Dental and Craniofacial Anomalies Associated with Axenfeld-Rieger Syndrome with PITX2 Mutation

Axenfeld-Rieger syndrome (ARS) (OMIM Nr.: 180500) is a rare autosomal dominant disorder (1  :  200000) with genetic and morphologic variability. Glaucoma is associated in 50% of the patients. Craniofacial and dental anomalies are frequently reported with ARS. The present study was designed as a multidisciplinary analysis of orthodontic, ophthalmologic, and genotypical features. A three-generation pedigree was ascertained through a family with ARS. Clinically, radiographic and genetic analyses were performed. Despite an identical genotype in all patients, the phenotype varies in expressivity of craniofacial and dental morphology. Screening for PITX2 and FOXC1 mutations by direct DNA-sequencing revealed a P64L missense mutation in PITX2 in all family members, supporting earlier reports that PITX2 is an essential factor in morphogenesis of teeth and craniofacial skeleton. Despite the fact that the family members had identical mutations, morphologic differences were evident. The concomitant occurrence of rare dental and craniofacial anomalies may be early diagnostic indications of ARS. Early detection of ARS and elevated intraocular pressure (IOP) helps to prevent visual field loss

Efficacy and outcome of expanded newborn screening for metabolic diseases - Report of 10 years from South-West Germany *

<p>Abstract</p> <p>Background</p> <p>National newborn screening programmes based on tandem-mass spectrometry (MS/MS) and other newborn screening (NBS) technologies show a substantial variation in number and types of disorders included in the screening panel. Once established, these methods offer the opportunity to extend newborn screening panels without significant investment and cost. However, systematic evaluations of newborn screening programmes are rare, most often only describing parts of the whole process from taking blood samples to long-term evaluation of outcome.</p> <p>Methods</p> <p>In a prospective single screening centre observational study 373 cases with confirmed diagnosis of a metabolic disorder from a total cohort of 1,084,195 neonates screened in one newborn screening laboratory between January 1, 1999, and June 30, 2009 and subsequently treated and monitored in five specialised centres for inborn errors of metabolism were examined. Process times for taking screening samples, obtaining results, initiating diagnostic confirmation and starting treatment as well as the outcome variables metabolic decompensations, clinical status, and intellectual development at a mean age of 3.3 years were evaluated.</p> <p>Results</p> <p>Optimal outcome is achieved especially for the large subgroup of patients with medium-chain acyl-CoA dehydrogenase deficiency. Kaplan-Meier-analysis revealed disorder related patterns of decompensation. Urea cycle disorders, organic acid disorders, and amino acid disorders show an early high and continuous risk, medium-chain acyl-CoA dehydrogenase deficiency a continuous but much lower risk for decompensation, other fatty acid oxidation disorders an intermediate risk increasing towards the end of the first year. Clinical symptoms seem inevitable in a small subgroup of patients with very early disease onset. Later decompensation can not be completely prevented despite pre-symptomatic start of treatment. Metabolic decompensation does not necessarily result in impairment of intellectual development, but there is a definite association between the two.</p> <p>Conclusions</p> <p>Physical and cognitive outcome in patients with presymptomatic diagnosis of metabolic disorders included in the current German screening panel is equally good as in phenylketonuria, used as a gold standard for NBS. Extended NBS entails many different interrelated variables which need to be carefully evaluated and optimized. More reports from different parts of the world are needed to allow a comprehensive assessment of the likely benefits, harms and costs in different populations.</p

Familiy history, genetic risk and risk factors in the glaucomas - Evaluation of 2170 patients with glaucoma or ocular hypertension

Bei 2170 Patienten mit Glaukom oder Okulärer Hypertension wurden die Häufigkeit eines Glaukoms in der Familienanamnese, das genetische Risikoprofil, sowie okuläre und allgemeine Risikofaktoren untersucht, um aus der Korrelation dieser Faktoren mit dem Schweregrad des Gesichtsfeldausfalls und dem Alter bei Diagnosesstellung Rückschlüsse auf die Bedeutung dieser Faktoren für die Pathogenese und Prognose der Glaukome ziehen zu können. Um zu untersuchen, bei welchen Verwandten die höchste Findungswahrscheinlichkeit einer Glaukomerkrankung besteht, haben z. B. 1335 Patienten mit GCS 5312 Verwandte mit einem standardisierten Fragebogen befragt. Die 10 wichtigsten neuen Erkenntnisse aus dieser Untersuchung sind: 1. Es besteht verglichen zum GCS, bei dem 40 % aller Patienten ein Glaukom in der Familienanamnese haben, kein signifikanter Unterschied in der Häufigkeit eines Glaukoms in der Familienanamnese bei Patienten mit NTG, OH, GCS mit engem KW und PG. Alle Glaukomformen haben somit eine genetische Disposition. 2. Patienten mit Glaukom in der Familienanamnese sind zum Zeitpunkt der Diagnosestellung signifikant jünger als Patienten ohne Glaukom in der Familienanamnese. Kenntnisse über die genetische Disposition der Glaukome führten somit früher zu Screeninguntersuchungen. 3. Patienten mit Glaukom in der Familienanamnese haben keine schlechtere Prognose für den Erhalt des Gesichtsfeldes als Patienten ohne Glaukom in der Familienanamnese. 4. Bei allen Glaukomformen besteht bei Untersuchung von Geschwistern und Müttern von Glaukompatienten die höchste Findungswahrscheinlichkeit einer Glaukomerkrankung. 5. Verglichen zum GCS besteht ein signifikanter Unterschied im Alter bei Diagnosestellung und damit im Erkrankungsbeginn bei unterschiedlichen Glaukomformen, was für die Wahl des ersten Untersuchungszeitpunkts bedeutend ist. 6. Eine rein altersabhängige Wahl des Screeningzeitpunkts bei GCS zwischen 51. und 60. Lebensjahr führte nicht zur Frühdiagnostik, da in diesem Diagnosezeitraum gleich häufig Patienten mit beginnendem, fortgeschrittenem und schwerem Gesichtsfeldausfall diagnostiziert wurden. 7. Die zeitliche Dynamik des Gesichtsfeldverfalls ist bei unterschiedlichen Glaukomformen unterschiedlich und abhängig von der Höhe des unbehandelten IOD max. Bei 20% der GCS und 40% der NTG Patienten liegen so schwere beidseitige Gesichtsfeldausfälle vor, dass sie kein Fahrzeug steuern können. 8. Die Untersuchung des Alters bei Diagnosestellung in Korrelation zum Stadium der Erkrankung ergibt, dass das NTG verglichen zum GCS nicht wie bisher angenommen eine Erkrankung des älteren Menschen ist, sondern eine Erkrankung ist, die häufiger als das GCS erst im fortgeschrittenen Stadium diagnostiziert wird. 9. Patienten mit NTG haben entgegen der bisherigen Annahme nicht häufiger Herzerkrankungen als Patienten mit GCS oder Patienten mit anderen Glaukomformen. Die Häufigkeit von Herzerkrankungen ist sowohl bei GCS als auch bei NTG rein altersabhängig. 10. Patienten mit NTG haben alterskorrigiert verglichen zu Patienten mit GCS eine um 63,5% höhere Wahrscheinlichkeit an Migräne zu leiden, wobei Frauen häufiger an Migräne erkrankt sind als Männer. Dies kann erklären, warum bei NTG Frauen häufiger erkrankt sind. Eine vaskuläre Dysregulation ist ein Risikofaktor für NTG. Durch humangenetische Untersuchungen könnte die Risikogruppe der Patienten mit Glaukom in der Familienanamnese möglicherweise auf eine Hochrisikogruppe von Personen mit Mutationen in Glaukomgenen eingegrenzt werden. Da Mutationen in den drei bisher bekannten Glaukomgenen jedoch nur bei 10% aller Glaukompatienten gefunden werden, ein GL in der FA hingegen bei 40% der Patienten vorliegt, definiert das Vorliegen eines Glaukoms in der Familienanamnese die Zielgruppe für ein effektives Glaukomscreening. Eine bessere Information der Bevölkerung, dass bei Vorliegen eines Glaukoms in der Familienanamnese Screeninguntersuchungen, besonders bei den Geschwistern der Patienten, erforderlich sind, kann zur Verbesserung der Frühdiagnose und damit der Prognose der Glaukomerkrankung beitragen.In 2170 patients with glaucoma or ocular hypertension the frequency of family history of glaucoma was evaluated. In addition the genetic risk profile in the glaucomas as well as ocular and general risk factors were assessed. From the correlation of these factors with the stage of visual field loss and the age of patients at diagnosis it was possible to gain information on the significance of these factors for the pathogenesis and prognosis of the glaucomas. In order to identify the groups of relatives with the highest detection probability for glaucoma, e.g. 1335 patients with primary open angle glaucoma (POAG) interviewed 5312 relatives by means of a detailed standardized questionnaire. The 10 most important new results from this evaluation are: 1. In POAG 40% of all patients have a family history of glaucoma. There is no significant difference in the frequency of family history of glaucoma between patients with POAG and patients with NTG, OH, PACG and PG. Therefore all types of glaucoma show a genetic disposition. 2. Patients with a family history of glaucoma are significantly younger at the time of diagnosis than patients without family history of glaucoma. This signifies that knowledge of the genetic disposition of the glaucomas led to earlier glaucoma screening. 3. Patients with family history of glaucoma do not have a higher risk of visual field progression than patients without family history of glaucoma. 4. In all types of glaucoma the highest detection probability for glaucoma was found in patients' siblings and mothers. 5. Compared to POAG there is a significant difference in the age at diagnosis between different types of glaucoma. This means that there is a difference in the onset of the disease and consequently in the adequate age for glaucoma screening between different glaucomas. 6. Age related screening for POAG in patients aged 51 to 60 years does not lead to early detection of glaucoma. This result is derived from the fact, that in this time period an equal proportion of patients with beginning, moderate and severe visual field loss were diagnosed with glaucoma. 7. The time dynamic of visual field loss progression differs between different types of glaucoma and depends on the level of the maximal intraocular pressure before treatment. 20% of patients with POAG and 40% of patients with NTG would not meet the driving standard because of severe bilateral visual field defects. 8. Evaluation of age at diagnosis in correlation to stage of visual field loss at diagnosis shows, that NTG is not a disease of the elderly compared to POAG, as has been described in literature previously, but that NTG is a disease with late diagnosis and consequently severe visual field defects at detection. 9. Patients with NTG do not show a higher frequency of heart disease compared to patients with POAG and other types of glaucoma. The frequency of heat disease is solely age dependant in NTG as well as in GCS. 10. Patients with NTG have a 63.5% higher probability to have migraine than patients with POAG. Women have a higher frequency of migraine than men. This could explain why NTG is more frequent in women than men. Vascular dysregulation seems to be a risk factor for NTG. Genetic testing could restrict the risk group of patients with family history of glaucoma to a high risk group of patients with mutations in glaucoma genes. Mutations in the three glaucoma genes detected so far are only found in 10% of all patients with glaucoma, whereas a family history of glaucoma is found in 40% of all patients. This signifies that family history of glaucoma does so far best identify people who should undergo glaucoma screening tests. Better information of the population that glaucoma screening is essential in people with family history of glaucoma and especially in siblings of glaucoma patients can lead to earlier diagnosis and therefore to a better prognosis of glaucoma

Vitamin-B12-Mangel im Neugeborenen- und Säuglingsalter – Ursachen, Früherkennung, Diagnostik und Vorstellung eines primär oralen Behandlungsschemas

&lt;jats:title&gt;Zusammenfassung&lt;/jats:title&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Hintergrund&lt;/jats:title&gt; &lt;jats:p&gt;Ein Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangel ist bei Neugeborenen meist bedingt durch einen mütterlichen Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangel. Beim Kind führt ein schwerer, unerkannter Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangel zu irreversiblen neurologischen Schädigungen und einer dauerhaften Entwicklungsstörung, die meist erst im zweiten Lebenshalbjahr klinisch erkannt wird. Eine Früherkennung durch das Neugeborenenscreening wird derzeit in Pilotprojekten evaluiert.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Fragestellung&lt;/jats:title&gt; &lt;jats:p&gt;Der vorliegende Beitrag gibt einen Überblick über mögliche Ursachen eines Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangels und präsentiert erfolgreiche Ansätze zur Früherkennung durch das Neugeborenenscreening sowie Empfehlungen zur Diagnostik bei Mutter und Kind. Für die Behandlung des Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangels im Neugeborenen- und Säuglingsalter wird bislang häufig zunächst eine intramuskuläre Applikation von Vitamin B&lt;jats:sub&gt;12&lt;/jats:sub&gt; verwendet. Als Alternative wird von den Autoren ein ausschließlich orales Supplementationsschema mit Vitamin B&lt;jats:sub&gt;12&lt;/jats:sub&gt; vorgestellt.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Ergebnisse&lt;/jats:title&gt; &lt;jats:p&gt;Im Rahmen des Pilotprojektes „Neugeborenenscreening 2020“ am Screeningzentrum Heidelberg wurde für die Behandlung von Kindern mit Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangel nach Detektion über das Neugeborenenscreening ein standardisiertes ausschließlich orales Supplementationsschema mit Vitamin B&lt;jats:sub&gt;12&lt;/jats:sub&gt; entwickelt und erfolgreich angewendet. Dieses besteht in der Verabreichung von Vitamin B&lt;jats:sub&gt;12&lt;/jats:sub&gt; 0,5 mg/Tag p.o. über 3 Tage in Form eines Flüssigpräparates, gefolgt von 0,1 mg/Tag p.o. Über die erste Woche erfolgt zusätzlich die Gabe von 0,4 mg Folsäure pro Tag p.o. Nach Normalisierung aller Parameter des Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Haushaltes (einschließlich der funktionellen Marker Homozystein und Methylmalonsäure) erfolgt während der Stillzeit eine Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Supplementation in Erhaltungsdosis von 5 µg/Tag p.o. bis zur sicheren Einführung fleischhaltiger Beikost bzw. von Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-haltiger Nahrung.&lt;/jats:p&gt; &lt;/jats:sec&gt;&lt;jats:sec&gt; &lt;jats:title&gt;Schlussfolgerung&lt;/jats:title&gt; &lt;jats:p&gt;Das hier dargestellte rein orale Behandlungsschema für den Vitamin‑B&lt;jats:sub&gt;12&lt;/jats:sub&gt;-Mangel stellt eine effektive, kostengünstige, schmerzlose und damit besonders kinderfreundliche Behandlung dar.&lt;/jats:p&gt; &lt;/jats:sec&gt

23rd Annual Meeting of the German Society for Newborn Screening (Deutsche Gesellschaft für Neugeborenenscreening, DGNS)

From 3–4 June, 2016, the 23rd Annual Meeting of the German Society for Newborn Screening (Deutsche Gesellschaft für Neugeborenenscreening, DGNS) was held at the University Hospital Heidelberg. The meeting was organized by PD Dr. med. Gwendolyn Gramer (conference president) from the Newborn Screening Centreat the University Hospital Heidelberg, Centre for Paediatric and Adolescent Medicine. Prof. Dr. med. Prof. h.c. mult. (RCH) Georg F. Hoffmann, PD Dr. phil. nat. Jürgen G. Okun and PD Dr. med. Gwendolyn Gramer formed the scientific board for the selection of presentations. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report

Incidence of maple syrup urine disease, propionic acidemia, and methylmalonic aciduria from newborn screening data

Incidence for the branched-chain intoxication-type disorders, maple syrup urine disease, propionic acidemia and methlymalonic aciduria is dependent on the population screened. Here newborn screening results from three world regions, state screening laboratories in the United States, a region in Germany and Kuwait provides new incidence numbers. Maple syrup urine disease incidence in the United States was calculated to be 1: 220219, in South-West Germany 1: 119573 (Germany nationwide 1:177978), and in Kuwait 1: 59426. Incidence of propionic acidemia alone is calculated to be 1: 242741 in the United States, 1: 284450 in South-West Germany (Germany nationwide 1:202617) and 1:59426 in Kuwait. Incidence of isolated methylmalonic aciduria alone is 1:69354 in the United States, 1:568901 in South-West Germany (Germany nationwide 1:159199) and 1: 19809 in Kuwait. In the United States several newborn screening laboratories combine their results for propionic acidemia and methylmalonic aciduria, and also include combined remethylation disorders in the respective category, resulting in an incidence of 1:50709. Combined evaluation of methylmalonic aciduria, propionic aciduria and combined remethylation disorders results in a similar incidence for Germany of 1:67539. This evaluation of newborn screening incidences reflects some population differences for three intoxication-type metabolic disorders. However, different sample sizes of the populations screened over different time periods, and differences in case definitions for methylmalonic acidurias have to be considered when interpreting these data

High incidence of maternal vitamin B12 deficiency detected by newborn screening: first results from a study for the evaluation of 26 additional target disorders for the German newborn screening panel

Background Newborn screening (NBS) in Germany currently includes 15 target disorders. Recent diagnostic improvements suggest an extension of the screening panel

New Cases of Maleylacetoacetate Isomerase Deficiency with Detection by Newborn Screening and Natural History over 32 Years: Experience from a German Newborn Screening Center

Newborn screening (NBS) for hepatorenal tyrosinemia type I (HT1) based on a determination of succinylacetone is performed in countries worldwide. Recently, biallelic pathogenic variants in GSTZ1 underlying maleylacetoacetate isomerase (MAAI) deficiency have been described as a differential diagnosis in individuals with slightly elevated succinylacetone detected by NBS. We report the experience with NBS for HT1 over 53 months in a large German NBS center and the identification and characterization of additional cases with MAAI deficiency, including one individual with a natural history over 32 years. A total of 516,803 children underwent NBS for HT1 at the NBS center in Heidelberg between August 2016 and December 2020. Of 42 children with elevated succinylacetone, HT1 was confirmed in two cases (1 in 258.401). MAAI deficiency was suspected in two cases and genetically confirmed in one who showed traces of succinylacetone in urine. A previously unreported pathogenic GSTZ1 variant was found in the index in a biallelic state. Segregation analysis revealed monoallelic carriership in the index case‘s mother and homozygosity in his father. The 32-year-old father had no medical concerns up to that point and the laboratory work-up was unremarkable. MAAI has to be considered a rare differential diagnosis in NBS for HT1 in cases with slight elevations of succinylacetone to allow for correct counselling and treatment decisions. Our observation of natural history over 32 years adds evidence for a benign clinical course of MAAI deficiency without specific treatment

Implementing a tracking system for confirmatory diagnostic results after positive newborn screening for cystic fibrosis—implications for process quality and patient care

Newborn screening for cystic fibrosis (CF-NBS) was introduced in Germany in 2016. Currently, systematic follow-up of positive CF-NBS results is not implemented or reimbursed in the NBS program. We investigated results of confirmatory testing over 24 months after implementation of CF-NBS for a large German NBS center before and after introduction of an active tracking system and performed a cost calculation for tracking. Results are compared with the federal state of Bavaria, where a centralized tracking system has been in place for many years. At the NBS center, 244 of 281,907 children had a positive CF-NBS result requiring diagnostic confirmation. Before implementation of a telephone tracking system, only 43% of confirmatory results were returned despite repeated written requests. The consecutive strategy including telephone tracking led to an increase of resolved cases to 84%. However, the centralized tracking system in Bavaria, assigning children with positive CF-NBS directly to a responsible CF-center, resolved 99% of cases. The calculated additional cost for a tracking system in Germany including telephone tracking is 1.20€ per newborn screened.Conclusion: The implementation of a tracking system achieves a distinct improvement in CF-NBS with justifiable costs. The effect can be limited by absence of centralized organization of confirmatory testing. What is Known: • Newborn screening for cystic fibrosis (CF-NBS) has been performed for many years in several countries worldwide • While many studies have focused on different CF-NBS strategies, the organization of confirmatory testing and process quality concerning returned information to the NBS center has so far received less attention. What is New: • The implementation of an active tracking system achieves a distinct improvement of clarified cases after positive CF-NBS with justifiable costs. • The effect of a tracking system can be limited by the absence of a centralized organization of confirmatory testing

Maternal Vitamin B12 Deficiency Detected by Newborn Screening&mdash;Evaluation of Causes and Characteristics

Vitamin B12 deficiency, mostly of maternal origin in newborns, is a well-treatable condition but can cause severe neurologic sequelae in infants. Early detection of vitamin B12 deficiency allows the pre-symptomatic treatment of affected children. This evaluation assesses the characteristics of maternal vitamin B12 deficiency detected by newborn screening. In a prospective single-center study, a systematic screening strategy for vitamin B12 deficiency using a combination of two second-tier strategies was applied. In addition to confirmatory diagnostics in children, the systematic work-up of vitamin B12 status was also performed for their mothers. Maternal characteristics were assessed including ethnic origin, diet, and vitamin supplementation during pregnancy. For affected mothers, a work-up by internal medicine was recommended. In total, 121 mother&ndash;infant couples were analyzed. 66% of mothers adhered to a balanced diet including meat. The cause of maternal vitamin B12 deficiency was unknown in 56% of cases, followed by dietary causes in 32%, and organic causes in 8%. All mothers following a vegan diet and most mothers with a vegetarian diet took vitamin preparations during pregnancy, whereas only 55.8% of mothers with a balanced diet took folic acid or other vitamins. Maternal vitamin B12, folic acid, and homocysteine levels were significantly correlated with the child&rsquo;s folic acid levels, and with homocysteine, methylmalonic, and methylcitric acid levels in first and second NBS dried blood spots. Most children had normal blood counts and showed normocytosis. Although 36.7% of mothers showed anemia, only one presented with macrocytosis. Adherence to vitamin supplementation in pregnancy is low despite the recommendation for supplementation of folic acid. Ideally, the evaluation of mothers for vitamin B12 levels and appropriate therapy should be initiated in early pregnancy. In infants detected through newborn screening, the multidisciplinary assessment and therapy of both children and mothers should be performed