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.

Biallelic human ITCH variants causing a multisystem disease with dysmorphic features: A second report.

We report a 23 year old female with biallelic truncating variants in the ITCH (Itchy E3 Ubiquitin protein ligase, mouse homolog of; OMIM60649) gene associated with marked short stature, severe early onset chronic lung disease resembling asthma, dysmorphic facial features, and symmetrical camptodactyly of the fingers but normal intellect. The condition has only been reported once previously (Lohr et al., American Journal of Human Genetics, 2010, 86, 447-453) in 10 children from an Old Order Amish family found to have a homozygous frameshift truncating variant in association with failure to thrive, chronic lung disease, motor and cognitive delay, and variable autoimmune diseases including autoimmune hepatitis, enteropathy, hypothyroidism, and diabetes. The condition is listed in OMIM as Autoimmune disease, Multisystem with Facial Dysmorphism (OMIM613385). The clinical course as well as the dysmorphic facial and limb features overlap closely with our patient. We believe the triad of marked syndromic short stature, chronic lung disease, and dysmorphism (with or without cognitive impairment and wider autoimmune involvement) is distinctive.

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.

Tumour compartment transcriptomics demonstrates the activation of inflammatory and odontogenic programmes in human adamantinomatous craniopharyngioma and identifies the MAPK/ERK pathway as a novel therapeutic target.

Adamantinomatous craniopharyngiomas (ACPs) are clinically challenging tumours, the majority of which have activating mutations in CTNNB1. They are histologically complex, showing cystic and solid components, the latter comprised of different morphological cell types (e.g. ß-catenin-accumulating cluster cells and palisading epithelium), surrounded by a florid glial reaction with immune cells. Here, we have carried out RNA sequencing on 18 ACP samples and integrated these data with an existing ACP transcriptomic dataset. No studies so far have examined the patterns of gene expression within the different cellular compartments of the tumour. To achieve this goal, we have combined laser capture microdissection with computational analyses to reveal groups of genes that are associated with either epithelial tumour cells (clusters and palisading epithelium), glial tissue or immune infiltrate. We use these human ACP molecular signatures and RNA-Seq data from two ACP mouse models to reveal that cell clusters are molecularly analogous to the enamel knot, a critical signalling centre controlling normal tooth morphogenesis. Supporting this finding, we show that human cluster cells express high levels of several members of the FGF, TGFB and BMP families of secreted factors, which signal to neighbouring cells as evidenced by immunostaining against the phosphorylated proteins pERK1/2, pSMAD3 and pSMAD1/5/9 in both human and mouse ACP. We reveal that inhibiting the MAPK/ERK pathway with trametinib, a clinically approved MEK inhibitor, results in reduced proliferation and increased apoptosis in explant cultures of human and mouse ACP. Finally, we analyse a prominent molecular signature in the glial reactive tissue to characterise the inflammatory microenvironment and uncover the activation of inflammasomes in human ACP. We validate these results by immunostaining against immune cell markers, cytokine ELISA and proteome analysis in both solid tumour and cystic fluid from ACP patients. Our data support a new molecular paradigm for understanding ACP tumorigenesis as an aberrant mimic of natural tooth development and opens new therapeutic opportunities by revealing the activation of the MAPK/ERK and inflammasome pathways in human ACP.

Medical management and antiepileptic drugs in hypothalamic hamartoma.

Hypothalamic hamartoma may present with epilepsy, specifically gelastic or dacrystic seizures, or endocrine dysfunction, commonly precocious puberty. The epilepsy in many patients is drug resistant, and has a high association with progressive cognitive, learning and behavioral difficulty. Medical treatment of seizures remains problematic, with many resistant to drug treatment. Surgical resection, or disconnection of the hamartoma provides the optimal chance of seizure control but with a relatively high risk of endocrine dysfunction, the result of interference with the hypothalamic-pituitary axis in many. Careful assessment and monitoring by specialist centers with discussion of optimal intervention is required for individual cases.

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.

Optic pathway glioma in children: does visual deficit correlate with radiology in focal exophytic lesions?

PURPOSE: Unlike pilocytic astrocytomas in other parts of the brain, optic pathway gliomas (OPG) are usually diffuse lesions involving the anterior optic pathways and hypothalamus. Their infiltrative nature often precludes complete surgical resection. We sought to determine whether careful magnetic resonance (MR) analysis, correlated with visual deficits, could be sufficient to identify those focal lesions that may be amenable to more aggressive surgical resection at presentation. METHODS: We retrospectively reviewed the medical records of patients from two sites: children under 20 years of age treated for OPG between 1985 and 2009 at St Jude's Children's Research Hospital and children under 16 years of age treated at Great Ormond Street Hospital, London, UK, between 1984 and 2011. Patients with isolated optic nerve tumors were excluded. Visual acuity and visual field data at presentation were reviewed and correlated with MR characteristics, including extent of optic pathway involvement, symmetry, and lateral extension. RESULTS: Two hundred and one children were treated for OPG between 1984 and 2011 in the two institutions; 74 had neurofibromatosis 1 (NF1). At presentation, visual loss was symmetrical in 132 patients and asymmetrical in 69. Potential correlation between pattern of visual loss and tumor characteristics on routine MRI was found in only 13 patients with asymmetrical vision. There was no difference between patients with and without NF1. CONCLUSION: The decision for aggressive surgical resection for optic pathway gliomas should be based on clinical criteria, particularly in children with good vision in one eye and poor vision in the other, as current MRI results do not reliably predict visual field deficits.

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 new era for optic pathway glioma: A developmental brain tumor with life-long health consequences.

Optic pathway and hypothalamic glioma (OPHG) are low-grade brain tumors that arise from any part of the visual pathways frequently involving the hypothalamus. The tumors grow slowly and present with features driven by their precise anatomical site, their age at presentation and the stage of growth and development of the host neural and orbital bony tissues. Up to 50% of optic pathway glioma arise in association with Neurofibromatosis type 1 (NF1), which affects 1 in 3,000 births and is a cancer predisposition syndrome. As low-grade tumors, they almost never transform to malignant glioma yet they can threaten life when they present under two years of age. The main risks are to threaten vision loss by progressive tumor damage to optic pathways; furthermore, invasion of the hypothalamus can lead to diencephalic syndrome in infancy and hypopituitarism later in life. Progressive cognitive and behavioural dysfunction can occur, as part of NF1 syndromic features and in sporadic cases where large bulky tumors compress adjacent structures and disrupt neuro-hypothalamic pathways. Persistently progressive tumors require repeated treatments to attempt to control vision loss, other focal brain injury or endocrine dysfunction. In contrast tumors presenting later in childhood can be seen to spontaneously arrest in growth and subsequently progress after periods of stability. These patterns are influenced by NF status as well as stages of growth and development of host tissues. The past two decades has seen an expansion in our understanding and knowledge of the clinical and scientific features of these tumors, their modes of presentation, the need for careful visual and endocrine assessment. This influences the decision-making surrounding clinical management with surgery, radiotherapy, chemotherapy and most recently, the potential benefit of molecularly targeted drug therapy. This article, based upon the authors' clinical and research experience and the published literature will highlight advances in approach to diagnosis, the established role of vision loss as justification of treatments and the emerging evidence of endocrine and neurological consequences that need to be incorporated into judgements for case selection for therapy or observation. Consideration is given to the current state of biological evidence justifying current trials of new therapies, the genetic studies of the NF1 gene and the potential for new approaches to OPHG detection and treatment. The outstanding health system priorities from the perspective of children, their parents and health system commissioners or insurers are discussed.

National UK guidelines for the management of paediatric craniopharyngioma.

Although rare, craniopharyngiomas constitute up to 80% of tumours in the hypothalamic-pituitary region in childhood. Despite being benign, the close proximity of these tumours to the visual pathways, hypothalamus, and pituitary gland means that both treatment of the tumour and the tumour itself can cause pronounced long-term neuroendocrine morbidity against a background of high overall survival. To date, the optimal management strategy for these tumours remains undefined, with practice varying between centres. In light of these discrepancies, as part of a national endeavour to create evidence-based and consensus-based guidance for the management of rare paediatric endocrine tumours in the UK, we aimed to develop guidelines, which are presented in this Review. These guidelines were developed under the auspices of the UK Children's Cancer and Leukaemia Group and the British Society for Paediatric Endocrinology and Diabetes, with the oversight and endorsement of the Royal College of Paediatrics and Child Health using Appraisal of Guidelines for Research & Evaluation II methodology to standardise care for children and young people with craniopharyngiomas.

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.

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 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.

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.

Treating papillary and follicular thyroid cancer in children and young people: Single UK-center experience between 2003 and 2018.

AIM: Differentiated thyroid cancer (DTC) in children and adolescents is rare and data about its presentation and management are not well known. The aim of this study was to provide evidence of the current practice in the United Kingdom before the launch of the Rare National Paediatric Endocrine Tumours Guidelines (to be published in 2020). METHODS: Seventy-two children and adolescents with DTC (<18 years) who were treated at our institution between 2003 and 2018 were identified and their presentation, treatment and outcomes were reviewed. RESULTS: Median age at presentation was 12.7 years [range: 1-18] and fifty-two (72%) were girls. Fifty (69.4%) children and adolescents presented with a thyroid nodule. Thirteen (18%) had cervical adenopathy and seven of them (54%) underwent an excision biopsy under GA. Eight patients (11%) had evidence of lung metastases at presentation. Twenty-four patients (33%) underwent a hemithyroidectomy and 22 of those had a completion thyroidectomy subsequently, ten (14%) a total thyroidectomy alone and 37 (51%) a total thyroidectomy with lymph nodes dissection. Seventy patients (97%) underwent adjuvant RAI at our institution. The median number of children and adolescents managed per year was five [range: 0-10]. After an overall median follow-up of 40 months, eight patients (11%) had developed recurrent disease. The 1- and 5-year recurrence-free-survival-rates were 93% and 87%, respectively. Overall survival was 100%, with eight children and adolescents (11%) being alive with disease. CONCLUSION: This study confirms that DTC in children and adolescents is uncommon, is frequently advanced at presentation and has considerable recurrence rates. Despite this, overall survival is excellent. Although the work-up was generally appropriate (image-guided cytology), open biopsy for the diagnosis of lymph node involvement was still employed. The introduction of a specific UK guideline for this age-group will likely result in more tailored-made treatment-pathways and thereby hopefully improve quality and outcomes even further. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level IV.

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.

Paediatric neuro-oncology rehabilitation in the UK: carer and provider perspectives.

OBJECTIVE: The provision of rehabilitation services after childhood brain tumour has not been established, despite a recent parliamentary call for urgent action. This service evaluation aimed to determine what specialist paediatric neuro-oncology rehabilitation services were available across the UK at the time of the surveys and whether the needs of patients and their families were being met. DESIGN: Cross-sectional on-line surveys. PARTICIPANTS: Survey 1: neuro-oncologist and nurse specialist members of the Children's Cancer and Leukaemia Group (CCLG) at Children's Principle Treatment Centres (PTCs) in the UK; Survey 2: parents of paediatric neuro-oncology patients belonging to The Brain Tumour Charity (TBTC) Research Involvement Network (RIN). RESULTS: 17 of the 20 (85%) PTCs in the UK and two teenagers and young adult cancer units responded to Survey 1, and 17 members of TBTC's RIN responded to Survey 2. Access to inpatient and outpatient neuro-oncology rehabilitation services after treatment for a central nervous system (CNS) tumour varied across regions in the UK. Service users in the RIN identified a need for an established neuro-oncology rehabilitation service for young people, a need for better communication across services and with families, and a need to fill gaps in multidisciplinary teams. CONCLUSION: The urgent need for specialist paediatric, teenage and young adult neuro-oncology rehabilitation services in the UK is often unmet, particularly for outpatients. Where services are not provided for those children and young people disadvantaged by the diagnosis of a CNS tumour, in clear breach of current guidelines, remedial action needs to be taken to ensure appropriate and equal access.