PA MediaCabinet Secretary Simon Case has been involved in a number of political controversiesThe most senior official in the civil service is taking time off from his job because of a private medical matter.
Simon Case, who has been cabinet secretary since 2020, is expected to return to work in a few weeks.
A No 10 source said Prime Minister Rishi Sunak "looks forward to him returning" and wishes him all the best.
The absence comes as the government grapples with challenges at home and abroad, ahead of a general election expected next year.
Mr Case was appointed to his role when Boris Johnson was prime minister and has been embroiled in a string of controversies, including the Partygate scandal, during his time in post.
When an internal investigation into lockdown parties in Downing Street was launched in 2021, Mr Case removed himself from the process after he admitted an event he did not attend was hosted in his office.
Mr Case was pictured at the birthday event the Metropolitan Police imposed fixed penalty fines on Mr Johnson and Mr Sunak for attending.
Since then, his name has come up in reports about the inquiry into bullying allegations against former Deputy Prime Minister Dominic Raab, and the arrangement of an £800,000 credit facility to Mr Johnson.
And last week, WhatsApp messages in which he complained about the influence of Mr Johnson's wife, Carrie Johnson, were released by the Covid-19 inquiry.
The head of the civil service said the government was looking like a "terrible, tragic joke", while Mrs Johnson was "the real person in charge".
The Covid-19 inquiry, which is examining the government's handling of the pandemic, was expected to hear Mr Case give evidence in the coming weeks.
Mr Case's brief absence was first reported by Politico, which said a number of other top officials would cover for him, instead of one civil servant taking on all of his duties.
A Cabinet Office spokesman said: "The cabinet secretary is taking a short period of leave because of a private medical matter and is due to return to work in a few weeks."
A Cambridge graduate with a PhD in political history, Mr Case ascended through the ranks of the civil service after joining in 2006.
He held roles in the UK's intelligence agency, GCHQ, and in the Royal Household on the way to the job top.
At the age of 41, Ms Case became the youngest cabinet secretary in recent times.
Given his relative lack of experience, his appointment surprised senior civil servants and was seen by critics as a political move by Mr Johnson, the then-prime minister.
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