It happened on US-59 just before the FM 961 and Highway 60 exit around 3:56 a.m., according to Wharton PD.
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A black Cadillac SUV was traveling southbound near the exit when it veered off the main lanes, drove through a grassy median and entered the northbound lanes, causing a collision with an oncoming Nissan Altima.
Police said the driver of the Cadillac SUV was found dead when they arrived.
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The three adults and the toddler in the Nissan Altima also died. Authorities said the child was 2 and a half years old.
A 6-month-old baby found riding in that vehicle was flown to a hospital for treatment.
Police were still investigating the area.