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Pigmented nodular adrenocortical disease, primary, 4(PPNAD4)

MedGen UID:
862862
Concept ID:
C4014425
Disease or Syndrome
Synonyms: CHROMOSOME 19p13 DUPLICATION SYNDROME; CUSHING SYNDROME, ADRENAL, DUE TO PPNAD4; PPNAD4
 
Gene (location): PRKACA (19p13.12)
 
Monarch Initiative: MONDO:0014359
OMIM®: 615830

Definition

Cushing syndrome is a clinical designation for the systemic signs and symptoms arising from excess cortisol production. Affected individuals typically show hypertension, impaired glucose tolerance, central obesity, osteoporosis, and sometimes depression. Corticotropin-independent Cushing syndrome results from autonomous cortisol production by the adrenal glands, often associated with adrenocortical tumors. Adrenocortical tumors are most common in adult females (summary by Cao et al., 2014; Sato et al., 2014). [from OMIM]

Clinical features

From HPO
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Increased body weight
MedGen UID:
12145
Concept ID:
C0043094
Finding
Abnormally increased body weight.
Depression
MedGen UID:
4229
Concept ID:
C0011581
Mental or Behavioral Dysfunction
Frequently experiencing feelings of being down, miserable, and/or hopeless; struggling to recover from these moods; having a pessimistic outlook on the future; feeling a pervasive sense of shame; having a low self-worth; experiencing thoughts of suicide and engaging in suicidal behavior.
Emotional lability
MedGen UID:
39319
Concept ID:
C0085633
Mental or Behavioral Dysfunction
Unstable emotional experiences and frequent mood changes; emotions that are easily aroused, intense, and/or disproportionate to events and circumstances.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Proximal muscle weakness
MedGen UID:
113169
Concept ID:
C0221629
Finding
A lack of strength of the proximal muscles.
Acne
MedGen UID:
152379
Concept ID:
C0702166
Disease or Syndrome
A skin condition in which there is an increase in sebum secretion by the pilosebaceous apparatus associated with open comedones (blackheads), closed comedones (whiteheads), and pustular nodules (papules, pustules, and cysts).
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Moon facies
MedGen UID:
568451
Concept ID:
C0332601
Sign or Symptom
A rounded, puffy face with fat deposits in the temporal fossa and cheeks, a double chin.
Alopecia
MedGen UID:
7982
Concept ID:
C0002170
Finding
A noncongenital process of hair loss, which may progress to partial or complete baldness.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Fragile skin
MedGen UID:
66826
Concept ID:
C0241181
Finding
Skin that splits easily with minimal injury.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.
Dorsocervical fat pad
MedGen UID:
636070
Concept ID:
C0520573
Finding
An area of fat accumulation at the back of the neck in the form of a hump.
Adrenal hyperplasia
MedGen UID:
301220
Concept ID:
C1621895
Disease or Syndrome
Enlargement of the adrenal gland.
Increased circulating cortisol level
MedGen UID:
871175
Concept ID:
C4025651
Finding
Overproduction of the hormone of cortisol by the adrenal cortex, resulting in a characteristic combination of clinical symptoms termed Cushing syndrome, with truncal obesity, a round, full face, striae atrophicae and acne, muscle weakness, and other features.
Primary hypercortisolism
MedGen UID:
892570
Concept ID:
C4025760
Disease or Syndrome
Hypercortisolemia associated with a primary defect of the adrenal gland leading to overproduction of cortisol.

Professional guidelines

PubMed

Vezzosi D, Tenenbaum F, Cazabat L, Tissier F, Bienvenu M, Carrasco CA, Laloi-Michelin M, Barrande G, Lefebvre H, Hiéronimus S, Tabarin A, Bertagna X, Legmann P, Vantyghem MC, Bertherat J
J Clin Endocrinol Metab 2015 Nov;100(11):4332-8. Epub 2015 Sep 21 doi: 10.1210/jc.2015-2174. PMID: 26390100
Storr HL, Mitchell H, Swords FM, Main KM, Hindmarsh PC, Betts PR, Shaw NJ, Johnston DI, Clark AJ, Reznek RH, Grossman AB, Savage MO
Clin Endocrinol (Oxf) 2004 Nov;61(5):553-9. doi: 10.1111/j.1365-2265.2004.02124.x. PMID: 15521956
Imai T, Funahashi H, Tanaka Y, Tobinaga J, Wada M, Morita-Matsuyama T, Ohiso Y, Takagi H
World J Surg 1996 Sep;20(7):781-6; discussion 786-7. doi: 10.1007/s002689900119. PMID: 8678951

Recent clinical studies

Etiology

Pitsava G, Zhu C, Sundaram R, Mills JL, Stratakis CA
Genet Med 2021 Jan;23(1):80-85. Epub 2020 Sep 7 doi: 10.1038/s41436-020-00956-3. PMID: 32893266Free PMC Article
Traynor MD Jr, Sada A, Thompson GB, Moir CR, Bancos I, Farley DR, Dy BM, Lyden ML, Habermann EB, McKenzie TJ
Pediatr Surg Int 2020 Feb;36(2):129-135. Epub 2019 Nov 5 doi: 10.1007/s00383-019-04589-9. PMID: 31691026
Memon SS, Thakkar K, Patil V, Jadhav S, Lila AR, Fernandes G, Bandgar TR, Shah NS
J Pediatr Endocrinol Metab 2019 Apr 24;32(4):391-397. doi: 10.1515/jpem-2018-0413. PMID: 30875328
Carney JA, Libé R, Bertherat J, Young WF
Am J Surg Pathol 2014 Sep;38(9):1266-73. doi: 10.1097/PAS.0000000000000220. PMID: 24805858
Libé R, Bertherat J
Eur J Endocrinol 2005 Oct;153(4):477-87. doi: 10.1530/eje.1.02004. PMID: 16189167

Diagnosis

Traynor MD Jr, Sada A, Thompson GB, Moir CR, Bancos I, Farley DR, Dy BM, Lyden ML, Habermann EB, McKenzie TJ
Pediatr Surg Int 2020 Feb;36(2):129-135. Epub 2019 Nov 5 doi: 10.1007/s00383-019-04589-9. PMID: 31691026
Memon SS, Thakkar K, Patil V, Jadhav S, Lila AR, Fernandes G, Bandgar TR, Shah NS
J Pediatr Endocrinol Metab 2019 Apr 24;32(4):391-397. doi: 10.1515/jpem-2018-0413. PMID: 30875328
Schernthaner-Reiter MH, Trivellin G, Stratakis CA
Neuroendocrinology 2016;103(1):18-31. Epub 2015 Jan 9 doi: 10.1159/000371819. PMID: 25592387Free PMC Article
Carney JA, Libé R, Bertherat J, Young WF
Am J Surg Pathol 2014 Sep;38(9):1266-73. doi: 10.1097/PAS.0000000000000220. PMID: 24805858
Jabbour SA, Davidovici BB, Wolf R
Clin Dermatol 2006 Jul-Aug;24(4):299-316. doi: 10.1016/j.clindermatol.2006.04.005. PMID: 16828412

Therapy

Pitsava G, Zhu C, Sundaram R, Mills JL, Stratakis CA
Genet Med 2021 Jan;23(1):80-85. Epub 2020 Sep 7 doi: 10.1038/s41436-020-00956-3. PMID: 32893266Free PMC Article
Memon SS, Thakkar K, Patil V, Jadhav S, Lila AR, Fernandes G, Bandgar TR, Shah NS
J Pediatr Endocrinol Metab 2019 Apr 24;32(4):391-397. doi: 10.1515/jpem-2018-0413. PMID: 30875328
Shapiro L, Elahi S, Riddoch F, Perry LA, Martin L, Akker SA, Monson JP, Drake WM, Grossman AB, Savage MO, Storr HL
Horm Res Paediatr 2016;86(1):21-6. Epub 2016 Jun 10 doi: 10.1159/000446913. PMID: 27287747
Carney JA, Libé R, Bertherat J, Young WF
Am J Surg Pathol 2014 Sep;38(9):1266-73. doi: 10.1097/PAS.0000000000000220. PMID: 24805858
Storr HL, Mitchell H, Swords FM, Main KM, Hindmarsh PC, Betts PR, Shaw NJ, Johnston DI, Clark AJ, Reznek RH, Grossman AB, Savage MO
Clin Endocrinol (Oxf) 2004 Nov;61(5):553-9. doi: 10.1111/j.1365-2265.2004.02124.x. PMID: 15521956

Prognosis

Kong G, Lee H, Vo TT, Juang U, Kwon SH, Park J, Park J, Kim SH
Mol Med Rep 2022 Oct;26(4) Epub 2022 Aug 5 doi: 10.3892/mmr.2022.12814. PMID: 35929507Free PMC Article
Pitsava G, Zhu C, Sundaram R, Mills JL, Stratakis CA
Genet Med 2021 Jan;23(1):80-85. Epub 2020 Sep 7 doi: 10.1038/s41436-020-00956-3. PMID: 32893266Free PMC Article
Memon SS, Thakkar K, Patil V, Jadhav S, Lila AR, Fernandes G, Bandgar TR, Shah NS
J Pediatr Endocrinol Metab 2019 Apr 24;32(4):391-397. doi: 10.1515/jpem-2018-0413. PMID: 30875328
Carney JA, Libé R, Bertherat J, Young WF
Am J Surg Pathol 2014 Sep;38(9):1266-73. doi: 10.1097/PAS.0000000000000220. PMID: 24805858
Shenoy BV, Carpenter PC, Carney JA
Am J Surg Pathol 1984 May;8(5):335-44. doi: 10.1097/00000478-198405000-00002. PMID: 6329005

Clinical prediction guides

Pitsava G, Zhu C, Sundaram R, Mills JL, Stratakis CA
Genet Med 2021 Jan;23(1):80-85. Epub 2020 Sep 7 doi: 10.1038/s41436-020-00956-3. PMID: 32893266Free PMC Article
Bram Z, Louiset E, Ragazzon B, Renouf S, Wils J, Duparc C, Boutelet I, Rizk-Rabin M, Libé R, Young J, Carson D, Vantyghem MC, Szarek E, Martinez A, Stratakis CA, Bertherat J, Lefebvre H
JCI Insight 2016 Sep 22;1(15):e87958. doi: 10.1172/jci.insight.87958. PMID: 27699247Free PMC Article
Vezzosi D, Tenenbaum F, Cazabat L, Tissier F, Bienvenu M, Carrasco CA, Laloi-Michelin M, Barrande G, Lefebvre H, Hiéronimus S, Tabarin A, Bertagna X, Legmann P, Vantyghem MC, Bertherat J
J Clin Endocrinol Metab 2015 Nov;100(11):4332-8. Epub 2015 Sep 21 doi: 10.1210/jc.2015-2174. PMID: 26390100
Carney JA, Libé R, Bertherat J, Young WF
Am J Surg Pathol 2014 Sep;38(9):1266-73. doi: 10.1097/PAS.0000000000000220. PMID: 24805858
Libé R, Bertherat J
Eur J Endocrinol 2005 Oct;153(4):477-87. doi: 10.1530/eje.1.02004. PMID: 16189167

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