Publications by authors named "Susann Empting"

11 Publications

  • Page 1 of 1

Case report: contradictory genetics and imaging in focal congenital hyperinsulinism reinforces the need for pancreatic biopsy.

Int J Pediatr Endocrinol 2020 31;2020:17. Epub 2020 Aug 31.

Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester, M13 9WL UK.

Background: Congenital Hyperinsulinism (CHI) is an important cause of severe hypoglycaemia in infancy due to excessive, dysregulated insulin secretion. In focal CHI, a localised lesion within the pancreas hypersecretes insulin and, importantly, hypoglycaemia resolution is possible through limited surgical resection of the lesion. Diagnosis of focal CHI is based on a crucial combination of compatible genetics and specialised imaging. Specifically, a focal lesion arises due to a paternal mutation in one of the ATP-sensitive potassium channel genes, or , in combination with post-zygotic loss of maternal heterozygosity within the affected pancreatic tissue. 6-[18F]Fluoro-L-3,4-dihydroxyphenylalanine (F-DOPA) positron emission tomography (PET)/computed tomography (CT) imaging is used to detect and localise the lesion prior to surgery. However, its accuracy is imperfect and needs recognition in individual case management.

Case Presentation: We report the case of an infant with hypoglycaemia due to CHI and a paternally inherited mutation, c.286G > A (p.Ala96Thr), leading to a high probability of focal CHI. However,F-DOPA PET/CT scanning demonstrated diffuse uptake and failed to conclusively identify a focal lesion. Due to unresponsiveness to medical therapy and ongoing significant hypoglycaemia, surgery was undertaken and a small 4.9 × 1.7 mm focal lesion was discovered at the pancreatic neck. This is the second case where this particular mutation has been incorrectly associated with diffuse F-DOPA uptake, in contrast to the correct diagnosis of focal CHI confirmed by pancreatic biopsy.

Conclusions: Identifying discrepancies between genetic and imaging investigations is crucial as this may negatively impact upon the diagnosis and surgical treatment of focal CHI. This case highlights the need for pancreatic biopsy when a strong suspicion of focal CHI is present even if F-DOPA imaging fails to demonstrate a discrete lesion.
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http://dx.doi.org/10.1186/s13633-020-00086-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457521PMC
August 2020

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome.

Wellcome Open Res 2019 4;4:149. Epub 2020 Aug 4.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome.  A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown.  We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. analysis of these genes highlighted and as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated.  Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.
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http://dx.doi.org/10.12688/wellcomeopenres.15465.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422856PMC
August 2020

Spontaneous Growth and Effect of Early Therapy with Calcitriol and Phosphate in X-linked Hypophosphatemic Rickets.

Pediatr Endocrinol Rev 2017 Nov;15(Suppl 1):119-122

Otto-von-Guericke-University Magdeburg. Dept. of Paediatrics, University Magdeburg Universitätsplatz 2, 39106 Magdeburg, Germany, E-mail:

Whereas nutritional vitamin D deficient rickets affects many people world-wide, X-linked hypophosphatemic rickets (XLH, MIM 307800) has a prevalence of only 1:25.000. Like other rare diseases burden of disease in XLH and the effect of the current standard of care are inadequately described. Only few height data of untreated patients with XLH have been published. Here we report on height before start of therapy of 127 patients with XLH from 49 centres. One investigator collected all data from patient files documented at regular visits by treating physicians. Height standard deviation score (HSDS) was calculated and the geometrical mean was analysed. At birth all patients had a documented height within the healthy reference population. In this cross-sectional analysis of documented height at time of diagnosis decelerates until a mean age of 4.3 years to a nadir, i.e. lowest HSDS of -3.2 HSDS. Afterwards a spontaneous catch-up growth of +1.3 HSDS occurs until start of puberty. To assess the impact of calcitriol and phosphate supplementation on growth we analysed from a cohort of 18 patients treated at the Dept. of Paediatrics at O.-v.-Guericke-University Magdeburg. In this subgroup, size at birth and all time lowest HSDS (r=0.56 p=0.002) are correlated as well as all time low HSDS and last height during puberty (r=0.62 p=0.001). 10 of 18 patients were treated before age 18 months. Within this group the mean HSDS decelerates to -2.2 SDS at age 4.4 y. and increased to -1.4 SDS at age 9.9 years. Adult height, i.e. mean age 17.6 years was -2.4 HSDS. In conclusion, untreated children with XLR are characterized by normal length at birth, diminished growth rate compared to reference children until 4.3 years and spontaneous catch-up growth of 1.3 HSDS until start of puberty. Improved growth rate in XLR children occured by combined phosphate and calcitriol treatment before 18 months.
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http://dx.doi.org/10.17458/per.vol15.2017.crb.spontaneousgrowtheffectDOI Listing
November 2017

A Multicenter Experience with Long-Acting Somatostatin Analogues in Patients with Congenital Hyperinsulinism.

Horm Res Paediatr 2018 14;89(2):82-89. Epub 2017 Dec 14.

Department of Pediatric Endocrinology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Background/aims: Congenital hyperinsulinism (CHI) is a rare disease characterized by recurrent severe hypoglycemia. In the diffuse form of CHI, pharmacotherapy is the preferred choice of treatment. Long-acting somatostatin analogues have been used in children as off-label medication. However, the efficacy, outcomes, and adverse effect profiles of long-acting somatostatin analogues have not been described in multicentered studies. The aim of this retrospective study is to summarize the experience with long-acting somatostatin analogues in a large group of children with CHI.

Methods: Data were obtained retrospectively from 27 patients with CHI who received long-acting somatostatin analogues in 6 different centers in Europe. These included information on glycemic stability, auxology, and adverse effect profile in clinical follow-up assessments.

Results: Blood glucose control improved in most patients (89%). No life-threatening side effects occurred. Thirteen patients (48%) experienced side effects; in 3 patients (11%), the side effects were the main reason for discontinuation of the treatment. The most frequent side effect was elevated liver enzymes (n = 10, 37%).

Conclusion: Long-acting somatostatin analogues are effective in glycemic control of patients with CHI. However, in 37% of all patients increased liver enzymes were observed. It is important to monitor liver function in all patients receiving long-acting somatostatin analogue therapy.
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http://dx.doi.org/10.1159/000485184DOI Listing
September 2018

Formal Neurocognitive Testing in 60 Patients with Congenital Hyperinsulinism.

Horm Res Paediatr 2018 17;89(1):1-6. Epub 2017 Nov 17.

Department of Pediatrics, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Background: Congenital hyperinsulinism (CHI) is hallmarked by persistent hypoketotic hypoglycemia in infancy. In the majority of all patients, CHI is caused by mutations in the KATP channel genes ABCC8 and KCNJ11, but other genes in the insulin-regulatory pathway have also been described. Repeated episodes of hypoglycemia include an increased risk of seizures and intellectual disability. So far, controlled psychometric studies on cognitive, motor, speech, and social-emotional outcome of CHI patients are missing. Until now, neurodevelopmental long-term outcome in CHI patients has only been measured by questionnaires, self-, parental-, or caregiver-administered instruments.

Methods: This is a prospective study of 60 patients (median age 3.3 years, range 3 months to 57 years): 48 with a diffuse, 9 with a focal, and 3 with an atypical histology. Neurodevelopmental outcome was assessed using standardized psychological tests and questionnaires.

Results: 28 of 60 patients showed developmental delay (46.7%). 9 of 57 patients had cognitive deficits (15.8%), 7 of 26 patients had speech problems (26.9%), and 17 of 44 patients had motor problems (38.6%). In 5 of 53 patients, social-emotional problems were reported. Outcome and the underlying genetic defect were not correlated.

Conclusions: Motor problems seem to be prominent in CHI patients. Despite a high incidence of developmental delay, a permanent cognitive defect was only detectable in 9 of 58 patients.
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http://dx.doi.org/10.1159/000481774DOI Listing
October 2018

Surgery in Focal Congenital Hyperinsulinism (CHI) - The "Hyperinsulinism Germany International" Experience in 30 Children.

Pediatr Endocrinol Rev 2016 Dec;14(2):129-137

Otto-von-Guericke-University, Pediatrics, Magdeburg, Germany.

Objectives: Results of surgery for focal CHI in 30 children PATIENTS AND METHODS: All showed an ABCC8 or KCNJ11 mutation. After PET/CT in 29 children and PET/MRT in 1 case, frozen-section guided resection was performed, in left-sided cases by laparoscopy. Mean age at surgery was 11.7 months (2-49).

Results: In 28/30 children, the PET/CT or MRT correlated with histopathology. In two cases, a focal lesion was undectable; one of these was cured, one not. In total, 24 children showed lesions with sizes of 5-12 mm. All were cured instantly. In four children with huge lesions in the pancreatic head, pathological cells remained at the resection margins. One child was cured instantly, two children after a 2nd surgery, and one child was not cured, even after three surgeries. The overall cure rate was 93%.

Conclusions: Imaging, surgical findings, histopathology and clinical outcome in surgery for focal CHI match in most, but not all cases.
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http://dx.doi.org/10.17458/PER.2016.BVE.SurgeryinfocalDOI Listing
December 2016

Therapy monitoring in congenital adrenal hyperplasia by dried blood samples.

J Pediatr Endocrinol Metab 2015 Jul;28(7-8):867-71

Careful monitoring of the therapy is crucial for patients with congenital adrenal hyperplasia (CAH) in order to prevent the effects of increased androgen production as well as life-threatening salt-wasting crisis. The key metabolite, 17α-hydroxyprogesterone (17-OHP) can be detected in serum, saliva or dried blood. In clinical practice there are challenges due to discomfort of venous blood sampling and complicated retrieval of saliva during infancy. Furthermore, the immunoassay method is limited in its specificity due to cross-reactions. In this observational study we prospectively examined over a period of 5 years, 20 patients with CAH due to 21-hydroxylase deficiency using standard immunoassays for serum samples (radioimmunoassay and enzyme immunoassay) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) in dried blood spots. Bland-Altman plots show goodness of agreement between both the methods for the desirable therapeutic concentration range of 17-OHP. LC-MS/MS is characterized by a high accuracy in the therapeutic concentration range of 17-OHP <100 nmol/L (r=0.91). Dried blood samples are convenient and reliable specimen for 17-OHP measured by LC-MS/MS. This method could be used for home monitoring of hydrocortisone replacement therapy both in salt-waster and simple virilizer CAH.
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http://dx.doi.org/10.1515/jpem-2014-0303DOI Listing
July 2015

Clinical and genetic evaluation of patients with KATP channel mutations from the German registry for congenital hyperinsulinism.

Horm Res Paediatr 2014 7;81(3):156-68. Epub 2014 Jan 7.

Department of Pediatrics, Otto von Guericke University Magdeburg, Magdeburg, Germany.

Congenital hyperinsulinism (CHI) causes hypoglycemia due to irregular insulin secretion. In infants, a rapid diagnosis and appropriate management to avoid severe hypoglycemia is mandatory. CHI is a heterogeneous condition at the clinical and genetic level, and disease-causing genes have been identified in about half of the patients. The majority of mutations have been identified in the ABCC8 and KCNJ11 genes encoding subunits of the KATP channel responsible for two distinct histological forms. The diffuse form is caused by autosomal recessive or dominant inherited mutations, whereas the focal form is caused by a paternally transmitted recessive mutation and a second somatic event. We report on an unselected cohort of 136 unrelated patients from the German CHI registry. Mutations in either the ABCC8 or KCNJ11 gene were identified in 61 of these patients (45%). In total, 64 different mutations including 38 novel ones were detected in this cohort. We observed biparental (recessive) inheritance in 34% of mutation-positive patients, dominant inheritance in 11% and paternal transmission of a mutation associated with a focal CHI type in 38%. In addition, we observed inheritance patterns that do not exactly follow the classical recessive or dominant mode, further adding to the genetic complexity of this disease.
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http://dx.doi.org/10.1159/000356905DOI Listing
December 2014

Glucose metabolism and neurological outcome in congenital hyperinsulinism.

Semin Pediatr Surg 2011 Feb;20(1):45-9

Department of Pediatrics, O. v. Guericke University, Magdeburg, Germany.

Advances in imaging and surgical techniques allow a complete cure for children with focal-type congenital hyperinsulinism (CHI). In contrast, management of diffuse-type CHI remains a matter of controversy. To prevent hypoglycemic brain damage, extensive surgery has been recommended in the past, resulting in diabetes. On the basis of 2 data sets of patients with congenital hyperinsulinism, the German registry for CHI with 235 patients (ages 1 day to 19 years) and the diabetes treatment register (Diabetes Patienten-Verlaufsdokumentationssystem initiative), a follow-up study was initiated for diabetes mellitus and the intellectual and physical development as well as motor function. In our ongoing study, we investigated 20 patients with CHI (12 male, mean ages 9.9 years). Six of 20 patients had undergone subtotal pancreatectomy. In early infantile development (0-3 years) we observed a trend to motor and speech delay. In early childhood (2.5-7 years) there appeared a trend to an advantage of results of nonverbal tasks compared with verbal tasks. Before 1990 most patients (∼75%) were treated by subtotal pancreatectomy; since 2000, a more conservative approach is obvious (4/68). All patients with diabetes (n = 25) developed the condition after undergoing subtotal pancreatectomy. No spontaneous manifestation of diabetes was noted before adulthood. There was a wide range of age (0-17.7 years) at manifestation indicating a long period during which glucose tolerance is compensated. Compared with >40.000 children with type 1 diabetes mellitus from the Diabetes Patienten-Verlaufsdokumentationssystem registry, we found significant differences with a tendency for being overweight as well as small stature. Mean daily insulin dose and HbA1c was comparable in both groups.
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http://dx.doi.org/10.1053/j.sempedsurg.2010.10.005DOI Listing
February 2011

Visualization of the focus in congenital hyperinsulinism by intraoperative sonography.

Semin Pediatr Surg 2011 Feb;20(1):28-31

Pediatric Radiology, O. v. Guericke University, Magdeburg, Germany.

In surgery for focal congenital hyperinsulinism (CHI), the identification and complete resection of the focus without collateral damage is of utmost importance. In a pilot study we applied intra-abdominal high-frequency sonography during surgery for focal CHI in 2 infants. The focus could be identified, its relation to the pancreatic and common bile duct could be shown, and the typical octopus-like tentacles could be demonstrated. In one case the resection was successful; in the other it was not. These preliminary results suggest that intraoperative sonography could be a valuable tool in the surgical therapy of focal CHI and warrants further evaluation in a clinical study.
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http://dx.doi.org/10.1053/j.sempedsurg.2010.10.011DOI Listing
February 2011

The Magdeburg Clinical Studies' Network for pediatric diseases.

Stud Health Technol Inform 2003 ;96:253-6

Dept. of Pediatrics, Medical Faculty, Otto-von-Guericke-University, Wiener Strasse, 39112 Magdeburg, Germany.

New pharmaceutical technologies had created either enthusiastic hope for major improvements in the medical treatment or major doubts on the use of research data and wrongdoing in clinical trials. Clinical investigators have to consider methodological and scientific principles, to stick to ethical rules, national law and international guidelines. With the invention of General Clinical Research Centres the necessary infrastructure in hospitals with well-trained personnel and the availability of laboratory, clinical and supporting service has been created in the US. Taking GCRC as a model to improve the clinical research in pediatrics, a formal collaboration between the Department of Pediatrics and the Institute for Biometry and Medical Informatics was established at the Otto-von-Guericke-University Magdeburg in 2001. Both nation-wide quality assurance programmes in Pediatric Endocrinology and clinical trials according to the principles of good clinical practice ('GCP') were planned and currently performed. Thus with the resources of the Medical faculty and additional project bound finances the necessary infrastructure has been developed.
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May 2004