Identification of a novel mutation of the PRKAR1A gene in a patient with Carney complex with significant osteoporosis and recurrent fractures

Papanastasiou, Labrini; Fountoulakis, Stelios; Voulgaris, N.; Kounadi, Theodora; Choreftaki, Theodosia; Kostopoulou, Akrivi; Zografos, George; Lyssikatos, Charalampos; Stratakis, Constantine A.; Piaditis, George

doi:10.14310/horm.2002.1627

Cited by 8 publications

(6 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To date, more than 125 PRKAR1A mutations have been described [24, 25]. Most PRKAR1A mutations are located in the exons encoding the cAMP-binding domain and are responsible for premature stop codon occurrence.…”

Section: Discussionmentioning

confidence: 99%

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

et al. 2018

View full text Add to dashboard Cite

Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

show abstract

Section: Discussionmentioning

confidence: 99%

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Increased levels of glucocorticoids directly limit osteoblast proliferation and differentiation, which lowers bone formation and increases osteoclast activity and bone resorption ( 22 ). By blocking the effects of vitamin D, glucocorticoids limit the expression of calcium channels in the duodenum, which results in secondary hyperparathyroidism and lowers calcium absorption in the intestine ( 23 ). PPNAD's negative feedback lowers ACTH levels, which reduces sex hormone synthesis and secretion as well as impairs bone metabolism and eventually results in osteopenia ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review

Yang,

Liang,

Qin

et al. 2024

Archives of Endocrinology and Metabolism

View full text Add to dashboard Cite

SUMMARY Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

show abstract

“…DNA sequencing identified a known pathogenic mutation of PRKAR1A . Taken together, our patient met the criteria for the diagnosis of CNC [ 2 ] : (1) spotty pigmentation with the typical distribution (face, lip, and sclera); (2) osteoporotic bone changes due primarily to glucocorticoid excess, which accelerates bone resorption and decreases intestinal calcium absorption and bone formation [ 16 ] (3); probable LCCST, as demonstrated by ultrasonography of the bilateral testes, which revealed multiple microcalcifications; and (4) Cushing syndrome, which may be ACTH-dependent or ACTH-independent (e.g., caused by PPNAD, as in our patient).…”

Section: Discussionmentioning

confidence: 99%

Carney complex with PRKAR1A gene mutation

et al. 2017

View full text Add to dashboard Cite

Rationale:Carney complex (CNC) is a multiple neoplasia syndrome with autosomal dominant inheritance. CNC is characterized by the presence of myxomas, spotty skin pigmentation, and endocrine overactivity. No direct correlation has been established between disease-causing mutations and phenotype.Patient concerns:A 16-year-old boy was admitted because of excessive weight gain over 3 years and purple striae for 1 year. Physical examination revealed Cushingoid features and spotty skin pigmentation on his face, lip, and sclera.Diagnoses:The patient was diagnosed as Carney complex.Interventions:the patient underwent right adrenalectomy and partial adrenalectomy of the left adrenal gland.Outcome:Results of imaging showed bilateral adrenal nodular hyperplasia, multiple microcalcifications of the bilateral testes, and compression fracture of the thoracolumbar spine. Histopathological results confirmed multiple pigmented nodules in the adrenal glands. DNA sequencing revealed a nonsense mutation in the gene encoding regulatory subunit type 1-alpha of protein kinase A (PRKAR1A; c.205C > T). After the second adrenalectomy, the Cushingoid features disappeared, and cortisol levels returned to normal.Lessons:Carney complex is a rare disease that lacks consistent genotype–phenotype correlations. Our patient, who carried a germline PRKAR1A nonsense mutation (c.205C > T), clinical features included spotty skin pigmentation, osteoporosis, and primary pigmented nodular adrenal disease. Adrenalectomy is the preferred treatment for Cushing syndrome due to primary pigmented nodular adrenal disease.

show abstract

Identification of a novel mutation of the PRKAR1A gene in a patient with Carney complex with significant osteoporosis and recurrent fractures

Cited by 8 publications

References 26 publications

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series

Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review

Carney complex with PRKAR1A gene mutation

Contact Info

Product

Resources

About