6775 Four Cases with the Beckwith-Wiedemann Syndrome Phenotype Caused by GNAS Defects

Abstract Disclosure: T. Urakawa: None. Y. Kanamaru: None. N. Amano: None. A. Uchida: None. J. Shin: None. M. Fukami: None. M. Kagami: None. Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder with a heterogeneous phenotypic spectrum, including macroglossia (MG), lateralized overgrowth (LO), and hyperinsulinism (HI). According to the BWS clinical scoring system, the consensus statement recommends conducting genetic testing for patients with two or more scores and doing the clinical diagnosis of BWS for patients with four or more scores. The etiologies of BWS consist of methylation abnormalities of differentially methylated regions (DMRs) on 11p15.5, paternal uniparental disomy of chromosome 11 (UPD(11)pat), and maternal loss of function variants of CDKN1C. However, in 20% of BWS cases, the genetic causes remain unclear. Here, we report on four cases of the BWS phenotype with GNAS defects, known to cause pseudohypoparathyroidism (PHP). Case presentation: Case 1 was born at 37 weeks of gestation with birth weight (BW) of 2964 g (+0.8 SD) and birth length (BL) of 50.5 cm (+1.3 SD) and had MG, LO, HI, ear creases (EC), naevus flammeus, umbilical hernia (UH), and postnatal overgrowth (PO) together with intellectual disability (BWS score 9). Case 2 was born at 32 weeks with BW of 1415 g (-1.4 SD) and BL of 40.0 cm (-0.8 SD), showing MG, HI, UH, and PO (BWS score 5). Case 3 was born at 36 weeks with BW of 2366 g (-0.5 SD) and BL of 44.0 cm (-1.1 SD), exhibiting MG, EC, UH, and PO (BWS score 4). Case 4 was born at 36 weeks with BW of 2762 g (+0.6 SD) and BL of 46.0 cm (-0.4 SD), presenting MG and PO (BWS score 2). Cases 3 and 4 showed elevated intact PTH levels. Genetic analysis: Methylation-specific MLPA (MS-MLPA) for multiple DMRs showed abnormal methylation in DMRs on the GNAS locus in cases 1-3, but normal methylation levels in DMRs on 11p15.5. Case 1 had multi-locus imprinting disturbance (MLID) detected by comprehensive methylation analysis (EPIC, Illumina) and a 9pter-9p24.2 deletion identified by array CGH analysis. Case 2 also had MLID together with UPD(20)pat detected by microsatellite marker analysis. Case 3 showed only abnormal methylation in the DMRs on the GNAS locus confirmed by a comprehensive methylation analysis. Case 4 showed no abnormal methylation in the DMRs examined by MS-MLPA and had a pathogenic variant in GNAS (F219L) detected by exome sequencing. Discussion: We identified GNAS defects in four cases with the BWS phenotype. MG and PO were observed in all cases, and other BWS features in each case. Some clinical features observed in 9p terminal deletion syndrome and PHP overlap those in BWS, such as HI, MG, and PO. Therefore, these diseases should be considered as the differential diagnosis of BWS. MLID was identified in two cases, but the methylation status of DMRs on 11p15.5 was normal. The impact of MLID on the BWS phenotype is unknown. Conclusion:GNAS defects can cause the BWS phenotype. Further genetic analysis including GNAS should be considered in cases with the BWS phenotype without 11p15.5 abnormalities. Presentation: 6/2/2024