Alex Corbisiero and Tom Croft will miss England's summer tour to New Zealand despite recovering from long-term injuries, while Tom Youngs will forego Test action to support his ill wife.
England's coaching staff will not risk fit-again duo Corbisiero and Croft for the three-Test All Blacks challenge next month.
Leicester and Lions hooker Youngs will miss the June Test series to look after his family, with England boss Stuart Lancaster firmly behind the move.
"Our thoughts are with Tom and Tiffany at this time and it is entirely right that he stays at home to support her and their daughter Maisie," said head coach Lancaster.
"Everyone in the England squad sends them our best wishes."
Youngs' absence in New Zealand adds to England's hooker shortage, with Dylan Hartley, Rob Webber and David Paice all battling for fitness to make the tour.
Harlequins' Dave Ward and Exeter's Luke Cowan-Dickie, both uncapped, could yet be pitched into action for England's first Test on 7 June in Auckland.
Wings Christian Wade and Jack Nowell will also definitely miss the New Zealand tour through injury, while doubts remain over the fitness of Gloucester centre Billy Twelvetrees and Bath hooker Rob Webber.
Twelvetrees suffered ankle trouble in Gloucester's 38-30 Aviva Premiership victory over London Irish on Saturday, and should learn the severity of his injury after scans on Thursday.
Webber suffered a knee injury in Bath's 19-19 draw with Northampton on Friday night and is now fighting to recover in time for England's summer tour.
Northampton prop Corbisiero is ready for club action after seven months on the sidelines with persistent knee problems, while Leicester flanker Croft is back after tearing knee ligaments on the season's opening day.