Abstract
Primary pigmented nodular adrenocortical disease (PPNAD) is a rare but important cause of adrenocorticotropic hormone (ACTH)-independent Cushing syndrome (CS). It usually presents as cyclical CS in young adults. Childhood onset of PPNAD is exceedingly rare. About 90% of cases of PPNAD are associated with Carney complex (CNC). Both PPNAD and CNC are linked to diverse pathogenic variants of the PRKAR1A gene, which encodes the regulatory subunit type 1 alpha of protein kinase A (PKA). Pathogenic variants of PRKACA gene, which encodes the catalytic subunit alpha of PKA, are extremely rare in PPNAD. We report a case of a female child, aged 8 years and 3 months, who presented with features suggestive of CS, including obesity, short stature, hypertension, moon facies, acne, and facial plethora but without classical striae or signs of CNC. Hormonal evaluation confirmed ACTH-independent CS. However, abdominal imaging revealed normal adrenal morphology. Genetic analysis identified a duplication of the PRKACA gene on chromosome 19p, which is linked to PPNAD. The patient underwent bilateral laparoscopic adrenalectomy, and histopathological study confirmed the PPNAD diagnosis. Postoperative follow-up showed resolution of cushingoid features and hypertension. To our knowledge, this is the first reported case of a female child with PRKACA duplication presenting as CS due to PPNAD.
Introduction
Endogenous Cushing syndrome (CS) is a multisystem disorder caused by excessive production of cortisol. It can result from either adrenocorticotropic hormone (ACTH)-dependent or ACTH-independent etiologies. The incidence of endogenous CS is estimated to be 0.7 to 2.4 cases per million annually, with 10% of cases occurring in children [1]. Adrenal causes account for 65% of endogenous CS in children and 2% of these are due to primary pigmented nodular adrenocortical disease (PPNAD) [2]. PPNAD is associated with Carney complex (CNC) in 90% of patients, while the remaining 10% occur as isolated cases [3]. CNC is an autosomal dominant disorder characterized by spotty skin pigmentation, mesenchymal tumors, peripheral nerve tumors, and various other neoplasms [2].
The PRKAR1A gene on chromosome 17 is most commonly implicated in CNC and PPNAD. It encodes the regulatory subunit type 1 alpha of protein kinase A (PKA) [4]. Pathogenic variants in the PDE11A gene, encoding phosphodiesterase 11A, are the second most common genetic abnormality in PPNAD [4]. PRKACA gene on chromosome 19 encodes the catalytic subunit alpha of PKA. Pathogenic variants in the PRKACA gene are rarely reported in PPNAD [5]. To date, only 3 cases of pathogenic variants in PRKACA have been reported as a cause of PPNAD, with 1 case occurring in childhood [6‐8]. We report a rare case of PPNAD in a female child, caused by a duplication of the PRKACA gene.
Case Presentation
A female child aged 8 years and 3 months presented with a 1-year history of acne, poor linear growth, and a weight gain of 9 kg over the past 6 months. She was the first-born child of non-consanguineous parents and had an uneventful perinatal and postnatal history until the age of 7 years. There were no episodes of vomiting, seizures, headache, visual disturbances, flushing, or abdominal pain. The family history was unremarkable with no similar symptoms reported in either siblings or parents. Auxological evaluation was carried out at the age of 8 years and 3 months, and it revealed a height of 114.5 cm, which was 2 SD below the mean for her age. The parental target height was 148.56 cm, which was 1.6 SD below the mean for adult height (Fig. 1). Her weight was 37 kg and body mass index (BMI) was 28.22 kg/m2, which was above the 95th percentile, categorizing her as obese. Tanner pubertal staging showed breast stage B1 bilaterally, pubic hair stage P1, and absent axillary hair. Physical examination revealed grade 3 acanthosis nigricans, moon facies, facial plethora, acne on the face, and a dorsocervical fat pad (Fig. 2). However, there were no characteristic wide purple striae, easy bruisability, or hyperpigmentation of the skin. Signs of hyperandrogenism, such as hirsutism or clitoromegaly were absent, except for facial acne. Cutaneous examination showed no features of CNC, such as spotty skin pigmentation, blue nevi, or cutaneous myxomas. Her blood pressure was 160/100 mm of Hg, exceeding the 99th percentile for her age and height, without a postural drop. Systemic examination was unremarkable, with no breast masses, nerve thickening, or other stigmata of CNC.
![Growth chart by the Indian Academy of Pediatrics [9] illustrating the patient's progression. At baseline, the patient's height was 114.5 cm, placing her below the 3rd percentile for her age, while her weight was 37 kg, corresponding to the 75th to 90th percentile range. Five months after bilateral adrenalectomy, she exhibited a 9-cm increase in height and a 10-kg reduction in weight.](https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/jcemcr/3/3/10.1210_jcemcr_luaf035/1/m_luaf035f1.jpeg?Expires=1744926171&Signature=U9wcN4m-6OBVqy1qW2hzP0U1HTDaqSDy6mDT7xw1vdiq1JBm4wxAOVuinLEAx4FtSRP-D4lkXL4XSxGxxdgWDrMv~xUODTHnuFsk2ZNllBmUvDOdqRKkgMxJIojneTHwRejb0FiKCxH2P1gbexSHmGytDmX4T8ATOCLQG7ODsAS-YUVAb1KpxasUwsJ6G4Yn0gRtDcVQJhmklW0PannLKrtY3Uel3xygiOSBs1YcYE9HME4cJYGWDYzU7ztPUObUaQT0Jd-Ds1tXNsm~1OtgICDML-cXJZk-Qp1-MrsBEQZVtmgFE3tm~LYbPpVwZJbfNZHn1N3bvZzMw-jREkAS5Q__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA)
Figure 1.
Growth chart by the Indian Academy of Pediatrics [9] illustrating the patient’s progression. At baseline, the patient’s height was 114.5 cm, placing her below the 3rd percentile for her age, while her weight was 37 kg, corresponding to the 75th to 90th percentile range. Five months after bilateral adrenalectomy, she exhibited a 9-cm increase in height and a 10-kg reduction in weight.
Figure 2.
A and B, clinical signs of Cushing syndrome observed during physical examination: moon facies, dorsocervical fat pad, generalized obesity, short stature, and facial acne. C, Follow-up photograph taken 5 months after bilateral adrenalectomy, showing a reduction in weight, resolution of facial acne and acanthosis, and an increase in height.
Diagnostic Assessment
Biochemical investigations revealed dyslipidemia, while fasting plasma glucose, 2-hour post-glucose plasma glucose, liver function tests, and renal function tests were within normal limits. Hematological evaluation showed neutrophilic leukocytosis. Fasting serum insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) were elevated, signifying marked insulin resistance (Table 1). Serum cortisol levels measured at 08:00 hours, 16:00 hours, and midnight were elevated, indicating a loss of the normal diurnal cortisol rhythm (Table 2). Serum cortisol levels following the overnight dexamethasone suppression test (ONDST), low-dose dexamethasone suppression test (LDDST), and high-dose dexamethasone suppression test (HDDST) were non-suppressible, confirming the presence of endogenous CS. There was no paradoxical rise in serum cortisol following HDDST. Serum ACTH levels were suppressed both at 08:00 hours and at midnight, indicating an ACTH-independent etiology of hypercortisolism (Table 2). The levels of androgens such as serum testosterone and dehydroepiandrosterone sulfate were within normal limits. Plasma aldosterone concentration (PAC), plasma renin activity (PRA) and PAC to PRA ratio were all within the normal range as shown in Table 2.
Results of biochemical and hematological testing
| Parameter (reference range) |
Value (baseline) |
Value (5 months postsurgery) |
Fasting plasma glucose
(70-100 mg/dL; 3.9-5.6 mmol/L) |
81 mg/dL(4.4 mmol/L) |
63 mg/dL (3.5 mmol/L) |
2-hour post-glucose plasma glucose
(70-100 mg/dL (3.9-7.8 mmol/L) |
110 mg/dL (6 mmol/L) |
79 mg/dL (4.4 mmol/L) |
| Serum insulin (3-35 mU/L; 21.5-251 pmol/L) |
44.6 mU/L (319.6 pmol/L) |
14 mU/L (100.3 pmol/L) |
HbA1c
(4-5.6%; 20-38 mmol/mol) |
5.5% (37 mmol/mol) |
5.5% (37 mmol/mol) |
HOMA-IR
(0.5-1.4) |
8.9 |
2.2 |
Serum total cholesterol
(<200 mg/dL; <5.2 mmol/L)
Age 0-19 years:
(<170 mg/dL; 4.3 mmol/L) |
188 mg/dL (4.9 mmol/L) |
130 mg/dL (3.4 mmol/L) |
Serum LDL
(<100 mg/dL; <2.6 mmol/L) |
123 mg/dL (3.2 mmol/L) |
85 mg/dL (2.2 mmol/L) |
Serum HDL
Males: (>40 mg/dL; >1 mmol/L)
Females: (>50 mg/dL; >1.3 mmol/L)
Age 0-19 years:
(>45 mg/dL; >1.2 mmol/L) |
46 mg/dL (1.2 mmol/L) |
23 mg/dL (0.6 mmol/L) |
Serum triglyceride
(<150 mg/dL; <1.7 mmol/L)
Age 0-9 years:
(<75 mg/dL; <1.0 mmol/L) |
93 mg/dL (1.0 mmol/L) |
85 mg/dL (0.9 mmol/L) |
Hemoglobin
(11-16 g/dL; 6.8-9.9 mmol/L) |
13.6 g/dL (8.4 mmol/L) |
12.7 g/dL (7.8 mmol/L) |
Total leukocyte count
(4000-11 000 cells/µL) |
16 170 cells/µL |
6550 cells/µL |
Total platelet count
(1.5–4×105 cells/µL) |
4.79×105 cells/µL |
2.00×105 cells/µL |
Differential count
Neutrophils
(40%-75%)
Lymphocytes
(20%-45%)
Eosinophils
(1%-6%)
Monocytes
(2%-10%)
Basophils
(0%-0.5%) |
71.8%
24%
1.2%
3%
0% |
41%
52%
5%
2%
0% |
Table 2.
Results of dynamic testing of serum cortisol, serum ACTH, and other hormonal assessment
| Parameter (reference range) |
Value |
| Serum cortisol |
|
| 0800 Am (5-25 µg/dL; 138-690 nmol/L) |
28.5 µg/dL (786.6 nmol/L) |
| 0400 Pm (3-10 µg/dL; 82.8-276 nmol/L) |
24.9 µg/dL (686.1 nmol/L) |
| Midnight (awake) (<7.5 µg/dL; <207 nmol/L) |
25.9 µg/dL (714.6 nmol/L) |
| Post ONDST (<1.8 µg/dL; <50 nmol/L) |
31.9 µg/dL (879.8 nmol/L) |
| Post LDDST (<1.8 µg/dL; <50 nmol/L) |
24.7 µg/dL (680.6 nmol/L) |
| Post HDDST (<1.8 µg/dL; <50 nmol/L) |
25 µg/dL (690 nmol/L) |
| Serum ACTH |
|
| Midnight (5-22 pg/mL; 1.1-4.8 pmol/L) |
1.5 pg/mL (0.34 pmol/L) |
| 0800 Am (10-60 pg/mL; 2.3-13.6 pmol/L) |
1.2 pg/mL (0.27 pmol/L) |
| Androgens |
|
| Serum DHEAS (10-193 µg/dL; 0.27-5.23 µmol/L) |
13.6 µg/dL(0.37 µmol/L) |
| Serum testosterone (5-13 ng/dL; 0.17-0.45 nmol/L) |
11.41 ng/dL(0.39 nmol/L) |
| Renin-aldosterone axis |
|
| PAC (<40 ng/dL; <1100 pmol/L) |
8 ng/dL (220 nmol/L) |
| PRA (0.8-2.0 ng/mL/h; 10.24-25.6 pmol/L/min) |
1.2 ng/mL/h (15.36 pmol/L/min) |
| PAC to PRA ratio (<30 ng/dL per ng/mL/h; <60 pmol/L per pmol/L/min) |
6.67 ng/dL per ng/mL/h (14.3 pmol/L per pmol/L/min) |
Adrenal imaging with both computed tomography (CT) and magnetic resonance imaging (MRI) showed no abnormalities in either adrenal gland (Fig. 3). Based on these clinical findings, hormonal profile, and normal imaging results, PPNAD was suspected.
Figure 3.
Adrenal computed tomography (CT) showing normal adrenals bilaterally (white arrows).
Blood was collected in an EDTA vial, and DNA was extracted for targeted gene capture using a custom kit. Sequences were aligned to the human reference genome (GRCh38) using BWA aligner (Sentieon, PMID: 20080505). Variants were identified with Sentieon haplotype caller, and copy number variants were detected using ExomeDepth (PMID: 22942019) method. This identified a heterozygous exonic duplication ∼24.97 Kb at genomic location chr19:g.(? 14092580)(14117547_? )dup on chromosome 19p13, which comprises the PRKACA gene. This was a heterozygous autosomal dominant variant and confirmed the diagnosis of PPNAD.
Treatment
The child was started on antihypertensive therapy, requiring a combination of 3 medications; amlodipine, enalapril, and spironolactone to achieve adequate blood pressure control. She subsequently underwent bilateral laparoscopic adrenalectomy at our institute. During the procedure, she received steroid coverage with a continuous infusion of hydrocortisone at 4 mg per hour, which was maintained for 48 hours postoperatively. This was followed by oral hydrocortisone replacement therapy at a dose of 15 mg/m²/day in 3 divided doses along with oral fludrocortisone at 100 µg/day. The intraoperative and postoperative periods were uneventful.
On gross examination, the excised adrenal glands appeared unremarkable (Fig. 4A). However, histopathological examination using hematoxylin and eosin (H&E) staining revealed multiple round-to-oval nodules within the adrenal cortex of both glands (Fig. 4B and 4C). Nodules were well-defined but unencapsulated. These nodules were composed of large polygonal lipid-poor cells with abundant eosinophilic granular cytoplasm containing lipofuscin granules. The peri-nodular cortex showed compression atrophy. These findings were consistent with a diagnosis of PPNAD [10].
Figure 4.
A, Gross image of the excised adrenal glands B, Histopathological findings of adrenal tissue stained with hematoxylin and eosin (H&E) stain, showing nonencapsulated micronodules (green arrows) with internodular cortical atrophy. C, Magnified image of a single cortical nodule showing an unencapsulated nodule composed of large polygonal lipid-poor cells with abundant eosinophilic granular cytoplasm with lipofuscin granules. Nuclei show prominent nucleoli. Peri-nodular cortex shows compression atrophy (H&E stain, 400X).
Outcome and Follow-Up
By postoperative day 7, the patient’s blood pressure had normalized, allowing discontinuation of antihypertensive medications. She was initially started on hydrocortisone in 3 divided doses which was later converted to 2 divided doses. She was stable and reported no adrenal crises during the follow-up period of 5 months. Throughout this period, she demonstrated consistent clinical improvement, with resolution of acne, improvement in cushingoid facies, and sustained normotension without the need for antihypertensive medications. At 5 months after surgery, she showed significant clinical recovery, evidenced by a weight loss of 10 kg, a height gain of 9 cm, and a reduction in BMI from 28.22 to 16 kg/m², as shown in Figs. 1 and 2. Biochemical analysis at this stage revealed normalization of serum insulin levels, a reduction in HOMA-IR, and a normalized lipid profile.
Discussion
The diagnosis of PPNAD is often challenging in the absence of characteristic features of CNC. Approximately 90% of PPNAD cases occur as part of CNC. CNC is associated with typical manifestations such as spotty skin pigmentation, blue cutaneous nevi, cardiac myxomas, and tumors at various sites [2, 3]. PPNAD typically presents in young adults, often as cyclical CS and less frequently as classical CS [11]. Childhood onset of PPNAD is exceedingly rare [12]. In the absence of CNC, certain diagnostic indicators, such as a paradoxical rise in serum cortisol following a HDDST, may serve as important clues for diagnosing PPNAD. However, no paradoxical rise was observed in our case. The utility of imaging in diagnosing PPNAD is limited, as adrenal CT scans are often unremarkable [13]. A case series of 88 patients with confirmed PPNAD reported normal-appearing adrenals in 45% of cases, while bilateral adrenal nodularity or enlargement was identified in only 12% and 27% of cases, respectively [14]. MRI adds minimal diagnostic value. Given these limitations, a high index of clinical suspicion and genetic analysis are crucial for establishing a definitive diagnosis of PPNAD. Genetic confirmation is particularly important, as bilateral adrenalectomy, which is curative, requires lifelong steroid replacement therapy. Pathogenic variants in the PRKAR1A gene are the most common genetic abnormality in PPNAD, found in 79.5% of cases. Pathogenic variants in the PDE11A gene are the second most common and are found in 26.5% cases [15].
PKA is a heterotetramer composed of 2 regulatory subunits and 2 catalytic subunits. Four regulatory subunits (RIα, RIβ, RIIα, and RIIβ) and 4 catalytic subunits (Cα, Cβ, Cγ and Prkx) have been identified [15]. In its inactive state, the regulatory subunits are bound to the catalytic subunits, maintaining the complex in an inhibited configuration. Under normal physiological conditions, ACTH binds to the melanocortin-2 receptor (MC2R) on zona fasciculata cells of the adrenal cortex, activating adenylate cyclase. Adenylate cyclase enhances the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP) [15]. Increased intracellular cAMP induces a conformational change in PKA, resulting in the release of the catalytic subunits. The liberated catalytic subunits phosphorylate downstream targets, such as cAMP–response element-binding protein (CREB), which in turn drives the transcription of genes involved in cortisol synthesis and adrenocortical cell proliferation. Duplication of PRKACA gene results in constitutive activation of the catalytic subunit alpha of PKA [16]. This aberrant activation enhances downstream signaling pathways of PKA, leading to increased cortisol biosynthesis and adrenocortical cell proliferation, ultimately culminating in PPNAD.
Pathogenic variants of the PRKACA gene causing PPNAD are exceedingly rare, with only 3 cases reported in the literature to date (Table 3) [6‐8]. To the best of our knowledge, the present case is the first reported female patient with PPNAD caused by a pathogenic variant of PRKACA gene, presenting in the first decade of life. This case highlights that PPNAD caused by pathogenic PRKACA variants can manifest as an isolated condition in childhood without other features of CNC.
Previously reported cases of PPNAD with pathogenic variants of PRKACA
| S. No. |
Age (years) |
Gender |
PRKACA defect |
Clinical features |
Authors (year of reporting) |
| 1. |
22 |
Female |
Copy number gain variation of size 431 kb spanning genomic region 19p13.13p13.12, which contains the PRKACA gene |
PPNAD with Cushing syndrome and features of CNC |
Wang-Rong Yang et al (2024) [6] |
| 2. |
8 |
Male |
Copy number duplication in PRKACA gene |
PPNAD with Cushing syndrome, without any features of CNC |
Xu Yuying et al (2023) [8] |
| 3. |
21 |
Female |
Point mutation in PRKACA gene at 95th nucleotide, substituting Adenine with Thymine (c.95 A > T) |
PPNAD with Cushing syndrome, without any features of CNC |
Wan Shuang et al (2022) [7] |
4.
(current case) |
8 |
Female |
Heterozygous duplication of size 24.9 kb, spanning genomic location chr19:g.(?_14092580)_(14117547_?)dup, comprising the PRKACA gene |
PPNAD with Cushing syndrome, without any features of CNC |
|
Learning Points
-
PRKACA duplication is a rare but important cause of PPNAD and should be considered during genetic testing, especially in the absence of pathogenic variants of PRKAR1A gene and classical CNC features.
-
Normal adrenal imaging and absence of CNC manifestations do not exclude the diagnosis of PPNAD, emphasizing the importance of comprehensive clinical evaluation and genetic testing.
-
The potential genotypic correlation between pathogenic variants of the PRKACA gene and CNC remains uncertain and requires further research.
Acknowledgments
We acknowledge the contributions of the Departments of Urology, Paediatric Surgery, Anaesthesiology and Paediatrics at our institute for surgical management and postoperative care of the reported case. We extend our sincere gratitude to Dr. Manoj Kumar Patro for his significant contributions to the histopathological evaluation of the case.
Contributors
All authors made individual contributions to authorship. P.R.K., D.K.D., D.P., B.D., J.K.M., and B.S.D. were involved in the diagnosis, management, and manuscript submission. All authors reviewed and approved the final draft.
Funding
No public or commercial funding.
Disclosures
None declared
Informed Patient Consent for Publication
Signed informed consent obtained directly from the patient’s relatives or guardians.
Data Availability Statement
Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Abbreviations
-
-
ACTH
adrenocorticotropic hormone
-
-
cAMP
cyclic adenosine monophosphate
-
-
HOMA-IR
homeostatic model assessment of insulin resistance
-
-
HDDST
high-dose dexamethasone suppression test
-
-
LDDST
low-dose dexamethasone suppression test
-
-
MRI
magnetic resonance imaging
-
-
ONDST
overnight dexamethasone suppression test
-
-
PAC
plasma aldosterone concentration
-
-
PPNAD
primary pigmented nodular adrenocortical disease
© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
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Filed under: Cushing's, Rare Diseases | Tagged: ACTH, Carney Complex, Cushing's Syndrome, PPNAD, Primary pigmented nodular adrenocortical disease | Leave a comment »
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