title: PRKAR1A-negative familial Cushing's syndrome: two case reports.
abstract: BACKGROUND
  Determining the etiology of Cushing's syndrome is very challenging to endocrinologists, with most of the difficulty arising from subtype differentiation of adrenocorticotropic hormone-dependent Cushing's syndrome. We present the pitfalls of evaluating a rare cause of adrenocorticotropic hormone-independent Cushing's syndrome in the transition period between adolescence and adulthood.
  
  
  METHODS
  A sibling pair with familial isolated primary pigmented nodular adrenocortical disease is described. The index case, a 20-year-old Chinese woman, presented with premenopausal osteoporosis with T12 compression fracture and young hypertension. Biochemical analysis confirmed adrenocorticotropic hormone-independent Cushing's syndrome (elevated 0800 h plasma cortisol 808 nmol/L with suppressed adrenocorticotropic hormone level <5 pg/ml). Computed tomography of her adrenal glands revealed a 0.7-cm left adrenal hypodense nodule. After a left adrenalectomy, she had residual hypercortisolism (progressive weight gain, new T10 compression fracture, and not glucocorticoid-dependent postoperatively). Completion of contralateral adrenalectomy was performed upon recognition of typical histologic characteristics of primary pigmented nodular adrenocortical disease found in an initial left adrenalectomy specimen. Similarly, her younger brother developed adrenocorticotropic hormone-independent Cushing's syndrome at age 18 years, with typical cushingoid habitus, but no osteoporosis or hypertension. His adrenal computed tomographic scans showed micronodularities over bilateral adrenal glands. He was successfully treated with bilateral adrenalectomy. Screening for Carney's complex and PRKAR1A gene mutation was negative. Signs and symptoms of Cushing's syndrome resolved after bilateral adrenalectomy for both patients. They were placed on lifelong glucocorticoid and mineralocorticoid replacement therapy and long-term surveillance for Carney's complex.
  
  
  CONCLUSIONS
  The cases of these two patients illustrate the difficulties involved in diagnosing primary pigmented nodular adrenocortical disease, a variant of adrenocorticotropic hormone-independent Cushing's syndrome that is managed with bilateral adrenalectomy. A high index of suspicion for this disease is needed, especially in adolescents with adrenocorticotropic hormone-independent Cushing's syndrome who have a significant family history, features of Carney's complex, and no resolution of Cushing's syndrome after unilateral adrenalectomy. Patients with primary pigmented nodular adrenocortical disease can either have bilateral/multiple adrenal nodules or normal adrenal glands visualized by computed tomography. Long-term surveillance is imperative in patients with confirmed Carney's complex and in those who have not undergone complete genetic testing to exclude this hereditary disorder.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. leelinglimll@gmail.com.
authors.forename: Lee Ling
authors.initials: LL
authors.lastname: Lim
authors.affiliation: Division of Endocrine Surgery, Department of Surgery, Putrajaya Hospital, Putrajaya, Malaysia. normayahkitan@yahoo.com.
authors.forename: Normayah
authors.initials: N
authors.lastname: Kitan
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. sharmsp13@gmail.com.
authors.forename: Sharmila Sunita
authors.initials: SS
authors.lastname: Paramasivam
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. jeyakantha_r@hotmail.com.
authors.forename: Jeyakantha
authors.initials: J
authors.lastname: Ratnasingam
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. kaposhkaposh@hotmail.com.
authors.forename: Luqman
authors.initials: L
authors.lastname: Ibrahim
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. spchan88@hotmail.com.
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Chan
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. atbtan@gmail.com.
authors.forename: Alexander Tong Boon
authors.initials: AT
authors.lastname: Tan
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, University of Malaya Medical Center, Lembah Pantai, 59100, Kuala Lumpur, Malaysia. shireene.vethakkan@gmail.com.
authors.forename: Shireene Ratna
authors.initials: SR
authors.lastname: Vethakkan
mesh_terms: D000293:Adolescent; D000311:Adrenal Glands / Q000473:pathology*; D000315:Adrenalectomy; D000324:Adrenocorticotropic Hormone / Q000097:blood; D003480:Cushing Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000601:surgery*; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D010375:Pedigree; D014057:Tomography, X-Ray Computed; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D000324:Adrenocorticotropic Hormone