Check for updates
AMERICAN JOURNAL OF medical genetics
PART WILEY A
Pediatric Cushing syndrome: An early sign of an underling cancer predisposition syndrome
Bahareh M. Schweiger 1,2 Chaya L. Esakhan3
David Frishberg 4 ID
|
Katheryn Grand1 İD Ruchira Garg1,2 | |
Pedro A. Sanchez-Lara1,2 İD
1Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, California
2Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, California
3Technion-Israel Institute of Technology American Medical School, Haifa, Israel
4Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California
Correspondence
Pedro A. Sanchez-Lara, MD, MSCE, Cedars Sinai Medical Center, 8635 W 3rd St. Suite 1165, Los Angeles, CA 90048, USA. Email: pedro.sanchez@cshs.org
Abstract
Beckwith-Wiedemann syndrome (BWS) is a genetic overgrowth and cancer predis- position syndrome that can be associated with a spectrum of clinical features includ- ing isolated lateralized overgrowth, macrosomia, macroglossia, organomegaly, omphalocele/umbilical hernia, and distinct facial features. Because of a range of clini- cal presentations and molecular defects involving Chromosome 11p15, many cases will fall within what is now being defined as the Beckwith-Wiedemann spectrum (BWSp). Cushing syndrome (CS) in infants is a rare neuroendocrinological disease associated with hypercortisolism that has rarely been reported in patients with BWS. Here, we describe the first case of a 5-month-old male with CS secondary to paternal uniparental disomy of Chromosome 11p without additional clinical signs or symp- toms of BWS. This case continues to expand the phenotypic spectrum of BWSp.
KEYWORDS
adrenocortical carcinoma, Beckwith-Wiedemann syndrome, cancer predisposition syndrome, chromosome microarray, Cushing syndrome, uniparental disomy
|
1 INTRODUCTION
Beckwith-Wiedemann syndrome (BWS; OMIM #130650) is a genetic overgrowth and cancer predisposition syndrome that is associated with isolated lateralized overgrowth, macrosomia, macroglossia, organomegaly, omphalocele/umbilical hernia, and distinct facial fea- tures. Patients with classic features of BWS and those that are included in the broader Beckwith-Wiedemann spectrum (BWSp) are also at an increased risk for embryonal tumors, such as hepato- blastoma, Wilms tumor, and neuroblastoma (Cöktü et al., 2020; Duffy et al., 2019). Benign and malignant adrenal masses have been reported at a higher frequency in BWS than in the general population (MacFarland et al., 2017).
BWS is caused by genetic or epigenetic changes on Chromosome 11p15. The specific genetic or epigenetic changes include loss of methylation at KCNQ1OT1:TSS differentially methylated region
(DMR; IC2 LOM), gain of methylation at H19/IGF2:IG-DMR (IC1 GOM), paternal uniparental isodisomy of Chromosome 11 (pUPD11), CDKN1C loss-of-function mutations, and chromosome abnormalities altering copy number or structure of 11p15.5. These genetic or epige- netic changes lead to dysregulation in genes affecting growth.
Cushing syndrome (CS) (also known as Cushing disease) is a rare neuroendocrine condition in the pediatric population characterized by weight gain, growth failure, and changes in facial appearance (Magiakou et al., 1994). Additional later signs include striae, obesity, emotional lability, hypertension, fatigue, and virilization (Savage & Storr, 2012). The most common cause of CS is iatrogenic because of chronic treatment with glucocorticoids for neuroendocrine diseases (Klein et al., 2014). The overall incidence of endogenous CS is 0.7-2.4 per million people per year with 10% being pediatric cases (Stratakis, 2012). The main cause of endogenous cases of pediatric CS are adrenocorticotropic hormone (ACTH) secreting pituitary adenoma for children over 7 years old and adrenocortical tumors for infants and toddlers (Creemers et al., 2015). Infantile adrenocortical tumors, 0s.2% of all pediatric tumors, are commonly associated with Li-
A
Fraumeni syndrome, and rarely associated with McCune Albright syn- drome or Carney complex, with respective mutations in TP53, GNAS, and PRKAR1A genes (Tatsi & Stratakis, 2018).
To date, CS has been reported in two individuals with BWS. Car- ney et al. (2012) reported on three individuals with CS due to adrenal enlargement. In this series, Patient 2 had a molecularly confirmed diagnosis of BWS, specifically due to pUPD11. Additionally, Brioude et al. (2016) reported on a 17-year-old patient with CS because of a pituitary microadenoma. This patient was found to have mosaic LOM IC2.
Here, we describe the first incidence of CS in a 5-month-old male with an adrenal cortical adenoma secondary to molecular findings of BWS without previously recognized symptoms. This patient further expands the phenotypic spectrum of BWSp and underscores the com- plexity of neuroendocrine disorders, thus highlighting the importance of genetic testing for efficient treatment, care, and interventions.
2 CLINICAL REPORT |
A 5-month-old male presented with progressive feeding issues, agita- tion, excessive weight gain, and slowing growth rate in length. His length was at 78% at birth but crossed percentiles to 1% by 5 months of age. Weight was at 48% at birth and then increased to 97% by 5 months of age. Weight for length was >99% and plotted 4 SDs above mean. He was irritable, had round facies, short neck with redundant folds, central adiposity, supple buffalo hump, and hirsutism on fore- head. He had no other signs or history that raised suspicion of BWS. He had normal growth parameters at birth, no history of neonatal hypoglycemia, no ear lobe creases, posterior auricular pits, mac- roglossia, asymmetry, or abdominal or inguinal hernias. He was also
noted to have a new onset heart murmur, tachycardia, and hyperten- sion. Echocardiogram findings were suggestive of severe obstructive hypertrophic cardiomyopathy including severe left ventricular outflow tract obstruction. Abdominal ultrasound revealed a hypoechoic solid mass posterior to the liver and superior to the right kidney. Subsequent abdominal magnetic resonance imaging demonstrated a large, cir- cumscribed lesion measuring approximately 6 x 7 mm in the right adre- nal gland (Figure 1). There was an elevated random cortisol 48 µg/dl with suppressed ACTH <5 pg/ml. Intravenous dexamethasone adminis- tration studies were consistent with a diagnosis of ACTH-independent CS. Immunostaining and histologic studies confirmed an adrenal cortical adenoma (Figure 2). Microscopic tumor features recapitulated various zones in the adrenal gland, with a nesting-to-trabecular pattern. Tumor cells lacked cytomegalic changes that are classically described in BWS (Figure 3). The tumor lacked definitive features of an adrenal cortical carcinoma, which typically have gross evidence of hemorrhage and necrosis, infiltrative borders, frequent capsular and vascular invasion, and marked pleomorphism and high mitotic rate. According to the criteria for malignancy in adrenal cortical neoplasms, the tumor was classified as an adrenal cortical neoplasm with a score of 1 out of 9, which is associated with good clinical outcome (Wieneke et al., 2003).
A chromosome microarray identified a mosaic long stretch of homozygosity (LCSH) in the short arm of Chromosome 11 from band p15.5 to p11.2, at least 44.33 Mb in size and reported as arr[GRCh37] 11p15.5p11.2(0_90150274)x2 mos hmz. Additional studies confirmed a loss of methylation at imprinting center 2 (IC2) and gain of methyla- tion at imprinting center 1 (IC1) suggestive of paternal-uniparental disomy 11p15.5, consistent with a diagnosis with increased cancer risks as others described as part of the BWSp (Duffy et al., 2019; Shu- man et al., 1993; Weksberg et al., 2010).
(a)
(b)
724
280
6.18 om
347
6.19 cm
-25
30
7.54 cm
5.40 cm
A
3 MANAGEMENT, OUTCOME, AND FOLLOW-UP |
Propranolol 10 mg every 8 h orally was initiated on admission with improvement in tachycardia, irritability, and hypertension within 24 h, suggesting that irritability was secondary to malignant hypertension. After complete surgical resection of the 7-cm right adrenocortical car- cinoma (or benign neoplasm of right adrenal gland), hydrocortisone (Cortef) 1.25 mg was administered orally twice daily. The systolic ejection murmur resolved within 6 days of tumor resection and maxi- mum instantaneous gradient through the left ventricular outflow tract improved by discharge 7 days postoperatively. Glucocorticoid treat- ment continued for 12 months until documented recovery of the hypothalamic-pituitary axis. Beta blockers were continued until com- pletion of steroid treatment, 10 months after initial diagnosis, as an attempt at discontinuation 3 months postoperatively was unsuccess- ful because of hypertension and tachycardia. Follow-up echocardio- gram at that time showed some mild residual left ventricular
CIS
CIS
hypertrophy and diastolic dysfunction. Through the course of follow- ups, the patient showed improvement in body mass, hirsutism, and cushingoid features.
The patient was put on the BWS screening protocol, consisting of abdominal ultrasounds to include the liver and kidney every 3 months until 7 years of age and serum alpha-fetoprotein levels every 3 months until 4 years of age (AACR Screening Guidelines 2017 reference BWS management consensus) (Achatz et al., 2017).
|
4 DISCUSSION
BWS is a genetic overgrowth and cancer predisposition syndrome that is associated with a range of clinical findings. CS is a very rare condition in adults and even more so in children. In most cases of CS, the etiology is exogenous glucocorticoid exposure, usually for treatment of a neuroendocrine condition. Rarely, CS endogenously manifests as a corollary to other overgrowth diseases of the adrenocorticoid-secreting pituitary gland or cortisol-secreting adrenal gland. CS has previously been reported in two molecularly confirmed cases of BWS: one neonate with pUPD11 and one 17-year-old patient with LOM IC2. Our patient was confirmed to have pUPD11. Left untreated CS adversely affects cardiac physiology, growth, and quality of life; however, with timely diagnosis and identification of the etiology, appropriate intervention and treatment can result in com- plete resolution of symptoms (Abraham et al., 2013).
In this case report, there were severe symptoms of CS including marked weight acceleration with simultaneous height deceleration, hypertension, facial puffiness and plethora, hirsutism, and buffalo pad-usually seen in adults. However, it was the new onset murmur because of the severe degree of obstructive left ventricular hypertro- phy that prompted the workup, revealing the culprit adrenal cortical adenoma. The diagnosis of BWSp informed ongoing management including surveillance for Wilms tumor and hepatoblastoma, which would not have been considered in this child’s long-term care without such timely genetic evaluation and testing (Brioude et al., 2018).
(a)
(b)
(c)
(d)
A
After surgical removal of the adrenal tumor, pharmacological interventions for hypertension, and glucocorticoid treatment, the patient showed improvements in his health. Since the patient was so significantly affected by CS at such an early age, close follow-up and monitoring of his growth (including risk of asymmetry) and develop- mental needs were indicated (Hamada et al., 2003; Zaidi & Arabia, 2011). Additionally, identification of BWSp as the etiology for CS warrants additional specific follow-up to proactively screen for secondary tumors, namely Wilms tumor and hepatoblastoma. Radiologic survey for the presence of involvement of the contralateral adrenal gland, other organ involvement, and metastatic disease is important, even with small adrenal cortical tumors. Close long-term follow-up is planned for evaluation of recurrence, periadrenal soft tis- sue involvement, and metastases.
In conclusion, we present a 5-month-old male with molecular findings of BWS whose clinical presentation of CS helped identify his underlying diagnosis and adrenal tumor. This case emphasizes the importance of genetic testing in individuals with CS and findings, sug- gestive of an underlying cancer predisposition syndrome. This case also expands the phenotypic spectrum of BWS and further elucidates genotype-phenotype correlations in this complex genetic syndrome. The significance of this new differential for early CS underscores the complexity of neuroendocrine disorders and the importance of genetic testing for efficient treatment, care, and interventions.
ACKNOWLEDGMENTS
We also thank our colleagues and the other clinicians who were con- sulted and have provided care for this patient.
CONFLICT OF INTEREST
The authors have no conflicts of interest to disclose.
AUTHOR CONTRIBUTIONS
The contributions of each of the authors are as listed: Conceptualiza- tion: Pedro A. Sanchez-Lara, Bahareh M. Schweiger, and Ruchira Garg. Patient recruitment and clinical assessment: Pedro A. Sanchez-Lara, Bahareh M. Schweiger, David Frishberg, and Ruchira Garg. Writing- original draft preparation: Chaya L. Esakhan, Ruchira Garg, Katheryn Grand, and Pedro A. Sanchez-Lara. Writing-review and editing: Chaya L. Esakhan, Bahareh M. Schweiger, Ruchira Garg, David Frishberg, Katheryn Grand, and Pedro A. Sanchez-Lara. Supervision: Bahareh M. Schweiger and Pedro A. Sanchez-Lara. All authors have read and agreed to the published version of the manuscript.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
ORCID
David Frishberg (D https://orcid.org/0000-0001-9604-1947
Katheryn Grand (D https://orcid.org/0000-0002-9411-2913
Ruchira Garg ID https://orcid.org/0000-0002-7258-6480
Pedro A. Sanchez-Lara (D https://orcid.org/0000-0003-1181-7828
REFERENCES
Abraham, S. B., Abel, B. S., Rubino, D., Nansel, T., Ramsey, S., & Nieman, L. K. (2013). A direct comparison of quality of life in obese and Cushing’s syndrome patients. European Journal of Endocrinology, 168(5), 787-793. https://doi.org/10.1530/eje-12-1078
Achatz, M. I., Porter, C. C., Brugières, L., Druker, H., Frebourg, T., Foulkes, W. D., Kratz, C. P., Kuiper, R. P., Hansford, J. R., Hernandez, H. S., Nathanson, K. L., Kohlmann, W. K., Doros, L., Onel, K., Schneider, K. W., Scollon, S. R., Tabori, U., Tomlinson, G. E., Evans, D. G. R., & Plon, S. E. (2017). Cancer screening recommenda- tions and clinical management of inherited gastrointestinal cancer syn- dromes in childhood. Clinical Cancer Research, 23(13), e107-e114. https://doi.org/10.1158/1078-0432.Ccr-17-0790
Brioude, F., Kalish, J. M., Mussa, A., Foster, A. C., Bliek, J., Ferrero, G. B., Boonen, S. E., Cole, T., Baker, R., Bertoletti, M., Cocchi, G., Coze, C., de Pellegrin, M., Hussain, K., Ibrahim, A., Kilby, M. D., Krajewska- Walasek, M., Kratz, C. P., Ladusans, E. J., … Maher, E. R. (2018). Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: An international consensus statement. Nature Reviews. Endocrinology, 14(4), 229-249. https://doi.org/10.1038/nrendo.2017.166
Brioude, F., Nicolas, C., Marey, I., Gaillard, S., Bernier, M., Das Neves, C., le Bouc, Y., Touraine, P., & Netchine, I. (2016). Hypercortisolism due to a pituitary adenoma associated with Beckwith-Wiedemann syndrome. Hormone Research in Pædiatrics, 86(3), 206-211. https://doi.org/10. 1159/000446435
Carney, J. A., Ho, J., Kitsuda, K., Young, W. F., Jr., & Stratakis, C. A. (2012). Massive neonatal adrenal enlargement due to cytomegaly, persistence of the transient cortex, and hyperplasia of the permanent cortex: Find- ings in Cushing syndrome associated with hemihypertrophy. The Amer- ican Journal of Surgical Pathology, 36(10), 1452-1463. https://doi.org/ 10.1097/PAS.0b013e31825d538b
Cöktü, S., Spix, C., Kaiser, M., Beygo, J., Kleinle, S., Bachmann, N., Kohlschmidt, N., Prawitt, D., Beckmann, A., Klaes, R., Nevinny-Stickel- Hinzpeter, C., Döhnert, S., Kraus, C., Kadgien, G., Vater, I., Biskup, S., Kutsche, M., Kohlhase, J., Eggermann, T., … Kratz, C. P. (2020). Cancer incidence and spectrum among children with genetically confirmed Beckwith-Wiedemann spectrum in Germany: A retrospective cohort study. British Journal of Cancer, 123(4), 619-623. https://doi.org/10. 1038/s41416-020-0911-x
Creemers, S. G., Hofland, L. J., Lamberts, S. W., & Feelders, R. A. (2015). Cushing’s syndrome: An update on current pharmacotherapy and future directions. Expert Opinion on Pharmacotherapy, 16(12), 1829- 1844. https://doi.org/10.1517/14656566.2015.1061995
Duffy, K. A., Cielo, C. M., Cohen, J. L., Gonzalez-Gandolfi, C. X., Griff, J. R., Hathaway, E. R., Kupa, J., Taylor, J. A., Wang, K. H., Ganguly, A., Deardorff, M. A., & Kalish, J. M. (2019). Characterization of the Beckwith-Wiedemann spectrum: Diagnosis and management. Ameri- can Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 181(4), 693-708. https://doi.org/10.1002/ajmg.c.31740
Hamada, Y., Takada, K., Fukunaga, S., & Hioki, K. (2003). Hepatoblastoma associated with Beckwith-Wiedemann syndrome and hemihypertrophy. Pediatric Surgery International, 19(1-2), 112-114. https://doi.org/10.1007/s00383-002-0734-2
Klein, J., Vuguin, P., & Hyman, S. (2014). Cushing syndrome. Pediatrics in Review, 35(9), 405-407. https://doi.org/10.1542/pir.35-9-405
MacFarland, S. P., Mostoufi-Moab, S., Zelley, K., Mattei, P. A., States, L. J., Bhatti, T. R., Duffy, K. A., Brodeur, G. M., & Kalish, J. M. (2017). Management of adrenal masses in patients with Beckwith-Wiedemann syndrome. Pediat- ric Blood & Cancer, 64(8), e26432. https://doi.org/10.1002/pbc.26432
Magiakou, M. A., Mastorakos, G., Oldfield, E. H., Gomez, M. T., Doppman, J. L., Cutler, G. B., Jr., Nieman, L. K., & Chrousos, G. P. (1994). Cushing’s syndrome in children and adolescents. Presentation, diagnosis, and therapy. The New England Journal of Medicine, 331(10), 629-636. https://doi.org/10.1056/nejm199409083311002
PART
A
Savage, M. O., & Storr, H. L. (2012). Pediatric Cushing’s disease: Manage- ment issues. Indian Journal of Endocrinology and Metabolism, 16(Suppl 2), S171-S175. https://doi.org/10.4103/2230-8210.104032
Shuman, C., Beckwith, J. B., & Weksberg, R. (1993). Beckwith-Wiedemann syndrome. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. H. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews. Univer- sity of Washington, Seattle.
Stratakis, C. A. (2012). Cushing syndrome in pediatrics. Endocrinology and Metabolism Clinics of North America, 41(4), 793-803. https://doi.org/ 10.1016/j.ecl.2012.08.002
Tatsi, C., & Stratakis, C. A. (2018). Neonatal Cushing syndrome: A rare but potentially devastating disease. Clinics in Perinatology, 45(1), 103-118. https://doi.org/10.1016/j.clp.2017.10.002
Weksberg, R., Shuman, C., & Beckwith, J. B. (2010). Beckwith-Wiedemann syndrome. European Journal of Human Genetics, 18(1), 8-14. https:// doi.org/10.1038/ejhg.2009.106
Wieneke, J. A., Thompson, L. D., & Heffess, C. S. (2003). Adrenal cortical neoplasms in the pediatric population: A clinicopathologic and
immunophenotypic analysis of 83 patients. The American Journal of Surgical Pathology, 27(7), 867-881. https://doi.org/10.1097/ 00000478-200307000-00001
Zaidi, Z. F., & Arabia, S. (2011). Body asymmetries: Incidence, etiology and clinical implications. Australian Journal of Basic and Applied Sciences, 5(9), 2157-2191.
How to cite this article: Schweiger, B. M., Esakhan, C. L., Frishberg, D., Grand, K., Garg, R., & Sanchez-Lara, P. A. (2021). Pediatric Cushing syndrome: An early sign of an underling cancer predisposition syndrome. American Journal of Medical Genetics Part A Part A, 1-5. https://doi.org/10.1002/ajmg.a. 62255