A case of primary pigmented nodular adrenocortical disease associated with germline PRKACA duplication variation

doi:10.3969/j.issn.1674-8115.2025.11.015

Abstract

Abstract:

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare subtype of adrenocorticotropic hormone (ACTH)-independent Cushing′s syndrome and the most common endocrine gland lesion in Carney complex (CNC). This article reported a case of PPNAD and CNC in an adult patient. The patient presented with speckled pigmentation around both eyes, lacked typical Cushingoid features, and exhibited symptoms of diabetes, hypertension, and osteoporosis. The circadian rhythm of blood cortisol levels disappeared, and neither the low-dose nor high-dose dexamethasone suppression tests were inhibited. The 24-hour urinary free cortisol was elevated. Enhanced adrenal computed tomography (CT) showed bilateral adrenal hyperplasia with uniform enhancement after contrast. Through genetic testing, an approximately 0.69Mbp duplication (copy number=3) was found in the 19p13.2-p13.12 region of the proband, which contained the protein kinase cAMP-dependent catalytic subunit α gene (PRKACA). The genetic test of the proband′s daughter also revealed the same genomic duplication. The patient was eventually diagnosed with PPNAD and CNC and underwent laparoscopic right adrenalectomy. Intraoperative pathology showed adrenal cortical hyperplasia and gray-brown nodules. Post-operative pathology confirmed adrenal cortical hyperplasia with abundant lipofuscin in the cytoplasm. The patient received short-term replacement therapy with prednisone acetate tablets, which was discontinued after 3 months. Currently, the patient′s condition is stable and further follow-up is in ongoing.

Key words: primary pigmented nodular adrenocortical disease (PPNAD), ACTH-independent Cushing′s syndrome, genomic duplication, protein kinase cAMP - dependent catalytic subunit α (PRKACA), Carney complex (CNC)

CLC Number:

R587

ZHOU Jianhua, ZHANG Hongli, LI Xiaohua. A case of primary pigmented nodular adrenocortical disease associated with germline PRKACA duplication variation[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(11): 1552-1558.

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References 21

[1]	詹维伟, 周建桥, 尹立雪等. 2020甲状腺结节超声恶性危险分层中国指南: C-TIRADS[J]. 中华超声影像学杂志, 2021, 30(3): 185-200.
	ZHAN W W, ZHOU J Q, YIN L X, et al. Chinese guidelines for ultrasound malignant risk stratification of thyroid nodules (C-TIRADS), 2020[J]. Chinese Journal of Ultrasonography, 2021, 30(3):185-200.
[2]	MEMON S S, THAKKAR K, PATIL V, et al. Primary pigmented nodular adrenocortical disease (PPNAD): single centre experience[J]. J Pediatr Endocrinol Metab, 2019, 32(4): 391-397.
[3]	BAVADIYA G, ROY A, SARKAR K K, et al. Primary pigmented nodular adrenocortical disease (ppnad) presenting as cushing syndrome in a child and review of literature[J]. Acta Endocrinol (Buchar), 2020, 16(3): 362-365.
[4]	LOUISET E, STRATAKIS C A, PERRAUDIN V, et al. The paradoxical increase in cortisol secretion induced by dexamethasone in primary pigmented nodular adrenocortical disease involves a glucocorticoid receptor-mediated effect of dexamethasone on protein kinase A catalytic subunits[J]. J Clin Endocrinol Metab, 2009, 94(7): 2406-2413.
[5]	COURCOUTSAKIS N A, TATSI C, PATRONAS N J, et al. The complex of myxomas, spotty skin pigmentation and endocrine overactivity (Carney complex): imaging findings with clinical and pathological correlation[J]. Insights Imaging, 2013, 4(1): 119-133.
[6]	SUN J L, DING L, HE L P, et al. The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review[J]. Front Endocrinol (Lausanne), 2024, 15: 1356870.
[7]	BEUSCHLEIN F, FASSNACHT M, ASSIÉ G, et al. Constitutive activation of PKA catalytic subunit in adrenal Cushing′s syndrome[J]. N Engl J Med, 2014, 370(11): 1019-1028.
[8]	MCGLACKEN-BYRNE S M, ABDELMAKSOUD A, HAINI M, et al. Mosaic PRKACA duplication causing a novel and distinct phenotype of early-onset Cushing′s syndrome and acral cutaneous mucinosis[J]. Eur J Endocrinol, 2022, 187(6): K55-K61.
[9]	许钰英, 李燕虹, 陈秋莉等. 体细胞PRKACA基因变异致原发性色素结节性肾上腺皮质病1例[J]. 中华儿科杂志, 2023, 61(1): 76-78.
	XU Y Y, LI Y H, CHEN Q L, et al. A case of primary pigmented nodular adrenocortical disease caused by somatic variation of the PRKACA gene [J]. Chinese Journal of Pediatrics, 2023, 61(1): 76-78.
[10]	LODISH M B, YUAN B, LEVY I, et al. Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations[J]. Eur J Endocrinol, 2015, 172(6): 803-811.
[11]	YANG W R, LIANG X H, QIN Y F, et al. Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review[J]. Arch Endocrinol Metab, 2023, 68: e220491.
[12]	LODISH M B, YUAN B, LEVY I, et al. Germline PRKACA amplification causes variable phenotypes that may depend on the extent of the genomic defect: molecular mechanisms and clinical presentations[J]. Eur J Endocrinol, 2015, 172(6): 803-811.
[13]	STRATAKIS C A, KIRSCHNER L S, CARNEY J A. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation [J]. J Clin Endocrinol Metab, 2001, 86(9): 4041-4046.
[14]	BOSCO SCHAMUN M B, CORREA R, GRAFFIGNA P, et al. Carney complex review: genetic features[J]. Endocrinol Diabetes Nutr (Engl Ed), 2018, 65(1): 52-59.
[15]	LIBÉ R, FRATTICCI A, COSTE J, et al. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors[J]. Clin Cancer Res, 2008, 14(12): 4016-4024.
[16]	CORREA R, SALPEA P, STRATAKIS C A. Carney complex: an update[J]. Eur J Endocrinol, 2015, 173(4): M85-M97.
[17]	POWELL A C, STRATAKIS C A, PATRONAS N J, et al. Operative management of Cushing syndrome secondary to micronodular adrenal hyperplasia[J]. Surgery, 2008, 143(6): 750-758.
[18]	XU Y Z, RUI W B, QI Y C, et al. The role of unilateral adrenalectomy in corticotropin-independent bilateral adrenocortical hyperplasias[J]. World J Surg, 2013, 37(7): 1626-1632.
[19]	KYRILLI A, LYTRIVI M, BOUQUEGNEAU M S, et al. Unilateral adrenalectomy could be a valid option for primary nodular adrenal disease: evidence from twins[J]. J Endocr Soc, 2018, 3(1): 129-134.
[20]	SARLIS N J, CHROUSOS G P, DOPPMAN J L, et al. Primary pigmented nodular adrenocortical disease: reevaluation of a patient with carney complex 27 years after unilateral adrenalectomy[J]. J Clin Endocrinol Metab, 1997, 82(4): 1274-1278.
[21]	CAMPO M R, LAMACCHIA O, FARESE A, et al. Mitotane and Carney Complex: ten years follow-up of a low-dose mitotane regimen inducing a sustained correction of hypercortisolism[J]. Hormones (Athens), 2015, 14(2): 300-304.

Time	8:00ACTH/ (pg·mL^-1)	8:00Cortisol/ (μg·dL^-1)	16:00ACTH/(pg·mL^-1)	16:00Cortisol/(μg·dL^-1)	24:00ACTH/(pg·mL^-1)	24:00Cortisol/(μg·dL^-1)	24hUFC/ (μg·dL^-1)
preoperative	<1	23.53	<1	25.34	<1	22.40	403.60
LDDST	‒	15.88	‒	‒	‒	‒	‒
HDDST	‒	16.24	‒	‒	‒	‒	701.80
postoperative	<1	10.51	<1	8.08	<1	8.09	90.00
1-year postoperative	<1	6.95	<1	5.92	<1	5.19	‒

Time	8:00ACTH/ (pg·mL^-1)	8:00Cortisol/ (μg·dL^-1)	16:00ACTH/(pg·mL^-1)	16:00Cortisol/(μg·dL^-1)	24:00ACTH/(pg·mL^-1)	24:00Cortisol/(μg·dL^-1)	24hUFC/ (μg·dL^-1)
preoperative	<1	23.53	<1	25.34	<1	22.40	403.60
LDDST	‒	15.88	‒	‒	‒	‒	‒
HDDST	‒	16.24	‒	‒	‒	‒	701.80
postoperative	<1	10.51	<1	8.08	<1	8.09	90.00
1-year postoperative	<1	6.95	<1	5.92	<1	5.19	‒