Successful Treatment of Hypoglycemia With Alpelisib in Pediatric Patients With PIK3CA-Related Overgrowth Spectrum.

Activating mutations in the PIK3CA gene, causing phosphoinositide 3-kinase (PI3K) hyperactivation, are rare causes of hypoglycemia. We report the novel use of alpelisib (a PI3K inhibitor) for the treatment of hypoketotic, hypoinsulinemic hypoglycemia in 2 children with PIK3CA-related overgrowth spectrum (PROS). Patient 1 was a 7-month-old girl who presented with a hypoglycemic seizure. Despite nutritional management including continuous feeds, she continued to have frequent hypoglycemia. At age 2.8 years, alpelisib was started at 50 mg daily and titrated to 100 mg daily. She was weaned off nocturnal continuous feeds by 8 months. She developed colitis when the alpelisib dose was increased to 125 mg, but this resolved with a dose decrease and medical management. At age 5.3 years, she was doing well with rare hypoglycemia. Her accelerated growth stabilized. Patient 2 was a 3-year-old boy who developed hypoglycemia in early infancy. Alpelisib 50 mg daily was started due to recurrent hypoglycemia despite nutritional management. He came off continuous feeds after 4 months, with decreased hypoglycemia frequency. At age 4.5 years, he had not experienced side effects from treatment. In conclusion, alpelisib appears to be effective in decreasing PROS-related hypoglycemia frequency and severity and should be considered for refractory hypoglycemia in this condition.

Surgical Decision-Making for Individuals with Differences of Sex Development: Stakeholders' views.

Introduction: Advocacy and human rights organizations have called for a moratorium on elective surgical procedures until the patient is able to fully participate in the decision-making process. Due to the controversial nature surrounding surgery in differences of sex development (DSD) care, we aimed to assess the factors that teens and adults with DSD, parents, healthcare providers and other allied professionals consider pertinent to complex surgical decisions in DSD. Methods: Stakeholders (n=110) in DSD care participated in semi-structured interviews exploring features and potential determinants of successful healthcare outcomes. Audio-recordings were transcribed, coded, and analyzed using qualitative data software. Codes for "Process of Decision-Making" and "Successful Outcome-Surgery/Appearance/Function" were further searched using keywords "surgery," "procedure," and "timing." Results: Several themes were identified: 1) The nature or type of the decision being made; 2) Who should be involved in the decision-making process; 3) Timing of conversations about surgery; 4) Barriers to decision-making surrounding surgery; 5) The elements of surgical decision-making; and 6) The optimal approach to surgical decision-making. Many stakeholders believed children and adolescents with DSD should be involved in the process as developmentally appropriate. Conclusion: DSD include a wide range of diagnoses, some of which may require urogenital reconstruction to relieve obstruction, achieve continence, and/or address other anatomical differences whether cosmetic or functional. Adolescents and adults with DSD desired autonomy and to be part of the decision-making process. Parents were divided in their opinion of who should be involved in making elective surgical decisions: the child or parents as proxy medical decision-makers. Providers and other professionals stressed the importance of process and education around surgical decisions. Ongoing research examines how decision-makers evaluate tradeoffs associated with decision options.

Appendicular lean mass index changes in patients with Duchenne muscular dystrophy and Becker muscular dystrophy.

INTRODUCTION: Mutations in the 79 exons of the dystrophin gene result in muscle wasting and weakness of varying clinical severity, ranging from severe/typical Duchenne muscular dystrophy (DMD) to intermediate DMD and mild Becker muscular dystrophy (BMD), depending on the frameshift of the mutation. We previously reported that males with DMD have progressively declining appendicular lean mass (ALM) and ALM index (ALMI) with age and worsening functional motor ability compared with healthy controls. These indices have not been studied in patients with intermediate DMD and BMD phenotypes and across DMD genotypes. In this study, we compared age-related trajectories of ALM and ALMI of patients who had (1) BMD without functional mobility deficits with patients who had DMD at different stages of disease and healthy controls; (2) a DMD intermediate phenotype with patients who had a typical DMD phenotype; and (3) DMD categorized by genotype. METHODS: We conducted a retrospective review of ALM and ALMI data from 499 patients (ages 5-23 years) with DMD (466 typical and 33 intermediate) and 46 patients (ages 5-21 years) with BMD (without functional mobility deficits and functional mobility score of 1). Patients were grouped according to age reflecting disease stage (ages 5 to <7, 7 to <10, 10 to <14, and 14 to <20 years) and genotype (mutations in exons 1-30, 31-44, 45-62, and 63-79). RESULTS: ALM and ALMI trajectories of patients with BMD paralleled those of healthy controls until adolescence, in contrast to patients with DMD. ALMI Z-scores of patients with BMD remained within ±2 SD without decline while those of patients with DMD fell below -2 SD around age 12 years. Patients with BMD had increasing ALM and ALMI with age, with peak accrual between ages 10 to <14 years. ALMI declined after age 14 years for those with intermediate DMD compared with 10 years for patients with typical DMD. Patients with mutations in exons 63-79 had a greater decline in ALMI as compared with those with other genotypes after age 10 years. CONCLUSIONS: Age-related changes in ALMI in patients with BMD and intermediate DMD differ from those with typical DMD, reflecting their clinical phenotypes. ALM and ALMI should be further studied in patients with BMD and DMD subtypes for their potential value as surrogate markers to characterize the severity of BMD and DMD and inform clinical care decisions and clinical trial designs.

"It became easier once I knew": Stakeholder perspectives for educating children and teenagers about their difference of sex development.

OBJECTIVE: Secrecy about a child's difference of sex development (DSD) can lead to internalized shame and stigma. We explored how teenagers and adults with DSD, parents, healthcare providers, and allied professionals value and perceive patient education. METHODS: Stakeholders (n = 110) completed qualitative semi-structured interviews. Relevant themes for educational content were queried and organized. RESULTS: Education was consistently identified as essential to successful outcomes. There was less consistency in how to educate patients. Disagreement existed regarding who should champion the education process. Participants believed medically relevant information should be shared gradually with attention to developmental capacity. Details were lacking regarding how much or what information to share. Participants noted that vetted resources were helpful. Benefits of sharing condition-specific information with patients included supporting their psychosocial development. Barriers included parental resistance to sharing information due to shame/stigma, and cultural and/or family dynamics. CONCLUSIONS: Stakeholders' different perspectives regarding patient DSD education warrant future research to focus on the design, evaluation, and implementation of education-focused interventions. PRACTICE IMPLICATIONS: Healthcare providers are responsible for supporting the education of children and teenagers with DSD about their condition. When considering barriers, adopting a cultural or family systems framework can reduce parental resistance and promote open dialogue.

Creation of an Electronic Resource Repository for Differences of Sex Development (DSD): Collaboration Between Advocates and Clinicians in the DSD-Translational Research Network.

INTRODUCTION: People with differences of sex development (DSD) and their families need education about these conditions while receiving emotional and peer support to participate in shared decision-making, reduce social isolation, and optimize physical and psychosocial outcomes. Barriers to education and support include limited knowledge and awareness by healthcare providers, tension among patient and medical communities, varied quality of educational resources, and the sensitive nature of DSD. We aimed to create an electronic repository of vetted quality online resources about DSD. METHODS: The electronic resource repository (e-RR) was a collaboration between affected individuals and advocates and healthcare providers in the DSD-Translational Research Network (DSD-TRN), an NIH-supported consortium of US teams committed to standardizing and optimizing care in DSD. The e-RR development and ongoing growth involved: (1) identification of resources by the project team (3 advocates and 1 physician), (2) evaluation and feedback by DSD-TRN clinical teams, (3) creation of the e-RR, and (4) review and revision. Twitter-like descriptions accompanied each entry; resources were categorized by target age, audience, and condition. RESULTS: Thirty-seven web-based educational, peer and advocacy support, and clinician-oriented resources were reviewed. Eight of 10 DSD-TRN teams responded to a survey regarding resource inclusion. Awareness of individual resources varied widely. Consensus was achieved when opinions differed; 30 resources were included. The e-RR is available online and as a downloadable booklet at http://www.accordalliance.org/resource-guide/. CONCLUSION: The e-RR increases awareness of and access to vetted educational and support resources for those with DSD and healthcare providers. It represents important collaboration between advocates and providers.

Defining successful outcomes and preferences for clinical management in differences/disorders of sex development: Protocol overview and a qualitative phenomenological study of stakeholders' perspectives.

INTRODUCTION: Utilizing a qualitative phenomenological design, the Defining Successful Outcomes and Trade-offs study examined stakeholder perspectives regarding optimal healthcare delivery and outcomes for individuals with a difference/disorder of sex development (DSD). OBJECTIVE: We describe study methods and provide an overview of themes and subthemes. STUDY DESIGN: Interviews were conducted with individuals with a DSD (n = 24), parents of those with a DSD (n = 19), healthcare providers (n = 37), and others (n = 30). Primary questions regarding clinical management of patients with DSD were: "What is a successful outcome?" and "How do you achieve it?" RESULTS: Themes included: understanding of DSD diagnosis and self-efficacy in management is necessary but complex; patient and family psychological well-being; support from others versus being stigmatized; affected person experiences physical health and accepts the implications of their condition; complexities in DSD decision making, roles and expectations; and knowledgeable providers and multidisciplinary teams are essential, notwithstanding persisting barriers. Participants recognized competing values potentially forcing trade-offs in decision making. DISCUSSION: Recognition of diverse and sometimes conflicting perspectives regarding optimal pathways of care and outcomes - both within and among those with DSD and their providers -promises to enhance shared decision making. CONCLUSION: Diverse perspectives and perceptions of trade-offs associated with DSD healthcare emphasize the need to tailor care for patients and families.

The effect of oral bisphosphonate therapy on vertebral morphometry and fractures in patients with Duchenne muscular dystrophy and glucocorticoid-induced osteoporosis.

INTRODUCTION/AIMS: Glucocorticoid-induced osteoporosis with vertebral fractures is frequent in patients with Duchenne muscular dystrophy (DMD). In this study, we evaluated the effects of oral bisphosphonate (BP) therapy on the prevalence and severity of vertebral fractures by vertebral morphometry assessment. METHODS: We reviewed the records and radiographs of patients with DMD who had been treated with oral BP (weekly alendronate) and had undergone routine spine radiographic monitoring for glucocorticoid-induced osteoporosis at Cincinnati Children's Hospital Medical Center between 2010 and 2017. Study outcomes were thoracic and lumbar vertebral fracture prevalence and severity, assessed by Genant semiquantitative grading of vertebral morphometry, for up to 5 years of treatment. RESULTS: Fifty-two patients (median age, 11.8 years; 88% prepubertal; 31% nonambulatory) had been treated with long-term glucocorticoids (median duration, 4.7 years at BP start). Most patients (75%) had mild vertebral height loss or fractures (Genant grade = 0 or 1) at baseline. The prevalence of vertebral fractures at each year of treatment was not statistically different from that at baseline (P = .08-1.00). Serial radiographs showed no longitudinal change in severity by Genant grade in most vertebrae (64%-80%). Improvement in vertebral fracture grade was observed in some patients. DISCUSSION: We observed stable prevalence of vertebral fractures and no change in severity by Genant grade in most vertebrae for up to 5 years of treatment. Oral BP may mitigate development or progression of vertebral fractures and be beneficial for secondary prevention of glucocorticoid-induced osteoporosis in this population.

The Effect of Adiposity on Cardiovascular Function and Myocardial Fibrosis in Patients With Duchenne Muscular Dystrophy.

Background Patients with Duchenne muscular dystrophy (DMD) develop cardiomyopathy because of a dystrophin deficiency causing fibrofatty replacement of the myocardium. Corticosteroid use and mobility limitations place these patients at risk for increased adiposity. We sought to determine the association of adiposity with cardiovascular dysfunction in patients with DMD. Methods and Results This was a retrospective review of patients with DMD who underwent both cardiac magnetic resonance imaging and dual-energy x-ray absorptiometry within 1 year. The cardiac magnetic resonance imaging parameters included left ventricular ejection fraction and the presence of late gadolinium enhancement (LGE positive [LGE+]). The adiposity indices, measured by dual-energy x-ray absorptiometry, included percentage of body fat, whole body fat mass indexed to height, and body mass index. A total of 324 patients were identified. Fifty-two percent had LGE+, and 36% had cardiac dysfunction (left ventricular ejection fraction <55%). Patients with cardiac dysfunction had higher whole body fat mass indexed to height and body mass index on univariate analysis (mean difference between patients with and without cardiac dysfunction: +2.9 kg/m, P=0.001; and +1.5 kg/m2, P=0.03, respectively). whole body fat mass indexed to height remained independently associated with cardiac dysfunction on multivariable analysis after adjusting for age, LGE+, and corticosteroid duration. High whole body fat mass indexed to height and percentage of body fat were associated with LGE+ on univariate analysis (mean difference between patients with and without LGE+: +2.0 kg/m, P=0.02; and +2.4%, P=0.02, respectively). Using multivariable analysis, including age and cardiac dysfunction, high percentage of body fat remained independently associated with LGE+. Conclusions This study demonstrates an independent association of adiposity with cardiac dysfunction and LGE+ in patients with DMD. Preventing adiposity may mitigate the later development of ventricular dysfunction in DMD.

Emergency Planning as Part of Healthcare Transition Preparation for Patients with Duchenne Muscular Dystrophy.

BACKGROUND: Emergency care planning is an important component of healthcare transition, particularly for patients with medical complexity. Duchenne muscular dystrophy (DMD) is a complex, progressive pediatric-onset disease affecting multiple organ systems including impairment of cardiac and pulmonary function, high risk for fractures, fat embolism, adrenal crisis and malignant hyperthermia. Appropriate interdisciplinary emergency management is critical for survival for these patients. The purpose of this quality improvement project was to develop a process to reliably share an individualized emergency care plan (ECP) with patients and their families as part of a larger plan to develop an integrated transition program. METHODS: An interdisciplinary team of nurses and clinicians used the principles of quality improvement to develop a reliable process to assure patients with DMD received an individualized, multidisciplinary ECP at routine interdisciplinary clinic visits. Additionally, the project used surveys to assess patient and family satisfaction with the letter and whether it improved their knowledge of emergency care. RESULTS: Sixty-two patients were seen during the study timeframe. All received an ECP. Sixty-two surveys were sent and twenty-three surveys were returned. Of those that responded, the majority stated the ECP increased their knowledge of emergency care. CONCLUSION: ECPs can be developed and disseminated to patients with DMD and their caregivers. This tool can potentially promote timely and appropriate emergency care for these patients with unique and complex medical needs.

Age-related changes in appendicular lean mass in males with Duchenne muscular dystrophy: A retrospective review.

BACKGROUND: Appendicular lean mass (ALM) trajectory in males with Duchenne muscular dystrophy (DMD) has potential applicability for treatment and research and has not been characterized. METHODS: This chart review included longitudinal data on 499 males with DMD receiving glucocorticoids and 693 controls, ages 5 to 22.9 y. ALM (kg) was measured by dual energy x-ray absorptiometry (DXA). Appendicular lean mass index (ALMI, kg/m2 ) was calculated for height adjustment. Reference centiles were generated using data from healthy controls, and ALM and ALMI Z-scores were calculated for patients with DMD. Generalized linear models were used to estimate median Z-scores by age and functional mobility status (FMS) score. ALM velocity by age was modeled using superimposition, translation and rotation (SITAR). RESULTS: Compared to controls, males with DMD had lower ALM from an early age. ALMI Z-scores dropped below 0 at age 8 y or FMS of 2, and below -2.0 at age 13 y or FMS of 3 (P < .05). Age at peak ALM velocity was similar in both groups, but the magnitude was higher in controls (3.5 vs. 0.7 kg/y, P < .0001). Patients with DMD had a transient loss of ALM around age 12 y, an increase at age 14 y, then a further decline at age 16 y, remaining low thereafter. CONCLUSIONS: Males with DMD have progressive decline in lean mass with age and worsening functional mobility. DXA measurement of ALM may be useful for monitoring lean mass status in patients with DMD, providing valuable information for individual treatment plans and research endeavors.

XY Gonadal Dysgenesis in a Phenotypic Female Identified by Direct-to-Consumer Genetic Testing.

We report a 16-year-old phenotypic female with 46,XY complete gonadal dysgenesis and metastatic dysgerminoma, unexpectedly discovered through direct-to-consumer (DTC) commercial genetic testing. This case underscores the importance of timely interdisciplinary care, including psychosocial intervention and consideration of gonadectomy, to optimize outcomes for individuals with differences of sex development. Her unique presentation highlights the implications of DTC genetic testing in a new diagnostic era and informs general pediatricians as well as specialists of nongenetic services about the value, capabilities, and limitations of DTC testing.

Newborn Screening Protocols and Positive Predictive Value for Congenital Adrenal Hyperplasia Vary across the United States.

Newborn screening for congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is mandated throughout the US. Filter paper blood specimens are assayed for 17-hydroxyprogesterone (17OHP). Prematurity, low birth weight, or critical illness cause falsely elevated results. The purpose of this report is to highlight differences in protocols among US state laboratories. We circulated a survey to state laboratory directors requesting qualitative and quantitative information about individual screening programs. Qualitative and quantitative information provided by 17 state programs were available for analysis. Disease prevalence ranged from 1:9941 to 1:28,661 live births. Four state laboratories mandated a second screen regardless of the initial screening results; most others did so for infants in intensive care units. All but one program utilized birthweight cut-points, but cutoffs varied widely: 17OHP values of 25 to 75 ng/mL for birthweights >2250-2500 g. The positive predictive values for normal birthweight infants varied from 0.7% to 50%, with the highest predictive values based in two of the states with a mandatory second screen. Data were unavailable for negative predictive values. These data imply differences in sensitivity and specificity in CAH screening in the US. Standardization of newborn screening protocols could improve the positive predictive value.

Oral bisphosphonate treatment in patients with Duchenne muscular dystrophy on long term glucocorticoid therapy.

Osteoporosis is a major problem in patients with Duchenne muscular dystrophy (DMD), due to glucocorticoid therapy and muscle weakness. Evidence on which to base optimal prevention and treatment strategies, including bisphosphonate use, in DMD are limited. Our objective was to describe bone health outcomes of oral alendronate treatment in patients with DMD and glucocorticoid-induced osteoporosis. We retrospectively studied 54 patients treated between 2005 and 2017, and assessed changes in dual-energy x-ray absorptiometry (DXA) whole body and lumbar spine bone mineral density and content, and lateral distal femur bone mineral density. We also examined vertebral fracture development in a subset with serial spine radiographs. Pre-alendronate DXA Z-score trajectories decreased progressively. Over three years post-alendronate initiation, Z-score trajectories improved (p<0.01) at most sites compared with pre-alendronate trajectories. Height-adjusted Z-score trajectories for lumbar spine bone mineral density (p = 0.01) and whole body bone mineral content (p = 0.0004) also improved. The positive trajectories did not seem to be sustained long term in those treated up to 6 years. Radiographic vertebral findings in 43 patients appeared stable. In conclusion, oral bisphosphonate therapy using alendronate was associated with improvement of DXA bone health indices during the first three years of treatment, and may help mitigate progression of osteoporosis in glucocorticoid-treated patients with DMD.

Recombinant human insulin-like growth factor-1 therapy for 6 months improves growth but not motor function in boys with Duchenne muscular dystrophy.

INTRODUCTION: Recombinant human insulin-like growth factor-1 (rhIGF-1) is a growth factor and has anabolic effects on muscle. We investigated whether rhIGF-1 therapy: 1) improves or preserves muscle function; and 2) improves growth in boys with Duchenne muscular dystrophy (DMD). METHODS: In this study we compared prepubescent, ambulatory, glucocorticoid-treated boys with DMD (n = 17) vs controls (glucocorticoid therapy only, n = 21) in a 6-month-long, prospective, randomized, controlled trial of subcutaneous rhIGF-1 therapy. The primary outcome was 6-minute walk distance (6MWD). Secondary outcomes included height velocity (HV), change in height standard deviation score (ΔHtSDS), motor function, cardiopulmonary function, body composition, insulin sensitivity, quality of life, and safety. RESULTS: Change in 6MWD was similar between groups (rhIGF-1 vs controls [mean ± SD]: 3.4 ± 32.4 vs -5.1 ± 50.2 meters, P = .53). Treated subjects grew more than controls (HV: 6.5 ± 1.7 vs 3.3 ± 1.3 cm/year, P < .0001; 6-month ΔHtSDS: 0.25, P < .0001). Lean mass and insulin sensitivity increased in treated subjects. DISCUSSION: In boys with DMD, 6 months of rhIGF-1 therapy did not change motor function, but it improved linear growth.

Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations.

Poorly differentiated thyroid carcinomas (PDTC) in young individuals are rare and their clinical and histopathologic features, genetic mechanisms, and outcomes remain largely unknown. Here, we report a detailed characterization of a series of six PDTC in patients ≤21 years old defined by Turin diagnostic criteria studied for mutations and gene fusions characteristic of thyroid cancer using targeted next-generation sequencing (NGS) and whole-exome sequencing (WES). All tumors had solid, insular, or trabecular growth pattern and high mitotic rate, and five out of six tumors showed tumor necrosis. Targeted NGS assay identified somatic mutations in the DICER1 gene in five of six (83%) tumors, all of which were "hotspot" mutations encoding the metal-ion binding sites of the RNase IIIb domain of DICER1. WES was performed in five cases which confirmed all hotspot mutations and detected two tumors with additional inactivating DICER1 alterations. Of these two, one was a germline pathogenic DICER1 variant and the other had loss of heterozygosity for DICER1. No other mutations or gene fusions characteristic of adult well-differentiated thyroid cancer and PDTC (BRAF, RAS, TERT, RET/PTC, and other) were detected. On follow-up, available for five patients, three patients died of disease 8-24 months after diagnosis, whereas two were alive with no disease. The results of our study demonstrate that childhood- and adolescent-onset PDTC are genetically distinct from adult-onset PDTC in that they are strongly associated with DICER1 mutations and may herald DICER1 syndrome in a minority. As such, all young persons with PDTC may benefit from genetic counseling. Furthermore, their clinically aggressive behavior contrasts sharply with the indolent nature of the great majority of thyroid tumors with DICER1 mutations reported to date.

Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations.

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development.

Central Diabetes Insipidus in a Patient With NFKB2 Mutation: Expanding the Endocrine Phenotype in DAVID Syndrome.

CONTEXT: Deficient anterior pituitary with variable immune deficiency (DAVID) syndrome is a recently described, rare disorder characterized by anterior pituitary hormone deficiencies and common variable immunodeficiency associated with NFKB2 mutations. Posterior pituitary hormone deficiencies have not been reported in patients with DAVID syndrome. CASE DESCRIPTION: We report a pediatric patient who initially presented with hypogammaglobulinemia and alopecia totalis, who was identified to have a de novo NFKB2 mutation at one year of age. He developed central diabetes insipidus and central adrenal insufficiency at three and four years of age, respectively. At seven years of age, he had not developed GH or TSH deficiencies. Whole exome sequencing ruled out known genetic causes of central diabetes insipidus, adrenal insufficiency, and hypopituitarism. CONCLUSION: This is a report of central diabetes insipidus in a patient with DAVID syndrome caused by an NFKB2 mutation. This case report expands the evolving endocrine phenotype associated with NFKB2 mutations beyond anterior pituitary deficiencies.

Comparison of Pulmonary Function Decline in Steroid-Treated and Steroid-Naïve Patients with Duchenne Muscular Dystrophy.

OBJECTIVE: To describe and compare the lung function decline in patients with Duchenne muscular dystrophy on glucocorticoid therapy in contrast with glucocorticoid-naïve patients, and to define the deciles of pulmonary decline in glucocorticoid-treated patients. STUDY DESIGN: This retrospective study examined lung function of patients with Duchenne muscular dystrophy over 6 years of age followed between 2001 and 2015 at 2 centers-glucocorticoid-treated patients in Cincinnati, Ohio, and glucocorticoid-naïve patients in Paris, France. Forced vital capacity (FVC, FVC%), forced expiratory volume in 1 second, maximal inspiratory pressure, maximal expiratory pressure, and peak expiratory flow data were analyzed. Only FVC data were available for the French cohort. RESULTS: There were 170 glucocorticoid-treated patients (92%), 5 patients (2.7%) with past glucocorticoid use, and 50 French glucocorticoid-naïve patients. The peak absolute FVC was higher and was achieved at earlier ages in glucocorticoid-treated compared with glucocorticoid-naïve patients (peak FVC, 2.4 ± 0.6 L vs 1.9 ± 0.7 L; P < .0001; ages 13.5 ± 3.0 years vs 14.3 ± 2.8 years; P = .03). The peak FVC% was also higher and was achieved at earlier ages in glucocorticoid-treated patients (peak FVC%, 105.1 ± 25.1% vs 56 ± 20.9%; P < .0001; ages 11.9 ± 2.9 years vs 13.6 ± 3.2 years; P = .002). Rates of decline for both groups varied with age. Maximal rates of decline were 5.0 ± 0.26% per year (12-20 years) for glucocorticoid-treated and 5.1 ± 0.39% per year for glucocorticoid-naïve patients (11-20 years; P = .2). Deciles of FVC% decline in glucocorticoid-treated patients show that patients experience accelerated decline at variable ages. CONCLUSIONS: These data describe nonlinear rates of decline of pulmonary function in patients with Duchenne muscular dystrophy, with improved function in glucocorticoid-treated patients. FVC% deciles may be a useful tool for clinical and research use.

Differentiated Thyroid Cancer in the Pediatric/Adolescent Population: Evolution of Treatment.

Differentiated thyroid cancer (DTC) is the most common cancer in adolescents and young adults. In 2015, the American Thyroid Association published guidelines for management of pediatric DTC. We report our institutional experience and highlight changing practices and new opportunities. A retrospective analysis of all patients diagnosed with DTC from 2001 to 2016 was performed. Among 59 eligible patients, 31 (53%), 15 (25%), and 13 (22%) had low-risk, intermediate-risk, and high-risk disease, respectively. Half (15/31) of low-risk and all intermediate-risk/high-risk patients received radioactive iodine (I-131) ablation. For low-risk patients, average I-131 dose decreased from 80 to 42.05 mCi, and the percentage of patients who received I-131 decreased over time. Eleven of 16 patients with tumor genomic data were found to have somatic targetable (n=6) or germline (n=5) mutations. Persistent/recurrent disease was only present in high-risk (n=8) and intermediate-risk (n=1) patients. Two patients with iodine-refractory disease received trametinib to enhance radioiodine uptake. All patients were alive at follow-up (median, 5 y; range, 1 to 15 y). Coincident with the recent American Thyroid Association guidelines, the use of I-131 in low-risk patients has decreased over time in our practice. Tumor sequencing and cancer genetic evaluation may help redefine opportunities for treatment of high-risk patients and family counseling.

Homozygous Calcium-Sensing Receptor Polymorphism R544Q Presents as Hypocalcemic Hypoparathyroidism.

Context: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by heterozygous activating mutations in the calcium-sensing receptor gene (CASR). Whether polymorphisms that are benign in the heterozygous state pathologically alter receptor function in the homozygous state is unknown. Objective: To identify the genetic defect in an adolescent female with a history of surgery for bilateral cataracts and seizures. The patient has hypocalcemia, hyperphosphatemia, and low serum PTH level. The parents of the proband are healthy. Methods: Mutation testing of PTH, GNA11, GCM2, and CASR was done on leukocyte DNA of the proband. Functional analysis in transfected cells was conducted on the gene variant identified. Public single nucleotide polymorphism (SNP) databases were searched for the presence of the variant allele. Results: No mutations were identified in PTH, GNA11, and GCM2 in the proband. However, a germline homozygous variant (c.1631G>A; p.R544Q) in exon 6 of the CASR was identified. Both parents are heterozygous for the variant. The variant allele frequency was near 0.1% in SNP databases. By in vitro functional analysis, the variant was significantly more potent in stimulating both the Ca2+i and MAPK signaling pathways than wild type when transfected alone (P < 0.05) but not when transfected together with wild type. The overactivity of the mutant CaSR is due to loss of a critical structural cation-π interaction. Conclusions: The patient's hypoparathyroidism is due to homozygosity of a variant in the CASR that normally has weak or no phenotypic expression in heterozygosity. Although rare, this has important implications for genetic counseling and clinical management.