@article {568, title = {Xq26.3 Duplication in a Boy With Motor Delay and Low Muscle Tone Refines the X-Linked Acrogigantism Genetic Locus.}, journal = {J Endocr Soc}, volume = {2}, year = {2018}, month = {2018 Oct 01}, pages = {1100-1108}, abstract = {

We describe a 4-year-old boy with developmental delay who was found to carry by clinical grade (CG) molecular cytogenetics (MCs) a chromosome Xq26 microduplication. The report prompted a referral of the patient for possible X-linked acrogigantism (X-LAG), a well-defined condition (MIM300942) due to chromosomal microduplication of a nearby region. The patient was evaluated clinically and investigated for endocrine abnormalities related to X-LAG and not only did he not have acrogigantism, but his growth parameters and other hormones were all normal. We then performed high definition MCs and the duplication copy number variant (CNV) was confirmed to precisely map outside the X-LAG critical region and definitely did not harbor the X-LAG candidate gene, . The patient{\textquoteright}s phenotype resembled that of other patients with Xq26 CNVs. The case is instructive for the need for high definition MCs when CG MCs{\textquoteright} results are inconsistent with the patient{\textquoteright}s phenotype. It is also useful for further supporting the contention that is the gene responsible for X-LAG.

}, issn = {2472-1972}, doi = {10.1210/js.2018-00156}, author = {Trivellin, Giampaolo and Sharwood, Erin and Hijazi, Hadia and Carvalho, Claudia M B and Yuan, Bo and Tatton-Brown, Katrina and Coman, David and Lupski, James R and Cotterill, Andrew M and Lodish, Maya B and Stratakis, Constantine A} } @article {113, title = {Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.}, journal = {Endocrine}, volume = {51}, year = {2016}, month = {2016 Feb}, pages = {236-44}, abstract = {

X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 {\texttimes} 23.9 {\texttimes} 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 {\texttimes} 58.1 {\texttimes} 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.

}, keywords = {Adenoma, Child, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Pituitary Neoplasms, Treatment Outcome}, issn = {1559-0100}, doi = {10.1007/s12020-015-0804-6}, author = {Naves, Luciana A and Daly, Adrian F and Dias, Luiz Augusto and Yuan, Bo and Zakir, Juliano Coelho Oliveira and Barra, Gustavo Barcellos and Palmeira, Leonor and Villa, Chiara and Trivellin, Giampaolo and J{\'u}nior, Armindo Jreige and Neto, Flor{\^e}ncio Figueiredo Cavalcante and Liu, Pengfei and Pellegata, Natalia S and Stratakis, Constantine A and Lupski, James R and Beckers, Albert} } @article {50, title = {Germline or somatic GPR101 duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.}, journal = {Acta Neuropathol Commun}, volume = {4}, year = {2016}, month = {2016 06 01}, pages = {56}, abstract = {

Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8~\%) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101\&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial~acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Female, Gene Duplication, Germ-Line Mutation, Gigantism, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Pituitary Neoplasms, Receptors, G-Protein-Coupled, Treatment Outcome, Young Adult}, issn = {2051-5960}, doi = {10.1186/s40478-016-0328-1}, author = {Iacovazzo, Donato and Caswell, Richard and Bunce, Benjamin and Jose, Sian and Yuan, Bo and Hern{\'a}ndez-Ram{\'\i}rez, Laura C and Kapur, Sonal and Caimari, Francisca and Evanson, Jane and Ferra{\`u}, Francesco and Dang, Mary N and Gabrovska, Plamena and Larkin, Sarah J and Ansorge, Olaf and Rodd, Celia and Vance, Mary L and Ram{\'\i}rez-Renteria, Claudia and Mercado, Mois{\'e}s and Goldstone, Anthony P and Buchfelder, Michael and Burren, Christine P and Gurlek, Alper and Dutta, Pinaki and Choong, Catherine S and Cheetham, Timothy and Trivellin, Giampaolo and Stratakis, Constantine A and Lopes, Maria-Beatriz and Grossman, Ashley B and Trouillas, Jacqueline and Lupski, James R and Ellard, Sian and Sampson, Julian R and Roncaroli, Federico and Korbonits, M{\'a}rta} } @article {76, title = {Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects.}, journal = {Endocr Relat Cancer}, volume = {23}, year = {2016}, month = {2016 04}, pages = {221-33}, abstract = {

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that include GPR101 We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8\%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold for GPR101 that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

}, keywords = {Adult, Female, Genetic Diseases, X-Linked, Gigantism, Humans, Male, Middle Aged, Mosaicism, Polymerase Chain Reaction, Syndrome, Young Adult}, issn = {1479-6821}, doi = {10.1530/ERC-16-0082}, author = {Daly, Adrian F and Yuan, Bo and Fina, Frederic and Caberg, Jean-Hubert and Trivellin, Giampaolo and Rostomyan, Liliya and de Herder, Wouter W and Naves, Luciana A and Metzger, Daniel and Cuny, Thomas and Rabl, Wolfgang and Shah, Nalini and Jaffrain-Rea, Marie-Lise and Zatelli, Maria Chiara and Faucz, Fabio R and Castermans, Emilie and Nanni-Metellus, Isabelle and Lodish, Maya and Muhammad, Ammar and Palmeira, Leonor and Potorac, Iulia and Mantovani, Giovanna and Neggers, Sebastian J and Klein, Marc and Barlier, Anne and Liu, Pengfei and Ouafik, L{\textquoteright}Houcine and Bours, Vincent and Lupski, James R and Stratakis, Constantine A and Beckers, Albert} } @article {167, title = {Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations.}, journal = {Eur J Endocrinol}, volume = {172}, year = {2015}, month = {2015 06}, pages = {803-11}, abstract = {

OBJECTIVE: We have recently reported five patients with bilateral adrenocortical hyperplasia (BAH) and Cushing{\textquoteright}s syndrome (CS) caused by constitutive activation of the catalytic subunit of protein kinase A (PRKACA). By doing new in-depth analysis of their cytogenetic abnormality, we attempted a better genotype-phenotype correlation of their PRKACA amplification.

DESIGN: This study is a case series.

METHODS: Molecular cytogenetic, genomic, clinical, and histopathological analyses were performed in five patients with CS.

RESULTS: Reinvestigation of the defects of previously described patients by state-of-the-art molecular cytogenetics showed complex genomic rearrangements in the chromosome 19p13.2p13.12 locus, resulting in copy number gains encompassing the entire PRKACA gene; three patients (one sporadic case and two related cases) were observed with gains consistent with duplications, while two sporadic patients were observed with gains consistent with triplications. Although all five patients presented with ACTH-independent CS, the three sporadic patients had micronodular BAH and underwent bilateral adrenalectomy in early childhood, whereas the two related patients, a mother and a son, presented with macronodular BAH as adults. In at least one patient, PRKACA triplication was associated with a more severe phenotype.

CONCLUSIONS: Constitutional chromosomal PRKACA gene amplification is a recently identified genetic defect associated with CS, a trait that may be inherited in an autosomal dominant manner or occur de novo. Genomic rearrangements can be complex and can result in different copy number states of dosage-sensitive genes, e.g., duplication and triplication. PRKACA amplification can lead to variable phenotypes clinically and pathologically, both micro- and macro-nodular BAH, the latter of which we speculate may depend on the extent of amplification.

}, keywords = {Adrenal Glands, Adrenalectomy, Adult, Child, Child, Preschool, Cushing Syndrome, Cyclic AMP-Dependent Protein Kinase Catalytic Subunits, DNA Copy Number Variations, Female, Gene Amplification, Humans, Hyperplasia, Male, Phenotype, Young Adult}, issn = {1479-683X}, doi = {10.1530/EJE-14-1154}, author = {Lodish, Maya B and Yuan, Bo and Levy, Isaac and Braunstein, Glenn D and Lyssikatos, Charalampos and Salpea, Paraskevi and Szarek, Eva and Karageorgiadis, Alexander S and Belyavskaya, Elena and Raygada, Margarita and Faucz, Fabio Rueda and Izzat, Louise and Brain, Caroline and Gardner, James and Quezado, Martha and Carney, J Aidan and Lupski, James R and Stratakis, Constantine A} } @article {189, title = {X-linked acrogigantism syndrome: clinical profile and therapeutic responses.}, journal = {Endocr Relat Cancer}, volume = {22}, year = {2015}, month = {2015 Jun}, pages = {353-67}, abstract = {

X-linked acrogigantism (X-LAG) is a new syndrome of pituitary gigantism, caused by microduplications on chromosome Xq26.3, encompassing the gene GPR101, which is highly upregulated in pituitary tumors. We conducted this study to explore the clinical, radiological, and hormonal phenotype and responses to therapy in patients with X-LAG syndrome. The study included 18 patients (13 sporadic) with X-LAG and microduplication of chromosome Xq26.3. All sporadic cases had unique duplications and the inheritance pattern in two families was dominant, with all Xq26.3 duplication carriers being affected. Patients began to grow rapidly as early as 2-3 months of age (median 12 months). At diagnosis (median delay 27 months), patients had a median height and weight standard deviation scores (SDS) of >+3.9 SDS. Apart from the increased overall body size, the children had acromegalic symptoms including acral enlargement and facial coarsening. More than a third of cases had increased appetite. Patients had marked hypersecretion of GH/IGF1 and usually prolactin, due to a pituitary macroadenoma or hyperplasia. Primary neurosurgical control was achieved with extensive anterior pituitary resection, but postoperative hypopituitarism was frequent. Control with somatostatin analogs was not readily achieved despite moderate to high levels of expression of somatostatin receptor subtype-2 in tumor tissue. Postoperative use of adjuvant pegvisomant resulted in control of IGF1 in all five cases where it was employed. X-LAG is a new infant-onset gigantism syndrome that has a severe clinical phenotype leading to challenging disease management.

}, keywords = {Acromegaly, Adenoma, Adolescent, Child, Child, Preschool, Chromosomes, Human, X, Female, Gigantism, Humans, Infant, Male, Pituitary Neoplasms, Young Adult}, issn = {1479-6821}, doi = {10.1530/ERC-15-0038}, author = {Beckers, Albert and Lodish, Maya Beth and Trivellin, Giampaolo and Rostomyan, Liliya and Lee, Misu and Faucz, Fabio R and Yuan, Bo and Choong, Catherine S and Caberg, Jean-Hubert and Verrua, Elisa and Naves, Luciana Ansaneli and Cheetham, Tim D and Young, Jacques and Lysy, Philippe A and Petrossians, Patrick and Cotterill, Andrew and Shah, Nalini Samir and Metzger, Daniel and Castermans, Emilie and Ambrosio, Maria Rosaria and Villa, Chiara and Strebkova, Natalia and Mazerkina, Nadia and Gaillard, St{\'e}phan and Barra, Gustavo Barcelos and Casulari, Luis Augusto and Neggers, Sebastian J and Salvatori, Roberto and Jaffrain-Rea, Marie-Lise and Zacharin, Margaret and Santamaria, Beatriz Lecumberri and Zacharieva, Sabina and Lim, Ee Mun and Mantovani, Giovanna and Zatelli, Maria Chaira and Collins, Michael T and Bonneville, Jean-Fran{\c c}ois and Quezado, Martha and Chittiboina, Prashant and Oldfield, Edward H and Bours, Vincent and Liu, Pengfei and W de Herder, Wouter and Pellegata, Natalia and Lupski, James R and Daly, Adrian F and Stratakis, Constantine A} } @article {207, title = {Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.}, journal = {N Engl J Med}, volume = {371}, year = {2014}, month = {2014 Dec 18}, pages = {2363-74}, abstract = {

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood.

METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly.

RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients{\textquoteright} pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells.

CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

}, keywords = {Acromegaly, Adolescent, Adult, Age of Onset, Child, Child, Preschool, Chromosome Duplication, Chromosomes, Human, X, Female, Gigantism, Human Growth Hormone, Humans, Infant, Male, Mutation, Phenotype, Protein Conformation, Receptors, G-Protein-Coupled}, issn = {1533-4406}, doi = {10.1056/NEJMoa1408028}, author = {Trivellin, Giampaolo and Daly, Adrian F and Faucz, Fabio R and Yuan, Bo and Rostomyan, Liliya and Larco, Darwin O and Schernthaner-Reiter, Marie Helene and Szarek, Eva and Leal, Let{\'\i}cia F and Caberg, Jean-Hubert and Castermans, Emilie and Villa, Chiara and Dimopoulos, Aggeliki and Chittiboina, Prashant and Xekouki, Paraskevi and Shah, Nalini and Metzger, Daniel and Lysy, Philippe A and Ferrante, Emanuele and Strebkova, Natalia and Mazerkina, Nadia and Zatelli, Maria Chiara and Lodish, Maya and Horvath, Anelia and de Alexandre, Rodrigo Bertollo and Manning, Allison D and Levy, Isaac and Keil, Margaret F and Sierra, Maria de la Luz and Palmeira, Leonor and Coppieters, Wouter and Georges, Michel and Naves, Luciana A and Jamar, Mauricette and Bours, Vincent and Wu, T John and Choong, Catherine S and Bertherat, Jerome and Chanson, Philippe and Kamenick{\'y}, Peter and Farrell, William E and Barlier, Anne and Quezado, Martha and Bjelobaba, Ivana and Stojilkovic, Stanko S and Wess, Jurgen and Costanzi, Stefano and Liu, Pengfei and Lupski, James R and Beckers, Albert and Stratakis, Constantine A} }