Di fronte a un bambino con bassa statura è necessaria un’accurata valutazione clinica che, se necessario, deve essere completata con le opportune indagini endocrine e genetiche al fine di identificare forme in cui è disponibile un’efficace terapia.
Alla luce di quanto emerso dai dati di questa tesi e dal confronto con quelli della letteratura, il razionale di una ricerca dell’aploinsufficienza del gene SHOX in bambini con bassa statura idiopatica, specie se disarmonica, deriva dalla sua relativa elevata frequenza. Una più diffusa conoscenza di questa patologia e l’introduzione di nuove tecniche di genetica molecolare hanno permesso un aumento della sensibilità diagnostica, tanto che ad oggi l’aploinsufficienza del gene è considerata la più frequente causa monogenica di ipostaturalità. I dati ottenuti in questa tesi dimostrano un’incidenza del 12,1%, che rientra nel range riscontrato anche in altri studi (Tabella 10). Tuttavia, questi risultati sono verosimilmente i più corrispondenti alla realtà in quanto si tratta di un’ampia casistica di pazienti selezionati mediante criteri omogenei e sui quali l’analisi mutazionale è stata effettuata mediante una combinazione di tecniche genetiche che permettono di rilevare sia le mutazioni puntiformi che delezioni/microduplicazioni del gene e/o delle regioni regolatorie. A questo proposito, un dato innovativo è rappresentato dall’elevata frequenza di mutazioni puntiformi di SHOX nella popolazione esaminata rispetto ai dati della letteratura, nella quale sono più frequentemente rilevate delezioni (Tabella 10). Sono state identificate 9 varianti de novo. Nel loro insieme, questi dati suggeriscono un probabile diverso background genetico nella popolazione italiana per quanto riguarda le mutazioni di SHOX, ma tale rilievo dovrà essere approfondito con un
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ampliamento della casistica. I dati di questa tesi confermano, inoltre, la variabile espressività clinica dell’aploinsufficienza di SHOX che può presentarsi solo con ipostaturalità più o meno grave, senza significativi ritardi dell’età ossea o alterate proporzioni corporee. Il follow-up a 2 anni di un sottogruppo di pazienti trattati con rGH, ha dimostrato un’evidente efficacia di questa terapia nell’incrementare la velocità di crescita e ridurre pertanto il deficit staturale. La risposta alla terapia sembra dipendere da una serie di variabili (età di inizio del trattamento, dose, anni di terapia, età di inizio e durata dello sviluppo puberale), ma solo il follow-up fino al raggiungimento della statura adulta potrà meglio definire il loro impatto sui risultati del trattamento. Nel futuro, un ulteriore caratterizzazione dei pathway SHOX-correlati potrà consentire l’introduzione di nuove strategie terapeutiche mirate a una correzione eziopatogenetica dei disordini da aploinsufficienza del gene SHOX.
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RINGRAZIAMENTI
Un ringraziamento di cuore al Prof. Diego Peroni e al Dott. Silvano Bertelloni che, grazie alla loro massima disponibilità, mi hanno permesso di frequentare il loro reparto e realizzare questo lavoro. È stata un’esperienza che mi ha arricchito sia da un punto di vista professionale che personale, facendomi capire l’importanza e la bellezza del lavoro che ho scelto di fare.
Grazie Mamma e Papà, a voi devo tutto. È grazie a voi se sono riuscita a raggiungere ogni mia aspirazione e a valicare ogni scoglio, se non ho mai perso la forza, l’ambizione e la forza di volontà in tutto ciò che ho fatto. Questo grande traguardo per me lo dedico a voi, perché non esiste cosa più bella e grande che la vita potesse donarmi.
Per te, Papà, trovare le parole è veramente difficile. Tu mi hai insegnato tanto o forse tutto, ma soprattutto mi hai insegnato che qualsiasi obiettivo si raggiunge con impegno, costanza e perseveranza, che non bisogna arrendersi mai anzi vedere sempre il lato positivo delle cose nella vita. Sei stato il supervisore di ogni mio passo e spero di ripagarti, in minima parte, per tutto quello che fai per me (per noi) con il bene immenso che ti voglio (che ti vogliamo).
E tu, Mamma, grazie per essere il mio riparo quotidiano, la mia complice, il mio pilastro. Con i tuoi modi dolci, premurosi e rassicuranti, mi hai reso indipendente senza lasciarmi mai sola. Anche io non lo farò mai con te. Grazie per ogni minuto che mi hai dedicato, per esserci sempre stata, di