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JCEM Case Rep
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JCEM Case Reports
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10.1210/jcemcr/luae158
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Case Report
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Impaired 11β-HSD1 Activity in a Male Patient With Cushing Disease Resulting in Lack of the Full Cushingoid Phenotype
Weber Robert J Department of Medicine, Division of Endocrinology, University of California, San Francisco, CA 94143, USA

Kawaja Christopher Independent Researcher, USA

Wallerstein Robert Department of Genetics, University of California, San Francisco, CA 94143, USA

Kunwar Sandeep M Department of Neurosurgery, University of California, San Francisco, CA 94143, USA

https://orcid.org/0000-0002-8521-3456
Liu Chienying Department of Medicine, Division of Endocrinology, University of California, San Francisco, CA 94143, USA

Correspondence: Chienying Liu, MD, Department of Medicine, Division of Endocrinology, University of California, San Francisco, 400 Parnassus Avenue, San Francisco, CA 94143, USA. Email: Chienying.Liu@ucsf.edu.
9 2024
05 9 2024
05 9 2024
2 9 luae15802 4 2024
16 8 2024
05 9 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.

Abstract

We present a patient who had surgically confirmed CD but without the full cushingoid phenotype despite markedly elevated cortisol. Nonpathologic causes of elevated ACTH and cortisol were eliminated as were pathogenic variants in the glucocorticoid receptor gene. Further studies of urine metabolites, cortisol half-life, and the ratios of cortisone to cortisol conversion revealed impaired 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity. There have only been 2 prior reports of impaired 11β-HSD1 resulting in lack of classic cushingoid features in the past 2 decades. Our patient's presentation and previous reports demonstrate the key role of 11β-HSD1 in modulating intracellular cortisol concentration, therefore shielding the peripheral tissues from the effects of excess cortisol. When patients present with markedly elevated cortisol but without classic cushingoid features, impaired 11β-HSD1 should be considered in the differential diagnosis.

11β hydroxy- steroid dehydrogenase
11β-HSD1
Cushing syndrome
National Institute of Diabetes and Digestive and Kidney Diseases 10.13039/100000062 DK007418
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pmcIntroduction

Cushing syndrome (CS) is a disease of supraphysiologic cortisol signaling through glucocorticoid receptor (GR) with stereotypical clinical features that include obesity, facial rounding, abnormal fat deposition in the dorsocervical and supraclavicular regions, violaceous striae, easy bruising, proximal muscle weakness, dysglycemia, hyperlipidemia, hypertension (HTN), low bone density, gonadal dysfunction, and psychiatric disturbances [1]. However, 2 women with CS were reported [2, 3] to lack cushingoid features, attributable to impaired 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity.

Two paired enzyme isoforms, 11β-HSD1 and 11β-hydroxysteroid dehydrogenase type 2, modulate intracellular concentrations of active cortisol and inactive cortisone. In aldosterone-targeted tissues, predominantly at the distal nephron, 11β-hydroxysteroid dehydrogenase type 2 converts cortisol into cortisone [4, 5] which defends the mineralocorticoid receptor from unregulated activation by cortisol. 11β-HSD1 is widely expressed including in liver, adipose tissue, and skeletal muscle, regenerating cortisol from cortisone in a nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-dependent manner (Fig. 1). This isoenzyme has been implicated in human obesity and metabolic syndrome [7, 8]. In mice, overexpression of 11β-HSD1 in adipose tissue led to obesity and metabolic syndrome [9], and knockout of 11β-HSD1 in rodents protected these animals [10] from effects of exogenous glucocorticoids.

Figure 1. Schematic of 11β hydroxysteroid reductase (11β-HSD1) activity, adapted from Lawson et al [6]. 11β-HSD1 is embedded in the membrane of the endoplasmic reticulum and converts cortisone into cortisol. The reduction requires the cofactor NADPH, which is the electron donor to convert the 11-ketone moiety into a hydroxyl group. NADPH is in turn produced by H6PDH. Mutations in either 11β-HSD1 or H6PDH can impair this reaction. Cortisol and cortisone are subsequently metabolized into tetrahydrocortisol (THF and allo-THF) and tetrahydrocortisone (THE) by alpha and beta reductases. These metabolites can be measured in urine samples to infer 11β-HSD1 activity.

11β-HSD activity can be inferred from urinary corticosteroids and their metabolites [11]. Cortisol and cortisone are metabolized by reductases into tetrahydrocortisol (THF) and tetrahydrocortisone (THE), respectively. Cortisol is metabolized to 5β-THF (THF) and 5α-THF (allo-THF). THF, allo-THF, and THE are measurable in urine and global 11β-HSD1 activity can be assessed by the ratio of THF and allo-THF to THE ((THF + allo-THF)/THE) (Fig. 1). A low ratio indicates impaired 11β-HSD1 activity resulting in a relative increase in cortisone and reduced cortisol regeneration [11].

In the initial report of the woman with Cushing disease (CD) without cushingoid features despite elevated cortisol, Tomlinson et al [2]. documented a low urinary (THF + allo-THF)/THE, indicating impaired 11β-HSD1 activity. Further, they demonstrated decreased conversion of oral cortisone acetate to cortisol and a lower cortisol half-life, confirming reduced 11β-HSD1 activity in regenerating cortisol. Performing the same evaluation, Arai et al [3] reported the second woman with adrenal CS also without cushingoid features resulting from impaired 11β-HSD1 activity.

More than a decade later, we report a third case and the first male patient with CD without the full cushingoid phenotype because of impaired 11β-HSD1 activity.

Case Presentation

A 46-year-old man obtained a urine hormone test for gradually decreasing libido, worsening HTN, sleep interruptions, higher glucoses at night on his continuous glucose monitoring device, and weight gain of 10 pounds over 6 years. Initially, he attributed these symptoms to normal aging. However, testing revealed elevated cortisol and an absent circadian rhythm. He then presented to our clinic for evaluation. He denied easy bruising and exercised without difficulty. His exercise routine consisted of two 30-minute upper body weight training sessions and low-intensity running or cycling for 100 to 200 minutes weekly. He reported a normal bone density (T score + 0.4) on an outside bone density scan. He denied taking exogenous steroids, hormones, and herbal supplements. Puberty occurred at age 10 years. HTN was diagnosed at age 25 years, initially controlled on losartan. Amlodipine was added shortly before the presentation. He had mild anxiety and depression diagnosed in his 30 seconds, well-controlled on citalopram. He had 5 episodes of central serous chorioretinopathy (CSCR) starting 4 years before his presentation. Additional medications included trazodone for sleep, over-the-counter probiotics, fish oil, magnesium, and vitamin B complex. Family history was notable for HTN: brother diagnosed in his 30s and father diagnosed in his 50s. The patient never smoked tobacco and drank 3 to 5 alcoholic beverages weekly.

Diagnostic Assessment

On examination, his body mass index was 25.7. Blood pressure was 130/82 mm Hg. He was muscular. Although slight facial rounding was noted compared to older pictures, he had no other apparent abnormal fat distribution (Fig. 2A). He did not have skin thinning, striae, nor ecchymoses. Laboratory evaluation (Table 1) showed elevated cortisol and ACTH at different times, multiple elevated late night salivary cortisol, and 3.5- to 6-fold elevated 24-hour urine free cortisol (UFC). Morning testosterone was in the low-normal range. Fasting plasma glucoses were 92 and 106 mg/dL (5.11 and 5.88 mml/L) (normal range, 65-99 mg/dL; 3.6-5.5 mmol/L), with normal fasting insulin and hemoglobin A1c. There was no overt dyslipidemia. Genetic testing (Fulgent Genetics) for the glucocorticoid receptor gene, nuclear receptor subfamily 3 group C member 1 (NR3C1), was performed by full-gene sequencing and deletion/duplication analysis by next-generation sequencing using transcript NM_001018077.1; it did not reveal known pathogenic variants. Whole-exome sequencing (WES) (Ambry Genetics) showed no variants that met criteria for reporting. Pituitary magnetic resonance imaging revealed a 3-mm microadenoma. Urinary steroid profiling by liquid chromatography-tandem mass spectrometry, high-resolution accurate mass (Mayo Clinic) showed a reduced (THF + allo-THF)/THE ratio of 0.75 (normal: 1.3 in males, 1.74 in CD) [11] (Tables 2 and 3). Inferior petrosal sinus sampling (IPSS) demonstrated a central source of ACTH.

Figure 2. Photos of our patient with hypercortisolemia and impaired 11β-HSD1 activity. (A) Before surgery, demonstrating lack of overt cushingoid features. (B) Eighteen months after surgery, demonstrating slimming of the face.

Figure 3. Additional cortisol metabolism measurements. (A) Cortisol to cortisone ratios following oral administration of 25 mg of cortisone, demonstrating lower cortisol to cortisone ratios compared to those of normal female controls in which the mean ratio is >12 at 30 minutes, >10 at 60 and 90 minutes, >8 at 120 and 180 minutes, and >5 at 240 minutes [2]. We do not have male normative data for cortisol to cortisone ratios. However, prior studies demonstrated men had a higher 11β-HSD1 activity compared to women [13]. (B) Cortisol half-life was measured after IV administration of 5 mg of hydrocortisone. A best-fit line is indicated by the dashed line. The best-fit formula for the line is Cortisol = 18.38 e(−0.01 x). The half-life was calculated to be 69.3 minutes (normal range: 78-102 minutes) [12].

Table 1. Laboratory data before and after surgerya

Tests	Before surgery	After surgery	Normal range	
Sodium	141 mEq/L
(141 mmol/L)	138 mEq/L
(138 mmol/L)	135-146 mEq/L
(135-146 mmol/L)	
Potassium	4.5 mEq/L
(4.5 mmol/L)	4.7 mEq/L
(4.7 mmol/L)	3.5-5.3 mEq/L
(3.5-5.3 mmol/L)	
Chloride	105 mEq/L
(105 mmol/L)	103 mEq/L
(103 mmol/L)	98-110 mEq/L
(98-110 mmol/L)	
Bicarbonate	29 mEq/L
(29 mmol/L)	26 mEq/L
(26 mmol/L)	20-32 mEq/L
(20-32 mmol/L)	
BUN	25 mg/dL
(9 mmol/L)	33 mg/dL
(11.8 mmol/L)	7-25 mg/dL
(2.5-9 mmol/L)	
Creatinine	1.12 mg/dL
(99 µmol/L))	0.98 mg/dL
(86.65 µmol/L))	0.60-1.35 mg/dL
(53-120 µmol/L)	
Fasting glucose	106 mg/dL (5.88 mmol/L)
92 mg/dL (5.11 mmol/L)	81 mg/dL (4.50 mmol/L)
83 mg/dL (4.66 mmol/L)	65-99 mg/dL
(3.6-5.5 mmol/L)	
24-h UFCb	326.8 µg (901.5 nmol) (UV 2L)
181.6 µg (497.6 nmol) (UV 1.8L)
216.6 µg (595.9 nmol) (UV 3L)		4.0-50 µg
(11-137 nmol)	
ACTH	8 Am: 118 pg/mL (25.98 pmol/L)
3 Pm: 125 pg/mL (27.53 pmol/L)
4 Pm: 110 pg/mL (24.22 pmol/L)	6 pg/mL (1.32 pmol/L)
1 M postop
23 pg/mL (5.06 pmol/L)
18 M postoperatively	6-50 pg/mL
(1.3-11.0 pmol/L)	
Cortisol	8 Am: 28.1 µg/dL (775 nmol/L)
3 Pm: 19 µg/dL (524 nmol/L)
4 Pm: 22.3 µg/dL (615 nmol/L)	<0.5 µg/dL (<13.8 nmol/L)
1 M postoperatively
9.9 µg/dL (273 nmol/L)
18 M postoperatively	4-22 µg/dL
(110-607 nmol/L)	
Late night
salivary cortisol	0.47 µg/dL (13 nmol/L)
0.58 µg/dL (16 nmol/L)
0.72 µg/dL (19.9 nmol/L)
0.31 µg/dL (8.6 nmol/L)
0.35 µg/dL (9.7 nmol/L)
0.41 µg/dL (11.3 nmol/L)	<0.03 µg/dL (0.83 nmol/L)	<0.09 µg/dL
(<2.48 nmol/L)	
Total testosteroneb	255 ng/dL (884 nmol/L)	373 ng/dL (1293 nmol/L)
554 ng/dL (1919 nmol/L)	250-1100 ng/dL
(866-3813 nmol/L)	
DHEA-S	272 µg/dL (0.74 µmol/L)		61-442 µg/dL
(0.17-1.20 µmol/L)	
Androstenedione	95 ng/dL (3.3 nmol/L)		40-190 ng/dL
(1.4-6.6 nmol/L)	
Aldosterone	2 ng/dL (55.5 pmol/L)		<28 ng/dL
(<776 pmol/L)	
PRA	4.42 ng/mL/h (4.42 µg/h/L)		0.25-5.82 ng/mL/h
(0.25-5.82 µg/h/L)	
HbA1c	5.4%, 5.6%	5.6%	<5.7%	
Fasting insulin	10.9 µU/mL
(78 pmol/L)		<19.6 µU/mL
(<140 pmol/L)	
Total cholesterol	240 mg/dL
(6.22 mmol/L)	250 mg/dL
(6.48 mmol/L)	<200 mg/dL
(< 5.18 mmol/L)	
HDL	88 mg/dL
(2.3 mmol/L)	78 mg/dL
(2.0 mmol/L)	> 40 mg/dL
(> 1 mmol/L)	
Triglycerides	63 mg/dL
(0.71 mmol/L)	90 mg/dL
(1.01 mmol/L)	<150 mg/dL
(<1.7 mmol/L)	
LDL	137 mg/dL
(3.55 mmol/L)	152 mg/dL
(3.94 mmol/L)	<100 mg/dL
(<2.6 mmol/L)	
Abnormal values are shown in bold font. Values in parenthesis are International System of Units (SI).

Abbreviations: DHEA-S, dehydroepiandrosterone sulfate; PRA, plasma renin activity; UFC, urinary free cortisol; UV, urine volume.

a Multiple data taken from different days.

b Measured by liquid chromatography–mass spectrometry.

Table 2. 24 -hour urine steroids and metabolites before surgerya

Steroid analyteb	Patient value	Reference rangec	
Cortisol	590 µg
(1628 nmol)	3.5-45.0 µg
(9.7-124.2 nmol)	
Cortisone	753 µg
(2078 nmol)	17.0-129.0 µg
(47.3-358.6 nmol)	
THF	11 184 µg
(30 868 nmol)		
Allo-THF	460 µg
(1270 nmol)		
THE	15 581 µg
(43 004 nmol)		
Values in parenthesis are International System of Units (SI).

Abbreviations: allo-THF, 5a-Tetrahydrocortisol; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

a Measured by liquid chromatography-tandem mass spectrometry, high-resolution accurate mass at Mayo Clinic.

b Only relevant analytes are shown.

c Normal reference range of the individual analyte from this urine steroid profiling for healthy controls is not available and not provided by Mayo Clinic. For reference, provided here are normal reference ranges for urine cortisol and cortisone measured by liquid chromatography-tandem mass spectrometry at Mayo Clinic.

Treatment

He underwent uncomplicated transsphenoidal surgery 3 months after his presentation. Histology revealed positive staining for TPIT and ACTH, consistent with a corticotroph adenoma. Postoperatively, cortisol was <1 mcg/dL (27.6 nmol/L) (normal range: 4-22 mcg/dL; 110-607 nmol/L), and he was placed on hydrocortisone (HC) 40 mg twice daily to minimize withdrawal symptoms because of high UFC and the possibility of enhanced cortisol clearance from impaired 11β-HSD1 activity. He was able to taper to 20 mg twice daily in 2.5 weeks.

Outcome and Follow-up

One month later, serum cortisol remained <1 mcg/dL (27.6 nmol/L) and ACTH was 6 pg/mL (1.32 pmol/L) (normal range 6-50 pg/mL; 1.32-11 pmol/L). Over the next 10 months, he was tapered off HC. A morning cortisol was 9.9 mcg/dL (273 nmol/L), and ACTH was 23 pg/mL (5.06 pmol/L) 18 months after surgery. His testosterone levels improved (Table 1). He reported lower glucose readings on his continuous glucose monitoring, and his fasting plasma glucose decreased to 81 mg/dL (4.505 mmol/L) and 83 mg/dL (4.66 mmol/L) on 2 separate measures. In contrast, hypercortisolism did not appear to have noticeable effects on hemoglobin A1c and the lipid profile, in both of which a reduction was not observed after surgery (Table 1). He reported improved libido and sleep. He lost about 1.3 kg, and his face was slimmer 18 months after surgery (Fig. 2B). His blood pressure also improved, although he still needed losartan for control. He has had no further exacerbation of CSCR.

Additional evaluation of 11β-HSD1 activity was undertaken as previously described [2]. The ability to convert cortisone to cortisol was assessed following 25 mg of oral cortisone acetate (Bausch Health, Canada) at 9 Am after omitting the preceding evening HC dose. Serial measurements of serum cortisol and cortisone were taken at 0, 30, 60, 90, 120, 180, and 240 minutes. Compared to prior data in female controls [2], low cortisol to cortisone (cortisol/cortisone) ratios were noted at all time points (Fig. 3A). Although we lack data from male controls, prior studies showed a higher 11β-HSD1 activity in men compared to women [13]. Cortisol half-life was determined by giving 2 mg of oral dexamethasone the preceding midnight followed by 5 mg of IV HC at 9 Am. Blood samples were taken from the contralateral arm at 0, 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, 180, 210, and 240 minutes. Using nonlinear regression, the half-life was determined to be 69.3 minutes (normal range: 78-102 minutes [12]) (Fig. 3B).

Discussion

We have described the first male patient with CD without the full cushingoid phenotype from impaired 11β-HSD1 activity, resulting in reduced cortisol regeneration, protecting him from the full deleterious effects of hypercortisolism.

Our report adds to the previous reports supporting the use of urinary (THF + allo-THF)/THE ratio in the evaluation of CS in the appropriate clinical setting because it may allow clinicians to differentiate nonpathologic CS from true pathologic hypercortisolism when the classic signs and symptoms of CS are absent or mild. Glucocorticoids increase 11β-HSD1 expression [8] and his low ratio of 0.74, compared to 1.30 in male controls and 1.74 in patients with CD was remarkable. All affected patients had lower cortisol/cortisone ratios and a lower cortisol half-life, which confirmed reduced 11β-HSD1 activity in regenerating cortisol form cortisone, resulting in increased clearance of cortisol (Table 3). In the initial report, the 20-year-old female with CD had secondary amenorrhea, which resolved after surgery [2]. In the second report, the 55-year-old woman was completely asymptomatic and adrenal CS was diagnosed during an evaluation for an incidentally discovered 3-cm left adrenal mass [3]. She had a hysterectomy at age 45 years. Our patient had CSCR, which is a rare retinal condition in which glucocorticoid use is considered a risk factor [14]. It has also been reported as a manifestation of CS [15, 16]. He had no further episodes after surgery. Other mild signs and symptoms improved postoperatively. The variable tissue-specific expressions of 11β-HSD1 may explain that our patient was not fully protected by reduced 11β-HSD1 activity, especially in tissues with little or no expression. Although urinary (THF + allo-THF)/THE ratio represents the sum of 11β-HSD1 activity from various tissues, it cannot assess the tissue-specific effects of 11β-HSD1 on local glucocorticoid metabolism [7, 8].

Table 3. Normative data compared to our patient and case reports for (THF + allo-THF)/THE ratio (mean ± SD) and cortisol half-life

Controls and patients	(THF + allo-THF)/THE ratio	Cortisol half-life	
Female controls	1.15 ± 0.11 (Ref [11])		
Male controls	1.30 ± 0.07 (Ref [11])	78-102 min (Ref [12])	
Cushing disease	1.74 ± 0.24 (Ref [11])		
Adrenal Cushing syndrome	1.7		
Patient in Tomlinson et al [2]	0.66	57.3 min	
Patient in Arai et al [3]	0.63	77 min	
The present patient	0.74	69.3 min	
Abbreviations: allo-THF, 5a-Tetrahydrocortisol; Ref, reference; THE, tetrahydrocortisone; THF, tetrahydrocortisol.

It is vital to secure the diagnosis of ACTH-dependent CS before transsphenoidal surgery. His mild symptoms, common in the general population, and lack of full classic features despite marked hypercortisolism warranted additional investigation. We considered nonpathological causes of elevated ACTH and cortisol, which include stress, sleep apnea, anorexia, excessive exercise, and pseudo-Cushing syndrome from significant alcohol intake or uncontrolled depression [17], none of which applied to our patient. UFC can be elevated when urine volume is 5 L or more [18]; our patient's urine volumes were 3 L or less (Table 1). Another potential diagnosis is glucocorticoid resistance because of mutations in the GR gene (NR3C1). This is a rare condition with significant clinical heterogeneity in which cortisol circadian rhythm is maintained [19]. His cortisol levels did not exhibit a circadian rhythm, and sequencing of NR3C1 did not reveal pathogenic variants. IPSS is the procedure of choice in differentiating CD from ectopic ACTH syndrome when magnetic resonance imaging does not reveal an adenoma larger than 6 mm [20]. However, IPSS can be misleading in patients who do not have pathological ACTH-dependent hypercortisolism or are eucortisolemic in cyclic CS at the time of the procedure [21]. The finding of reduced urinary (THF + allo-THF)/THE ratio was crucial, explaining his lack of the full stereotypical cushingoid phenotype. Late night salivary cortisol remained elevated before IPSS, making cyclic CS unlikely.

We are unable to attribute the reduced 11β-HSD1 activity to mutations based on WES. Rare individuals with complete loss of 11β-HSD1 activity were found to have exon variants in either the 11β-HSD1 gene or hexose-6-phosphate dehydrogenase (H6PDH) [6, 22], the protein product that supplies the requisite cofactor, NADPH (Fig. 1). These cases are characterized by chronically elevated ACTH, elevated adrenal androgens, and precocious puberty [6, 22], which our patient did not have. WES evaluates exons, not the noncoding introns. An intronic variant could affect gene function or transcription levels [6, 23, 24].

Research in both rodent models and humans has underscored the critical role of 11β-HSD1 in amplifying local cortisol signaling and regulating glucocorticoid metabolism in peripheral tissues [7, 8, 25]. There has been an ongoing interest in targeting 11β-HSD1 to limit the deleterious effects of CS and exogenous glucocorticoids [26‐28]. Our patient and previous reports serve as real-life examples demonstrating that reduced 11β-HSD1 activity can ameliorate the deleterious effects of hypercortisolism.

There are 2 limitations in our report. First, GH inhibits 11β-HSD1 expression in certain tissues [29, 30]; unfortunately, we do not have data on GH or IGF-1. Our patient did not appear acromegalic and denied any illicit hormone use. Second, urine steroid profiling was measured by liquid chromatography-tandem mass spectrometry high-resolution accurate mass to calculate the urinary (THF + allo-THF)/THE ratio, whereas in historical data, steroids and metabolites were measured by gas chromatography/mass spectrometry [11]. Therefore, our comparison to the historical data needs be interpreted with caution, although both methods have high specificity to measure steroids and their metabolites.

Learning Points

Impaired 11β-HSD1 activity decreases cortisol regeneration and modulates cortisol actions at the cellular and tissue levels.

Patients with CS may not have the full clinical phenotype if 11β-HSD1 activity is impaired.

Impaired 11β-HSD1 activity should be considered in the differential diagnosis of CS when there are no apparent clinical signs and symptoms in the appropriate clinical context, and urinary (THF + allo-THF)/THE ratio can be helpful in securing the diagnosis.

Acknowledgments

The authors thank Jeremy Tomlinson and Paul Stewart for sharing their experience of their case report and advice on additional testing, evaluating 11β-HSD1 activity, Theodore Kurtz for support with laboratory testing, and Samantha Liang for assistance with Fig. 1. The authors also thank the patient for his permission to publish this report and his generous support to our research and education programs.

Contributors

C.L. diagnosed and managed the patient. R.W. performed genetic counseling and testing. S.M.K. was responsible for transsphenoidal surgery. R.J.W., C.L., and C.K. prepared the manuscript. All authors reviewed and approved the final draft.

Funding

R.J.W. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases, T32 (DK007418).

Disclosures

None declared.

Informed Patient Consent for Publication

Signed informed consent obtained directly from patient.

Data Availability Statement

Original data generated and analyzed for this case report are included in this published article.

Abbreviations

11β-HSD1 11β-hydroxysteroid dehydrogenase type 1

CD Cushing disease

CS Cushing syndrome

CSCR central serous chorioretinopathy

GR glucocorticoid receptor

HC hydrocortisone

HTN hypertension

IPSS inferior petrosal sinus sampling

NADPH nicotinamide adenine dinucleotide phosphate hydrogen

THE tetrahydrocortisone

THF tetrahydrocortisol

UFC urine free cortisol

WES whole-exome sequencing
==== Refs
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