James Maddison has withdrawn from the latest England squad through injury, compounding Tottenham's injury crisis ahead of Saturday's visit to Wolves.
The midfielder was taken off at the end of the first half against Chelsea on Monday, but Ange Postecoglou sounded optimistic after the game that the injury was not serious and Maddison's substitution was more of a precautionary measure after Cristian Romero's red card.
"He got a knock on the ankle," Postecoglou told BBC Sport. "We were down one man already. It made sense to make a couple of changes at that point."
But, on Friday morning, Spurs confirmed Maddison would take no part in international duty over the next two weeks to effectively rule the midfielder out of Saturday's Premier League trip to Wolves.
A statement read: "We can confirm that James Maddison has been withdrawn from the England squad due to an ankle injury.
"The midfielder will not feature in the Three Lions' UEFA EURO 2024 qualifiers against Malta and North Macedonia, and will remain at Hotspur Way for rehabilitation with the Club's medical staff."
Southgate played down concerns over Maddison's fitness after including him in his squad.
When asked at his squad announcement press conference on Thursday about injury concerns, which includes the likes of Maddison, Bukayo Saka, Jude Bellingham and Callum Wilson, Southgate said: "Some of those, we could lose one today after a scan, we could lose one tomorrow. We don't really know.
"You'd be amazed at how complicated it is picking a squad because all clubs are of course sensitive to information and you're trying to piece everything together.
"So I couldn't be certain that everybody that is in that squad will be there on Sunday night [when the players report for duty], varying levels of doubt. Callum is probably the biggest level of doubt, but equally, I'm pretty confident that the others can get through and they're all keen to be in the squad so that's a really good sign."
It is not clear if Southgate will call up a replacement for the games against Malta and North Macedonia, although the England manager yesterday name-checked Newcastle's Anthony Gordon and Chelsea's Cole Palmer, while insisting that the door was "100 open" for Raheem Sterling to return to the squad in future.
As for Spurs, Maddison's absence means Giovani Lo Celso could at Molineux make his first start in the Premier League since October 2021.
Since the Chelsea game, Spurs head coach Ange Postecoglou has also lost Richarlison, who had minor groin surgery yesterday, Micky van de Ven to a serious hamstring injury, and defenders Cristian Romero and Destiny Udogie to suspension.
Spurs boss Ange Postecoglou will provide a further update at his pre-match press conference at 1pm on Friday, November 10.