X-LAG: How did they grow so tall? Beckers, Albert; Rostomyan, Liliya; Potorac, Iulia ...
Annales d'endocrinologie,
06/2017, Letnik:
78, Številka:
2
Journal Article, Web Resource
Recenzirano
Odprti dostop
Abstract X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101 gene. XLAG has a remarkably distinct phenotype with disease ...onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history.
Introduction
Pituitary gigantism is a rare condition caused by growth hormone secreting hypersecretion, usually by a pituitary tumor. Acromegaly and gigantism cases that have a genetic cause are ...challenging to treat, due to large tumor size and poor responses to some medical therapies (e.g.
AIP
mutation affected cases and those with X-linked acrogigantism syndrome).
Materials and methods
We performed a retrospective study to identify gigantism cases among 160 somatotropinoma patients treated between 1985 and 2015 at the University Hospital of Caracas, Venezuela. We studied clinical details at diagnosis, hormonal responses to therapy and undertook targeted genetic testing. Among the 160 cases, eight patients (six males; 75 %) were diagnosed with pituitary gigantism and underwent genetic analysis that included array comparative genome hybridization for Xq26.3 duplications.
Results
All patients had GH secreting pituitary macroadenomas that were difficult to control with conventional treatment options, such as surgery or primary somatostatin receptor ligand (SRL) therapy. Combined therapy (long-acting SRL and pegvisomant) as primary treatment or after pituitary surgery and radiotherapy permitted the normalization of IGF-1 levels and clinical improvement. Novel
AIP
mutations were the found in three patients. None of the patients had Xq26.3 microduplications.
Conclusions
Treatment of pituitary gigantism is frequently challenging; delayed control increases the harmful effects of GH excess, such as, excessive stature and symptom burden, so early diagnosis and effective treatment are particularly important in these cases.
To search for a possible role of Peroxisome Proliferator-Activated Receptor α (PPARα), a molecular partner of the Aryl hydrocarbon receptor Interacting Protein (AIP), in somatotropinomas.
Tumours ...from 51 acromegalic patients were characterized for PPARα and AIP expression by immunohistochemistry (IHC) and/or Real Time RT-PCR. Data were analysed according to tumour characteristics and pre-operative treatment with somatostatin analogues (SSA). The effects of fenofibrate were studied in GH3 cells in vitro.
PPARα was expressed in most somatotropinomas. A modest relationship was found between PPARα and AIP expression, both being significantly higher in the presence of pre-operative SSA. However, only AIP expression was influenced by the response to treatment. Dual effects of fenofibrate were observed in GH3 cells, consisting of cell growth inhibition and an increase in GH secretion inhibited by octreotide.
PPARα is a new player in somatotropinomas. Potential interactions between PPARα agonists and SSA may deserve further investigation.
•PPARα, a molecular partner of AIP, is commonly expressed in somatotropinomas.•PPARα is unlikely to play a major role in AIP-related somatotroph tumorigenesis.•Somatostatin analogues (SSA) increase PPARα expression in somatotroph tumours.•Fenofibrate has differential effects on GH3 cell growth and hormone secretion.•Potential interactions between PPRAα agonists and SSA deserve further investigation.
PURPOSE: To search for a possible role of Peroxisome Proliferator-Activated Receptor alpha (PPARalpha), a molecular partner of the Aryl hydrocarbon receptor Interacting Protein (AIP), in ...somatotropinomas. METHODS: Tumours from 51 acromegalic patients were characterized for PPARalpha and AIP expression by immunohistochemistry (IHC) and/or Real Time RT-PCR. Data were analysed according to tumour characteristics and pre-operative treatment with somatostatin analogues (SSA). The effects of fenofibrate were studied in GH3 cells in vitro. RESULTS: PPARalpha was expressed in most somatotropinomas. A modest relationship was found between PPARalpha and AIP expression, both being significantly higher in the presence of pre-operative SSA. However, only AIP expression was influenced by the response to treatment. Dual effects of fenofibrate were observed in GH3 cells, consisting of cell growth inhibition and an increase in GH secretion inhibited by octreotide. CONCLUSIONS: PPARalpha is a new player in somatotropinomas. Potential interactions between PPARalpha agonists and SSA may deserve further investigation.
New genetic cause of gigantism and FIPA Rostomyan, Liliya; Adrian, F Daly; Trivellin, Giampaolo ...
Acta clinica belgica (English ed. Online),
03/2016, Letnik:
71, Številka:
S2
Journal Article
Recenzirano
Acromegaly and gigantism result from excessive production and secretion of growth hormone (GH), usually by a pituitary adenoma, and are considered as very rare conditions. Gigantism occurs in the ...period of linear growth and is poorly understood disorder. Although previous studies have identified the various alterations in predisposing genes in somatotropinomas, genetic cause in majority of cases of acromegaly and gigantism remains unclear. We studied gigantism for genetic defects. We conducted an international study (clinical and genetic) on the pituitary gigantism. In total 208 patients were enrolled with growth hormone excess and abnormal growth for age or final height > 2SD above country local standards. Genome-wide analyses was performed in 46 patients with gigantism and 248 patients with acromegaly. Genetic or hereditary characteristics were observed in 46% of patients and included FIPA, McCune- Albright syndrome, Carney complex, and MEN type 1. AIP mutations accounted for about one third of cases. We observed a microduplication in a region of about 500 kb on chromosome Xq26.3 in samples from 17 patients with gigantism. Four were obtained from members of two FIPA families, and 13 were sporadic cases. All sporadic cases had an original duplication, while familial cases had inherited identical duplications. In all patients, the disease appeared in infancy. None of patients with gigantism that do not bear the Xq26.3 microduplication, has grown excessively before age of 5 years. Genomic characterization of Xq26.3 region suggests that microduplications are generated during chromosome replication. Patients with X-linked infantile gigantism have a common area of overlap that involves four genes, including GPR101 gene, which encodes a receptor coupled to a G protein with seven transmembrane domains. Only this gene is strongly overexpressed in pituitary tumors from two patients with infantile gigantism. A new pediatric syndrome (we called X-LAG for X-linked acrogigantism) is caused by the genomic microduplication on chromosome Xq26.3 and characterized by early onset of gigantism resulting from an excess of growth hormone. X-LAG syndrome is most likely caused by duplication of GPR101 gene.
X-linked acrogigantism (X-LAG) syndrome is a newly-described form of inheritable pituitary gigantism that begins in early childhood and is usually associated with markedly elevated growth hormone ...(GH) and prolactin secretion by mixed pituitary adenomas/hyperplasia. Microduplications on chromosome Xq26.3 including the GPR101 gene cause X-LAG syndrome. In individual cases random GH-releasing hormone (GHRH) levels have been elevated. We performed a series of hormonal profiles in a young female sporadic X-LAG syndrome patient and subsequently undertook in vitro studies of primary pituitary tumor culture following neurosurgical resection. The patient demonstrated consistently elevated circulating GHRH levels throughout preoperative testing, which was accompanied by marked GH and prolactin hypersecretion; GH demonstrated a paradoxical increase following TRH administration. In vitro, the pituitary cells showed baseline GH and prolactin release that was further stimulated by GHRH administration. Co-incubation with GHRH and the GHRH receptor antagonist, acetyl-(D-Arg(2))-GHRH (1-29) amide, blocked the GHRH-induced GH stimulation; the GHRH receptor antagonist alone significantly reduced GH release. Pasireotide, but not octreotide, inhibited GH secretion. A ghrelin receptor agonist and an inverse agonist led to modest, statistically significant increases and decreases in GH secretion, respectively. GHRH hypersecretion can accompany the pituitary abnormalities seen in X-LAG syndrome. These data suggest that the pathology of X-LAG syndrome may include hypothalamic dysregulation of GHRH secretion, which is in keeping with localization of GPR101 in the hypothalamus. Therapeutic blockade of GHRH secretion could represent a way to target the marked hormonal hypersecretion and overgrowth that characterizes X-LAG syndrome.
Le forme familiari di adenoma ipofisario D’Andrea, Settimio; Auriemma, Renata S.; Rostomyan, Liliya ...
L'Endocrinologo,
2017/2, Letnik:
18, Številka:
1
Journal Article
Recenzirano
Sommario
Gli adenomi ipofisari insorgono nel 5–6% dei casi in un contesto familiare, nell’ambito di sindromi come le Neoplasia Endocrine Multiple (MEN1, MEN4) o in forma isolata (
Familial Isolated ...Pituitary Adenomas
, FIPA). Negli ultimi anni sono state riconosciute nuove entità e nuovi geni di predisposizione tra cui, in particolare, il gene
Aryl hydrocarbon receptor Interacting Protein
(AIP). Il riconoscere una predisposizione genetica, anche in forme apparentemente sporadiche, è essenziale non solo per il caso indice ma anche per la sua famiglia.
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