Primary pigmented nodular adrenocortical disease (PPNAD): single centre experience
-
Saba Samad Memon
and
Nalini S. Shah
Abstract
Background
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing’s syndrome (CS) in childhood. We describe a case series of patients presenting at our centre along with a review of the literature.
Methods
A retrospective analysis of six index cases and one family were done for demographic features, hormonal profile, imaging findings, genetic mutation status, histopathologic findings and follow-up details. Diagnosis was based on biochemistry and confirmed with histopathology and or genetic mutation. All patients had suppressed 8 am adrenocorticotropic hormone (ACTH) (<10 pg/mL) despite evidence of hypercortisolism.
Results
The mean age in our cohort was 8.2 years (range 15 months to 20 years). All patients presented with overt CS, including one patient with cyclic Cushing’s. Three patients had additional features of Carney complex (CNC). Imaging did not reveal any obvious mass lesions on computed tomography (CT), the classical beaded appearance was present in only two of the patients. Mutation analysis was positive in three patients. Five patients underwent bilateral adrenalectomy and had features of PPNAD on histopathology.
Conclusions
PPNAD is a rare cause of ACTH-independent CS in childhood and may signal underlying CNC. Patients with younger age of onset with overt CS may still have a mutation in the PRKAR1A gene and warrant genetic testing.
Acknowledgments
We acknowledge Dr. Constantine A. Stratakis, Scientific Director, NICHD, NIH and his team at NIH Institute for providing reports of genetic analyses of our patients through GeneDx.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Stratakis CA. Cushing syndrome caused by adrenocortical tumors and hyperplasias (corticotrophin-independent Cushing syndrome). Endocr Dev 2008;13:117–32.10.1159/000134829Search in Google Scholar PubMed PubMed Central
2. Stratakis CA, Boikos SA. Genetics of adrenal tumors associated with Cushing’s syndrome: a new classification for bilateral adrenocortical hyperplasias. Nat Clin Pract Endocrinol Metab 2007;3:748–57.10.1038/ncpendmet0648Search in Google Scholar PubMed
3. Katanić D, Kafka D, Živojinov M, Vlaški J, Budakov Z, et al. Primary pigmented nodular adrenocortical disease: literature review and case report of a 6-year-old boy. J Pediatr Endocrinol Metab 2017;30:603–9.10.1515/jpem-2016-0249Search in Google Scholar PubMed
4. Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol 2015;173:M85–97.10.1530/EJE-15-0209Search in Google Scholar PubMed PubMed Central
5. Budyal S, Jadhav SS, Kasaliwal R, Patt H, Khare S, et al. Is it worthwhile to screen patients with type 2 diabetes mellitus for subclinical Cushing’s syndrome? Endocr Connect 2015;4:242–8.10.1530/EC-15-0078Search in Google Scholar PubMed PubMed Central
6. Pereira AM, Hes FJ, Horvath A, Woortman S, Greene E, et al. Association of the M1V PRKAR1A mutation with primary pigmented nodular adrenocortical disease in two large families. J Clin Endocrinol Metab 2010;95:338–42.10.1210/jc.2009-0993Search in Google Scholar PubMed PubMed Central
7. Chen S, Li R, Lu L, Duan L, Zhang X, et al. Efficacy of dexamethasone suppression test during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome. Endocrine 2018;59:183–90.10.1007/s12020-017-1436-9Search in Google Scholar PubMed PubMed Central
8. Stratakis CA, Kirschner LS, Carney JA. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab 2001;86:4041–6.10.1210/jcem.86.9.7903Search in Google Scholar PubMed
9. Lowe KM, Young WF, Lyssikatos C, Stratakis CA, Carney JA. Cushing syndrome in Carney complex: clinical, pathologic, and molecular genetic findings in the 17 affected Mayo clinic patients. Am J Surg Pathol 2017;41:171–81.10.1097/PAS.0000000000000748Search in Google Scholar PubMed PubMed Central
10. Bertherat J, Horvath A, Groussin L, Grabar S, Boikos S, et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5′-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab 2009;94:2085–91.10.1210/jc.2008-2333Search in Google Scholar PubMed PubMed Central
11. Carney JA, Gordon H, Carpenter PC, Shenoy BV, Go VL, et al. The complex of myxomas, spotty pigmentation, and endocrine overactivity. Medicine (Baltimore) 1985;64:270–83.10.1097/00005792-198507000-00007Search in Google Scholar PubMed
12. Vezzosi D, Tenenbaum F, Cazabat L, Tissier F, Bienvenu M, et al. Hormonal, radiological, NP-59 scintigraphy, and pathological correlations in patients with Cushing’s syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). J Clin Endocrinol Metab 2015;100:4332–8.10.1210/jc.2015-2174Search in Google Scholar PubMed
13. Gunther DF, Bourdeau I, Matyakhina L, Cassarino D, Kleiner DE, et al. Cyclical Cushing syndrome presenting in infancy: an early form of primary pigmented nodular adrenocortical disease, or a new entity? J Clin Endocrinol Metab 2004;89:3173–82.10.1210/jc.2003-032247Search in Google Scholar PubMed
14. Groussin L, Jullian E, Perlemoine K, Louvel A, Leheup B, et al. Mutations of the PRKAR1A gene in Cushing’s syndrome due to sporadic primary pigmented nodular adrenocortical disease. J Clin Endocrinol Metab 2002;87:4324–9.10.1210/jc.2002-020592Search in Google Scholar PubMed
15. Hofland J, de Herder WW, Derks L, Hofland LJ, van Koetsveld PM, et al. Regulation of steroidogenesis in a primary pigmented nodular adrenocortical disease-associated adenoma leading to virilization and subclinical Cushing’s syndrome. Eur J Endocrinol 2013;168:67–74.10.1530/EJE-12-0594Search in Google Scholar PubMed PubMed Central
16. Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, et al. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Ann Intern Med 1999;131:585–91.10.7326/0003-4819-131-8-199910190-00006Search in Google Scholar PubMed
17. Mabuchi T, Shimizu M, Ino H, Yamguchi M, Terai H, et al. PRKAR1A gene mutation in patients with cardiac myxoma. Int J Cardiol 2005;102:273–7.10.1016/j.ijcard.2004.05.053Search in Google Scholar PubMed
18. Stratakis CA, Kirschner LS. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res 1998;30:456–63.10.1055/s-2007-978914Search in Google Scholar PubMed
19. Powell AC, Stratakis CA, Patronas NJ, Steinberg SM, Batista D, et al. Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia. Surgery 2008;143:750–8.10.1016/j.surg.2008.03.022Search in Google Scholar PubMed PubMed Central
20. Guanà R, Gesmundo R, Morino M, Matarazzo P, Pucci A, et al. Laparoscopic unilateral adrenalectomy in children for isolated primary pigmented nodular adrenocortical disease (PPNAD): case report and literature review. Eur J Pediatr Surg 2010;20:273–5.10.1055/s-0029-1243203Search in Google Scholar PubMed
21. Xu Y, Rui W, Qi Y, Zhang C, Zhao J, et al. The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias. World J Surg 2013;37:1626–32.10.1007/s00268-013-2059-9Search in Google Scholar PubMed
22. Campo MR, Lamacchia O, Farese A, Conserva A, Picca G, et al. Mitotane and Carney complex: ten years follow-up of a low-dose mitotane regimen inducing a sustained correction of hypercortisolism. Horm Athens Greece 2015;14:300–4.10.14310/horm.2002.1514Search in Google Scholar PubMed
©2019 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Review
- The importance of anthropological methods in the diagnosis of rare diseases
- Original Articles
- PON1 arylesterase activity, HDL functionality and their correlation in malnourished children
- Prevalence of dyslipidemia and factors affecting dyslipidemia in young adults with type 1 diabetes: evaluation of statin prescribing
- Myocardial dysfunction in relation to serum thiamine levels in children with diabetic ketoacidosis
- Evaluation of long-term follow-up and methimazole therapy outcomes of pediatric Graves’ disease: a single-center experience
- Endocrine consequences of neuroblastoma treatment in children: 20 years’ experience of a single center
- Analysis of diabetes-associated autoantibodies in children and adolescents with autoimmune thyroid diseases
- Adrenal function of extremely premature infants in the first 5 days after birth
- Atypical presentation of Leydig cell tumour in three prepubertal patients: diagnosis, treatment and outcomes
- The diagnosis of cystinosis in patients reveals new CTNS gene mutations in the Chinese population
- Comparing the validity of continuous metabolic syndrome risk scores for predicting pediatric metabolic syndrome: the CASPIAN-V study
- Primary pigmented nodular adrenocortical disease (PPNAD): single centre experience
- Short Communication
- Classical galactosemia patients can achieve high IQ scores
- Case Reports
- Idiopathic gonadotropin-independent precocious puberty – is regular surveillance required?
- MYT1L mutation in a patient causes intellectual disability and early onset of obesity: a case report and review of the literature
- A case report and literature review of monoallelic mutation of GHR
- Pitfalls in the diagnosis of insulin autoimmune syndrome (Hirata’s disease) in a hypoglycemic child: a case report and review of the literature
