Aaron Ramsey has withdrawn from the Wales squad for the Euro 2020 qualifying match against Azerbaijan next month.
Ramsey, 28, has not played a full match since injuring a hamstring playing for Arsenal in April.
He has made only one appearance off the bench since his transfer to Juventus, in a friendly against Triestina when he played 20 minutes.
Dylan Levitt steps up from the under-21 side to replace him in the squad.
It is understood Ryan Giggs' management team are concerned about Ramsey's match fitness after such a long lay-off without a competitive game.
Juventus said on their official website Ramsey had missed club training because of a back problem.
Wales are fourth in Group E after away defeats against Croatia and Hungary in June.
They started their campaign with a 1-0 win at home against Slovakia, and desperately need a positive result against Azerbaijan at Cardiff City Stadium on 6 September before a friendly against Belarus at the same venue three days later.
It means Giggs' side will be without another experienced player following the omission of long-time captain Ashley Williams from the squad.
Ramsey has scored 14 goals in 58 Wales appearances, but has yet to make an appearance in the current campaign.
Uncapped Manchester United Academy player Levitt, 18, was an unused substitute for Wales' 2-1 defeat against Croatia in Osijek on 8 June.
Wayne Hennessey (Crystal Palace), Danny Ward (Leicester City), Adam Davies (Stoke City), Chris Gunter (Reading), Ben Davies (Tottenham Hotspur), Neil Taylor (Aston Villa), Connor Roberts (Swansea City), Ethan Ampadu (RB Leipzig, on loan from Chelsea), Chris Mepham (Bournemouth), Tom Lockyer (Charlton Athletic), James Lawrence (Anderlecht), Joe Rodon (Swansea City), Dylan Levitt (Manchester United), Joe Allen (Stoke City), Jonny Williams (Charlton), Harry Wilson (Bournemouth, on loan from Liverpool), Matthew Smith (QPR, on loan from Manchester City), Daniel James (Manchester United), Will Vaulks (Cardiff City), Joe Morrell (Lincoln City, on loan from Bristol City), Gareth Bale (Real Madrid), Sam Vokes (Stoke City), Tom Lawrence (Derby County), Ben Woodburn (Oxford United, on loan from Liverpool), Ryan Hedges (Aberdeen), Kieffer Moore (Wigan Athletic).
BBC Wales Football Correspondent Rob Phillips:
At the squad announcement Giggs spoke of his excitement of having his two best players - Bale and Ramsey - in harness for the first time in these qualifiers, so this withdrawal will be frustrating.
Wales have often shown they can win without playing well because of Bale. But, invariably when things have gone well, they have needed Ramsey pulling the strings in midfield as well.