Mutations In GNAS Gene Research Articles

Identification of a novel GNAS mutation in a family with pseudohypoparathyroidism type 1A

BackgroundPseudohypoparathyroidism (PHP) is caused by loss-of-function mutations at the GNAS gene (as in the PHP type 1A; PHP1A), de novo or inherited at heterozygous state, or by epigenetic alterations at the GNAS locus (as in the PHP1B). The condition of PHP refers to a heterogeneous group of disorders that share common clinical and biological features of PTH resistance. Manifestations related to resistance to other hormones are also reported in many patients with PHP, in association with the phenotypic picture of Albright hereditary osteodystrophy characterized by short stature, round facies, subcutaneous ossifications, brachydactyly, mental retardation and, in some subtypes, obesity. The purpose of our study is to report a new mutation in the GNAS gene and to describe the significant phenotypic variability of three sisters with PHP1A bearing the same mutation.Case presentationWe describe the cases of three sisters with PHP1A bearing the same mutation but characterized by a significantly different phenotypic picture at onset and during follow-up in terms of clinical features, auxological pattern and biochemical changes. Clinical exome sequencing revealed a never before described heterozygote mutation in the GNAS gene (NM_000516.5 c.118_139 + 51del) of autosomal dominant maternal transmission in the three siblings, confirming the diagnosis of PHP1A.ConclusionsThis study reported on a novel mutation of GNAS gene and highlighted the clinical heterogeneity of PHP1A characterized by wide genotype–phenotype variability. The appropriate diagnosis has crucial implications for patient care and long-term multidisciplinary follow-up.

THU235 Usefulness Of Digital Droplet Polymerase Chain Reaction (ddPCR) For Molecular Diagnosis Of McCune-Albright Syndrome In DNA From Peripheral Blood Leukocytes

Abstract Disclosure: A.G. de Faria: None. L.R. Montenegro: None. A.A. Jorge: None. R.S. Jallad: None. R.M. Martin: None. M.C. Fragoso: None. A.P. Canton: None. C.E. Seraphim: None. F.R. Tinano: None. N.C. Pinto: None. B.B. Mendonca: None. A. Latronico: None. V.N. Brito: None. Background: McCune-Albright Syndrome (MAS) is a rare congenital disorder caused by post-zygotic activating mutations in GNAS gene. Due to the mosaic pattern of this disease, mutation abundance is frequently low in several tissues, including blood cells. The emergence of digital droplet Polymerase Chain Reaction (ddPCR) is a breakthrough technology of quantitative PCR useful for a targeted detection and quantification of rare events. Objective: This study aims to identify the GNAS mutation in peripheral blood leukocytes of patients with MAS using ddPCR. Patients and Methods: Thirty-four patients (25 female and 9 male) with typical (classic triad) or atypical (one or two features) MAS were included. DNA was extracted from peripheral blood and was analyzed through ddPCR method. Two ddPCR mutation detection assays were used, each one targeting the p.R201C or p.R201H mutations. For each assay, the Taqman PCR system was used with two fluorescence probes: the first labeled with HEX, targeting de (WT allele), and the second labeled 6-FAM, targeting the (mutated allele). The mixture (reagents + DNA) was divided into 20,000 nanodrops, which was placed on a PCR plate and amplified by PCR. After amplification by PCR, the fluorescence of each droplet was read on the 200 Droplet Digital PCR system (Bio-Rad), being classified as positive (drop containing the target sequence) or negative. Results were analyzed using Quantasoft software (Bio-Rad) to determine the total amount of positive droplets in the original sample. The results were reported in fractional abundance (FA), corresponding to the percentage of mutated alleles within the total alleles. Results: Among all patients, the most common MAS feature was osteofibrous dysplasia (OFD) (73.5%), followed by peripheral precocious puberty (PPP) (64.7%), and café-au-lait skin spots (52.9%). Acromegaly or hyperthyroidism was diagnosed in 6 and 4 patients, respectively. Classical MAS triad, 2 clinical features, or 1 clinical feature (PPP or OFD) were present in 15, 9, and 10 patients, respectively. GNAS mutations were identified in 12/34 (35.3%) MAS patients: the p.R201C in 5 and the p.R201H in 7. Among them, 8 patients presented typical MAS and 4 patients with two MAS clinical features, respectively. Considering only typical MAS group, the positive molecular test rate was 53.3% (8/15). GNAS mutations were not identified in patients with only one MAS feature. There was a positive correlation between a positive molecular test and the number of MAS clinical features (p = 0.01). Median FA was 1.45%, ranged from 0.25% to 8.4%. There was no association between FA rate and the number of MAS clinical features (p=1.0). Conclusion: ddPCR representeds a more sensitive tool for identifying GNAS mutations in peripheral blood leukocytes, even with low abundance, in patients with classical and atypical MAS. Presentation: Thursday, June 15, 2023

Clinical Case of Mccune-Albright-Braitsev Syndrome (MAS)

The presented clinical case describes orphan disease known as MAS with manifested symptoms of precocious puberty, recurrent ovarian cysts, fibrous dysplasia, café-au-lait skin pigmentation and abnormal cardiac conduction. The pathogenesis is based on the GNAS gene mutation that cause hyperactivation of glycoprotein hormone receptors and hypersecretion. There are genetic tests that confirm the diagnosis, however, given the high percentage of false negative results, in most cases the disease is diagnosed based on a combination of clinical and laboratory-instrumental data. Given the high clinical variability and absence of management algorithms for patient with this syndrome, the article pinpoints the necessity of thorough examination of patients to select further management tactics. Multidisciplinary approach and collegiate case management will improve diagnosis of the disease and prevent the development of severe complications.

GNAS gene mutations affecting XLαs and bone health: A long neglected relationship.

The GNAS locus is an imprinted site. The α-subunit of the stimulatory G protein (Gsα) and extralarge variant (XLαs) are the two important products of the GNAS locus. The abnormal expression of Gsα is associated with pseudohypoparathyroidism (PHP) and related disorders, including Albright hereditary osteodystrophy (AHO), pseudopseudohypoparathyroidism (PPHP), and progressive osseous heteroplasia (POH). XLαs protein can mimic the catalytic intracellular synthesis of cyclic adenosine monophosphate (cAMP) by Gsα in response to parathyroid hormone (PTH) stimulation, which may be involved in the pathogenesis of PPHP and POH in patients with paternal GNAS defects. A paternally inherited nonsense variant in the first exon of XLαs in an adult patient may be associated with fractures and osteopetrosis. The relationship between the XLαs product of the GNAS locus and bone remodeling may have been overlooked. Here, we summarize the phenotypes of genetic mouse models and clinical cases of XLαs variations and suggest that the abnormal paternal expression of XLαs may be associated with the development of POH and affect osteoblast and osteoclast differentiation.

Current concepts of craniofacial fibrous dysplasia: pathophysiology and treatment.

Fibrous dysplasia is an uncommon genetic disorder in which bone is replaced by immature bone and fibrous tissue, manifesting as slowgrowing lesions. Sporadic post-zygotic activating mutations in GNAS gene result in dysregulated GαS-protein signaling and elevation of cyclic adenosine monophosphate in affected tissues. This condition has a broad clinical spectrum, ranging from insignificant solitary lesions to severe disease. The craniofacial area is the most common site of fibrous dysplasia, and nine out of 10 patients with fibrous dysplasia affecting the craniofacial bones present before the age of 5. Surgery is the mainstay of treatment, but the technique varies according to the location and severity of the lesion and associated symptoms. The timing and indications of surgery should be carefully chosen with multidisciplinary consultations and a patient-specific approach.

Progressive osseous heteroplasia in a 5-year-old boy with a novel mutation in exon 2 of GNAS: a case presentation and literature review

BackgroundProgressive osseous heteroplasia (POH) is a rare genetic condition that causes progressive ossification. This usually results from an inactivating mutation of the paternal GNAS gene. Herein, we report a case of POH caused by a novel mutation in exon 2 of the GNAS gene.Case presentationA 5-year-old Chinese boy was referred to our hospital for a growing mass in his right foot. Although laboratory findings were normal, radiographic imaging revealed severe ossification in his right foot and smaller areas of intramuscular ossification in his arms and legs. A de novo mutation (c.175C > T, p.Q59X) in exon 2 of the GNAS gene was identified, prompting a diagnosis of POH. We conducted a systematic literature review to better understand this rare disease.ConclusionWe have discovered that a de novo nonsense mutation in exon 2 of GNAS can lead to POH. Our literature review revealed that ankylosis of the extremities is the primary clinical outcome in patients with POH. Unlike other conditions such as fibrodysplasia ossificans progressiva (FOP), patients with POH do not experience respiratory failure. However, much remains to be learned about the relationship between the type of GNAS gene mutation and the resulting POH symptoms. Further research is needed to understand this complex and rare disease. This case adds to our current understanding of POH and will contribute to future studies and treatments.

A Case Report of Polyostotic form of Fibrous Dysplasia: Imaging Features in Radiograph, Computed Tomography and Magnetic Resonance Imaging

Fibrous dysplasia is a disease that causes aberrant development of osteoblasts, which results in fibrous stroma replacing normal bone. Lichtenstein first described it in 1938. It is a sporadic disorder caused due to a postzygotic mutation in the GNAS1 gene. It can affect a single bone (monostotic) or several bones (polyostotic). The most common locations are the skull & ribs. It is typically an incidental finding and asymptomatic. When a pathologic fracture or malignant alteration complicates it, symptoms could develop. As polyostotic FD is a rare disorder that only occasionally occurs in 20–25% of patients, therefore the aim of this article is to report such a rare case of polyostotic FD in a 30-year-old female patient showing the characteristic changes. Keywords: Polyostotic fibrous dysplasia, GNAS1 gene mutation, Sporadic disorder

A GNAS Gene Mutation's Independent Expression in the Growth of Colorectal Cancer: A Systematic Review and Meta-Analysis.

Globally, colorectal carcinoma CRC is the third most common cancer and the third most common reason for cancer-associated mortality in both genders. The GNAS mutations are significantly linked with poor prognosis and failed treatment outcomes in CRC. A systematic review and meta-analysis of multiple studies executed following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria and registered with PROSPERO (registration number: CRD42021256452). The initial search includes a total of 271 publications; however, only 30 studies that merit the eligibility criteria were eventually chosen. Data analysis via OpenMeta Analyst and comprehensive meta-analysis 3.0 (CMA 3.0) software were used to investigate the prevalence of GNAS gene mutation among CRC patients. The meta-analysis consisted of 10,689 participants with most being males 6068/10,689 (56.8%). Overall, prevalence of GNAS mutations was 4.8% (95% CI: 3.1-7.3) with I2 = 94.39% and (p < 0.001). In 11/30 studies, the frequency of GNAS gene mutations was majorly in codons R201C [40.7% (95% CI: 29.2-53.2%)] and in codon R201H [39.7% (95% CI = 27.1-53.8)]. Overall prevalence of GNAS mutations was highest among the male gender: 53.9% (95% CI: 48.2-59.5%: I2 = 94.00%, (p < 0.001), tumour location (colon): 50.5% (95% CI: 33.2-67.6%: I2 = 97.93%, (p < 0.001), tumour grade (Well): 57.5% (95% CI: 32.4-79.2%: I2 = 98.10%, (p < 0.001) and tumour late stage: 67.9% (95% CI: 49.7-84.3%: I2 = 98.%, (p < 0.001). When stratified according to study location, a higher prevalence was observed in Japan (26.8%) while Italy has the lowest (0.4%). Overall prevalence of GNAS gene mutations was 4.8% with codons R201C and R201H being the most mutated, and the results conformed with numerous published studies on GNAS mutation.

A recurrent somatic missense mutation in GNAS gene identified in familial thyroid follicular cell carcinomas in German longhaired pointer dogs

BackgroundWe previously reported a familial thyroid follicular cell carcinoma (FCC) in a large number of Dutch German longhaired pointers and identified two deleterious germline mutations in the TPO gene associated with disease predisposition. However, the somatic mutation profile of the FCC in dogs has not been investigated at a genome-wide scale.ResultsHerein, we comprehensively investigated the somatic mutations that potentially contribute to the inherited tumor formation and progression using high depth whole-genome sequencing. A GNAS p.A204D missense mutation was identified in 4 out of 7 FCC tumors by whole-genome sequencing and in 20 out of 32 dogs’ tumors by targeted sequencing. In contrast to this, in the human TC, mutations in GNAS gene have lower prevalence. Meanwhile, the homologous somatic mutation in humans has not been reported. These findings suggest a difference in the somatic mutation landscape between TC in these dogs and human TC. Moreover, tumors with the GNAS p.A204D mutation had a significantly lower somatic mutation burden in these dogs. Somatic structural variant and copy number alterations were also investigated, but no potential driver event was identified.ConclusionThis study provides novel insight in the molecular mechanism of thyroid carcinoma development in dogs. German longhaired pointers carrying GNAS mutations in the tumor may be used as a disease model for the development and testing of novel therapies to kill the tumor with somatic mutations in the GNAS gene.

Large café-au-lait spots on a 5-year-old boy

Large café-au-lait spots on a 5-year-old boy

Abstract #1175512: A Case of McCune Albright Syndrome with Multiple Associated Endocrinopathies

McCune-Albright Syndrome (MAS) is a rare genetic disorder classically defined by a triad of fibrous dysplasia of bone, café-au-lait spots, and precocious puberty. The underlying pathophysiology of this disorder is an activating somatic mutation of GNAS gene at 20q13 – which codes for the alpha subunit of the Gs protein. In addition to gonadotropin independent precocious puberty, MAS is associated with other endocrinopathies including hyperthyroidism, hyperparathyroidism, growth hormone excess, and Cushing syndrome.

Polyostotic fibrous dysplasia: imaging findings of a controversial case

Fibrous dysplasia is a rare non-neoplastic tumor-like congenital bone disease that is most likely associated with GNAS gene mutations, with a broad spectrum of clinical presentations, ranging from isolated monostotic and polyostotic forms to other extra-skeletal associated manifestations as in McCuneAlbright syndrome. It is responsible for bones weakening and increased fragility, making it prone to fractures.
 A 65-year-old female patient was referred to our radiology department for cervical and dorsal pain, with a previous diagnosis of incidental cervical and dorsal bone lesions that are suspected for metastases. X-ray, computed tomography, and magnetic resonance imaging were performed with a precise diagnostic suspicion of fibrous dysplasia that is confirmed by bone biopsy.
 Fibrous dysplasia principally affects the bone and is characterized by bone replacement itself by dysplastic fibrous tissue. According to the number of affected bones and their association to endocrine alterations, it is classified into three categories monostotic, polyostotic, and Albrights disease. Differential diagnosis with multiple myeloma among others and the best treatment decision was made.

Coexistence of craniopharyngioma and cranial fibrous dysplasia: a case series of clinicopathological study

BackgroundCraniopharyngioma (CP) and cranial fibrous dysplasia (CFD) are rare embryonic benign cranial diseases that most commonly present during childhood or adolescence. The coexistence of CP and CFD is extremely rare and has not yet been reported.MethodsWe retrospectively reviewed the data of five patients with concomitant CP and CFD treated at Beijing Tiantan Hospital from January 2003 to January 2021 and summarized their clinicopathological features, treatment modalities, and outcomes. We also performed a comprehensive literature review, tested the patients for characteristic GNAS gene mutations related to CFD, and tested the CP specimens for corresponding Gsα protein to explore the potential connection leading to the coexistence of CP and CFD.ResultsThe cohort comprised four men and one woman (median age, 39 years). The symptoms mainly included headache, dizziness, fatigue, polyuria/polydipsia, hypogonadism, and blurred vision. CFD most commonly involved the sphenoid bone (n = 4). Four patients underwent surgery to remove the CP (one trans-sphenoidal and three transcranial resections); complete and subtotal resection were achieved in two patients, respectively. The tumor subtype was adamantinomatous in three patients and unknown in one. The common postoperative complications were panhypopituitarism, diabetes insipidus, and hypothyroidism. The mean follow-up duration was 57.2 months. Two patients required postoperative hormone replacement therapy. Three patients underwent genetic study of the tumor specimens; GNAS mutations were not detected, but these patients were positive for Gsα protein.ConclusionsAlthough a definite causative relationship has not been proved, the coexistence of CP and CFD means that potential interplay or an atypical fibrous dysplasia course as uncommon manifestations of CP cannot be excluded. It is more challenging to initiate prompt diagnosis and appropriate treatment for concomitant CP and CFD than for solitary CP because of skull base deformations. Current management strategies are aimed at surgical treating the CP and regularly monitoring the CFD.

McCune-Albright syndrome associated with pituitary adenoma: a clinicopathological study of ten cases and literature review

Background McCune-Albright syndrome (MAS) is a rare genetic, non-inheritable disease and is characterized by fibrous dysplasia, hyperendocrinism, and café-au-lait macules. Pituitary adenomas could be concurrent with this syndrome but clinicopathological features and the surgical management of such disorders is unclear. Methods We retrospectively reviewed ten MAS-associated pituitary adenoma patients with follow-up in Beijing Tiantan Hospital and analyzed their clinicohistological data, surgical strategies, neuro-imaging, genetic mutations, and prognosis. Moreover, a critical review of the English language literature was also conducted. Results All of the ten MAS-associated adenoma patients underwent surgeries to remove the tumor (nine transsphenoidal approaches and one transcranial approach). None of these patients had a decompression of the optic canal. Notably, the growth hormone (GH), prolactin (PRL), and IGF-1 level had a significant reduction after the resection of the tumor while vision improvement was observed in most patients (6/7) with visual deficits. No tumor recurrence was observed during the follow-up from 16 to 150 months. The pathological examination showed a moderate Ki-67 LI (mean 1.19%, range from 0.1% to 3.3%) and the positive staining of Gsα and PKA C-beta. GNAS gene mutation (R201C) was detected in one patient. Conclusions Hormone excess (including GH and PRL) could be significantly reduced and the visual deficits are greatly improved after the surgery without the decompression of the optic canal. In addition, MAS-associated pituitary adenomas have a moderate expression of Ki-67 and positive expression of Gsα and PKA C-beta, indicating a mildly proliferative nature of these tumors and the possible linking between MAS and adenomas.

Detection of Gene Mutation for Patients with McCune- Albright Syndrome and Diagnosis Experience: A Report of Two Cases and Literature Review

Background: McCune-Albright Syndrome (MAS) is a rare disease characterized by a broad spectrum of syndromes, including hyperfunctioning endocrinopathies, café-au-lait leisions, and multiple bone fibrous dysplasias. The diagnosis of MAS is usually based on clinical symptoms. However, most of MAS patients may not display typical symptoms, which make the early diagnosis and treatment of MAS difficult. Cases: Patient 1, a 7-year and 4-month-old girl, developed vaginal bleeding with no apparent cause. A Café-au-lait macule patch could be seen on the right trunk. E2 was 914pmol/L. FSH <0.1IU/L, Luteinizing Hormone (LH) <0.1IU/L. Performing ultrasound, there was a cystic mass in the left accessory area with ovarian echo. There were bone abnormalities in the long bones of the extremities. Patient 2, a girl aged 4 years and 9 months, has abnormal enlarged breasts with no obvious cause. There was a cystic mass in the left accessory area with ovarian echo No apparent Café-au-lait macule hyperpigmented skin macule was seen. E2 is 800pg/ml, FSH <0.1IU/L, LH is 0.2IU/L. GNAS mutation were both positive in the cyst tissue but was negative in the peripheral blood. Conclusion: Gene sequencing is the confirmable proof in diagnosis of MAS. Negative GNAS gene mutation results in the peripheral blood and skin cannot completely rule out the possibility of MAS. Biopsy of the lesion tissues, such as ovarian tissue, may present more efficient results. New detection techniques have higher sensitivity and make molecular diagnosis more accurate.

MANAGEMENT OF ENDOCRINE DISEASE: Etiology and outcome of acromegaly in patients with a paradoxical GH response to glucose.

To gain more insight on the pathogenesis of somatotroph pituitary adenomas, recent studies have focused on a subgroup of patients with acromegaly displaying a paradoxical growth hormone (GH) response during oral glucose tolerance test (OGTT). The paradoxical rise of GH after oral glucose intake occurs in about one-third of acromegaly patients and has been pathogenetically linked, by analogy to glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome, to the ectopic expression of GIP receptor (GIPR) in somatotroph adenoma cells. GIPR-expressing adenomas are negative for activating GNAS gene mutations and display distinct cytogenetic and DNA methylation profiles, highlighting their unique molecular pathogenesis. Acromegaly patients with a paradoxical GH response pattern seem to display higher insulin-like growth factor-1 (IGF-1) concentrations and harbour smaller adenomas that are more often of the densely granulated phenotype. They seem also to show a better response to somatostatin receptor ligands. In addition, persistent paradoxical GH response after surgery may be a biological marker of the residual disease postoperatively. Targeted therapy to antagonize GIP receptor on GIPR-expressing somatotroph adenomas could be a new treatment approach for acromegaly patients with a paradoxical pattern of GH response to OGTT.

Rare and novel GNAS gene mutations in Chinese patients with thyroid cancer

AbstractBackgroundA large number of novel, rare, and uncharacterized mutations in Tumors including thyroid cancer (TC) have been discovered. In this study, we reported two GNAS mutations in Chinese TC patients, and assessed the functional impact.MethodsTwo hundred and twenty five formalin‐fixed, paraffin‐embedded (FFPE) tissue specimens from Chinese TC patients were tested by NGS. The functional impact of GNAS mutations was assessed using sorting intolerant from tolerant tools (SIFT), polymorphism phenotyping v2 (POLYPHEN‐2) and the mutation assessor. The GNAS protein structure was modeled by Iterative Threading ASSEmbly Refinement (I‐TASSER), and modeling of mutations was performed and visualised by PyMOL.ResultsTwo somatic missense GNAS gene mutations including a rare c.956A>G(p.D319G) and a novel c.1399G>T(p.A467S) were detected in 225 TC tissues (2/225, 0.89%). The novel GNAS mutation c.1399G>T(p.A467S) was predicted to benign and low impact on the protein. SIFT and Mutation Assessor predicted c.956A>G(p.D319G) will be neutral and have low impact, while Polyphen‐2 indicated the mutation may be probably damaging. c.1399G>T(p.A467S) and c.956A>G(p.D319G) molecular modeling data showed two mutations not changed in Gsα, and showed little predicted effect on protein structure.ConclusionsA rare somatic GNAS gene mutations c.956A>G(p.D319G) and a novel somatic GNAS mutation c.1399G>T(p.A467S) were found in the present study, which appeared to be associated with low impact on the protein.

Symptoms: Clogged Ears and Muffled Hearing

Symptoms: Clogged Ears and Muffled Hearing

P0907STRIKING NOVEL MULTI-MISMUTATIONS ON GNAS1,FGF23,FGFR3 GENES IN CKD WITH SECONDARY HYPERPARATHYROIDISM.(SH).SAGLIKER SYNDROME(SS).SS IS A COMBINATION-COMPULSION OF BONE DYSPLASIAS-HEREDITARY OSTEODYSTROPHİES AND SH AND CKD

Abstract Background and Aims Sagliker Syndrome seems to be related to CKD and the consequent SH.SS starts and develops particularly before puberty while CKD reaches stage III level with overt SH. Since it occurs in some patients, it is plausible to think SS is genetically predisposed.GNAS1, FGF23 and FGFR3 genes' mismutations on the genesis of SS is unclear, and no data are available. Method We conducted clinical, radiological, laboratory studies and screening for mutations in GNAS1 gene in 23 patients, FGF23 and FGFR3 genes in 17 patients.DNA isolations were performed from blood samples and mutations regions were amplified by Polymerase Chain Reaction (PCR). Results In 73.9% (17/23) patients, 17 different genetic abnormalities in GNAS1 were detected.Seven (58.3% ) of the 12 nucleotide alterations comprised novel missense mutations in different manners. There were also 6 heterozygous tranversion polymorphism in exons.Six of them were introngenic mismutations found in exons (introns; 65626, 70387 and 70817).We found 10 different mismutations in FGF23 gene. 8 were novel mismutations and are defined first in our study. 3 of them were in intronic region near exon 2.In FGFR3 gene we also found 22 different mutations. 16 were novel mismutations defined first in our study.8 of them were in intronic region near exon 11,last 2 were in non-coding exonic region of exon 18. Twelve mismutations were found in exons, 8 were found in introns and 2 were found in non-coding exonic regions. One was in the exon-exon junction region between exon 11 and 12 Therefore this mutation might be preventing splicing of this intron. Conclusion There are plenty of mutations on those three genes in Sagliker Syndrome and are consistent with an insufficiency of those three genes playing a role in the clinical phenotype of loss of function mutations and with functional alleles having predominant roles in preventing the hormonal resistance.Since the incidence of CKD late stage III is around 8% in the world but the incidence of Sagliker Syndrome is around 0.5% in CKD patients, these gene mismutations might be responsible for bone Displasias-- Hereditary Osteodystrophies such as Mc Cune- Albright syndrome, achondroplasias etc.., although our patients were not resembling any of them but they could be in between and Sagliker Syndrome might be a combination-compulsion of Bone displasias-Hereditary Osteodystrophies and SH and CKD.

Molecular profiling for acromegaly treatment: a validation study.

Pharmacologic treatment of acromegaly is currently based upon assay-error strategy, the first-generation somatostatin receptor ligands (SRL) being the first-line treatment. However, about 50% of patients do not respond adequately to SRL. Our objective was to evaluate the potential usefulness of different molecular markers as predictors of response to SRL. We used somatotropinoma tissue obtained after surgery from a national cohort of 100 acromegalic patients. Seventy-one patients were treated with SRL during at least 6 months under maximal therapeutic doses according to IGF1 values. We analyzed the expression of SSTR2, SSTR5, AIP, CDH1 (E-cadherin), MKI67 (Ki-67), KLK10, DRD2, ARRB1, GHRL, In1-Ghrelin, PLAGL1 and PEBP1 (RKIP) by RT-qPCR and mutations in GNAS gene by Sanger sequencing. The response to SRL was categorized as complete response (CR), partial (PR) or non-response (NR) if IGF1 was normal, between >2<3 SDS or >3 SDS IGF1 at 6 months of follow-up, respectively. From the 71 patients treated, there were 27 CR (38%), 18 PR (25%) and 26 NR (37%). SSTR2, Ki-67 and E-cadherin were associated with SRL response (P < 0.03, P < 0.01 and P < 0.003, respectively). E-cadherin was the best discriminator for response prediction (AUC = 0.74, P < 0.02, PPV of 83.7%, NPV of 72.6%), which was validated at protein level. SSTR5 expression was higher in patients pre-treated with SRL before surgery. We conclude that somatotropinomas showed heterogeneity in the expression of genes associated with SRL response. E-cadherin was the best molecular predictor of response to SRL. Thus, the inclusion of E-cadherin in subsequent treatment-decision after surgical failure may be useful in acromegaly.