Thin Skin in Cushing’s Syndrome

Posted on March 23, 2025 by MaryO

Abstract

A 53-year-old woman with a history of metastatic small-cell lung cancer was evaluated during an inpatient admission for Cushing’s syndrome on the basis of new findings of hypertension, hypokalemia, hyperglycemia, and metabolic alkalosis.
A focused physical examination was performed to assess for the antianabolic effects of excess cortisol. The thickness of the skin on the back of her third finger was 1.2 mm (reference value, >1.8) when measured with skin calipers (Panels A and B). Thin skin — a clinical sign strongly suggestive of hypercortisolism — results from inhibition of collagen synthesis by glucocorticoids.
To avoid interference from subcutaneous fat, skin thickness should be measured on the backs of the fingers. The measurement can be done with skin calipers (see Video 1) or electrocardiogram calipers (see Video 2). Levels of random plasma cortisol, midnight plasma cortisol, 24-hour urine cortisol, and corticotropin were elevated.
Magnetic resonance imaging of the brain showed no pituitary abnormalities. Whole-body restaging imaging showed new metastatic lesions in the lungs, bones, liver, and meninges. A diagnosis of Cushing’s syndrome — presumed to be paraneoplastic — was made.
After discussing her prognosis with her physicians, the patient opted for palliative care and died 1 week later.

Filed under: Cancer, Cushing's, Rare Diseases, symptoms | Tagged: , , , , , , | Leave a comment »

Leukocytosis in Cushing’s Syndrome Persists Post-Surgical Remission and Could Predict a Lower Remission Prognosis in Patients with Cushing’s Disease

Posted on March 21, 2025 by MaryO

Abstract

Context

Leukocytosis frequently noted in Cushing’s syndrome (CS), along with other blood cell changes caused by direct and indirect cortisol effects.

Objective

Assess baseline white blood cell (WBC) profile in CS patients compared to controls and WBC changes pre- and post-remission after surgical treatment for CS.

Design

A comparative nationwide retrospective cohort study.

Setting

Data from Clalit Health Services database.

Patients

297 patients (mean age 51 ± 16.1 years, 73.0% women) with CS and 997 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS or adrenal cancer patients were excluded.

Main outcome measure

Mean WBC, neutrophils, and neutrophil-to-lymphocyte ratio (NLR) two-years before and after pituitary or adrenal surgery. WBC and neutrophils are expressed as Kcells/µl.

Results

At baseline, leukocytosis was observed in 21.5% of patients with CS vs. 8.9% of controls (P < 0.001). Patients with CS had significantly higher WBC (8.8 ± 2.88 vs. 7.54 ± 2.45, p < 0.0001), neutrophils (5.82 ± 2.38 vs. 4.48 ± 1.97, p < 0.0001), and NLR (3.37 ± 2.63 vs. 2.27 ± 1.86, p < 0.0001) compared to controls, regardless of pituitary or adrenal source of hypercortisolemia. Post-surgery, patients with CS experienced significant decreases in mean WBC (-0.57 ± 2.56, p < 0.0001), neutrophils (-0.84 ± 2.55, p < 0.0001), and NLR (-0.63 ± 2.7, p < 0.0001). Despite achieving disease remission, patients with CS still had higher WBC (8.11 ± 2.4 vs. 7.46 ± 2.17, p = 0.0004) and neutrophils (4.71 ± 2.10 vs. 4.41 ± 1.87, p = 0.03) compared to controls. Patients with CD and baseline leukocytosis had lower remission rate than those with normal WBC (36.7% vs. 63.9%, p = 0.01).

Conclusions

At diagnosis, CS patients have elevated WBC, neutrophils, and NLR compared to controls. Remission does not normalize WBC levels in all patients, and baseline leukocytosis predicts a poorer remission prognosis in CD.

From https://link.springer.com/article/10.1007/s40618-025-02535-2

Filed under: Cushing's, symptoms | Tagged: , , , | Leave a comment »

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
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Treatment-Resistant Cushing Disease and Acromegaly in a Young Woman: A Case Of Functional Pituitary Macroadenoma

Posted on March 14, 2025 by MaryO

Abstract

Cushing disease and acromegaly are common endocrine disorders caused by excessive cortisol and growth hormone production, respectively. Both conditions can co-occur due to functioning pituitary adenomas, which are typically benign pituitary gland tumors. This report discusses a 30-year-old woman with hyperpituitarism leading to treatment-resistant Cushing disease and acromegaly caused by a functional pituitary macroadenoma.
A 30-year-old woman presented with a history of excessive weight gain, facial puffiness, fatigue, persistent headaches, and visual disturbances. Clinical examination revealed features consistent with Cushing disease and acromegaly, including a moon face, central obesity, and large hands and feet—the ophthalmologic evaluation identified bitemporal hemianopia, suggesting optic chiasm compression. Laboratory results showed elevated ACTH, IGF-1, and prolactin levels, alongside confirmed hypercortisolism. The patient also had secondary diabetes mellitus and galactorrhea—initial treatment with octreotide provided limited benefit, with persistent hormone elevations and insufficient symptom control. The patient underwent endonasal endoscopic transsphenoidal resection of the pituitary macroadenoma, leading to marked symptomatic and hormonal improvements. This underscores the diagnostic challenge and treatment complexity of such cases. Early diagnosis is critical for optimizing outcomes in patients with hyperpituitarism and mitigating complications. This case highlights the importance of multidisciplinary management and the necessity of long-term follow-up to monitor for recurrence and ensure sustained remission.

Introduction

Pituitary adenomas are benign tumors arising from the pituitary gland, often referred to as the “master gland” due to its central role in regulating key physiological processes such as growth, metabolism, and reproduction [1,2]. These tumors are classified by size into microadenomas (<10 mm) and macroadenomas (≥10 mm) and by hormonal activity into functioning and nonfunctioning adenomas. Functioning adenomas actively secrete hormones, leading to distinct syndromes such as prolactinomas, acromegaly (from growth hormone overproduction), and Cushing disease (from excess ACTH). In contrast, nonfunctioning adenomas do not secrete hormones but may cause symptoms due to mass effects, such as visual disturbances or hypopituitarism [[3], [4], [5]].
The simultaneous occurrence of Cushing disease and acromegaly is rare and presents a significant diagnostic and therapeutic challenge. Both conditions stem from hyperpituitarism, typically due to a functional pituitary adenoma [6,7]. Cushing disease results from ACTH hypersecretion, causing excessive cortisol production and features such as central obesity, hypertension, hyperglycemia, and muscle weakness [[8], [9], [10]]. Prolonged cortisol exposure can lead to severe complications, including cardiovascular diseases and osteoporosis. Acromegaly, on the other hand, arises from growth hormone overproduction, leading to elevated IGF-1 levels and characteristic features such as enlarged extremities, facial changes, and systemic complications like insulin resistance and joint abnormalities [[11], [12], [13]].
The coexistence of Cushing disease and acromegaly within the same affected person is extraordinarily rare, making this particular case record particularly noteworthy [14,15].
The simultaneous presentation of these 2 endocrine problems in a young lady because of a hormonally functioning pituitary macroadenoma presents a unique scientific venture [16,17]. The pituitary macroadenoma, defined as a tumor more than 10 mm in diameter, can compress adjoining structures within the sella turcica and enlarge into surrounding areas, leading to signs and symptoms with complications, visible disturbances, and hyperpituitarism. In this case, the patient presented with both Cushing disease and acromegaly, at the same time symptoms as a result of the mass impact of the macroadenoma.
The case of a 30-year-old female with hyperpituitarism, characterized with the aid of drug-resistant Cushing disease and acromegaly, highlights the complexities intricately associated with the analysis and control of a couple of endocrine issues bobbing up from a single pituitary macroadenoma. Her medical presentation changed into one marked by a history of noticeable weight gain, facial puffiness, fatigue, chronic complications, and visual disturbances. A thorough physical exam found traits consistent with each Cushing disorder and acromegaly, which include a moon face, vital weight problems, and enlarged arms and toes. The ophthalmologic exam confirmed bitemporal hemianopia, indicative of optic chiasm compression with the aid of the pituitary macroadenoma. Early recognition and multidisciplinary management are essential to mitigate the significant morbidity associated with these conditions. This case report highlights a rare instance of concurrent Cushing disease and acromegaly due to a functional pituitary macroadenoma, underscoring the importance of timely diagnosis and treatment.

Case presentation

This case of a 30-year-old female highlights the complexities of diagnosing and managing a functional pituitary macroadenoma presenting with overlapping features of Cushing disease and acromegaly, along with secondary diabetes mellitus.
The patient demonstrated classic signs of hypercortisolism, including central obesity with a “moon face” and “buffalo hump,” skin thinning, easy bruising, and muscle weakness. Cortisol’s catabolic effects were evident in her limb wasting and truncal obesity. Metabolic complications included hypertension and secondary diabetes mellitus, supported by elevated random blood sugar (22 mmol/L) and postprandial blood sugar levels (27 mmol/L). Laboratory findings showed significantly elevated ACTH levels (670 pg/mL; normal: 10–60 pg/mL) and increased morning urine cortisol levels.
The patient also exhibited hallmark features of acromegaly, including enlarged hands and feet, necessitating larger shoe and glove sizes, and distinct facial changes such as mandibular prognathism, frontal bossing, and nasal broadening. Soft tissue swelling and fatigue were also noted, alongside joint pain likely resulting from cartilage and bone overgrowth. Her IGF-1 levels were markedly elevated (798 ng/mL; normal: 100–300 ng/mL).
Hyperprolactinemia (643 ng/mL; normal: 5–25 ng/mL) caused galactorrhea, likely resulting from tumor compression of the pituitary stalk or direct prolactin secretion. Diabetes mellitus, secondary to insulin resistance driven by excess cortisol and growth hormone, further complicated her clinical picture (Table 1).

Table 1. Markedly elevated hormone levels preoperatively and their postoperative normalization.

Hormone Patient’s level (Preoperative) Postoperative levels Normal reference value
ACTH 670 pg/mL 90 pg/mL 10–60 pg/mL
IGF-1 798 ng/mL 280 ng/mL 100–300 ng/mL (age-dependent)
Prolactin 643 ng/mL 42 ng/mL 5–25 ng/mL
Morning Urine Cortisol Elevated Normal <50 mcg/24 h
Random Blood Sugar 22 mmol/L 6.5 mmol/L 4.0–7.8 mmol/L
2-Hour Postprandial Blood Sugar 27 mmol/L 7.0 mmol/L <7.8 mmol/L
TSH (Thyroid-Stimulating Hormone) 0.8 mIU/L 1.2 mIU/L 0.5–5.0 mIU/L
FT3 (Free Triiodothyronine) 4.5 pmol/L 4.0 pmol/L 3.5–7.7 pmol/L
FT4 (Free Thyroxine) 15 pmol/L 16 pmol/L 12–22 pmol/L
Secondary diabetes mellitus is a common trouble in sufferers with Cushing disease and acromegaly, stemming from the insulin resistance brought about by persistent hypercortisolism and hypersecretion of GH. This patient’s multiplied blood sugar also reflects tremendous impairment in glucose metabolism. Polyuria, polydipsia, and unexplained weight loss are classic signs of diabetes that could have been found in her clinical history but are frequently overshadowed by the traits of the more distinguished functions of her endocrine disorders. The affected person additionally experienced galactorrhea, an odd milk discharge from the breasts, that’s on account of her expanded prolactin levels (643 ng/mL, ordinary range: 2-29 ng/mL). Hyperprolactinemia inside the context of a pituitary macroadenoma can result from the tumor’s direct secretion of prolactin or from the stalk effect, where the tumor compresses the pituitary stalk, disrupting dopamine inhibition of prolactin secretion.
MRI was the primary imaging modality, revealing a large pituitary macroadenoma centered within the sella turcica and extending suprasellar. The tumor demonstrated homogeneous postcontrast enhancement and exerted mass effects, including optic chiasm compression correlating with bitemporal hemianopia. Other modalities, such as CT, were not considered due to MRI’s superior resolution for pituitary evaluation.
The MRI scans of the patient reveal a large, well-defined pituitary macroadenoma centered within the sella turcica, exhibiting significant suprasellar extension. On sagittal T1-weighted postcontrast imaging (Fig. 1), the lesion demonstrates homogeneous enhancement with clear, well-defined borders, expanding superiorly into the suprasellar region. Coronal T2-weighted images (Fig. 2) further delineate this suprasellar extension, with the mass exerting mass effect on adjacent structures.
Fig 1:

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Fig. 1. This sagittal T1-weighted postcontrast MRI of the brain, specifically focusing on the sella turcica region, reveals a large, homogeneously enhancing mass centered within the sella turcica, consistent with a pituitary macroadenoma. The mass exhibits clear, well-defined borders and appears to expand the sella, with extension into the suprasellar region (marked by circle).

Fig 2:

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Fig. 2. This image shows MRI scan of the brain in coronal T2-weighted images which reveals large suprasellar mass (marked by circles).

Additional sagittal T1-weighted postcontrast imaging (Fig. 3) confirms the uniform enhancement of the macroadenoma, filling the sella turcica and extending upward. Coronal T2-weighted MRI (Fig. 4) reveals the lesion as hyperintense, extending into the suprasellar region and displacing the optic chiasm. The imaging highlights the well-defined borders of the mass and the potential mass effect on adjacent structures.
Fig 3:

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Fig. 3. Sagittal T1-weighted postcontrast MRI depicting a large, homogeneously enhancing pituitary macroadenoma within the sella turcica, expanding into the suprasellar region with well-defined borders (marked by arrows).

Fig 4:

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Fig. 4. Coronal T2-weighted MRI demonstrating a large, hyperintense pituitary macroadenoma within the sella turcica, extending into the suprasellar region (marked by arrows). The lesion displaces the optic chiasm and exhibits well-defined borders, suggesting potential mass effect.

Axial T2-weighted MRI images (Fig. 5) depict a hyperintense lesion in the basal ganglia and thalamus, appearing as a bright, well-defined signal. This finding suggests a potential coexisting pathology affecting deep brain structures, which may or may not be related to the primary pituitary lesion. The characteristics and location of the pituitary macroadenoma correspond with the patient’s clinical presentation of bitemporal hemianopia, likely caused by compression of the optic chiasm.
Fig 5:

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Fig. 5. Axial T2-weighted MRI images of the brain showing a hyperintense lesion in the region of the basal ganglia and thalamus, indicated by white arrows. The lesion appears as a well-defined, bright signal, suggestive of a pathology affecting deep brain structure.

The overall imaging features, including homogeneous enhancement, well-defined borders, and suprasellar extension, are hallmark characteristics of pituitary macroadenomas. The potential lateral extension toward the cavernous sinus warrants further evaluation, while the hyperintense lesion in the basal ganglia and thalamus may indicate secondary effects or unrelated CNS pathology.
The imaging findings collectively support the diagnosis of a large, functioning pituitary macroadenoma, exceeding 10 mm in diameter. The mass’s size and anatomical impact align with the patient’s clinical presentation, which includes headaches, visual field deficits, and hormonal imbalances. The documented compression of the optic chiasm and possible involvement of the cavernous sinus provide a radiological explanation for the patient’s visual symptoms and hormonal disruptions. This MRI assessment substantiates the diagnosis of a pituitary macroadenoma with significant suprasellar extension and compression effects, consistent with the patient’s symptomatology and clinical findings.
The conglomeration of her clinical presentations, elevated hormone levels, and MRI findings of a big suprasellar mass pretty suggestive of a pituitary macroadenoma showed the analysis of a functioning pituitary adenoma. The preliminary treatment control with octreotide, a somatostatin analog, aimed to control both acromegaly and Cushing disorder by inhibiting GH and ACTH secretion. However, the suboptimal reaction highlighted the undertaking of achieving hormone manipulation in sufferers with massive, competitive adenomas.
Given the patient’s persistent symptoms and the insufficient biochemical response to medical therapy, surgical intervention was considered imperative. The patient underwent endonasal endoscopic transsphenoidal resection of the pituitary gland, a minimally invasive surgical approach targeting the tumor via the nasal passages. This approach was preferred over traditional craniotomy due to its demonstrated efficacy in reducing tumor size and lowering elevated hormone levels with fewer complications, reduced morbidity, shorter hospital stays, and faster recovery times. Additionally, the endoscopic technique offers superior visualization of the surgical field, which aids in precise tumor resection and preservation of normal pituitary tissue.
During the surgery, the tumor was noted to be soft and well-circumscribed, with no significant adherence to adjacent structures such as the cavernous sinus or optic chiasm. This facilitated a complete resection of the tumor, minimizing the risk of residual disease. There were no notable intraoperative complications, such as cerebrospinal fluid leakage or significant bleeding, underscoring the safety and efficacy of the chosen approach. Postoperatively, the patient demonstrated marked clinical improvement in her symptoms, accompanied by a significant reduction in hormone levels to within normal reference ranges. This confirmed the diagnosis and highlighted the effectiveness of the surgical intervention. Specifically, there was a substantial decrease in ACTH, IGF-1, and prolactin levels, leading to clinical remission of Cushing disease and acromegaly.
In the postoperative period, the patient did not require immediate hormone replacement therapy, as her endocrine functions remained stable. However, long-term monitoring is planned to assess for potential hormone deficiencies, disease recurrence, or other complications. The follow-up plan includes regular clinical evaluations, hormonal assays, and periodic imaging studies to ensure sustained remission and to promptly address any residual or recurrent tumor growth. This case highlights the crucial role of surgical intervention in managing functional pituitary macroadenomas, particularly when medical therapy fails. The successful outcome underscores the importance of a multidisciplinary approach and the need for lifelong surveillance to optimize long-term outcomes for such patients. This case scenario also underscores the complexities interwoven in diagnosing and coping with hyperpituitarism because of a pituitary macroadenoma, emphasizing the warrant for a complete and multidisciplinary approach. Early recognition of symptoms, correct diagnostic workup, and timely endocrine disorders.

Discussion

The case of this 30-year-old woman with concurrent refractory Cushing disease and acromegaly due to a functional pituitary macroadenoma highlights the challenges inherent in diagnosing and managing multiple endocrine disorders. Recognizing overlapping clinical features was central to reaching the diagnosis. Classic symptoms of Cushing disease, such as a moon face and central obesity, coupled with acromegalic features, including enlarged extremities, underscored the complexity of the case. The presence of bitemporal hemianopia further pointed to a large pituitary mass compressing the optic chiasm, necessitating imaging studies for confirmation. This case underscores the need for clinicians to remain vigilant when evaluating overlapping endocrine features to avoid delays in diagnosis and treatment [[18], [19], [20]].
Laboratory evaluations were pivotal, revealing markedly elevated ACTH, IGF-1, and prolactin levels, in addition to evidence of hypercortisolism and secondary diabetes mellitus. These findings highlighted the intricate interplay of hypersecreted pituitary hormones and the systemic consequences of unregulated hormone production. MRI findings of a large suprasellar pituitary tumor were instrumental in confirming the diagnosis of a functional macroadenoma and guided subsequent treatment decisions.
The patient’s suboptimal response to octreotide therapy underscored the limitations of medical treatments in addressing aggressive, hormone-secreting pituitary macroadenomas. While somatostatin analogs are effective in many cases of acromegaly and can provide symptomatic relief, their efficacy is limited in patients with large adenomas and significant hormonal hypersecretion. This case highlights the necessity of early consideration of definitive surgical intervention when medical therapy fails to achieve adequate biochemical control [[21], [22], [23]].
Endonasal endoscopic transsphenoidal surgery was selected for this patient due to its minimally invasive approach, superior visualization of the sellar region, and lower complication rates compared to traditional craniotomy. Intraoperatively, the tumor’s soft consistency and lack of adherence to adjacent structures facilitated a complete resection. Notably, the absence of significant complications, such as cerebrospinal fluid leakage or vascular injury, reflected the safety and precision of this surgical approach [[24], [25], [26]].
Postoperatively, the patient experienced substantial improvement in symptoms, with normalization of ACTH, IGF-1, and prolactin levels. This outcome underscores the efficacy of surgical intervention in achieving hormonal remission and alleviating symptoms in patients with functional macroadenomas. The resolution of her secondary diabetes mellitus and galactorrhea further reinforced the success of treatment [[27], [28], [29]].
Managing such complex endocrine disorders necessitates a multidisciplinary approach, with endocrinologists, radiologists, and neurosurgeons collaborating to ensure accurate diagnosis and effective treatment planning. Radiologists play a critical role in identifying and characterizing pituitary tumors, while endocrinologists monitor hormonal responses and guide perioperative management [[30], [31], [32]]. Neurosurgeons provide expertise in resecting these challenging lesions and optimizing patient outcomes.
The prognosis for patients undergoing surgical resection of functional pituitary macroadenomas is generally favorable when hormonal remission is achieved. However, long-term follow-up is critical to monitor for potential disease recurrence and manage any residual hormone deficiencies. Lifelong surveillance, including periodic hormonal assays and imaging studies, is recommended. Although the patient did not require immediate hormone replacement therapy, ongoing assessment of endocrine function remains essential to address emerging deficiencies promptly [[33], [34], [35], [36]].
This case exemplifies the importance of integrating current evidence-based practices into patient care. Recent guidelines and studies emphasize the role of endoscopic surgery as the preferred approach for resecting pituitary tumors due to its high success rates and reduced morbidity compared to older techniques.

Conclusion

This case highlights the pivotal role of surgical intervention in managing hormone-resistant pituitary macroadenomas underscoring the role of a multidisciplinary approach involving endocrinology, radiology, and neurosurgery, demonstrating its effectiveness in resolving hormonal overproduction and alleviating symptoms. Long-term follow-up is indispensable to monitor for recurrence, address emerging complications, and ensure sustained remission, reinforcing the need for vigilance and specialized endocrine care in managing these complex disorders.

Patient consent

Written informed consent for publication of this case report was obtained from the patient(s). The patient(s) were provided with sufficient information regarding the nature of the publication, including the details to be disclosed and potential implications. The patient(s) have confirmed their understanding and voluntarily agreed to the publication of this case report.

References

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Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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