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Genetic Investigation of Patients with Tall Stature

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2 182 E Vasco de Albuquerque Genetic investigation of tall 182:2 139–147 Clinical Study Albuquerque and others stature patients Genetic investigation of patients with tall stature Edoarda Vasco de Albuquerque Albuquerque1, Mariana Ferreira de Assis Funari2, Elisângela Pereira de Souza Quedas1, Rachel Sayuri Honjo Kawahira3, Raquel Soares Jallad4, Thaís Kataoka Homma1, Regina Matsunaga Martin2,5, Vinicius Nahime Brito2, Alexsandra Christianne Malaquias1,6, Antonio Marcondes Lerario1,7, Carla Rosenberg8, Ana Cristina Victorino Krepischi8, Chong Ae Kim3, Ivo Jorge Prado Arnhold2 and Alexander Augusto de Lima Jorge1 1Unidade de Endocrinologia Genética (LIM25), 2Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular (LIM42), Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brasil, 3Unidade de Genética do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil, 4Unidade de Neuroendocrinologia, 5Unidade de Doenças Osteometabólicas, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brasil, 6Unidade de Endocrinologia Pediátrica, Correspondence Departamento de Pediatria, Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo, Brasil, 7Division of should be addressed Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, to A A L Jorge Michigan, USA, and 8Instituto de Biociências (IB), Universidade de São Paulo (USP), São Paulo, Brasil Email [email protected] Abstract Context: Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach. Objective: To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder. Design: Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31). European Journal of Endocrinology Patients and methods: We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups. Main outcome measures: Frequencies of pathogenic findings. Results: We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith–Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients. Conclusion: A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup. European Journal of Endocrinology (2020) 182, 139–147 https://eje.bioscientifica.com © 2020 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0785 Printed in Great Britain Downloaded from Bioscientifica.com at 09/27/2021 05:46:43AM via free access -19-0785 Clinical Study E Vasco de Albuquerque Genetic investigation of tall 182:2 140 Albuquerque and others stature patients Introduction Endocrinology outpatient clinic in a tertiary center. Seven patients were already followed in Genetic Endocrinology Tall stature is defined as a height above 2 standard-deviation Unit, and the remaining patients were initially followed score (SDS) from the mean of a specific population after in other outpatient clinics and recruited from Medical adjustment for gender and age and can also be defined as a Genetics (n = 12), Neuroendocrinology (n = 9) and other height above 2 SDS from mid-parental height (1). Similarly endocrinology units (n = 11) at the same tertiary center. to short stature cases, tall individuals are commonly Eight patients were referred from other medical specialties referred to an endocrinologic evaluation of the GH/IGF1 and private clinics during the recruitment period. The axis, and in most patients, there is no evidence of abnormal study was approved by the Hospital das Clinicas Ethics GH secretion leading to enhanced growth (1). Committee (CAPPesq; approval number 1.854.859). After a careful clinical evaluation and a few Patients or parents (or legal guardians) provided written complementary tests to detect hidden congenital informed consent after careful explanation and all malformations (1), tall individuals can be classified procedures were in accordance with local ethical standards as syndromic or non-syndromic. Syndromic patients and the Declaration of Helsinki. show a combination of relevant alterations, such as All patients were submitted to a careful clinical neurodevelopmental delay, macrocephaly, major cardiac assessment and physical examination was performed by a abnormalities, facial dysmorphic features and skeletal geneticist (R S H K or C A K) and/or by an endocrinologist alterations, and these characteristics usually cluster in with expertise in dysmorphology (A A L J) in order to unique, classical phenotypes that lead to the identification detect dysmorphic features, neurodevelopmental delay, of the underlying genetic etiology. However, many of macrocephaly and family history of tall stature. Patients these conditions, such as Sotos (OMIM 117550), Weaver were classified as syndromic if they showed developmental (OMIM 277590) and Malan (OMIM 614753) syndromes, delay/autism spectrum disorder/intellectual disability, have overlapping phenotypes, making it very difficult to if they showed multiple major malformations or if they clinically distinguish these conditions, especially later had multiple dysmorphic features. Pubertal status was in life (2, 3, 4, 5). Besides, most genes already associated assessed according to Tanner and Marshall stages (10, with generalized overgrowth are large and do not have 11). Standing and sitting heights were measured using a hotspots, which makes an approach by candidate gene a calibrated stadiometer to the nearest 0.1 cm, and weight time and labor-consuming option to attempt diagnosis was measured using an electronic scale. BMI was calculated confirmation (3, 6). as the division between weight in kilograms and height European Journal of Endocrinology Few studies were published aiming to identify the in square meters. Measurements were converted to SDS etiology of the growth disorder of these patients, mostly using age- and sex-specified norms 12( , 13). Arm span and only when a clinical suspicion arose (7, 8, 9). To our head circumference were obtained using a measuring tape. knowledge only one report has systematically investigated Abnormal body proportion was defined by sitting height/ a selected cohort of individuals with intellectual disability height ratio SDS <−2 or arm span/height ratio >1.05 (2, and overgrowth (tall stature and/or macrocephaly) using 14). Measures were also obtained from all available relatives a multigene analysis approach, reaching a diagnostic rate and mid-parental height was calculated using the formula of 50% (9). ((father’s height + mother’s height ± 13 cm)/2) and then After the spread of multigene analysis techniques such expressed in SDS. We had no access to the measurements as targeted panel and whole exome sequencing (WES), of 15 parents (mother and/or father) since they were either the genetic evaluation of patients with tall stature became deceased or unavailable due to social problems. feasible even in cases without prior clinical diagnosis. In Laboratory work-up included basal IGF1, TSH, free this context, the present study prospectively evaluated a T4, LH, FSH and testosterone/estradiol (according to the cohort of patients with tall stature, both syndromic and patient sex) measurements. All hormones were assessed non-syndromic, using targeted panel and/or WES, after an by an electrochemiluminescence method (Cobas e601, initial laboratory and genetic assessment. Roche Diagnostics). IGF1 levels were expressed as SDS for age and sex according to reference values provided Patients and methods by the assay manufacturer. When IGF1 SDS >2, an oral glucose tolerance test was performed and only individuals We enrolled 46 children and adults referred for evaluation who achieved GH suppression <1 μg/L were included in of tall stature from January 2016 to June 2019 in our Genetic this study (15). Four individuals were excluded due to https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 09/27/2021 05:46:43AM via free access Clinical Study E Vasco de Albuquerque Genetic investigation of tall 182:2 141 Albuquerque and others stature patients pituitary gigantism. Children with precocious puberty in five patients (three syndromic and two non-syndromic). were also excluded, except for one syndromic female One non-syndromic patient was analyzed together with patient who achieved an adult height SDS >2 even an affected brother and two others with their unaffected without appropriate treatment. Subjects were submitted relative,
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