The identity of Isaac II's first wife is unknown, but her name, Herina (i.e., Eirene), is found on the necrology of Speyer Cathedral, where their daughter Irene is interred. (It must be noted, however, that it would have been extremely unusual for a mother and daughter to bear the same name, unless the mother's name was monastic.) Isaac's wife may have been a member of the Palaiologos family. Their third child was born in 1182 or 1183 and she was dead or divorced by 1185, when Isaac remarried. Their children were:

Euphrosyne Angelina, a nun
Irene Angelina, married first to Roger III of Sicily, and secondly to Philip of Swabia
Alexios IV Angelos


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