

Pegvisomant therapy in pituitary gigantism: successful treatment in a 12-year-old girl.

OBJECTIVE: The use of a growth hormone (GH) receptor antagonist, pegvisomant has shown great promise in adults with acromegaly, but experience in paediatric patients is lacking. We aimed to describe the results of pegvisomant therapy in a 12-year-old girl with an aggressive GH-secreting pituitary tumour. DESIGN: To evaluate the ability of pegvisomant therapy to control the effects of peripheral GH excess in a case of pituitary gigantism. METHODS: Pegvisomant was introduced at 10 mg/day, given subcutaneously, and gradually increased to 20 mg/day until serum IGF-I was normal for age. RESULTS: A large pituitary adenoma with suprasellar extension was diagnosed in a 12-year-old girl with progressive tall stature (178 cm), GH hypersecretion without suppression during oral glucose loading (nadir serum GH, 90 mU/l), high serum IGF-I and serum prolactin levels. Surgical extirpation was not possible because tumour tissue was fibrous and adherent to the optical nerves. Histological examination showed a mixed GH- and prolactin-secreting adenoma with lymphocytic infiltration of B and T cells. Treatment with a dopamine agonist, cabergoline, normalized serum prolactin, but GH secretion was resistant to both somatostatin analogue, octreotide and cabergoline. Radiation followed by pegvisomant therapy titrated up in dose to 20 mg/day led to a marked reduction in GH secretion and normalization of IGF-I, and to growth arrest and improvement of well-being. CONCLUSIONS: We suggest that treatment in pituitary gigantism with pegvisomant is safe and may normalize IGF-I levels and effectively stop growing.

Long-term follow-Up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr).

UNLABELLED: A 18-year clinical follow-up period in a male patient with a germline TSH-R gene mutation (Met453Thr) is described. Nonautoimmune thyrotoxicosis was diagnosed at the age of 7 months. The patient had exophthalmus, failure to thrive, advanced bone age and no goiter. Long-term antithyroid drug treatment (ATD) was necessary during childhood. At the age of 7 years he developed a goiter. Subtotal thyroidectomy was performed at the age of 9 years, followed by repeated ablative radiotherapy at the age of 9.5-13 years due to a toxic multinodular goiter. After 13 years ATD could be discontinued and the patient was euthyroid until 16 years of age, where L-thyroxine substitution had to be started. The exophthalmus diminished, and had disappeared at the age of 18 years, when CT scan of the orbit was performed. CONCLUSION: TSH-R mutation must be considered in early nonautoimmune thyrotoxicosis. A very aggressive treatment strategy is necessary.

An association of hypothalamic hamartoma, central precocious puberty and juvenile granulosa cell tumour in early childhood.

A case of central precocious puberty from infancy due to a hypothalamic hamartoma and associated with an ovarian juvenile granulosa cell tumour is presented. Central precocious puberty was diagnosed by gonadotropin stimulation tests and LHRH agonist therapy was successful. A MR scan, but not a CT scan, demonstrated the hypothalamic hamartoma. The possible influence of early LH stimulation for the development of the granulosa cell tumour is discussed.

Clinical aspects and treatment of juvenile Graves' disease.

Thyrotoxicosis in childhood and adolescence is a rare disease most frequently due to Graves' disease, but non-autoimmune adenomatous goiters are also found. A strong correlation to HLA class II DRB1*0301 and a protective role of DRB1*0701 has been established in juvenile Graves' disease. The natural course of the disease seem to be remission in many, if enough observation time is allowed. Apart from goiter size and the severity of disease at onset, no certain prognostic factors has yet been identified. The treatment modality chosen is not evidence based, but rather tradition, personal experience and pragmatic handling of cases. Prospective, multicenter studies are still in need to answer the questions asked to ensure rational guidelines and consensus. Such studies should also address the essential problem of compliance, one of the important issues in longterm medical treatment.