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Cerebral palsy (CP) is the most common childhood motor disability, yet its link to single-gene disorders is under-characterized. To explore the genetic landscape of CP, we conducted whole exome sequencing (WES) in a cohort of patients with CP.We performed comprehensive phenotyping and WES on a prospective cohort of individuals with cryptogenic CP (who meet criteria for CP; have no risk factors), non-cryptogenic CP (who meet criteria for CP; have at least one risk factor), and CP masqueraders (who could be diagnosed with CP, but have regression/progressive symptoms). We characterized motor phenotypes, ascertained medical comorbidities, and classified brain MRIs. We analyzed WES data using an institutional pipeline.We included 50 probands in this analysis (20 females, 30 males). Twenty-four had cryptogenic CP, 20 had non-cryptogenic CP, five had CP masquerader classification, and one had unknown classification. Hypotonic-ataxic subtype showed a difference in prevalence across the classification groups (p = 0.01). Twenty-six percent of participants (13/50) had a pathogenic/likely pathogenic variant in 13 unique genes (ECHS1, SATB2, ZMYM2, ADAT3, COL4A1, THOC2, SLC16A2, SPAST, POLR2A, GNAO1, PDHX, ACADM, ATL1), including one patient with two genetic disorders (ACADM, PDHX) and two patients with a SPAST-related disorder. The CP masquerader category had the highest diagnostic yield (n = 3/5, 60%), followed by the cryptogenic CP category (n = 7/24, 29%). Fifteen percent of patients with non-cryptogenic CP (n = 3/20) had a Mendelian disorder on WES.WES demonstrated a significant prevalence of Mendelian disorders in individuals clinically diagnosed with CP, including in individuals with known CP risk factors.

BackgroundArthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management.MethodsMulti-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis.ResultsNinety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI − 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003).ConclusionThe primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism.Trial registration detailsAustralia New Zealand Clinical Trials Registry reference:ACTRN12615001177549. Trial registered 2/11/2015.

The goals of this undertaking were to assess the outcomes of thyroid screening tests and adherence to thyroid screening guidelines across five Down syndrome (DS) specialty clinics in various states. Data related to thyroid screening were collected for 663 individuals across five clinics specializing in the comprehensive care of individuals with DS for a period of 1 year. Of the 663 participants, 47.7% of participants had a TSH and free T4 ordered at their DS specialty clinic visit. Approximately 19.0% (60/316) had a new thyroid disorder diagnosis made. We conclude that a sizable proportion of the patients with DS are not up-to-date on current guidelines when they present to a DS specialty clinic, while adherence to thyroid screening guidelines helps facilitate early diagnoses. Hypothyroidism is prevalent in the population, consistent with reported literature. DS specialty clinics can help patients stay current on screening guidelines.

CASE Grant is a 13-year-old boy with trisomy 21 who presents with his mother for concerns regarding the emergence of several new disruptive behaviors. While he is verbal, he also communicates through an augmentative communication device. He currently attends a residential school. Over the past 2 months, he has begun spitting at the staff, engaging in self-injurious behaviors, placing his hands in his pants, and frequently talking about "pee and poop." Notably, Grant has undergone several changes to his educational placement and medical health over the past several months. He recently transferred to his current residential school from another placement to be closer to his family, although this has meant that Grant was unable to work with his long-time aide. Additionally, most of the students at Grant's current school are significantly lower functioning than him, such that Grant is one of the few verbal children.Approximately 3 months ago, Grant underwent significant dental work under anesthesia. Grant had previously taken an alpha-agonist for behavioral management, although he was weaned off this 4 months ago because of increasing somnolence increasing somnolence. Grant's recent behavioral challenges make performing community and home activities more challenging.Grant's behavioral history is notable for a previous episode of behavioral and emotional challenges 18 months ago. This occurred in the setting of transitioning to a new classroom with higher academic and behavioral expectations and decreased time spent with his family. These behaviors had consisted of self-injurious behaviors and tantrums consisting of crying and social withdrawal. This was managed by increased behavioral and academic supports via trained teachers and aides, medication management, and optimizing his augmentative communication. After these interventions, Grant's behavioral and emotional functioning improved and remained stable until this current episode.Grant's mother is concerned about what may be causing these emerging behaviors and wondering if any of the recent educational and medical stressors could be contributing. What do you do next?

Obstructive sleep apnea (OSA) occurs frequently in people with Down syndrome (DS) with reported prevalences ranging between 55% and 97%, compared to 1–4% in the neurotypical pediatric population. Sleep studies are often uncomfortable, costly, and poorly tolerated by individuals with DS. The objective of this study was to construct a tool to identify individuals with DS unlikely to have moderate or severe sleep OSA and in whom sleep studies might offer little benefit. An observational, prospective cohort study was performed in an outpatient clinic and overnight sleep study center with 130 DS patients, ages 3–24 years. Exclusion criteria included previous adenoid and/or tonsil removal, a sleep study within the past 6 months, or being treated for apnea with continuous positive airway pressure. This study involved a physical examination/medical history, lateral cephalogram, 3D photograph, validated sleep questionnaires, an overnight polysomnogram, and urine samples. The main outcome measure was the apnea-hypopnea index. Using a Logic Learning Machine, the best model had a cross-validated negative predictive value of 73% for mild obstructive sleep apnea and 90% for moderate or severe obstructive sleep apnea; positive predictive values were 55% and 25%, respectively. The model included variables from survey questions, medication history, anthropometric measurements, vital signs, patient’s age, and physical examination findings. With simple procedures that can be collected at minimal cost, the proposed model could predict which patients with DS were unlikely to have moderate to severe obstructive sleep apnea and thus may not need a diagnostic sleep study.

Objective The objective of the present study is to examine the craniofacial development of patients with Down syndrome (DS) and compare them with a neurotypical population. Methods This study is a cross-sectional analysis of lateral cephalometric radiographs of participants with DS. The study population consisted of children and young adults with DS aged 3–25 years. Cephalometric data were summarized by age and sex. Raw and normalized z-scores were computed. One-sample t tests were used to test whether mean z-scores differed from zero. The demographic characteristics between those with or without lateral cephalograms among all study participants were compared by Fisher’s exact tests. Results The study sample comprised of 27 participants with DS. Study subjects demonstrated a class III skeletal pattern. This was more pronounced in the older age groups as compared to younger age groups. Subjects also had an increased proportionate lower anterior face height to total facial height compared to normative standards. Gonial angles, mandibular plane angles, and airway measurements increased with age. Conclusions Patients with Down syndrome present typically with class III skeletal pattern and long lower anterior facial heights. In patients with Down syndrome, comprehensive phase of orthodontic treatment may be best initiated following cessation of growth.

The main purposes of this undertaking were to determine how often patients with Down syndrome (DS) are screened for celiac disease (CD) across five DS specialty clinics, which symptoms of CD are most often reported to DS specialty providers at these clinics, and, how many individuals were diagnosed with CD by these clinics. This was accomplished by following 663 individuals with DS for 1 year, across five clinics in different states specializing in the comprehensive care of people with DS. Of the 663 participants, 114 individuals were screened for CD at their visit to a DS specialty clinic. Protracted constipation (43.2%) and refractory behavioral problems (23.7%) were symptoms most often reported to DS specialty providers. During the 1 year study period, 13 patients screened positive for CD by serology. Of those, eight underwent duodenal biopsy, and three were diagnosed with CD. We conclude that CD is an important consideration in the comprehensive care of individuals with DS. However, while symptoms are common, diagnoses are infrequent in DS specialty clinics. © 2016 Wiley Periodicals, Inc.

We investigated what added value, if any, a Down syndrome specialty clinic brings to the healthcare needs of children and adolescents with Down syndrome. For this quality improvement study, we performed a retrospective chart review of 105 new patients with Down syndrome, ages 3 and older, seen during the inaugural year of our specialty clinic. We asked how many of our patients were already up-to-date on the healthcare screenings recommended for people with Down syndrome. We further analyzed what tests we ordered, which referrals we suggested, and, ultimately, what new diagnoses of co-occurring medical conditions were made. Only 9.8% of our patients were current on all of the recommended Down syndrome healthcare screenings. Parents came to clinic with a variety of concerns, and after laboratory tests, radiologic studies, and subspecialty referrals, we made many new diagnoses of gastrointestinal conditions (e.g., constipation and celiac disease), seasonal allergies, dermatologic conditions (e.g., xerosis), behavioral diagnoses (e.g., autism spectrum disorder and disruptive behavior not otherwise specified), and clarifications of neurologic conditions. A Down syndrome specialty clinic can identify and address many healthcare needs of children and adolescents with Down syndrome beyond that which is provided in primary care settings.

Objective Clinical guidelines recommend that patients who sustain a minimal trauma fracture (MTF) should receive a bone mineral density (BMD) scan and bisphosphonate (or equivalent) therapy if diagnosed with osteoporosis. A pilot fracture liaison service (FLS) was implemented in regional NSW to improve adherence to the guidelines. Design Prospective cohort study with an historical control. Setting Primary care. Participants Control (n = 47) and cohort (n = 93) groups comprised patients consenting to interview who presented with a MTF to the major referral hospital 4 months before and 12 months after FLS implementation respectively. Main outcome measures Primary outcome measures were the rates of BMD scans and anti-osteoporotic medication initiation/review after MTF. Hospital admission data were also examined to determine death and refracture rates for all patients presenting during the study period with a primary diagnosis of MTF within 3 years of their initial fracture. Results Although there was no improvement in BMD scanning rates, the reported rate of medication initiation/review after fracture was significantly higher (P < 0.05) in the FLS cohort. However, once adjusted for age, this association was not significant (P = 0.086). There was a lower refracture rate during the cohort period (P = 0.013), however, there were significantly more deaths (P = 0.035) within 3 years of initial fracture. When deaths were taken into account via competing risk regression, patients in the cohort period were significantly less likely to refracture than those in the control period (Hazard ratio = 0.576, P = 0.032). Conclusions A rurally based nurse-led FLS was associated with modest improvement after MTF. Consideration should be given to ways to strengthen the model of care to improve outcomes.

While the benefits of testosterone (T) therapy are well documented with regard to the clinical signs and symptoms of T deficiency, there is still a fear among the medical community that T therapy could be a stimulus for the emergence of prostate cancer (PCa) or promote its progression. However, the evidence shows that T appears to have limited stimulatory effects on the prostate. Several studies suggest that T stimulates the growth of prostatic neoplasia only at very low concentrations, and variations in the endogenous T levels within the physiological range or above do not appear to influence prostate growth or function, as measured by markers such as prostate-specific antigen. The recognition of the finite ability of androgens to stimulate prostate growth, called the saturation model, has led to important changes in medical practice, especially with regard to consideration of T therapy for men with a history of PCa. Recent clinical experiences with men with PCa have suggested that T therapy is not as risky as once believed. Studies regarding T administration in hypogonadal men after PCa treatment have shown no evidence of worse oncologic prognosis. Even in patients in active surveillance protocols, T has been administrated with no modification of oncologic outcomes, suggesting that T therapy is safe when correctly indicated and strictly monitored.

The Down Syndrome Study Group (DSSG) was founded in 2012 as a voluntary, collaborative effort with the goal of supporting evidenced-based health care guidelines for individuals with Down syndrome (DS). Since then, 5 DS specialty clinics have collected prospective, longitudinal data on medical conditions that co-occur with DS. Data were entered by clinical staff or trained designees into the National Down Syndrome Patient Database, which we created using REDCap software. In our pilot year, we enrolled 663 participants across the U.S., ages 36 days to 70 years, from multiple racial and ethnic backgrounds. Here we report: (i) the demographic distribution of participants enrolled, (ii) a detailed account of our database infrastructure, and (iii) lessons learned during our pilot year to assist future researchers with similar goals for other patient populations.

Objectives: Children with Down syndrome (DS) have increased difficulty initiating and maintaining sleep (DIMS), excessive daytime sleepiness (EDS), and obstructive sleep apnea (OSA). As part of a quality improvement initiative, parents of children enrolled in the Children’s Hospital Boston Down Syndrome Program were surveyed about their child’s sleep and breathing patterns while asleep. Methods: An anonymous Internet-based questionnaire was used in the study. Results: The completion rate was 46.5% (255/548). DIMS and EDS were frequently/almost always present in more than half the children. Among parents unconcerned about their child’s breathing, 11.8% witnessed apnea and 4.2% gasping/choking more than once monthly. Parents of children status post adenotonsillectomy (AT) reported witnessed apnea (47.5%), gasping/choking (28.9%) more than once monthly. Discussion: There is room for improved screening of sleep disturbances, OSA in children with DS. The high frequency of persistence of OSA following AT should prompt for continued screening following AT.

Objective: To survey pediatric residents' attitudes toward caring for children with severe disabilities. Design: A cross-sectional survey of residents in a university-affiliated pediatric residency program between October and December 2005. Residents were asked to complete a newly designed, 13-item survey. For each item, participants selected the degree to which they did or did not agree with a statement about disabilities or caring for children with severe disabilities. Results: Fifty-five (43%) of 129 eligible residents participated. Eighty-nine percent felt that caring for children with severe disabilities was as rewarding as caring for other children. Ninety-two percent felt that there is a societal responsibility to care for such children; 98% felt families of children with disabilities love their children as much as other families. Two-thirds (66%) admitted frustration related to caring for children who cannot be cured or function independently, and 71 % questioned the aggressive treatment of such children. Residents in their second and third postgraduate years were more likely to question the aggressive treatment compared with their junior colleagues. Conclusions: Although pediatric residents had positive attitudes toward children with severe disabilities, emotional and moral tensions did arise around their care.