Abstract
Background
Several disease-causing genes have been implicated in Carney complex (CNC), including PRKAR1A, PDE8B(Phosphodiesterase 8B),and PDE11A (Phosphodiesterase 11A). The purpose of this study was to describe the clinical features of CNC in a Chinese patient and identify potential pathogenic mutations.
Methods
Genomic DNA was extracted from the peripheral venous blood obtained from one Chinese CNC family from Shandong province. Subsequently, targeted region sequencing (TRS) and Sanger sequencing validation were performed to identify and validate likely pathogenic mutations.
Results
Genetic analyses revealed a novel PDE11A variant that was predicted to lead to CNC. The patient's mother presented with the same genetic mutation.
Conclusion
This study identifies new genetic mutation in CNC（PDE11A: NM_016953: exon11: c1921A>G (p./p.Lys641Glu). CNC patients presenting with subclinical Cushing's syndrome should be treated.
Keywords: Subclinical Cushing syndrome, Carney complex, Primary pigmented nodular adrenocortical disease, Adrenal tumors, PDE11A
Subclinical Cushing syndrome; Carney complex; Primary pigmented nodular adrenocortical disease; Adrenal tumors; PDE11A.
1. Introduction
Carney complex is a rare autosomal dominant inherited disease characterized by abnormal skin and mucosal pigmentation, myxomas predominantly of the heart, skin, and breast, endocrine tumors, mammary ductal adenomas, osteochondromyxomas, and other non-endocrine tumors. It was first reported by Carney in 1985 [1]. There are reports suggesting that patients with a previous diagnosis of "freckles, atrial myxoma, myxoid fibroma, and blue nevus" should also be diagnosed with CNC [2, 3]. Of the CNC cases identified thus far, 70% are familial and 30% are sporadic [4]. The age at diagnosis of currently diagnosed cases ranges from 2 to 50 years; the median age at diagnosis is 20 years [5], and it is more common in women than in men (37% in men and 63% in women) [6].
The following genes are reportedly related to CNC: PRKAR1A, PDE8B, and PDE11A. More than 70% of patients with CNC carry PRKAR1A mutations [6], all of which promote the occurrence of CNC by regulating the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway. PKA is the main transmitter of cAMP signaling and a key enzyme that controls a variety of cellular functions. It is a tetrameric enzyme containing two regulatory subunits and two catalytic subunits [7, 8]. PRKAR1A encodes the most highly expressed regulatory subunit. The inactivating mutation in PRKAR1A leads to the constitutive activation of the cAMP/PKA pathway by loss of regulation of the PKA catalytic subunitv [9, 10, 11]. Phosphodiesterases (PDEs) are negative regulators of the cAMP/PKA pathway, converting cAMP to inactive AMP [12].
Here, we report a case of childhood-onset CNC in a Chinese family caused by a heterozygous variant of PDE11A. This mutation site has not yet been reported. In this study, we recorded the patient's significant family history, detailed clinical manifestations, complex clinical progression, and abnormal laboratory test results. This study may broaden the clinical spectrum of CNC associated with PDE11A mutations, and lay the foundation for further studies on the pathogenesis and genetic therapy of CNC.
2. Materials and methods
2.1. Ethical compliance
The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the ethics committee (number of local approval: QYFY WZLL 26993).
2.2. Genomic DNA extraction
Peripheral blood samples (500 μL) were collected from the proband (III-6), father (II-1), mother (II-2), grandfather (I-1) (Figure 1). Genomic DNA was isolated from peripheral blood samples using a TIANamp Blood DNA Kit (Tiangen Biotech, Beijing, China) according to the manufacturer's instructions.
Figure 1.
Pedigree of the family with CNC. The arrowhead shows the proband; red shapes represent the patient; white shapes indicate the unaffected family members; squares represent male family members; circles represent female family members; dots denote carriers; N denotes undetected family members; n denotes untested family members.
2.3. TRS for mutation detection
Three known and potential CNC-related candidate genes were identified through literature review [13], namely, PRKAR1A, PDE8B,and PDE11A. All exons and intron-exon boundaries of the 3 target genes were sequenced using TRS technology.
2.4. Sanger sequencing validation
Candidate variants detected by targeted region sequencing (TRS) were validated using Sanger sequencing of other family members. Primers were designed using Primer Premier 5 software. DNA fragments were amplified in a 20-μL reaction system with the following steps: predenaturation at 94 °C for 5 min; 35 cycles of denaturation at 94 °C for 30 s, annealing at 55 °C for 30 s, and elongation at 72 °C for 30 s; and a final extension at 72 °C for 10 min. The PCR-amplified were sequenced by capillary electrophoresis using a 3130XL sequencer. After finding the reference sequence, the "Mutation Surveyor" software was used to analyze the reference sequence and raw data. The sequence was compared with the standard reference sequence of the National Center Biotechnology Information (NCBI) website (https://www.ncbi.nlm.nih.gov/).
2.5. Pathogenicity assessment
Several variant prediction websites were used to predict the pathogenicity of detected mutations, such as PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) and REVEL (https://www merriam-webster.com/dictionary/revel).
3. Results
3.1. Clinical manifestations
A 14-year-old girl presents to a hospital for 1 month with low back pain. CT of the lower abdomen revealed the possibility of adrenal adenoma on the right and left ureteral calculi. Because the hospital did not have the ability to diagnose and treat, the patient was transferred to the Affiliated Hospital of Qingdao University. The patient did not have dizziness or headache during the onset of the disease. Her body weight had increased by 5 kg compared to the previous period. She denied a history of hypertension. Her menstrual cycle lasted 1–2 months, she had a younger brother and sister in good health. At the time of admission, her was BMI 24.3 kg/m2. We noted abdominal obesity, moon face, short neck, low hairline, no pigmentation on face, increased facial vellus hair, small hairs visible on upper lip, supraclavicular fat pad, and irregular menstruation over the past six months. Laboratory examinations (Table 1) revealed mild anemia and insulin resistance.
Table 1.
Laboratory and endocrinological data.
| Test | Result | Reference range |
|---|---|---|
| Blood routine examination | ||
| White blood cells | 5.21 × 109/L | 4–10 × 109/L |
| Red blood cells | 4.6 × 1012/L | 3.5–5.5 × 1012/L |
| Hemoglobin | 106 g/L | 110–150 g/L |
| Platelets | 448 × 109/L | 100–300 × 109/L |
| Biochemistry | ||
| Sodium | 142 mmol/L | 135–145 mmol/L |
| Potassium | 4.45 mmol/L | 3.5–5.5 mmol/L |
| Chloride | 107 mmol/L | 96–106 mmol/L |
| Calcium | 2.19 mmol/L | 2.25–2.75 mmol/L |
| Total cholesterol | 4.99 mmol/L | 2.85–5.69 mmol/L |
| Fasting blood glucose | 4.6 mmol/L | 3.89–6.11 mmol/L |
| Function of thyroid gland | ||
| Free triiodothyronine | 3.96 pmol/L | 0.92–2.79 pmol/L |
| Free thyroxine | 9.97 pmol/L | 5.81–161.3 pmol/L |
| Hypersensitive thyroid-stimulating hormone | 0.731 μIU/mL | 0.55–4.78 μIU/mL |
| Other hormones | ||
| Insulin | 23.8 μIU/mL | 5–20 μIU/mL |
Endocrine findings (Table 2) showed that the circadian rhythm of cortisol disappeared, and her serum cortisol level was not suppressed by the low-dose dexamethasone suppression test (LDDST) or high-dose dexamethasone suppression test (HDDST).
Table 2.
Endocrinological examinations.
| Examinations | Result | ||
|---|---|---|---|
| Endocrinology data | Lying Position | Erect Position | |
| Plasma aldosterone concentration (pg/ml) | 5.58 | 11.23 | |
| Plasma renin concentration (μIU/ml) | 160.5 | 200.7 | |
| Circadian rhythm | |||
| Clock time | 8 am | 4 pm | 0 am |
| Adrenocorticotropic hormone (pg/ml) | 1.95 | 1.82 | 1.56 |
| Cortisol (nmol/L) | 270 | 297 | 306 |
| Dexamethasone suppression tests (1 mg) | Before | After | |
| Adrenocorticotropic hormone (pg/ml) | 246 | 268 | |
| Cortisol (nmol/L) | 1.65 | <1.5 | |
| Dexamethasone suppression tests (8 mg) | |||
| Adrenocorticotropic hormone (pg/ml) | 285 | 243 | |
| Cortisol (nmol/L) | 1.78 | <1.5 | |
Enhanced CT of the lower abdomen revealed the possibility of adrenal adenoma on the right (about 22 mm in diameter), upper ureteral calculi on the left (a diameter of about 5.5 mm)with mild dilation of the upper part (Figure 2). Magnetic resonance imaging (MRI) enhancement of the pituitary gland showed that the possibility of pituitary microadenoma was high (a maximum height of 7 mm) (Figure 3). Thyroid color Doppler ultrasound revealed nodular goiter (TI-RADS category 3); (Figure 4). 24 hours ambulatory blood pressure monitoring showed that the maximum systolic blood pressure was 141 mmHg and the maximum diastolic blood pressure was 82 mmHg. The average pressure was recorded at 98 mmHg.Considering all the signs, symptoms, and laboratory examinations, the patient was diagnosed as having adrenocorticotropic hormone (ACTH)-independent subclinical Cushing syndrome, adrenal cortical adenoma, pituitary microadenoma, thyroid nodules, mild anemia, and ureteral stones.
Figure 2.
CT of the patient's adrenal glands. A: Preoperative CT with contrast enhancement of the lower abdomen. B: Plain CT of the lower abdomen after surgery.
Figure 3.
Preoperative coronal MRI of the pituitary gland (A: Preoperative enhancement; B: Postoperative plain scan). Sagittal MRI of the patient's pituitary gland before surgery (C: Preoperative enhancement; D: Postoperative plain scan).
Figure 4.
Thyroid ultrasound of patient before operation (A) and after operation (B).
Thereafter, a right partial adrenalectomy was performed. We observed that some tumor cells increased in size with enlarged nuclei. Cells were small in size with pigment in parts of the cytoplasm, and noted interstitial cells with more lymphocyte infiltration and focal fat cells (Figure 5). Immunohistochemistry results showed Syn (+), CgA focus (+), Inhibinα (+), MelanA (+), Calretinin (+), the Ki-67 positive rate was approximately 5%, and ACTH foci were weak (+). The diagnosis was a primary pigmented nodular adrenocortical disease (PPNAD).
Figure 5.
Pathological changes in the right adrenal gland of the patient (A: HE staining × 200; B: HE staining × 200). HE: hematoxylin and eosin.
The patient presented with PPNAD with a thyroid nodule and pituitary microadenoma. According to the diagnostic criteria [14], the patient was diagnosed with Carney syndrome. Carney complex is a hereditary disease, but the patient's father showed no related manifestations. The patient's mother presented with adrenal adenoma, high blood pressure, adrenal hyperplasia, impaired diabetes, and nodular goiter. The patient's mother did not present with Carney complex. The patient's grandfather had bilateral adrenal nodular hyperplasia, hypertension, an empty sella, and nodular goiter. Therefore, we conducted genetic testing to determine whether the patient had a gene variant, as well as the source of the variant.
3.2. Genetic analyses
TRS and Sanger sequencing identified heterozygous mutations in PDE11A (NM_016953) in the proband (c.1921A>G/p.Lys641Glu) in exon 11 that were inherited from the mother (Figure 6). Results revealed a remarkable family history.
Figure 6.
Genetic testing results of proband and parents. P：proband,F: father,M:mother.
3.3. Bioinformatic analyses
The variant (c. 1921A>G) has not been reported so far. We used some biological prediction tools to predict the damage of c.1921A>G.The scores of the c. 1921A>G variant on PolyPhen2 and REVEL were 0.983 and LD (potentially harmful), respectively. The c. 1921A>G heterozygous mutation of maternal origin led to a change from lysine to glutamate at codon 641.
3.4. Follow-up
After the operation, the patient received intravenous hydrocortisone (100 mg) twice daily. The patient then received oral methylprednisolone (8 mg) twice daily after nine days. During the postoperative two months follow-up, methylprednisolone was gradually discontinued. Approximately six months later, the patient presented with an ACTH concentration of 75.8 pg/mL and a cortisol concentration of 287 nmol/L. The patient's height increased by 4 cm, BMI decreased from 24.3 to 21.4, insulin resistance improved, blood pressure normalized, Cushing's face improved, her menstrual cycle became regular, thyroid nodules and cysts appeared reduced. At present, the follow-up has been 2 years, the patient's ACTH and cortisol continue to be within the normal range and the circadian rhythm has returned to normal, and follow-up is still continued.
4. Discussion
The patient presented with PPNAD with a thyroid nodule and pituitary microadenoma. The patient was diagnosed with Carney complex. Patients with CNC can present with both CS and SCS [4, 15]. The diagnostic criteria for subclinical Cushing's syndrome are cortisol excess with no classic clinical manifestations of overt Cushing's syndrome (ie, dorsocervical fat pad, moon facies, abdominal striae, proximal myopathy, easy bruising). The patient's cortisol levels are not as high in this patient but with altered circadian rhythms. Based on the clinical symptoms of this patient, the diagnosis of SCS was made. The proband's clinical symptoms were relieved after surgery, which confirmed the diagnosis.
The proband is SCS with metabolic abnormalities. CNC presenting as subclinical CS is also susceptible to metabolic diseases, such as hypertension, obesity, and abnormal glucose metabolism [16]. As the course of the disease progresses, the above metabolic abnormalities can be aggravated, and long-term remission can be achieved after subtotal adrenalectomy and unilateral resection [17, 18, 19]. The proband's clinical symptoms were relieved after surgery. Therefore, Patients diagnosed with SCS require intervention.
More than 70% of CNC patients carry PRKAR1A mutations [6]. However, this patient presented with a heterozygous variant in PDE11A (PDE11A: NM_016953: exon11: c1921A>G; p.K641E), and this mutation site has not been reported in patients with CNC. Phosphodiesterases (PDEs) can catalyze the hydrolysis of 3050-cAMP and 3050-cyclic guanosine monophosphate (cGMP) to inactive 50 monophosphates [20]. Varient in PDE11A lead to enhanced cAMP activity, increased cAMP-PKA signaling, decreased PDE activity, adrenal subcapsular hyperplasia, corticosterone secretion [9, 21]. In addition, abnormal cAMP signaling is related to the genetic form of cortisol excess, which can lead to Cushing's syndrome and related adrenal hyperplasia [22]. PDE11A was expressed in pituitary, hepatic skeletal muscle, pancreas, kidney and prostate [23]. PDE11A is a susceptibility gene for pituitary tumors [24]. Therefore, this patient did not display typical hyperpigmentation, myxoma, or other manifestations, but only manifested as PPNAD, pituitary microadenoma, and thyroid nodules.
Based on the genetic test results, her mutated gene was inherited from her mother. The patient's mother this patient presented with a heterozygous variant in PDE11A (PDE11A: NM_016953: exon11: c1921A>G; p. K641E). The patient's mother presented with adrenal adenoma, high blood pressure, adrenal hyperplasia, impaired diabetes, and nodular goiter. The patient did not present with Carney complex. A genome-wide association study previously found that low-penetrance susceptibility factors for CNC and other related abnormalities include PDE11A sequencing defects [25]. The patient's grandfather had bilateral adrenal nodular hyperplasia, hypertension, an empty sella, and nodular goiter. Genetic testing of PDE11A: NM_016953: exon11: c1921A>G showed no mutation at this locus. Considering the grandfather's various endocrine system disorders, we suspected that he may have mutations in other genetic loci. Our next step was to conduct genetic testing for the entire family, focusing on full genetic testing of the proband's aunt and grandfather.
Hormone replacement therapy after bilateral adrenalectomy is currently recommended [26, 27], and regular follow-up with echocardiography, ovarian ultrasound, thyroid ultrasound, routine dermatological examination, and MRI scans of the spine, chest, abdomen, retroperitoneum, and pelvis should be performed to prevent Psammomatous melanotic schwannomab [5], The patient's adrenal CT showed a right adrenal tumor, only the right adrenal gland was removed, and after two months after the exogenous glucocorticoid supplementation was stopped, the subclinical CS symptoms were relieved and hormone levels recovered to normal levels. Continuous follow-up of the abovementioned examinations and adrenal CT, pituitary MRI, cortisol, ACTH, etc. are still required to prevent recurrence.
5. Conclusion
The manifestations of CNC vary. Clinically, patients with subclinical Cushing's syndrome, especially those with a variety of endocrine tumors, such as adrenal adenoma, must be alert to CNC to avoid misdiagnosis, regardless of whether there is pigmentation or the appearance of myxoma in various organs. We should request the family history from the patient and perform genetic testing, if necessary, to avoid misdiagnosis and missed diagnosis. Genetic testing results of PRKAR1A, PRKACB, or PDE11A mutations are helpful for the diagnosis of CNC.
Declarations
Author contribution statement
Qian Sun: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Caixia Cao, Jie Song, Wenjing Feng, Chengqin Wang, Xuecheng Yang, Mingxin Zhang: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper.
Funding statement
This work was supported by Shandong Provincial Natural Science Foundation [ZR2020MH104].
Data availability statement
The authors do not have permission to share data.
Declaration of interest's statement
The authors declare no conflict of interest.
Additional information
No additional information is available for this paper.
Appendix. ASupplementary data
The following is the supplementary data related to this article:
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