Health-related quality of life of children with X-linked hypophosphatemia in Germany.

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare inherited phosphate-wasting disorder associated with bone and dental complications. Health-related quality of life (HRQoL) is reduced in XLH patients on conventional treatment with phosphate supplements and active vitamin D, while information on patients treated with burosumab is rare. METHODS: HRQoL was assessed in 63 pediatric XLH patients participating in a prospective, observational study and patient registry in Germany using the KIDSCREEN-52 survey instrument and standardized qualitative interviews. RESULTS: The median age of the XLH patients was 13.2 years (interquartile range 10.6 - 14.6). At the time of the survey, 55 (87%) patients received burosumab and 8 (13%) conventional treatment. Forty-six patients (84%) currently being treated with burosumab previously received conventional treatment. Overall, HRQoL was average compared to German reference values (mean ± SD: self-report, 53.36 ± 6.47; caregivers' proxy, 51.33 ± 7.15) and even slightly above average in some dimensions, including physical, mental, and social well-being. In general, XLH patients rated their own HRQoL higher than their caregivers. In qualitative interviews, patients and caregivers reported that, compared with conventional therapy, treatment with burosumab reduced stress, bone pain, and fatigue, improved physical health, and increased social acceptance by peers and the school environment. CONCLUSIONS: In this real-world study in pediatric XLH patients, HRQoL was average or even slightly above that of the general population, likely due to the fact that the vast majority of patients had their treatment modality switched from conventional treatment to burosumab resulting in improved physical health and well-being.

Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants.

The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism.

Clinical characteristics and cardiovascular risk profile in children and adolescents with latent autoimmune diabetes: Results from the German/Austrian prospective diabetes follow-up registry.

AIMS: To characterize children and adolescents with latent autoimmune diabetes of the young (LADY), and to assess the utility of classifying individuals as LADYs regarding their cardiovascular (CV) risk factors. METHODS: Data from 25,520 individuals (age at diagnosis <18 years) of the Prospective Diabetes Follow-up Registry Diabetes-Patienten Verlaufsdokumentation (DPV) were analyzed. LADY was defined as positivity of ≥one islet autoantibody (iAb+) and an insulin-free interval of ≥6 months upon diabetes diagnosis. LADYs were compared to iAb+ individuals immediately requiring insulin ("immunologically confirmed" type 1 diabetes, T1DM), iAb-/Ins- individuals ("classical" T2DM) and to those clinically defined as T2DM (iAbs not measured). RESULTS: Clinical characteristics of LADYs (n = 299) fell in between those with T1DM (n = 24,932) and T2DM (iAb-/Ins-, n = 152) or suspected T2DM (iAB not measured, n = 137). Stratifying LADYs according to their clinical diagnosis however revealed two distinct populations, highly resembling either T1DM or T2DM. Particularly, CV risk profile, precisely prevalence rates of arterial hypertension and dyslipidemia, was significantly higher in LADYs clinically classified as T2DM compared to LADYs classified as T1DM, and did not differ from those with "classical" T2DM. CONCLUSIONS: In terms of CV risk, classifying children and adolescents with diabetes as LADYs provides no additional benefit. Instead, clinical diagnosis seems to better assign individuals to appropriate risk groups for increased CV risk profiles.

Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration.

Diabetes mellitus and neurodegeneration are common diseases for which shared genetic factors are still only partly known. Here, we show that loss of the BiP (immunoglobulin heavy-chain binding protein) co-chaperone DNAJC3 leads to diabetes mellitus and widespread neurodegeneration. We investigated three siblings with juvenile-onset diabetes and central and peripheral neurodegeneration, including ataxia, upper-motor-neuron damage, peripheral neuropathy, hearing loss, and cerebral atrophy. Exome sequencing identified a homozygous stop mutation in DNAJC3. Screening of a diabetes database with 226,194 individuals yielded eight phenotypically similar individuals and one family carrying a homozygous DNAJC3 deletion. DNAJC3 was absent in fibroblasts from all affected subjects in both families. To delineate the phenotypic and mutational spectrum and the genetic variability of DNAJC3, we analyzed 8,603 exomes, including 506 from families affected by diabetes, ataxia, upper-motor-neuron damage, peripheral neuropathy, or hearing loss. This analysis revealed only one further loss-of-function allele in DNAJC3 and no further associations in subjects with only a subset of the features of the main phenotype. Our findings demonstrate that loss-of-function DNAJC3 mutations lead to a monogenic, recessive form of diabetes mellitus in humans. Moreover, they present a common denominator for diabetes and widespread neurodegeneration. This complements findings from mice in which knockout of Dnajc3 leads to diabetes and modifies disease in a neurodegenerative model of Marinesco-Sjögren syndrome.

Continuing role for classical cytogenetics: Case report of a boy with ring syndrome caused by complete ring chromosome 4 and review of literature.

Constitutional ring chromosomes can be found for all human chromosomes and are very rare chromosomal abnormalities. A complete ring chromosome without loss of genetic material results from fusion of subtelomeric regions or telomere-telomere fusion. In cases of complete ring chromosome, an increased incidence of severe growth failure with no or only minor anomalies has been observed and attributed to ring syndrome. Ring syndrome is thought to be caused by "dynamic mosaicism" due to ring instability. We report a 6-year-old boy with de novo ring chromosome 4 and typical characteristics of the ring syndrome, namely, proportionate severe growth failure, microcephaly, and minor anomalies. Cytogenetic studies showed complete ring chromosome 4 with mitotic instability. Microarray gave normal results, thus excluding the loss of detectable genetic material. The literature of complete ring chromosome 4 is reviewed. Our case report supports the theory of ring syndrome. No studies about the effects and possible side effects of growth hormone therapy on patients with ring chromosomes have yet been published. We suggest that cytogenetic monitoring of the rate of secondary aberrations in patients with ring chromosome undergoing growth hormone therapy might be feasible. Since the diagnosis would have been missed by molecular karyotyping, our case report underlines the continuing role of classical cytogenetics for the evaluation of structural chromosomal abnormalities in patients with mental and/or physical anomalies. Standard karyotyping is still indispensable and should have an ongoing role as first-tier analysis together with molecular karyotyping. © 2017 Wiley Periodicals, Inc.

Continuous glucose monitoring versus blood glucose monitoring for risk of severe hypoglycaemia and diabetic ketoacidosis in children, adolescents, and young adults with type 1 diabetes: a population-based study.

BACKGROUND: The effect of continuous glucose monitoring on the risk of severe hypoglycaemia and ketoacidosis in patients with diabetes is unclear. We investigated whether rates of acute diabetes complications are lower with continuous glucose monitoring, compared with blood glucose monitoring, and which metrics predict its risk in young patients with type 1 diabetes. METHODS: In this population-based cohort study, patients were identified from 511 diabetes centres across Austria, Germany, Luxembourg, and Switzerland participating in the Diabetes Prospective Follow-up initiative. We included people with type 1 diabetes aged 1·5-25·0 years, with a diabetes duration of more than 1 year, who had been treated between Jan 1, 2014, and June 30, 2021, and had an observation time of longer than 120 days in the most recent treatment year. Severe hypoglycaemia and ketoacidosis rates during the most recent treatment year were examined in people using continuous glucose monitoring and in those using blood glucose monitoring. Adjustments of statistical models included age, sex, diabetes duration, migration background, insulin therapy (pump or injections), and treatment period. Rates of severe hypoglycaemia and diabetic ketoacidosis were evaluated by several continuous glucose monitoring metrics, including percentage of time below target glucose range (<3·9 mmol/L), glycaemic variability (measured as the coefficient of variation), and mean sensor glucose. FINDINGS: Of 32 117 people with type 1 diabetes (median age 16·8 years [IQR 13·3-18·1], 17 056 [53·1%] males), 10 883 used continuous glucose monitoring (median 289 days per year), and 21 234 used blood glucose monitoring. People using continuous glucose monitoring had lower rates of severe hypoglycaemia than those using blood glucose monitoring (6·74 [95% CI 5·90-7·69] per 100 patient-years vs 8·84 [8·09-9·66] per 100 patient-years; incidence rate ratio 0·76 [95% CI 0·64-0·91]; p=0·0017) and diabetic ketoacidosis (3·72 [3·32-4·18] per 100 patient-years vs 7·29 [6·83-7·78] per 100 patient-years; 0·51 [0·44-0·59]; p<0·0001). Severe hypoglycaemia rates increased with percentage of time below target glucose range (incidence rate ratio 1·69 [95% CI 1·18-2·43]; p=0·0024, for 4·0-7·9% vs <4·0% and 2·38 [1·51-3·76]; p<0·0001, for ≥8·0% vs <4·0%) and glycaemic variability (coefficient of variation ≥36% vs <36%; incidence rate ratio 1·52 [95% CI 1·06-2·17]; p=0·022). Diabetic ketoacidosis rates increased with mean sensor glucose (incidence rate ratio 1·77 [95% CI 0·89-3·51], p=0·13, for 8·3-9·9 mmol/L vs <8·3 mmol/L; 3·56 [1·83-6·93], p<0·0001, for 10·0-11·6 mmol/L vs <8·3 mmol/L; and 8·66 [4·48-16·75], p<0·0001, for ≥11·7 mmol/L vs <8·3 mmol/L). INTERPRETATION: These findings provide evidence that continuous glucose monitoring can reduce severe hypoglycaemia and ketoacidosis risk in young people with type 1 diabetes on insulin therapy. Continuous glucose monitoring metrics might help to identify those at risk for acute diabetes complications. FUNDING: German Center for Diabetes Research, German Federal Ministry of Education and Research, German Diabetes Association, and Robert Koch Institute.

Effects of Burosumab Treatment on Mineral Metabolism in Children and Adolescents With X-linked Hypophosphatemia.

CONTEXT: Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking. OBJECTIVE: To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH. DESIGN: Prospective national registry. SETTING: Hospital clinics. PATIENTS: A total of 93 patients with XLH (65 children, 28 adolescents). MAIN OUTCOME MEASURES: Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. RESULTS: At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01). CONCLUSIONS: In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

Health and quality of life in adults with Noonan syndrome.

OBJECTIVE: To obtain information on health and quality of life in adults with Noonan syndrome. STUDY DESIGN: From a cohort of 144 children with the diagnosis of Noonan syndrome whose height data had been published 23 years ago, 103 pediatric files providing adequate data were identified. Participants were sent questionnaires and asked to provide saliva for DNA analysis and to return for physical examination. RESULTS: Ten of 103 individuals had died, 3 of them suddenly (standardized mortality ratio, 3.00; 95% CI, 1.44-5.52). Eighty-one individuals could be contacted by mail, with a positive response from 45. Genotyping in 36 of 45 participants revealed characteristic mutations in 61%. Median age at follow-up was 42.8 years. Mean adult heights were 169.2 cm (men) and 154.4 cm (women). In comparison with the general population, participants had lower educational status and lived more frequently without any partner. According to the response to the Short Form-36 questionnaire, quality of life was not impaired. CONCLUSIONS: Individuals with Noonan syndrome have higher mortality, lower education, and rarely partnership. Quality of life according to self-reported Short Form-36 was good. Men grew taller than previously reported from this cohort.

A de novo interstitial deletion of 2p23.3-24.3 in a boy presenting with intellectual disability, overgrowth, dysmorphic features, skeletal myopathy, dilated cardiomyopathy.

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations.

Diabetes management in Wolcott-Rallison syndrome: analysis from the German/Austrian DPV database.

BACKGROUND: Wolcott-Rallison syndrome (WRS) is characterized by permanent early-onset diabetes, skeletal dysplasia and several additional features, e.g. recurrent liver failure. This is the first multicentre approach that focuses on diabetes management in WRS. We searched the German/Austrian Diabetes-Patienten-Verlaufsdokumentation (DPV) registry and studied anthropometric characteristics, diabetes treatment, glycaemic control and occurrence of severe hypoglycaemia (SH) and diabetic ketoacidosis (DKA) in 11 patients with WRS. Furthermore, all local treatment centres were personally contacted to retrieve additional information on genetic characteristics, migration background and rate of consanguinity. RESULTS: Data were analysed at diabetes onset and after a median follow-up period of 3 (1.5-9.0) years (time from diagnosis to latest follow-up). Median age at diabetes onset was 0.2 (0.1-0.3) years, while onset was delayed in one patient (aged 16 months). Seventy percent of patients manifested with DKA. At follow-up, 90% of patients were on insulin pump therapy requiring 0.7 [0.5-1.0] IU of insulin/kg/d. More than two third of patients had HbA1c level ≥ 8%, 40% experienced at least one episode of SH in the course of the disease. Three patients died at 0.6, 5 and 9 years of age, respectively. To the best of our knowledge three patients carried novel mutations in EIF2AK3. CONCLUSION: Insulin requirements of individuals with WRS registered in DPV appear to be comparable to those of preschool children with well-controlled type 1 diabetes, while glycaemic control tends to be worse and episodes of SH tend to be more common. The majority of individuals with WRS in the DPV registry does not reach glycaemic target for HbA1c as defined for preschool children (< 7.5%). International multicentre studies are required to further improve our knowledge on the care of children with WRS.

Deficient knowledge in adult Turner syndrome care as an incentive to found Turner centers in Germany.

OBJECTIVE: Turner syndrome (TS) is characterized by the complete or partial loss of the second sex chromosome and associated with a wide range of clinical manifestations. We aimed to assess the medical care of adult patients with TS in Germany. DESIGN: Retrospective multicenter observational study. METHODS: Data were collected from medical records of 258 women with TS treated between 2001 and 2017 in five non-university endocrinologic centers in Germany. RESULTS: Mean age was 29.8 ± 11.6 years, mean height 152 ± 7.7 cm, and mean BMI 26.6 ± 6.3 kg/m2. The karyotype was known in 50% of patients. Information on cholesterol state, liver enzymes, and thyroid status was available in 81-98% of women with TS; autoimmune thyroiditis was diagnosed in 37%. Echocardiography was performed in 42% and cardiac MRI in 8.5%, resulting in a diagnosis of cardiovascular disorder in 28%. Data on growth hormone therapy were available for 40 patients (15%) and data concerning menarche in 157 patients (61%). CONCLUSION: In 258 women with TS, retrospective analysis of healthcare data indicated that medical management was focused on endocrine manifestations. Further significant clinical features including cardiovascular disease, renal malformation, liver involvement, autoimmune diseases, hearing loss, and osteoporosis were only marginally if at all considered. Based on this evaluation and in accordance with recent guidelines, we compiled a documentation form facilitating the transition from pediatric to adult care and further medical management of TS patients. The foundation of Turner Centers in March 2019 will improve the treatment of TS women in Germany.

Novel Insights into 46,XY Disorders of Sex Development due to NR5A1 Gene Mutation.

The differential diagnosis of 46,XY disorders of sex development (DSD) is based on the distinction between forms of gonadal dysgenesis and disorders of androgen biosynthesis and action. However, clinical and endocrine evaluations are often not conclusive. Here, we describe an adolescent female with hirsutism and hyperandrogenization at puberty. Her karyotype was 46,XY, and clinical investigation demonstrated clitoromegaly, but no uterine remnants were detected. Histology of the gonads revealed a testicular structure with a Sertoli-cell-only pattern. Endocrine evaluation showed hypergonadotropic hypogonadism, and the Sertoli cell markers inhibin B and anti-Müllerian hormone were also low. Several molecular genetic studies were initiated. While analyses of the androgen receptor gene, the SRD5A2 gene and HSD17B3 gene were uninformative, a novel p.L230R mutation was found in the NR5A1 gene. A mutant construct proved a severe dysfunction of this variant in functional analysis after recreation and transfection into HeLa cells. We conclude that the NR5A1 p.L230R mutation most likely leads to a spatial and time-dependent Leydig cell and Sertoli cell dysfunction during development not causing the classical gonadal dysgenesis phenotype. This case demonstrates that the current classification should be updated to encompass the overlapping phenotypes of some genetic conditions within 46,XY DSD.

Higher relative risk for multiple sclerosis in a pediatric and adolescent diabetic population: analysis from DPV database.

OBJECTIVE Type 1 diabetes and multiple sclerosis (MS) are typical autoimmune diseases in children and young adults. We assessed the co-occurrence of type 1 diabetes and MS by estimating the relative risk (RR) for MS in a pediatric and adolescent diabetic population and looked for possible influencing factors. RESEARCH DESIGN AND METHODS Within the Diabetes Patienten Verlaufsdokumentation (DPV)-Wiss Project, from January 1995 to October 2012, data from 56,653 patients with type 1 diabetes were collected in 248 centers in Germany and Austria. Published data on German and Mid-European MS prevalence were taken for comparison. Multivariable regression analysis was used to identify confounders for co-occurrence of type 1 diabetes and MS. RESULTS The RR for MS in patients with type 1 diabetes was estimated at 3.35-4.79 (95% CI 1.56-7.21 and 2.01-11.39, respectively). Immigration status in all patients (P < 0.05) and the presence of thyroid antibodies in male patients only (P = 0.05) were identified as influencing factors on MS incidence within the DPV database. The month-of-birth pattern revealed that risk was higher during the spring and summer months in the population with type 1 diabetes and MS in comparison with the population with type 1 diabetes. CONCLUSIONS The present cohort study demonstrates a higher risk of co-occurrence of MS in a pediatric and adolescent diabetic population. Immigration status and thyroid antibodies in male patients were independent risk indicators for the incidental rate of MS. Diabetic patients born during spring and summer had a higher risk for the development of MS. We suggest that environmental factors modulate the individual's risk for the co-occurrence of both diseases.

Two cases of thyroid dysgenesis caused by different novel PAX8 mutations in the DNA-binding region: in vitro studies reveal different pathogenic mechanisms.

BACKGROUND: Mutations in PAX8, a transcription factor gene, cause thyroid dysgenesis (TD). The extreme variability of the thyroid phenotype makes it difficult to identify individuals harboring PAX8 gene mutations. Here we describe two patients with TD and report two novel PAX8 gene mutations (S54R and R133Q). We performed in vitro studies to functionally characterize these mutations. METHODS: Using PAX8 expression vectors, we investigated whether the PAX8 mutants localized correctly to the nucleus. To analyze the DNA-binding properties of S54R and R133Q, electrophoretic mobility shift assays were performed. Furthermore, we measured whether the mutant PAX8 proteins were able to activate the thyroglobulin (TG)- and the thyroperoxidase (TPO)-promoters. RESULTS: S54R had an impaired binding to DNA and a negligible activity on the TG- and the TPO-promoters. The DNA-binding property of R133Q, which is located in the highly conserved terminal portion of the PAX8 DNA-binding domain, was normal. Interestingly, it also exhibited dramatically impaired activation of the TG- and TPO-promoters. However, R133Q has no dominant negative effect on the WT protein in vitro. Thus, the underlying molecular mechanism by which the function of R133Q is impaired remains to be elucidated. CONCLUSIONS: We identified and functionally characterized two novel mutations of the PAX8 gene that lead to TD by distinct mechanisms. A structural defect of the mutant R133Q leading to a reduced capability for induced fit upon DNA interaction might explain the disparity between its apparently normal binding to DNA, but lack of promoter activation.