Beckwith-Wiedemann syndrome mimicking the classical form of congenital adrenal hyperplasia in newborn screening

Abstract

Beckwith-Wiedemann syndrome (BWS) is a common genetic congenital disease characterized by somatic overgrowth and its broad clinical spectrum includes pre- and post-natal macrosomia, macroglossia, visceromegaly, increased risk of neonatal hypoglycemia, and development of embryonic tumors. BWS occurs due to genetic/epigenetic changes involving growth-regulating genes, located on region 11p15, with an important genotype-phenotype correlation. Congenital adrenal hyperplasia (CAH) comprises a spectrum of autosomal recessive diseases presenting a variety of clinical manifestations due to a deficiency in one of the enzymes involved in cortisol secretion. Early diagnosis based on newborn screening prevents the adrenal crisis and early infant death. However, high 17-hydroxyprogesterone (17-OHP) levels can occur in newborns or premature infants without CAH, in situations of stress due to maternal or neonatal factors. Here, we report new cases of false-positive diagnosis of 21-hydroxylase deficiency during newborn screening - two girls and one boy with BWS. Methylation-specific multiplex ligation-dependent probe amplification revealed a gain of methylation in the H19 differentially methylated region. Notably, all three cases showed a complete normalization of biochemical changes, highlighting the transient nature of these hormonal findings that imitate the classical form of CAH. This report sheds light on a new cause of false-positive 21-hydroxylase deficiency diagnosis during newborn screening: Beckwith-Wiedemann syndrome.

Figure 1. MS-MLPA results for Beckwith-Wiedemann syndrome. Probe ratios are indicated by dots. Blue and red lines are the 95% confidence interval (CI) of the reference samples. Black dots: within the 95% CI. Blue dots: outside the 95% CI. A, B, and C show normal copy number variation (CNV) and a gain of methylation (GOM) at ICR1 as the signal of the four probes for ICR1 increase to approach one. (A) Patient 1. (B) Patient 2. (C) Patient 3.