INTRODUCTION: Among children born small for gestational age, 10-15% fail to catch up and remain short (SGA-SS). The underlying mechanisms are mostly unknown. We aimed to decipher genetic aetiologies of SGA-SS within a large single-centre cohort. METHODS: Out of 820 patients treated with growth hormone (GH), 256 were classified as SGA-SS (birth length and/or birth weight <-2 SD for gestational age and life-minimum height <-2.5 SD). Those with the DNA triplet available (child and both parents) were included in the study (176/256). Targeted testing (karyotype/FISH/MLPA/specific Sanger sequencing) was performed if a specific genetic disorder was clinically suggestive. All remaining patients underwent MS-MLPA to identify Silver-Russell syndrome, and those with unknown genetic aetiology were subsequently examined using whole-exome sequencing or targeted panel of 398 growth-related genes. Genetic variants were classified using ACMG guidelines. RESULTS: The genetic aetiology was elucidated in 74/176 (42%) children. Of these, 12/74 (16%) had pathogenic or likely pathogenic (P/LP) gene variants affecting pituitary development (LHX4, OTX2, PROKR2, PTCH1, POU1F1), the GH-IGF-1 or IGF-2 axis (GHSR, IGFALS, IGF1R, STAT3, HMGA2), 2/74 (3%) the thyroid axis (TRHR, THRA), 17/74 (23%) the cartilaginous matrix (ACAN, various collagens, FLNB, MATN3), and 7/74 (9%) the paracrine chondrocyte regulation (FGFR3, FGFR2, NPR2). In 12/74 (16%), we revealed P/LP affecting fundamental intracellular/intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2). SHOX deficiency was found in 7/74 (9%), Silver-Russell syndrome in 12/74 (16%) (11p15, UPD7), and miscellaneous chromosomal aberrations in 5/74 (7%) children. CONCLUSIONS: The high diagnostic yield sheds a new light on the genetic landscape of SGA-SS, with a central role for the growth plate with substantial contributions from the GH-IGF-1 and thyroid axes and intracellular regulation and signalling.
- MeSH
- dítě MeSH
- gestační stáří MeSH
- hypotrofický novorozenec MeSH
- insulinu podobný růstový faktor I MeSH
- lidé MeSH
- lidský růstový hormon * genetika MeSH
- nanismus * MeSH
- novorozenec MeSH
- poruchy růstu genetika diagnóza MeSH
- protein SHOX MeSH
- Silverův-Russellův syndrom * genetika MeSH
- tělesná výška genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
Kostní dysplazie jsou širokou, heterogenní skupinou chorob. Thanatoforická dysplazie patří mezi nejčastější letální kostní dysplazie. Základem diagnostiky je kvalitní ultrazvukové vyšetření ve II. trimestru a nejnovější metody genetického testování vč. vyšetření klinického exomu. Znalost správné diagnózy je klíčová pro budoucnost plodu i páru.
Bone dysplasias are a broad, heterogeneous group of diseases. Thanatophoric dysplasia is a rare bone dysplasia, but it is the most common lethal skeletal dysplasias. The major role in diagnostics plays a high-quality ultrasound examination in the 2nd trimester and the latest methods of genetic testing, including clinical exome testing. Knowing the correct diagnosis is crucial for the future of the fetus and the couple.
- MeSH
- dospělí MeSH
- indukovaný potrat MeSH
- lidé MeSH
- nemoci plodu diagnostické zobrazování genetika patologie MeSH
- progrese nemoci MeSH
- sekvenování exomu * MeSH
- těhotenství MeSH
- thanatoforní dysplazie * diagnostické zobrazování genetika patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- chorea komplikace MeSH
- dítě MeSH
- kongenitální hypotyreóza diagnóza farmakoterapie MeSH
- lidé MeSH
- mutace genetika MeSH
- nemoci svalů * diagnóza genetika MeSH
- poruchy řeči etiologie MeSH
- svalová hypotonie diagnóza MeSH
- thyroxin terapeutické užití MeSH
- výsledek terapie MeSH
- vzácné nemoci * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- endemická struma MeSH
- hormony štítné žlázy nedostatek toxicita MeSH
- jod nedostatek zásobování a distribuce MeSH
- kongenitální hypotyreóza farmakoterapie metabolismus MeSH
- lidé MeSH
- mladiství MeSH
- nádory štítné žlázy chirurgie diagnóza krev MeSH
- štítná žláza * abnormality cytologie diagnostické zobrazování MeSH
- struma diagnostické zobrazování diagnóza farmakoterapie krev patofyziologie prevence a kontrola MeSH
- tyreoiditida MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- přehledy MeSH
AIM: To date, there is a lack of international guidelines regarding the management of the endocrine features of individuals with Noonan syndrome (NS). The aim was to develop a clinical practice survey to gather information on current treatment and management of these patients across Europe. MATERIALS AND METHODS: A group of 10 experts from three clinical specialities involved in the management of NS patients (clinical geneticists, paediatric endocrinologists, and paediatric cardiologists) developed a 60-question clinical practice survey. The questionnaire was implemented in Survey Monkey and sent to physicians from these three specialities via European/national societies. Contingency tables and the Chi-Squared test for independence were used to examine differences between specialities and countries. RESULTS: In total, responses of 364 specialists (paediatric endocrinologists, 40%; geneticists, 30%; paediatric cardiologists, 30%) from 20 European countries were analysed. While endocrinologists mostly referred to national growth charts for the general population, geneticists mostly referred to NS-specific growth charts. Approximately half of the endocrinologists perform growth hormone (GH) stimulation tests in short patients with low IGF1 levels. Two thirds of endocrinologists begin GH treatment for short patients in early childhood (4-6.9 years), and over half of them selected a threshold of -2 standard deviation score (SDS) according to national growth charts. The main concerns about GH treatment appear to be presence of hypertrophic cardiomyopathy (HCM) (59%), increased risk of malignancy (46%), and limited efficacy (31%). When asked if they consider HCM as a contraindication for GH treatment, one third of respondents skipped this question, and among those who replied, two thirds selected 'cannot answer', suggesting a high level of uncertainty. A total of 21 adverse cardiac responses to GH treatment were reported. Although most respondents had not encountered any malignancy during GH treatment, six malignancies were reported. Finally, about half of the endocrinologists expected a typical final height gain of 1-1.5 SDS with GH treatment. CONCLUSION: This survey describes for the first time the current clinical practice of endocrine aspects of NS across Europe and helps us to identify gaps in the management but also in the knowledge of this genetic disorder.
- MeSH
- endokrinologové MeSH
- lékařská praxe - způsoby provádění MeSH
- lidé MeSH
- lidský růstový hormon terapeutické užití MeSH
- nanismus diagnóza farmakoterapie MeSH
- Noonanové syndrom diagnóza farmakoterapie MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
Activating mutations in the FGFR3 receptor tyrosine kinase lead to most prevalent form of genetic dwarfism in humans, the achondroplasia. Many features of the complex function of FGFR3 in growing skeleton were characterized, which facilitated identification of therapy targets, and drove progress toward treatment. In August 2021, the vosoritide was approved for treatment of achondroplasia, which is based on a stable variant of the C-natriuretic peptide. Other drugs may soon follow, as several conceptually different inhibitors of FGFR3 signaling progress through clinical trials. Here, we review the current achondroplasia therapeutics, describe their mechanisms, and illuminate motivations leading to their development. We also discuss perspectives of curing achondroplasia, and options for repurposing achondroplasia drugs for dwarfing conditions unrelated to FGFR3.
Consanguineous families have often played a role in the discovery of novel genes, especially in paediatric endocrinology. At this time, it has been estimated that over 8.5% of all children worldwide have consanguineous parents. Consanguinity is linked to demographic, cultural, and religious practises and is more common in some areas around the world than others. In children with endocrine conditions from consanguineous families, there is a greater probability that a single-gene condition with autosomal recessive inheritance is causative. From 1966 and the first description of Laron syndrome, through the discovery of the first KATP channel genes ABCC8 and KCNJ11 causing congenital hyperinsulinism (CHI) in the 1990s, to recent discoveries of mutations in YIPF5 as the first cause of monogenic diabetes due to the disruption of the endoplasmic reticulum (ER)-to-Golgi trafficking in the β-cell and increased ER stress; positive genetic findings in children from consanguinity have been important in elucidating novel genes and mechanisms of disease, thereby expanding knowledge into disease pathophysiology. The aim of this narrative review was to shed light on the lessons learned from consanguineous pedigrees with the help of 3 fundamental endocrine conditions that represent an evolving spectrum of pathophysiological complexity - from CHI, a typically single-cell condition, to monogenic diabetes which presents with uniform biochemical parameters (hyperglycaemia and glycosuria), despite varying aetiologies, up to the genetic regulation of human growth - the most complex developmental phenomenon.
- MeSH
- diabetes mellitus * genetika MeSH
- dítě MeSH
- KATP kanály genetika MeSH
- lidé MeSH
- mutace MeSH
- nanismus * MeSH
- pokrevní příbuzenství MeSH
- vrozený hyperinzulinismus * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Achondroplasia (ACH) is one of the most prevalent genetic forms of short-limbed skeletal dysplasia, caused by gain-of-function mutations in the receptor tyrosine kinase FGFR3. In August 2021, the C-type natriuretic peptide (CNP) analog vosoritide was approved for the treatment of ACH. A total of six other inhibitors of FGFR3 signaling are currently undergoing clinical evaluation for ACH. This progress creates an opportunity for children with ACH, who may gain early access to the treatment by entering clinical trials before the closure of their epiphyseal growth plates and cessation of growth. Pathophysiology associated with the ACH, however, demands a long observational period before admission to the interventional trial. Public patient registries can facilitate the process by identification of patients suitable for treatment and collecting the data necessary for the trial entry. RESULTS: In 2015, we established the prospective ACH registry in the Czechia and the Slovak Republic ( http://www.achondroplasia-registry.cz ). Patient data is collected through pediatric practitioners and other relevant specialists. After informed consent is given, the data is entered to the online TrialDB system and stored in the Oracle 9i database. The initial cohort included 51 ACH children (average age 8.5 years, range 3 months to 14 years). The frequency of selected neurological, orthopedic, or ORL diagnoses is also recorded. In 2015-2021, a total of 89 measurements of heights, weights, and other parameters were collected. The individual average growth rate was calculated and showed values without exception in the lower decile for the appropriate age. Evidence of paternal age effect was found, with 58.7% of ACH fathers older than the general average paternal age and 43.5% of fathers older by two or more years. One ACH patient had orthopedic limb extension and one patient received growth hormone therapy. Low blood pressure or renal impairment were not found in any patient. CONCLUSION: The registry collected the clinical information of 51 pediatric ACH patients during its 6 years of existence, corresponding to ~ 60% of ACH patients living in the Czechia and Slovak Republic. The registry continues to collect ACH patient data with annual frequency to monitor the growth and other parameters in preparation for future therapy.
- MeSH
- achondroplazie * epidemiologie genetika MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mutace MeSH
- předškolní dítě MeSH
- prospektivní studie MeSH
- receptor fibroblastových růstových faktorů, typ 3 genetika MeSH
- registrace MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
Východiska: Poškození DNA ionizujícím zářením je hlavním mechanizmem účinku radioterapie (RT) a výsledek léčby a poradiační toxicitu zdravých tkání ovlivňuje řada faktorů zevních a vnitřních, mezi které patří i mutace v genech pro reparaci DNA vedoucí k různým poruchám rozpoznávání poškozené DNA a jejich oprav. Poruchy reparace DNA se mohou projevovat zvýšenou citlivostí k onkologické léčbě. Cíl: Mechanizmus opravy DNA a přehled genetických syndromů s mutacemi genů účastnících se reparace DNA objasňuje urychlenou kancerogenezi a zvýšenou radiosenzitivitu při RT nádorových onemocnění. Většina radiosenzitivních syndromů je autozomálně recesivně dědičná, příkladem jsou ataxia teleangiectasia, Nijmegenský syndrom lomivosti, xeroderma pigmentosum, Cockaynův syndrom, Bloomův syndrom a Wernerův syndrom. Závěr: Radioterapie je u většiny homozygotních pacientů s recesivními radiosenzitivními syndromy kontraindikována. Asymptomatičtí heterozygoti mohou mít zvýšené riziko vzniku nádorů a malá část pacientů i mírně zvýšené riziko intolerance RT, nicméně indikaci k RT to nelimituje. Vysoké riziko sekundárních malignit po radioterapii je kontraindikací adjuvantní RT u Li-Fraumeniho syndromu.
Background: Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment. Purpose: The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Most radiosensitivity syndromes are autosomal recessively inherited; examples are ataxia teleangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome and Werner syndrome. Conclusion: Radiotherapy is contraindicated in most homozygous patients with recessive radiosensitivity syndromes. Asymptomatic heterozygotes may have an increased risk of tumor incidence and a small part of them slightly increased risk of RT intolerance; however, this does not limit RT treatment. The high risk of secondary malignancies after radiotherapy is a contraindication to adjuvant RT in Li-Fraumeni syndrome.
- MeSH
- Cockayneův syndrom genetika MeSH
- lidé MeSH
- mutace MeSH
- oprava DNA genetika MeSH
- tolerance záření * genetika MeSH
- xeroderma pigmentosum genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Úvod: laboratorní novorozenecký screening (LNS) je preventivní celopopulační program, který umožňuje včasnou diagnostiku a účinnou léčbu pacientům s vybranými vrozenými a dědičnými nemocemi a podstatně zlepšuje kvalitu jejich života. Metodika: vyšetření kapilární krve odebrané mezi 48. až 72. hodinou života ve formě suché krevní kapky metodami tandemové hmotnostní spektrometrie, fluorimetrie, imunoeseje či molekulárně genetickými. Výsledky: v České republice byl LNS zahájen v roce 1975 vyhledáváním fenylketonurie (PKU), dále se rozšířil v roce 1985 o kongenitální hypotyreózu (CH), v roce 2006 o kongenitální adrenální hyperplazii (CAH), v roce 2009 o cystickou fibrózu (CF) a dalších 9 dědičných poruch metabolismu. K dalšímu rozšíření počtu onemocnění došlo v roce 2016. V letech 2010–2020 bylo vyšetřením více než 1,2 milionu novorozenců zachyceno pomocí LNS celkem 1100 pacientů s některou z cílových nemocí. Kumulativní novorozenecká prevalence všech 18 nemocí činí 1 : 1100. Mezi nejčastější patří CH, PKU, CF a parciální deficit biotinidázy. Od roku 2022 je plánován start pilotního programu dalšího rozšíření LNS o spinální svalovou atrofii a těžké kombinované imunodeficity. Závěr: LNS programy se díky pokrokům v technologiích a léčbě celosvětově rozšiřují za dodržení stále platných kritérií WHO dle Wilsona a Jungnera.
Introduction: laboratory newborn screening (LNS) is a preventive population-wide program that enables early diagnosis and efficient treatment of patients with selected congenital and hereditary diseases and improves significantly their quality of life. Methodology: analysis of capillary blood collected between 48 and 72 hours of life in the form of a dried blood spot by tandem mass spectrometry, fluorimetry, immunoassay and molecular genetic methods. Results: in the Czech Republic, LNS was started in 1975 with a search for phenylketonuria (PKU), further expanded in 1985 by congenital hypothyroidism (CH), in 2006 by congenital adrenal hyperplasia (CAH), in 2009 by cystic fibrosis (CF) and 9 other inborn metabolic diseases. The number of diseases was further expanded in 2016. In 2010-2020, a total of 1,100 patients with one of the target diseases were diagnosed with LNS by analysing more than 1.2 million newborns. The cumulative neonatal prevalence of all 18 diseases is 1: 1,100. The most common diseases are CH, PKU, CF and partial biotinidase deficiency. From 2022, the start of a pilot program for further LNS expansion by adding spinal muscular atrophy and severe combined immunodeficiencies is planned. Conclusion: advances in technology and treatment enable expansion of LNS programs worldwide in compliance with the still valid WHO criteria according to Wilson and Jungner.
- MeSH
- cystická fibróza diagnóza MeSH
- fenylketonurie diagnóza MeSH
- klinické laboratorní techniky metody MeSH
- kongenitální adrenální hyperplazie diagnóza MeSH
- kongenitální hypotyreóza diagnóza MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecký screening * metody MeSH
- vrozené poruchy metabolismu diagnóza MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
