Heddy Landau

A Nonsense Mutation in the Inward Rectifier Potassium Channel Gene, Kir6.2, Is Associated With Familial Hyperinsulinism

ATP-sensitive potassium (KATP) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet β-cells. These channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family. Mutations in the SUR1 subunit are associated with familial hyperinsulinism (HI) (MIM:256450), an inherited disorder characterized by hyperinsulinism in the neonate. Since the Kir6.2 gene maps to human chromosome 11p15.1 (1,2), which also encompasses a locus for HI, we screened the Kir6.2 gene for the presence of mutations in 78 HI probands by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses. A nonsense mutation, Tyr→Stop at codon 12 (designated Y12X) was observed in the homozygous state in a single proband. 86Rb+ efflux measurements and single-channel recordings of COS-1 cells co-expressing SUR1 and either wild-type or Y12X mutant Kir6.2 proteins confirmed that KATP channel activity was abolished by this nonsense mutation. The identification of an HI patient homozygous for the Kir6.2/Y12X allele affords an opportunity to observe clinical features associated with mutations resulting in an absence of Kir6.2. These data provide evidence that mutations in the Kir6.2 sub-unit of the islet β-cell KATP channel are associated with the HI phenotype and also suggest that the majority of HI cases are not attributable to mutations in the coding region of the Kir6.2 gene.

Persistent hyperinsulinemic hypoglycemia of infancy: Long-term octreotide treatment without pancreatectomy

Eight patients with persistent hyperinsulinemic hypoglycemia of infancy who were treated with octreotide without pancreatectomy are described. All had severe, early-onset disease that would have required partial pancreatectomy had octreotide not been available. Along with octreotide, frequent feedings and raw cornstarch at night were required by all. Octreotide was given in three or four daily subcutaneous injections in four patients and in a continuous subcutaneous infusion with an insulin infusion pump in four. All had mild, transient gastrointestinal symptoms (vomiting, abdominal distention, steatorrhea) after the start of therapy. Asymptomatic gallstones were found in 1 patient after 1 year of treatment. No other long-term untoward effects were noted, including no detrimental effect on psychomotor development. Growth was not affected in five of six patients treated for more than 6 months. In five patients, octreotide was discontinued after 9 months to 5 1/2 years; patients were given diazoxide instead, two required percutaneous gastrostomy, and one 5 1/2-year-old child required no further treatment. The remaining three patients (aged 5 to 9 months) are still being treated with octreotide. We conclude that, with the use of octreotide, pancreatectomy can be avoided in some patients. Particularly in light of our findings of a high incidence of diabetes years after partial pancreatectomy, and clinical improvement after months to years of octreotide treatment, we believe that aggressive medical therapy, when effective, is preferable to partial pancreatectomy.

Treatment of Congenital Hyperinsulinism with Lanreotide Acetate (Somatuline Autogel)

CONTEXT Congenital hyperinsulinism (CH) may be treated conservatively in many children with octreotide given by multiple sc injections or via an insulin pump. OBJECTIVE We describe two children treated with a once-monthly injection of a long-acting somatostatin analog. PATIENTS AND METHODS Both patients presented with hypoglycemia 30 min after birth and were subsequently diagnosed with CH. Patients were initially treated with diazoxide, hydrochlorothiazide, frequent feedings, and octreotide via an insulin pump. With this therapy, they were normoglycemic with a good growth rate, normal weight gain, and excellent neurodevelopment. Treatment with the long-acting somatostatin analog lanreotide acetate (Somatuline Autogel), administered by deep sc injection of 30 mg once a month, was started at the ages of 4½ and 4 yr, respectively. Octreotide infusion was gradually weaned over 1 month. Continuous glucose monitoring after discontinuation of pump therapy showed normoglycemia. The first patient has now been treated with the lanreotide acetate for over 5 yr, and the second for 3 yr. Treatment is well-tolerated, and both the patients and their parents are satisfied with the transition from pump therapy to once-a-month injection and prefer it to pump therapy. CONCLUSION Lanreotide acetate may be a safe and effective alternative to octreotide pump therapy in patients with CH, offering an improved quality of life. Longer follow-up of a larger patient group is needed.

PERSISTENT HYPERINSULINAEMIC HYPOGLYCAEMIA OF INFANCY: LONG‐TERM TREATMENT WITH THE SOMATOSTATIN ANALOGUE SANDOSTATIN†

Six infants with severe, persistent hyperinsulinaemic hypoglycaemia were treated with the long‐acting somatostatin analogue SMS 201–995 (Sandostatin, Sandoz, Basle, Switzerland). Effective control of hypoglycaemia without the need for parenteral glucose was achieved in five of the six cases with doses ranging from 10 to 40 μg/kg day given either by four S.C. injections per day, or by continuous subcutaneous infusion (CSI). One has been well controlled on SMS 10 μg/kg day for 17 months as an out‐patient without requiring surgery, while the five others underwent sub‐total pancreatectomy after receiving short courses of the drug. In two patients where hypoglycaemia persisted after sub‐total pancreatectomy SMS was effective in inhibiting insulin secretion and preventing hypoglycaemia. Plasma somatomedin concentrations and linear growth were not suppressed in any patient. It is concluded that Sandostatin is useful in the pre and post‐operative management of most infants with this syndrome. In selected cases this analogue of somatostatin may also be a long‐term treatment option in place of pancreatectomy.

GONADOTROPHIN, THYROTROPHIN AND PROLACTIN RESERVE IN β THALASSAEMIA

Gonadotrophin (Gn), thyrotrophin (TSH) and prolactin (PRL) reserve was evaluated in patients (aged 12–26 years old) with β thalassaemia. Abnormalities were detected in Gn reserve only. When compared with young adult controls, three of the four female patients and one of the two adult males had markedly impaired Gn responses to LH‐releasing hormone (LHRH). Of the five prepubertal males, one had no Gn rise following LHRH, while responses in the other four patients were comparable to those in boys with delayed puberty. Only one adult male had an exaggerated LH response to LHRH. TSH and PRL dynamics were normal. No correlation could be found between the severity of the disturbance in the gonadal axis and the total number of blood transfusions. Our findings correlate best with the severity of the disease process itself.

Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism

BACKGROUND Congenital hyperinsulinism (CH) is treated surgically in many centers (near-total and partial pancreatectomy for diffuse and focal disease respectively). Most patients treated with near-total pancreatectomy developed diabetes during childhood/puberty. CH patients are at increased risk of neurodevelopmental disorders, some being severe, which are reported to occur in 14-44% of patients from highly heterogenous cohorts. Over the last few decades, we have treated children with CH conservatively without surgery. The aim of this study was to assess the neurodevelopmental outcome of these patients. DESIGN AND METHODS The study included 21 Ashkenazi CH medically treated patients: 11 homozygotes (diffuse disease) and 9 heterozygotes with mutations on the paternal allele (presumed focal disease). The mean age was 13.7 years (range 8-23). Neurodevelopmental outcomes were assessed by telephone interviews of parents, using a standard questionnaire. Closest age siblings of CH patients served as controls. RESULTS Ten CH patients had perinatal seizures of short duration. Four had post-neonatal seizures, which remitted entirely. During early childhood, four patients (19%) had hypotonia, eight (38%) had fine motor problems, seven (33%) had gross motor problems (clumsiness), and one had mild cerebral palsy. Three patients (14%) had speech problems. Eight patients required developmental therapy, compared to one in the control group. Most of these problems were resolved by age 4-5 years. At school age, all were enrolled in regular education, some excelled in their studies, 6 out of 21 patients (29%) had learning problems (2 out of 21 controls). None had overt diabetes. CONCLUSIONS Good neurodevelopmental outcome was observed in our conservatively treated CH patients, with no diabetes as reported in patients undergoing pancreatectomy.

Final height after growth hormone therapy in peripubertal boys with a subnormal integrated concentration of growth hormone.

The aim of this study was to test the effect of growth hormone (GH) therapy on final height in peripubertal boys with idiopathic short stature in whom a subnormal integrated concentration of GH (< 3.2 micrograms/l) was found. Twenty-eight peripubertal children were studied. Height was below 2 SD for age, growth velocity was < 4.5 cm/year, bone age was more than 2 SD below mean for age and GH response to provocative tests was more than 10 micrograms/l. Eleven subjects (group B) were treated with recombinant GH 0.75 unit/kg/week, divided into 3 weekly doses for 2 years, and then the same weekly dose divided into daily injections was administered until final height was attained. Seventeen untreated children (group A) who were followed until cessation of growth served as controls. The GH-treated patients reached their target heights (-2.1 +/- 0.5, mean +/- SD in SDS) and predicted heights (-1.8 +/- 0.8) determined by the Bayley and Pinneau method, while the final heights of the untreated patients were significantly lower than their target heights and their predicted final heights (-2.7 +/- 0.7, -1.8 +/- 1.0 and -2.7 +/- 0.7, respectively). The main effect of GH was observed during the 1st year of treatment when height velocity was significantly higher in the GH-treated group than in the untreated one (9.3 +/- 2.1 vs. 5.3 +/- 1.1, respectively, p < 0.001). The high cost of the treatment in this specific age group should be weighed against the results.

Age as a determinant of the impact of growth hormone therapy on predicted adult height

OBJECTIVE Final adult height is determined by both childhood and pubertal growth. The later is a function of growth velocity and bone maturation, and both are regulated by growth hormone. In a study of the safety and efficacy of GH therapy, we analysed the Impact of age on bone maturation and predicted adult height.

ABCC8 mutation allele frequency in the Ashkenazi Jewish population and risk of focal hyperinsulinemic hypoglycemia

Purpose: Congenital hyperinsulinism of infancy (OMIM# 256450) is a devastating disease most commonly caused by dominant or recessive mutations in either ABCC8 or KCNJ11, the genes that encode for the β-cell adenosine triphosphate-regulated potassium channel. A unique combination of a paternally inherited germline mutation and somatic loss-of-heterozygosity causes the focal form of the disease (Focal-congenital hyperinsulinism of infancy [Focal-CHI]), the incidence of which in genetically susceptible individuals is not known.Methods: We genotyped 21,122 Ashkenazi Jewish individuals for two previously identified ABCC8 founder mutations and utilized a clinical database of 61 unrelated Ashkenazi patients with congenital hyperinsulinism of infancy to obtain an estimate of the risk of Focal-CHI in a genetically susceptible fetus.Results: The combined mutation carrier rate in Ashkenazi Jews was 1:52, giving an estimated frequency of homozygosity or compound heterozygosity of 1:10,816 in this population. The risk of Focal-CHI is 1:540 per pregnancy in offspring of carrier fathers.Conclusion: We recommend that these mutations be included in the genetic screening program for the Ashkenazi Jewish population. As the risk of Focal-CHI is not expected to be mutation specific, the data reported in this study are useful for counseling all families in which the father was found to carry a recessive ABCC8 or KCNJ11 mutation.

Cognitive and developmental outcome of conservatively treated children with congenital hyperinsulinism.

Abstract Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants. Its management can be extremely complicated, and may involve medical therapy and surgery. The mainstay of the treatment is to maintain normoglycemia, since hypoglycemia during infancy can have severe neurological consequences. Objective: To assess the cognitive and developmental levels and the adaptive skills achieved by children with CHI who were treated medically over the past decade. Subjects and methods: Fourteen children with CHI, under the age of 10 years, who received medical treatment only, underwent a physical and neurological examination and standardized assessments that included the Bayley Scale of Infant and Toddler Development, 3rd Edition, or Kaufman Assessment Battery for Children, the Vineland Adaptive Behavior Scales and the Achenbach Child Behavior Checklist (CBCL) parent questionnaire form. Results: Twelve children (86%) achieved normal range scores in the cognitive and development assessments (Bayley Scale of Infant and Toddler Development or Kaufman Assessment Battery for Children). Only two showed cognitive achievements below the normal range. The Vineland questionnaire, which was based on parental report, showed below normal adaptive skills in eight patients (57%). Conclusions: In contrast to previous studies showing a high prevalence of neurodevelopmental difficulties in children with congenital hyperinsulinism, our study showed normal cognitive achievements in most children. This may be attributed to the earlier recognition and better management of the disease in the past decade.