Stanovení genetické příčiny malého vzrůstu jako cesta k pochopení patofyziologických mechanismů ovlivňujících růst člověka

• Název práce v češtině: Stanovení genetické příčiny malého vzrůstu jako cesta k pochopení patofyziologických mechanismů ovlivňujících růst člověka
• Název v anglickém jazyce: Determining the genetic cause of short stature as a way to understand the pathophysiological mechanisms affecting human growth
• Klíčová slova: Familiárně malý vzrůst, léčba růstovým hormonem, malý vzrůst, poruchy růstové ploténky, porucha růstu, růstová ploténka, sekvenování nové generace
• Klíčová slova anglicky: Familial short stature, growth disorders, growth hormone treatment, growth plate, growth plate disorders, next-generation sequencing, short stature
• Akademický rok vypsání: 2016/2017
• Typ práce: disertační práce
• Jazyk práce: čeština
• Ústav: Pediatrická klinika (13-350)
• Vedoucí / školitel: doc. MUDr. Štěpánka Průhová, Ph.D.
• Řešitel: skrytý - zadáno a potvrzeno stud. odd.
• Datum přihlášení: 28.10.2016
• Datum zadání: 28.10.2016
• Datum potvrzení stud. oddělením: 28.10.2016
• Datum a čas obhajoby: 23.09.2021 10:00
• Datum odevzdání elektronické podoby: 23.04.2021
• Datum odevzdání tištěné podoby: 24.04.2021
• Datum proběhlé obhajoby: 23.09.2021
• Oponenti: doc. MUDr. Jiřina Zapletalová, Ph.D.

Seznam odborné literatury

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13.

Předběžná náplň práce

Malý vzrůst patří mezi nejčastější poruchy, se kterými se dětský endokrinolog zabývá. Patofyziologické mechanismy vedoucí k růstové poruše jsou komplexní, jednoznačná příčina je ale většinou neznámá. Naše studie je první prací, která se komplexně zabývala etiopatogenezí familiárně malého vzrůstu (FSS). Cílem práce bylo pomocí metod sekvenování nové generace (NGS) objasnit monogenní příčinu poruchy růstu u skupiny rodin s FSS, a přispět tak k pochopení patofyziologických mechanismů vedoucích k této specifické růstové poruše, a následně u vybraných genetických diagnóz popsat fenotyp včetně odpovědi na léčbu GH. V rámci centra pro léčbu GH ve FN Motol jsme sestavili unikátní kohortu 98 rodin s FSS s jednoznačným vymezením výšky <-2 SD u dítěte před léčbou GH i menšího rodiče. Pomocí NGS byla etiologie FSS objasněna u 40/98 (41 %) rodin; 32/40 neslo geneticky podmíněnou poruchu růstové ploténky. V rámci kohorty byly nalezeny tři geneticky homogenní podskupiny rodin (porucha kolagenů růstové ploténky – 10/98 [10,2 %] rodin, deficit proteinu SHOX – 6/98 [6,1 %] rodin a porucha receptoru natriuretického peptidu typu C – 4/98 [4,1 %] rodin). Ve fenotypu všech podskupin dominovala růstová porucha bez výraznějších přidružených patologií. Popsali jsme nový fenotyp kolagenopatií růstové ploténky, jež byly doposud známy jen jako příčina syndromického malého vzrůstu. Navrhli jsme klinické prediktory pro monogenní formu FSS. U všech podskupin byla zjištěna dobrá odpověď na léčbu GH.

Předběžná náplň práce v anglickém jazyce

Short stature is one of the most common disorders followed-up by a paediatric endocrinologist. Pathophysiologic mechanisms leading to growth disorders are complex, however, the exact cause is mostly unknown. Our study is the first to evaluate the aetiopathogenesis of familial short stature (FSS). Using next-generation sequencing (NGS) techniques, we aimed to describe the monogenic aetiology of growth impairment in a group of FSS families, and therefore to elucidate mechanisms leading to this specific growth disorder. In selected genetic diagnoses, we additionally aimed to describe the phenotype including GH treatment response. Within Motol University Hospital centre for GH therapy, we formed a group of 98 FSS families with clear height definition in ≤-2 SD in both the child height before GH therapy and in his shorter parent. Using NGS, the FSS aetiology was elucidated in 40/98 (41%) families; 32/40 had a genetic growth plate disorder. Within the cohort, three genetically homogeneous subgroups of families were described (collagenopathies – 10/98 [10.2%] families, SHOX deficiency – 6/98 [6.1%] families, and C type natriuretic peptide receptor disorder – 4/98 [4.1%] families). Dominant phenotype in all the subgroups was the growth disorder without apparent associated pathologies. As mutations in growth plate collagen genes have previously been known only to cause syndromic short stature, a new phenotype has been revealed. Moreover, the clinical predictors for monogenic FSS have been proposed. All the subgroups responded well to GH treatment.