OBJECTIVE: To analyze the mutational spectrum, clinical characteristics, genotype-phenotype correlations, testicular adrenal rests tumor prevalence, and role of neonatal screening in congenital adrenal hyperplasia (CAH) patients from Slovakia and Slovenia. DESIGN AND METHODS: Data were obtained from 104 patients with CAH registered in Slovak and Slovenian databases. Low-resolution genotyping was performed to detect the most common point mutations. To detect deletions, conversions, point mutations, or other sequence changes in the CYP21A2 gene, high-resolution genotyping was performed. Genotypes were classified according to residual 21-hydroxylase activity (null, A, B, C). RESULTS: 64% of the individuals had the salt-wasting form (SW-CAH), 15% the simple virilizing form (SV-CAH), and 21% the non-classic (NC-CAH). CYP21A2 gene deletion/conversion and c.293-13A/C>G pathogenic variant accounted together for 55.5% of the affected alleles. In SV-CAH p.Ile172Asn was the most common pathogenic variant (28.13%), while in NC-CAH p.Val282Leu (33.33%), CYP21A2 gene deletion/conversion (21.43%), c.293-13A/C>G (14.29%), Pro30Leu (11.90%). The frequency of alleles with multiple pathogenic variants was higher in Slovenian patients (15.83% of all alleles). Severe genotypes (0 and A) correlated well with the expected phenotype (SW in 94.74% and 97.3%), while less severe genotypes (B and C) correlated weaklier (SV in 50% and NC in 70.8%). The median age of SW-CAH patients at the time of diagnosis was 6 days in Slovakia vs. 28.5 days in Slovenia (p=0.01). Most of the Slovak patients in the cohort were detected by NBS. (24 out of 29). TARTs were identified in 7 out of 24 male patients, of whom all (100%) had SW-CAH and all had poor hormonal control. The median age at the diagnosis of TARTs was 13 years. CONCLUSION: The study confirmed the importance of neonatal screening, especially in the speed of diagnosis of severe forms of CAH. The prediction of the 21-OH deficiency phenotype was reasonably good in the case of severe pathogenic variants, but less reliable in the case of milder pathogenic variants, which is consistent compared to data from other populations. Screening for TARTs should be realized in all male patients with CAH, since there is possible remission when identified early.
- MeSH
- kongenitální adrenální hyperplazie * epidemiologie genetika diagnóza MeSH
- lidé MeSH
- nádor ze zbytků nadledviny * epidemiologie genetika MeSH
- steroid-21-hydroxylasa genetika MeSH
- testikulární nádory * epidemiologie genetika MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Slovenská republika MeSH
Newborn screening (NBS) is an important part of public healthcare systems in many countries. The provision of information to parents about NBS is now recognised as an integral part of the screening process. Informing parents on all aspects of screening helps to achieve the benefits, promote trust and foster support for NBS. Therefore, policies and guidelines should exist to govern how the information about NBS is provided to parents, taking into account evidence-based best practices. The purpose of our survey was to explore whether any legally binding provisions, guidelines or recommendations existed pertaining to the provision of information about NBS to parents across Europe. Questions were designed to determine the regulatory process of when, by whom and how parents should be informed about screening. Twenty-seven countries participated in the survey. The results indicated that most countries had some sort of legal framework or guidelines for the provision of information to parents. However, only 37% indicated that the provision of information was required prenatally. The majority of countries were verbally informing parents with the aid of written materials postnatally, just prior to sample collection. Information was provided by a neonatologist, midwife or nurse. A website dedicated to NBS was available for 67% of countries and 89% had written materials about NBS for parents. The survey showed that there is a lack of harmonisation among European countries in the provision of information about NBS and emphasised the need for more comprehensive guidelines at the European level.
- MeSH
- Evropská unie MeSH
- genetické testování zákonodárství a právo normy MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecký screening zákonodárství a právo normy MeSH
- organizační politika * MeSH
- průzkumy a dotazníky MeSH
- rodiče * MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- zveřejnění zákonodárství a právo normy MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.
- Publikační typ
- časopisecké články MeSH
3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare autosomal recessively inherited metabolic disorder. Patients suffer from avoidable neurologically devastating metabolic decompensations and thus would benefit from newborn screening (NBS). The diagnosis is currently made by measuring dry blood spot acylcarnitines (C5OH and C6DC) followed by urinary organic acid profiling for the differential diagnosis from several other disorders. Using untargeted metabolomics (reversed-phase UHPLC coupled to an Orbitrap Elite hybrid mass spectrometer) of plasma samples from 5 HMGCLD patients and 19 age-matched controls, we found 3-methylglutaconic acid and 3-hydroxy-3-methylglutaric acid, together with 3-hydroxyisovalerylcarnitine as the most discriminating metabolites between the groups. In order to evaluate the NBS potential of these metabolites we quantified the most discriminating metabolites from untargeted metabolomics in 23 blood spots from 4 HMGCLD patients and 55 controls by UHPLC tandem mass spectrometry. The results provide a tool for expanded NBS of HMGCLD using tandem mass spectrometry. Selected reaction monitoring transition 262/85 could be used in a first-tier NBS analysis to screen for elevated 3-hydroxyisovalerylcarnitine. In a positive case, a second-tier analysis of 3-hydroxy-3-methylglutaric acid and 3-methylglutaconic acid in a dry blood spot using UHPLC tandem mass spectrometry instruments confirms the diagnosis. In conclusion, we describe the identification of new diagnostic biomarkers for HMGCLD and their application in NBS in dry blood spots. By using second-tier testing, all patients with HMGCLD were unequivocally and correctly diagnosed.
- Publikační typ
- časopisecké články MeSH
Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein with tyrosine-kinase signaling activity, involved in many cellular functions including cell growth and differentiation. Germ line loss-of-function mutations in EGFR lead to a severe neonatal skin disorder (Online Mendelian Inheritance in Man #131550). We report 18 premature Roma children from 16 families with birthweights ranging 440-1470 g and multisystem diseases due to the homozygous mutation c.1283G˃A (p.Gly428Asp) in EGFR. They presented with thin, translucent, fragile skin (14/15), skin desquamation (10/17), ichthyosis (9/17), recurrent skin infections and sepsis (9/12), nephromegaly (10/16) and congenital heart defects (7/17). Their prognosis was poor, and all died before the age of 6 months except one 13-year-old boy with a severe skin disorder, dentinogenesis imperfecta, Fanconi-like syndrome and secondary hyperaldosteronism. Management of ion and water imbalances and extremely demanding skin care may improve the unfavorable outcome of such patients.
- MeSH
- dentinogenesis imperfecta diagnóza genetika mortalita MeSH
- dítě MeSH
- erbB receptory nedostatek genetika MeSH
- homozygot MeSH
- ichtyóza diagnóza genetika mortalita MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mutace ztráty funkce MeSH
- nemoci ledvin vrozené diagnóza genetika mortalita MeSH
- novorozenec nedonošený MeSH
- novorozenec s velmi nízkou porodní hmotností MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Romové genetika MeSH
- sekvenování exomu MeSH
- stupeň závažnosti nemoci MeSH
- syndrom MeSH
- vrozené srdeční vady diagnóza genetika mortalita MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
Autori prezentujú 10-ročné skúsenosti so skríningom cystickej fibrózy (NSCF) na Slovensku (2009–2018), pomocou novej súpravy neo-IRT ILMA. Metodika: Počas testovania súpravy (2007) až 31 % detí s vysokou hladinou IRT bolo rómskeho etnika. Pre riziko neprimerane vysokého percenta falošnej pozitivity si to vyžiadalo stanovenie vyššieho cut-off limitu pre rómskych novorodencov formou prospektívnej štúdie porovnávajúcej hladiny IRT1a IRT2 v majoritnom (M) a rómskom (R) etniku. Po ich zavedení do praxe sú vyhodnotené výsledky 10 rokov NSCF. Výsledky: Na súbore 8742 novorodencov M skupiny a 1500 novorodencov R skupiny boli zistené vysoko štatisticky signifikantné rozdiely hladín IRT (p <0,001) a boli stanovené cut-off limity IRT1 = 72 ng/ml, IRT2 = 60 ng/ml pre M skupinu a IRT1 = 84 ng/ml, IRT2 = 72 ng/ml pre R skupinu. Za 10 rokov NSCF bolo celkom vyšetrených 558 938 novorodencov (85,2 % M a 14,8 % R skupiny), percento pozitivity IRT (recall rate) bolo napriek vyššiemu cut-off limitu vyššie v skupine R (0,48 % vs. 0,28 %). Celkom bolo zachytených a potvrdených 75 prípadov CF, všetky v skupine M, ani jeden prípad nebol zistený u rómskeho novorodenca. Celková incidencia CF v súbore bola 1:7452, prepočítane na M populáciu 1:5110 živonarodených detí. Závery: Etnicky vykonávaný NSCF potvrdil potrebu rozdielnych cut-off limitov IRT vzhľadom na jeho vyššie hodnoty u rómskeho etnika, ako aj prakticky nulový výskyt CF v 10-ročnom súbore rómskeho etnika na Slovensku. Tento prístup môže v etnicky zmiešaných populáciách znížiť neprimerane vysoký recall a tým stres rodiny etnika s vyššími IRT a posunúť aj poznatky o reálnej incidencii CF v daných podmienkach.
The authors present 10 years of experience with neonatal screening of cystic fibrosis (NSCF) in Slovakia (2009–2018), using the new neo-IRT ILMA kit. Method: During the kit test (2007), up to 31% of high IRT children were Roma. For the risk of a disproportionately high percentage of false positivity, this required a higher cut-off limit for Roma neonates in the form of a prospective study comparing IRT1 and IRT2 levels in majority (M) and Roma (R) ethnicity. After their introduction into practice, the results of 10 years of NSCF are evaluated. Results: In a group of 8742 newborn M groups and 1500 newborn infants in the R group, there were highly statistically significant differences in IRT levels (p<0.001) and IRT1 cut-off limits were determined = 72 ng/ml, IRT2 = 60 ng/ml for M group and IRT1 = 84 ng/ml, IRT2 = 72 ng/ml for R group. In 10 years of NSCF, 558938 newborns (85.2% M and 14.8% R groups) were examined, the IRT (recall rate) percentage was higher in the R group despite the higher cut-off limit (0.48% vs. 0.28%). A total of 75 CF cases, all in the M group, were detected and confirmed, and none of the cases were found in the Roma newborn. The overall incidence of CF in the pool was 1:7452, calculated on an M population of 1:5110 live births. Conclusions: The ethnically performed NSCF confirmed the need for different IRT cut-off limits due to its higher values in the Roma ethnic group, as well as virtually no CF in the 10-year Roma population in Slovakia. This approach may reduce the excessively high recall and thus the stress of the ethnic family with higher IRTs in ethnically mixed populations, and shift the knowledge of the real incidence of CF under given conditions.
- MeSH
- cystická fibróza * diagnóza genetika MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecký screening * MeSH
- prospektivní studie MeSH
- Romové MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Geografické názvy
- Slovenská republika MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
