Preserving reproductive capacity in young boys with cancer

In this article, the authors explore the possibilities and particular developmental and ethical issues surrounding sperm cryopreservation in young boys with cancer, and examine the unique legal implications of fertility counselling in adolescence

Chapter 11a: Pituitary and hypothalamic tumour syndromes in childhood

Central nervous system (CNS) tumours are the second commonest childhood malignancy. and survial has increased as a result of improved multimodality cancer therapies and better supportive care. Measurements of PRL, AFP and β-hCG are essential prior to commencement of any therapy. Craniopharyngiomas and low grade gliomas account for most tumors, while pituitary adenomas are rare. Non-neoplastic masses include pituitary hyperplasia and Rathke’s cleft cysts. Neurological syndromes and endocrine dysfunction must be recognized both before treatment and after. Both the original tumor and its treatment may disturb GH secretion, cause gonadotophin deficiency, or Posterior Pituitary Dysfunction, and less commonly reduce thyroid or adrenal function. The “hypothalamic syndrome” including variable hypothalamic dysfunction and morbid obesity is a common sequelae of surgical treatment, presumably caused by dysregulation of anorexigenic and orexigenic hormone signals

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

Long-term follow-up of survivors of childhood cancer (SIGN Clinical Guideline 132)

Five-year childhood cancer survival rates have increased to 80–90% for some tumours due to intensified treatments and better supportive care imposed on an incidence stable over four decades.1 ,2 Between 2005 and 2012, the number of UK survivors has risen from 26 000 to 33 000, or from 1:1000 to 1:715 UK adults.3 ,4 However, 40% experience chronic severe or life-threatening consequences (‘late effects’) of their tumour and/or its treatment.5 The recent National Cancer Survivorship Initiative (NCSI) has highlighted the unmet need in service provision for adult childhood cancer survivors, with a proposed survivorship framework and stratified care pathways modelled on >20 years’ prior experience.6 ,7 In March 2013, the Scottish Intercollegiate Guidelines Network (SIGN) published updated guidance on long-term follow-up of childhood cancer survivors to aid the ‘identification, assessment and management of late effects’ aimed at primary, secondary and tertiary healthcare practitioners.8 The Guideline Development Group (GDG) included representatives from paediatric haematology, oncology, endocrinology, reproductive medicine, cardiology, general paediatrics and general practice, as well as a survivor

Treatment-resistant pediatric giant prolactinoma and multiple endocrine neoplasia type 1

Background Pediatric pituitary adenomas are rare, accounting for <3 % of all childhood intracranial tumors, the majority of which are prolactinomas. Consequently, they are often misdiagnosed as other suprasellar masses such as craniopharyngiomas in this age group. Whilst guidelines exist for the treatment of adult prolactinomas, the management of childhood presentations of these benign tumors is less clear, particularly when dopamine agonist therapy fails. Given their rarity, childhood-onset pituitary adenomas are more likely to be associated with a variety of genetic syndromes, the commonest being multiple endocrine neoplasia type 1 (MEN-1). Case description We present a case of an early-onset, treatment-resistant giant prolactinoma occurring in an 11-year-old peripubertal boy that was initially sensitive, but subsequently highly resistant to dopamine agonist therapy, ultimately requiring multiple surgical debulking procedures and proton beam irradiation. Our patient is now left with long-term tumor- and treatment-related neuroendocrine morbidities including blindness and panhypopituitarism. Only after multiple consultations and clinical data gained from 20-year-old medical records was a complex, intergenerationally consanguineous family history revealed, compatible with MEN-1, with a splice site mutation (c.784-9G > A) being eventually identified in intron 4 of the MEN1 gene, potentially explaining the difficulties in management of this tumor. Genetic counseling and screening has now been offered to the wider family. Conclusions This case emphasizes the need to consider pituitary adenomas in the differential diagnosis of all pediatric suprasellar tumors by careful endocrine assessment and measurement of at least a serum prolactin concentration. It also highlights the lack of evidence for the optimal management of pediatric drug-resistant prolactinomas. Finally, the case we describe demonstrates the importance of a detailed family history and the role of genetic testing for MEN1 and AIP mutations in all cases of pediatric pituitary adenoma

Neuroendocrine morbidity after pediatric optic gliomas: a longitudinal analysis of 166 children over 30 years

Context: 50% of pediatric low-grade gliomas affect the optic pathway, hypothalamus and suprasellar areas (OP/HSGs) resulting in significant long-term neuroendocrinopathy. Objective: To dissect tumor- from treatment-related risk factors for OP/HSG-associated neuroendocrinopathy. Design: Retrospective case notes analysis of 166 children with newly-diagnosed OP/HSGs at our quaternary center between 1980 –2010 by multivariate Cox, linear and logistic regression. Results: Patients were of median (range) age 4.9 (0.2–15.4) years at diagnosis and followed up for 8.3 (0.04 –26.8) years. Despite high 20-year overall survival (81.0%), progression-free and endocrine event-free (EEFS) survival were 47.2% and 20.8% respectively. EEFS declined up to 15 years postdiagnosis, with hypothalamic involvement (p0.001) being implicated more than radiotherapy (p0.008) in earlier endocrinopathy; the reverse being true of its density (radiotherapy p0.001; hypothalamic involvement p0.006). GH deficiency (GHD) was commonest (40.3%), followed by central precocious puberty (CPP, 26.0%), gonadotropin (GnD, 20.4%), TSH (13.3%), and ACTH (13.3%) deficiencies. GHD increased with later treatment eras (p0.01), but replacement did not increase progression. CPP was associated with future GnD (p0.05). Posterior pituitary dysfunction (PPD, 7.2%) occurred in 57.9% after only biopsies or shunt procedures, and was associated with 6/13 deaths. 50.2% became obese. Tumor extent, surgery and increased endocrinopathy, rather than radiotherapy, predicted visuo-cognitive morbidity. Conclusions: This first longitudinal OP/HSG-specific study demonstrates that hypothalamo-pituitary dysfunction evolves hierarchically over decades. Tumor location predicts its speed of onset and radiotherapy its density. GnD can evolve from previous CPP, whilst life-threatening PPD can occur after any surgery. Our data suggest that recent radiation-avoiding chemotherapeutic strategies have increased GHD without improving survival

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

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

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

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

A single-center, observational study of 607 children & young people presenting with Differences in Sex Development (DSD)

Context Differences in 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. Design A retrospective, observational cohort study was undertaken of all children and young people (CYP) referred to a DSD multi-disciplinary team over 25 years (1995-2019). Setting A single tertiary paediatric center. Participants In total, 607 CYP (520 regional referrals) were included. Main Outcome Measures Data were analyzed for diagnosis, sex-assignment, age and mode of presentation, additional phenotypic features, mortality, and approximate point prevalence. Results Amongst the three 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 herniae. 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 6,347 births, and 1 in 5,101 overall throughout childhood. Conclusions DSD represent a diverse range of conditions that can present at different ages. Pathways for expert diagnosis and management are important to optimize care