While acne is a common skin disorder in adolescents, providers should have increased awareness when there are clinical signs and symptoms that may indicate the patient may not have "typical teenage acne." Uncommon causes of severe adolescent acne are summarized in Table 1. A simplified diagnostic approach is presented in Fig. 6. Two common non-syndromic entities associated with severe acne are AF and AC. Explosive ulcerative acne with systemic symptoms should raise suspicion for AF, and concurrent treatment with systemic corticosteroids and isotretinoin is key to management. The presence of widespread comedones, cysts, abscesses, and draining sinus tracts with a more chronic course is suggestive for AC. Rarer autoinflammatory syndromic causes of acne include SAPHO, PAPA, PASH, and PAPASH syndromes. These are characterized by features such as recurrent febrile outbreaks, osteoarticular involvement, and neutrophilic dermatoses. PCOS accounts for the majority of acne associated with excess androgen states, while HAIR-AN and SAHA syndromes are less common. Finally, drug-induced acne should be considered in unique adolescent populations such as transgender individuals on gender-affirming medications, athletes using anabolic steroids, patients receiving molecular targeted therapies, and cystic fibrosis patients using newer combination CFTR modulators.