Publications by authors named "Klaus Mohnike"

52 Publications

Gonadectomy In Conditions Affecting Sex Development - A Registry-Based Cohort Study.

Eur J Endocrinol 2021 Mar 1. Epub 2021 Mar 1.

S Ahmed, Developmental Endocrinology Research Group, University of Glasgow, Glasgow, United Kingdom of Great Britain and Northern Ireland.

Objectives: To determine trends in clinical practice for individuals with DSD requiring gonadectomy.

Design: Retrospective cohort study.

Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist center; and location of center from cases reported to the International DSD Registry and who were over 16 years old in January 2019.

Results: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centers. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centers in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n=311, p<0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centers, 17 (5%) at 9 centers had undergone gonadectomy before their first presentation to the specialist center. Median age at gonadectomy of cases from high income countries and low/middle income countries (LMIC) was 13.0 yrs (0.1, 68) years and 16.5 yrs (1, 28), respectively (p<0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries.

Conclusions: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.
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http://dx.doi.org/10.1530/EJE-20-1058DOI Listing
March 2021

Lifetime impact of achondroplasia: Current evidence and perspectives on the natural history.

Bone 2021 May 3;146:115872. Epub 2021 Feb 3.

Murdoch Children's Research Institute, Royal Children's Hospital, University of Melbourne, Parkville, Victoria, Australia.

Achondroplasia, the most common form of disproportionate short stature, is caused by a variant in the fibroblast growth factor receptor 3 (FGFR3) gene. Advances in drug treatment for achondroplasia have underscored the need to better understand the natural history of this condition. This article provides a critical review and discussion of the natural history of achondroplasia based on current literature evidence and the perspectives of clinicians with extensive knowledge and practical experience in managing individuals with this diagnosis. This review draws evidence from recent and ongoing longitudinal natural history studies, supplemented with relevant cross-sectional studies where longitudinal research is lacking, to summarize the current knowledge on the nature, incidence, chronology, and interrelationships of achondroplasia-related comorbidities across the lifespan. When possible, data related to adults are presented separately from data specific to children and adolescents. Gaps in knowledge regarding clinical care are identified and areas for future research are recommended and discussed.
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http://dx.doi.org/10.1016/j.bone.2021.115872DOI Listing
May 2021

Semen quality and testicular adrenal rest tumour development in 46,XY congenital adrenal hyperplasia: the importance of optimal hormonal replacement.

Eur J Endocrinol 2021 Apr;184(4):487-501

Department of Pediatric Endocrinology and Diabetes, Children's Hospital, University of Münster, Münster, Nordrhein-Westfalen, Germany.

Objective: To study the impact of the quality of therapeutic control on fertility and on the prevalence of testicular adrenal rest tumours (TART) in young males with congenital adrenal hyperplasia (CAH).

Design: Combined cross-sectional and retrospective clinical study.

Methods: Twenty-nine patients and age-matched controls underwent clinical investigation, including semen analysis, testicular and adrenal ultrasound imaging, and serum and hair steroid analysis. The quality of therapeutic control was categorized as 'poor', 'moderate' or 'medium'. Evaluation of current control was based on concentrations of 17-hydroxy-progesterone and androstenedione in serum and 3 cm hair; previous control was categorized based on serum 17-hydroxy-progesterone concentrations during childhood and puberty, anthropometric and puberty data, bone age data and adrenal sizes.

Results: Semen quality was similar in males with CAH and controls (P = 0.066), however patients with 'poor' past control and large TART, or with 'poor' current CAH control had low sperm counts. Follicle-stimulating hormone was decreased, if current CAH control was 'poor' (1.8 ± 0.9 U/L; 'good': 3.9 ± 2.2 U/L); P = 0.015); luteinizing hormone was decreased if it was 'poor' (1.8 ± 0.9 U/L; P = 0.041) or 'moderate' (1.9 ± 0.6 U/L; 'good': 3.0 ± 1.3 U/L; P = 0.025). None of the males with 'good' past CAH control, 50% of those with 'moderate' past control and 80% with 'poor past control had bilateral TART. The prevalence of TART in males with severe (class null or A) CYP21A2 mutations was 53% and 25% and 0% in those with milder class B and C mutations, respectively.

Conclusions: TART development is favoured by inadequate long-term hormonal control in CAH. Reduced semen quality may be associated with large TART. Gonadotropin suppression by adrenal androgen excess during the latest spermatogenic cycle may contribute to impairment of spermatogenesis.
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http://dx.doi.org/10.1530/EJE-20-1154DOI Listing
April 2021

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

Eur J Endocrinol 2021 Apr;184(4):553-563

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH.

Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry.

Methods: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits.

Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement.

Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.
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http://dx.doi.org/10.1530/EJE-20-1249DOI Listing
April 2021

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

J Clin Endocrinol Metab 2021 Jan;106(1):e192-e203

Developmental Endocrinology Research Group, School of Medicine, Dentistry & Nursing, University of Glasgow, Glasgow, UK.

Background: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear.

Methods: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC.

Results: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively.

Conclusions: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.
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http://dx.doi.org/10.1210/clinem/dgaa694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990061PMC
January 2021

Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: a randomised, double-blind, phase 3, placebo-controlled, multicentre trial.

Lancet 2020 09;396(10252):684-692

BioMarin (UK), London, UK.

Background: There are no effective therapies for achondroplasia. An open-label study suggested that vosoritide administration might increase growth velocity in children with achondroplasia. This phase 3 trial was designed to further assess these preliminary findings.

Methods: This randomised, double-blind, phase 3, placebo-controlled, multicentre trial compared once-daily subcutaneous administration of vosoritide with placebo in children with achondroplasia. The trial was done in hospitals at 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the USA, and the UK). Eligible patients had a clinical diagnosis of achondroplasia, were ambulatory, had participated for 6 months in a baseline growth study and were aged 5 to less than 18 years at enrolment. Randomisation was done by means of a voice or web-response system, stratified according to sex and Tanner stage. Participants, investigators, and trial sponsor were masked to group assignment. Participants received either vosoritide 15·0 μg/kg or placebo, as allocated, for the duration of the 52-week treatment period administered by daily subcutaneous injections in their homes by trained caregivers. The primary endpoint was change from baseline in mean annualised growth velocity at 52 weeks in treated patients as compared with controls. All randomly assigned patients were included in the efficacy analyses (n=121). All patients who received one dose of vosoritide or placebo (n=121) were included in the safety analyses. The trial is complete and is registered, with EudraCT, number, 2015-003836-11.

Findings: All participants were recruited from Dec 12, 2016, to Nov 7, 2018, with 60 assigned to receive vosoritide and 61 to receive placebo. Of 124 patients screened for eligibility, 121 patients were randomly assigned, and 119 patients completed the 52-week trial. The adjusted mean difference in annualised growth velocity between patients in the vosoritide group and placebo group was 1·57 cm/year in favour of vosoritide (95% CI [1·22-1·93]; two-sided p<0·0001). A total of 119 patients had at least one adverse event; vosoritide group, 59 (98%), and placebo group, 60 (98%). None of the serious adverse events were considered to be treatment related and no deaths occurred.

Interpretation: Vosoritide is an effective treatment to increase growth in children with achondroplasia. It is not known whether final adult height will be increased, or what the harms of long-term therapy might be.

Funding: BioMarin Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(20)31541-5DOI Listing
September 2020

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

Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation.

J Inherit Metab Dis 2020 07 21;43(4):671-693. Epub 2020 Apr 21.

Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

Mannose phosphate isomerase-congenital disorder of glycosylation (MPI-CDG) deficiency is a rare subtype of congenital disorders of protein N-glycosylation. It is characterised by deficiency of MPI caused by pathogenic variants in MPI gene. The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment. It is also one of the few treatable subtypes of CDGs with proven effect of oral mannose. This article covers a complex review of the literature and recommendations for the management of MPI-CDG with an emphasis on the clinical aspect of the disease. A team of international experts elaborated summaries and recommendations for diagnostics, differential diagnosis, management, and treatment of each system/organ involvement based on evidence-based data and experts' opinions. Those guidelines also reveal more questions about MPI-CDG which need to be further studied.
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http://dx.doi.org/10.1002/jimd.12241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574589PMC
July 2020

Quality of life of children with achondroplasia and their parents - a German cross-sectional study.

Orphanet J Rare Dis 2019 08 9;14(1):194. Epub 2019 Aug 9.

Institute of Medical Psychology, University of Hamburg-Eppendorf, Martinistraße 52 W26, 20246, Hamburg, Germany.

Background: Achondroplasia is the most common form of disproportionate short stature and might affect not only the quality of life of the affected child but also that of the parents.

Objectives: We aimed to investigate the quality of life of children with achondroplasia from child- and parent perspective as well as the parental quality of life.

Methods: Forty-seven children with achondroplasia and 73 parents from a German patient organization participated. We assessed children's quality of life using the generic Peds QL 4.0™ as self-reports for children aged 8-14 and parent-reports for children aged 4-14 years. Parental quality of life we assessed using the short-form 8-questionnaire.

Results: Children with achondroplasia showed significantly lower quality of life scores compared to a healthy reference population from both the child- and parent-report (p = ≤.01), except the child-report of the emotional domain (t (46) = - 1.73, p = .09). Parents reported significantly lower mental health in comparison with a German reference population (t (72) = 5.64, p ≤ .01) but no lower physical health (t (72) = .20, p = .85). While the parental quality of life was a significant predictor of parent-reported children's quality of life (F (6,66) = 2.80, p = .02), it was not for child-reported children's quality of life (F (6,66) = .92, p = .49).

Conclusions: Achondroplasia is chronically debilitating. Thus special efforts are needed to address patients' and parent's quality of life needs. This special health condition may influence the daily life of the entire family because they have to adapt to the child's particular needs. Therefore, clinicians should not only focus on the child's quality of life but also those of the parents.
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http://dx.doi.org/10.1186/s13023-019-1171-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688231PMC
August 2019

[Medical care of young women with Turner syndrome in Germany].

Dtsch Med Wochenschr 2020 02 24;145(4):e18-e23. Epub 2019 Jul 24.

Universitätskinderklinik, Pädiatrische Endokrinologie und Diabetologie, Bonn.

Background: Many recommendations for medical care for women with Turner syndrome (TS) have been published in the past. There are no studies that analyse the care situation of the women in Germany until now.

Methods: The study was performed in 2015 based on a questionnaire that was completed by TS women (aged ≥ 18 years; median: 25 years). The questionnaire was devised by a French team and used with their permission. All women had received growth hormone treatment during childhood. The women were identified and addressed in writing through eleven cooperating centers and the support group. In all, 130 questionnaires were evaluated.

Results: 79 of the 130 women (61 %) stated that they had health problems. 38 % of the women were under medical care by only one physician and 42 % by two physicians. The gynecologist was mentioned most often (by 80.3 %), followed by the family physician (53.8 %). ENT was mentioned as a problem system by 35 %, but only 3 % of the women attended an ENT physician. The question as to whether at least one of the following examinations (measurements of blood pressure, blood sugar, blood fats, liver function and/or thyroid hormones, echocardiographic and/or audiogram examination) had been performed during a period of 4 years was answered as follows: blood pressure (85 %), blood sugar (47 %), blood fats (41 %), liver function (46 %), thyroid hormones (44 %), echocardiography (57 %) and audiogram (35 %). A comprehensive examination was performed in 9.8 % of the women. 103 women (80.5 %) received sexual hormone replacement therapy. 76 women were on further drugs; thyroid hormones (44 %) and antihypertensive drugs (11 %) were stated most often.

Conclusions: This is the first study which analyses the current situation of medical care of TS women in Germany. Our data show that medical care of young adult TS women is not optimal. The study cannot clarify the reasons. Due to the numerous and different comorbidities, the medical care of TS women is complex and should therefore be provided multidisciplinarily by different specialists under the direction of one physician.
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http://dx.doi.org/10.1055/a-0923-4191DOI Listing
February 2020

Meeting report from the achondroplasia foramen magnum workshop, Salzburg, Austria 22nd June 2019.

Bone 2019 10 17;127:499-502. Epub 2019 Jul 17.

University of Magdeburg, Magdeburg, Germany. Electronic address:

A pre-meeting workshop on foramen magnum stenosis in children with achondroplasia was held in Salzburg, Austria at the 9th International Conference on Children's Bone Health (ICCBH) 22-25 June 2019. The screening, monitoring and surgical approach to foramen magnum stenosis still remains controversial with conflicting guidance in the literature. The structure of the workshop consisted of lectures, a debate, expert and delegate discussion and concluded with a research proposal and further next steps. In total, representation by 40 institutions from 22 different countries that care for approximately 1375 children with achondroplasia, were in attendance.
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http://dx.doi.org/10.1016/j.bone.2019.07.020DOI Listing
October 2019

Quality of Life of Short-Statured Children Born Small for Gestational Age or Idiopathic Growth Hormone Deficiency Within 1 Year of Growth Hormone Treatment.

Front Pediatr 2019 29;7:164. Epub 2019 Apr 29.

Clinic for Children and Adolescents, Erlangen-Nürnberg Universtiy, Erlangen, Germany.

Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency ( = 65), born small for gestational age ( = 58), and idiopathic short stature ( = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.
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http://dx.doi.org/10.3389/fped.2019.00164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6501464PMC
April 2019

Cross-cultural selection and validation of instruments to assess patient-reported outcomes in children and adolescents with achondroplasia.

Qual Life Res 2019 Sep 15;28(9):2553-2563. Epub 2019 May 15.

Department of Medical Psychology, University Medical Center Hamburg-Eppendorf, Martinistraße 52 | W 26, 20246, Hamburg, Germany.

Purpose: Achondroplasia, as the most common form of disproportionate short stature, potentially impacts the health-related quality of life (HRQOL) and functioning of people with this condition. Because there are no psychometrically validated patient-reported outcome (PRO) condition-specific instruments for achondroplasia, this study selected and tested available generic, disease-specific and under development questionnaires for possible use in multinational clinical research.

Methods: A three-step approach was applied. First, a literature review and clinician/expert opinions were used to select relevant PRO questionnaires. Second, focus group discussions, including a group cognitive debriefing for piloting of the questionnaires with children/adolescents with achondroplasia and their parents, were performed in Spain and Germany. Third, a field-test study was conducted to test the psychometric properties of these instruments.

Results: Six questionnaires were identified as potentially relevant in children with achondroplasia. In each country, five focus groups including a cognitive debriefing were conducted, and the results narrowed the possibilities to three instruments as most appropriate to assess HRQOL (the generic PedsQL, the height-specific QoLISSY, and the achondroplasia-specific APLES). Results of the field study indicate the QoLISSY and the PedsQL questionnaires to be most appropriate for use in clinical research at this time.

Conclusion: This selection study is a step forward in assessing the impact of achondroplasia on HRQOL. Of the instruments examined, the QoLISSY and the PedsQL both capture items relevant to children with achondroplasia and have met the psychometric validation criteria needed for use in research. The APLES instrument is a promising tool that should be revisited upon psychometric validation.
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http://dx.doi.org/10.1007/s11136-019-02210-zDOI Listing
September 2019

[Life Situation of Young women with Turner Syndrome: Results of a Questionnaire-based Study in Germany].

Dtsch Med Wochenschr 2019 07 14;144(14):e87-e93. Epub 2019 Mar 14.

Universitäts-Kinderklinik, Pädiatrische Endokrinologie und Diabetologie, Bonn.

Introduction: Psychosocial problems such as anxious personality, low self-esteem, late separation from home and/or late sexual experience have been described in girls and women with Turner syndrome (TS).

Methods: The study was performed in 2015 based on a questionnaire that was sent out to 779 women with TS aged 25 years (median). The questionnaire was devised by a French team and used with their permission. In all, 130 questionnaires (16.7 %) could be evaluated. The questions from the individual topics were not always completely answered.

Results: (mean ± SD).: 116 women (89.9 %) were not married; 52 women (40 %) lived in their parents' home. 47.6 % had a high-school/technical diploma or university degree. 60 women (46 %) had a job; 51 women (39 %) had not completed vocational training. Puberty was induced at the age of 14.2 ± 2.1 years in 78 % of the women. 80 % of the women received hormone replacement therapy at the time of the questionnaire survey. 66 of 93 women (71 %) found that the disease had a negative influence on emotional life. "Love life and sexual relationship" was the topic mentioned most frequently by 44 women (66.6 %). 116 women answered questions on sexuality. Here, 77 % had the first French kiss at the age of 16.4 ± 3.6 years and 62.4 % had sexual intercourse for the first time at the age of 19.0 ± 3.4 years. 81 % of the women stated that they had a partner relationship for more than 6 months (94 women had a male partner and 5 had a female partner). The question as to the wish to have children was answered in the affirmative by 89 of 124 women (71.8 %); 38.2 % desired spontaneous pregnancy and 44.9 % had considered in vitro fertilization or adoption.

Discussion: The women's answers show that care needs to be improved. There are deficits in the topics of family, emotional life, relationships, sexuality, fertility and pregnancy. Therefore, the medical team should also include psychologists and social workers.
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http://dx.doi.org/10.1055/a-0841-9918DOI Listing
July 2019

Genotype/phenotype correlations in 538 congenital adrenal hyperplasia patients from Germany and Austria: discordances in milder genotypes and in screened versus prescreening patients.

Endocr Connect 2019 Feb;8(2):86-94

Department of Pediatrics, Pediatric Endocrinology, Otto von Guericke Universität Magdeburg, Magdeburg, Germany.

Congenital adrenal hyperplasia (CAH) due to CYP21A2 gene mutations is associated with a variety of clinical phenotypes (salt wasting, SW; simple virilizing, SV; nonclassical, NC) depending on residual 21-hydroxylase activity. Phenotypes and genotypes correlate well in 80-90% of cases. We set out to test the predictive value of CAH phenotype assignment based on genotype classification in a large multicenter cohort. A retrospective evaluation of genetic data from 538 CAH patients (195 screened) collected from 28 tertiary centers as part of a German quality control program was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C) and assigned clinical phenotypes correlated with predicted phenotypes, including analysis of Prader stages. Ultimately, concordance of genotypes with clinical phenotypes was compared in patients diagnosed before or after the introduction of nationwide CAH-newborn screening. Severe genotypes (null and A) correlated well with the expected phenotype (SW in 97 and 91%, respectively), whereas less severe genotypes (B and C) correlated poorly (SV in 45% and NC in 57%, respectively). This was underlined by a high degree of virilization in girls with C genotypes (Prader stage >1 in 28%). SW was diagnosed in 90% of screening-positive babies with classical CAH compared with 74% of prescreening patients. In our CAH series, assigned phenotypes were more severe than expected in milder genotypes and in screened vs prescreening patients. Diagnostic discrimination between phenotypes based on genotypes may prove overcome due to the overlap in their clinical presentations.
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http://dx.doi.org/10.1530/EC-18-0281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365666PMC
February 2019

Characterization of diabetes following pancreatic surgery in patients with congenital hyperinsulinism.

Orphanet J Rare Dis 2018 12 22;13(1):230. Epub 2018 Dec 22.

Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany.

Background: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycaemia in infancy that leads to unfavourable neurological outcome if not treated adequately. In patients with severe diffuse CHI it remains under discussion whether pancreatic surgery should be performed or intensive medical treatment with the acceptance of recurrent episodes of mild hypoglycaemia is justified. Near-total pancreatectomy is associated with high rates of insulin-dependent diabetes mellitus and exocrine pancreatic insufficiency. Little is known about the management and long-term glycaemic control of CHI patients with diabetes after pancreatic surgery. We searched the German/Austrian DPV database and compared the course of 42 CHI patients with diabetes to that of patients with type 1 diabetes mellitus (T1DM). Study groups were compared at diabetes onset and after a follow-up period of 6.1 [3.3-9.7] (median [interquartile range]) years.

Results: The majority of CHI patients with diabetes were treated with insulin (85.2% [70.9-99.5] at diabetes onset, and 90.5% [81.2-99.7] at follow-up). However, compared to patients with T1DM, significantly more patients in the CHI group with diabetes were treated with conventional insulin therapy (47.8% vs. 24.4%, p = 0.03 at diabetes onset, and 21.1% vs. 6.4% at follow-up, p = 0.003), and only a small number of CHI patients were treated with insulin pumps. Daily insulin dose was significantly lower in CHI patients with diabetes than in patients with T1DM, both at diabetes onset (0.3 [0.2-0.5] vs. 0.6 IE/kg/d [0.4-0.8], p = 0.003) and follow-up (0.8 [0.4-1.0] vs. 0.9 [0.7-1.0] IE/kg/d, p = 0.02), while daily carbohydrate intake was comparable in both groups. Within the first treatment year, HbA1c levels were significantly lower in CHI patients with diabetes (6.2% [5.5-7.9] vs. 7.2% [6.5-8.2], p = 0.003), but increased to a level comparable to that of T1DM patients at follow-up. Interestingly, in CHI patients, the risk of severe hypoglycaemia tends to be higher only at diabetes onset (14.8% vs. 5.8%, p = 0.1).

Conclusions: In surgically treated CHI patients insulin treatment needs to be intensified in order to achieve good glycaemic control. Our data furthermore emphasize the need for improved medical treatment options for patients with diazoxide- and/or octreotide-unresponsive CHI.
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http://dx.doi.org/10.1186/s13023-018-0970-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304089PMC
December 2018

Bilirubin, urobilinogen, pancreas elastase and bile acid in drain fluid. The GBUP-study: Analysis of biomarkers for a colorectal anastomotic leakage.

Ann Med Surg (Lond) 2018 Nov 21;35:44-50. Epub 2018 Sep 21.

Department of General, Visceral and Cancer Surgery, HELIOS Klinikum Berlin-Buch, Berlin, Germany.

Purpose: A colorectal anastomotic leakage (CAL) is a major complication after colorectal surgery and leads to high rates of morbidity and prolonged hospital stay. The study aims to evaluate the benefit of using bilirubin, urobilinogen, pancreas elastase and bile acid in the drain fluid (DF) as a predictive marker for the CAL.

Methods: From June 2015 to October 2017 100 patients, who underwent left hemicolectomy (LH), sigma resection (SR), high anterior resection (HAR), low anterior resection (LAR) or reversal of Hartmann's Procedure (ROHP) were included in this monocentric non-randomized prospective clinical trial. During the first four postoperative days (POD) the concentration of bilirubin, urobilinogen, pancreas elastase and bile acid in the DF was measured.

Results: In total 100 patients were recruited. 17 were excluded due to intraoperative decisions to conduct a protective stoma. 6 patients had a CAL. The patients of the control group (n = 77) and the patients who suffered from a CAL (n = 6) had no increased concentration of urobilinogen and pancreas elastase in the DF. The concentration of bile acid in the DF of the patients who suffered from a CAL differed from those of the control group on the 4th POD (p = 0.055).The concentration of bilirubin in the DF of the patients who suffered from a CAL significantly differed from those of the control group on the 1st POD (p = 0.031) and on the 3rd POD (p = 0.041).

Conclusion: Bilirubin and bile acid in the DF may function as a predictive marker for a CAL.
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http://dx.doi.org/10.1016/j.amsu.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170325PMC
November 2018

Development of body proportions in achondroplasia: Sitting height, leg length, arm span, and foot length.

Am J Med Genet A 2018 09 27;176(9):1819-1829. Epub 2018 Aug 27.

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

The aims of this study was to construct references for sitting height, leg length, arm span, relative sitting height (sitting height/height), and foot length and to discuss the development for these anthropometric variables in achondroplasia. Sex-specific references covering ±2 SD are presented for ages 2-20 years. Legs and arms in achondroplasia are already at 2 years of age considerably shorter than in the general population and this deviation increases with age. At adult ages, legs are almost 50% shorter than in the general population and arm span roughly 35% shorter. As sitting height is only mildly affected, relative sitting height position develops far beyond normal ranges. Foot length is also not as affected as limbs.
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http://dx.doi.org/10.1002/ajmg.a.40356DOI Listing
September 2018

Growth in achondroplasia: Development of height, weight, head circumference, and body mass index in a European cohort.

Am J Med Genet A 2018 08 2;176(8):1723-1734. Epub 2018 Aug 2.

Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.

As growth references for achondroplasia are limited to reports from United States, Japan, Argentina, and Australia, the aim of this study was to construct growth references for height, weight, head circumference, and body mass index (BMI) from a European cohort of children with achondroplasia and to discuss the development of these anthropometric variables. A mix of cross-sectional and longitudinal, retrospective, and prospective data from 466 children with achondroplasia and 4,375 measuring occasions were modeled with generalized additive model for location, scale and shape (GAMLSS) to sex-specific references for ages 0 to 20 years. Loss in height position, that is, reduction in height standard deviation scores, occurred mainly during first 2 years of life while pubertal growth seemed normal if related to adult height. Adult height was 132 cm in boys and 124 cm in girls with a variability comparable to that of the general population and seems to be remarkably similar in most studies of children with achondroplasia. BMI had a syndrome-specific development that was not comparable to BMI development in the general population. Weight and BMI might be misleading when evaluating, for example, metabolic health in achondroplasia. Head circumference reached adult head size earlier than in the general population. Increased tempo of head circumference growth necessitates thus close clinical follow-up during first postnatal years.
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http://dx.doi.org/10.1002/ajmg.a.38853DOI Listing
August 2018

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

Aggrecan Mutations in Nonfamilial Short Stature and Short Stature Without Accelerated Skeletal Maturation.

J Endocr Soc 2017 Aug 28;1(8):1006-1011. Epub 2017 Jun 28.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892.

Aggrecan, a proteoglycan, is an important component of cartilage extracellular matrix, including that of the growth plate. Heterozygous mutations in , the gene encoding aggrecan, cause autosomal dominant short stature, accelerated skeletal maturation, and joint disease. The inheritance pattern and the presence of bone age equal to or greater than chronological age have been consistent features, serving as diagnostic clues. From family 1, a 6-year-old boy presented with short stature [height standard deviation score (SDS), -1.75] and bone age advanced by 3 years. There was no family history of short stature (height SDS: father, -0.76; mother, 0.7). Exome sequencing followed by Sanger sequencing identified a novel heterozygous frameshift mutation in (c.6404delC: p.A2135Dfs). From family 2, a 12-year-old boy was evaluated for short stature (height SDS, -3.9). His bone age at the time of genetic evaluation was approximately 1 year less than his chronological age. Family history was consistent with an autosomal dominant inheritance of short stature, with several affected members also showing early-onset osteoarthritis. Exome sequencing, confirmed by Sanger sequencing, identified a novel nonsense mutation in (c.4852C>T: p.Q1618X), which cosegregated with the phenotype. In conclusion, patients with mutations may present with nonfamilial short stature and with bone age less than chronological age. These findings expand the known phenotypic spectrum of heterozygous mutations and indicate that this diagnosis should be considered in children without a family history of short stature and in children without accelerated skeletal maturation.
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http://dx.doi.org/10.1210/js.2017-00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686699PMC
August 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

Two patients with MIRAGE syndrome lacking haematological features: role of somatic second-site reversion SAMD9 mutations.

J Med Genet 2018 02 24;55(2):81-85. Epub 2017 Nov 24.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.

Background: Myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (MIRAGE) syndrome is a recently described congenital disorder caused by heterozygous mutations. The phenotypic spectrum of the syndrome remains to be elucidated.

Methods And Results: We describe two unrelated patients who showed manifestations compatible with MIRAGE syndrome, with the exception of haematological features. Leucocyte genomic DNA samples were analysed with next-generation sequencing and Sanger sequencing, revealing the patients to have two mutations on the same allele (patient 1 p.[Gln695*; Ala722Glu] and patient 2 p.[Gln39*; Asp769Gly]). In patient 1, p.Gln695* was absent in genomic DNA extracted from hair follicles, implying that the non-sense mutation was acquired somatically. In patient 2, with the 46,XX karyotype, skewed X chromosome inactivation pattern was found in leucocyte DNA, suggesting monoclonality of cells in the haematopoietic system. expression experiments confirmed the growth-restricting capacity of the two missense mutant SAMD9 proteins that is a characteristic of MIRAGE-associated mutations.

Conclusions: Acquisition of a somatic nonsense mutation in the cells of the haematopoietic system might revert the cellular growth repression caused by the germline mutations (ie, second-site reversion mutations). Unexpected lack of haematological features in the two patients would be explained by the reversion mutations.
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http://dx.doi.org/10.1136/jmedgenet-2017-105020DOI Listing
February 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

Growth and Final Height Among Children With Phenylketonuria.

Pediatrics 2017 Nov;140(5)

Center for Pediatric Research Leipzig, Department of Women and Child Health, Hospital for Children and Adolescents, University Hospitals,

Background And Objectives: Growth is an important criterion to evaluate health in childhood and adolescence, especially in patients depending on special dietary treatment. Phenylketonuria (PKU) is the most common inherited disease of amino acid metabolism. Patients with PKU depend on a special phenylalanine-restricted diet, low in natural protein. The study aimed to evaluate growth, growth rate, and target height in 224 patients with PKU.

Methods: Retrospective, longitudinal analysis of standardized, yearly measurements of height, weight, and calculated growth rate (SD score [SDS]) of patients with PKU aged 0 to 18 years were conducted by using the national computerized CrescNet database. Inclusion was restricted to patients carried to term with a confirmed diagnosis of PKU or mild hyperphenylalaninemia determined by newborn screening and early treatment initiation.

Results: From birth to adulthood, patients with PKU were significantly shorter than healthy German children (height SDS at 18 years: -0.882 ± 0.108, < .001). They missed their target height by 3 cm by adulthood (women: = .02) and 5 cm (men: = .01). In patients receiving casein hydrolysate during childhood, this was more pronounced compared with patients receiving amino acid mixtures ( < .001). Growth rate was significantly reduced during their first 2 years of life and in puberty (growth rate SDS: -1.1 to -0.5 m/year, < .001 and -0.5; < .02).

Conclusions: Early diagnosed, treated, and continuously monitored patients with PKU showed reduced height from birth onward. During the last 2 decades, this phenomenon attenuated, probably because of advances in PKU therapy related to protein supplements and special low-protein foods.
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http://dx.doi.org/10.1542/peds.2017-0015DOI Listing
November 2017

Sodium Chloride Supplementation Is Not Routinely Performed in the Majority of German and Austrian Infants with Classic Salt-Wasting Congenital Adrenal Hyperplasia and Has No Effect on Linear Growth and Hydrocortisone or Fludrocortisone Dose.

Horm Res Paediatr 2018 26;89(1):7-12. Epub 2017 Oct 26.

Pediatric Endocrinology, Department of Pediatrics, Otto von Guericke Universität Magdeburg, Magdeburg, Germany.

Introduction: Sodium chloride supplementation in salt-wasting congenital adrenal hyperplasia (CAH) is generally recommended in infants, but its implementation in routine care is very heterogeneous.

Objective: To evaluate oral sodium chloride supplementation, growth, and hydrocortisone and fludrocortisone dose in infants with salt-wasting CAH due to 21-hydroxylase in 311 infants from the AQUAPE CAH database.

Results: Of 358 patients with classic CAH born between 1999 and 2015, 311 patients had salt-wasting CAH (133 females, 178 males). Of these, 86 patients (27.7%) received oral sodium chloride supplementation in a mean dose of 0.9 ± 1.4 mmol/kg/day (excluding nutritional sodium content) during the first year of life. 225 patients (72.3%) were not treated with sodium chloride. The percentage of sodium chloride-supplemented patients rose from 15.2% in children born 1999-2004 to 37.5% in children born 2011-2015. Sodium chloride-supplemented and -unsupplemented infants did not significantly differ in hydrocortisone and fludrocortisone dose, target height-corrected height-SDS, and BMI-SDS during the first 2 years of life.

Conclusion: In the AQUAPE CAH database, approximately one-third of infants with salt-wasting CAH receive sodium chloride supplementation. Sodium chloride supplementation is performed more frequently in recent years. However, salt supplementation had no influence on growth, daily fludrocortisone and hydrocortisone dose, and frequency of adrenal crisis.
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http://dx.doi.org/10.1159/000481775DOI 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

Outcome after Hypospadias Repair: Evaluation Using the Hypospadias Objective Penile Evaluation Score.

Eur J Pediatr Surg 2018 Jun 15;28(3):268-272. Epub 2017 May 15.

Division of Pediatric Surgery, Department of General, Abdominal & Vascular Surgery, University Hospital, Magdeburg, Sachsen-Anhalt, Germany.

Introduction:  The Hypospadias Objective Penile Evaluation Score (HOPE-Score) is a concise and reproducible way to describe hypospadias severity. We classified boys undergoing primary hypospadias repair to determine the correlation between the HOPE-Score and the severity of hypospadias first and the outcome after surgery second.

Materials And Methods:  Patients who underwent primary hypospadias repair from 2005 to 2014 were identified. An independent physician assessed retrospectively the HOPE-Score, using photographies of the patients before, after primary surgery, and after all necessary surgeries. The correlation between the HOPE-Score and the severity of hypospadias, on the one hand, and the outcome after surgery, on the other hand, were analyzed.

Results:  The HOPE-Score was assessed preoperatively for 79 boys, postoperatively for 66, and after all necessary surgeries for 21 patients. Mean HOPE-Score reached 30.2 ± 5.9 before surgery, 42.2 ± 6.1 after primary surgery, and 43.7 ± 3.4 after all necessary surgeries. A significant correlation between the HOPE-Score and the severity of hypospadias before surgery was observed. The boys with glanular hypospadias scored significantly higher (36.3 ± 5.4) than those with distal (29.6 ± 4.4) and proximal hypospadias (21.1 ± 3.5). Furthermore, a significant correlation between the HOPE-Score and the outcome after hypospadias repair was observed. Patients who needed no reintervention after primary hypospadias repair scored significantly higher postoperatively (45.1 ± 5.4) than those who needed a second (40.8 ± 4.2) or more than two surgeries (36.9 ± 7.4).

Conclusion:  The HOPE-Score is a good system to assess the severity of hypospadias and the cosmetic outcome after hypospadias repair.
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http://dx.doi.org/10.1055/s-0037-1602252DOI Listing
June 2018

Diagnosis and management of Silver-Russell syndrome: first international consensus statement.

Nat Rev Endocrinol 2017 02 2;13(2):105-124. Epub 2016 Sep 2.

AP-HP, Hôpitaux Universitaires Paris Est (AP-HP) Hôpital des Enfants Armand Trousseau, Service d'Explorations Fonctionnelles Endocriniennes, 26 avenue du Dr Arnold Netter, 75012 Paris, France.

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.
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http://dx.doi.org/10.1038/nrendo.2016.138DOI Listing
February 2017