Bendt Brock Jacobsen

High prevalence of coeliac disease in Danish children with type I diabetes mellitus

The purpose of this population‐based study was to determine the prevalence of coeliac disease (CD) in 106 Danish children (age 2‐18 y) with type I diabetes mellitus compared with 106 age‐and sex‐matched healthy controls. Serum samples were analysed for immunoglobulin A (IgA) and IgG gliadin antibodies by enzyme‐linked immunosorbent assay (ELISA), for IgA endomysium antibodies (EMA) by immunofluorescence and for IgA tissue transglutaminase antibodies (tTGA) by ELISA. None of the controls had EMA or tTGA. Two diabetics previously diagnosed with CD were antibody negative on a gluten‐free diet. Ten diabetics had both EMA and tTGA. Intestinal biopsy was performed in nine of them. All biopsies showed a histological picture of partial or total villous atrophy confirming the diagnosis of CD. Diabetics with CD were significantly younger (p= 0.026), had an earlier onset of diabetes (p= 0.005), had a lower height standard deviation score (p= 0.019) and more often had thyroid antibodies (p= 0.040) compared with diabetics without CD.

Mediastinal germ cell tumour associated with Klinefelter syndrome: A report of case and review of the literature

A 14-year-old boy with Klinefelter syndrome (KS) and a large mediastinal tumour is presented. Human chorionic gonadotropin and oestradiol were markedly increased. An attempt at radical resection was performed. Histological examination revealed a malignant germ cell tumour of mixed histologic pattern composed of choriocarcinoma and components of mature teratoma. Four courses of cisplatin, bleomycin, and etoposide were given. The patient is without any evidence of tumour recurrence 20 months after diagnosis. A review of the literature revealed another 40 cases of primary mediastinal germ cell tumour (PMGCT) associated with KS. Compiled data from larger series demonstrate that at least 8% of male patients with PMGCT have KS, 50 times the expected frequency. In contrast to PMGCT in patients without KS, all tumours were of nonseminomatous histology, and the average age was considerably lower, Tumours in prepubertal boys were associated with precocious puberty.

Activating glucokinase (GCK) Mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation

OBJECTIVE Activating glucokinase (GCK) mutations are a rarely reported cause of congenital hyperinsulinism (CHI), but the prevalence of GCK mutations is not known. METHODS From a pooled cohort of 201 non-syndromic children with CHI from three European referral centres (Denmark, n=141; Norway, n=26; UK, n=34), 108 children had no K(ATP)-channel (ABCC8/KCNJ11) gene abnormalities and were screened for GCK mutations. Novel GCK mutations were kinetically characterised. RESULTS In five patients, four heterozygous GCK mutations (S64Y, T65I, W99R and A456V) were identified, out of which S64Y was novel. Two of the mutations arose de novo, three were dominantly inherited. All the five patients were medically responsive. In the combined Danish and Norwegian cohort, the prevalence of GCK-CHI was estimated to be 1.2% (2/167, 95% confidence interval (CI) 0-2.8%) of all the CHI patients. In the three centre combined cohort of 72 medically responsive children without K(ATP)-channel mutations, the prevalence estimate was 6.9% (5/72, 95% CI 1.1-12.8%). All activating GCK mutations mapped to the allosteric activator site. The novel S64Y mutation resulted in an increased affinity for the substrate glucose (S(0.5) 1.49+/-0.08 and 7.39+/-0.05 mmol/l in mutant and wild-type proteins respectively), extrapolating to a relative activity index of approximately 22 compared with the wild type. CONCLUSION In the largest study performed to date on GCK in children with CHI, GCK mutations were found only in medically responsive children who were negative for ABCC8 and KCNJ11 mutations. The estimated prevalence (approximately 7%) suggests that screening for activating GCK mutations is warranted in those patients.

Long-Term Follow-Up of an Infant with Thyrotoxicosis due to Germline Mutation of the TSH Receptor Gene (Met453Thr)

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 agressive treatment strategy is necessary.

Treatment of Cryptorchidism with Human Chorionic Gonadotropin or Gonadotropin Releasing Hormone

We have conducted a modified double-blind study on the effect of human chorionic gonadotropin (hCG), gonadotropin releasing hormone (GnRH) and placebo on bilateral and unilateral maldescended testes. One hundred and fifty-five boys with bilateral and 88 boys with unilateral cryptorchidism fulfilled the inclusion criteria and completed the treatment protocol. The boys were between 1 and 13 years of age. hCG was administered as intramuscular injections twice weekly for 3 weeks. GnRH and placebo were given intranasally. hCG was superior to GnRH and placebo in the treatment of bilateral maldescended testes (p = 0.0009). Both testes descended in 25% of the boys following treatment with hCG, and improvement in the position of the testes was obtained in a further 25% of the cases. hCG administration resulted in complete testicular descent in 14% of boys with unilateral cryptorchidism compared with 3 and 0% after placebo and GnRH, respectively (p = 0.07). The testis had moved to a more distal position in 46% of the boys treated with hCG. There was no significant difference between the treatment groups with regard to age or initial position of the testes. We conclude that a success rate of 25% justifies the use of hCG in the treatment of maldescended testes, whereas the study did not support a general use of GnRH administered intranasally.

Hormonal treatment of cryptorchidism—hCG or GnRH—a multicentre study

In a modified, double‐blind controlled study, 163 prepubertal boys (aged 1.8–13.0 years) with bilateral and 94 (aged 1.5–13.1 years) with unilateral cryptorchidism were allocated to treatment with either human chorionic gonadotropin (im), gonadotrophin releasing hormone (intranasally) or placebo (intranasally). In individuals with the bilateral condition treatment with human chorionic gonadotrophin resulted in complete descent of both testes in 23% of patients. Treatment with human chorionic gonadotrophin in unilateral cryptorchidism resulted in complete descent in 19% of patients; all results were significantly better than those obtained with gonadotrophin releasing hormone or placebo. Linear and logistic regression analysis of the results obtained by treatment of bilateral disease showed that all treatments were more successful the younger the age of the boys. The data indicated that bilateral and unilateral cryptorchidism respond differently to hormonal treatment. We suggest that human chorionic gonadotrophin should be the first choice of treatment for prepubertal boys older than one year.

Atrophic, autoimmune thyroiditis in infancy. A case report.

Autoimmune thyroiditis in infancy is a very rare condition. Only 1 case has been reported previously. In the present patient an acquired primary hypothyroidism with high titers of thyroid microsomal antibodies was diagnosed at the age of 7 months. The patient died at 9 months of age in a sepsis-like condition. Autopsy revealed an atrophic thyroiditis. The more severe and complex clinical picture of autoimmune thyroiditis in infancy compared to that later in childhood is discussed.

Prolonged intrathecal chemotherapy replacing cranial irradiation in high-risk acute lymphatic leukaemia: Long-term follow up with cerebral computed tomography scans and endocrinological studies

Cranial irradiation in children with acute lymphatic leukaemia (ALL) decreases the risk of CNS relapse but is associated with serious long-term side-effects. We present the long-term outcome of 21 children with high-risk ALL who received prolonged intrathecal chemotherapy instead of the recommended cranial irradiation. Intrathecal triple therapy (methotrexate, hydrocortisone, and cytarabine) was administered every 2nd month throughout the maintenance phase. The average number of courses of intrathecal methotrexate was 8.7 and of triple 9.0. The 5-year event-free survival was 79%. No CNS relapses occurred. CT scan was performed at diagnosis, at cessation of therapy, and 3 years thereafter. No density abnormalities, pathological contrast enhancement, ventricular dilatation, or calcifications were found. One child showed cortical atrophy both at diagnosis and at cessation of therapy. There was a slight decrease in height SDS with time but no change in weight SDS. Delayed bone age was found in 5 children. No abnormalities of growth hormone, thyroid, adrenal, or gonadal function were observed.ConclusionThe study indicates that extended intrathecal chemotherapy in children with high-risk ALL may provide an effective protection from CNS relapses and is associated with a low risk of long-term side-effects.

Norditropin® SimpleXxTM: A Liquid Human Growth Hormone Formulation, a Pen System and an Auto-Insertion Device

Patient compliance is of vital importance for the outcome of any medical therapy. Compliance is especially a problem in long-term treatment of non-life threatening diseases, such as growth retardation in children. Until recently, all human growth hormone (hGH) products required a reconstitution process. Norditropin^® SimpleXx^TM is a liquid formulation of the biosynthetic hGH product Norditropin^®, and, together with an improved NovoPen^® 1.5, NordiPen^TM, and an auto-insertion device, PenMate^TM/NordiPenMate^TM, it has been developed in order to ease the injection process for patients. A randomized, open, multicentre, crossover trial compared Norditropin^® SimpleXx^TM/improved NovoPen^® 1.5 with freeze-dried Norditropin^® PenSet^®/Nordiject^®. A total of 67 children with GH deficiency, aged 5–18 years, were treated with either Norditropin^® SimpleXx^TM for 6 weeks followed by Norditropin^® for 6 weeks or the opposite (sequences I and II, respectively). Acceptability/convenience and pain perception were evaluated by questionnaire after each period. The function and handling of the PenMate^TM were evaluated in a Dutch trial by 27 GH-treated children with intrauterine growth retardation, aged 4–16 years, and their parents. All children were accustomed to using the Nordiject^® pen. The evaluation of the PenMate^TM was based on a questionnaire. A similar trial was conducted in England, in which the NordiPen^TM and the NordiPenMate^TM were evaluated by 25 GH-treated children and their parents. Norditropin^® SimpleXx^TM was found to be easier to inject by 64% of the children, and 98% of the children found the system easier to use overall. There was no difference in pain perception between the two administration systems, as judged by questionnaires and visual analogue scale score. Three out of four patients preferred to continue treatment with Norditropin^® SimpleXx^TM. The safety profiles of the two systems were similar. In the Dutch trial, the PenMate^TM was found to be easy and safe to handle, even for very young children (aged 4–5 years). Of patients who took a long time to get used to the injections, 73% found that the new pen would help. A total of 88% of the children would prefer to use the PenMate^TM in the future. Positive results of the handling tests were also reported in the British trial. The use of Norditropin^® SimpleXx^TM and the auto-insertion device may improve patient compliance.

Rapid Genetic Analysis in Congenital Hyperinsulinism

Backgound: In severe, medically unresponsive congenital hyperinsulinism (CHI), the histological differentiation of focal versus diffuse disease is vital, since the surgical management is completely different. Genetic analysis may help in the differential diagnosis, as focal CHI is associated with a paternal germline ABCC8 or KCNJ11 mutation and a focal loss of maternal chromosome 11p15, whereas a maternal mutation, or homozygous/compound heterozygous ABCC8 and KCNJ11 mutations predict diffuse-type disease. However, genotyping usually takes too long to be helpful in the absence of a founder mutation. Methods: In 4 patients, a rapid genetic analysis of the ABBC8 and KCNJ11 genes was performed within 2 weeks on request prior to the decision of pancreatic surgery. Results: Two patients had no mutations, rendering the genetic analysis non-informative. Peroperative multiple biopsies showed diffuse disease. One patient had a paternal KCNJ11 mutation and focal disease confirmed by positron emission tomography scan and biopsies. One patient had a de novo heterozygous ABBC8 mutation and unexplained diffuse disease confirmed by positron emission tomography scan and biopsies. Conclusion: A rapid analysis of the entire ABBC8 and KCNJ11 genes should not stand alone in the preoperative assessment of patients with CHI, except for the case of maternal, or homozygous/compound heterozygous disease-causing mutations.