Case: John is a 4-year-old boy with autism spectrum disorder (ASD) and developmental delay who presented with concerns about increasing aggressive behavior at a follow-up visit with his developmental-behavioral pediatrician. Diagnosis of ASD was made via Diagnostic and Statistical Manual of Mental Disorders, 5th version criteria at initial evaluation at 34 months. Medical history at that time was pertinent for rapid linear growth since the age of 1 and recent pubic hair growth and penile enlargement. Family history was significant for early puberty in a maternal uncle and 4 distant maternal relatives. Standardized testing included administration of the Childhood Autism Rating Scale 2-Standard, which was consistent with severe symptoms of ASD, and the Mullen Scales of Early Learning, which indicated moderate delay in fine motor skills and expressive language and severe delay in receptive language and visual receptive skills.At initial assessment, John's parents also reported a pattern of aggressive behavior, which included frequent hitting of other children at childcare, consistently forceful play with peers and family members, and nightly tantrums with hitting and throwing at bedtime. Triggers of aggressive behavior included other children taking his toys, transition away from preferred activities, and being told "no."John was concurrently evaluated by a pediatric endocrinologist at 34 months. At that assessment, his height Z-score was +2.5, and he had Tanner 2 pubic hair, Tanner 3 genitalia, and 6 cc testicular volumes. Radiograph of the hand revealed a bone age of 6 years (+7.8 S.D.). Laboratory studies revealed a markedly elevated testosterone level and low gonadotropin (luteinizing hormone [LH] and follicle-stimulating hormone) levels and a normal dehydroepiandrosterone sulfate, suggestive of peripheral precocious puberty. Targeted genetic testing with sequencing of the LHCGR gene revealed a heterozygous D578G mutation resulting in the rare condition Familial Male-Limited Precocious Puberty (FMPP), characterized by constitutive activation of the LH receptor. FMPP, also referred to as testotoxicosis, was attributed as the cause of John's peripheral precocious puberty.By the age of 4, John's height Z-score was +3.1, his genitalia larger, and his bone age 10 years (+10.3 S.D.). His parents elected to start off-label therapy with bicalutamide (a nonsteroidal antiandrogen) and anastrazole (an aromatase inhibitor), recommended by the endocrinologist. Unexpectedly, as John's hyperandrogenism was treated, John's family reported intensified aggression toward other children and adults, especially at school, in addition to multiple daily instances of biting when upset. What is your next step in John's treatment of his challenging behavior?
Reference: 1. Shenker A, Laue L, Kosugi S, et al. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature. 1993;365:652-654.