Pope Francis on Sunday offered prayers and solidarity to the family of a Vatican schoolgirl who went missing 40 years ago in one of Italy's most enduring mysteries.

Emanuela Orlandi, the 15-year-old daughter of a Vatican usher, failed to return home on June 22, 1983, after a music lesson in central Rome.

The case has drawn renewed worldwide attention following the release of the Netflix series "Vatican Girl" late last year.

Referring to the 40th anniversary of the disappearance, Francis said he wanted "to express once again my closeness to her family, especially her mother, assuring my prayers".

Delivering his Angelus message, Francis addressed crowds in St Peter's Square including Orlandi's brother Pietro, who has long campaigned for the Vatican to shed light on the mystery.

Pietro Orlandi was standing with a group of supporters holding up photographs and banners that called for "truth" and "justice". 

He welcomed the pope's remarks, calling them "a positive signal" and "a good step forward", in comments to Italian news agency ANSA.

Foul play has long been suspected in the Orlandi case, and this year both Vatican and Italian investigators have reopened investigations into it, with possible new leads. 

Theories about Orlandi's disappearance have run the gamut from speculation it was linked to a plot to kill Pope John Paul II, to suggestions that she was kidnapped by the Rome underworld, to accusations she was the victim of a priestly paedophile group.

Earlier this year, Pietro Orlandi played an audio tape on Italian television from an alleged gangster who said girls were brought into the Vatican to be molested and that John Paul II knew about it.

In April, Pope Francis called the allegations "offensive and unfounded insinuations".