A Rare Case of PRKACA Duplication–Associated Childhood-Onset Primary Pigmented Nodular Adrenocortical Disease

Posted on March 19, 2025 by MaryO

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.

PPNAD, PRKACA, Carney complex, Cushing syndrome
Issue Section:

Case Report

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.

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.

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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.

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.

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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.

Table 1.
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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%

Abbreviations: HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; HOMA-IR, homeostatic model assessment of insulin resistance; LDL, low-density lipoprotein.

Table 2.

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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)

Abbreviations: ACTH, adrenocorticotropic hormone; DHEAS, dehydroepiandrosterone sulfate; HDDST, high-dose dexamethasone suppression test; LDDST, low-dose dexamethasone suppression test; ONDST, overnight dexamethasone suppression test; PAC, plasma aldosterone concentration; PRA, plasma renin activity.

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.

Adrenal computed tomography (CT) showing normal adrenals bilaterally (white arrows).

Figure 3.

Adrenal computed tomography (CT) showing normal adrenals bilaterally (white arrows).

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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].

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).

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).

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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.

Table 3.

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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

Abbreviations: CNC, Carney complex; PPNAD, primary pigmented nodular adrenocortical disease; PRKACA, catalytic subunit alpha of protein kinase A.

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

 

    • BMI

      body mass index

 

    • cAMP

      cyclic adenosine monophosphate

 

    • CNC

      Carney complex

 

    • CS

      Cushing syndrome

 

    • CT

      computed tomography

 

    • 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

 

    • PKA

      protein kinase A

 

    • PPNAD

      primary pigmented nodular adrenocortical disease

 

  • PRA

    plasma renin activity

© The Author(s) 2025. Published by Oxford University Press on behalf of the Endocrine Society.
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Ectopic CRH/ACTH-Co-Secreting Neuroendocrine Tumors Leading to Cushing’s Disease

Posted on March 17, 2025 by MaryO

Abstract

Adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) are essential regulators of cortisol production within the hypothalamic-pituitary-adrenal (HPA) axis. Elevated cortisol levels, resulting from excessive ACTH, can lead to Cushing’s syndrome, a condition with significant morbidity. Neuroendocrine tumors (NETs) can ectopically produce both ACTH and CRH, contributing to this syndrome. This review discusses the pathophysiology, types, clinical presentation, diagnosis, and management of these tumors. Emphasis is placed on the importance of identifying dual CRH/ACTH secretion, which complicates diagnosis and necessitates tailored therapeutic strategies. Furthermore, the review highlights the prognosis, common complications, and future directions for research in this area.

We report the case of a 53-year-old female patient who presented with severe Cushing’s syndrome and was diagnosed with ectopic ACTH syndrome. Despite initial indications pointing towards pituitary-dependent hypercortisolism, further investigations revealed the presence of a highly differentiated atypically located tumor in the upper lobe of the left lung, adjacent to the mediastinum. Immunohistochemistry of the tumor tissue demonstrated not only ACTH but also CRH and CRH-R1 expression. The simultaneous expression of these molecules supports the hypothesis of the presence of a positive endocrine feedback loop within the NET, in which the release of CRH stimulates the expression of ACTH via binding to CRH-R1. This case report highlights the challenges in diagnosing and managing ectopic ACTH syndrome, emphasizing the importance of a comprehensive diagnostic approach to identify secondary factors impacting cortisol production, such as CRH production and other contributing neuroendocrine mechanisms.

Journal Section:

Review Article

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The Author(s). Published by S. Karger AG, Basel
Open Access License / Drug Dosage / Disclaimer
This article is licensed under the Creative Commons Attribution 4.0 International License (CC BY). Usage, derivative works and distribution are permitted provided that proper credit is given to the author and the original publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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Personalized Noninvasive Diagnostic Algorithms Based on Urinary Free Cortisol in ACTH-dependant Cushing’s Syndrome

Posted on November 9, 2024 by MaryO

Julie Lavoillotte, Kamel Mohammedi, Sylvie Salenave, Raluca Maria Furnica, Dominique Maiter, Philippe Chanson, Jacques Young, Antoine Tabarin
The Journal of Clinical Endocrinology & Metabolism, Volume 109, Issue 11, November 2024, Pages 2882–2891
https://doi.org/10.1210/clinem/dgae258

Abstract

Context

Current guidelines for distinguishing Cushing’s disease (CD) from ectopic ACTH secretion (EAS) are questionable, as they use pituitary magnetic resonance imaging (MRI) as first-line investigation for all patients. CRH testing is no longer available, and they suggest performing inferior petrosal sinus sampling (BIPPS), an invasive and rarely available investigation, in many patients.

Objective

To establish noninvasive personalized diagnostic strategies based on the probability of EAS estimated from simple baseline parameters.

Design

Retrospective study.

Setting

University hospitals.

Patients

Two hundred forty-seven CD and 36 EAS patients evaluated between 2001 and 2023 in 2 French hospitals. A single-center cohort of 105 Belgian patients served as external validation.

Results

Twenty-four-hour urinary free cortisol (UFC) had the highest area under the receiver operating characteristic curve for discrimination of CD from EAS (.96 [95% confidence interval (CI), .92–.99] in the primary study and .99 [95% CI, .98–1.00] in the validation cohort). The addition of clinical, imaging, and biochemical parameters did not improve EAS prediction over UFC alone, with only BIPPS showing a modest improvement (C-statistic index .99 [95% CI, .97–1.00]). Three groups were defined based on baseline UFC: < 3 (group 1), 3–10 (group 2), and > 10 × the upper limit of normal (group 3), and they were associated with 0%, 6.1%, and 66.7% prevalence of EAS, respectively. Diagnostic approaches performed in our cohort support the use of pituitary MRI alone in group 1, MRI first followed by neck-to-pelvis computed tomography scan (npCT) when negative in group 2, and npCT first followed by pituitary MRI when negative in group 3. When not combined with the CRH test, the desmopressin test has limited diagnostic value.

Conclusion

UFC accurately predicts EAS and can serve to define personalized and noninvasive diagnostic algorithms.

Read the article here: https://academic.oup.com/jcem/article/109/11/2882/7645065

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Sparrow Pharmaceuticals Announces Completion of Phase 2 Trial and FDA Orphan Drug Designation of Clofutriben for Endogenous Cushing’s Syndrome

Posted on November 1, 2024 by MaryO

Sparrow Pharmaceuticals, a clinical-stage biopharmaceutical company developing novel, targeted therapies to address unmet needs in both endocrinology and immunology, today announced that the Phase 2 RESCUE trial of clofutriben, a potent and selective HSD-1 inhibitor, for the treatment of endogenous Cushing’s syndrome is complete. All eligible patients who completed the trial elected to continue treatment with clofutriben in an open label extension (OLE) protocol. The promising results observed to date have catalyzed planning for the next phase of development to begin next year. In addition, Sparrow announced that clofutriben has been granted Orphan Drug Designation by the US Food and Drug Administration (FDA) for the treatment of endogenous Cushing’s syndrome.

The RESCUE trial was a randomized, placebo-controlled trial of clofutriben for ACTH-dependent endogenous Cushing’s syndrome, a rare disease caused by a tumor that leads to hypersecretion of cortisol. HSD-1 inhibition with clofutriben lowers intracellular cortisol in key tissues where excess cortisol causes toxicity, thereby potentially reducing morbidity from cortisol excess. “HSD-1 inhibition with clofutriben is a completely novel approach to the treatment of endogenous Cushing’s syndrome that may overcome many of the serious problems with current therapies, including major safety, tolerability, and complexity issues such as the risk of adrenal insufficiency and adrenal crisis,” commented Sparrow Chief Medical Officer Frank Czerwiec, MD, PhD. “One of the most encouraging observations is that, given the option to continue clofutriben or switch to another treatment at the end of the trial, patients chose to continue clofutriben in the OLE. We are working closely with our medical, scientific, and patient advisors on plans to present these data and on designs for our next phase of clinical trials to startup next year.”

Sparrow also announced that clofutriben has been granted Orphan Drug Designation (ODD) by the FDA for the treatment of endogenous Cushing’s syndrome. “ODD qualifies sponsors for incentives including tax credits for qualified clinical trials, exemption from user fees, and a potential seven years of market exclusivity after NDA approval,” added Jamie MacPherson, PharmD, Sparrow’s SVP of Regulatory Affairs and Quality. “We are pleased that the FDA has recognized the potential for clofutriben to treat this devastating disease.”

Clofutriben is a potent and selective HSD-1 inhibitor that is in clinical testing for endogenous Cushing’s syndrome (EnCS) and autonomous cortisol secretion (ACS), a milder and more prevalent, yet still serious, form of hypercortisolism than EnCS. HSD-1 is an intracellular enzyme that activates glucocorticoids in target tissues in which glucocorticoids such as cortisol are associated with morbidity including liver, adipose, brain, bone, muscle, and skin. Additionally, clofutriben in combination with the glucocorticoid medicine prednisolone is in Phase 2 clinical trials for the treatment of immunological disorders, beginning with polymyalgia rheumatica (PMR), a prevalent autoimmune disease that mainly affects people over 50. Clofutriben co-administration is intended to reduce the side effects of prednisolone while maintaining its immune suppressive and anti-inflammatory benefits, thereby unlocking the potential of a class of medicines that has been limited in utility for more than 75 years by severe toxicity.

To learn more about Sparrow Pharmaceuticals and clofutriben, visit www.sparrowpharma.com.

About Sparrow Pharmaceuticals

Sparrow Pharmaceuticals was founded to spare patients the ravages of steroids. Leveraging underappreciated scientific insights into glucocorticoid biology, the company is working to provide better treatment options for serious disorders of hypercortisolism, and to revolutionize the treatment of autoimmune and inflammatory conditions. Its lead product, clofutriben (previously SPI-62), is an oral, small molecule, novel therapeutic treatment designed to target a source of active intracellular glucocorticoids in key tissues.

From https://www.morningstar.com/news/business-wire/20241028067997/sparrow-pharmaceuticals-announces-completion-of-phase-2-trial-and-fda-orphan-drug-designation-of-clofutriben-for-endogenous-cushings-syndrome

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Insights on Diagnosing and Managing Cushing’s Syndrome

Posted on August 18, 2024 by MaryO

Cushing’s syndrome, or endogenous hypercortisolemia, is a rare condition that both general practice clinicians and endocrinologists should be prepared to diagnose and treat. Including both the pituitary and adrenal forms of the disease, the Endocrine Society estimates that the disorder affects 10 to 15 people per million every year in the United States. It is more common in women and occurs most often in people between the ages of 20 and 50.

Even though Cushing’s remains a rare disease, cortisol recently made waves at the American Diabetes Association 84th Scientific Session. A highlight of the meeting was the initial presentation of data from the CATALYST trial, which assessed the prevalence of hypercortisolism in patients with difficult-to-control type 2 diabetes (A1c 7.5+).

CATALYST is a prospective, Phase 4 study with two parts. In the prevalence phase, 24% of 1,055 enrolled patients had hypercortisolism, defined as an overnight dexamethasone suppression test (ODST) value greater than 1.8 µg/dL and dexamethasone levels greater than 140 µg/dL. Results of CATALYST’s randomized treatment phase are expected in late 2024.

Elena Christofides, MD, FACE, founder of Endocrinology Associates, Inc., in Columbus, OH, believes the CATALYST results will be a wake-up call for both physicians and patients seeking to advocate for their own health. “This means that nearly 1 in 4 patients with type 2 diabetes have some other underlying hormonal/endocrine dysfunction as the reason for their diabetes, or significant contribution to their diabetes, and they should all be screened,” she said. “All providers need to get comfortable with diagnosing and treating hypercortisolemia, and you need to do it quickly because patients are going to pay attention as well.”

In Dr. Christofides’ experience, patients who suspect they have a hormonal issue may start with their primary care provider or they may self-refer to an endocrinologist. “A lot of Cushing’s patients are getting diagnosed and treated in primary care, which is completely appropriate. But I’ve also met endocrinologists who are uncomfortable diagnosing and managing Cushing’s because it is so rare,” she said. “The important thing is that the physician is comfortable with Cushing’s or is willing to put in the work get comfortable with it.”

According to Dr. Christofides, the widespread popular belief that “adrenal fatigue” is causing millions of Americans to feel sick, tired, and debilitated may be creating barriers to care for people who may actually have Cushing’s. “As physicians, we know that adrenal fatigue doesn’t exist, but we should still be receptive to seeing patients who raise that as a concern,” said Dr. Christofides. “We need to acknowledsalige their lived experience as being very real and it can be any number of diseases causing very real symptoms. If we don’t see these patients, real cases of hypercortisolemia could be left undiagnosed and untreated.”

Dr. Christofides, who also serves as a MedCentral Editor-at-Large, said she reminds colleagues that overnight dexamethasone suppression test (ODST) should always be the first test when you suspect Cushing’s. “While technically a screening test, the ODST can almost be considered diagnostic, depending on how abnormal the result is,” she noted. “But I always recommend that you do the ODST, the ACTH, a.m. cortisol, and the DHEAS levels at the same time because it allows you to differentiate more quickly between pituitary and adrenal problems.”

Dr. Christofides does see a place for 24-hour urine collection and salivary cortisol testing at times when diagnosing and monitoring patients with Cushing’s. “The 24-hour urine is only positive in ACTH-driven Cushing’s, so an abnormal result can help you identify the source, but too many physicians erroneously believe you can’t have Cushing’s if the 24-hour urine is normal,” she explained. “Surgeons tend to want this test before they operate and it’s a good benchmark for resolution of pituitary disease.” She reserves salivary cortisol testing for cases when the patient’s ODST is negative, but she suspects Cushing’s may be either nascent or cyclical.

Surgical resection has long been considered first-line treatment in both the pituitary and adrenal forms of Cushing’s. For example, data shared from Massachusetts General Hospital showed that nearly 90% of patients with microadenomas did not relapse within a 30-year period. A recent study found an overall recurrence rate of about 25% within a 10-year period. When reoperation is necessary, remission is achieved in up to 80% of patients.

As new medications for Cushing’s syndrome have become available, Dr. Christofides said she favors medical intervention prior to surgery. “The best part about medical therapy is you can easily stop it if you’re wrong,” she noted. “I would argue that every patient with confirmed Cushing’s deserves nonsurgical medical management prior to a consideration of surgery to improve their comorbidities and surgical risk management, and give time to have a proper informed consent discussion.”

In general, medications to treat Cushing’s disease rely on either cortisol production blockade or receptor blockade, said Dr. Christofides. Medications that directly limit cortisol production include ketoconazole, osilodrostat (Isturisa), mitotane (Lysodren), levoketoconazole (Recorlev), and metyrapone (Metopirone). Mifepristone (Korlym, Mifeprex) is approved for people with Cushing’s who also have type 2 diabetes to block the effects of cortisol. Mifepristone does not lower the amount of cortisol the body makes but limits its effects. Pasireotide (Signifor) lowers the amount of ACTH from the tumor. Cabergoline is sometimes used off-label in the US for the same purpose.

Following surgery, people with Cushing’s need replacement steroids until their adrenal function resumes, when replacement steroids must be tapered. But Dr. Christofides said she believes that all physicians who prescribe steroids should have a clear understanding of when and how to taper patients off steroids.

“Steroid dosing for therapeutic purposes is cumulative in terms of body exposure and the risk of needing to taper. A single 2-week dose of steroids in a year does not require a taper,” she said. “It’s patients who are getting repeated doses of more than 10 mg of prednisone equivalent per day for 2 or more weeks multiple times per year who are at risk of adrenal failure without tapering.”

Physicians often underestimate how long a safe, comfortable taper can take, per Dr. Christofides. “It takes 6 to 9 months for the adrenals to wake up so if you’re using high-dose steroids more frequently, that will cause the patient to need more steroids more frequently,” she explained. “If you’re treating an illness that responds to steroids and you stop them without tapering, the patient’s disease will flare, and then a month from then to 6 weeks from then you’ll be giving them steroids again, engendering a dependence on steroids by doing so.”

When developing a steroid taper plan for postoperative individuals with Cushing’s (and others), Dr. Christofides suggests basing it on the fact that 5 mg of prednisone or its equivalent is the physiologic dose. “Reduce the dose by 5 mg per month until you get to the last 5 mg, and then you’re going to reduce it by 1 mg monthly until done,” she said. “If a patient has difficulty during that last phase, consider a switch to hydrocortisone because a 1 mg reduction of hydrocortisone at a time may be easier to tolerate.”

Prednisone, hydrocortisone, and the other steroids have different half-lives, so you’ll need to plan accordingly, adds Dr. Christofides. “If you do a slower taper using hydrocortisone, the patient might feel worse than with prednisone unless you prescribe it BID.” She suggests thinking of the daily prednisone equivalent of hydrocortisone as 30 mg to allow for divided dosing, rather than the straight 20 mg/day conversion often used.

What happens after a patient’s Cushing’s has been successfully treated? Cushing’s is a chronic disease, even in remission, Dr. Christofides emphasized. “Once you have achieved remission, my general follow-up is to schedule visits every 6 months to a year with scans and labs, always with the instruction if the patient feels symptomatic, they should come in sooner,” she said.

More on Cushing’s diagnosis and therapies.

https://www.medcentral.com/endocrinology/cushings-syndrome-a-clinical-update

Filed under: adrenal, adrenal crisis, Cushing's, Diagnostic Testing, pituitary, Treatments | Tagged: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , | Leave a comment »

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