Kinderklinik Regensburg

Autologous Matrix-Induced Chondrogenesis (AMIC ® ) utilizing a type I/III collagen membrane was compared with microfracture (MFx) alone in focal cartilage lesions of the knee at one, two and five years. Forty-seven patients (aged 37 ± 10 years, mean defect size 3.6 ± 1.6 cm 2 ) were randomized and treated either with MFx, with sutured or glued AMIC ® in a prospective multicentre clinical trial. After improvement for the first two years in all subgroups, a progressive and significant score degradation was observed in the MFx group, while all functional parameters remained stable for least five years in the AMIC ® groups. At two and five years, MRI defect filling was more complete in the AMIC ® groups. No treatment-related adverse events were reported. AMIC ® is an effective cartilage repair procedure in the knee resulting in stable clinical results significantly better than the MFx group at five years.

BACKGROUND: Atopic dermatitis (AD) is a major inflammatory condition of the skin caused by inherited skin barrier deficiency, with mutations in the filaggrin gene predisposing to development of AD. Support for barrier deficiency initiating AD came from flaky tail mice, which have a frameshift mutation in Flg and also carry an unknown gene, matted, causing a matted hair phenotype. OBJECTIVE: We sought to identify the matted mutant gene in mice and further define whether mutations in the human gene were associated with AD. METHODS: A mouse genetics approach was used to separate the matted and Flg mutations to produce congenic single-mutant strains for genetic and immunologic analysis. Next-generation sequencing was used to identify the matted gene. Five independently recruited AD case collections were analyzed to define associations between single nucleotide polymorphisms (SNPs) in the human gene and AD. RESULTS: The matted phenotype in flaky tail mice is due to a mutation in the Tmem79/Matt gene, with no expression of the encoded protein mattrin in the skin of mutant mice. Matt(ft) mice spontaneously have dermatitis and atopy caused by a defective skin barrier, with mutant mice having systemic sensitization after cutaneous challenge with house dust mite allergens. Meta-analysis of 4,245 AD cases and 10,558 population-matched control subjects showed that a missense SNP, rs6684514, [corrected] in the human MATT gene has a small but significant association with AD. CONCLUSION: In mice mutations in Matt cause a defective skin barrier and spontaneous dermatitis and atopy. A common SNP in MATT has an association with AD in human subjects.

Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.

Objective A systematic review and meta-analysis of Autologous Matrix-Induced Chondrogenesis (AMIC®) outcomes for grade III/IV chondral and osteochondral lesions of the knee treated with Chondro-Gide®. Design Studies with a minimum follow-up of 1 year providing clinical results of AMIC repair in the knee were included based on PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Methodological quality was assessed by the modified Coleman Methodology Score (mCMS). The meta-analysis was comparing pain VAS (Visual Analog Scale), Lysholm score, and IKDC score (International Knee Documentation Committee) between baseline and follow-up after 1 or 2 years and after >3 years. Results Twelve studies (375 patients) were included. The mCMS demonstrated a suboptimal study design (ranking between 52 and 80). The mean age was 36.2 years (14-70 years). The mean defect size was 4.24 cm 2 (0.8-22 cm 2 ). The results from the random effects model indicated a clinically significant ( P < 0.05) improvement of pain VAS from baseline to follow-up at year 1 to 2 of −4.02(confidence interval −4.37; −3.67), still significant after 3 years. Lysholm score at year 1 or 2 improved significantly and remained highly significant after 3 years. IKDC score showed highly significant improvement of 32.61 between 1 and 2 years versus baseline values maintained after 3 years. Conclusions The AMIC procedure significantly improved the clinical status and functional scoring versus preoperative values. Evidence was obtained in a non-selected patient population, corresponding to real-life treatment of knee chondral and osteochondral defects. The evidence is sufficient to recommend AMIC in this indication.

The aim of this study was to assess individual and social antecedents of attachment security and attachment disorganization of infants as assessed by the Strange Situation. Observations from two longitudinal studies, with a parallel assessment schedule yielding a total sample of 88 infant-mother pairs, formed the database of the study. Newborn behavioral organization, in terms of orienting ability and regulation of state, and maternal sensitivity assessed several times during the infant's first year were used to predict the security of infant-mother attachment and the status of disorganization of attachment behavior strategies at the age of 12 months. Whereas attachment security was significantly associated only with maternal sensitivity, the status of disorganization was only predicted by newborn behavioral organization. The findings are discussed with respect to specific assumptions about individual and social contribution to the development of infant-mother attachment on the background of maternal attachment representation.

In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.

BACKGROUND: Recent investigations have reported an influence of thrombophilic mutations and antithrombotic risk factors with development of intraventricular hemorrhage. It was our objective for this study to investigate the impact of genetic polymorphisms of hemostasis genes on the primary outcome measures of sepsis, bronchopulmonary dysplasia, intraventricular hemorrhage, and periventricular leukomalacia in a large cohort of very low birth weight infants. METHODS: There were 586 very low birth weight infants enrolled prospectively in a multicenter trial between September 2003 and July 2005, and an additional 595 very low birth weight infants, who had been recruited in a previous prospective trial, were studied. DNA samples were taken by buccal swab, and genotypes of factor V Leiden mutation, prothrombin G20210A mutation, the factor VII-323 del/ins polymorphism, and the factor XIII-Val34Leu polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. RESULTS: In contrast to data published previously, the frequency of intraventricular hemorrhage or periventricular leukomalacia was not significantly influenced by any of the genetic variants tested. Carriers of the factor XIII-Val34Leu polymorphism, however, had a higher sepsis rate and a longer period of hospital care compared with noncarriers. The factor VII-323 del/ins polymorphism was found to be a potential protective factor against bronchopulmonary dysplasia. CONCLUSIONS: We could not confirm previously reported associations of hemostasis gene variants and development of intraventricular hemorrhage in very low birth weight infants. To better understand gene-disease associations in very low birth weight infants, the prospective development of large-scale cohorts with well-defined phenotypes and corresponding DNA samples is essential.

This report concerns three unrelated floppy infants, two girls and one boy, each biopsied at the age of 1 month. They were hypotonic since birth and required artificial ventilation. The two girls died at the ages of 4 and 3 1/2 months, respectively, the boy is still alive at the age of 2 years, but requires assisted ventilation. Each of the three infants showed, by muscle biopsy, abundant intranuclear rods, the boy and one girl also had sarcoplasmic rods, which were not present in the other girl's muscle. Absence of sarcoplasmic rods, but the presence of intranuclear rods could also be documented in her autopsied muscle. Using an antibody against alpha-actinin, immunoelectron microscopy showed reaction of the sarcoplasmic and intranuclear rods demonstrating their Z-band origin. To our knowledge, this is the first report on rod myopathy with intranuclear rods only and of an immunoelectron microscopic demonstration of alpha-actinin in intranuclear rods. The presence of intranuclear rods in infants with nemaline myopathy also appears to indicate a grave prognosis of their rod myopathy.

BACKGROUND: The harbour porpoise is exposed to increasing pressure caused by anthropogenic activities in its marine environment. Numerous offshore wind farms are planned or under construction in the North and Baltic Seas, which will increase underwater noise during both construction and operation. A better understanding of how anthropogenic impacts affect the behaviour, health, endocrinology, immunology and physiology of the animals is thus needed. The present study compares levels of stress hormones and mRNA expression of cytokines and acute-phase proteins in blood samples of harbour porpoises exposed to different levels of stress during handling, in rehabilitation or permanent human care.Free-ranging harbour porpoises, incidentally caught in pound nets in Denmark, were compared to harbour porpoises in rehabilitation at SOS Dolfijn in Harderwijk, the Netherlands, and individuals permanently kept in human care in the Dolfinarium Harderwijk and Fjord & Belt Kerteminde, Denmark. Blood samples were investigated for catecholamines, adrenaline, noradrenaline and dopamine, as well as for adrenocorticotropic hormone (ACTH), cortisol, metanephrine and normetanephrine. mRNA expression levels of relevant cell mediators (cytokines IL-10 and TNFα, acute-phase proteins haptoglobin and C-reactive protein and the heat shock protein HSP70) were measured using real-time PCR. RESULTS: Biomarker expression levels varied between free-ranging animals and porpoises in human care. Hormone and cytokine ranges showed correlations to each other and to the health status of investigated harbour porpoises. Hormone concentrations were higher in free-ranging harbour porpoises than in animals in human care. Adrenaline can be used as a parameter for the initial reaction to acute stress situations; noradrenaline, dopamine, ACTH and cortisol are more likely indicators for the following minutes of acute stress. There is evidence for different correlations between production of normetanephrine, metanephrine, cortisol and the expression of IL-10, HSP70 and haptoglobin. CONCLUSIONS: The expression patterns of the selected molecular biomarkers of the immune system are promising to reflect the health and immune status of the harbour porpoise under different levels of stress.

INTRODUCTION: Inpatient rehabilitation is an important contributor to the treatment of child and adolescent obesity with comorbidity in Germany. Thus far outpatient follow-up care has not been subject to research. The main goal of this study is the development and longer-term evaluation of a programme for structured outpatient follow-up care by primary care physicians after inpatient rehabilitation of obese children and adolescents. METHODS: This multicentre, randomized, parallel controlled clinical trial enrolled 521 children and adolescents aged 9 - 16 (avg. 13.3) years in 7 cooperating specialized rehabilitation facilities. The patients were randomized at the end of their multimodal inpatient treatment that lasted for 5.9 (+/- 1.2) weeks. The intervention consisted of 12 half-hour outpatient consultations by the primary care physicians utilizing a modular consultation guideline and an internet-based training programme. The control group received standard care. Outcome variables included anthropometric measures, questionnaires on eating behaviour, physical activity, quality of life, self-efficacy and subjective rating of the intervention. Measurements were performed at the beginning (t1) and end (t2) of inpatient rehabilitation as well as 6 (t3) and 12 (t4) months after discharge. RESULTS: There was a highly significant improvement of BMI-z-score (standard deviation score of the Body Mass Index), relevant behaviour, quality of life and self-efficacy between t1 and t4. On intention to treat analysis no differences were detected between intervention and control groups. The intervention was utilized by only 50 % of entitled. The BMI-z-score reached a minimum at t3 (6-month follow-up). Predictors of longer-term BMI-z-score decline were psychological suffering, poor eating behaviour, low physical activity and high socio-economic status. In multivariate linear regression improvement of eating behaviour and physical activity correlated with the improvement of BMI-z-score. DISCUSSION: This low-level outpatient intervention did not improve the demonstrated longer-term effectiveness of inpatient rehabilitation. An interdisciplinary outpatient follow-up care in groups with inclusion of the parents is recommended.

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785). The primary outcome was preterm vs.term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infant's factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singleton VLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7-8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12-2.5, p=0.007) and the lower frequency of infant's factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29-0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01). The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.

This evidence-based clinical guideline provides consensus-recommendations for the treatment and care of patients with primary antibody deficiencies (PADs). The guideline group comprised 20 clinical and scientific expert associations of the German, Swiss, and Austrian healthcare system and representatives of patients. Recommendations were based on results of a systematic literature search, data extraction, and evaluation of methodology and study quality in combination with the clinical expertise of the respective representatives. Consensus-based recommendations were determined via nominal group technique. PADs are the largest clinically relevant group of primary immunodeficiencies. Most patients with PADs present with increased susceptibility to infections, however immune dysregulation, autoimmunity, and cancer affect a significant number of patients and may precede infections. This guideline therefore covers interdisciplinary clinical and therapeutic aspects of infectious (e.g., antibiotic prophylaxis, management of bronchiectasis) and non-infectious manifestations (e.g., management of granulomatous disease, immune cytopenia). PADs are grouped into disease entities with definitive, probable, possible, or unlikely benefit of IgG-replacement therapy. Summary and consensus-recommendations are provided for treatment indication, dosing, routes of administration, and adverse events of IgG-replacement therapy. Special aspects of concomitant impaired T-cell function are highlighted as well as clinical data on selected monogenetic inborn errors of immunity formerly classified into PADs (APDS, CTLA-4-, and LRBA-deficiency).

E.I. Schwartz, S.P. Shevtsov, A.P. Kuchinski, Yu.P. Kovalev, O.V. Plutalov, Yu.A. Berlin; Approach to identification of a point mutation in apo B100 gene by mea

In recent years, intrathecal baclofen (ITB) has attained an important role in the treatment of severe spasticity and dystonia in children. There are principal differences between the use of ITB in children and its use in neurology and oncology in adults. Here, we present a consensus report on best practice for the treatment of severe spastic and dystonic movement disorders with ITB. Using a problem-orientated approach to integrate theories and methods, the consensus was developed by an interdisciplinary group of experienced ITB users and experts in the field of movement disorders involving 14 German centers. On the basis of the data pooled from more than 400 patients, the authors have summarized their experience and supporting evidence in tabular form to provide a concise, but still a comprehensive information base that represents our current understanding regarding ITB treatment options in children and adolescents.

BACKGROUND: The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE-ins/del) and the angiotensin II type 1 receptor 1166A/C polymorphism (ATR1166A/C) were reported to be associated with several unfavorable outcome parameters in preterm infants like bronchopulmonary dysplasia, persistent ductus arteriosus and impaired insulin sensitivity. OBJECTIVE: To confirm the above-mentioned associations in a large cohort of very-low-birthweight (VLBW) infants. METHOD: Clinical data of VLBW infants were prospectively recorded. The ACE-ins/del polymorphism and the ATR1166A/C polymorphism were determined by polymerase chain reaction in 1,209 and 1,168 infants, respectively. RESULTS: There was no significant association between ACE-ins/del or ATR1166A/C genotype and outcome parameters (death, intraventricular hemorrhage, sepsis, bronchopulmonary dysplasia, ventilation, supplemental oxygen at discharge, postnatal treatment with insulin, surgery for intestinal perforation/necrotizing enterocolitis/retinopathy of prematurity/persistent ductus arteriosus. CONCLUSION: Both known functional polymorphisms of the renin-angiotensin system do not seem to be associated with the outcome of VLBW infants.

Developmentally pathological conditions of the anterior pituitary cells include failed separation of the primary pituitary gland into sellar and pharyngeal ones, ectopic migration into the subarachnoid space, and basophil invasion into the posterior lobe although the last is a physiological phenomenon with pathological potentiality in certain circumstances. Pituitary primordium appears at about 4 weeks of gestation. One of the causes of the pituitary gland agenesis may be a formation of the primary hypothalamic ganglionic hamartoma just at the time of occurrence of the pituitary primordium, as analyzed in cases of Pallister-Hall syndrome. A double pituitary in a single individual is a rare malformation. Its pathogenesis is considered as a result of notochordal anomaly. In the 8th gestational week, the primary pituitary gland separates into sellar and pharyngeal parts. The disturbance of this histogenesis results in a rare pituitary malformation, a "pharyngosellar pituitary." Despite the failed separation in this case, differentiation of the pituitary cells proceeds and the hormone production of this malformed pituitary gland can be displayed immunohistochemically. In this case, the distribution of the different hormone producing cells was atypical, particularly in those of gonadotropic hormones and ACTH. Life-long existence of the pharyngeal pituitary is a normal anatomical state in humans. Cell differentiation (hormone production) in the pharyngeal pituitary occurs about 4-10 weeks later than in the sellar pituitary. In pharyngeal pituitary, all kinds of adenohypophyseal hormones are produced. Extracranial pituitary adenomas (with intact sellar pituitary), exclusively found in the nasopharynx, sphenoid sinus, and clivus, may occur from the pharyngeal pituitary while another tumorigenesis can develop from the residual tissue fragment in the craniopharyngeal canal. The "overshoot" of the adenohypophyseal cell migration in the distal part of the sellar pituitary is frequently observed in the leptomeninges of the peri-infundibular or peri-hypothalamic region as ectopic pituitary cell clusters that are apparently independent of the pars tuberalis. It is suggested that these cells, frequently found in "normal" individuals, may be one of the possible origins of the intracranial ectopic pituitary adenomas. However, the reason why a majority of the reported intracranial ectopic pituitary tumors are ACTH-adenomas remains unexplained, since the ectopic cells, found in "normal" individuals, consist of fairly different hormone-producing cells. A further enigmatic phenomenon is a "basophil invasion." ACTH-positive cells invade from the pars intermedia into the posterior lobe of the pituitary. This invasion increases in intensity and frequency according to increase in age. However, the invasion of ACTH cells is observed as early as in the fetal life. The invasive cells display occasionally cell atypia as well as mitotic activity. The origin of extremely rare pituitary adenomas inside the posterior lobe can be explained by the existence and proliferative activity of basophil invasion.

Abstract Purpose Autologous matrix-induced chondrogenesis (AMIC ® ) and microfracture are established treatments for focal chondral defects in the knee, but there are little clinical data concerning these procedures over the long term. This study evaluates the outcomes of AMIC ® compared to microfracture over 10-year follow-up. Methods Forty-seven patients were randomized and treated either with MFx ( n = 13), sutured AMIC ® ( n = 17) or glued AMIC ® ( n = 17) in a prospective, randomized, controlled multicentre trial. The Modified Cincinnati Knee Score, a visual analogue scale for pain and MOCART score were used to assess outcomes over 10 years post-operatively. Results All treatment arms improved in the first 2 years, but a progressive and significant deterioration in scores was observed in the MFx group, while both AMIC ® groups remained stable. MOCART scores were comparable between groups. Conclusion The AMIC ® procedure results in improved patient outcomes in comparison with microfracture up to 10 years following surgery for the repair of focal chondral defects in the knee. ClinicalTrials.gov Identifier: NCT02993510

Fertility preservation in women with Turner syndrome is highly controversial. Some strongly recommend freezing of ovarian tissue at a young age, others do not. The controversy is partly due to different perspectives and professions. Biologists prefer to freeze young ovaries with high follicle density, reproductive physicians want to avoid risky operations and iatrogenic infertility by removing one ovary, and cardiologists and obstetricians warn against the risks of later pregnancies. Accordingly, fertility preservation in young women with Turner syndrome is more than just the freezing of ovarian tissue or oocytes. Fertility preservation requires a balanced decision considering the conservation of fertility, the protection of reproductive health, and future health consequences. Therefore, fertility preservation strategies should be based not only on the individual ovarian reserve but also on the genotype and the expected cardiac health status to decide what is the best option: to freeze tissue or alternatively to wait and see.

The natural history of patients with spinal muscular atrophy (SMA) has changed due to advances in standard care and development of targeted treatments. Nusinersen was the first drug approved for the treatment of all SMA patients. The transfer of clinical trial data into a real-life environment is challenging, especially regarding the advice of patients and families to what extent they can expect a benefit from the novel treatment. We report the results of a modified Delphi consensus process among child neurologists from Germany, Austria and Switzerland about the indication or continuation of nusinersen treatment in children with SMA type 1 based on different clinical case scenarios.

Chromosomal microarray testing is commonly used to identify disease causing de novo copy number variants in patients with developmental delay and multiple congenital anomalies. In such a patient we now observed an 150 kb deletion on chromosome 7q21.11 affecting the first exon of the axon guidance molecule gene SEMA3A (sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3A). This deletion was inherited from the healthy father, but considering the function of SEMA3A and phenotypic similarity to the knock-out mice, we still assumed a pathogenic relevance and tested for a recessive second defect. Sequencing of SEMA3A in the patient indeed revealed the de novo in-frame mutation p.Phe316_Lys317delinsThrSerSerAsnGlu. Cloning of the mutated allele in combination with two informative SNPs confirmed compound heterozygosity in the patient. While the altered protein structure was predicted to be benign, aberrant splicing resulting in a premature stop codon was proven by RT-PCR to occur in about half of the transcripts from this allele. Expression profiling in human fetal and adult cDNA panels, confirmed a high expression of SEMA3A in all brain regions as well as in adult and fetal heart and fetal skeletal muscle. Normal intellectual development in the patient was surprising but may be explained by the remaining 20% of SEMA3A expression level demonstrated by quantitative RT-PCR. We therefore report a novel autosomal recessive syndrome characterized by postnatal short stature with relative macrocephaly, camptodactyly, septal heart defect and several minor anomalies caused by biallelic mutations in SEMA3A.