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.

Hypogonadotropic hypogonadism due to variants in RAB3GAP2: expanding the phenotypic and genotypic spectrum of Martsolf syndrome.

Biallelic pathogenic variants in RAB3GAP2 cause Warburg Micro syndrome (WARBM) and Martsolf syndrome (MS), two rare, phenotypically overlapping disorders characterized by congenital cataracts, intellectual disability, and hypogonadism. Although the initial report documented hypergonadotropic hypogonadism (implying a gonadal defect), an adolescent girl with WARBM/MS was subsequently reported to have hypogonadotropic hypogonadism (implying a central defect in either the hypothalamus or anterior pituitary). However, in adult MS, hypogonadotropism has not been convincingly demonstrated. Additionally, the correlation between the pathogenic severity of variants in RAB3GAP2 and the phenotypic severity also remains unclear. Here we present a clinical report of a woman with congenital cataracts, apparent intellectual disability, and pubertal failure who underwent exome sequencing (ES) to determine a precise molecular diagnosis. Reproductive phenotypes reported previously in individuals with MS and the genotypic spectrum of previous RAB3GAP2 variants were also reviewed. The ES identified pathogenic compound heterozygous RAB3GAP2 variants (c.387-2A > G; p.(Arg428Glu)) combined with her phenotypic features, which enabled a unifying molecular diagnosis of MS. Reproductive evaluation confirmed a normosmic idiopathic hypogonadotropic hypogonadism. Review of the RAB3GAP2 allelic spectrum in WARBM/MS suggests that although variants resulting in complete abrogation of RAB3GAP2 protein function cause severe WARBM, variants associated with partially preserved RAB3GAP2 function cause milder MS. This report expands the genotypic and phenotypic spectrum of MS and demonstrates hypogonadotropic hypogonadism as a key pathophysiologic abnormality in MS. Genotype-phenotype associations of previously reported RAB3GAP2 variants indicate that variants that fully abolish RAB3GAP2 function result in WARBM, whereas MS is associated with variants of lesser severity with residual RAB3GAP2 function.

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis.

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING: The study was conducted at university hospitals. PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME: Outcomes included genetic screening and clinical characteristics. RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

Uncertainties in endocrine substitution therapy for central hypocortisolism.

Central hypocortisolism is common, and has multiple potential causes. However, the treatment aims remain the same whatever the cause: to maximize quality of life, while minimizing treatment-related adverse effects. The majority of patients with central hypocortisolism now receive hydrocortisone in two to three divided doses with a total daily dose of 10-20mg, or a weight-based regimen of 8.1mg/m(2)/day. However, various areas of controversy remain: how to assess the patient with suspected hypocortisolism, which is the optimal agent to use, what is the optimal total daily dose, how to administer divided daily doses, how to monitor therapy and individually tailor doses, whether to replace other adrenal androgens, how to approach the patient with adrenal suppression, and how to best educate patients with hypocortisolism and treat them in emergency situations. This chapter will discuss the evidence behind each of these controversial areas in turn. The evidence for newer agents such as prolonged- and delayed-release preparations of hydrocortisone will also be explored, with a discussion on their potential role in the future management of this major clinical problem.

Focal radiation therapy for patients with persistent/recurrent pituitary adenoma, despite previous radiotherapy.

With the stricter endocrine definitions of cure following conventionally planned and fractionated radiotherapy for functioning pituitary adenomas, together with the move in the profession (since the advent of high quality MRI) to postpone radiation therapy until macroscopic disease appears after surgery, it is now realised that cure rates following conventional radiotherapy approximate three out of four rather than the >90% cited for more than a decade. Patients with persistent active tumours may be successfully further treated by focal radiation therapy by one of the stereotactic focal techniques. We have experience of such re-treatment radiation therapy in 50 patients. With careful case selection, we here demonstrate that in acromegaly, for example, normalisation of both GH and IGF levels may be achieved in 37-58% of these previously irradiated patients with low risk of late morbidity. Unquestionably, growth delay occurs in many cases but the long term tumour control rate has yet to be established.

Constitutive activation of the human ACTH receptor resulting from a synergistic interaction between two naturally occurring missense mutations in the MC2R gene.

Two mutations in the same allele of the ACTH receptor (melanocortin 2 receptor, MC2R) associated with clinical hypersensitivity to ACTH have been described in a single case report. Using a stable Y6 cell expression system, we demonstrate that either the C21R or S247G mutations alone produce an inactive receptor with loss of ligand binding and responsiveness. However, the presence of both mutations in the same molecule leads to a receptor with a highly significant elevation in constitutive activity (basal cAMP accumulation for wild type expressing cells 199 +/- 11 pmol/mg protein; double mutant: 374 +/- 29 pmol/mg protein, P < 0.005. The co-expression of the normal MC2R allele results in the retention of a normal dose response to ACTH despite the presence of constitutive activity.

Expression, desensitization, and internalization of the ACTH receptor (MC2R).

Research into the functions and mechanisms of action of the melanocortin 2 receptor (MC2R) has been severely hampered by difficulties in expressing this gene in heterologous cells. This probably arises because of the need for a cofactor for cell surface expression. Using either the Y1 cell line that expresses endogenous MC2R or the Y6 cell line that expresses this putative expression factor, we have explored the mechanisms of desensitization and internalization after agonist stimulation. Protein kinase A dependence of desensitization has been demonstrated, although internalization is apparently independent of this kinase and dependent on a G protein receptor kinase. Possible underlying reasons for this paradox are discussed.

Impaired desensitization of a mutant adrenocorticotropin receptor associated with apparent constitutive activity.

A naturally occurring ACTH receptor [melanocortin 2 receptor (MC2R)] mutation (F278C) has been identified in a subject with ACTH-independent Cushing's syndrome. Functional characterization of this mutant receptor reveals that it is associated with elevated basal cAMP accumulation when compared with wild-type receptor-expressing cell lines. Dose responsiveness is similar between wild-type and mutant receptors in cell lines expressing similar numbers of binding sites. In view of the location of this mutation in the C-terminal tail of the MC2R, desensitization and internalization were investigated and found to be impaired. Inhibition of protein kinase A by H89 blocks wild-type MC2R desensitization and also results in increased basal activity, as does alanine substitution of Ser 280 in the C-terminal tail. Alanine substitution of Ser 208, the consensus protein kinase A phosphorylation target in the third cytoplasmic loop also results in a reduction in desensitization without significant change in basal activity or internalization. These findings suggest a novel mechanism is involved in the apparently constitutive activation of the MC2R in which failure of desensitization appears to be associated with enhanced basal receptor activity.