Lipoprotein particles in patients with pediatric Cushing disease and possible cardiovascular risks.

BACKGROUND: Cardiovascular (CV) complications are the most significant cause of mortality in adults with Cushing disease (CD); little is known about CV risk factors in children with CD. Measurement of lipoprotein particles by nuclear magnetic resonance (NMR) spectroscopy is a novel technology to assess CV risk. The objective of the current study is to analyze the NMR lipid profile in pediatric CD patients before and 1 year after remission. METHODS: NMR lipid profile was obtained via the Vantera NMR analyzer, using frozen serum samples from 33 CD patients (mean age 13.8 ± 4.0 years) evaluated between 1997 and 2017 at the National Institutes of Health (NIH) Clinical Center (CC). RESULTS: GlycA (glycosylated acute-phase proteins), triglyceride-rich particles (TRLP medium and very small sizes), low-density lipoprotein (LDL) particles (LDLP total and large size), high-density lipoprotein (HDL) particles (HDLP total, medium and small sizes), total cholesterol, LDL-cholesterol, HDL-cholesterol, GlycA inflammatory biomarker, and apolipoprotein B and apolipoprotein A1 (ApoA1) concentrations showed statistically significant changes after remission of CD (p < 0.05). CONCLUSION: In our study population, most of the lipid variables improved post-CD remission, with the exception of HDL and ApoA1, indicating that NMR lipoprotein profile may be a helpful tool in assessing the CV risk in pediatric patients with CD.

Optical Imaging Technology: A Useful Tool to Identify Remission in Cushing Disease After Surgery.

We recently reported the use of optical imaging technology to quantify facial plethora in endogenous Cushing syndrome (CS). In the present study, we studied a larger cohort of patients with Cushing disease (CD) and examined water content fraction as well as blood volume fraction as bio-optic markers for determining the efficacy of this methodology as a predictor of lasting remission after surgery for CS. We imaged 49 patients before and after transsphenoidal surgery (TSS) for Cushing disease (CD); 22 patients were also seen at 3-6 months, and 13 patients 12 months post-operatively. On all patients, we used multi-spectral imaging (MSI) to evaluate hemodynamic distributions as well as water content at a specific area of the face. We found a decrease in blood volume fraction after vs. before surgical treatment in the tested facial area in 37 of the 40 patients, as determined with biochemical markers (p<0.001). All patients that were followed up for up to 12 months showed the same decrease from preoperative values and they remained in remission from CD. We conclude that MSI can be used for the evaluation of remission from CD, at least in the immediate post-operative period and up to one year after surgery. The use of this technology can supplement biochemical and other testing for the evaluation of the various treatment modalities available for patients with CD.

Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome.

BackgroundHypercortisolemia results in changes of the immune system and elevated infection risk, but data on the WBC changes in pediatric Cushing syndrome (CS) are not known. We describe the changes of the WBC lineages in pediatric endogenous hypercortisolemia, their associations with the markers of disease severity, and the presence of infections.MethodsWe identified 197 children with endogenous CS. Clinical and biochemical data were recorded. Sixty-six children with similar age and gender, and normocortisolemia served as controls.ResultsThe absolute lymphocyte count of CS patients was significantly lower than that of controls, while the total WBC and the absolute neutrophil counts were significantly higher. These changes correlated with several markers of CS severity and improved after resolution of hypercortisolemia. Infections were identified in 35 patients (17.8%), and their presence correlated to elevated serum morning cortisol, midnight cortisol, and urinary free cortisol levels, as well as with the decrease in absolute lymphocyte count.ConclusionsChildren with endogenous CS have abnormal WBC counts, which correlate with the severity of CS, and normalize after cure. Infections are common in this population; clinicians should be aware of this complication of CS and have low threshold in diagnosis and treating infections in CS.

Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children.

Glucocorticoids are widely used for immunosuppression in autoimmune diseases. After the resolution of hypercortisolemia, the immune system recovers allowing for autoimmune diseases to manifest. Here we investigated the presence of autoimmune and related diseases that developed after cure of endogenous Cushing syndrome (CS) in children. We identified 129 children who were diagnosed and successfully treated for endogenous CS at the National Institutes of Health from 1997 until 2017, and who were followed for at least 6 months after treatment. We performed a retrospective chart review analysis to identify the presence of autoimmune or related diseases after cure. Ten children were diagnosed with a new autoimmune or related disorder after resolution of hypercortisolemia. This results in a frequency of 7.8% of our pediatric CS population. The identified patients had a shorter duration of hypercortisolemia prior to diagnosis, but did not otherwise differ from the remaining patients. The various identified diseases were: celiac disease (n=1), psoriasis (n=1), Hashimoto thyroiditis (n=1), Graves disease (n=1), optic neuritis (n=2), skin hypopigmented lesions/vitiligo (n=2), allergic rhinitis/asthma (n=1), and neuropathy responding to glucocorticoid treatment (n=1). The reported time between the treatment of CS and diagnosis of autoimmune disorder ranged from 6 to 19 months. The presence of autoimmune or related diseases might be masked by the hypercortisolemic state in endogenous CS. After resolution of hypercortisolemia, the presentation of new autoimmune diseases or recurrence of previously known autoimmune conditions should be considered when concerning symptoms arise.

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.

Coagulation Profile in Patients with Different Etiologies for Cushing Syndrome: A Prospective Observational Study.

Previous studies reported a higher prevalence of venous-thromboembolic events among patients with Cushing disease (CD) compared to those with ACTH-independent Cushing syndrome (CS) from adrenal sources. The objective of the current study was to evaluate the coagulation profile of patients with CS from different etiologies. A prospective observational study was conducted at a clinical research center. The study included adult patients admitted for evaluation of suspected CS (n=85), that were divided into 3 groups: CD (n=22), ACTH-independent CS from an adrenal tumor/hyperplasia (adrenal CS, n=21), and a control group consisting of subjects with negative screening for CS (rule-out CS, n=42). Coagulation profiles were drawn before and 8.5±4.3 months after surgery (trans-sphenoidal or adrenalectomy, n=18), and included fibrinogen, Factor VIII (FVIII), von Willebrand factor antigen (vWF:Ag), plasminogen activator inhibitor-1 (PAI-1), antithrombin III (ATIII), Protein C (PC), Protein S (PS), α2-antiplasmin (α2AP), and aPTT measurements. Patients with CD had higher baseline mean cortisol levels, ATIII activity and vWF:Ag levels compared with adrenal CS. Differences in ATIII activity and vWF:Ag levels remained even after controlling for BMI, and ATIII after also controlling for 24-h urinary free cortisol collections. Our study showed for the first time the differences in coagulation profiles between various etiologies of CS. We assume that the higher cortisol burden among CD patients may explain the differences found in the coagulation profile as well as the higher risk for VTE compared with primary adrenal CS patients.

3D Volumetric Measurements of GH Secreting Adenomas Correlate with Baseline Pituitary Function, Initial Surgery Success Rate, and Disease Control.

There is scarce data on the clinical utility of volume measurement for growth hormone (GH)-secreting pituitary adenomas. The current study objective was to assess the association between pituitary adenoma volumes and baseline endocrine evaluation, initial surgical success rate, and disease control among patients with acromegaly. A retrospective cohort study was conducted at a clinical research center including patients with acromegaly due to GH-secreting pituitary adenomas. Baseline hormonal evaluation and adenoma characteristics according to MRI were collected. Volumetric measurements of pituitary adenomas were performed using a semi-automated lesion segmentation and tumor-volume assessment tools. Rates of post-operative medical treatment, radiation therapy, and re-operation were gathered from the patients' medical records. Twenty seven patients (11 females) were included, median age 21.0 years (interquartile range 29 years, range 3-61 years). Patients harboring adenomas with a volume <2 000 mm3 had higher chance to achieve disease remission [94.1% (n=16) vs. 50.0% (n=4), p<0.05]. Adenoma volumes positively correlated with baseline plasma GH levels before and after oral glucose administration, and with plasma IGF-I and PRL levels. Adenoma volume had negative correlation with morning plasma cortisol levels. Finally, patients harboring larger adenomas required 2nd surgery and/or medical treatment more often compared with subjects with smaller adenomas. Accurate 3D volume measurement of GH-secreting pituitary adenomas may be used for the prediction of initial surgery success and for disease control rates among patients with a GH-secreting pituitary adenomas and performs better than standard size assessments.

Sporadic melanotic schwannoma with overlapping features of melanocytoma bearing a GNA11 mutation in an adolescent girl.

Melanotic schwannoma (MS) is a soft tissue neoplasm that shares histologic features with melanocytic tumors and schwannomas. A type of MS, called psammomatous MS (PMS), is associated with Carney complex (CNC), which is caused by PRKAR1A mutations. Other pigmented neoplasms, such as uveal melanomas and melanocytomas (MCs), are associated with genetic defects in other genes including GNA11. We report an adolescent female with a large sporadic mesenteric MS with complex histologic findings reminiscent of both PMS and MC. The lesion carried a mutation of the GNA11 gene. We conclude that sporadic MSs may occur rarely in adolescents without CNC; MSs may also be associated with somatic GNA11 mutations.

Death in pediatric Cushing syndrome is uncommon but still occurs.

UNLABELLED: Cushing syndrome (CS) in children is rare. Delayed diagnosis and treatment of CS may be associated with increased morbidity and, unfortunately, mortality. We performed a retrospective review of all patients with CS under the age of 18 years referred to the National Institutes of Health (NIH) from 1998 to 2013 in order to describe deceased patients among cases of pediatric CS referred to the National Institutes of Health (NIH). The deaths of four children (three females and one male), aged 7.5-15.5 years (mean age 11.2 years) with length of disease 2-4 years, were recorded among 160 (2.5 %) children seen at or referred to the NIH over the last 15 years. All died at different institutions, prior to coming to the NIH (two) or after leaving NIH (two). Presenting symptoms included increasing weight and decreasing height gain, facial plethora, dorsocervical fat pad (webbed neck), striae, headache, vision disturbances, and depression and other mood or behavior changes; there were no differences between how these patients presented and the others in our cohort. The causes of CS in the deceased patients were also not different, in fact, they spanned the entire spectrum of CS: pituitary disease (one), ectopic corticotropin production (one), and primary adrenal hyperplasia (one). In one patient, the cause of CS could not be verified. Three died of sepsis and one due to residual disease and complications of the primary tumor. CONCLUSIONS: Despite the advances in early diagnosis and treatment of pediatric CS, a 2.5 % mortality rate was identified in a large cohort of patients with this condition referred to an experienced, tertiary care referral center (although these deaths occurred elsewhere). Pediatricians need to recognize the possibility of death, primarily due to sepsis, in a patient with pediatric CS and treat accordingly.

Fracture discrimination capability of ulnar flexural rigidity measured via Cortical Bone Mechanics Technology: study protocol for The STRONGER Study.

Osteoporosis is characterized by low bone mass and structural deterioration of bone tissue, which leads to bone fragility (ie, weakness) and an increased risk for fracture. The current standard for assessing bone health and diagnosing osteoporosis is DXA, which quantifies areal BMD, typically at the hip and spine. However, DXA-derived BMD assesses only one component of bone health and is notably limited in evaluating the bone strength, a critical factor in fracture resistance. Although multifrequency vibration analysis can quickly and painlessly assay bone strength, there has been limited success in advancing a device of this nature. Recent progress has resulted in the development of Cortical Bone Mechanics Technology (CBMT), which conducts a dynamic 3-point bending test to assess the flexural rigidity (EI) of ulnar cortical bone. Data indicate that ulnar EI accurately estimates ulnar whole bone strength and provides unique and independent information about cortical bone compared to DXA-derived BMD. Consequently, CBMT has the potential to address a critical unmet need: Better identification of patients with diminished bone strength who are at high risk of experiencing a fragility fracture. However, the clinical utility of CBMT-derived EI has not yet been demonstrated. We have designed a clinical study to assess the accuracy of CBMT-derived ulnar EI in discriminating post-menopausal women who have suffered a fragility fracture from those who have not. These data will be compared to DXA-derived peripheral and central measures of BMD obtained from the same subjects. In this article, we describe the study protocol for this multi-center fracture discrimination study (The STRONGER Study).

The L-enantiomer of ß- aminobutyric acid (L-BAIBA) as a potential marker of bone mineral density, body mass index, while D-BAIBA of physical performance and age.

Background: As both L- and D-BAIBA are increased with exercise, we sought to determine if circulating levels would be associated with physical performance. Method: Serum levels of L- and D-BAIBA were quantified in 120 individuals (50% female) aged 20-85 years and categorized as either a "low" (LP), "average"(AP) or "high" performer (HP).Association analysis was performed using Spearman (S) and Pearson (P) rank correlation. Results: Using the Spearman (S) rank correlation, L-BAIBA positively associated with BMI (0.23) and total fat mass (0.19) in the 120 participants, with total fat mass in the 60 males (0.26) but with both BMI (0.26) and BMD (0.28) in the 60 females. In the HP females, L-BAIBA positively associated with BMD (0.50) and lean mass (0.47).Using the Pearson (P) rank correlation D-BAIBA was positively associated with age (0.20) in the 120 participants and in the LP females (0.49). D-BAIBA associated with gait speed (S 0.20) in the 120 participants. In HP males, this enantiomer had a negative association with appendicular lean/height (S -0.52) and in the AP males with BMD (S -0.47). No associations were observed in HP or AP females, whereas, in LP females, in addition to a positive association with age, a positive association was observed with grip strength (S 0.45), but a negative with BMD (P -0.52, S -0.63) and chair stands (P -0.47, S -0.51). Conclusions: L-BAIBA may play a role in BMI and BMD in females, not males, whereas D-BAIBA may be a marker for aging.

L-ß-aminoisobutyric acid, L-BAIBA, a marker of bone mineral density and body mass index, and D-BAIBA of physical performance and age.

As both L- and D-BAIBA are increased with exercise, we sought to determine if circulating levels would be associated with physical performance. Serum levels of L- and D-BAIBA were quantified in 120 individuals (50% female) aged 20-85 years and categorized as either a "low" (LP), "average" (AP) or "high" performing (HP). Association analysis was performed using Spearman (S) and Pearson (P) correlation. Using Spearman correlation, L-BAIBA positively associated with (1) body mass index BMI (0.23) and total fat mass (0.19) in the 120 participants, (2) total fat mass in the 60 males (0.26), and (3) bone mineral density, BMD, (0.28) in addition to BMI (0.26) in the 60 females. In HP females, L-BAIBA positively associated with BMD (0.50) and lean mass (0.47). D-BAIBA was positively associated with (1) age (P 0.20) in the 120 participants, (2) age (P 0.49) in the LP females and (3) with gait speed (S 0.20) in the 120 participants. However, in HP males, this enantiomer had a negative association with appendicular lean/height (S - 0.52) and in the AP males a negative correlation with BMD (S - 0.47). No associations were observed in HP or AP females, whereas, in LP females, a positive association was observed with grip strength (S 0.45), but a negative with BMD (P - 0.52, S - 0.63) and chair stands (P - 0.47, S - 0.51). L-BAIBA may play a role in BMI and BMD in females, not males, whereas D-BAIBA may be a marker for aging and physical performance. The association of L-BAIBA with BMI and fat mass may reveal novel, not previously described functions for this enantiomer.

γ-Aminobutyric acids (GABA) and serum GABA/AABA (G/A) ratio as potential biomarkers of physical performance and aging.

Declining physical performance with age and disease is an important indicator of declining health. Biomarkers that identify declining physical performance would be useful in predicting treatment outcomes and identifying potential therapeutics. γ-aminobutyric acid (GABA), a muscle autocrine factor, is a potent inhibitor of muscle function and works as a muscle relaxant. L-α-aminobutyric acid (L-AABA) is a biomarker for malnutrition, liver damage, and depression. We sought to determine if GABA and L-AABA may be useful for predicting physical performance. Serum levels of GABA and L-AABA were quantified in 120 individuals divided by age, sex, and physical capacity into low, average, and high performer groups. Analyses explored correlations between serum levels and physical performance. Both GABA and the ratio of GABA/AABA (G/A), but not AABA, were highly positively associated with age (Pearson correlations r = 0.35, p = 0.0001 for GABA, r = 0.31, p = 0.0007 for G/A, n = 120). GABA showed negative associations in the whole cohort with physical performance [fast gait speed, 6 min walk test (6MWT), PROMIS score, and SF36PFS raw score] and with subtotal and femoral neck bone mineral density. L-AABA was positively associated with usual gait speed, 6MWT, total SPPB score, and SF36PFS raw score in the total cohort of 120 human subjects, also with 6MWT and SF36PFS raw score in the 60 male subjects, but no associations were observed in the 60 females. As both GABA and L-AABA appear to be indicative of physical performance, but in opposite directions, we examined the G/A ratio. Unlike GABA, the G/A ratio showed a more distinct association with mobility tests such as total SPPB score, usual and fast gait speed, 6MWT, and SF36PFS raw score in the males, regardless of age and metabolic status. Serum G/A ratio could be potentially linked to physical performance in the male population. Our findings strongly suggest that GABA, L-AABA, and the G/A ratio in human serum may be useful markers for both age and physical function. These new biomarkers may significantly enhance the goal of identifying universal biomarkers to accurately predict physical performance and the beneficial effects of exercise training for older adults.

Recurrent left atrial myxomas in Carney complex: a genetic cause of multiple strokes that can be prevented.

BACKGROUND: Intracardiac myxomas in Carney complex are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. The genetic, clinical, and laboratory characteristics of Carney complex-related strokes from atrial myxomas have not been described. The regulatory subunit (R1A) of the protein kinase gene (PRKAR1A) is mutated in >60% of patients with Carney complex. METHODS: We studied patients with strokes and cardiac myxomas that were hospitalized in our institution and elsewhere; a total of 7 patients with 16 recurrent atrial myxomas and >14 episodes of strokes were identified. RESULTS: Neurologic deficits were reported; in 1 patient, an aneurysm developed at the site of a previous stroke. All patients were females, were also diagnosed with Cushing syndrome, and all had additional tumors or other Carney complex manifestations. Other than gender, although there was a trend for patients being overweight and hypertensive, no other risk factors were identified. A total of 5 patients (71%) had a PRKAR1A mutation; all mutations (c418_419delCA, c.340delG/p.Val113fsX15, c.353_365del13/p.Ile118fsX6, c.491_492delTG/p.Val164fsX4, and c.177+1G>A) were located in exons 3 to 5 and introns 2 to 3, and all led to a non-sense PRKAR1A mRNA. CONCLUSIONS: Female patients with Carney complex appear to be at a high risk for recurrent atrial myxomas that lead to multiple strokes. Early identification of a female patient with Carney complex is of paramount importance for the early diagnosis of atrial myxomas and the prevention of strokes.

Copeptin Levels Before and After Transsphenoidal Surgery for Cushing Disease: A Potential Early Marker of Remission.

Context: Arginine-vasopressin and CRH act synergistically to stimulate secretion of ACTH. There is evidence that glucocorticoids act via negative feedback to suppress arginine-vasopressin secretion. Objective: Our hypothesis was that a postoperative increase in plasma copeptin may serve as a marker of remission of Cushing disease (CD). Design: Plasma copeptin was obtained in patients with CD before and daily on postoperative days 1 through 8 after transsphenoidal surgery. Peak postoperative copeptin levels and Δcopeptin values were compared among those in remission vs no remission. Results: Forty-four patients (64% female, aged 7-55 years) were included, and 19 developed neither diabetes insipidus (DI) or syndrome of inappropriate anti-diuresis (SIADH). Thirty-three had follow-up at least 3 months postoperatively. There was no difference in peak postoperative copeptin in remission (6.1 pmol/L [4.3-12.1]) vs no remission (7.3 pmol/L [5.4-8.4], P = 0.88). Excluding those who developed DI or SIADH, there was no difference in peak postoperative copeptin in remission (10.2 pmol/L [6.9-21.0]) vs no remission (5.4 pmol/L [4.6-7.3], P = 0.20). However, a higher peak postoperative copeptin level was found in those in remission (14.6 pmol/L [±10.9] vs 5.8 (±1.4), P = 0.03]) with parametric testing. There was no difference in the Δcopeptin by remission status. Conclusions: A difference in peak postoperative plasma copeptin as an early marker to predict remission of CD was not consistently present, although the data point to the need for a larger sample size to further evaluate this. However, the utility of this test may be limited to those who develop neither DI nor SIADH postoperatively.

Liver findings in patients with Carney complex, germline PRKAR1A pathogenic variants, and link to cardiac myxomas.

This study aimed to evaluate liver involvement in patients with Carney complex (CNC) based on a large cohort and to analyze any germline PRKAR1A genotype-phenotype association of liver disease. The study included 83 patients with CNC, followed between 1995 and 2018 at a tertiary research center. We reviewed liver images, recorded types and number of lesions and analyzed per genotype: all patients were sequenced for the PRKAR1A gene. A total of 29/83 patients (24.0%) had liver radiological findings. Patients with liver lesion had a significantly higher rate of pathogenic variants detected in the PRKAR1A gene (72.4 vs 38.9%, P = 0.005, respectively). Patients with a pathogenic variant detected on germline PRKAR1A analysis had a higher risk for having a liver lesion compared with patients with wild-type (WT) PRKAR1A alleles (21/42 (50.0%) vs 8/41 (19.5%), respectively, P = 0.004). Among patients with liver lesions, those with a nonsense PRKAR1A pathogenic-variant had more liver lesions (7/7) than among those with other pathogenic-variant types (8/22, P = 0.001). In multivariable analysis, detection of liver lesion(s) was associated with an odds ratio of 5.2 for cardiac myxomas (95% CI 1.55-17.49, P = 0.008). In conclusion, patients with CNC, particularly with a PRKAR1A pathogenic variant, have a higher rate of liver lesions. Additionally, liver lesions are associated with a high risk for cardiac myxomas in this population.

A novel mutation in the glucocorticoid receptor gene as a cause of severe glucocorticoid resistance complicated by hypertensive encephalopathy.

BACKGROUND: Glucocorticoid resistance syndrome (GRS) is caused by mutations of the glucocorticoid receptor (coded by the NR3C1 gene) and presents with signs of mineralocorticoid and/or androgen excess. PATIENT: A female patient presented at the age of almost 3 years with hypertensive and hypoglycemic seizure. She was diagnosed with GRS and was treated with antihypertensive medications and dexamethasone. She was later found to have MRI findings of punctuate microinfarcts at the basal ganglia, left thalamus and pons, possibly associated with uncontrolled hypertension. Increase of the dexamethasone dose up to 14 mg/day resulted in sufficient control of her symptoms. RESULTS: Two mutations in the NR3C1 gene were identified: a novel mutation in exon 2 (p.E198X), and a previously described mutation in exon 8 (p.R714Q). CONCLUSION: GRS may present with life-threatening complications; this is the first report of hypertensive encephalopathy in association with GRS. Successful management of patients might require high doses of dexamethasone to control blood pressure.

Somatic PRKAR1A Gene Mutation in a Nonsyndromic Metastatic Large Cell Calcifying Sertoli Cell Tumor.

Large cell calcifying Sertoli cell tumors (LCCSCTs) are rare testicular tumors, representing <1% of all testicular neoplasms. Almost 40% of patients with LCCSCTs will present in the context of an inherited tumor predisposition condition, such as Carney complex (CNC) or Peutz-Jeghers syndrome. We report the case of a 42-year-old man who had presented with a right testicular mass, and was diagnosed with metastatic LCCSCT. The patient underwent radical orchiectomy, achieving initial remission of his disease. However, lymph node and hepatic metastases were identified. He received chemotherapy without response, and he died of complications of his disease 4 years after the initial diagnosis. Genetic analysis of the tumor and a lymph node metastasis identified a somatic frameshift mutation in the PRKAR1A gene (c.319delG, p.E107fs*22). The mutation was predicted to result in premature termination of the PRKAR1A protein and, thus, not be expressed at the protein level, consistent with other PRKAR1A nonsense mutations. The patient was extensively screened for signs of CNC, but he had no stigmata of the complex. To the best of our knowledge, the present report is the first of a somatic mutation in the PRKAR1A gene shown to be associated with a seemingly sporadic case of LCCSCT. Somatic PRKAR1A mutations are rare in sporadic tumors, and it is unknown whether this mutation was causative of LCCSCT in our patient who did not have CNC, or contributed to the malignancy of the tumor, which might have been caused by additional mutations.