Familial Isolated Pituitary Adenomas Research Articles

Familial isolated pituitary adenoma is independent of Ahr genotype in a novel mouse model of disease

Human familial isolated pituitary adenoma (FIPA) has been linked to germline heterozygous mutations in the gene encoding the aryl hydrocarbon receptor-interacting protein (AIP, also known as ARA9, XAP2, FKBP16, or FKBP37). To investigate the hypothesis that AIP is a pituitary adenoma tumor suppressor via its role in aryl hydrocarbon receptor (AHR) signaling, we have compared the pituitary phenotype of our global null Aip (AipΔC) mouse model with that of a conditional null Aip model (Aipfx/fx) carrying the same deletion, as well as pituitary phenotypes of Ahr global null and Arnt conditional null animals. We demonstrate that germline AipΔC heterozygosity results in a high incidence of pituitary tumors in both sexes, primarily somatotropinomas, at 16 months of age. Biallelic deletion of Aip in Pit-1 cells (Aipfx/fx:rGHRHRcre) increased pituitary tumor incidence and also accelerated tumor progression, supporting a loss-of-function/loss-of-heterozygosity model of tumorigenesis. Tumor development exhibited sexual dimorphism in wildtype and Aipfx/fx:rGHRHRcre animals. Despite the role of AHR as a tumor suppressor in other cancers, the observation that animals lacking AHR in all tissues, or ARNT in Pit-1 cells, do not develop somatotropinomas argues against the hypothesis that pituitary tumorigenesis in AIP-associated FIPA is related to decreased activities of either the Ahr or Arnt gene products.

Tumor predisposition in endocrinology - from MEN to FIPA

Understanding genetic predisposition has a significant impact on the management of patients with endocrine tumours, including therapy, early detection and prevention. These tumours, which develop as part of a familial predisposition, often manifest early in life and frequently affect several endocrine organs. In the following article, both common syndromes, such as multiple endocrine neoplasia (MEN) syndromes, and rare syndromes, such as familial isolated pituitary adenoma (FIPA), are presented based on their indicator diseases.

THU079 Danio Rerio (Zebrafish): A New Model Of AIP Loss Of Function

Abstract Disclosure: X. Wang: None. A. Leggieri: None. S. Anagianni: None. C.H. Brennan: None. M. Korbonits: None. Background: Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene account for 10% of cases with familial isolated pituitary adenoma (FIPA). The main features of patients carrying heterozygous AIP mutations include young-onset, large and invasive growth hormone and/or prolactin-secreting pituitary tumours, although a milder spectrum of presentation has been also described. In several animal models (mouse, fruit fly, round worm), homozygous deletion of AIP results in embryonic mortality. In mice abnormal cardiac development has been observed. Objective: The aim of this study was to generate a zebrafish loss-of-function model to explore the cellular biological processes affected by heterozygous or homozygous aip mutations. Methods: Zebrafish homologue of human AIP was identified by EMBOSS Needle program. We used CRISPR/Cas9 to generate a line of fish carrying loss-of-function mutations targeting zebrafish aip exon 2. aip RNA expression was examined using in situ hybridisation. The growth rate and cardiac function were assessed using a stereo microscope with an integrated camera. The videos and pictures were analysed in ImageJ. Antisense in situ hybridisation with probes to growth hormone 1 (gh1), prolactin (prl) and proopiomelanocortin a (pomca) was used to assess pituitary phenotypes. Results: Zebrafish aip shows 78.8% of homology to human AIP. aip mRNA is expressed throughout the developing zebrafish embryo until 28 hours post fertilisation (hpf) stage when it becomes more strongly expressed in the head. We generated a 29 bp deletion in exon 2 of the zebrafish aip gene. These mutant animals showed reduced aip expression. No significant gross morphology differences were observed at 3 to 7 days post fertilisation (dpf) between wildtype (WT) and heterozygote (Het) animals. At 5dpf, WTs showed an increased heart rate than Hets (P=0.033). Conclusion: We have generated an aip loss of function zebrafish line that provides an ideal opportunity to analyse the role of aip in development. Presentation: Thursday, June 15, 2023

Low frequency of AIP mutations in patients with young-onset sporadic pituitary macroadenomas

PurposeMutations in the aryl hydrocarbon receptor interacting protein (AIP) gene cause familial isolated pituitary adenomas (FIPA). AIP mutations have also been found in patients with apparently sporadic pituitary adenomas, particularly in young patients with large adenomas. The aim of this study was to determine the frequency of AIP germline mutations in patients with young-onset sporadic pituitary macroadenomas.MethodsThe AIP gene was sequenced in 218 Portuguese patients with sporadic pituitary macroadenomas diagnosed before the age of 40 years.ResultsHeterozygous rare sequence variants in AIP were identified in 18 (8.3%) patients. However, only four (1.8%) patients had pathogenic or likely pathogenic variants. These consisted of two already known mutations (p.Arg81* and p.Leu115Trpfs*41) and two novel mutations (p.Glu246*, p.Ser53Thrfs*36). All four patients had GH-secreting adenomas diagnosed between the ages of 14 and 25 years. The frequency of AIP pathogenic or likely pathogenic variants in patients under the age of 30 and 18 years was 3.4% and 5.0%, respectively.ConclusionThe frequency of AIP mutations in this cohort was lower than in other studies. Previous reports may have overestimated the contribution of AIP mutations due to the inclusion of genetic variants of uncertain significance. The identification of novel AIP mutations expands the known spectrum of genetic causes of pituitary adenomas and may help understand the role of AIP mutations in the molecular mechanisms underlying pituitary tumorigenesis.

Abstract #1413664: A Case of Familial Isolated Pituitary Adenoma Emphasizing an Often-Overlooked Aspect of Medical History

Familial Isolated pituitary adenoma (FIPA) is a rare cause of pituitary adenoma and underscores the importance of family history and the knowledge of screening guidelines in these patients. A 26-year-old female presented with secondary amenorrhea, galactorrhea, headaches and dizziness. Labs showed Prolactin 501 ng/ml (3.3-26.7 ng/mL) and IGF 391 ng/ml (96-301 ng/mL). MRI of the brain showed a 12 x 14 x 15 mm pituitary mass. Acromegaly was confirmed with glucose suppression test with growth hormone (GH) lowering to 1.08 ng/ml (< 0.8 ng/ml). Further history revealed a paternal cousin with gigantism diagnosed at the age of 17. She underwent transsphenoidal resection of the adenoma which stained positive for GH and prolactin. Post operative labs show improved levels: Prolactin 31 ng/mL (3.3-26.7 ng/mL) and IGF 317 ng/mL (96-301 ng/mL). Genetic evaluation showed a pathogenic mutation in AIP (aryl hydrocarbon receptor-interacting protein). Labs 4 months later- Prolactin 36.1 ng/mL (3.3-26.7 ng/mL), IGF 209 ng/mL (96-301 ng/mL), and GH 0.1 ng/mL (0.05-8.00 ng/mL). She was amenorrheic post surgery and with hormone replacement therapy, regular menstrual cycles ensued. Surveillance showed consistently normal IGF but prolactin levels were trending upwards. Prolactin: 80 ng/mL (3.3-26.7 ng/mL). A repeat MRI brain did not show any adenoma. She was started on Cabergoline and that helped with normalization of prolactin levels. FIPA is a rare hereditary disorder responsible for less than 2% of pituitary adenomas. Mutation of AIP is seen in 20% cases and associated with worse outcomes. The peak age of onset is between 10-30 years of age. Affected patients tend to have larger tumors than non-FIPA which increases the risk of pituitary apoplexy. GH secretion is the most common; followed by prolactin, GH-Prolactin co-secretion, non-functional and rarely TSH secreting. It has an autosomal dominant transmission but with incomplete penetrance often skipping generations making the diagnosis even more challenging. Obtaining detailed family history in any patient with pituitary adenoma is essential in uncovering the inheritance pattern of this disease. Screening for FIPA and AIP is recommended if patients are noted to have- 1. GH secreting adenoma diagnosed before the age of 18 2. Pituitary macroadenoma (>10 mm) diagnosed before the age of 30 3. Any pituitary adenoma with a family history of pituitary adenoma in more than one member First degree family members of patients with FIPA and AIP need to be tested for the mutation. Patients with positive mutation are recommended to undergo screening evaluation as follows- 1. Growth assessment and evaluation for signs and symptoms of pituitary adenoma with pituitary function tests a. Age 4-30 years: annually b. Age 30-50 years: every 5 years 2. Pituitary MRI a. Age 10-30 years: every 5 years Prospective observational data shows genetic testing followed by clinical screening leads to early detection of pituitary disease which results in early interventions and better outcomes. This highlights the importance of recognition of FIPA in patients presenting with any kind of pituitary adenomas.

Clinical and molecular features of four Brazilian families with multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília. From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected. Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found. The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília.

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

Up to 5% of all pituitary tumors are hereditary e.g. due to MEN1 or aryl hydrocarbon receptor-interacting protein (AIP) genes mutations. The 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. The 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. AIP 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. 24mm, 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). In 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.

The Spectrum of Familial Pituitary Neuroendocrine Tumors.

Hereditary pituitary tumorigenesis is seen in a relatively small proportion (around 5%) of patients with pituitary neuroendocrine tumors (PitNETs). The aim of the current review is to describe the main clinical and molecular features of such pituitary tumors associated with hereditary or familial characteristics, many of which have now been genetically identified. The genetic patterns of inheritance are classified into isolated familial PitNETs and the syndromic tumors. In general, the established genetic causes of familial tumorigenesis tend to present at a younger age, often pursue a more aggressive course, and are more frequently associated with growth hormone hypersecretion compared to sporadic tumors. The mostly studied molecular pathways implicated are the protein kinase A and phosphatidyl-inositol pathways, which are in the main related to mutations in the syndromes of familial isolated pituitary adenoma (FIPA), Carney complex syndrome, and X-linked acrogigantism. Another well-documented mechanism consists of the regulation of p27 or p21 proteins, with further acceleration of the pituitary cell cycle through the check points G1/S and M/G1, mostly documented in multiple endocrine neoplasia type 4. In conclusion, PitNETs may occur in relation to well-established familial germline mutations which may determine the clinical phenotype and the response to treatment, and may require family screening.

A review of multiomics platforms in pituitary adenoma pathogenesis.

Pituitary adenomas (PA), or pituitary neuroendocrine tumors (PitNETs), represent 15% of all central nervous system tumors. Classic description of PitNETs solely by hormonal classification has given way to key transcription factors that play a role in the pathology of PitNETs including steroidogenic factor-1 (SF-1), t-box pituitary transcription factor (TPIT), and pituitary transcription factor 1 (PIT-1). Germline mutations in various familial PitNETs are discussed including those in familial isolated pituitary adenoma (FIPA), multiple endocrine neoplasia (MEN), neurofibromatosis 1 (NF1), and Carney complex. Recent advances in next generation sequencing have improved insight into the pathogenesis of PitNETs. A review of key studies in evaluating the genomic analysis of PitNETs was performed. Chromosomal mutations, whole exome sequencing, microRNA genomics, methylomics and transcriptomics were analyzed. Moreover, the multiomic analysis of various genomic panels has helped to better understand PA classification.

The expression and prognostic value of REXO4 in hepatocellular carcinoma.

Globally, one of the dominant causes of cancer-related mortality is liver cancer. Identification of potent biomarkers for initial stage diagnosis and prognosis is a key factor to ensure efficient therapy and reduce the mortality rate in liver cancer patients. REXO4 has been reported in neuropathic pain and familial isolated pituitary adenoma (FIPA), however, its relationship with liver cancer is still elusive. In an attempt to scrutinize the expression of REXO4 in liver cancer, the Oncomine, and TCGA databases were analyzed. Real-time PCR was employed to identify the REXO4 mRNA levels in 45 patient tissue samples and western blot was used to detect the REXO4 protein levels in hepatocellular carcinoma (HCC) cells. Evaluation of the prognostic value of REXO4 in liver cancer was made using Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier plots. Tumor-associated biological processes related to REXO4 were revealed by LinkedOmics. The correlation of REXO4 and immune infiltration was evaluated using the TIMER database. REXO4 is significantly up-regulated in liver cancer in comparison with the nontumor controls. Moreover, poor progression-free survival and overall survival is a frequent outcome related to high expression of REXO4, highlighting it as a risk factor in case of liver cancer. Additionally, the plausible role of REXO4 in tumor-immune interactions was also investigated and it was revealed that the immune infiltration and immune activation of liver cancer might have an association with REXO4. REXO4 has a significant expression in liver cancer and could potentially become a predictor for the prognosis of liver cancers and a biomarker for targeted therapeutic regimens. Significant overexpression of REXO4 in HCC was revealed by the bioinformatics analysis, with REXO4 overexpression being related to a negative outcome in HCC patients, in addition, REXO4 might be associated with the immune infiltration in liver cancer. Such a vital understanding of the functioning of REXO4 may furnish a foundation for new targeted drug therapy as well as a new direction for additional investigation into the underlying mechanisms of REXO4 carcinogenesis in liver cancer.

Prolactinoma in Two Brothers - Unidentified Genetic Cause Versus Co-Incidence?

Background: Most prolactinomas occur sporadically. Familial prolactinomas are uncommon. Clinical Case(s): A 35 YO male with no significant past medical history presented to endocrine clinic with c/o fatigue, decreased libido, and erectile dysfunction. Labs showed low total testosterone of 177 ng/dl (normal range 250-1100 ng/dl), low free testosterone of 19.9 pg/ml (normal range 46-224), low LH 1.1 (normal range 1.5-9.3 mIU/ml) with elevated prolactin of 47 ng/ml (normal range 2-18). MRI pituitary showed a 4.2x4x6 mm pituitary microadenoma. Physical exam was unremarkable except for obese body habitus. No known family history of MEN syndromes or parathyroid /calcium disorders. Dopamine agonist therapy resulted in significant improvement in testosterone levels, fatigue, and libido. One year after patient’s diagnosis his 32 YO younger brother was evaluated for c/o fatigue, inability to lose weight, left breast enlargement, galactorrhea, and decreased libido. Work up showed markedly elevated prolactin levels of 2405 ng/ml (normal range 4-15), decreased total testosterone of 70 ng/dl (normal range 249-836), low free testosterone of 4.8 pg/ml (normal range 8.7 to 25.1), FSH <0.1 mIU/ml (normal range 1.4-15.4), LH < 0.1 mIU/ml (normal range 1.7-8.6). MRI Pituitary showed a 25x28x20 mm pituitary macroadenoma invading the right cavernous sinus, encasing the right internal carotid artery, and abutting the optic chiasma. Our patient had genetic testing done for sequencing and deletion/duplication analysis of MEN1 and AIP (Aryl hydrocarbon receptor interacting protein) genes—two well identified causes of familial pituitary adenomas—and tested negative for both. His brother was treated with dopamine agonists with marked improvement in Prolactin to undetectable levels within a few weeks. His energy levels, headaches, and sexual function improved and galactorrhea resolved. However, testosterone levels remained below normal range even after 11 months, despite normal prolactin levels. Discussion: Prolactinomas are the most common functional pituitary adenomas, majority of them sporadic. Familial pituitary adenomas in non-syndromic form are rare. Familial isolated pituitary adenoma (FIPA) and Multiple endocrine neoplasia type 1(MEN 1) are two main causes of familial pituitary adenomas. In FIPA, pituitary adenomas occur as a result of mutations or deletions in aryl hydrocarbon receptor interacting protein gene (AIP). Identifying these mutations is important as pituitary adenomas in FIPA tend to be more aggressive, present at a younger age and are resistant to treatment. Our patient tested negative for both MEN 1 and AIP gene mutations. Whether our patient has an unidentified genetic cause or whether it was a coincidence that two brothers have prolactinomas is unclear.

Acromegaly in a Young Women With Pituitary Hyperplasia Secondary to a Neuroendocrine Tumor

Acromegaly is rarely due to an excess of the GH-releasing hormone (GHRH) and pituitary hyperplasia on histology should alert to its presence. Clinical Case: A 35-year-old was referred to surgery with a confirmed diagnosis of symptomatic acromegaly. Her GH failed to suppress during an oral glucose tolerance test (OGTT), her IGF-1 and prolactin was high. Her serum calcium was normal and her chromogranin B was high. MRI scan suggested microadenoma. Her surgery was deferred because of Covid 19, and she was treated with somatostatin analog (SSA). She finally had surgery in July. The histology and immunocytochemistry suggested pituitary hyperplasia with diffuse positivity for chromogranin and synaptophysin. GH was positive in the majority of the cells with many cells positive for Prolactin and ACTH. FSH and LH were positive in scattered cells with patchy positivity of TSH. A solitary nodule was noted in her neck during an examination. We arranged to look for conditions associated with pituitary hyperplasia resulting in GHRH production, including the genetic tests for inherited conditions. Her calcitonin level was normal. She had an ultrasound scan guided fine needle aspiration of the thyroid nodule, this showed Thy3f oncocytic nodule with no features of medullary thyroid carcinoma. She had an NMGa68DOTATATE whole body PET CTand the scan showed a large DOTATAE avid mass from the right adrenal gland compatible with Pheochromocytoma. Her 24 hours total urinary metadrenaline and normetadrenalin was high. Her genetic test for MEN1, CDKN1B, and MEN2 are negative. We have requested the GHRH measurement. After a pituitary surgery, her GH suppressed adequately on OGTT. Her IGF-1 and prolactin is low and her hypogonadism is resolved. Conclusion: Excess production GHRH can result from neuroendocrine tumors of the lung, pancreas, thyroid (medullary thyroid cancer), or pheochromocytomas and hypothalamic gangliocytomas.Several familial syndromes, multiple endocrine neoplasia type 1 (MEN1) and 4 (MEN4), familial isolated pituitary adenoma (FIPA), Carney complex, and sporadic germline mosaic disorder McCune-Albright disease predispose to pituitary hyperplasia. GHRH acromegaly should be suspected in a patient with biochemical/clinical features of acromegaly in the presence of co-existing neuroendocrine tumors when there is diffuse pituitary enlargement on imaging or resolution of acromegaly after the surgical resection of the primary neuroendocrine tumour or persistent acromegaly after surgery if there is histological evidence of somatotroph hyperplasia.

Isolated Macroprolactinomas in Four Young Adult Males Harboring a Variant of the Aryl Hydrocarbon Interacting Protein (AIP) Gene: Isn’t It Too Much of a Coincidence?

Background: Germline mutations in the Aryl hydrocarbon receptor-Interacting Protein (AIP) gene are associated with pituitary adenomas in young patients usually in the setting of Familial Isolated Pituitary Adenomas (FIPA). The majority of these adenomas are somatotropinomas followed by prolactinomas, and rarely non-secreting adenomas. AIP-mutation-related prolactinomas predominantly affect men, as opposed to sporadic prolactinomas, that typically affect women. Clinical Case: We previously described an AIP gene mutation in two patients affected by prolactinomas. During the past years, we continued our study and have identified two more male patients with macroprolactinomas originally from the same small village and harboring the same AIP gene mutation. These male patients aged 19 to 44 years at the time of diagnosis. Two of them had neurological manifestations as the first clinical manifestation of the disease, one was studied because of hypogonadism and two patients had visual field defects. All of them had prolactin levels above 1000 ng/dl (mean 2946.5±948.7 ng/dl, reference range 10-21). In the imaging exams (CT/MRI) they presented pituitary adenomas larger than 20 mm (macroprolactinomas) and in two of the cases, the adenomas were even larger than 40 mm (giant prolactinomas). In order to exclude mutations most often associated with prolactinomas, DNA samples were obtained and analyzed by Next Generation Sequencing (NGS) using TruSightCancer Gene Set (Illumina) methodology. Investigation of significant deletions and/or duplications was performed using the MLPA (Multiplex ligation-dependent probe amplification) technique. None of the patients were positive for mutations of Multiple Endocrine Neoplasia type 1 (MEN1) gene. A variant of the AIP gene c.47G>A, expecting to lead to a substitution of arginine by histidine at position 16 (p.Arg16His) of the AIP was found in these four patients, including a father and his son. Seven asymptomatic carriers were identified among their first-degree relatives. In silico analysis and the information available in the literature, as well as in databases is not in agreement with the pathogenicity of this variant of the AIP gene. However, our findings point to a founder effect transmitted as a dominant trait with incomplete penetrance (4 out of 11 patients, 36%). Conclusion: The variant of the AIP gene identified in our patients behaved as a pathogenic mutation and was only associated with prolactinomas, including two giant prolactinomas.

Proteína moduladora de la actividad del receptor de aril hidrocarburos (AIP): genética, bioquímica e impacto clínico

El gen AIP (proteína moduladora de la actividad del receptor de aril hidrocarburos) se localiza en la región 11q13.2 y codifica para una proteína de 330 aminoácidos que interactúa con el factor de transcripción AhR (receptor para aril hidrocarburos). Las mutaciones en este gen se han asociado con adenomas pituitarios aislados de tipo familiar (APAF). Se caracterizan por una presentación temprana (alrededor de 20 años), por lo regular producen hormona de crecimiento y/o prolactina, tienen un comportamiento clínico agresivo y poca respuesta a análogos de somatostatina.

Семейные изолированные аденомы гипофиза (FIPA): клинический случай пролактиномы в одной семье

Семейные изолированные аденомы гипофиза (FIPA): клинический случай пролактиномы в одной семье

Genetics of Acromegaly and Gigantism.

Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune–Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.

ACROMEGALY COMBINED WITH GIGANTISM ASSOCIATED WITH THE AIP-GENE MUTATION: A CLINICAL CASE

Pituitary gigantism is an extremely rare disorder: the incidence of pituitary tumors in children is approximately 0.1 in one million, and only about 1 to 10% of the pituitary tumors secrete the GH in childhood. Gigantism should be suspected if the patient's height is 3 standard deviations above the normal average height or 2 standard deviations above the corrected height of parents. When pituitary gigantism is suspected, the clinician should consider the presence of disorders, known to be associated with the GH-secreting pituitary tumors, including the McCune Albright syndrome (MAS), Carney complex (CNC), multiple endocrine neoplasia, types 1 and 4 (MEN 1, MEN 4), Familial isolated pituitary adenoma (FIPA), the paraganglioma, pheochromocytoma and pituitary adenoma association (PAA) due to succinate dehydrogenase defects, and X-linked acrogigantism (X-LAG). The molecular genetics of the AIP-associated FIPA, MAS, CNC, and MEN 1 has been extensively studied and reviewed, especially in children and young adults. The GH-secreting adenomas seem to be more invasive and aggressive in childhood than in adulthood. Data on a rare disease — gigantism combined with phenotypic signs of acromegaly in a young patient are presented. Clinical and laboratory parameters, data of histological and genetic analysis are described. Genetic analysis performed by AIP gene by Sequencing, proved a rare mutation in the locus of exons 1-6 of the AIP gene. The presented clinical case describes a rare fact of the AIP-gene mutation in the p.Cys238Tyr locus, which is associated with the occurrence of a giant pituitary adenoma in childhood. Aggressive growths of the pituitary tumor, its high proliferative and hormonal activity, clinical manifestations of gigantism in combination with severe phenotypic signs of acromegaly have also been noticed. Resistance to the therapy with somatostatin analogs has been revealed in this case. Considering the absence of genetic predisposition to a pituitary adenoma in the patient, this case can be regarded as a sporadic pituitary adenoma variant due to the abnormal AIP-gene expression and the disturbance of regulation during tumorigenesis.

Exceptional Localization of a Prolactinoma as Part of Familial Isolated Pituitary Adenomas

The syndrome of familial isolated pituitary adenomas (FIPA) or predisposition to pituitary adenomas (PAP) is characterized by the presence within the same family of at least two isolated pituitary adenomas without any other type of associated endocrine tumor. These pituitary tumors may present as homogenous with the same tumor phenotype or heterogeneous with different patterns of pituitary tumor phenotypes (GH, Prolactine, ACTH secretion or non-functioning pituitary adenomas) within the same kindred. Patients with FIPA are significantly younger at diagnosis and have significantly larger pituitary adenomas than matched sporadic pituitary adenoma counterparts. We report the case of a prolactinoma attached to the pituitary stalk as part of FIPA, revealed by erectile dysfunction.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: The roles of AIP and GPR101 in familial isolated pituitary adenomas (FIPA).

Familial isolated pituitary adenoma (FIPA) is one of the most frequent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of pituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy.

Pituitary Disease in AIP Mutation-Positive Familial Isolated Pituitary Adenoma (FIPA): A Kindred-Based Overview.

Clinically-relevant pituitary adenomas occur in about 1:1000 of the general population, but only about 5% occur in a known genetic or familial setting. Familial isolated pituitary adenomas (FIPA) are one of the most important inherited settings for pituitary adenomas and the most frequent genetic cause is a germline mutation in the aryl hydrocarbon receptor-interacting protein (AIP) gene. AIP mutations lead to young-onset macroadenomas that are difficult to treat. Most are growth hormone secreting tumors, but all other secretory types can exist and the clinical profile of affected patients is variable. We present an overview of the current understanding of AIP mutation-related pituitary disease and illustrate various key clinical factors using examples from one of the largest AIP mutation-positive FIPA families identified to date, in which six mutation-affected members with pituitary disease have been diagnosed. We highlight various clinically significant features of FIPA and AIP mutations, including issues related to patients with acromegaly, prolactinoma, apoplexy and non-functioning pituitary adenomas. The challenges faced by these AIP mutation-positive patients due to their disease and the long-term outcomes in older patients are discussed. Similarly, the pitfalls encountered due to incomplete penetrance of pituitary adenomas in AIP-mutated kindreds are discussed.