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Pediatric Summary Report Secondary Findings in Pediatric Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening Permalink P Current Version Rule-Out Dashboard Release History Status (Pediatric): Passed (Consensus scoring is Complete) Curation Status (Pediatric): Released 1.0.4 Status (Adult): Passed (Consensus scoring is Complete) A

GENE/GENE PANEL: PRKAR1A

Condition: Carney Complex

Mode(s) of Inheritance: Autosomal Dominant

Actionability Assertion

Gene Condition Pairs(s)

Final Assertion

PRKAR1A⇔0008057 (carney complex, type 1)

Strong Actionability

Actionability Rationale

All experts agreed with the assertion computed according to the rubric.

Final Consensus Scoresa

Outcome / Intervention Pair

Severity

Likelihood

Effectiveness

Nature of the
Intervention

Total
Score

Gene Condition Pairs: PRKAR1A ⇔ 0008057 (OMIM:160980)

Morbidity and mortality from cardiac myxomas / Cardiac imaging to detect and guide excision of tumors

11CC

Morbidity from primary pigmented nodular adrenocortical disease / Biochemical and imaging surveillance to detect tumors and guide treatment

10CD

a. To see the scoring key, please go to : https://www.clinicalgenome.org/site/assets/files/2180/actionability_sq_metric.png

Topic

Narrative Description of Evidence

Ref

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The prevalence of Carney complex (CNC) is unknown. CNC is a rare disease, though more than 700 individuals with CNC are known, including cases from North and South America, Europe, Australia, and Asia.

1 2 3

Clinical Features
(Signs / symptoms)

CNC is associated with skin pigmentary abnormalities, myxomas, endocrine tumors or overactivity, and schwannomas. The most common skin pigmentary abnormality in CNC is pale brown to black lentigines which can appear anywhere on the body including the face, lips, and mucosa. Other skin pigmentary abnormalities include epithelioid-type blue nevi, combined nevi, café au lait macules, and depigmented lesions. Most individuals with CNC have multiple myxomas which can occur on the heart, skin, and breast (typically bilateral). Cardiac myxomas can manifest as obstruction of blood flow, embolic phenomenon, heart failure, and sudden death due to occlusion of a valvular orifice. Other sites for myxomas are the oropharynx, nipple, female genital tract, and bone (usually in nasal sinuses and long bones). Primary pigmented nodular adrenocortical disease (PPNAD) is the most common endocrine tumor, is usually bilateral, and causes Cushing syndrome. Other endocrine tumors include growth hormone (GH)-producing adenoma (acromegaly), large-cell calcifying Sertoli cell tumors (LCCSCTs; often multicenter, bilateral, and typically benign), multiple thyroid nodules (mostly nonfunctioning thyroid follicular adenomas), and ovarian cysts. Thyroid carcinomas, both papillary and follicular, can occur. Papillary carcinoma can be multiple and sometimes quite aggressive. Psammomatous melanotic schwannoma (PMS), a rare tumor of the nerve sheath, may occur anywhere in the central and peripheral nervous system; it is most frequently found in the nerves of the gastrointestinal tract and paraspinal sympathetic chain. Breast ductal adenoma is a benign tumor of the mammary gland ducts and is also seen in CNC.

1 2 3 4

Natural History
(Important subgroups & survival / recovery)

Lentigines are the most common presenting feature of CNC and may be present at birth. Typically, they increase in number at puberty, fade after the fourth decade, but may still be evident in the eighth decade. Cutaneous myxomas appear between birth and the fourth decade. Cardiac myxomas may occur at a young age. Breast myxomas occur in females after puberty. Males and females may develop nipple myxomas at any age. In a minority of individuals, PPNAD presents in the first two to three years; in the majority, it presents in the second or third decade. LCCSCT often present in the first decade. Signs and symptoms of CNC may be present at birth, but the median age of diagnosis is 20 years. Most patients with CNC present with a mild increase in GH. However, clinically evident acromegaly is a relatively frequent manifestation of CNC, occurring in approximately 10% of adults at the time of presentation. Most individuals with CNC have a normal life span. However, because some die at an early age, the average life expectancy for individuals with CNC is 50 years. Causes of death include complications of cardiac myxoma (myxoma emboli, cardiomyopathy, cardiac arrhythmia, and surgical intervention), metastatic or intracranial PMS, thyroid carcinoma, and metastatic pancreatic and testicular tumors.

1 3

2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.

Patient Management

To establish the extent of disease and needs in an individual diagnosed with CNC, the following evaluations are recommended:

• Imaging or biochemical screening for endocrine tumors.

• Thyroid ultrasonography is recommended as a satisfactory, cost-effective method for determining thyroid involvement in pediatric and young adults with CNC. Its value, however, is questionable in older individuals.

• In males, testicular ultrasonography.

• In females, transabdominal ultrasonography. (Tier 4)

The only preventive measure in an asymptomatic individual is surgical removal of a heart tumor (cardiac myxoma) prior to the development of heart dysfunction, stroke, or other embolism. Cardiac myxomas should be diagnosed early through regular screening. (Tier 4)

1 2 3

Patients with CNC who have cardiac myxomas have an increased chance of sudden death. This risk justifies frequent clinic visits with serial surveillance. Detection of a cardiac myxoma via surveillance prompts surgical excision. Combining sporadic and familial cases, there is 81-96% long-term survival rate after surgical resection. However, this data does not account for multiple resections which are common for CNC given the risk for recurrence of cardiac myxomas, around 10-21%. There is little evidence as to how many cardiac operations one patient may experience in a lifetime. (Tier 5)

Development of metabolic abnormalities from Cushing syndrome or arthropathy and other complications from acromegaly may be prevented by medical or surgical treatment of the respective endocrine manifestations. (Tier 4)

1 3

Surveillance

It is recommended that patients with CNC have lifelong follow-up tests for cardiac myxoma and other associated disease (testicular tumors, acromegaly, and thyroid lesions). (Tier 2)

Recommended clinical surveillance in prepubertal pediatric individuals with CNC include:

• Cardiac myxoma surveillance, though guidelines differ on suggested modality (echocardiogram or ultrasound) and frequency (every 6 months to annually)

• Close monitoring of growth rate and pubertal staging which includes biological and hormonal work-up and imaging (annually or dependent on prior findings). (Tier 4)

1 3

Recommended clinical surveillance in postpubertal pediatric and adult individuals with CNC include:

• Cardiac myxoma surveillance, though guidelines differ on suggested modality (echocardiogram or ultrasound) and frequency (every 6 months to annually)

• Testicular ultrasound (annually)

• Urinary free cortisol levels (annually)

• Serum IGF-1 levels (annually). (Tier 4)

1 3

Circumstances to Avoid

No circumstances-to-avoid recommendations have been provided for the Pediatric context.

3. What is the chance that this threat will materialize?

Mode of Inheritance

Autosomal Dominant

1 2 3 4

Prevalence of Genetic Variants

The frequency of PRKAR1A pathogenic variants in the general population was not identified.

About 70% of cases of CNC are found to have a variant in PRKAR1A. The frequency of PRKAR1A pathogenic variants is higher in patients with Cushing syndrome, about 80%. (Tier 3)

Penetrance
(Include any high risk racial or ethnic subgroups)

The overall penetrance of CNC in those with a PRKAR1A pathogenic variant is greater than 95% by age 50 years. (Tier 4)

Estimated frequencies of the main features of CNC are listed below:

• PPNAD: 25-60%

• Cushing syndrome due to PPNAD: 25-30%

• Cardiac myxoma: 30-60%

• Skin myxoma: 20-63%

• Lentiginosis: 60-70%

• Breast ductal adenoma: 25%

• LCCSCT (in males): 33-56%

• Ovarian cyst (in females): 20-67%

• Acromegaly: 10%

• Thyroid tumor: 10-25%

• Melanotic schwannoma: 8-18%

• Osteochondromyxoma: <10%. (Tier 3)

Though clinically evident acromegaly is evident in approximately 10% of adults at the time of presentation, asymptomatic increased serum concentration of GH and insulin-like growth factor type-1 (IGF-1), as well as subtle hyperprolactinemia, may be present in up to 75% of individuals with CNC. (Tier 4)

Relative Risk
(Include any high risk racial or ethnic subgroups)

Information on relative risk was not available for the Pediatric context.

Expressivity

The manifestations of CNC vary greatly among patients. Even in the same kindred, phenotypic variability can be observed. (Tier 4)

4. What is the Nature of the Intervention?

Nature of Intervention

The interventions described in this report include multiple and frequent surveillance recommendations and surgical removal of cardiac myxomas. Perioperative mortality in the surgical resection of cardiac myxomas is rare. Perioperative complications occasionally involve strokes from embolization during the procedure. Acute postoperative complications involve atrial fibrillation, embolic strokes, and decreased cardiac output. Twenty-six percent of patients develop postoperative supraventricular arrhythmias, but they are easily managed with appropriate medications and are typically discharged in sinus rhythm. Long-term postoperative complications tend to arise from congestive heart failure and myocardial infarction. Multiple cardiac surgeries may cause cardiac dysfunction due to repeated periods of ischemic arrest.

1 3 5

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

Cardiac myxoma may be the cause of the high rate (16%) of sudden death historically reported in CNC families, thus underlying the importance of its early diagnosis. Diagnosis of Cushing syndrome due to PPNAD is often difficult because hypercortisolism can develop progressively over years. (Tier 4)

Description of sources of evidence:

Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.

Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.

Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.

Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.

Tier 5: Evidence from a non-systematically identified source.

Date of Search: 08.06.2019

Gene Condition Associations

Gene

Condition Associations

OMIM Identifier

Primary MONDO Identifier

Additional MONDO Identifiers

PRKAR1A

160980

0008057

0008057, 0015285

Reference List

1. CA Stratakis, M Raygada. Carney Complex. 2003 Feb 05 [Updated 2018 Aug 16]. In: MP Adam, HH Ardinger, RA Pagon, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1286

2. Carney complex. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=1359

3. Bertherat J. Carney complex (CNC). Orphanet J Rare Dis. (2006) 1:21.

4. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. CARNEY COMPLEX, TYPE 1; CNC1. MIM: 160980: 2019 Apr 29. World Wide Web URL: http://omim.org.

5. Siordia JA. Medical and Surgical Management of Carney Complex. J Card Surg. (2015) 30(7):560-7.

6. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. (2015) 100(8):2807-31.