Editorial
Genetic Testing in Pituitary Adenomas: What, How, and In Whom?
Genética en adenomas hipofisarias: ¿qué, cómo y a quién?
Adrian F. Daly
, Albert Beckers
Autor para correspondencia
Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Liège University, Domaine Universitaire du Sart Tilman, 4000, Liège, Belgium
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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "71" "paginaFinal" => "73" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Adrian F. Daly, Albert Beckers" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Adrian F." "apellidos" => "Daly" "email" => array:1 [ 0 => "adrian.daly@ulg.ac.be" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Albert" "apellidos" => "Beckers" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Department of Endocrinology, Centre Hospitalier Universitaire de Liège, Liège University, Domaine Universitaire du Sart Tilman, 4000, Liège, Belgium" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Autor para correspondencia." ] ] ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Genética en adenomas hipofisarias: ¿qué, cómo y a quién?" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Clinically diagnosed pituitary adenomas have a prevalence of approximately 1 per 1000 in the general population in Europe and are therefore encountered regularly by clinical endocrinologists in everyday practice<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>. Currently, it is believed that most pituitary adenomas arise from a clonal expansion derived from a somatic mutation in a single cell. For instance, a somatic mutation in <span class="elsevierStyleItalic">GNAS</span> is found in up to 40% of somatotropinomas in patients with acromegaly, while somatic <span class="elsevierStyleItalic">USP8</span> mutations are now known to account for many cases of Cushing's disease<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a>. Such pituitary level mutations are only discovered <span class="elsevierStyleItalic">post hoc</span> following tumor resection, cannot readily be predicted in advance and are not inheritable. Germline mutations in genes associated with pituitary adenomas are quite rare, and overall, pituitary adenomas occurring in an inheritable or familial setting account for about 5% of cases<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>. As they are rare, generalized screening of pituitary adenoma patient populations to identify genetic mutation carriers is not currently a scientifically or economically valid approach. Most of these genetic causes are associated with a clinical presentation that differs from other pituitary adenomas, and these characteristics can be used to refine screening significantly.</p><p id="par0010" class="elsevierStylePara elsevierViewall">In general, when considering genetic analyses in pituitary adenoma patients a good first step is to determine if the tumor is isolated to the pituitary or forms part of a multi-organ tumor syndrome. Pituitary adenomas can form part of classical endocrine tumor syndromes, such as, multiple endocrine neoplasia types 1 (MEN1) and 4 (MEN4), Carney complex and McCune-Albright syndrome (MAS)<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>. The initial clinical investigation of the patient with a pituitary adenoma should include a detailed personal and family history about tumors and pathologies at other sites, particularly in endocrine tissues<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6,7</span></a>. Similarly, the family history should specifically search for related individuals with pituitary adenomas.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The focus for genetic testing in pituitary adenomas should primarily be on three main groups: pediatric-adolescent patients, those with a family history of pituitary adenomas and patients with a personal/family history suggestive of an endocrine tumor syndrome.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Pediatric and adolescent patients are a particularly important population, as certain genetic abnormalities leading to pituitary adenomas present more often in the young. For example, in MEN1, pituitary adenomas can have an early age at presentation, and testing guidelines recommend surveillance beginning as early as 5 years of age<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>. In MEN1, pituitary adenomas are generally larger and more difficult to control hormonally than non-MEN1 cases. Pituitary gigantism, by definition a disease that begins at an early age, is a high priority for genetic testing as nearly 50% of cases have a known genetic cause, such as <span class="elsevierStyleItalic">AIP</span> mutations/deletions (29%), X-LAG syndrome (10%), McCune-Albright syndrome (5%), and MEN1 or Carney complex (1% each) <a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Isolated pituitary adenomas can also occur in a hereditary setting as part of familial isolated pituitary adenomas (FIPA); FIPA is diagnosed in kindreds that have at least two pituitary adenomas in related individuals but in the absence of syndromic features in other organs, such as, MEN1<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>. Mutations in the <span class="elsevierStyleItalic">AIP</span> gene explain about 15-25% of FIPA families. <span class="elsevierStyleItalic">AIP</span> mutations have quite a low penetrance and about 20% of mutation carriers will develop a clinically significant pituitary adenoma<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>. While <span class="elsevierStyleItalic">AIP</span> mutations can lead to all subtypes of pituitary adenomas, they usually cause growth hormone-secreting (GH) or mixed GH-prolactin secreting pituitary macroadenomas during childhood or adolescence. While they most often occur in the setting of FIPA, <span class="elsevierStyleItalic">AIP</span> mutation related pituitary adenomas also can occur in isolated patients with young onset, large macroadenomas. In acromegaly, <span class="elsevierStyleItalic">AIP</span> mutated patients can be difficult to control, due to high levels of hormonal secretion and poor hormonal and tumoral responses to first-generation somatostatin analogs<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>.</p><p id="par0030" class="elsevierStylePara elsevierViewall">X-linked acrogigantism (X-LAG) syndrome is rare but has a very typical presentation as isolated GH-secreting pituitary adenoma and/or hyperplasia causing overgrowth that begins usually in the first 12 months of life<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a>. It is due to a microduplication on chromosome Xq26.3 that encompasses the gene <span class="elsevierStyleItalic">GPR101</span> and if untreated leads to very severe pituitary gigantism. Diagnosis is made using array comparative genome hybridisation (aCGH). X-LAG syndrome can occur in rare gigantism-only FIPA families<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a>. Also, low-level somatic mosaicism is seen in male sporadic patients, which can be detected using specific ddPCR assays<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a>.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Apart from MEN1 some other syndromic conditions include pituitary adenomas <a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>. MEN4 is due to <span class="elsevierStyleItalic">CDKN1B</span> mutations, and is a rare syndrome seen in MEN1 negative individuals and kindreds. As relatively few pituitary adenomas have been described in MEN4, there is no specific phenotype to direct genetic testing and <span class="elsevierStyleItalic">CDKN1B</span> mutations have not been reported in patients with isolated pituitary adenomas. Carney complex is due to germline <span class="elsevierStyleItalic">PRKAR1A</span> mutations and is a multiorgan syndrome involving the adrenals, skin, testes and many other sites. Pituitary adenomas (generally GH secreting) occur in 10% of patients with Carney complex, although many patients will have disorders of GH, insulin-like growth factor 1 (IGF1) or prolactin on hormonal testing in the absence of a pituitary adenoma. <span class="elsevierStyleItalic">MEN1</span>, <span class="elsevierStyleItalic">CDKN1B</span> and <span class="elsevierStyleItalic">PRKAR1A</span> mutations are not considered to be an important cause of isolated sporadic pituitary adenomas.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Mosaicism may also occur in patients with isolated and syndromic pituitary adenomas. In McCune-Albright syndrome, for instance, a post-zygotic, activating mutation in the <span class="elsevierStyleItalic">GNAS</span> gene can lead to variable proportions of mutated and wild-type cells across different tissues. Traditional sequencing of <span class="elsevierStyleItalic">GNAS</span> for mutations in McCune-Albright syndrome is often negative for technical reasons due to low levels of mutated allele in blood or tumor specimens. Recently, droplet digital PCR (ddPCR) and related techniques have been validated to diagnose very low levels of the mutant <span class="elsevierStyleItalic">GNAS</span> allele in blood and tissue DNA, thereby facilitating routine diagnosis<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a>. Early genetic confirmation of MAS is important for disease surveillance in the affected individual (it is not currently believed to be hereditary). This is particularly true for somatotropinomas in MAS which can have an early onset, exacerbate co-existing craniofacial fibrous dysplasia and are challenging to treat.</p><p id="par0045" class="elsevierStylePara elsevierViewall">One further syndromic situation of growing interest is the potential for a pituitary adenoma, pheochromocytoma/paraganglioma association (3PA)<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a>. In individuals or kindreds presenting with 3PA, a number of mutated genes have been identified, including the succinate dehydrogenase subunit genes (SDHx); recently, mutations and intragenic deletions in <span class="elsevierStyleItalic">MAX</span> have also been implicated in 3PA<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>.</p><p id="par0050" class="elsevierStylePara elsevierViewall">The increasing number of genes associated with pituitary adenomas has also been accompanied by an expansion in the methodologies needed to correctly identify pathological variations. Rather than Sanger sequencing of individual genes, most reference laboratories have migrated to Next Generation Sequencing (NGS) panels, which allow for parallel analyses of multiple potential genetic targets. Other methodologies need to be considered for specific conditions, such as aCGH for XLAG syndrome, or digital PCR, as mentioned above. Also, multiplex ligation dependent probe amplification (MLPA) kits are available to identify whole or partial gene deletions. MLPA has proven useful in identifying whole or intragenic deletions in genes such as <span class="elsevierStyleItalic">MEN1</span>, <span class="elsevierStyleItalic">AIP</span>, <span class="elsevierStyleItalic">SDHx</span>, and <span class="elsevierStyleItalic">MAX</span>, in patients and families with normal sequencing results.</p><p id="par0055" class="elsevierStylePara elsevierViewall">Although rare, genetic causes of pituitary adenomas are important to be aware of, as their overall clinical course is often complicated by aggressive tumor characteristics and treatment is more difficult. Early diagnosis of genetic causes is important to allow for proper screening for syndromic disease and to counsel and identify at-risk mutation carriers. The increasing number of causative genes and emerging clinical syndromes means that clinical endocrinologists will increasingly act in partnership with clinical geneticists to optimise the management of patients with pituitary adenomas.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2019-01-04" "fechaAceptado" => "2019-01-10" "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "High prevalence of pituitary adenomas: A cross-sectional study in the province of Liège Belgium" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "A.F. Daly" 1 => "M. Rixhon" 2 => "C. Adam" 3 => "A. Dempegioti" 4 => "M.A. Tichomirowa" 5 => "A. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 3 | 0 | 3 |
| 2024 Octubre | 9 | 1 | 10 |
| 2024 Septiembre | 6 | 3 | 9 |
| 2024 Agosto | 6 | 4 | 10 |
| 2024 Julio | 5 | 4 | 9 |
| 2024 Junio | 9 | 0 | 9 |
| 2024 Mayo | 7 | 4 | 11 |
| 2024 Abril | 20 | 2 | 22 |
| 2024 Marzo | 14 | 5 | 19 |
| 2024 Febrero | 11 | 3 | 14 |
| 2024 Enero | 10 | 6 | 16 |
| 2023 Diciembre | 7 | 1 | 8 |
| 2023 Noviembre | 4 | 6 | 10 |
| 2023 Octubre | 8 | 9 | 17 |
| 2023 Septiembre | 6 | 3 | 9 |
| 2023 Agosto | 5 | 2 | 7 |
| 2023 Julio | 8 | 1 | 9 |
| 2023 Junio | 7 | 1 | 8 |
| 2023 Mayo | 27 | 5 | 32 |
| 2023 Abril | 5 | 1 | 6 |
| 2023 Marzo | 6 | 0 | 6 |
| 2023 Febrero | 9 | 0 | 9 |
| 2023 Enero | 8 | 4 | 12 |
| 2022 Diciembre | 10 | 6 | 16 |
| 2022 Noviembre | 7 | 2 | 9 |
| 2022 Octubre | 8 | 6 | 14 |
| 2022 Septiembre | 5 | 3 | 8 |
| 2022 Agosto | 10 | 3 | 13 |
| 2022 Julio | 8 | 8 | 16 |
| 2022 Junio | 4 | 5 | 9 |
| 2022 Mayo | 5 | 9 | 14 |
| 2022 Abril | 11 | 5 | 16 |
| 2022 Marzo | 8 | 4 | 12 |
| 2022 Febrero | 10 | 4 | 14 |
| 2022 Enero | 13 | 4 | 17 |
| 2021 Diciembre | 7 | 5 | 12 |
| 2021 Noviembre | 5 | 9 | 14 |
| 2021 Octubre | 8 | 5 | 13 |
| 2021 Septiembre | 8 | 8 | 16 |
| 2021 Agosto | 5 | 8 | 13 |
| 2021 Julio | 6 | 4 | 10 |
| 2021 Junio | 7 | 14 | 21 |
| 2021 Mayo | 9 | 7 | 16 |
| 2021 Abril | 16 | 12 | 28 |
| 2021 Marzo | 8 | 4 | 12 |
| 2021 Febrero | 7 | 10 | 17 |
| 2021 Enero | 5 | 7 | 12 |
| 2020 Diciembre | 11 | 7 | 18 |
| 2020 Noviembre | 6 | 5 | 11 |
| 2020 Octubre | 8 | 7 | 15 |
| 2020 Septiembre | 5 | 6 | 11 |
| 2020 Agosto | 7 | 5 | 12 |
| 2020 Julio | 7 | 13 | 20 |
| 2020 Junio | 7 | 2 | 9 |
| 2020 Mayo | 8 | 6 | 14 |
| 2020 Abril | 5 | 1 | 6 |
| 2020 Marzo | 5 | 1 | 6 |
| 2020 Febrero | 7 | 1 | 8 |
| 2020 Enero | 8 | 2 | 10 |
| 2019 Diciembre | 8 | 8 | 16 |
| 2019 Noviembre | 7 | 4 | 11 |
| 2019 Octubre | 5 | 1 | 6 |
| 2019 Septiembre | 4 | 2 | 6 |
| 2019 Agosto | 4 | 0 | 4 |
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