ESPE2022 Poster Category 2 Growth and Syndromes (44 abstracts)
Coexistence of (likely) pathogenic variants in two genes, EZH2 and PTEN, contribute to overgrowth and developmental delay phenotype in a female patient
Sofia Suco 1 , Paula Scaglia 1,2 , Maria Esnaola Azcoiti 1,2 , Romina Armando 3 , Debora Braslavsky 1 , Nora Sanguineti 1 , Claudia Arberas 3 , Maria Gabriela Ropelato 1,2 , Agustin Izquierdo 1,2 , Ignacio Bergada 1 & Ana Keselman 1
1Centro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; 2Unidad de Medicina Traslacional. Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; 3Servicio de Genética Médica. Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
Introduction: Overgrowth syndromes comprise an heterogeneous group of rare disorders characterized by generalized or segmental excessive growth commonly associated with additional features, such as developmental delay, visceromegaly and macrocephaly. They may present with inherent health concerns and, in some instances, an increased risk of tumor development requiring prompt diagnosis and appropriate referral.
Objective: to describe a female patient with an overgrowth syndrome and developmental delay with variants in EZH2 and PTEN genes. Variants were classified according to ACMG guidelines and ClinGen PTEN Expert Panel Specifications.
Case: a 7-month-old female patient was referred due to overgrowth and developmental delay. She was born from non-consanguineous parents at 37 weeks of gestational age, birth weight: 3575 gr (+1.85 SD), length: 48 cm (+0.74 SD) and head circumference (HC): 33 cm (+0.34 SD). Target Height was normal (+ 0.34 SD). At first visit, height was 72.5 cm (+2.44 SD), weight: 10.4 Kg (+3.3 SD) and HC: 48.2 cm (+3.9 SD). Physical examination showed macrocephaly, hypertelorism, hypermetropia, depressed nasal bridge, long philtrum, microretrognathia, low set ears, hoarse voice, broad thumbs, developmental delay and hypotonia. Bone age was advanced in 1.5 years. Clinical exome sequencing (TSO-Illumina) revealed a likely pathogenic heterozygous variant in EZH2 gene: NM_004456.4:c.475G>A, p.(Gly159Arg), described in Weaver syndrome, and a pathogenic heterozygous variant in PTEN gene: NM_000314.4:c.388C>T, p.(Arg130Ter), described in PTEN hamartoma tumor syndrome (PHTS). Segregation analysis suggests that both variants have arisen de novo in this patient. Last visit at 5.3 years height was 119 cm (+1.7 SD), weight: 24 Kg (+1.4 SD) and HC: 56.3 cm (+3.9 SD). Two previously undetected lipomas (clavicular area and leg), clinical findings suggestive of PHTS, were found on physical examination.
Conclusion: The coexistence of pathogenic variants in two genes, EZH2 and PTEN, contribute to overgrowth and developmental delay phenotype in this girl, associating both, Weaver syndrome and PHTS. Surveillance program for early tumor detection is warranted because of the risk of early, bilateral and/or multifocal neoplasia associated to pathogenic PTEN variants.
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