Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations.

Tumours of the anterior part of the pituitary gland represent just 1% of all childhood (aged <15 years) intracranial neoplasms, yet they can confer high morbidity and little evidence and guidance is in place for their management. Between 2014 and 2022, a multidisciplinary expert group systematically developed the first comprehensive clinical practice consensus guideline for children and young people under the age 19 years (hereafter referred to as CYP) presenting with a suspected pituitary adenoma to inform specialist care and improve health outcomes. Through robust literature searches and a Delphi consensus exercise with an international Delphi consensus panel of experts, the available scientific evidence and expert opinions were consolidated into 74 recommendations. Part 1 of this consensus guideline includes 17 pragmatic management recommendations related to clinical care, neuroimaging, visual assessment, histopathology, genetics, pituitary surgery and radiotherapy. While in many aspects the care for CYP is similar to that of adults, key differences exist, particularly in aetiology and presentation. CYP with suspected pituitary adenomas require careful clinical examination, appropriate hormonal work-up, dedicated pituitary imaging and visual assessment. Consideration should be given to the potential for syndromic disease and genetic assessment. Multidisciplinary discussion at both the local and national levels can be key for management. Surgery should be performed in specialist centres. The collection of outcome data on novel modalities of medical treatment, surgical intervention and radiotherapy is essential for optimal future treatment.

Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 2, specific diseases.

Pituitary adenomas are rare in children and young people under the age of 19 (hereafter referred to as CYP) but they pose some different diagnostic and management challenges in this age group than in adults. These rare neoplasms can disrupt maturational, visual, intellectual and developmental processes and, in CYP, they tend to have more occult presentation, aggressive behaviour and are more likely to have a genetic basis than in adults. Through standardized AGREE II methodology, literature review and Delphi consensus, a multidisciplinary expert group developed 74 pragmatic management recommendations aimed at optimizing care for CYP in the first-ever comprehensive consensus guideline to cover the care of CYP with pituitary adenoma. Part 2 of this consensus guideline details 57 recommendations for paediatric patients with prolactinomas, Cushing disease, growth hormone excess causing gigantism and acromegaly, clinically non-functioning adenomas, and the rare TSHomas. Compared with adult patients with pituitary adenomas, we highlight that, in the CYP group, there is a greater proportion of functioning tumours, including macroprolactinomas, greater likelihood of underlying genetic disease, more corticotrophinomas in boys aged under 10 years than in girls and difficulty of peri-pubertal diagnosis of growth hormone excess. Collaboration with pituitary specialists caring for adult patients, as part of commissioned and centralized multidisciplinary teams, is key for optimizing management, transition and lifelong care and facilitates the collection of health-related quality of survival outcomes of novel medical, surgical and radiotherapeutic treatments, which are currently largely missing.

A Single-Center, Observational Study of 607 Children and Young People Presenting With Differences of Sex Development (DSD).

Context: Differences of sex development (DSD) represent a wide range of conditions presenting at different ages to various health professionals. Establishing a diagnosis, supporting the family, and developing a management plan are important. Objective: We aimed to better understand the presentation and prevalence of pediatric DSD. Methods: A retrospective, observational cohort study was undertaken in a single tertiary pediatric center of all children and young people (CYP) referred to a DSD multidisciplinary team over 25 years (1995-2019). In total, 607 CYP (520 regional referrals) were included. Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results: Among the 3 major DSD categories, sex chromosome DSD was diagnosed in 11.2% (68/607) (most commonly 45,X/46,XY mosaicism), 46,XY DSD in 61.1% (371/607) (multiple diagnoses often with associated features), while 46,XX DSD occurred in 27.7% (168/607) (often 21-hydroxylase deficiency). Most children (80.1%) presented as neonates, usually with atypical genitalia, adrenal insufficiency, undescended testes or hernias. Those presenting later had diverse features. Rarely, the diagnosis was made antenatally (3.8%, n = 23) or following incidental karyotyping/family history (n = 14). Mortality was surprisingly high in 46,XY children, usually due to complex associated features (46,XY girls, 8.3%; 46,XY boys, 2.7%). The approximate point prevalence of neonatal referrals for investigation of DSD was 1 in 6347 births, and 1 in 5101 overall throughout childhood. Conclusion: DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care.

Paediatric differentiated thyroid carcinoma: a UK National Clinical Practice Consensus Guideline.

This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi Consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of paediatric patients with differentiated thyroid carcinoma.

A 40-Year Cohort Study of Evolving Hypothalamic Dysfunction in Infants and Young Children (<3 years) with Optic Pathway Gliomas.

Despite high survival, paediatric optic pathway hypothalamic gliomas are associated with significant morbidity and late mortality. Those youngest at presentation have the worst outcomes. We aimed to assess presenting disease, tumour location, and treatment factors implicated in the evolution of neuroendocrine, metabolic, and neurobehavioural morbidity in 90 infants/children diagnosed before their third birthday and followed-up for 9.5 years (range 0.5-25.0). A total of 52 (57.8%) patients experienced endo-metabolic dysfunction (EMD), the large majority (46) of whom had hypothalamic involvement (H+) and lower endocrine event-free survival (EEFS) rates. EMD was greatly increased by a diencephalic syndrome presentation (85.2% vs. 46%, p = 0.001)), H+ (OR 6.1 95% CI 1.7-21.7, p 0.005), radiotherapy (OR 16.2, 95% CI 1.7-158.6, p = 0.017) and surgery (OR 4.8 95% CI 1.3-17.2, p = 0.015), all associated with anterior pituitary disorders. Obesity occurred in 25% of cases and was clustered with the endocrinopathies. Neurobehavioural deficits occurred in over half (52) of the cohort and were associated with H+ (OR 2.5 95% C.I. 1.1-5.9, p = 0.043) and radiotherapy (OR 23.1 C.I. 2.9-182, p = 0.003). Very young children with OPHG carry a high risk of endo-metabolic and neurobehavioural comorbidities which deserve better understanding and timely/parallel support from diagnosis to improve outcomes. These evolve in complex, hierarchical patterns over time whose aetiology appears predominantly determined by injury from the hypothalamic tumour location alongside adjuvant treatment strategies.

Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors.

Endocrine disorders in survivors of childhood, adolescent, and young adult (CAYA) cancers are associated with substantial adverse physical and psychosocial effects. To improve appropriate and timely endocrine screening and referral to a specialist, the International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) aims to develop evidence and expert consensus-based guidelines for healthcare providers that harmonize recommendations for surveillance of endocrine disorders in CAYA cancer survivors. Existing IGHG surveillance recommendations for premature ovarian insufficiency, gonadotoxicity in males, fertility preservation, and thyroid cancer are summarized. For hypothalamic-pituitary (HP) dysfunction, new surveillance recommendations were formulated by a guideline panel consisting of 42 interdisciplinary international experts. A systematic literature search was performed in MEDLINE (through PubMed) for clinically relevant questions concerning HP dysfunction. Literature was screened for eligibility. Recommendations were formulated by drawing conclusions from quality assessment of all evidence, considering the potential benefits of early detection and appropriate management. Healthcare providers should be aware that CAYA cancer survivors have an increased risk for endocrine disorders, including HP dysfunction. Regular surveillance with clinical history, anthropomorphic measures, physical examination, and laboratory measurements is recommended in at-risk survivors. When endocrine disorders are suspected, healthcare providers should proceed with timely referrals to specialized services. These international evidence-based recommendations for surveillance of endocrine disorders in CAYA cancer survivors inform healthcare providers and highlight the need for long-term endocrine follow-up care in subgroups of survivors and elucidate opportunities for further research.

Management of children and young people with idiopathic pituitary stalk thickening, central diabetes insipidus, or both: a national clinical practice consensus guideline.

Unexplained or idiopathic pituitary stalk thickening or central diabetes insipidus not only harbours rare occult malignancies in 40% of cases but can also reflect benign congenital defects. Between 2014 and 2019, a multidisciplinary, expert national guideline development group in the UK systematically developed a management flowchart and clinical practice guideline to inform specialist care and improve outcomes in children and young people (aged <19 years) with idiopathic pituitary stalk thickening, central diabetes insipidus, or both. All such cases of idiopathic pituitary stalk thickening and central diabetes insipidus require dynamic pituitary function testing, specialist pituitary imaging, measurement of serum ß-human chorionic gonadotropin and alpha-fetoprotein concentrations, chest x-ray, abdominal ultrasonography, optometry, and skeletal survey for occult disease. Stalk thickening of 4 mm or more at the optic chiasm, 3 mm or more at pituitary insertion, or both, is potentially pathological, particularly if an endocrinopathy or visual impairment coexists. In this guideline, we define the role of surveillance, cerebrospinal fluid tumour markers, whole-body imaging, indications, timing and risks of stalk biopsy, and criteria for discharge. We encourage a registry of outcomes to validate the systematic approach described in this guideline and research to establish typical paediatric stalk sizes and the possible role of novel biomarkers, imaging techniques, or both, in diagnosis.

Long-term cognitive outcome in adult survivors of an early childhood posterior fossa brain tumour.

PURPOSE: Posterior fossa brain tumours (PFT) and their treatment in young children are often associated with subsequent cognitive impairment. However, reported follow-up periods rarely exceed 10 years. This study reports very long-term cognitive consequences of surviving an early childhood PFT. METHODS: 62 adult survivors of a PFT, ascertained from a national register, diagnosed before 5 years of age, and a sibling control, received a single IQ assessment an average of 32 years (range 18-53) after initial diagnosis, using the Weschler Abbreviated Scale of Intelligence. Regression models were fitted to survivor-sibling pair differences on verbal and performance IQ (VIQ and PIQ) scores to investigate whether increasing time between PFT diagnosis and follow-up IQ assessment contributed to survivor-sibling IQ differences. RESULTS: At follow-up, survivors had, on average, VIQ 15 points and PIQ 19 points lower than their siblings. There was no significant effect of time since diagnosis on survivor-sibling VIQ difference. Survivors who received radiotherapy showed no significant effect of time since diagnosis on survivor-sibling PIQ difference. Survivors who did not receive radiotherapy demonstrated a trend for it to reduce. CONCLUSIONS: VIQ and PIQ deficits persist in adulthood, suggesting the effect of a fixed injury imposing on cognitive development, rather than an ongoing pathological process. IMPLICATIONS FOR CANCER SURVIVORS: The findings will help parents and others supporting survivors of an early life PFT to identify and plan for possible cognitive outcomes, and highlight the importance of early interventions to optimize cognitive function during the developmental period.

Craniopharyngioma in children: trends from a third consecutive single-center cohort study.

OBJECTIVE: The management of children with craniopharyngioma has evolved over time, with a trend toward less invasive neurosurgical approaches as surgeons have sought to balance oncological control and treatment-related morbidity. To this end, the aim of this study was to evaluate the safety and effectiveness of the current management of children with craniopharyngioma compared to the previous management methods used at the authors' treatment center. METHODS: A prospectively maintained database was searched over a 14-year period between January 1, 2005, and December 31, 2018, to identify all children 17 years of age or younger with a new diagnosis of craniopharyngioma. A retrospective case note review was performed for each child to extract data on the presentation, investigation, treatment, and outcome of their illness. Morbidity was assessed in the same fashion as in previous cohorts, according to the following categories: visual loss, pituitary dysfunction, hypothalamic dysfunction, neurological deficits, and cognitive impairment. RESULTS: In total, 59 children were identified with craniopharyngioma during the study period. A total of 92 operations were performed, including cyst drainage (35/92; 38.0%), craniotomy and resection (30/92; 32.6%), and transsphenoidal resection (16/92; 17.4%). Approximately two-thirds of all operations were performed using image guidance (66/92; 71.7%) and one-third were performed using endoscopy (27/92; 29.3%). The majority of children had adjuvant therapy comprising proton beam therapy (18/59; 30.5%) or conventional radiotherapy (16/59; 27.1%). The median follow-up duration was 44 months (range 1-142 months), and approximately one-half of the children had no evidence of residual disease on MRI studies (28/59; 47.5%). Of the remaining 31 children, there was a reduction in the volume of residual disease in 8 patients (8/59; 13.6%), stable residual disease in 18 (18/59; 30.5%), and tumor growth in 5 patients (5/59; 8.5%). There was significantly reduced morbidity (p < 0.05) in all categories in the current cohort compared with our last cohort (1996-2004). CONCLUSIONS: The authors' institutional experience of pediatric craniopharyngioma confirms a trend toward less invasive neurosurgical procedures, most of which are now performed with the benefit of image guidance or endoscopy. Moreover, the authors have identified an expanding role for more targeted radiotherapy for children with residual disease. These advances have allowed for tumor control comparable to that achieved in previous cohorts, but with significantly reduced morbidity and mortality.

Neuropsychiatric profile of paediatric hypothalamic hamartoma: systematic review and case series.

AIM: To evaluate neuropsychiatric comorbidities in children and adolescents with hypothalamic hamartoma. METHOD: We retrospectively analysed case notes for all individuals with hypothalamic hamartoma referred to Great Ormond Street Hospital, London, between 2000 and 2016. In addition, a systematic review aiming to identify all previous paediatric case series was performed. Psychiatric symptoms, demographics, physical comorbidities, and cognitive functioning were recorded for all cases where possible. Analyses were performed to determine which factors were associated with psychopathology and potential mechanisms investigated. RESULTS: Forty-six cases were included in the case series (28 males, 18 females; mean age at assessment 11y 8mo [1y 11mo-16y 11mo, SD 4y 0mo]). Twenty-nine papers representing data from 264 cases met inclusion criteria for the systematic review. Overall, at least 50% of cases presented with psychopathology. Epilepsy, intellectual disability, and male sex were associated with externalizing disorders (attention-deficit/hyperactivity disorder, conduct and oppositional defiance disorders, and rage attacks). Intellectual disability mediated the effects of epilepsy on externalizing psychopathology. No factors were associated with internalizing disorders (anxiety and depressive disorders), although these were not well reported. INTERPRETATION: Psychiatric comorbidities are highly prevalent in the presentation of paediatric hypothalamic hamartoma. The aetiology of psychopathology comprises a range of interacting biological and psychosocial factors with particular influence from epilepsy. Further research is required to achieve an evidence base for treatment. WHAT THIS PAPER ADDS: Over half of children with hypothalamic hamartoma present with psychiatric comorbidity. Externalizing and internalizing disorders are present in approximately 60% and 30% of children with hypothalamic hamartomas respectively. Epilepsy and male sex are associated with externalizing psychopathology. Intellectual disability mediates the association between epilepsy and externalizing symptoms. No clear associations are evident for internalizing disorders or precocious puberty.

PERFIL NEUROPSIQUIÁTRICO DEL HAMARTOMA HIPOTALÁMICO EN PEDIATRÍA: REVISIÓN SISTEMÁTICA Y SERIE DE CASOS: OBJETIVO: Evaluar las comorbilidades neuropsiquiátricas en niños y adolescentes con hamartoma hipotalámico. MÉTODO: En este estudio analizamos retrospectivamente las notas de los casos de todos los individuos con hamartoma hipotalámicos referidos al Great Ormond Street Hospital, London, entre el 2000 y 2016. Además, realizamos una revisión bibliográfica sistemática dirigida a identificar la serie de casos pediátricos. Síntomas psiquiátricos, demográfico, comorbilidades físicas y funcionamiento cognitivo fueron recolectados en todos los casos posibles.Se efectuaron análisis para determinar qué factores se asociaron con psicopatología y se investigaron mecanismos potenciales. RESULTADOS: En total 46 casos fueron incluidos en la serie de casos (28 masculinos, 18 femeninos, media de edad a la evaluación 11 años y 8 meses, DS 4 años y 0 mes). La revisión bibliográfica identifico 29 artículos describiendo 264 casos que reunieron criterios de inclusión para la extracción de datos. En total, al menos 50% de casos presentaban psicopatología. Epilepsia, discapacidad intelectual, y sexo masculino fueron asociados con desórdenes externos (déficit de atención con hiperactividad, desórdenes conductuales y oposicional desafiante, ataques de furia). Ningún factor fue asociado con la internalización de desórdenes neuropsiquiátricos (desórdenes de ansiedad y depresión), aunque éstos no fueron bien reportados. INTERPRETACIÓN: Las comorbilidades psiquiátricas son altamente prevalentes en la presentación del hamartoma hipotalámico pediátrico. La etiología de la psicopatología comprende un rango de interacciones biológicas y factores psicosociales con particular influencia de la epilepsia. Se requiere más información de investigación para reunir evidencia científica que guie el tratamiento.

PERFIL NEUROPSIQUIÁTRICO DO HAMARTOMA HIPOTALÂMICO PEDIÁTRICO: REVISÃO SISTEMÁTICA E SÉRIE DE CASOS: OBJETIVO: Avaliar comorbidades neuropsiquiátricas em crianças e adolescentes com hamartoma hipotalâmico. MÉTODO: Nós analisamos retrospectivamente os registros de casos de todos os indivíduos encaminhados para o Hospital Great Ormond Street, Londres, entre 2000 e 2016. Além disso, uma revisão sistemática visando identificar todos os casos pediátricos prévios foi realizada. Sintomas psiquiátricos, dados demográficos, comorbidades físicas, e funcionamento cognitivo foram registrados para todos os casos em que foi possível. Análises foram realizadas para determinar quais fatores se associavam com psicopatologia e potenciais mecanismos foram investigados. RESULTADOS: Quarenta e seis casos foram incluídos na série de casos (28 do sexo masculino, 18 do sexo feminino; média de idade na avaliação 11a 8m (1a 11m-16a 11m, DP 4a 0m). Vinte e nove artigos representando dados de 264 casos atenderam aos critérios de inclusão para a revisão sistemática. No total, pelo menos 50% dos casos apresentaram psicopatologia. Epilepsia, deficiência intelectual, e sexo masculino eram associados com desordens externalizantes (transtorno de déficit de atenção e hiperatividade, transtornos de conduta e de desafio oposicional, e ataques de raiva). A deficiência intelectual mediou os efeitos da epilepsia e da psicopatologia externalizante. Nenhum fator foi associado com transtornos internalizantes (ansiedade e transtornos depressivos), embora estes não tenham sido bem reportados. INTERPRETAÇÃO: Comorbidades psiquiátricas são altamente prevalentes na apresentação do hamartoma hipotalâmico pediátrico. A etiologia da psicopatologia envolve uma variedade de fatores biológicos e psicossociais que interagem, com particular influência da epilepsia. Mais pesquisas são necessárias para se atingir uma base de evidências para o tratamento.

Improved adherence and growth outcomes with jet-delivered growth hormone.

Background We previously reported improved persistence and adherence to daily recombinant growth hormone (rGH) in children using jet transjection delivery compared to using needle-based devices. This study examines the relationship between improved adherence and medium-term growth outcomes in children receiving jet-delivered rGH (JrGH) at a single centre. Methods This was a retrospective longitudinal follow-up study of children (<16 years) treated with daily JrGH (somatropin; Ferring Pharmaceuticals) in the form of Zomacton® with the Zomajet® device. Delivery schedules of home distribution services were utilised to calculate adherence, quantified as the proportion of days covered (PDC) index (PDC > 0.8 adherent, PDC ≤ 0.8 less adherent). Demography, patient history, height standard deviation scores (HTSDS) and difference from mid-parental height SDS (MPHSDS - HTSDS) were extracted from hospital records for up to 3 years of treatment. Results Of 75 patients eligible for JrGH, 52 had PDC treatment and height data for at least 1 year and 22 for 3 years. A greater proportion of patients were classified as adherent in both 1- and 3-year treated cohorts (adherent 30 [57.7%] and 14 [63.6%], less adherent 22 [42.3%] and 8 [36.4%]). After 1 year of JrGH treatment, HTSDS was not significantly different in either adherence group. After 3 years, only adherent patients demonstrated sustained year-on-year increments in HTSDS and significant improvement in target HTSDS positions (by 1.32 SDS) compared to baseline (p = 0.0008). MPHSDS - HTSDS showed a similar significant improvement at 3 years in adherent patients only (p = 0.0043). Conclusions Patients adherent to JrGH demonstrate significant growth improvement compared to baseline over 3 years.

Predicted Benign and Synonymous Variants in CYP11A1 Cause Primary Adrenal Insufficiency Through Missplicing.

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that can present with nonspecific features and can be difficult to diagnose. We undertook next generation sequencing in a cohort of children and young adults with PAI of unknown etiology from around the world and identified a heterozygous missense variant (rs6161, c.940G>A, p.Glu314Lys) in CYP11A1 in 19 individuals from 13 different families (allele frequency within undiagnosed PAI in our cohort, 0.102 vs 0.0026 in the Genome Aggregation Database; P < 0.0001). Seventeen individuals harbored a second heterozygous rare disruptive variant in CYP11A1 and two had very rare synonymous changes in trans (c.990G>A, Thr330 = ; c.1173C>T, Ser391 =). Although p.Glu314Lys is predicted to be benign and showed no loss-of-function in an Escherichia coli assay system, in silico and in vitro studies revealed that the rs6161/c.940G>A variant, plus the c.990G>A and c.1173C>T changes, affected splicing and that p.Glu314Lys produces a nonfunctional protein in mammalian cells. Taken together, these findings show that compound heterozygosity involving a relatively common and predicted "benign" variant in CYP11A1 is a major contributor to PAI of unknown etiology, especially in European populations. These observations have implications for personalized management and demonstrate how variants that might be overlooked in standard analyses can be pathogenic when combined with other very rare disruptive changes.

Intracystic interferon-alpha in pediatric craniopharyngioma patients: an international multicenter assessment on behalf of SIOPE and ISPN.

BACKGROUND: Craniopharyngiomas are frequent hypothalamo-pituitary tumors in children, presenting predominantly as cystic lesions. Morbidity from conventional treatment has focused attention on intracystic drug delivery, hypothesized to cause fewer clinical consequences. However, the efficacy of intracystic therapy remains unclear. We report the retrospective experiences of several global centers using intracystic interferon-alpha. METHODS: European Société Internationale d'Oncologie Pédiatrique and International Society for Pediatric Neurosurgery centers were contacted to submit a datasheet capturing pediatric patients with cystic craniopharyngiomas who had received intracystic interferon-alpha. Patient demographics, administration schedules, adverse events, and outcomes were obtained. Progression was clinical or radiological (cyst reaccumulation, novel cysts, or solid growth). RESULTS: Fifty-six children (median age, 6.3 y) from 21 international centers were identified. Median follow-up from diagnosis was 5.1 years (0.3-17.7 y). Lesions were cystic (n = 22; 39%) or cystic/solid (n = 34; 61%). Previous progression was treated in 43 (77%) patients before interferon use. In such cases, further progression was delayed by intracystic interferon compared with the preceding therapy for cystic lesions (P = 0.0005). Few significant attributable side effects were reported. Progression post interferon occurred in 42 patients (median 14 mo; 0-8 y), while the estimated median time to definitive therapy post interferon was 5.8 (1.8-9.7) years. CONCLUSIONS: Intracystic interferon-alpha can delay disease progression and potentially offer a protracted time to definitive surgery or radiotherapy in pediatric cystic craniopharyngioma, yet demonstrates a favorable toxicity profile compared with other therapeutic modalities-important factors for this developing age group. A prospective, randomized international clinical trial assessment is warranted.

Management of Cushing syndrome in children and adolescents: experience of a single tertiary centre.

UNLABELLED: The diagnosis and management of paediatric Cushing syndrome (CS) is highly challenging. This study aims to characterise its presentation, diagnosis, management and outcome by a retrospective case review of 30 patients (14 females) followed at a single tertiary paediatric endocrinology centre over a 30-year period. At presentation, median age was 8.9 years (0.2-15.5) and the commonest manifestations were weight gain (23/30), hirsutism (17/30), acne (15/30) and hypertension (15/30). Growth retardation was present in 11/30. Median body mass index (BMI) was +2.1 standard deviation score (SDS) (-6.5 to +4.6). Urinary free cortisol (UFC) was abnormal in 17/18 (94 %), midnight cortisol in 27/27 (100 %) and low-dose dexamethasone suppression (LDDS) test in 20/20 (100 %). High-dose dexamethasone suppression (HDDS) test was abnormal in 6/6 (100 %) of adrenal tumours, 1/10 (10 %) of Cushing disease (CD) and 1/2 (50 %) of ectopic tumours. Bilateral inferior petrosal sinus sampling (IPSS) identified five CD cases and one ectopic tumour. All patients underwent surgery and subsequently required cortisol replacement. Final diagnoses were 16 CD, 11 adrenal disease, 2 ectopic ACTH-secreting lesions and 1 case of unidentified aetiology. One year post-diagnosis, median BMI was 0.5 SDS (-2.5 to +3.7), hypertension was present in 4/14 (28 %), and 43 % (12/30) of individuals were off hydrocortisone. CONCLUSION: The prevalence of the clinical manifestations differs from that reported in other series. Screening tests were highly sensitive, with UFC, midnight cortisol and LDDS performing well. One year post-treatment, BMI and BP normalised in the majority of patients and almost half of them were able to discontinue replacement hydrocortisone. WHAT IS KNOWN: •Cushing syndrome is an extremely rare entity in the paediatric and adolescent age groups, so not many cohort studies have been published in this population. •Several tests can be employed to firstly diagnose hypercortisolaemia and secondly identify the source of origin of it. The efficacy and safety of these tests in children is still uncertain. What is New: •This study includes cases due to the different aetiologies of endogenous hypercortisolaemia (pituitary, adrenal and ectopic hypercortisolaemia) allowing us to compare the differences in presentation, diagnosis, management and long-term outcome between the groups. •There is a difference in the prevalence of Cushing syndrome symptoms and in the performance of the tests in our cohort compared to previously published studies in the literature.

Quality of survival assessment in European childhood brain tumour trials, for children aged 5 years and over.

INTRODUCTION: There is increasing recognition of the long-term sequelae of brain tumours treated in childhood. Five year survival rates now exceed 75% and assessing the quality of survival (QoS) in multiple domains is essential to any comparison of the benefits and harms of treatment regimens. AIM: The aim of this position statement is to rationalise assessments and facilitate collection of a common data set across Europe. Sufficient numbers of observations can then be made to enable reliable comparisons between outcomes following different tumour types and treatments. METHODS: This paper represents the consensus view of the QoS working group of the Brain Tumour group of the European Society of Paediatric Oncology regarding domains of QoS to prioritise for assessment in clinical trials. This consensus between clinicians and researchers across Europe has been arrived at by discussion and collaboration over the last eight years. RESULTS: Areas of assessment discussed include core medical domains (e.g. vision, hearing, mobility, endocrine), emotion, behaviour, adaptive behaviour and cognitive functioning. CONCLUSIONS: A 'core plus' approach is suggested in which core assessments (both direct and indirect tests) are recommended for all clinical trials. The core component is a relatively brief screening assessment that, in most countries, is a sub-component of routine clinical provision. The 'plus' components enable the addition of assessments which can be selected by individual countries and/or tumour-, age-, and location-specific groups. The implementation of a QoS protocol common to all European clinical studies of childhood brain tumours is also discussed.

Maintaining persistence and adherence with subcutaneous growth-hormone therapy in children: comparing jet-delivery and needle-based devices.

PURPOSE: Persistence and adherence with subcutaneous growth hormone (GH; somatropin) therapy in children is widely acknowledged to be suboptimal. This study aimed to investigate how the use of a jet-delivery device, ZomaJet(®), impacts on medication-taking behaviors compared to needle-based devices. MATERIALS AND METHODS: A retrospective cohort study of children aged ≤18 years was conducted using a UK-based, nationwide database of GH home-delivery schedules. Data were evaluated for the period between January 2010 and December 2012 for 6,061 children receiving either Zomacton(®) (somatropin) via the ZomaJet jet-delivery device or one of six brands of GH all administered via needle-based devices. Persistence was analyzed for patients with appropriate data, measured as the time interval between first and last home deliveries. An analysis of adherence was conducted only for patients using ZomaJet who had appropriate data, measured by proportion of days covered. Brand switches were identified for all patients. RESULTS: Persistence with GH therapy was significantly longer in patients using ZomaJet compared to needle-based devices (599 days versus 535 days, respectively, n=4,093; P<0.001); this association was observed in both sexes and across age subgroups (≤10 and 11-16 years). The majority (58%) of patients using ZomaJet were classed as adherent (n=728). Only 297 patients (5%) switched GH brand (n=6,061), and patients tended to use ZomaJet for longer than other devices before switching. CONCLUSION: It appears important that the choice of a jet-delivery device is offered to children prescribed daily GH therapy. These devices may represent a much-needed effective strategy for maintaining persistence with subcutaneous GH administration in children, potentially offering better clinical outcomes and greater cost-efficiency.

Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyperfractionated versus conventional radiation therapy for standard-risk medulloblastoma.

PURPOSE: To compare quality of survival in "standard-risk" medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial. METHODS AND MATERIALS: Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded. RESULTS: Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011). CONCLUSIONS: Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.

Prevalence, associations, and predictors of apathy in adult survivors of infantile (<5 years of age) posterior fossa brain tumors.

BACKGROUND: Apathy is associated with pervasive and disadvantageous effects on daily functioning. It has been observed transiently in some children after surgery for posterior fossa tumors. In this study, our objective was to examine prevalence, associations, and predictors of apathy in adult survivors of an infantile posterior fossa brain tumor (PFT). METHODS: One hundred seventeen adult survivors of a childhood PFT diagnosed before age 5 years and 60 of their siblings were assessed in a cross-sectional study a mean of 32 years (range, 18-53 years) after survivors' initial tumor diagnoses, using the Marin Apathy Evaluation Scale (AES), the Weschler Abbreviated Scale of Intelligence and the Composite International Diagnostic Interview for psychiatric disorders. RESULTS: Marin Apathy Evaluation Scale, the Weschler Abbreviated Scale of Intelligence reached or exceeded a criterion score for clinically significant apathy in 35% of survivors, compared with 18% in a sibling comparison group. In both siblings and survivors, apathy was associated with lower verbal and full-scale IQ and, among survivors, with having undergone partial rather than total tumor resection (independent of irradiation status). Apathy was not related to presence of concurrent International Classification of Diseases, 10(th) Revision, depression. Female sex was associated with late apathy after a PFT, with increased likelihood of women reaching the apathy criterion relative to men if they were survivors. CONCLUSIONS: Clinically significant and potentially treatable apathy occurs relatively commonly in adult survivors of an infantile childhood PFT, particularly women. Clinicians, including those managing posterior fossa pathology in very young children, should be aware of this association, and future research should clarify whether specific treatment-related variables are implicated in increasing this risk of apathy.