For the visitors, despite Gianluigi Buffon's decision to reverse his global retirement in hopes of unifying the squad, AC Milan's teenage goalkeeping sensation Gianluigi Donnarumma is expected to record some minutes.
With Butland and Pickford both yet to make double digits in caps for England, this could be considered a wise decision.
England kept a fifth successive clean sheet when their three-man defence kept the Netherlands at bay in the 1-0 win in Amsterdam on Friday and Southgate is in no doubt that good defending will be key to England's success in Russian Federation.
However, the knee issue, which the Three Lions boss described as "not ideal", will force further doubt into the mind of the 47-year-old and his ability to rely on Wilshere's fitness in Russian Federation this summer.
"It's not too late for anybody".
"Lots of positions of the field we have really good options".
"I can't predict if Joe will play for England before the World Cup".
Pickford was involved in the build-up to Jesse Lingard's victor and his abilities complement a young defence showing a "different skill-set" to the previous generation.
"I don't know exactly when he'll be back, but he was very confident it would be sooner rather than later". He is the best goalkeeper in the England squad with the ball at his feet. "You need a clear understanding of how we want to play but then there's the additional pressure of knowing you've got to play well to keep your place".
"The profile of all of that defence and goalkeeper allowed us to do that".
While England largely dominated proceedings in Amsterdam they still lack something in central midfield.
Jordan Henderson and Alex Oxlade-Chamberlain did well in Amsterdam behind Lingard playing as No 8, while Jack Wilshere would have played had he not suffered a knee issue on the eve of the game.
It bodes well then ahead of Tuesday night's friendly against Italy, another big name, but there's a sense that in terms of the World Cup this summer we've been here before.
"It's one of the real highlights of being in the role - that you are not a threat to anybody so you can pick their brains". Walker is the surprise name here with the other four players having been mentioned in the past alongside Gary Cahill but as we'll see below he seems unlikely to go to Russian Federation.
"It's obviously more hard because there's a couple of guys who have been in squads but haven't had the chance to play for us".
"The aim will be will make some changes", said Southgate.
"We have got to assess (the injury record) with every player", Southgate added.
"Certainly, some of those guys we want to see on the pitch".
"There are 31 or 32 players that will be in contention and no one knows what will happen over the next few weeks". He's comfortable to speak up for the group. "He has a mindset for the collective, not just self and that's obviously a hugely important attribute for a captain to have".
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