Deficits in reciprocal social behavior are a characterizing feature of autism spectrum disorder (ASD). Autism‐related variation in reciprocal social behavior (AVR) in the general population is continuously distributed and highly heritable—a function of additive genetic influences that overlap substantially with those which engender clinical autistic syndromes. This is the first long‐term prospective study of the stability of AVR from childhood through early adulthood, conducted via serial ratings using the Social Responsiveness Scale, in a cohort‐sequential study involving children with ASD, other psychiatric conditions, and their siblings ( N = 602, ages = 2.5–29). AVR exhibits marked stability throughout childhood in individuals with and without ASD.
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.1 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.
The muscular ventricular septum separates the flow of oxygenated and de-oxygenated blood in air-breathing vertebrates. Defects within it, termed muscular ventricular septal defects (VSDs), are common, yet less is known about how they arise than rarer heart defects. Mutations of the cardiac transcription factor NKX2-5 cause cardiac malformations, including muscular VSDs. We describe here a genetic interaction between Nkx2-5 and Sarcospan (Sspn) that affects the risk of muscular VSD in mice. Sspn encodes a protein in the dystrophin-glycoprotein complex. Sspn knockout (SspnKO) mice do not have heart defects, but Nkx2-5+/−/SspnKO mutants have a higher incidence of muscular VSD than Nkx2-5+/− mice. Myofibers in the ventricular septum follow a stereotypical pattern that is disrupted around a muscular VSD. Subendocardial myofibers normally run in parallel along the left ventricular outflow tract, but in the Nkx2-5+/−/SspnKO mutant they commonly deviate into the septum even in the absence of a muscular VSD. Thus, Nkx2-5 and Sspn act in a pathway that affects the alignment of myofibers during the development of the ventricular septum. The malalignment may be a consequence of a defect in the coalescence of trabeculae into the developing ventricular septum, which has been hypothesized to be the mechanistic basis of muscular VSDs.
Dexter is a 12-year-old boy who presents with his maternal grandmother for follow-up to primary care for secondary encopresis. Dexter presented, 18 months ago, with a 3-month history of secondary encopresis. At that time, a comprehensive assessment revealed functional constipation resulting in encopresis. Dexter's symptoms resolved with a combination of medication management and behavioral strategies; laxatives were discontinued 12 months ago.Dexter's grandmother reports that for the past 6 months, her grandson developed encopresis once again. However, she notes that, although Dexter had small-volume episodes of soiling in the past, he is now passing fully formed stools into his underwear. These episodes usually occur once a day, either at home or at school. Frustrated, Dexter's grandmother has transitioned him to adult diapers.Dexter denies hematochezia, pain, dysuria, hematuria, urinary incontinence, dietary changes, or weight loss. He passes soft stool in his underwear once daily without blood or pain. When interviewed alone, Dexter denies drug use, depression, or significant social stressors. Surprisingly, he seems unconcerned about depression, drugs and social stress, and frequently laughs when discussing them. His physical examination, including a rectal examination, is normal.Dexter's medical history is notable for attention-deficit hyperactivity disorder, treated with stimulant medication. He was toilet trained at 3 years without any difficulty. He lives with his grandmother, who is his legal guardian; his mother has chronic mental health problems and substance abuse. Dexter maintains regular contact with his mother and reports that their relationship is positive.Dexter's grandmother is extremely distressed by his current presentation and notably, Dexter is not. What would you do next?
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