[Rare diseases, digitization, and the National Action League for People with Rare Diseases (NAMSE)]. / Seltene Erkrankungen und Digitalisierung im Kontext des Nationalen Aktionsbündnisses für Menschen mit Seltenen Erkrankungen (NAMSE).

People with rare diseases face specific challenges within the healthcare system. Due to the rarity of the individual diseases, both medical care and research are made difficult for structural, medical, and economic reasons. In 2010, the National Action League for People with Rare Diseases (NAMSE) was founded by the German Federal Ministry of Health, the German Federal Ministry of Education and Research, the Alliance for Chronic Rare Diseases, as well as 25 other partners. Since then, NAMSE has been the central coordination and communications platform for people with rare diseases in Germany and aims to improve the health and quality of life of those affected.As part of the consensus process, NAMSE has formulated requirements regarding digitization in the German healthcare system. These requirements aim towards connecting healthcare institutions, generating knowledge for research purposes, and improving the flow of information. The main objective is a collective and secure health data space with interoperable clinic information systems and uniform semantic standards. The precise coding of rare diseases is of particular importance.In the coming years, important processes that have already been initiated must be designed and supported in the interest of people with rare diseases. These include the German genome initiative genomDE, the implementation of the electronic patient record, and activities towards a European Health Data Space. In order for the diverse initiatives and projects to mesh, clear objectives are required as part of an overall digital concept to which NAMSE makes important contributions.

WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations.

Werner syndrome (WS) is an autosomal recessive segmental progeroid syndrome caused by null mutations at the WRN locus, which codes for a member of the RecQ family of DNA helicases. Since 1988, the International Registry of Werner syndrome had enrolled 130 molecularly confirmed WS cases from among 110 worldwide pedigrees. We now report 18 new mutations, including two genomic rearrangements, a deep intronic mutation resulting in a novel exon, a splice consensus mutation leading to utilization of the nearby splice site, and two rare missense mutations. We also review evidence for founder mutations among various ethnic/geographic groups. Founder WRN mutations had been previously reported in Japan and Northern Sardinia. Our Registry now suggests characteristic mutations originated in Morocco, Turkey, The Netherlands and elsewhere.

Age at menarche in childhood cancer survivors: results of a nationwide survey in Germany.

BACKGROUND/AIMS: With rising cure rates of childhood cancer, side effects of treatment are attracting increasing interest. The present analysis evaluates the influence of tumor localization, radiotherapy and chemotherapy on the age of menarche. METHODS: 4,689 former pediatric oncology patients, diagnosed 1980-2004, were contacted in collaboration with the German Childhood Cancer Registry. RESULTS: 1,036 out of 1,461 female participants reported their age at menarche and had an oncological diagnosis before menarche. The median age at menarche was 13 years, compared to 12.8 years in the German general population. A significant delay of menarche was seen in patients with pituitary radiation doses of ≥30 Gy (mean 13.6 years, SD 2.2) compared to <30 Gy (mean 12.5 years, SD 1.4, p = 0.05). Patients with additional spinal radiation were even older at menarche (mean 14.4 years, SD 2.5). Pelvic and pelvic-near radiation significantly delayed onset of menarche (mean 14.0 years, SD 1.9 and mean 14.3, SD 2.6, respectively, p < 0.001). Only some chemotherapeutic agents (carboplatin/cisplatin, etoposide) were associated with a menarcheal delay of <1 year. CONCLUSION: Overall, female childhood cancer survivors showed a normal menarcheal age. Pituitary radiation dosage of ≥30 Gy, spinal and pelvic radiotherapy were associated with a moderate delay in the occurrence of menarche.

Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young.

AIMS: HNF1B-maturity-onset diabetes of the young is caused by abnormalities in the HNF1B gene encoding the transcription factor HNF-1beta. We aimed to investigate detailed clinical features and the type of HNF1B gene anomaly in five pediatric cases with HNF1B-MODY. METHODS: From a cohort of 995 children and adolescents with diabetes, we analyzed the most frequent maturity-onset diabetes of the young genes (GCK, HNF1A, HNF4A) including HNF1B sequencing and deletion analysis by quantitative Multiplex-PCR of Short Fluorescent Fragments (QMPSF) if patients were islet autoantibody-negative and had one parent with diabetes or associated extrapancreatic features or detectable C-peptide outside honeymoon phase. Presence and size of disease-causing chromosomal rearrangements detected by QMPSF were further analyzed by array comparative genomic hybridization. RESULTS: Overall, five patients had a heterozygous HNF1B deletion, presenting renal disease, elevated liver enzymes, and diabetes. Diabetes was characterized by insulin resistance and adolescent onset of hyperglycemia. Additionally, clinical features in some patients were pancreas dysplasia and exocrine insufficiency (two of five patients), genital defects (three of five), mental retardation (two of five), and eye abnormalities (coloboma, cataract in two of five). One case also had severe growth deficit combined with congenital cholestasis, and another case had common variable immune deficiency. All patients reported here had monoallelic loss of the entire HNF1B gene. Whole genome array comparative genomic hybridization confirmed a precurrent genomic deletion of approximately 1.3-1.7 Mb in size. CONCLUSION: The clinical data of our cases enlarge the wide spectrum of patients with HNF1B anomaly. The underlying molecular defect in all cases was a 1.3- to 1.7-Mb deletion, and paired, segmental duplications along with breakpoints were most likely involved in this recurrent chromosomal microdeletion.