Received: 17 August 2019
Pediatric Blood & Cancer
SOCIÉTÉ INTERNATIONALE D’ONCOLOGIE PÉDIATRIQUE SKOP INTERNATIONAL SOCIETY OF PAEDIATRIC ONCOLOGY
aspho The American Society of Pediatric Hematology/Oncology
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WILEY
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 present with 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 characterized by hemihypertrophy, macrosomia, macroglos- sia, 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 chromo- some 11p15.5 region including loss of methylation (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), CDKN1C mutations, 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 2 months of age (Figure 1A 1 B). She was born at term following an in vitro fertilization (IVF) pregnancy to non- consanguineous parents with no family history of malignancies or pre- vious 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 x 4 cm mass in the right lumbar quadrant with ill-defined borders. She had Tanner stage 2 pubic hair. Other system examinations 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 com- plete restoration of gain in height and head circumference (Figure 1C- E). 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 rec- ommends molecular testing in any suspected cases of BWS with a clin- ical 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 adreno- cortical 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 sub- groups of BWS that are at highest risk and that children with IC2 LOM should not be offered routine US.2 However, our patient, together with the earlier reports of IC2 LOM and ACC, suggest that tumor surveil- lance in BWS with IC2 LOM may be required and that the guideline may 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 mon- itoring head circumference in neonatal/infantile CS, before and after treatment.
A
B
C
D
cm
110
52
cm
E
Head
97
51
circumference
90
100
50
97
100
75
90
50
49
75
25
48
90
10
90
50
3
47
25
46
10
80
80
45
44
3
70
70
43
Height
42
60
Age (months)
41
21
24
27
40
12
15
18
18
50
97
39
6
9
90
0
3
16
38
75
kg
50
14
37
25
12
10
12
36
3
10
10
35
8
8
34
6
6
33
4
Weight
4
32
Age (months)
2
31
0
2
4
6
8
10
12
14
16
18
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
ACKNOWLEDGMENT
Authors are thankful to the patient and her family.
ORCID
Tulay Guran ID https://orcid.org/0000-0003-2658-6866
Mehmet Eltan1 Esra Arslan Ates2 Kivilcim Cerit3 Tuba Seven Menevse1 Sare Betul Kaygusuz1 Nursah Eker4 Pelin Bagci5 Rabia Ergelen6 Serap Turan1 Abdullah Bereket1 Tulay Guran1 İD
1 Department of Paediatric Endocrinology and Diabetes, School of Medicine, Marmara University, Istanbul, Turkey
2 Department of Medical Genetics, School of Medicine, Marmara University, Istanbul, Turkey
3 Department of Paediatric Surgery, School of Medicine, Marmara University, Istanbul, Turkey
4 Department of Paediatric Oncology, School of Medicine, Marmara University, Istanbul, Turkey
5 Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
6 Department of Radiology, School of Medicine, Marmara University, Istanbul, Turkey
Correspondence
Tulay Guran, Department of Paediatric Endocrinology and Diabetes, School of Medicine, Marmara University, Fevzi Cakmak Mh. Mimar Sinan Cd. No 41, Ustkaynarca/Pendik, 34899 Istanbul, Turkey
Email: tulayguran@yahoo.com
This work has been presented in ENDO 2019 meeting (J Endocr Soc. 2019 Apr 15; 3 (Suppl 1): MON-LB061. Published online 2019 Apr 30. doi: 10.1210/js.2019-MON-LB061, PMCID: PMC6551134). The parents have given their written informed consent to publish their case (including publication of images).
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