England must launch their Six Nations title defence without Joe Marler and have also learnt that flanker James Haskell has suffered another setback in his return from a lengthy lay-off.
On a day of disappointing injury bulletins, Marler has been ruled out of the opening two fixtures against France and Wales due to a fractured leg while the concussed Haskell is to miss Wasps' Champions Cup clash with Toulouse on Sunday.
Offering some comfort, however, is the news that outstanding back-row prospect Sam Underhill is to leave the Ospreys for Bath next season, making him eligible for England selection.
It is the news that Marler's injury is worse than initially feared that will cause the greatest angst as Eddie Jones has now lost two high-quality players at loosehead.
Mako Vunipola is not expected to recover from his knee problem until the end of February at the earliest - a more definitive date for his comeback is due next week -- so Marler had been earmarked to start against France on Feb. 4.
But England must now tackle the first two Championship assignments with Matt Mullan in the number three jersey while the uncapped Nathan Catt offers cover from the bench.
Vunipola emerged as a world class prop during last year's flawless run of 13 successive Test wins and while Marler lacks his dynamism and natural ability, he is a more forceful defender who possesses greater set-piece expertise.
Either would have served the Grand Slam champions well, but now Mullan steps into the breach with Catt poised to make his debut.
The blow to the head that ended Haskell's comeback against Leicester on Sunday will see him sit out the visit of Toulouse to Coventry, leaving just one last club fixture to prove his match fitness before England go into camp.
Having spent seven months on the sidelines following foot surgery, Haskell's appearance as a replacement lasted a mere 35 seconds.
"James is fine within himself, but he took a significant bang to the head on Sunday and we don't feel it right to push him to meet the tight deadline for a six-day turnaround," Wasps director of rugby Dai Young said.
"We would obviously all like for James to be involved in our big game against Toulouse, James included, but the most important thing is for him to feel completely right and under no pressure to make the game this weekend.
"This is first time he has suffered concussion and we have told him to take extra time, with the aim of being fit for Zebre in the final pool round."
Joe Launchbury is poised to make his comeback from a calf injury against Toulouse after Jones initially feared that he would be unavailable against France.
"The rehab has gone really well. As soon as I did it I was always really hopeful for this weekend," Launchbury said.
"I'm delighted how it's gone and how the calf feels so I'm ready to go again."
Launchbury's availability has grown in significance after Chris Robshaw underwent shoulder surgery, a development that means Maro Itoje is likely to move to blindside flanker with either Launchbury or Courtney Lawes partnering George Kruis at lock.
Underhill will be eligible for England later this year after agreeing a three-year deal with Bath that means Twickenham's edict on not selecting players based outside the Aviva Premiership does not apply.
The highly-regarded 20-year-old flanker could make his debut on the summer tour to Argentina.