Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas

Piscina, Idoia Martinez de la; Najera, Nancy Portillo; Rica, Itxaso; Gaztambide, Sonia; Webb, Susan M.; Santos, Alicia; Moure, Maria Dolores; Fano, Miguel Paja; Hernández, María Isabel; Chueca-Guindelain, Maria Jesús; Hernández-Ramírez, Laura C.; Soto, Alfonso; Valdés, Nuria; Castaño, Luís

doi:10.1530/eje-21-0075

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…Regarding pituitary neoplasms, up to now, some cases of these tumours were described in patients with MEN4 (43%) [12,38,45,47,49,50,52,53]. These findings agree with the estimated prevalence of pituitary tumours in patients with MEN1 (40%).…”

Section: Discussionsupporting

confidence: 81%

“…However, the clinical course of patients affected by mutations in CKDIs is still poorly understood since few cases have been reported until now. We reviewed medical literature and genetic databases (ClinVar, HGMD) and found that a few more than 100 cases with MEN4, including 52 different variants of CDKN1B, have been reported to date [12,16,20,29,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. As supplementary material, we added a table with the total number of CDKIs pathogenic/likely pathogenic/VUS germline variants thus far reported along with the type of parathyroid lesion or other tumours found (if reported) and pathogenicity level of the variants, which was assessed following the ACMG guidelines [26] (see supplementary material Appendix 1).…”

Section: Discussionmentioning

confidence: 99%

“…These findings agree with the estimated prevalence of pituitary tumours in patients with MEN1 (40%). Recently, in a large cohort of 211 patients (mostly paediatric) with Cushing disease, five germline CDKN1B variants were identified (2.6%) [50]. In addition, three germline CDKN1B variants were detected in three paediatric patients with pituitary adenomas, with no other manifestations related to MEN4 [47].…”

Section: Discussionmentioning

confidence: 99%

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Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

Mazarico-Altisent

Capel

Baena

et al. 2022

J Endocrinol Invest

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Purpose CDKN1B mutations were established as a cause of multiple endocrine neoplasia 4 (MEN4) syndrome in patients with MEN1 phenotype without a mutation in the MEN1 gene. In addition, variants in other cyclin-dependent kinase inhibitors (CDKIs) were found in some MEN1-like cases without the MEN1 mutation. We aimed to describe novel germline mutations of these genes in patients with primary hyperparathyroidism (PHPT). Methods During genetic screening for familial hyperparathyroidism, three novel CDKIs germline mutations in three unrelated cases between January 2019 and November 2021 were identified. In this report, we describe clinical features, DNA sequence analysis, and familial segregation studies based on these patients and their relatives. Genome-wide DNA study of loss of heterozygosity (LOH), copy number variation (CNV), and p27/kip immunohistochemistry was performed on tumour samples. Results DNA screening was performed for atypical parathyroid adenomas in cases 1 and 2 and for cystic parathyroid adenoma and young age at diagnosis of PHPT in case 3. Genetic analysis identified likely pathogenic variants of CDKN1B in cases 1 and 2 and a variant of the uncertain significance of CDKN2C, with uniparental disomy in the tumour sample, in case 3. Neoplasm screening of probands showed other non-endocrine tumours in case 1 (colon adenoma with dysplasia and atypical lipomas) and case 2 (aberrant T-cell population) and a non-functional pituitary adenoma in case 3. Conclusion Germline mutations in CDKIs should be included in gene panels for genetic testing of primary hyperparathyroidism. New germline variants here described can be added to the current knowledge.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

Mazarico-Altisent

Capel

Baena

et al. 2022

J Endocrinol Invest

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“…Prolactinoma in a paediatric patient should raise suspicion for the presence of germline MEN1 and AIP mutations 159 . Pituitary adenomas with these mutations could have a more aggressive behaviour than those without 160 (see Supplementary Box 7).…”

Section: Consensus Statementmentioning

confidence: 99%

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement

Petersenn,

Fleseriu,

Casanueva

et al. 2023

Nat Rev Endocrinol

112

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This Consensus Statement from an international, multidisciplinary workshop sponsored by the Pituitary Society offers evidence-based graded consensus recommendations and key summary points for clinical practice on the diagnosis and management of prolactinomas. Epidemiology and pathogenesis, clinical presentation of disordered pituitary hormone secretion, assessment of hyperprolactinaemia and biochemical evaluation, optimal use of imaging strategies and disease-related complications are addressed. In-depth discussions present the latest evidence on treatment of prolactinoma, including efficacy, adverse effects and options for withdrawal of dopamine agonist therapy, as well as indications for surgery, preoperative medical therapy and radiation therapy. Management of prolactinoma in special situations is discussed, including cystic lesions, mixed growth hormone-secreting and prolactin-secreting adenomas and giant and aggressive prolactinomas. Furthermore, considerations for pregnancy and fertility are outlined, as well as management of prolactinomas in children and adolescents, patients with an underlying psychiatric disorder, postmenopausal women, transgender individuals and patients with chronic kidney disease. The workshop concluded that, although treatment resistance is rare, there is a need for additional therapeutic options to address clinical challenges in treating these patients and a need to facilitate international registries to enable risk stratification and optimization of therapeutic strategies. Sections Clinical presentation Hyperprolactinaemia and hypogonadism• The presence of a sellar mass on imaging requires evaluation for hyperprolactinaemia (strong). • Galactorrhoea should trigger investigation for hyperprolactinaemia, except for known physiological reasons (for example, pregnant or lactating women) (strong). Importantly, absence of galactorrhoea does not exclude hyperprolactinaemia (strong).

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“…In a sporadic cohort of patients diagnosed with macroadenomas ≤30 years or with pituitary adenomas ≤18 years of age, Marques et al found AIP alterations in 6.8% of cases (23). In contrast, in a Spanish cohort of 235 apparently sporadic adenomas in patients ≤30 years of age, pathogenic AIPvar were detected in 3.8 of cases (24). The higher incidence of pathogenic mutations in some of the above-mentioned studies is mainly because the pediatric population was not included in our analysis.…”

Section: Discussionmentioning

confidence: 95%

AIP gene germline variants in adult Polish patients with apparently sporadic pituitary macroadenomas

Trofimiuk–Müldner

Domagała²,

Sokołowski³

et al. 2023

Front. Endocrinol.

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IntroductionUp to 5% of all pituitary tumors are hereditary e.g. due to MEN1 or aryl hydrocarbon receptor-interacting protein (AIP) genes mutations.ObjectivesThe study was aimed at the assessment of the frequency and characteristics of AIP-mutation related tumors in patients with apparently sporadic pituitary macroadenomas in the Polish population.Materials and methodsThe study included 131 patients (57 males, 74 females; median age 42 years) diagnosed with pituitary macroadenomas, and with a negative family history of familial isolated pituitary adenoma (FIPA) or multiple endocrine neoplasia type 1 (MEN1) syndromes. Sanger sequencing was used for the assessment of AIP gene variants. The study was approved by the Ethics Board of JUMC.ResultsAIP variants were identified in five of the 131 included subjects (3.8%): one diagnosed with Cushing’s disease, two with acromegaly, and two with non-secreting adenomas. Patients harboring hereditary AIP gene alterations did not differ from the rest of the study group in median age at diagnosis (41.0 vs. 42.5 years, P=0.8), median largest tumor diameter (25 vs. 24 mm, P=0.6), gender distribution (60.0% vs. 56.3% females, P=0.8), secreting tumor frequency (60.0% vs. 67.5%, P=0.7), or acromegaly diagnosis frequency (40.0% vs.37.3%, P=0.9).ConclusionsIn our series of apparently sporadic pituitary macroadenomas, AIP gene variant carriers did not differ substantially from patients with negative genetic testing. A risk factor-centred approach to AIP genetic screening may result in missing germline variants. Considering the clinical impact of such genetic variants and their relatively low penetrance, it is, however, doubtful if general genetic screening benefits the whole cohort of pituitary macroadenoma patients and their families.

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Clinical and genetic characteristics in patients under 30 years with sporadic pituitary adenomas

Cited by 14 publications

References 49 publications

Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism

Diagnosis and management of prolactin-secreting pituitary adenomas: a Pituitary Society international Consensus Statement

AIP gene germline variants in adult Polish patients with apparently sporadic pituitary macroadenomas

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