Gene expression signatures predict response to therapy with growth hormone.

Recombinant human growth hormone (r-hGH) is used as a therapeutic agent for disorders of growth including growth hormone deficiency (GHD) and Turner syndrome (TS). Treatment is costly and current methods to model response are inexact. GHD (n = 71) and TS patients (n = 43) were recruited to study response to r-hGH over 5 years. Analysis was performed using 1219 genetic markers and baseline (pre-treatment) blood transcriptome. Random forest was used to determine predictive value of transcriptomic data associated with growth response. No genetic marker passed the stringency criteria for prediction. However, we identified an identical set of genes in both GHD and TS whose expression could be used to classify therapeutic response to r-hGH with a high accuracy (AUC > 0.9). Combining transcriptomic markers with clinical phenotype was shown to significantly reduce predictive error. This work could be translated into a single genomic test linked to a prediction algorithm to improve clinical management. Trial registration numbers: NCT00256126 and NCT00699855.

Chitayat-Hall and Schaaf-Yang syndromes:a common aetiology: expanding the phenotype of MAGEL2-related disorders.

BACKGROUND: Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified. METHODS AND RESULTS: We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion. CONCLUSIONS: Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.

Genetic variations at the human growth hormone receptor (GHR) gene locus are associated with idiopathic short stature.

GH plays an essential role in the growing child by binding to the growth hormone receptor (GHR) on target cells and regulating multiple growth promoting and metabolic effects. Mutations in the GHR gene coding regions result in GH insensitivity (dwarfism) due to a dysfunctional receptor protein. However, children with idiopathic short stature (ISS) show growth impairment without GH or GHR defects. We hypothesized that decreased expression of the GHR gene may be involved. To test this, we investigated whether common genetic variants (microsatellites, SNPs) in regulatory regions of the GHR gene region were associated with the ISS phenotype. Genotyping of a GT-repeat microsatellite in the GHR 5'UTR in a Montreal ISS cohort (n = 37 ISS, n = 105 controls) revealed that the incidence of the long/short (L/S) genotype was 3.3× higher in ISS children than controls (P = 0.04, OR = 3.85). In an Italian replication cohort (n = 143 ISS, n = 282 controls), the medium/short (M/S) genotype was 1.9× more frequent in the male ISS than controls (P = 0.017, OR = 2.26). In both ISS cohorts, logistic regression analysis of 27 SNPs showed an association of ISS with rs4292454, while haplotype analysis revealed specific risk haplotypes in the 3' haploblocks. In contrast, there were no differences in GT genotype frequencies in a cohort of short stature (SS) adults versus controls (CARTaGENE: n = 168 SS, n = 207 controls) and the risk haplotype in the SS cohort was located in the most 5' haploblock. These data suggest that the variants identified are potentially genetic markers specifically associated with the ISS phenotype.

Characterization of facial phenotypes of children with congenital hypopituitarism and their parents: a matched case-control study.

Congenital Hypopituitarism (CH) has traditionally been associated with specific facial phenotypes subsumed under the term midface retrusion, based on cephalometric studies. In this study, we used a systematic anthropometric approach to facial morphology in 37 individuals with CH and their parents, primarily of French Canadian ancestry, and compared them to a control group of 78 French Canadian patients with well-controlled type 1 diabetes and their parents. We were able to demonstrate clear morphological differences, which were more prevalent in the affected group than in the control group. More specifically, we showed the presence of a shorter skull base width (P < 0.001) and reduced inner canthal distance (P = 0.006) in the CH face, as well as a relative underdevelopment of the mandible (P = 0.001). These findings were present in individuals of all ages, and were independent of the duration of growth hormone treatment (median treatment 90.8 months; range 7.2-175.8 months). In addition, skull base width was significantly reduced in both mothers and fathers of affected children compared to the parents of the controls (P < 0.001), despite comparable parental heights, supporting an underlying genetic etiology. Such extensive phenotypic studies have not been done in congenital hypopituitarism and will provide further opportunities for data mining.

Mutation in the nuclear-encoded mitochondrial isoleucyl-tRNA synthetase IARS2 in patients with cataracts, growth hormone deficiency with short stature, partial sensorineural deafness, and peripheral neuropathy or with Leigh syndrome.

Mutations in the nuclear-encoded mitochondrial aminoacyl-tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short-stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole-exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl-tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.

Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement.

Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Abnormal motor cortex excitability is associated with reduced cortical thickness in X monosomy.

Turner syndrome (TS) is a noninherited genetic disorder caused by the absence of one or part of one X chromosome. It is characterized by physical and cognitive phenotypes that include motor deficits that may be related to neuroanatomical abnormalities of sensorimotor pathways. Here, we used transcranial magnetic stimulation (TMS) and cortical thickness analysis to assess motor cortex excitability and cortical morphology in 17 individuals with TS (45, X) and 17 healthy controls. Exploratory analysis was performed to detect the effect of parental origin of the X chromosome (X(mat), X(pat)) on both measures. Results showed that long-interval intracortical inhibition was reduced and motor threshold (MT) was increased in TS relative to controls. Areas of reduced thickness were observed in the precentral gyrus of individuals with TS that correlated with MT. A significant difference between X(mat) (n = 11) and X(pat) (n = 6) individuals was found on the measure of long-interval intracortical inhibition. These findings demonstrate the presence of converging anatomical and neurophysiological abnormalities of the motor system in X monosomy.

A search for variables predicting cortisol response to low-dose corticotropin stimulation following supraphysiological doses of glucocorticoids.

OBJECTIVES: To determine which biological or clinical variables may predict cortisol response to low-dose adrenocorticotropic hormone (ACTH) stimulation following supraphysiological doses of glucocorticoids in children. STUDY DESIGN: This retrospective study included all patients who underwent ACTH testing (1 µg) between October 2008 and June 2010 at the Sainte-Justine University Hospital Center, Montreal, after supraphysiological doses of glucocorticoids. RESULTS: Data from 103 patients (median age, 8.0 years; range, 0.6-18.5 years; 57 girls) were analyzed, revealing growth deceleration in 37% and excessive weight gain in 33%. Reasons for glucocorticoid treatment included asthma (n = 30) and hematologic (n = 22), dermatologic (n = 19), rheumatologic (n = 16), and miscellaneous (n = 16) disorders. The following information was recorded: duration of glucocorticoid treatment (median, 374 days; range, 5-4226 days); duration of physiological hydrocortisone replacement (median, 118 days; range, 0-1089 days); maximum daily (median, 200 mg/m(2)/day; range, 12-3750 mg/m(2)/day) and cumulative (median, 16 728 mg/m(2); range, 82-178 209 mg/m(2)) doses, in hydrocortisone equivalents; and interval since the last dose (median, 43 days; range, 1-1584 days). Sixty-two patients (58%) exhibited a normal response (ie, peak cortisol >500 nmol/L) to ACTH stimulation. Peak cortisol level was not related to sex, prior morning cortisol level, duration of treatment, or cumulative glucocorticoid dose; 28% of the patients with normal baseline cortisol levels nevertheless demonstrated a subnormal response to ACTH. CONCLUSION: Given the absence of clinical or biological predictors of the cortisol response to ACTH after suppressive doses of glucocorticoids, physicians have only 2 options: (1) empirically advocate glucocorticoid stress coverage during 18 months after cessation of high-dose glucocorticoid treatment; or (2) perform serial ACTH testing in all such patients until a normal peak cortisol level is attained.

Thyroid function from birth to adolescence in Prader-Willi syndrome.

OBJECTIVES: To describe the response of thyroid-stimulating hormone (TSH) to thyroid-releasing hormone in children and adolescents with Prader-Willi syndrome (PWS), and to compare TSH and total thyroxine (TT4) concentrations measured on neonatal screening for congenital hypothyroidism in children with PWS and controls. STUDY DESIGN: All participants had genetically confirmed PWS. The TSH responses to thyroid-releasing hormone, free thyroxine (fT4), and free triiodothyronine (fT3) were measured in 21 subjects (14 females and 7 males; mean age, 6.4 years). Capillary TT4 was measured on neonatal screening samples from 23 subjects with PWS (14 females and 9 males), each of whom was matched for birth weight and sex with 4 anonymized controls. RESULTS: One subject with PWS had tertiary hypothyroidism. TSH level increased from 1.37 mU/L at baseline to 39.6 mU/L at 20 minutes, 47.2 mU/L at 40 minutes, 44.5 mU/L at 60 minutes, and 47.2 mU/L at 120 minutes. fT4 concentration was 6.3 pmol/L, and fT3 concentration was 4.6 pmol/L. In the other 20 subjects, mean TSH level was 1.9 mU/L (range, 0.8-4.2 mU/L) at baseline and 21.8 mU/L (range, 10.0-46.7 mU/L) at 20 minutes (peak). Mean fT4 concentration (10.4 pmol/L; range, 8.2-13.5 pmol/L) was in the lower one-third of the normal range in 18 subjects, and mean fT3 concentration (6.1 pmol/L; range, 4.8-8.4 pmol/L) was above the median in 13 subjects. In neonates, mean TSH level was 3.1 mU/L (range, 0.4-10.0 mU/L) in subjects with PWS versus 3.3 mU/L (range, 0.0-7.0 mU/L) in controls, and mean TT4 in subjects with PWS was 111% (range, 17%-203%) that of controls (P = not significant). CONCLUSION: Thyroid function was normal in our newborn subjects. In older children, frank hypothyroidism was found in only 1 of our 21 subjects. Thus, levothyroxine treatment should not be routinely prescribed to youth with PWS.

Quality of referral of short children to the paediatric endocrinologist and impact of a fax communication system.

BACKGROUND/OBJECTIVES: In 2001, a chart review of children referred to the authors' endocrine clinic because of short stature revealed that many were referred with insufficient baseline data, had normal height velocity and were within genetic target height. Therefore, a two-way fax communication system was implemented between referring physicians and the authors' service before the first visit. Aspects that were assessed included whether this system increased the information accompanying the patient at referral, resulted in children with nonpathological shortness not being seen in the clinic, and was used differently by paediatricians and general practitioners. STUDY DESIGN: Between January and December 2006, 138 referrals for short stature, diagnosed with familial short stature, constitutional delay or idiopathic short stature, were audited (69 with and 69 without previous fax communication). Data collected included source of referral, clinical information provided, available growth measurements, and results from laboratory and imaging studies. RESULTS: Fax communication resulted in growth curves being provided more often (95.6% of cases versus 40.5% of cases without fax communication [P<0.001]) and more investigations being performed by the referring physician (median [range]: six [zero to 13] investigations versus one [zero to 11]; P<0.001), as well as a diagnosis of nonpathological short stature being given to 31 children based on the growth curve, laboratory and imaging results, without the children being seen in the endocrine clinic. Fax communication was also used more frequently by paediatricians (84%) than by general practitioners (15%). CONCLUSION: The fax communication system resulted in a more complete evaluation of referred patients by their physicians and reduced the number of unnecessary visits to the authors' specialty clinic while promoting medical education.

HISTORIQUE ET OBJECTIFS: En 2001, un examen des dossiers d'enfants aiguillés vers la clinique d'endocrinologie des auteurs en raison de leur petite taille a révélé que bon nombre des aiguillages ne s'accompagnaient pas de données de base suffisantes et que les patients aiguillés présentaient une croissance normale et une taille qui respectait leur cible génétique. C'est pourquoi un système de communication bidirectionnelle par télécopieur a été mis sur pied entre les médecins traitants et le service d'endocrinologie avant le premier rendez-vous. Les auteurs ont évalué si le système permettait d'avoir plus d'information au sujet du patient lors de l'aiguillage, s'il évitait que les patients dont la petite taille n'était pas d'origine pathologique soient vus à la clinique et s'il était utilisé de manière différente par les pédiatres et les omnipraticiens. MÉTHODOLOGIE: De janvier à décembre 2006, les auteurs ont évalué 138 aiguillages en raison d'une petite taille, diagnostiquée comme une petite taille familiale, un retard constitutionnel ou une petite taille idiopathique (69 avec et 69 sans communication antérieure par télécopieur). Les données colligées incluaient la source de l'aiguillage, l'information clinique fournie, les mesures de croissance transmises et les résultats des études de laboratoire et d'imagerie. RÉSULTATS: La communication par télécopieur a permis d'obtenir plus souvent les courbes de croissance (95,6 % des cas plutôt que 40,5 % [P<0,001]) et de faire faire plus d'examens par le médecin traitant (médiane [plage] : six [zéro à 13] examens au lieu d'un [zéro à 11]; P<0,001), ainsi que de poser un diagnostic de petite taille non pathologique chez 38 enfants d'après la courbe de croissance et les résultats de laboratoire et d'imagerie, sans qu'ils soient vus à la clinique d'endocrinologie. Par ailleurs, la communication par télécopieur était plus utilisée par les pédiatres (84 %) que par les omnipraticiens (15 %). CONCLUSION: Le système de communication par télécopieur a donné lieu à une évaluation plus complète des patients aiguillés par leur médecin et réduit le nombre de rendez-vous inutiles à la clinique spécialisée des auteurs, tout en favorisant la formation médicale.

Challenges in the care of individuals with severe primary insulin-like growth factor-I deficiency (SPIGFD): an international, multi-stakeholder perspective.

BACKGROUND: Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care. OBJECTIVE: To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally. METHODS: An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD. RESULTS: As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing. CONCLUSIONS: To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.

Meier-Gorlin syndrome: growth and secondary sexual development of a microcephalic primordial dwarfism disorder.

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by primordial dwarfism, microtia, and patellar aplasia/hypoplasia. Recently, mutations in the ORC1, ORC4, ORC6, CDT1, and CDC6 genes, encoding components of the pre-replication complex, have been identified. This complex is essential for DNA replication and therefore mutations are expected to impair cell proliferation and consequently could globally reduce growth. However, detailed growth characteristics of MGS patients have not been reported, and so this is addressed here through study of 45 MGS patients, the largest cohort worldwide. Here, we report that growth velocity (length) is impaired in MGS during pregnancy and first year of life, but, thereafter, height increases in paralleled normal reference centiles, resulting in a mean adult height of -4.5 standard deviations (SD). Height is dependent on ethnic background and underlying molecular cause, with ORC1 and ORC4 mutations causing more severe short stature and microcephaly. Growth hormone therapy (n = 9) was generally ineffective, though in two patients with significantly reduced IGF1 levels, growth was substantially improved by GH treatment, with 2SD and 3.8 SD improvement in height. Growth parameters for monitoring growth in future MGS patients are provided and as well we highlight that growth is disproportionately affected in certain structures, with growth related minor genital abnormalities (42%) and mammary hypoplasia (100%) frequently present, in addition to established effects on ears and patellar growth.

The Efficacy, Safety, and Pharmacology of a Ghrelin O-Acyltransferase Inhibitor for the Treatment of Prader-Willi Syndrome.

CONTEXT: Acylated ghrelin (AG) stimulates appetite and is elevated compared to its unacylated (UAG) counterpart in Prader-Willi syndrome (PWS). GLWL-01 is a selective, reversible inhibitor of ghrelin O-acyltransferase (GOAT), the enzyme that converts UAG into AG. OBJECTIVE: This work aimed to assess the efficacy, pharmacokinetics, pharmacodynamics, and safety of GLWL-01 in the treatment of PWS patients. METHODS: A double-blind, placebo-controlled, phase 2 crossover study was conducted with 2 active treatment periods of 28 days in 19 patients (aged 16-65 years; body mass index (BMI) ≥ 28) with genetically confirmed PWS. The study took place in 7 hospital-based study centers in the United States and Canada. Patients received placebo or GLWL-01 (450 mg twice daily) orally after lead-in placebo and washout periods. The Hyperphagia Questionnaire for Clinical Trials and Caregiver Global Impression of Change were used to measure reductions in hyperphagia. Plasma concentrations of AG and UAG were evaluated as correlates. RESULTS: Treatment resulted in statistically significant differences compared to placebo in plasma AG (P = .0002), UAG (P = .0488), and AG/UAG (P = .0003). GLWL-01 did not statistically significantly reduce hyperphagia-related behavior or bring about changes in global clinical end points, as assessed by caregivers. Anthropometric and clinical parameters correlated with obesity did not statistically significantly change in response to treatment. Less than half of patients reported a treatment-emergent adverse event (TEAE). No deaths, serious adverse events, or severe TEAEs were reported. CONCLUSION: GLWL-01 is safe and well tolerated. Pharmacological parameters confirmed the inhibition of GOAT following administration of GLWL-01. Patients' eating behaviors, BMI, blood glucose, and total cholesterol, among other similar measures, were not modified.

Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study.

CONTEXT: Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). OBJECTIVE: We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. METHODS: In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. RESULTS: HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). CONCLUSION: The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).

Are guidelines for glucocorticoid coverage in adrenal insufficiency currently followed?

OBJECTIVES: To search for evidence of acute adrenal failure linked to inappropriate use of stress management protocols. STUDY DESIGN: Patients followed up for primary adrenal insufficiency (n = 102) or secondary adrenal insufficiency (n = 34) between 1973 and 2007 were included. All hospitalizations, both urgent (n = 157) and elective (n = 90), were examined. We recorded clinical evidence of acute adrenal failure, parental management before admission, and details of glucocorticoid prescription and administration in the hospital setting. RESULTS: For urgent hospitalizations, subgroup and time period did not influence the percentage of patients hospitalized (primary adrenal insufficiency 45%; secondary adrenal insufficiency 38%; P = .55). The use of stress glucocorticoid doses by parents increased significantly after 1997 (P < .05), although still only 47% increased glucocorticoids before hospitalization. Stress doses were more frequently administered on arrival in our emergency department after 1990 (P < .05); patients with signs or symptoms of acute adrenal failure decreased to 27% after 1997 (P < .01). Twenty-four percent of all hospitalizations were marked by suboptimal adherence to glucocorticoid stress protocols, with rare but significant clinical consequences. CONCLUSIONS: In spite of an increased use of glucocorticoid stress dose protocols by parents and physicians, patients remain at risk of morbidity and death from acute adrenal failure. This risk may be minimized with conscientious application of stress protocols, but other patient-specific risk factors may also be implicated.

Insulin-like Growth Factor 1, but Not Insulin-Like Growth Factor-Binding Protein 3, Predicts Central Precocious Puberty in Girls 6-8 Years Old: A Retrospective Study.

BACKGROUND: Central precocious puberty (CPP) in females is characterized by thelarche before 8 years of age. Evidence of reproductive axis activation confirms the diagnosis (basal serum luteinizing hormone (LH) ≥0.3 IU/L or LH-releasing hormone (LHRH)-stimulated LH ≥5 IU/L). Stimulation testing is the diagnostic gold standard but is time-consuming and costly. Serum levels of insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-binding protein 3 (IGFBP-3) are increased in girls with CPP. OBJECTIVE: The aim of the study was to assess the utility of serum IGF-1 and IGFBP-3 in identifying CPP in girls aged 6-8 years. METHODS: The study was a single-center retrospective study. Girls with confirmed CPP (n = 44) and isolated premature precocious adrenarche/ precocious thelarche (PA/PT, n = 16) had baseline biochemical profiling and LHRH stimulation testing. Serum IGF-1 and IGFBP-3 results were converted to standard deviation scores (SDS). Correlations were calculated and receiver operating characteristic curves were plotted. RESULTS: Girls with CPP had higher basal and peak LH, IGF-1 SDS, and growth velocity (p < 0.05). IGF-1 SDS correlated positively with basal and peak LH (p < 0.05). IGF-1 SDS (1.75-2.15) differentiated CPP and PA/PT with 89% sensitivity and 56% specificity (basal LH) and 94% specificity and 55% sensitivity (peak LH). IGFBP-3 SDS did not differ between groups or by CPP parameters. CONCLUSIONS: In clinical practice, IGF-1 SDS may be an additional tool for identifying CPP in girls aged 6 to 8 years when baseline clinical and laboratory diagnostic criteria are inconclusive, possibly avoiding more time-consuming and costly procedures.

Clinical Outcomes and Complications of Pituitary Blastoma.

CONTEXT: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. OBJECTIVE: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. DESIGN AND SETTING: A multi-institutional case series is presented from tertiary pediatric oncology centers. PATIENTS: Patients included children with pituitary blastoma. INTERVENTIONS: Genetic testing, surgery, oncologic therapy, endocrine support are reported. OUTCOME MEASURES: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. RESULTS: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. CONCLUSIONS: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.