The Clinical characteristics of X-linked acro-gigantism syndrome

Endocrine Abstracts (2015) 37 OC12.5 | DOI:10.1530/endoabs.37.OC12.5

The clinical characteristics of X-linked acro-gigantism

syndrome

Adrian Daly1_{, Giampaolo Trivellin}2_{, Liliya Rostomyan}1_{, Bo Yuan}3_{, Catherine Choong}4_{, Jacques} Young5_{, Giovanna Mantovani}6_{, Luciana Naves}7_{, Philippe Lysy}8_{, Tim Cheetham}9_{, Nalini Shah}10_, Daniel Metzger11_{, Maria Chiara Zatelli}12_{, Natalia Strebkova}13_{, Nadia Mazerkina}14_{, Michael} Collins15_{, Maya Beth Lodish}2_{, James Lupski}3_{, Constantine Stratakis}2 _{& Albert Beckers}1 1_{Department of Endocrinology, CHU de Liège, University of Liège, Liège, Belgium;} 2_{Program on}

Developmental Endocrinology and Genetics, Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA; 3_{Department of Molecular and Human Genetics, Baylor College of Medicine,}

Houston, Texas, USA; 4_{Department of Pediatric Endocrinology and Diabetes, Princess Margaret Hospital}

for Children, Subiaco, Western Australia, Australia; 5_{INSERM U693, GHU Paris‐Sud, Hôpital de}

Bicêtre, Paris, France; 6_{Endocrinology and Diabetology Unit, Fondazione IRCCS Ca’ Granda Ospedale}

Maggiore Policlinico, University of Milan, Milan, Italy; 7_{Department of Endocrinology, University of}

Brasilia, Brasilia, Brazil; 8_{Pediatric Endocrinology Unit, Université Catholique de Louvain, Brussels,}

Belgium; 9_{Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle University,}

Newcastle‐Upon‐Tyne, UK; 10_{Department of Endocrinology, KEM Hospital, Mumbai, India;} 11_{Endocrinology and Diabetes Unit, BC Children’s Hospital, Vancouver, British Columbia, Canada;} 12_Section

of Endocrinology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 13_{Institute of}

Pediatric Endocrinology, Endocrinological Research Centre, Moscow, Russia; 14_{Burdenko Neurosurgery}

Institute, Moscow, Russia; 15_{Skeletal Clinical Studies Unit, National Institute of Dental and Craniofacial}

Research, NIH, Bethesda, Maryland, USA.

X-linked acro-gigantism (X-LAG) is a rare novel genomic syndrome of pituitary gigantism that has a typical onset within the first year of life in children of normal or even low birth weight. X-LAG patients have a microduplications on chromosome Xq26.3 that includes a gene GPR101, which is highly upregulated in pituitary tumor tissue of affected patients. We performed a study of all 18 known X-LAG syndrome patients currently in the NICHD-University of Liège database to describe the clinical phenotype and therapy responses. All 13 sporadic cases had unique duplications; the inheritance pattern in familial cases was X-linked dominant. Typically, the abnormal growth was noted within the first year of life but could begin in the initial months of infancy. Despite significant somatic overgrowth (~+4 SDS height/weight), diagnoses of pituitary macroadenoma/hyperplasia were not made until usually >2 years after excessive growth began. A number of familiar acromegaly signs/symptoms accompanied somatic overgrowth, including acral enlargement and facial changes (including widely spaced teeth in some cases). About 25% of cases had increased appetite, and signs of insulin resistance (e.g. acanthosis nigricans) were reported. At diagnosis, patients had extremely elevated GH and IGF1 levels, which were accompanied by variably severe hyperprolactinemia. Control of growth was difficult to achieve in many cases, particularly those where primary neurosurgery did not fully resect the involved tissue. Efficacy of traditional somatostatin analogs was notably poor, whereas adjuvant pegvisomant therapy did provide control of IGF1 and slowed growth. However, due to the need for aggressive therapy to arrest excessive growth, postoperative hypopituitarism was frequent. The mechanisms behind the excessive stimulation of pituitary growth and elevated hormonal output are being studied, but both pituitary and hypothalamic aetiologies are possible, for example, due to high levels of GHRH-receptor staining in pituitary tumors in the face of normal or elevated circulating GHRH in some patients.

Disclosure: This work was supported by U.S. DHHS-NIH-NICHD (Z01-HD008920); U.S. Department of Health and Human Services-National Institutes of Health-National Human Genome Research Institute