IMPE2023 Poster Presentations Growth and Syndromes (15 abstracts)
Beckwith-Wiedemann Syndrome with growth failure. An oxymoron or two different diagnoses?
Anna Rothenfusser 1 , Debora Braslavsky 1 , Barbara Casali 1 , Sebastian A Vishnopolska 2 , Maria Andrea Camilletti 2 , Ana Keselman 1 , Maria Gabriela Ballerini 1 , Nora Sanguineti 1 , Julian Martinez Mayer 2 , Jacob O Kitzman 3 , Sally A Camper 3 , Paula Scaglia 1 , Maria Ines Perez-Millan 1 , Gabriela Ropelato 1 & Ignacio Bergadá 1
1Centro de Investigaciones Endocrinológicas Dr. Cesar Bergadá (CEDIE), CONICET – FEI – División de Endocrinología, Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires, Argentina. 2Instituto de Biociencias, Biotecnología y Biología Traslacional (iB3), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina. 3Dept. of Human Genetics, University of Michigan Medical School, MI 48198-5618, Ann Arbor, USA
Introduction: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by genetic or epigenetic defects within the chromosome 11p15.5 region. BWS growth pattern with accelerated growth during infancy is widely known, and whenever there is a change in the expected growth, further investigation is warranted.
Objective: To describe a patient with BWS and growth failure.
Case report: A 3-month-old male infant born from non-consanguineous and healthy parents with history of polyhydramnios. Preterm with macrosomia (weight +2.03 DSD), presented with persistent episodes of hypoglycemia, macroglossia, nephromegaly, hepatomegaly, umbilical hernia, and typical ear creases. He was clinically diagnosed with classical BWS, scoring 10 on a scale where a score >4 is sufficient for the diagnosis. Recurrent hypoglycemia, as part of BWS at the time, was treated with diet adjustment, and the last episode was observed at age 1.5 years. At the age of 1 year, growth slowed down (growth velocity < 3rd centile), and at age of 3.5 years height was -4.2 SDS. Diagnosis of isolated growth hormone deficiency (GHD) was confirmed (maximum peak at GH provocative test of 0.96 ng/dL), and recombinant rhGH was started. Tumor surveillance remained negative.
Methods: Genetic testing was performed to find unique causes for both disorders. Genomic DNA was isolated from peripheral lymphocytes. The GHD was investigated using a custom exon capture panel based on single-molecule molecular inversion probes sequencing (MIPS) containing 104 genes relevant for pituitary development. MS-MLPA (probemix ME030 targeting the imprinting center IC1 and IC2 in 11p15.5) was performed to evaluate epigenetic defects in 11p15.5.
Results: NGS revealed a homozygous pathogenic variant in the GH releasing hormone receptor (GHRHR): NC_000007.13(NM_000823.4):c.57+1G>A, chromosome 7, position 31003741 (GRCh37), known as “the Itabaianinha GHRHR mutation”. MS-MLPA showed a gain of methylation in IC1 and a loss of methylation in the IC2, confirming BWS with paternal uniparental disomy.
Conclusions: Our patient presents both BWS and GHD, leading to two concomitant pathogenic mechanisms of action affecting growth in opposite ways (overgrowth/growth retardation), and allowing for two different mechanisms of action for the development of hypoglycemia. Knowing the pathophysiology and the natural course of known diseases helped us to guide and reevaluate the diagnostic approach.
1 Brioude F. Nat Rev Endocrinol. 2018 Apr;14(4):229-249. doi: 10.1038/nrendo.2017.166.
2 Marinho CG, Growth Horm IGF Res. 2018 Aug;41:71-74. doi: 10.1016/j.ghir.2018.03.004.
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