Diaphragm reconstruction using a TachoSil patch as alternative to intrasellar packing for small focal diaphragm defects in pituitary surgery: a cohort study.

BACKGROUND: During pituitary surgery, CSF leaks are often treated by intrasellar packing, using muscle or fat grafts. However, this strategy may interfere with the interpretation of postoperative MRI and may impact the quality of resection in cases of second surgery, due to the existence of additional fibrous tissue. We present an alternative technique, using a diaphragm reconstruction with a heterologous sponge combining fibrinogen and thrombin (TachoSil), applied in selected patients with low-flow CSF leaks. This study investigates the surgical outcome of patients treated with this strategy. METHODS: From a cohort of 2231 patients treated from June 2011 to June 2023 by endoscopic endonasal approach for pituitary surgery, the surgical technique of diaphragm repair with TachoSil patch performed in 55 patients (2.6%) was detailed, and the rate of closure failure was analyzed at 6 months postoperatively. No intrasellar packing was used and sellar floor reconstruction was performed whenever possible. The rate of postoperative CSF leak was compared with that reported in three previous publications that also used the TachoSil patch technique. RESULTS: Patients were mostly women (F/M ratio: 1.2) with a median age of 53.6 years. Surgery was indicated for non-functioning adenomas, Cushing's disease, acromegaly, and Rathke's cleft cysts in 38/55 (69.1%), 6/55 (10.9%), 5/55 (9.1%) and 6/55 (10.9%) patients respectively. The rate of postoperative CSF leak was 1.8% (n = 1/55), which was not significantly different from that reported in the three cohorts from the literature (2.8%, p > 0.05). No postoperative meningitis was recorded. CONCLUSIONS: In highly selected patients with low-flow CSF leaks related to small focal diaphragm defects, diaphragm reconstruction using a TachoSil patch can be a safe and valuable alternative to intrasellar packing.

Endoscopic endonasal access to the lateral recess of the sphenoid sinus.

BACKGROUND: The standard endoscopic endonasal approach gives access to the median sphenoid sinus, but not to its lateral part. We propose an endoscopic technique for lesions in the lateral sphenoid sinus. METHOD: Based on our experience with 28 patients, we have developed a less invasive approach to the lateral recess of the sphenoid sinus, limiting the opening of the maxillary sinus while avoiding resection of the inferior turbinate and ethmoidal cells. The technique is described. CONCLUSION: The proposed endoscopic approach is reliable and safe to treat CSF leak or tumours located within the lateral recess of the sphenoid sinus.

Pituitary surgery outcome in patients 75 years and older: a retrospective study.

BACKGROUND: As the population ages, the number of elderly patients with an indication for pituitary surgery is rising. Information on the outcome of patients aged over 75 is limited. This study reports a large series assessing the feasibility of surgical resection in this specific age range, focusing on surgical complications and postoperative results. METHODS: A retrospective cohort study of patients with pituitary adenomas and Rathke's cleft cysts was conducted. All patients were aged 75 years or over and treated by a single expert neurosurgical team. A control population included 2379 younger adult patients operated by the same surgeons during the same period. RESULTS: Between 2008 and 2022, 155 patients underwent surgery. Indication was based on vision impairment in most patients (79%). Median follow-up was 13 months (range: 3-96). The first surgery was performed with an endoscopic transsellar approach, an extended endonasal transtuberculum approach and a microscopic transcranial approach in 96%, 3%, and 1% of patients, respectively. Single surgery was sufficient to obtain volume control in 97% of patients. From Kaplan-Meier estimates, 2-year and 5-year disease control with a single surgery were 97.3% and 86.2%, respectively. Resection higher than 80% was achieved in 77% of patients. No vision worsening occurred. In acromegaly and Cushing's disease, endocrine remission was obtained in 90% of non-invasive adenomas. Surgical complications were noted in 5% of patients, with 30-day mortality, hematoma, cerebrospinal fluid leak, meningitis, and epistaxis occurring in 0.6%, 0.6%, 1.9%, 0.6%, and 1.3% respectively. New endocrine anterior deficits occurred in only 5%, while no persistent diabetes insipidus was noted. Compared with younger patients, the complication rate was not statistically different. CONCLUSIONS: Surgery beyond the age of 75, mainly relying on an endoscopic endonasal transsellar approach, is effective and safe, provided that patients are managed in tertiary centers.

Expanded endoscopic endonasal approach for the resection of midline craniopharyngiomas with hypothalamic involvement.

BACKGROUND: With relevant surrounding neurological structures and potential involvement of the hypothalamus, the surgical management of craniopharyngiomas is complex. Compared to the transcranial approach, the expanded endoscopic endonasal approach provides direct access to the supradiaphragmatic and retrochiasmatic areas without crossing nerves and arteries. METHOD: Based on our substantial experience of 68 patients operated on between 2008 and 2022 by endoscopic surgery, our strategy has evolved such that all of our midline infundibular craniopharyngiomas with hypothalamic involvement are currently treated with an expanded endonasal route, except for tumours isolated to the third ventricle. Vascularized mucosal nasoseptal flaps are required for closure. Fine details of the related anatomy and surgical technique are described. CONCLUSION: Expanded endoscopic endonasal approach is a safe and effective route for resection of midline suprasellar craniopharyngiomas with hypothalamic involvement in centres of expertise.

Double pedicled nasoseptal flap for skull base repair after endoscopic expanded endonasal approach.

BACKGROUND: Expanded endonasal approach offers a spectacular corridor for skull base tumour resection but requires reliable multilayer reconstruction techniques with a vascularized nasoseptal flap. METHOD: On the basis on our substantial experience of 136 patients operated on between January 2008 and January 2020, the double pedicled nasoseptal flap technique was developed for skull base repair. The technique is finely detailed. The nasal floor mucosa was preserved. CSF leakage occurred in 4% of patients. CONCLUSION: Double pedicled nasoseptal flap is a reproducible and efficient technique for skull base reconstruction after expanded endonasal approach and is associated with limited rhinological complications.

Pituitary surgery for Cushing's disease.

BACKGROUND: Surgery is currently the first-line treatment of Cushing's disease. Surgery for Cushing's patients requires technical specificity, especially if no adenoma is identified on dedicated preoperative pituitary MRI. METHOD: From 2006 to 2020, 683 patients with Cushing's disease were operated on with a mononostril endoscopic endonasal approach by the same two senior neurosurgeons. Here, we report the particularities of this challenging surgery. CONCLUSION: A rigorous and planned surgical strategy avoids the pitfalls of Cushing's disease surgery and leads to a high rate of endocrine remission.

Mononostril endoscopic endonasal approach for pituitary surgery.

BACKGROUND: Most surgical teams currently consider that endoscopy has become the "gold standard" technique for the transsphenoidal approach to pituitary surgery. Pituitary adenomas are commonly benign tumours and should benefit from the least invasive approach. METHOD: In Foch Hospital, from 2006 to 2020, 2835 patients with pituitary adenomas were treated with a mononostril endoscopic endonasal approach. Here we describe the fine details of the nasal, sphenoidal and sellar steps of this technique. CONCLUSION: Complete preservation of the nasal corridor, luxation of the nasal septum and tailored sellar bone resection are essential for safe resection of pituitary adenomas.

Efficacy of endoscopic endonasal transsphenoidal surgery for Cushing's disease in 230 patients with positive and negative MRI.

OBJECT: The primary objective was to assess the remission rate, and the secondary objectives were to evaluate the early complications and recurrence rate and to define the predictive factors for the remission and recurrence rates. PATIENTS AND METHODS: This prospective single-center study included 230 consecutive patients, operated on by a single surgeon for Cushing's disease via a transsphenoidal endoscopic endonasal approach, over a 6-year period (2008-2013). The patients included in this series were all adults (>18 years of age), who presented with clinical and biological characteristics of Cushing's disease confirmed based on dedicated MRI pituitary imaging. Biochemical remission was defined as a postoperative serum cortisol level <5 µg/dl on the 2nd day following surgery that required glucocorticoid replacement therapy. RESULTS: The remission rate for the global population (n = 230) with a follow-up of 21 ± 19.2 months concerned 182 patients (79.1%) divided into 132 patients (82.5%) with positive MRI and 50 patients (71.4%) with negative MRI with no statistically significant difference (p = 0.077). Complications occurred in 77 patients with no deaths. A total of 22% of patients had transient diabetes insipidus and 6.4% long-term diabetes insipidus, and no postoperatively CSF leakage was observed. The recurrence rate was 9.8% with a mean time of 32.7 ± 15.2 months. The predictive factors for the remission rate were the presence of pituitary microadenoma and a positive histology. No risk factors were involved regarding the recurrence rate. CONCLUSION: Whatever the MRI results, the transsphenoidal endonasal endoscopic approach remains the gold standard treatment for Cushing's disease. It was maximally effective with a remission rate of 79.1% and lower morbidity.

Silent, but not unseen: multimicrocystic aspect on T2-weighted MRI in silent corticotroph adenomas.

OBJECTIVE: Silent corticotroph adenomas (SCAs) present as nonfunctional pituitary tumours in routine pre-operative evaluation. The objective of this study was to evaluate the diagnostic accuracy of MRI T2-weighted sequences for detecting the corticotroph subtype pre-operatively. DESIGN: The pre-operative T2-weighted MRI sequences were retrospectively evaluated in patients with SCA and two control groups: clinically manifest corticotroph macroadenomas (CSMs) and nonfunctional gonadotroph macroadenomas (NFGMs). All were selected from a registry of 1096 patients in whom transsphenoidal surgery was performed in the same tertiary reference centre. T2-weighted MRI sequences were independently classified by one senior endocrinologist and one senior radiologist who were blinded to the clinical and histological features. PATIENTS: Seventeen patients with SCA, 14 with CSM and 60 with NFGM were included in this study. MEASUREMENTS: Pituitary MRI with T2-weighted sequences. Two aspects were retained: multiple microcysts (MMs) and the absence of microcysts. Hormonal data included plasma prolactin, IGF-1, testosterone or oestradiol, LH, FT4, TSH, morning plasma cortisol and an ACTH-stimulation test, when available. RESULTS: Multiple microcysts were present in 76% (13/17) of SCAs, 21% (3/14) of CSMs and 5% (3/60) of NFGMs. The presence of MMs in clinically nonfunctioning macroadenomas had a sensitivity of 76% and a specificity of 95% for predicting SCA. CONCLUSION: The presence of MMs in T2-weighted MRI is a good diagnostic tool to suggest the corticotroph subtype in an apparently nonfunctional pituitary tumour.

Gonadotropic status in adult women with pituitary stalk interruption syndrome.

OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is a rare cause of congenital hypopituitarism. Limited data exist on the gonadotropic status and fertility of adult women with PSIS. Our study aims to describe pubertal development and the evolution of gonadotropic function and fertility in adult women with PSIS. DESIGN: A retrospective multicentric French study. METHODS: We described gonadotropic function in 56 adult women with PSIS from puberty onward. We compared live birth rates per woman with PSIS with age-matched controls from the large French epidemiological cohort (CONSTANCES). Additionally, we assessed height, body mass index (BMI), blood pressure, other metabolic parameters, and socioeconomic status. RESULTS AND CONCLUSIONS: Among 56 women with PSIS, 36 did not experience spontaneous puberty. Of these, 13 underwent ovarian stimulation, resulting in 7 women having a total of 11 children. In the subgroup with spontaneous puberty (n = 20), 4 had a total of 8 pregnancies, while 6 developed secondary gonadotropic deficiency. Women with PSIS had fewer children than controls (0.33 vs 0.63, P = .04). Median height was also lower (160.5 vs 165.0 cm, P < .0001). Although mean blood pressure was lower in women with PSIS compared with controls (111.3/65.9 ± 11.2/8.1 vs 118.7/72.1 ± 10.1/7.7 mmHg, P < .001), there were no significant differences in other metabolic parameters, notably BMI and lipid profile. Employment/academic status was not different in the 2 groups, but fewer women with PSIS were in relationships (42% vs 57.6% in controls, P = .02). The fertility prognosis in patients with PSIS needs optimization. Patients should be informed about the likelihood of declining gonadotropic function over time.

Prognostic impact of hypothalamic perforation in adult patients with craniopharyngioma: a cohort study.

CONTEXT: Outcome of craniopharyngioma is related to its locoregional extension, which impacts resectability and the risk of surgical complications. To maximize resection and minimize complications, optic tract localization, temporal lobe extension and hypothalamic involvement are essential for surgical management. OBJECTIVE: To assess the outcome of craniopharyngiomas depending on their relation to the hypothalamus location. METHODS: We conducted a retrospective analysis of 79 patients with a craniopharyngioma who underwent surgery from 2007 to 2022. Craniopharyngiomas were classified in three groups, depending on the type of hypothalamus involvement assessed by preoperative MRI: infra-hypothalamic (type A, n=33); perforating the hypothalamus (type B, n=40); supra-hypothalamic (type C, n=6). Surgical strategy was guided by the type of hypothalamic involvement, favoring endonasal approaches for type A and type B, and transcranial approaches for type C. RESULTS: Long-term disease control was achieved in 33/33 (100%), 37/40 (92%) and 5/6 (83%) patients in type A, B and C respectively. In type B, vision was improved in 32/36 (89%) patients, while hypothalamic function was improved, stable or worsened in 6/40 (15%), 32/40 (80%) and 2/40 (5%) patients respectively. Papillary craniopharyngiomas were found in 5/33 (15%), 9/40 (22%) and 3/6 (50%) patients in types A, B and C respectively. In four patients, BRAF/MEK inhibitors were used, with significant tumor shrinkage in all cases. CONCLUSION: Craniopharyngiomas located below the hypothalamus or perforating it can be safely treated by transsphenoidal surgery. For supra-hypothalamic craniopharyngiomas, postoperative results are less favorable, and documenting a BRAF-mutation may improve outcome, if targeted therapy was efficient enough to replace surgical debulking.

PIT-EASY survey: validation of the European Pituitary Pathology Group proposal for reporting pituitary neuroendocrine tumors.

The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for pituitary neuroendocrine tumors (PitNETs) to improve the quality of their histological diagnosis. Each center performed at least 30 histological cases of PitNETs using the EPPG tools and assessed their value using a scorecard with 10 questions. For each center, the histological cases were carried out by pathologists with varying levels of expertise in pituitary pathology defined as junior, intermediate, and expert. Two hundred and ninety histological cases were collected from six French and Italian centers. The three EPPG tools were validated and regarded as helpful for a more accurate and time-efficient diagnosis. The usefulness of level 2 and level 3 of the "EPPG's multi-step approach for immunohistochemistry" including pituitary transcription factors (PIT1, TPIT, and SF1) and chromogranin, SSTRs, and P53 respectively was higher in "other non-functioning" (silent plurihormonal PIT1, silent corticotroph, and null cell): 88% vs 32%, p < 10-6 and 42% vs 14%, p = 0.002, respectively. The diagnostic algorithm proved more useful for junior pathologists (p = 0.0001) and those with intermediate experience. PIT-EASY survey confirmed the importance of a standardized approach to PitNETs for an accurate and reproducible diagnosis and served as validation of the EPPG proposal. The tool appeared to be of practical value to junior participants and staff with intermediate experience for safe routine diagnostic reporting.

A suggested protocol for the endocrine postoperative management of patients undergoing pituitary surgery.

PURPOSE: Endocrine disorders are the most frequent postoperative complications in patients undergoing pituitary surgery. Given the absence of recent guidelines on the postoperative care following pituitary surgery, this article summarizes the available evidence on the topic. METHOD: We conducted a systematic search of PubMed up to 2021 and updated the search in December 2022. We retrieved 119 articles and included 53 full-text papers. RESULTS: The early postoperative care consists of the assessment for cortisol deficiency and diabetes insipidus (DI). Experts suggest that all patients should receive a glucocorticoid (GC) stress dose followed by a rapid taper. The decision for GC replacement after discharge depends on the morning plasma cortisol level on day 3 after surgery. Experts suggest that patients with a morning plasma cortisol<10 mcg/dL should receive GC replacement at discharge, and those with 10-18 mcg/dL a morning dose only, with formal assessment of the hypothalamic-pituitary-adrenal axis at week 6 postoperatively. When the cortisol level is>18 mcg/dL, the patient can be discharged safely without GC, as suggested by observational studies. Postoperative care also includes a close monitoring of water balance. If DI develops, desmopressin is used only in case of uncomfortable polyuria or hypernatremia. The assessment of other hormones is indicated at 3 months postoperatively and beyond. CONCLUSION: The evaluation and treatment of patients following pituitary surgery are based on expert opinion and a few observational studies. Further research is needed to provide additional evidence on the most appropriate approach.

The World Health Organization classifications of pituitary neuroendocrine tumours: a clinico-pathological appraisal.

The classification of tumours of the pituitary gland has recently been revised in the 2021 5th edition World Health Organization (WHO) Classification of Central Nervous System Tumours (CNS5) and 2022 5th edition WHO Classification of Endocrine and Neuroendocrine Tumours (ENDO5). This brief review aims to appraise the most relevant changes and updates introduced in the two classifications. A new nomenclature has been introduced in CNS5 and ENDO5 to align adenohypophyseal tumours with the classification framework of neuroendocrine neoplasia. The term pituitary neuroendocrine tumour (PitNET) with subtype information has therefore been adopted and preferred to adenoma. Pituitary carcinoma has been replaced by metastatic PitNET. The ICD-O coding has been changed from benign to malignant in line with NETs from other organs. Histological typing and subtyping based on immunohistochemistry for lineage-restricted pituitary transcription factors are regarded as the cornerstone for accurate classification. Such an approach does not fully reflect the complexity and dynamics of pituitary tumorigenesis and the variability of transcription factors expression. ENDO5 does not support a grading and/or staging system and argues that histological typing and subtyping are more robust than proliferation rate and invasiveness to stratify tumours with low or high risk of recurrence. However, the prognostic and predictive relevance of histotype is not fully validated. Recent studies suggest the existence of clinically relevant molecular subgroups and emphasize the need for a standardized, histo-molecular integrated approach to the diagnosis of PitNETs to further our understanding of their biology and overcome the unsolved issue of grading and/or staging system.

Proton therapy for adult craniopharyngioma: Experience of a single institution in 91 consecutive patients.

BACKGROUND: Craniopharyngioma (CP) in adults is a rare benign tumor associated with many morbidities, with limited contemporary studies to define treatment, and follow-up guidelines. METHODS: A single-center retrospective study was conducted on patients aged ≥ 18 years from 2006-2018 with CP and who were treated with proton therapy (PT). Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS), local recurrence-free survival (LRFS), and toxicity were characterized using Kaplan-Meier and Cox regression analyses. RESULTS: Ninety-one patients met the criteria, with a median age of 37 years (range 18-82 years). PT was conducted after tumor resection in 88 patients (97%), in 64 patients (70.3%) as an adjuvant strategy and in 27 (29.7%) after recurrent disease. Three patients received exclusive PT. A median MRI follow-up of 39 months revealed 35.2% complete response, 49.5% partial response, and 9.9% stable disease. Five patients developed local recurrence (LR). The pattern of failure study showed that these five LR were within the GTV volume. The 5-year LRFS was 92.0% [CI 95% 84.90-99.60]. All the patients were alive at the end of the follow-up. Patients requiring treatment adaptation during PT tend to have a higher risk of LR (P = .084). Endocrinopathy was the most frequent grade ≥ 2 late toxicity. Among patients who were symptom-free before the start of treatment, none developed hearing toxicity but four (9.8%) developed visual disorders and 10 (11.3%) symptomatic memory impairment. Patients with large tumors had a higher risk of developing symptomatic memory impairment (P = .029). CONCLUSION: Adults with CP treated with PT have favorable survival outcomes, with acceptable late toxicity. Prospective quality-of-life and neurocognitive studies are needed to define late adverse effects better.

In Vivo 2-Hydroxyglutarate Monitoring With Edited MR Spectroscopy for the Follow-up of IDH-Mutant Diffuse Gliomas: The IDASPE Prospective Study.

BACKGROUND AND OBJECTIVES: D-2-hydroxyglutarate (2HG) characterizes IDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels. METHODS: MEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS). RESULTS: MEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3; p = 0.02), voxel coverage (>75%; p = 0.002), and expansive presentation (defined by equal size of T1 and FLAIR abnormalities, p = 0.04). 2HG levels were positively correlated with IDH-mutant allelic fraction (p = 0.03) and total choline levels (p < 0.001) and were higher in IDH2-mutant compared with IDH1 R132H-mutant and non-R132H IDH1-mutant patients (p = 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities. DISCUSSION: MEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy of IDH inhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Prevalence and clinical correlations of SF3B1 variants in lactotroph tumours.

OBJECTIVE: A somatic mutational hotspot in the SF3B1 gene was reported in lactotroph tumours. The aim of our study was to examine the prevalence of driver SF3B1 variants in a multicentre independent cohort of patients with lactotroph tumours and correlate with clinical data. DESIGN AND METHODS: This was a retrospective, multicentre study involving 282 patients with lactotroph tumours (including 6 metastatic lactotroph tumours) from 8 European centres. We screened SF3B1 exon 14 hotspot for somatic variants using Sanger sequencing and correlated with clinicopathological data. RESULTS: We detected SF3B1 variants in seven patients with lactotroph tumours: c.1874G > A (p.Arg625His) (n = 4, 3 of which metastatic) and a previously undescribed in pituitary tumours variant c.1873C > T (p.Arg625Cys) (n = 3 aggressive pituitary tumours). In two metastatic lactotroph tumours with tissue available, the variant was detected in both primary tumour and metastasis. The overall prevalence of likely pathogenic SF3B1 variants in lactotroph tumours was 2.5%, but when we considered only metastatic cases, it reached the 50%. SF3B1 variants correlated with significantly larger tumour size; higher Ki67 proliferation index; multiple treatments, including radiotherapy and chemotherapy; increased disease-specific death; and shorter postoperative survival. CONCLUSIONS: SF3B1 variants are uncommon in lactotroph tumours but may be frequent in metastatic lactotroph tumours. When present, they associate with aggressive tumour behaviour and worse clinical outcome.

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. Following the identification of a loss-of-function variant (p.Arg703Gln) in the PAM gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated pituitary adenomas kindreds for PAM variants. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. No germline CNVs or somatic single nucleotide variants (SNVs) were identified. We detected seven likely pathogenic heterozygous missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with GH excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or with different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, for splicing by minigene assays, and for amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs to diagnoses linked to pituitary gland hyperfunction. Identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion.

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.