Phil Jones had left the camp before the game in Germany with a suspected broken toe after an innocent collision with his Manchester United team-mate Smalling in training.
It has subsequently transpired the knock that forced off Smalling late in the game in Dortmund is serious enough for him to be sent home before the game against Lithuania, although at this stage there are no indications as to how much of United’s nine-game April schedule he will miss.
Southgate has his own problem as the injuries start to coalesce into one major headache – can he consider continuing with his three-at-the-back system with such limited resources?
Ben Gibson, 24, was immediately called up for the first time to the England squad with Chelsea's Gary Cahill also missing through suspension.
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Gareth Southgate faces a selection dilemma
Phil Jones and Chris Smalling are missing through injury
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That said, it would be a brave man indeed to put the Middlesbrough player alongside Wednesday’s debutant Michael Keane in a game where there are World Cup points at stake.
John Stones and Eric Dier could complete the triumvirate with Keane at the heart of the defence but it would leave a somewhat lightweight pairing of Jake Livermore and Alex Oxlade-Chamberlain as his central midfield.
In the absence of Jordan Henderson and Danny Drinkwater, then, the back three has to be put on hold. The indications are that Southgate was set to revert for a four as the better way to open up Lithuania anyway.
Raheem Sterling is an injury doubt but fits a 4-2-3-1 better and with Jamie Vardy picking up a knock against Germany, it could by a chance for Marcus Rashford to be given his head from the start after livening up England’s forlorn hope for an equaliser in Dortmund.
Ben Gibson has been called into the England squad
That said, if the England manager is desperate for a bit of experience, Jermain Defoe could come back from the international wilderness to lead the line. Such a move would perhaps disappoint the Wembley crowd but one man would be happy.
It would be the first time since September 2013 that England started a competitive international without a United player in the starting XI.
Jose Mourinho would be over the moon.