Adrenocortical carcinoma in atypical Beckwith‐Wiedemann syndrome due to loss of methylation at imprinting control region 2

To the Editor: Neonatal Cushing syndrome (CS) is an extremely rare disorder, which is caused by exogenous or endogenous hypercortisolemia. Most of the cases presentwith an isolated adrenocortical tumor (ACT), often an adrenocortical carcinoma (ACC). Neonatal CS may present as part of a Beckwith-Wiedemann syndrome (BWS) due to an ACC.1 BWS is characterizedbyhemihypertrophy,macrosomia,macroglossia, organomegaly, hyperinsulinism, omphalocele/umbilical hernia, and distinct facial features.2 Patients with BWS have an increased risk of developing intrabdominal embryonal tumors early in life.2 BWS is usually caused by genetic or epigenetic defects within the chromosome11p15.5 region including loss ofmethylation (LOM) at imprinting control region 2 (IC2, also known as KCNQ1OT1:transcriptional start site [TSS] differentially methylated region [DMR] or KCNQ1OT1:TSS DMR), gain of methylation (GOM) at imprinting control region 1 (IC1, also known as H19/IGF2 DMR), paternal uniparental disomy (pUPD), CDKN1Cmutations, and chromosomal rearrangements. Here, we present a young infant with CS due to an ACC. She was later diagnosed as “atypical BWS” due to LOM at IC2 (KCNQ1OT1:TSS DMR). A 5-month-old female child patient was evaluated for excessive weight gain, arrested gain in height and head circumference, voracious appetite, and irritability from 2months of age (Figure 1A 1 B). She was born at term following an in vitro fertilization (IVF) pregnancy to nonconsanguineous parents with no family history of malignancies or previous antenatal losses. On examination, she had signs of CS, nevus flammeus between the eyebrows and microcephaly (Figure 1B). Her growth chart showed a decrease in height and head circumference percentiles (Figure 1E). Her blood pressure was greater than 95th centile for age. There was a palpable 3 × 4 cm mass in the right lumbar quadrant with ill-defined borders. She had Tanner stage 2 pubic hair. Other systemexaminations were unremarkable. Her biochemical (Table S1) and imaging studies established the diagnosis of ACT in the right adrenal gland as the cause of CS (Figure S1). Right adrenalectomy and resection of the adrenal mass was performed. Histopathological examination was compatible with an ACC with a modified Weiss score of 4 (Figure S1). There was no adrenal cortex cytomegaly on histopathological evaluation. Genetic testing revealed LOM at IC2 (KCNQ1OT1:TSS DMR) in the infant’s leucocyte DNA (80% LOM) and in the ACT tissue (85% LOM). Methylation of IC1 was normal. Copy number variation testing by SNP-array excluded chromosomal aberrations at 11p15.5. She had an uneventful postoperative recovery period with a complete restoration of gain in height and head circumference (Figure 1CE). Atypical BWS develops as a result of (epi) genetic changes at the BWS locus, with fewer characteristic features of BWS.2 Our patient had ACC and nevus flammeus, resulting in a BWS clinical score of 2 according to the international BWS consensus statement, which recommendsmolecular testing in any suspected cases of BWSwith a clinical score of ≥2.2 Conception by IVF has been associated with BWS because molecular studies have shown that >90% of children with BWS conceived by assisted reproduction technologies have a LOM in KCNQ1OT1 at IC2, as in our patient.3,4 ACC constitutes only 3% of all tumors seen in BWS.5 ACC was not reported in a large BWS case series in association with LOM at IC2.5 There are a few case reports of ACT associated with LOM of the KCNQ1OT1 gene.6,7 Vijnen et al reported two cases with LOM of KCNQ1OT1 with adrenal adenoma and ACC, respectively.8 Similar to our patient, neither of these cases had no phenotypic features of BWS. They suggested that KCNQ1OT1 LOM should be considered in all cases of apparently sporadic and isolated adrenocortical adenoma and carcinoma, not just in those with a clear BWS phenotype.8 The international BWS consensus group suggested that tumor surveillance, including abdominal ultrasonography (US) and serum alpha-fetoprotein screening, is appropriate for those molecular subgroups of BWS that are at highest risk and that children with IC2 LOM should not be offered routineUS.2 However, our patient, togetherwith the earlier reports of IC2 LOM and ACC, suggest that tumor surveillance inBWSwith IC2LOMmaybe requiredand that theguidelinemay need reconsideration. One interesting clinical observation in our case was the presence of microcephaly at presentation. In the growing infant, one of the most important early signs of CS is height deceleration together with continuous weight gain. In the first months of life, there is a considerable increase in head circumference that may be impaired in young babies with CS. However, microcephaly may go unnoticed and has only been reported in neonatal CS once previously.9 Head circumference stagnation may also be related to cerebral atrophy in infants with CS.10 We have demonstrated catch-up growth in head circumference along with restoration of height and weight after the surgical removal of ACC.We wish to highlight the importance of monitoring head circumference in neonatal/infantile CS, before and after treatment.