The centre-back picked up his fifth Premier League booking of the season last weekend against Arsenal, when he was shown a yellow card in the second half for dissent.
Kevin Danso is therefore set to come in as Spurs look to win at home in the Premier League for the first time since the opening weekend of the season.
With Romero out, Frank could look for more ball-playing qualities in midfield and that could see Archie Gray handed a rare league start.
The youngster shone against Paris Saint-Germain on Wednesday night and will hope to start, potentially alongside Joao Palhinha after he was rested in midweek.
There could be a refreshed forward line too. Mohammed Kudus, Xavi Simons and Wilson Odobert all started on the bench against PSG but will hope to come into the side here.
Unless Frank sticks with the same 4-2-2-2 he used in Paris, at least one of Lucas Bergvall or Pape Matar Sarr are likely to drop out.
In attack, Randal Kolo Muani and Richarlison both impressed in the Champions League and scored three goals between them.
Kolo Muani has been in better form and offers more of an all-round threat and could get the nod, with Frank confirming he is fit to start again against Fulham.