Germany coach Joachim Low revealed Marco Reus has "massive health problems" after excluding him from his final 23-man squad for Euro 2016 on Tuesday.
Reus, who also missed the 2014 World Cup after sustaining an injury on the eve of Germany's departure for Brazil, has a mysterious injury which Low says means he "can only run in a straight line".
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Given the strains of potentially six weeks of action in France, Low said he simply could not take the risk and include the Borussia Dortmund midfielder.
"With Marco Reus, the situation is the doctors cannot give me any definite forecast," Low said at a press conference.
"Marco has serious health problems. At the moment, he can only run in a straight line.
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"The doctors are sceptical that he will be fully fit in the coming weeks and with these demanding games.
"Therefore, it's a bitter decision for us and for him, and disappointing for everybody - he would have been a huge enrichment for us."
Low also sent Karim Bellarabi, Julian Brandt and Sebastian Rudy back from Germany's training camp in Ascona, Switzerland, admitting it had been a difficult decision.
"Of course from a human perspective, the decisions hurt me too," Low said. "I know how big a disappointment it is for the players.
"On the other hand, they must see this as a chance and use it as motivation for the years to come.
"I want to thank all four of them. They've been very good in training and given everything, and I hope they put this disappointment behind them well.
"It's not that I've opted against these four players, I've chosen in favour of the other 23."
Germany's 23-man squad, which includes Manchester United's Bastian Schweinsteiger, despite concerns over his condition, will remain in Ascona until Friday in preparation for their final warm-up game ahead of Euro 2016 against Hungary in Gelsenkirchen.
"The doctors have confirmed that Bastian and Mats Hummels are both going to be fit to play," reported Low.
The squad will then have two days' rest before moving into their camp for the tournament in Evian. Germany's first group game is against Ukraine on June 12 in Lille.
Germany squad for Euro 2016:
Goalkeepers: Manuel Neuer (Bayern Munich), Bernd Leno (Bayer Leverkusen), Marc-Andre ter Stegen (Barcelona)
Defenders: Jerome Boateng (Bayern Munich), Mats Hummels (Borussia Dortmund), Shkodran Mustafi (Valencia), Benedikt H?wedes (Schalke), Jonas Hector (Cologne), Emre Can (Liverpool), Antonio Rudiger (Roma)
Midfielders: Bastian Schweinsteiger (Manchester United), Sami Khedira (Juventus), Mesut Ozil (Arsenal), Toni Kroos (Real Madrid), Mario Gotze (Bayern Munich), Thomas Muller (Bayern Munich), Julian Draxler (Wolfsburg), Leroy Sane (Schalke), Andre Schurrle (Wolfsburg), Joshua Kimmich (Bayern Munich), Julian Weigl (Borussia Dortmund)
Forwards: Lukas Podolski (Galatasaray), Mario Gomez (Besiktas)