Albert Beckers’s research while affiliated with Centre Hospitalier Universitaire de Liège and other places

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Publications (314)


Impact of inter- and intra-TAD duplications on chromatin organization at the X-LAG locus. A Schematic representation of the extended X-LAG locus (hg19, chrX:135,336,766–136,561,684), delineating the genomic position of an invariant TAD border (red hexagon). Below, the position of partially overlapping tandem duplications involving GPR101 from subjects with X-LAG (highlighted by blue boxes) [16] that traverse the TAD border (inter-TAD duplications), alongside duplications from subjects of the current study (yellow boxes) that remain within TAD boundaries (intra-TAD duplications). B and C HiC at the X-LAG locus, showing normalized contact matrices at 10-kb resolution from the X-LAG subject S7 and non-X-LAG subject F2A in a side-by-side comparison to controls. Normal TAD configuration at the locus is highlighted by red arrows. Additional chromatin interactions, induced by inter- and intra-TAD duplications, are denoted by black arrows. HiC difference maps relative to controls (D and E) depict the increase in chromatin interactions (black arrows) in subject S7 and F2A. Below, corresponding 4C-seq profiles originating from the GPR101 viewpoint (black triangle) are displayed, alongside the genomic position of the duplication and the subtraction profiles relative to control samples. Inter-TAD duplications in X-LAG (B and D) result in increased chromatin interaction of GPR101 with regions centromeric of the TAD border (neo-TAD formation). Intra-TAD duplications, confined to GPR101 and excluding the invariant TAD border (C and E), exhibit increased telomeric chromatin interactions
Modulation of GPR101 chromatin interactions by inter- and intra-TAD duplications. Schematic representation of the extended X-LAG locus (hg19, chrX:135,336,766–136,561,684), delineating the genomic positions of putative pituitary enhancers (green boxes) and an invariant TAD border (red hexagon), which separates GPR101 from pituitary activity in normal conditions. Below, heatmap showing differential chromatin contacts at a 50-kb genomic bin size in X-LAG and non-X-LAG subject samples compared to controls, as inferred from 4C-seq experiments with a viewpoint located at the GPR101 promoter. The genomic bin containing the viewpoint is indicated by a black arrowhead. All X-LAG subjects exhibit similar patterns of ectopic chromatin interactions from GPR101 with the centromeric region containing putative pituitary enhancers. This pattern is absent in non-X-LAG subjects. The 4C-seq data from X-LAG subjects S6, S9, S13, S7, S2, and S17 and their respective controls (described in Franke et al. [16]) were retrieved from the GEO database under accession code GSE193114 [29]
Disease mechanism induced by inter- and intra-TAD duplications at the X-LAG locus. Schematic illustrating the configuration of TAD boundaries at the X-LAG locus with a linear genomic view (left) and a schematic representation of TAD configuration (right). A Under normal conditions, GPR101 is separated by a TAD boundary (red hexagon) from putative pituitary enhancers (green ovals). B Inter-TAD duplications associated with X-LAG, spanning the TAD boundary, lead to the formation of a neo-TAD (blue) that involves ectopic chromatin interactions between GPR101 and pituitary enhancers, consequently causing GPR101 misexpression and gigantism. C Intra-TAD duplications of GPR101 that “preserve” the TAD boundary do not generate a neo-TAD. As a result, the additional copy of GPR101 remains segregated from pituitary enhancers. Note that the size and position of duplications are indicated by overlap in the schematic representation
Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus
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September 2024

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57 Reads

Genome Medicine

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Leslie A. Dunnington

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David F. Rodriguez-Buritica

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Background X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits. Methods We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls. Results We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up. Conclusions This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.

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The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism

May 2024

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57 Reads

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3 Citations

Endocrine Reviews

Pituitary gigantism is a rare manifestation of chronic growth hormone (GH) excess that begins before closure of the growth plates. Nearly half of patients with pituitary gigantism have an identifiable genetic cause. X-linked acrogigantism (X-LAG; 10% of pituitary gigantism) typically begins during infancy and can lead to the tallest individuals described. In the 10 years since its discovery, about 40 patients have been identified. Patients with X-LAG usually develop mixed GH and prolactin macroadenomas with occasional hyperplasia that secrete copious amounts of GH, and frequently prolactin. Circulating GH-releasing hormone is also elevated in a proportion of patients. X-LAG is caused by constitutive or sporadic mosaic duplications at chromosome Xq26.3 that disrupt the normal chromatin architecture of a topologically associating domain (TAD) around the orphan G-protein–coupled receptor, GPR101. This leads to the formation of a neo-TAD in which GPR101 overexpression is driven by ectopic enhancers (“TADopathy”). X-LAG has been seen in 3 families due to transmission of the duplication from affected mothers to sons. GPR101 is a constitutively active receptor with an unknown natural ligand that signals via multiple G proteins and protein kinases A and C to promote GH/prolactin hypersecretion. Treatment of X-LAG is challenging due to the young patient population and resistance to somatostatin analogs; the GH receptor antagonist pegvisomant is often an effective option. GH, insulin-like growth factor 1, and prolactin hypersecretion and physical overgrowth can be controlled before definitive adult gigantism occurs, often at the cost of permanent hypopituitarism.


Clinical features in a patient with X-LAG. (A) Height chart from diagnosis to last follow-up in a female patient with X-LAG. Data derived from Italian reference dataset and standard deviation scores are shown alongside the individual growth curve (24). (B) Increased interdental spaces, and (C) abdominal lipohypertrophy associated with pegvisomant treatment. (D) Hormonal responses to treatment over time (IGF-1 on the left vertical axis, circles; prolactin on the right vertical axis, squares). The upper limit of normal for age and sex for IGF-1 is shown as a variable horizontal red line, while the upper limit for prolactin is shown as a horizontal blue line. CAB, cabergoline; i.m., intramuscular; LAN, lanreotide autogel; OCT, octreotide long-acting repeatable; pegV, pegvisomant; s.c., subcutaneous; ULN, upper limit of normal.
MRI images of the pituitary macroadenoma (17 × 12 mm) at diagnosis (sagittal T1-weighted image (A), coronal T2-weighted image (B)). Note the hypo-intensity of the T2-weighted image as compared with the temporal lobe gray matter. The post-operative MRI images ((C) sagittal T1-weighted; (D) T2-weighted coronal)) show the effect of gross visual resection of the pituitary adenoma and a remaining tiny region of normal anterior pituitary tissue.
A mixed somatotroph–lactotroph PitNET/adenoma (A) composed of two distinct cell populations: somatotropes and lactotropes (×20 magnification). A combination of densely/sparsely granulated somatotropes mixed with sparsely granulated lactotropes was present ((B) ×40 magnification). Staining for reticulin fibers ((C) ×10 magnification) indicates the lobular and cordonal appearance of the X-LAG-related PitNEt/adenoma. Densely granulated (DG) somatotropes (GH staining (D)) represent the predominant component, while neoplastic lactotropes appear as smaller areas (PRL staining (E)). Less numerous and mostly interspersed among the acidophilic cells were slightly smaller chromophobic cells with eccentric nuclei. These sparsely granulated (SG) somatotrope cells showed a weak GH expression (D). All tumor cellular components express Pit-1 (F). A low molecular weight cytokeratin CAM 5.2 (CAM 5.2) immunostain revealed perinuclear expression in DG somatotropes (G) and dot-like expression of CAM 5.2 in fibrous bodies of SG somatotrophs (G). The Ki67 labeling index was low (<2% (H)). Membranous and cytoplasmic SSTR2A staining was moderately positive (immunoreactive score, 4 out of 8 (I)). Magnification in (D–I), ×20.
4C-seq showing ectopic chromatin interactions from GPR101 due to the formation of a neo-TAD. Note the increase of GPR101 interactions with potential pituitary enhancers (black arrows), while other duplicated genes show normal interaction patterns. The red triangles indicate the genomic position of viewpoints in the promoters of GPR101, RBMX and VGLL1 (top to bottom). The conserved TAD border that is disrupted by duplications in X-LAG is highlighted by a red hexagon icon (“B”).
Case report: Management of pediatric gigantism caused by the TADopathy, X-linked acrogigantism

February 2024

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110 Reads

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3 Citations

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.




Consensus on criteria for acromegaly diagnosis and remission

November 2023

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1,013 Reads

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67 Citations

Pituitary

Purpose The 14th Acromegaly Consensus Conference was convened to consider biochemical criteria for acromegaly diagnosis and evaluation of therapeutic efficacy. Methods Fifty-six acromegaly experts from 16 countries reviewed and discussed current evidence focused on biochemical assays; criteria for diagnosis and the role of imaging, pathology, and clinical assessments; consequences of diagnostic delay; criteria for remission and recommendations for follow up; and the value of assessment and monitoring in defining disease progression, selecting appropriate treatments, and maximizing patient outcomes. Results In a patient with typical acromegaly features, insulin-like growth factor (IGF)-I > 1.3 times the upper limit of normal for age confirms the diagnosis. Random growth hormone (GH) measured after overnight fasting may be useful for informing prognosis, but is not required for diagnosis. For patients with equivocal results, IGF-I measurements using the same validated assay can be repeated, and oral glucose tolerance testing might also be useful. Although biochemical remission is the primary assessment of treatment outcome, biochemical findings should be interpreted within the clinical context of acromegaly. Follow up assessments should consider biochemical evaluation of treatment effectiveness, imaging studies evaluating residual/recurrent adenoma mass, and clinical signs and symptoms of acromegaly, its complications, and comorbidities. Referral to a multidisciplinary pituitary center should be considered for patients with equivocal biochemical, pathology, or imaging findings at diagnosis, and for patients insufficiently responsive to standard treatment approaches. Conclusion Consensus recommendations highlight new understandings of disordered GH and IGF-I in patients with acromegaly and the importance of expert management for this rare disease.


Comparisons between groups with AIPvar-related, unselected and DA-resistant prolactinomas in terms of age at first symptoms (A), age at diagnosis (B), maximum tumor diameter at diagnosis (C) and prolactin secretion at diagnosis (D). Box and whisker plots show medians as horizontal lines and the lower and upper limits of the box correspond to the first and third quartiles; the whiskers extend the box to 1.5 times the inter-quartile range (IQR) or to the most extreme values if they lie within this range.
Dopamine agonist treatment of prolactinomas. Comparisons between groups with AIPvar-related, unselected and DA-resistant prolactinomas according to median weekly dose of cabergoline (A); median percentage reduction from baseline at maximum cabergoline dose in the three study groups (B); a waterfall plot depicts the individual reductions in prolactin from baseline to nadir levels under maximum cabergoline doses in the three groups (C). The relationship of prolactinoma maximum diameter and prolactin secretion at baseline across the three study groups was compared in panel (D) Box and whisker plots show medians as horizontal lines and the lower and upper limits of the box correspond to the first and third quartiles; the whiskers extend the box to 1.5 times the inter-quartile range (IQR) or to the most extreme values if they lie within this range.
The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene

August 2023

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85 Reads

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4 Citations

Introduction Prolactinomas are the most frequent type of pituitary adenoma encountered in clinical practice. Dopamine agonists (DA) like cabergoline typically provide sign/ symptom control, normalize prolactin levels and decrease tumor size in most patients. DA-resistant prolactinomas are infrequent and can occur in association with some genetic causes like MEN1 and pathogenic germline variants in the AIP gene (AIPvar). Methods We compared the clinical, radiological, and therapeutic characteristics of AIPvar-related prolactinomas (n=13) with unselected hospital-treated prolactinomas (“unselected”, n=41) and genetically-negative, DA-resistant prolactinomas (DA-resistant, n=39). Results AIPvar-related prolactinomas occurred at a significantly younger age than the unselected or DA-resistant prolactinomas (p<0.01). Males were more common in the AIPvar (75.0%) and DA- resistant (49.7%) versus unselected prolactinomas (9.8%; p<0.001). AIPvar prolactinomas exhibited significantly more frequent invasion than the other groups (p<0.001) and exhibited a trend to larger tumor diameter. The DA-resistant group had significantly higher prolactin levels at diagnosis than the AIPvar group (p<0.001). Maximum DA doses were significantly higher in the AIPvar and DA-resistant groups versus unselected. DA-induced macroadenoma shrinkage (>50%) occurred in 58.3% in the AIPvar group versus 4.2% in the DA-resistant group (p<0.01). Surgery was more frequent in the AIPvar and DA- resistant groups (43.8% and 61.5%, respectively) versus unselected (19.5%: p<0.01). Radiotherapy was used only in AIPvar (18.8%) and DA-resistant (25.6%) groups. Discussion AIPvar confer an aggressive phenotype in prolactinomas, with invasive tumors occurring at a younger age. These characteristics can help differentiate rare AIPvar related prolactinomas from DA-resistant, genetically-negative tumors.


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

June 2023

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98 Reads

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11 Citations

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.


Figure 4. Functional studies of the c.2332-2A>T (p.His778fs) truncating variant
Figure 5. WT and mutant PAM promoter activity
Figure 6. PHM and PAL activity in human sera
Figure 7. Gene-and variant-based association analyses for PAM in the UKBB
Figure 8. Biological processes and cellular components that might be affected by PAM
Germline loss-of-function PAM variants are enriched in subjects with pituitary hypersecretion

January 2023

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153 Reads

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.


Citations (51)


... lead to the formation of a neo-TAD that places GPR101 under the control of ectopic centromeric enhancers that drive overexpression of GPR101 in somatotropes of the anterior pituitary [16]. In all cases of X-LAG described to date, GPR101 duplications cause disease, and the condition can be inherited in an X-linked dominant manner [38,39]. In the current study, we addressed a series of clinically derived findings that apparently challenged this link between GPR101 duplication and pituitary disease. ...

Reference:

Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus
The Genetic Pathophysiology and Clinical Management of the TADopathy, X-Linked Acrogigantism
  • Citing Article
  • May 2024

Endocrine Reviews

... The median GH level was 16.1 (5.8-40) ng/ml. Median maximum tumor diameter was 20 [16,17,18,19,20,21,22,23,24,25,26,27,28] mm. Macro-adenoma was found in 50 (94.3%) ...

Consensus on criteria for acromegaly diagnosis and remission

Pituitary

... Hence, the highest prolactin levels are found in patients with larger macroprolactinomas, as shown in the present study and in many others (1,5,16,23,24). Some authors have recently described that young patients with invasive macroprolactinomas may present higher prolactin levels when these tumors are resistant to dopamine agonists, which may be associated with genetic causes like multiple endocrine neoplasia (MEN) 1 and pathogenic germline variants in the AIP gene (AIPvar) (25). ...

The clinical and therapeutic profiles of prolactinomas associated with germline pathogenic variants in the aryl hydrocarbon receptor interacting protein (AIP) gene

... PTPRN2 has also been reported to be enriched in the membranes of b-cell secretory granules (44). Proteomics analysis also revealed the presence of PTPRN and PTPRN2, as well as peptidyl-glycine-a-amidating monooxygenase (PAM), a neuropeptide processing enzyme (45), in insulin secretory granules (46). PTPRN has also been identified in the secretory granules of chromaffin cells (47). ...

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

... A characteristic radiological feature attributed to ectopic acromegaly is the presence of T2-weighted hypointensity on MRI, which was present in 83% (25/30) of cases in a previous series. Rarely, microcysts (2.1% to 9.5% in some series) have been reported (21). Although T2 hypointense signal may be present in eutopic acromegaly as well, the prevalence is much lower (52.9%), as observed in a large series of 297 patients (22). ...

Pituitary MRI Features in Acromegaly due to Ectopic GHRH Secretion from a Neuroendocrine Tumor: Analysis of 30 cases
  • Citing Article
  • May 2022

The Journal of Clinical Endocrinology and Metabolism

... Pituitary adenomas are benign neoplasms arising from differentiated epithelial cells of the anterior pituitary. They are common indolent neoplasms [1,2]. They may cause morbidity through excessive hormone production, local sellar growth and very rarely through malignant transformation. ...

Clinical Biology of the Pituitary Adenoma

Endocrine Reviews

... This percentage can increase to 87% when a 3 Tesla resonator is used with dynamic protocols ( 17 ). However, the main inconvenient is the presence of false positives, particularly when the tumor measures < 6 mm, considering that there is a prevalence of approximately 10% of incidentally found pituitary lesions in the general population ( 18 ). On the other hand, there are ACTH-producing NENs, which, unlike small-cell lung carcinomas, may be more challenging to locate due to their small size and usual location in the middle third of the lung, adjacent to the pulmonary vasculature ( 2 ). ...

Pituitary MRI in Cushing’s Disease ‐ An Update
  • Citing Article
  • March 2022

Journal of Neuroendocrinology

... Most adenomas secrete growth hormone, but other secretory or non-secretory adenomas also occur [93]. Another FIPAassociated syndrome is X-lag, caused by a microduplication within the GPR101 gene (located on the X chromosome), manifesting with a non-X-linked early-onset pituitary adenomas secreting growth hormone and gigantism [94,95]. ...

Duplications disrupt chromatin architecture and rewire GPR101-enhancer communication in X-linked acrogigantism

The American Journal of Human Genetics

... In three cases, pasireotide normalized IGF-I in patients resistant to fg-SRL with AIP-mutations (Rostomyan et al. 2017, Daly et al. 2019. However, in ours and in another case, normalization of IGF-I was not seen (van Santen et al. 2021), illustrating that AIP variants might be involved in treatment resistance. Pegvisomant may be an alternative; however, AIP-mutated tumors are often more aggressive, and pegvisomant has no tumoral effect (Giustina et al. 2017). ...

Complicated clinical course in incipient gigantism due to a treatment resistant, AIP-mutated pediatric somatotropinoma

AACE Clinical Case Reports

... However, the analysis of the frequency of the extension within each subtype showed that Null Cell, Prl, GH, and plurihormonal PitNets have more suprasellar than parasellar extension. In a study of 202 cases of PitNets carried out by Le Brass et al., it was found that of the PitNets classified in grades III and IV on the Hardy scale, those that showed the highest frequency were PH-PitNets (44.4% n = 4/ 9) and GH (41.7% n = 5/12), which shows that in our population the frequency of these tumor subtypes is higher, highlighting that the number of cases per group is small, as in our study [49]. ...

Pituitary adenoma in patients with multiple endocrine neoplasia type 1 - a cohort study
  • Citing Article
  • October 2021

European Journal of Endocrinology