Pituitary Gigantism Research Articles

Chromatin conformation capture in the clinic: 4C-seq/HiC distinguishes pathogenic from neutral duplications at the GPR101 locus

BackgroundX-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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.

Germline AIP variants in sporadic young acromegaly and pituitary gigantism: clinical and genetic insights from a Han Chinese cohort.

Variants in the Aryl hydrocarbon receptor-interacting protein (AIP) gene have been identified in sporadic acromegaly and pituitary gigantism, especially in young patients, with a predisposition to aggressive clinical phenotype and poor treatment efficacy. The clinical characteristics of patients with sporadic acromegaly and pituitary gigantism as well as AIP variants in Han Chinese have been rarely reported. We aimed to identify AIP gene variants and analyze the clinical characteristics of patients with sporadic acromegaly and pituitary gigantism in Han Chinese. The study included 181 sporadic acromegaly (N = 163) and pituitary gigantism (N = 18) patients with an onset age of no more than 45 years old, who were diagnosed, treated, and followed up in Huashan Hospital. All 6 exons and their flanking regions of the AIP gene were analyzed with Sanger sequencing or NGS. The clinical characteristics were compared between groups with and without AIP variants. Germline AIP variants were found in 15/181 (8.29%) cases. In patients with an onset age ≤30 years old, AIP variants were identified in 12/133 (9.02%). Overall, 13 variants were detected. The pathogenic (P) variants p.R304X and p.R81X were identified in four cases, with two instances of each variant. Six exon variants (p.C254R, p.K103fs, p.Q228fs, p.Y38X, p.Q213*, and p.1115 fs) have not been reported before, which were likely pathogenic (LP). Patients with P/LP variants had younger onset ages, a higher prevalence of pituitary gigantism, larger tumor volumes, and a higher percentage of Ki-67-positive cells in tumors. In addition, the group with P/LP variants showed a less significant reduction of GH levels in an acute octreotide suppression test (OST) [17.7% (0, 65.0%) vs. 80.5% (63.9%, 90.2%), P = 0.001], and a trend of less GH decrease after the 3-month treatment with long-acting somatostatin analogs (SSAs). Germline AIP variants existed in sporadic Chinese Han acromegaly and pituitary gigantism patients and were more likely to be detected in young patients. AIP variants were associated with more aggressive tumor phenotypes and less response to SSA treatment.

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

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.

A complex case of pituitary gigantism: overcoming challenges in diagnosis and treatment

A complex case of pituitary gigantism: overcoming challenges in diagnosis and treatment

FRI307 Gigantism Due To Transcriptional Activation Of GHRH: The First Case Of Hormone-encoding Gene Overexpression Underlying A Congenital Disorder

Abstract Disclosure: A. Hattori: None. Y. Katoh-Fukui: None. R. Zhang: None. M. Terao: None. S. Takada: None. K. Nakabayashi: None. K. Hata: None. Y. Yamada: None. N. Matsuura: None. M. Fukami: None. Background: Pituitary gigantism is characterized by tall stature due to GH overproduction. To date, known genetic causes of pituitary gigantism are invariably associated with predispositions to tumors producing GH or GHRH. Clinical and genetic findings of the patient: The patient was a Japanese woman who was born mildly large for gestational age. Her overgrowth started in her first year of life. Despite radiation and pharmacotherapy starting at age three years, she reached an adult height of 197 cm (+7.4 SD). She developed panhypopituitarism associated with empty sella in adulthood and was deceased during sleep at age 53 years. Exome sequencing identified no pathogenic variant causing acromegaly or gigantism. Chromosomal microarray analysis detected a 752-kb deletion upstream of GHRH. This deletion was predicted to create a chimeric gene consisting of the 5´-UTR of TTI1, a ubiquitously expressed gene, and the coding region of GHRH. Reverse transcription PCR (RT-PCR) using mRNA of immortalized lymphoblastoid cells detected the chimeric transcript. Analysis of model mice: We established a mouse model harboring a 676-kb deletion upstream of Ghrh using the CRISPR/Cas9 system. RT-PCR detected a chimeric transcript consisting of the 5´-UTR of Tti1 and the coding region of Ghrh, which mimicked the patient’s chimeric transcript. Mutant mice started to overgrow at two weeks of age and showed high serum GH levels and long tibia at 12-13 weeks of age. Quantitative RT-PCR showed that the median level of Ghrh expression in the hypothalamus of the mutant mice was three-fold higher than that of the wildtype mice. Furthermore, the mutant mice had ectopic Ghrh expression in all analyzed tissues (the pituitary, thymus, heart, liver, and gonad). Discussion: Our findings propose a novel etiology of gigantism. In the present case, the GHRH gene obtained a constitutively active promoter through germline genomic microdeletion. The newly acquired promoter likely led to the constant expression of GHRH in various tissues including the hypothalamus. Possible explanations for GH overproduction in the present case include (1) GHRH overproduction in the hypothalamus, (2) paracrine and autocrine effects of GHRH secreted from the pituitary, and (3) endocrine effects of GHRH produced outside the hypothalamic-pituitary unit. The patient’s clinical course suggests that prenatal GHRH overproduction only mildly affects human growth. More importantly, this is the first case in which transcriptional activation of a hormone-encoding gene caused a human congenital disorder. Presentation: Friday, June 16, 2023

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

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. 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. 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. The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function.

Awaken a sleeping giant: Incidentally discovered pituitary gigantism

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Chromosomal microdeletion leading to pituitary gigantism through hormone-gene overexpression.

Pituitary gigantism is a rare endocrinopathy characterized by tall stature due to growth hormone (GH) hypersecretion. This condition is generally linked to a genetic predisposition to tumors that produce GH or GH-releasing hormone (GHRH). Here, we report a Japanese woman who exhibited prominent body growth from infancy to reach an adult height of 197.4cm (+7.4 standard deviation). Her blood GH levels were markedly elevated. She carried no pathogenic variants in known growth-controlling genes but had a hitherto unreported 752 kb heterozygous deletion at 20q11.23. The microdeletion was located 8.9 kb upstream of GHRH and encompassed exons 2-9 of a ubiquitously expressed gene TTI1 together with 12 other genes, pseudogenes and non-coding RNAs. Transcript analyses of the patient's leukocytes showed that the microdeletion produced chimeric mRNAs consisting of exon 1 of TTI1 and all coding exons of GHRH. In silico analysis detected promoter-associated genomic features around TTI1 exon 1. Genome-edited mice carrying the same microdeletion recapitulated accelerated body growth from a few weeks after birth. The mutant mice developed pituitary hyperplasia and exhibited ectopic Ghrh expression in all tissues examined. Thus, the extreme phenotype of pituitary gigantism in the patient likely reflects GHRH overexpression driven by an acquired promoter. The results of this study indicate that germline submicroscopic deletions have the potential to cause conspicuous developmental abnormalities due to gene overexpression. Furthermore, this study provides evidence that constitutive expression of a hormone-encoding gene can result in congenital disease.

Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil

Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil

Diagnostic problems and management of pituitary gigantism leading to ischemic stroke and atrial myxoma in young adult patient: a case report

Background: Gigantism is the excessive secretion of growth hormones (GH) during childhood and is mostly caused by benign pituitary adenomas. The signs and symptoms are not specific in early childhood due to growth spurt. An ischemic stroke is rarely present in pituitary adenoma, and here we present a case of ischemic stroke and atrial myxoma associated with pituitary gigantism. Case Presentation: The patient was an 18-year-old male who complained of continuous growth. In June 2016, the patient suffered from an embolic stroke, and in January 2017 he complained of fatigue and shortness of breath. The echocardiography showed a mass in the left atrium that was removed in March 2017 through open-heart surgery; the pathological histology confirmed a myxoma. The brain magnetic resonance imaging (MRI) showed a pituitary macroadenoma, and the growth hormone (GH) level was 20.6 ng/mL. In October 2019, the patient was referred to Dr. Soetomo Hospital. The height increased from 185 cm in 2017 to 205 cm in 2019. The height was 205cm, weight 85kg, body mass index 20.2 kg/m2, GH level >40 ng/mL, cortisol 11.24 ug/dL, prolactin 1.21 ng/mL, testosterone 425.6 ng/dL, free thyroxine (FT4) 1.03 ng/dL, and insulin-like growth factor 1 (IGF-1) 688 ng/mL. The patient was administered oral cabergoline 0.25 mg twice a week and had endoscopic endonasal transsphenoidal hypophysectomy (EETH). The patient developed postoperative polyuria after surgery which indicated diabetes insipidus, and the patient was administered desmopressin 0.05mg/12 h with fluid restriction. One week later, the morning cortisol level was low, and hydrocortisone therapy was administered and was tap-off. One month-post surgery, the level of morning serum cortisol was 0.86 µg/dL. Conclusion: This case is extremely rare and we demonstrated that the EETH surgery the stability of GH could be achieved.

EP114: De novo prenatal diagnosis of X-linked Acromegaly Gigantism (X-LAG)

X-Linked Acromegaly Gigantism (X-LAG) is a rare monogenic cause of pituitary gigantism with 34 cases reported in the literature. It is characterized by infant or childhood-onset pituitary gigantism and caused by microduplications of Xq26.3. This region includes GPR101 which is believed to drive growth in pituitary tumors and promote secretion of prolactin and growth hormone. Pituitary gigantism arises from an excess of growth hormone prior to the fusion of the growth plates, from a GH secreting pituitary adenoma or pituitary hyperplasia.

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

X-linked acrogigantism (X-LAG) is the most severe form of pituitary gigantism and is characterized by aggressive growth hormone (GH)-secreting pituitary tumors that occur in early childhood. X-LAG is associated with chromosome Xq26.3 duplications (the X-LAG locus typically includes VGLL1, CD40LG, ARHGEF6, RBMX, and GPR101) that lead to massive pituitary tumoral expression of GPR101, a novel regulator of GH secretion. The mechanism by which the duplications lead to marked pituitary misexpression of GPR101 alone was previously unclear. Using Hi-C and 4C-seq, we characterized the normal chromatin structure at the X-LAG locus. We showed that GPR101 is located within a topologically associating domain (TAD) delineated by a tissue-invariant border that separates it from centromeric genes and regulatory sequences. Next, using 4C-seq with GPR101, RBMX, and VGLL1 viewpoints, we showed that the duplications in multiple X-LAG-affected individuals led to ectopic interactions that crossed the invariant TAD border, indicating the existence of a similar and consistent mechanism of neo-TAD formation in X-LAG. We then identified several pituitary active cis-regulatory elements (CREs) within the neo-TAD and demonstrated in vitro that one of them significantly enhanced reporter gene expression. At the same time, we showed that the GPR101 promoter permits the incorporation of new regulatory information. Our results indicate that X-LAG is a TADopathy of the endocrine system in which Xq26.3 duplications disrupt the local chromatin architecture forming a neo-TAD. Rewiring GPR101-enhancer interaction within the new regulatory unit is likely to cause the high levels of aberrant expression of GPR101 in pituitary tumors caused by X-LAG.

The intriguing giant deer from the Bate cave (Crete): could paleohistological evidence question its taxonomy and nomenclature?

The research describes for the first time a possible case of pituitary gigantism in fossil mammals, precisely in deer. The pathology was detected in 2 long bones (tibia and metatarsus) belonging to an individual of an unusual large size found at the Bate cave (Rethymnon, Northern Crete). It formed the basis of Candiacervus major, the largest among the endemic deer species recorded in the Pleistocene‐Early Holocene of Crete. Radiological and histomorphological examinations highlighted a reduction in cortical bone thickness and the presence of wide lacunae inside of the bone tissue. The pathological conditions suggest a pituitary gigantism diagnosis also supported by some morphological evidence, such as the extremely elongated distal part of the metatarsal diaphysis, the proportionally small proximal epiphysis, and some bone gracility. The diagnosis of a case of pituitary gigantism as presumed responsible for the extraordinary elongation of the tibia and the metatarsal bone is intriguing as they are, respectively, the paratype and the holotype of the C. major. The species represents a case of a deviation from the “island rule” in Pleistocene large mammals. The new evidence recommends a taxonomic and nomenclatural revision of this species. The main outcomes of this research are as follows: (i) a case of pituitary gigantism is described for the first time in an extinct mammal; (ii) it is underlined that paleohistology may provide interesting clues for disentangling taxonomic and nomenclatural issues; (iii) one of the very few cases of gigantism in insular mammals is being questioned.

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.

Genetic and Epigenetic Causes of Pituitary Adenomas.

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8, USP48, and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis.

The X-linked acrogigantism-associated gene gpr101 is a regulator of early embryonic development and growth in zebrafish

We recently described X-linked acrogigantism (X-LAG), a condition of early childhood-onset pituitary gigantism associated with microduplications of the GPR101 receptor. The expression of GPR101 in hyperplastic pituitary regions and tumors in X-LAG patients, and GPR101's normally transient pituitary expression during fetal development, suggest a role in the regulation of growth. Nevertheless, little is still known about GPR101's physiological functions, especially during development. By using zebrafish models, we investigated the role of gpr101 during embryonic development and somatic growth. Transient ectopic gpr101 expression perturbed the embryonic body plan but did not affect growth. Loss of gpr101 led to a significant reduction in body size that was even more pronounced in the absence of maternal transcripts, as well as subfertility. These changes were accompanied by gastrulation and hypothalamic defects. In conclusion, both gpr101 loss- and gain-of-function affect, in different ways, fertility, embryonic patterning, growth and brain development.

Genetics, clinical features and outcomes of non-syndromic pituitary gigantism: experience of a single center from Sao Paulo, Brazil.

Non-syndromic pituitary gigantism (PG) is a very rare disease. Aryl hydrocarbon receptor-interacting protein (AIP) and G protein-coupled receptor 101 (GPR101) genetic abnormalities represent important etiologic causes of PG and may account for up to 40% of these cases. Here, we aimed to characterize the clinical and molecular findings and long-term outcomes in 18 patients (15 males, three females) with PG followed at a single tertiary center in Sao Paulo, Brazil. Genetic testing for AIP and GPR101 were performed by DNA sequencing, droplet digital PCR and array comparative genomic hybridization (aCGH). Pathogenic variants in the AIP gene were detected in 25% of patients, including a novel variant in splicing regulatory sequences which was present in a sporadic male case. X-LAG due to GPR101 microduplication was diagnosed in two female patients (12.5%). Of interest, these patients had symptoms onset by age 5 and 9years old and diagnosis at 5 and 15years, respectively. X-LAG, but not AIP, patients had a significantly lower age of symptoms onset and diagnosis and a higher height Z-score when compared to non-X-LAG. No other differences in clinical features and/or treatment outcomes were observed among PG based on their genetic background. We characterize the clinical and molecular findings and long-term outcome of the largest single-center PG cohort described so far.

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.

HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: GPR101, an orphan GPCR with roles in growth and pituitary tumorigenesis.

We recently described X-linked acrogigantism (X-LAG) in sporadic cases of infantile gigantism and a few familial cases of pituitary gigantism in the context of the disorder known as familial isolated pituitary adenomas. X-LAG cases with early onset gigantism (in infants or toddlers) shared copy number gains (CNG) of the distal long arm of chromosome X (Xq26.3). In all patients described to date with Xq26.3 CNG and acro-gigantism, the only coding gene sequence shared by all chromosomal defects was that of GPR101. GPR101 is a class A, rhodopsin-like orphan guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) with no known endogenous ligand. We review what is known about GPR101, specifically its expression profile in human and animal models, the evidence supporting causation of X-LAG and possibly other roles, including its function in growth, puberty and appetite regulation, as well as efforts to identify putative ligands.

Pituitary gigantism. The possibility of medical treatment

Pituitary gigantism is a disease caused by an excess of growth hormone and characterized by tallness with a proportional increase in all parts of the body. Almost always in patients with pituitary gigantism found pituitary adenoma, producing growth hormone (somatotropin). In rare cases, there is excess production of somatoliberin by the hypothalamus or tumors outside the brain. Somatotropinoma can be sporadic or caused by a disease with genetic defects: multiple endocrine neoplasia type 1, McCuneAlbright syndrome, Carney complex, X-LAG syndrome, AIP-mutation. All associated with genetic defects somatotropinoma more invasive and less amenable to drug therapy than sporadic. Clinical recommendations (protocols) for the treatment of pituitary gigantism in children currently does not exist. The issue of preliminary medical treatment to improve the outcome of neurosurgical interventions has not been resolved, and further methodologically based studies are needed to clarify this point. The article presents a clinical case of pituitarygigantism caused by pituitary adenoma, which produces growth hormone in a 12-year-old boy. The diagnosis was established on the basis of clinical and anamnestic, laboratory data and magnetic resonance imaging. Clinical and laboratory manifestations of hypopituitarism and diabetes insipidus, visual field disorders, neurological symptoms, as well as signs of genetic diseases in the patient were not noted. Treatment with bromocriptin gave a partial positive effect: the size of the formation in the pituitary gland decreased, but the target hormonal parameters were not achieved. A trial administration of octreotide subcutaneously was carried out, as a result of which the level of growth hormone decreased to the target values, no side effects of the drug were noted, which led to the choice of a conservative method as the first line of therapy. Thedecision to treat with bromocryptine in combination with octreotide extended action. The dynamics of tumor sizeonthebackgroundofconservative therapy will answer the question of the need for subsequent neurosurgical treatment.