Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

The occurrence of delirium diagnosis among youth hospitalizations in the United States: A Kids' Inpatient Database analysis.

OBJECTIVES: Delirium is an acute neuropsychiatric condition associated with increased morbidity and mortality. There is increasing recognition of delirium as a substantial health burden in younger patients, although few studies have characterized its occurrence. This study analyzes the occurrence of delirium diagnosis, its comorbidities, and cost among youth hospitalized in the United States. METHODS: The Kids' Inpatient Database, a national all-payers sample of pediatric hospitalizations in general hospitals, was examined for the year 2019. Hospitalizations with a discharge diagnosis of delirium among patients aged 1-20 years were included in the analysis. RESULTS: Delirium was diagnosed in 43,138 hospitalizations (95% CI: 41,170-45,106), or 2.3% of studied hospitalizations. Delirium was diagnosed in a broad range of illnesses, with suicide and self-inflicted injury as the most common primary discharge diagnosis among patients with delirium. In-hospital mortality was seven times greater in hospitalizations caring a delirium diagnosis. The diagnosis of delirium was associated with an adjusted increased hospital cost of $8648 per hospitalization, or $373 million in aggregate cost. CONCLUSIONS: Based on a large national claims database, delirium was diagnosed in youth at a lower rate than expected based on prospective studies. The relative absence of delirium diagnosis in claims data may reflect underdiagnosis, a failure to code, and/or a lower rate of delirium in general hospitals compared with other settings. Further research is needed to better characterize the incidence and prevalence of delirium in young people in the hospital setting.

Recent Updates in Psychopharmacology for the Core and Associated Symptoms of Autism Spectrum Disorder.

PURPOSE OF REVIEW: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core deficits in social communication and restricted, repetitive patterns of behavior. This article aims to review the recent literature pertaining to psychopharmacology for the core and associated symptoms of ASD including social impairment, repetitive behaviors, irritability, and language impairment. RECENT FINDINGS: Recent medication trials targeting social impairment in ASD have focused on neuropeptides (oxytocin and vasopressin) and memantine. None of these three medications has demonstrated consistent benefit for social impairment in ASD; however, additional studies are underway. Two double-blind, placebo-controlled studies on selective serotonin reuptake inhibitors (SSRIs) provide evidence against the use of SSRIs for repetitive behaviors in youth with ASD. Preliminary studies have investigated cannabidiol (CBD) for irritability in ASD but further studies are needed to demonstrate safety and efficacy. Finally, three double-blind, placebo-controlled studies provide preliminary evidence for folinic acid for the treatment of verbal language deficits in children with ASD. The identification of safe and effective pharmacological treatments to ameliorate the core and associated symptoms of ASD has proven difficult.

Challenges in the Medical Care of Patients With Autism Spectrum Disorder: The Role of the Consultation-Liaison Psychiatrist.

BACKGROUND: Autism spectrum disorder (ASD) is a common neurodevelopmental disorder that affects one in 40 children. Individuals with ASD have high rates of medical comorbidity, excess mortality, high health care expenditures, and difficulty accessing coordinated medical care. As the prevalence of ASD rises, consultation-liaison (C-L) psychiatrists will be increasingly called upon to assist patients with ASD both in inpatient and outpatient medical settings. METHODS: In this article, we review the patient, provider, and systems factors that converge to create challenges for delivering high-quality, patient-centered medical care for patients with ASD. CONCLUSION: Strategies to optimize the care of patients with ASD in medical settings include previsit planning, anticipating and reducing sources of distress, facilitating a patient- and family-centered multidisciplinary approach, employing environmental interventions, and using psychopharmacologic treatments.

Hospital Length of Stay With a Proactive Psychiatric Consultation Model in the Medical Intensive Care Unit: A Prospective Cohort Analysis.

BACKGROUND: Previous studies have demonstrated that proactive psychiatric consultation reduces hospital length of stay (LOS) in the general medical setting; however this model has not been studied in the intensive care unit (ICU). OBJECTIVE: To compare outcomes between a conventional consultation model and a proactive psychiatric consultation model. METHODS: Two medical ICUs (MICUs) were randomized to proactive psychiatric consultation vs conventional consultation psychiatric models. Proactive consultation included embedding a psychiatrist into daily MICU team rounds on all patients. In the conventional consultation MICU, psychiatric consultations were activated when deemed necessary. Primary outcomes were hospital LOS and MICU LOS. Secondary outcomes included delirium-coma-free hours and ventilator-free hours. RESULTS: A total of 429 patients were admitted to the proactive consultation MICU; 393 patients were admitted to the conventional consultation MICU. The consultation rate for the intervention group was 24.2% vs 6.1% in the control group (p < 0.001). Time to psychiatric consultation was shorter in the intervention group. Median hospital LOS was 6.92 days, interquartile range 3.70-14.31 in the intervention group vs 7.69 days, interquartile range 3.95-16.21 in the control group (p = 0.113). MICU LOS, delirium-coma-free hours, and ventilator-free hours were not significantly different between the 2 groups. Among the respiratory failure subgroup, hospital LOS was shorter in the intervention vs control group (median 9.46 days, interquartile range 4.95-17.56 vs 12.29 days, interquartile range 6.58-21.10, p = 0.011). CONCLUSIONS: Proactive psychiatric consultation in a MICU was associated with decreased time to consultation among all patients and shorter hospital LOS among patients with respiratory failure.

Sexual Behavior Among Persons With Cognitive Impairments.

Although the cognitively impaired are frequently included in heterogeneous studies of problematic sexual behavior, the epidemiology, etiology, and approach to assessment and treatment of persons with dementia and intellectual disability are distinct from those of the general population. The incidence of inappropriate sexual behavior among the intellectually disabled is 15-33%; however, the nature tends to be more socially inappropriate than with violative intent. Limited sociosexual education is a large contributor, and better addressing this area offers a target for prevention and treatment. A thorough clinical assessment of problematic sexual behaviors in the cognitively impaired requires understanding the patient's internal experience, which can be challenging. Assessment tools validated for the general population have not been validated for this population. Very few studies have assessed treatment approaches specifically among the cognitively impaired; however, research does suggest utility in habilitative, psychotherapeutic, and pharmacologic approaches which have been validated among the general population.

Psychiatric and behavioral manifestations of Williams syndrome.

PURPOSE OF REVIEW: The purpose of this review is to synthesize recent advances in the psychiatric and behavioral manifestations of Williams syndrome, a rare genetic syndrome. Recent advances have focused on more deeply characterizing the social phenotype and developing social skill interventions, improving the assessment and treatment of anxiety, and exploring eating behaviors. RECENT FINDINGS: The social cognitive phenotype in Williams syndrome, which consists of both high social drive and social cognition deficits, is present cross-culturally and may be related to reduced eye gaze. Social skills training for adults with Williams syndrome has demonstrated promise. Adapted exposure therapy and cognitive behavioral therapy programs for children and adults respectively, have been piloted in Williams syndrome. The majority of adults with Williams syndrome are either underweight or overweight, and problematic food-related behaviors likely contribute to bodyweight status. SUMMARY: Williams syndrome is associated with a number of core social and psychiatric difficulties which have a significant impact on functioning and quality of life. Recent work has begun to utilize a more nuanced understanding of the clinical presentations of these problems to develop interventions tailored to this unique population. However, larger trials, particularly those inclusive of a more diverse Williams syndrome population, are needed.

Buspirone for the treatment of anxiety in Williams syndrome: a retrospective chart review study.

BACKGROUND: Williams syndrome (WS) is a rare genetic disorder associated with a high prevalence of anxiety disorders. Evidence-based pharmacologic treatments for anxiety in WS are lacking. The purpose of this study is to provide naturalistic data on the use of buspirone for the treatment of anxiety in WS. RESEARCH DESIGN AND METHODS: Medical records of 24 individuals with Williams syndrome (ages 7-47 years) and anxiety who received treatment with buspirone were reviewed. Treatment response to buspirone was rated by assigning a retrospective Clinical Global Impression Improvement subscale (CGI-I) score. RESULTS: Twenty-three of 24 (96%) patients completed at least a 16-week treatment course with buspirone. Sixteen patients (67%; 95% CI 47%, 82%) were treatment responders (CGI-I ≤ 2). Only 1 (4%) patient discontinued buspirone due to a treatment-emergent side effect (nausea and vomiting). The most common side effect was nausea (13%). Twenty (84%) patients remained on buspirone at the time of their most recent follow-up visit. CONCLUSIONS: In this retrospective study, the majority of patients responded to a 16-week course of buspirone. Prospective studies are warranted to further assess the efficacy and tolerability of buspirone for anxiety in WS.

AACAP Endorses the Inclusion of Methylphenidate in the WHO Model Lists of Essential Medicines.

Despite decades of clinical use and a large body of evidence, the WHO continues to exclude methylphenidate for attention-deficit/hyperactivity disorder (ADHD) from its EML.1 The exclusion of methylphenidate has dire implications for millions of individuals with ADHD worldwide, especially those living in low and low-middle income countries (LMIC), where governmental decisions to make medicines available are contingent on EML listing.

Guanfacine for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Down Syndrome: A Retrospective Chart Review.

Study Design: Retrospective case series. Objectives: The objective of this study was to provide naturalistic data on the use of guanfacine for the treatment of attention-deficit/hyperactivity disorder (ADHD) in a clinically referred sample of youth with Down syndrome (DS). Methods: The medical records of children and adolescents with DS who received guanfacine for the treatment of ADHD from a multidisciplinary neurodevelopmental disorder clinic between September 1, 2011, and September 10, 2021, were reviewed. Demographic and clinical characteristics, guanfacine dose and treatment duration, and adverse effects were recorded. Clinical Global Impression Scale (CGI) scores for ADHD symptom severity (S) and improvement (I) were retrospectively assigned by a child and adolescent psychiatrist based on review of the clinic notes. Response to guanfacine was defined as completion of at least 12 weeks of treatment and a Clinical Global Impression Improvement subscale rating ≤2 (1 = "very much improved" or 2 = "much improved"). Results: Twenty-one patients were eligible for inclusion, of whom 17 (81%) completed at least 12 weeks of guanfacine. Ten of the 21 patients (48%; 95% confidence interval [CI]: 28%-68%) responded to treatment. The median time on guanfacine treatment covered by the clinic notes was 50.4 weeks, with a range of 0.3 weeks to 7.5 years. Thirteen patients (62%) remained on guanfacine at the time of their most recent clinic note. Nine patients had adverse events documented in their clinic notes (43%; 95% CI: 24%-63%), most commonly sleepiness (n = 7) and constipation (n = 2). Conclusion: About half of patients with DS responded to guanfacine for the treatment of ADHD and many tolerated long-term use. Study limitations primarily relate to the retrospective nature of the study and small sample size.

In vivo translocator protein in females with autism spectrum disorder: a pilot study.

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)-a mitochondrial protein-in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET-MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

A translational approach to congenital non-obstructive hydronephrosis.

Congenital hydronephrosis, defined as congenital dilatation of one or more components of the renal collecting system, is detected in 1-2% of all pregnancies. The majority of antenatally detected hydronephrosis is non-obstructive and either resolves or stabilizes. Management of persistently severe cases may include surgical intervention, the only available treatment. Recent data demonstrate that hedgehog signaling plays a critical role in regulating the structure and function of the collecting system in a manner dependent on the formation of GLI3 repressor. Here, we review the pathobiology and clinical management of non-obstructive hydronephrosis and describe how inhibitors of GLI3 repressor formation may serve as novel therapies for this disorder.

Repetitive Thoughts and Behaviors in Autism Spectrum Disorder: A Symptom-Based Framework for Novel Therapeutics.

While the core symptoms of autism spectrum disorder include repetitive thoughts and repetitive behaviors, repetitive phenomena also occur in many other psychiatric disorders. Types of repetitive thoughts include preoccupations, ruminations, obsessions, overvalued ideas, and delusions. Types of repetitive behaviors include tics, stereotypies, compulsions, extrapyramidal symptoms, and automatisms. We provide a description of how to recognize and classify different types of repetitive thoughts and behaviors in autism spectrum disorder, providing clarity on which phenomena should be considered a core feature of autism spectrum disorder and which phenomena are indicative of a comorbid psychiatric disorder. Clinical features that can be used to differentiate types of repetitive thoughts include whether they are distressing and the degree of insight the individual has, while repetitive behaviors can be classified based on whether they are voluntary, goal-directed/purposeful, and rhythmic. We present the psychiatric differential diagnosis of repetitive phenomena within the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) framework. Careful clinical consideration of these transdiagnostic features of repetitive thoughts and behaviors can improve diagnostic accuracy and treatment outcomes, and influence future research.

Clozapine for treatment refractory catatonia in individuals with autism spectrum disorder: a retrospective chart review study.

BACKGROUND: Catatonia is increasingly recognized in individuals with autism spectrum disorder (ASD). Empirical data on treating catatonia in this population are limited. The purpose of this study is to provide naturalistic data on the use of clozapine for the treatment of catatonia in patients with ASD. RESEARCH DESIGN AND METHODS: Medical records of 12 individuals with ASD and catatonia who received treatment with clozapine were reviewed. Treatment response to clozapine was rated by assigning a retrospective Clinical Global Impression Improvement scale (CGI-I) score. RESULTS: Mean (SD) and median (IQR) age at initiation of clozapine treatment were 22.1 (7.7) and 20.4 (9.7) years, with a range of 10-39 years. Eleven of the 12 patients had received treatment with lorazepam prior to initiating clozapine and 9 of the 12 patients received concomitant treatment with lorazepam and clozapine. Eleven of the 12 patients (92%; 95% CI: 65%, 99%) responded to clozapine. All 12 patients remained on clozapine at the time of their most recent clinical note. All 12 patients (100%; 95% CI: 76%, 100%) experienced one or more adverse events, the most common of which was sedation (n = 11, 92%). CONCLUSIONS: Overall, clozapine was associated with a high response rate for the treatment of catatonia in patients with ASD. These naturalistic data support the use of clozapine for the treatment of catatonia in patients with ASD for whom lorazepam is either ineffective or partially effective.

Diversity of Participants in Williams Syndrome Intervention Studies.

PURPOSE: This study describes participant diversity in Williams syndrome (WS) intervention studies. METHODS: A literature search was conducted to identify prospective treatment studies including participants with WS. Data was extracted on the reporting of and information provided on age, sex, cognitive ability, socioeconomic status, race, and ethnicity. RESULTS: Eleven eligible articles were identified. Reporting rates of demographic factors varied considerably, with the highest rates for age and sex (100%) and the lowest reporting rates for race (18%) and ethnicity (9%). Combining demographic data from the two studies that reported on race and/or ethnicity (n = 33), 88% of participants were White. The combined participant mean age was 20.9 years. CONCLUSION: There is a low frequency of reporting on several demographic factors including socioeconomic status, race, and ethnicity in WS intervention studies. There is a need for increased representation of racial and ethnic minority groups, older participants, and more cognitively impaired patients in WS research.

Neuroimaging research in Williams syndrome: Beginning to bridge the gap with clinical care.

Williams syndrome (WS) is a genetic disorder affecting multiple organ systems. Cardinal features include cardiovascular disease, distinct facies, and a unique cognitive profile characterized by intellectual disability, hypersociability, and visuospatial weaknesses. Here, we synthesize neuroimaging research in WS with a focus on how the current literature and future work may be leveraged to improve health and quality of life in WS. More than 80 neuroimaging studies in WS have been conducted, the vast majority of which have focused on identifying morphometric brain differences. Aside from decreased volume of the parieto-occipital region and increased cerebellar volume, morphometric findings have been variable across studies. fMRI studies investigating the visuospatial deficit have identified dorsal stream dysfunction and abnormal activation of the hippocampal formation. Minimal work has been done using PET or MRS. Future approaches that conduct neuroimaging in tandem with clinical phenotyping, utilize novel imaging techniques to visualize brain vasculature or provide biochemical and molecular information, and include more homogenous age groups across the lifespan, have significant potential to advance clinical care.

Clinical Challenges and Solutions in Adapting Cognitive Behavioral Therapy for Anxiety in Adults With Intellectual Disability.

While cognitive behavioral therapy (CBT) is a first-line treatment for anxiety, it is not typically offered to those with intellectual disability (ID). In this article, we provide a historical perspective on the treatment of mental health concerns in adults with ID, describe an adapted CBT treatment for anxiety in adults with Williams syndrome (WS) and mild to moderate ID, and discuss general modifications to CBT for adults with ID. Strategies used to successfully adapt CBT for adults with WS that may generalize for adults with ID more broadly include: (a) using child-based CBT manuals as a framework; (b) involving a caregiver as a therapy partner; (c) incorporating a high level of repetition; (d) simplifying language; (e) slowing the pace of instruction; and (f) incorporating specific examples and adaptations for WS.

Stimulant intolerance in children with Angelman syndrome with hyperactivity: a case series.

OBJECTIVES: Angelman syndrome is a neurogenetic disorder resulting from the loss of expression of the ubiquitin-protein ligase E3A gene on chromosome 15. Problematic behaviors including attention-deficit/hyperactivity disorder (ADHD) symptoms of hyperactivity, impulsivity and inattention are highly prevalent in Angelman syndrome. The efficacy, safety and tolerability of stimulant medications in children with Angelman syndrome for the treatment of ADHD symptoms have not been previously reported. METHODS: We describe three boys with Angelman syndrome who were treated with open-label stimulant medications for ADHD symptoms. RESULTS: Stimulant medications were highly intolerable, and treatment had to be discontinued after limited dosing in all three cases due to marked increases in hyperactivity and impulsivity along with worsened distractibility. CONCLUSION: The findings of this study suggest that stimulant medications may be ineffective and poorly tolerated in children with Angelman syndrome.

Case Reports: Clozapine for the Treatment of Catatonia in Autism Spectrum Disorder.

Catatonia is a severe clinical syndrome which has been increasingly reported in autism spectrum disorder (ASD). The prevalence of catatonia in ASD is unknown. Diagnosing catatonia in ASD is complicated by overlapping clinical features such as mutism, stereotypies, and echophenomena. Here, we present the clinical histories of two individuals with ASD and catatonia who were successfully treated with clozapine. We have reported on a novel potential treatment option for catatonia in ASD. Additional studies are needed to evaluate the safety, efficacy, and tolerability of clozapine for the treatment of catatonia in ASD.