Acanthosis nigricans

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Acanthosis nigricans
Acanthosis-nigricans4.jpg
Acanthosis nigricans on axilla
Specialty Dermatology

Acanthosis nigricans is a medical sign characterised by brown-to-black, poorly defined, velvety hyperpigmentation of the skin. [1] It is usually found in body folds, [2] such as the posterior and lateral folds of the neck, the armpits, groin, navel, forehead and other areas. [1]

Contents

It is associated with endocrine dysfunction, especially insulin resistance and hyperinsulinaemia, as seen in diabetes mellitus. This activates the insulin-like growth factor receptors, which leads to proliferation of keratinocytes, fibroblasts and other cells in the skin. Activation of other growth factor receptors such as fibroblast growth factor receptors or epidermal growth factor receptor can also be responsible. [3]

Signs and symptoms

Acanthosis nigricans appears as dark brown-black, poorly defined, velvety patches of skin, typically affecting the face, neck, underarms, genitals, groin, elbows, knees, anus, umbilicus and nasal crease. [1]

Causes

It typically occurs in individuals younger than age 40, is associated with insulin resistance, Type 2 diabetes, obesity or endocrinopathies, such as hypothyroidism, acromegaly, polycystic ovary syndrome or Cushing's disease, and may be genetically inherited. [4] [5]

Type I – familial

Familial acanthosis [6] : 86  may arise as a result of an autosomal dominant trait, presenting at birth or developing during childhood. [7] : 506  [8] : 676 

Type II – endocrine

Endocrine syndromes associated with acanthosis nigricans [7] : 506–7  can develop in many conditions, particularly: [9] : 978  [6] : 86 

Acanthosis nigricans associated with endocrine dysfunction is more insidious in its onset, is less widespread, and the patients are often concurrently obese. [8] : 676 

Type III – obesity and pseudoacanthosis nigricans

In young persons, acanthosis nigricans is a visible marker which strongly suggests insulin resistance. Higher than normal insulin levels in the blood stream cause the growth of darkened skin over certain areas of the body. No skin treatment will cure it, but acanthosis nigricans may lighten up and possibly disappear by treating the root cause, insulin resistance, but it can take months or years to do so. [11] Insulin resistance syndromes may be divided into type A (HAIR-AN) and type B syndromes. [9] : 978 

The majority of cases of acanthosis nigricans are associated with obesity and otherwise idiopathic. This is likely because of insulin resistance and more likely to occur in darker-skinned persons. [9] : 968  This can also be referred to as pseudoacanthosis nigricans. [6] : 86  In some cases, AN attributable to obesity and insulin resistance will occur on ones face. Most typically it will be present as a horizontal band on the forehead, but may also appear as perioral hyperpigmentation, periorbital hyperpigmentation, or generalized facial skin darkening. [12]

Acanthosis nigricans has been linked to the use of nicotinic acid, [9] glucocorticoid use, combined oral contraceptive pills, and growth hormone therapy. [6] : 86 

Type V – malignancy

Malignant acanthosis nigricans [6] : 86  refers to acanthosis nigricans occurring as a paraneoplastic syndrome associated with a cancer. Malignant acanthosis nigricans is most commonly associated with gastrointestinal adenocarcinomas, as well as genitourinary cancers such as those of the prostate, breast, and ovary. Other cancers, such as those of the lung, stomach, and lymphoma, are occasionally associated with acanthosis nigricans. [6] : 86  [13]

This form of acanthosis nigricans is more likely to involve mucous membranes (25–50% of cases) [14] [15] Malignant acanthosis nigricans that may either precede (18%), accompany (60%), or follow (22%) the onset of an internal cancer. [7] : 506  Malignancy-associated acanthosis nigricans is usually rapid in onset and may be accompanied by skin tags, multiple seborrheic keratoses, or tripe palms. [8] : 676 

Acral acanthotic anomaly

Acral acanthotic anomaly refers to a variant of acanthosis nigricans limited to the elbows, knees, knuckles, and dorsal surfaces of the feet, in the absence of any other findings, in otherwise healthy individuals. [16] [17] [18] [19] While the etiology remains unknown, [19] its presence does not suggest a likelihood of malignancy. [19]

Pathophysiology

Acanthosis nigricans is caused by increased activation of growth factor receptor proteins, usually due to endocrine dysfunction. This is most commonly insulin-mediated activation of IGF receptors on keratinocytes, as a result of hyperinsulinaemia or insulin resistance, as seen in diabetes mellitus. [3]

Factors involved in the development of acanthosis nigricans include:

In conjunction with increased end levels of IGF, it is likely that perspiration and friction may be necessary predeterminants for lesions, since the level of insulin is usually not enough to activate IGF receptors across the body. [3]

Diagnosis

Acanthosis nigricans is typically diagnosed clinically. [9] A skin biopsy may be needed in unusual cases. If no clear cause is obvious, it may be necessary to search for one. Blood tests, an endoscopy, or X-rays may be required to eliminate the possibility of diabetes or cancer as the cause. [6] : 87 

On biopsy, hyperkeratosis, epidermal folding, leukocyte infiltration, and melanocyte proliferation may be seen. [9] : 979  [6] : 87 

Classification

Acanthosis nigricans is conventionally divided into benign and malignant forms, [9] [14] although may be divided into syndromes according to cause: [7] : 506 

An alternate classification system still used to describe acanthosis nigricans was proposed in 1994. It delineates acanthosis nigricans syndromes according to their associated syndromes, including benign and malignant forms, forms associated with obesity and drugs, acral acanthosis nigricans, unilateral acanthosis nigricans, and mixed and syndromic forms. [20] [21]

Treatment

People with acanthosis nigricans should be screened for diabetes and, although rare, cancer. Controlling blood glucose levels through exercise and diet often improves symptoms. Topical fade creams (normally used for eliminating age spots) can lighten skin cosmetically in less severe cases. Selenium sulfide topical 2 percent applied in thin layer to dry skin ten minutes prior to bathing may clear symptoms. Selenium sulfide applied to dry scalp or skin is an inexpensive well tolerated treatment to balance skin's biome and works by drying fungus like tinea versicolor that can coexist with acanthosis and exacerbate discoloration. Acanthosis nigricans maligna may resolve if the causative tumor is successfully removed. [22]

Prognosis

Acanthosis nigricans is likely to improve in circumstances where a known cause is removed. For example, obesity-related acanthosis nigricans will improve with weight loss, and drug-induced acanthosis nigricans is likely to resolve when the drug is ceased. Hereditary variants may or may not fade with age, and malignancy-associated variants may, after a malignancy is removed, fade. [6] : 87 

History

AN was first reported by Unna in 1889. [23]

Related Research Articles

A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.

<span class="mw-page-title-main">Epidermis</span> Outermost of the three layers that make up the skin

The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water released from the body into the atmosphere through transepidermal water loss.

<span class="mw-page-title-main">Insulin receptor</span> Cell receptor found in humans

The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeostasis; a functional process that under degenerate conditions may result in a range of clinical manifestations including diabetes and cancer. Insulin signalling controls access to blood glucose in body cells. When insulin falls, especially in those with high insulin sensitivity, body cells begin only to have access to lipids that do not require transport across the membrane. So, in this way, insulin is the key regulator of fat metabolism as well. Biochemically, the insulin receptor is encoded by a single gene INSR, from which alternate splicing during transcription results in either IR-A or IR-B isoforms. Downstream post-translational events of either isoform result in the formation of a proteolytically cleaved α and β subunit, which upon combination are ultimately capable of homo or hetero-dimerisation to produce the ≈320 kDa disulfide-linked transmembrane insulin receptor.

<span class="mw-page-title-main">Insulin-like growth factor 1</span> Protein found in humans

Insulin-like growth factor 1 (IGF-1), also called somatomedin C, is a hormone similar in molecular structure to insulin which plays an important role in childhood growth, and has anabolic effects in adults. In the 1950s IGF-1 was called "sulfation factor" because it stimulated sulfation of cartilage in vitro, and in the 1970s due to its effects it was termed "nonsuppressible insulin-like activity" (NSILA).

<span class="mw-page-title-main">Leser–Trélat sign</span> Onset of multiple seborrheic keratoses

The Leser–Trélat sign is the explosive onset of multiple seborrheic keratoses, often with an inflammatory base. This can be a sign of internal malignancy as part of a paraneoplastic syndrome. In addition to the development of new lesions, preexisting ones frequently increase in size and become symptomatic.

<span class="mw-page-title-main">Pattern hair loss</span> Medical condition

Pattern hair loss is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front hairline, loss of hair on the crown and vertex of the scalp, or a combination of both. Female-pattern hair loss (FPHL) typically presents as a diffuse thinning of the hair across the entire scalp.

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<span class="mw-page-title-main">Laron syndrome</span> Medical condition

Laron syndrome (LS), also known as growth hormone insensitivity or growth hormone receptor deficiency (GHRD), is an autosomal recessive disorder characterized by a lack of insulin-like growth factor 1 production in response to growth hormone. It is usually caused by inherited growth hormone receptor (GHR) mutations.

Rabson–Mendenhall syndrome is a rare autosomal recessive disorder characterized by severe insulin resistance. The disorder is caused by mutations in the insulin receptor gene. Symptoms include growth abnormalities of the head, face and nails, along with the development of acanthosis nigricans. Treatment involves controlling blood glucose levels by using insulin and incorporating a strategically planned, controlled diet. Also, direct actions against other symptoms may be taken This syndrome usually affects children and has a prognosis of 1–2 years.

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<span class="mw-page-title-main">FGF10</span> Protein-coding gene in humans

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Florid cutaneous papillomatosis (FCP), is an obligate paraneoplastic syndrome.

<span class="mw-page-title-main">Arsenical keratosis</span> Medical condition

An arsenical keratosis is a growth of keratin on the skin caused by arsenic, which occurs naturally in the Earth's crust and is widely distributed in the environment, Arsenical compounds are used in industrial, agricultural, and medicinal substances. Arsenic is also found to be an environmental contaminant in drinking water and an occupational hazard for miners and glass workers. Arsenic may also causes other conditions including: Bowen's disease, cardiovascular diseases, developmental abnormalities, neurologic and neurobehavioral disorders, diabetes, hearing loss, hematologic disorders, and various types of cancer. Arsenical keratoses may persist indefinitely, and some may develop into invasive squamous cell carcinoma. Metastatic arsenic squamous cell carcinoma and arsenic-induced malignancies in internal organs such as the bladder, kidney, skin, liver, and colon, may result in death.

Familial partial lipodystrophy, also known as Köbberling–Dunnigan syndrome, is a rare genetic metabolic condition characterized by the loss of subcutaneous fat.

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Photoaging or photoageing is a term used for the characteristic changes to skin induced by chronic UVA and UVB exposure. Tretinoin is the best studied retinoid in the treatment of photoaging.

Tripe palms, also known as acanthosis palmaris, is a medical sign characterized by thick ridged velvety palms, typically as part of a paraneoplastic syndrome. It resembles the lining of the stomach of some animals (tripe). Other signs that may be noted at the same time include most frequently acanthosis nigricans (AN), and less commonly finger clubbing and Leser-Trélat sign.

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<span class="mw-page-title-main">Donohue syndrome</span> Medical condition

Donohue syndrome is an extremely rare and severe genetic disorder. Leprechaunism derives its name from the hallmark elvish features exhibited by the affected individuals. The disease is caused by a mutation in the INSR gene, which contains the genetic information for the formation of insulin receptors. As a result, affected individuals have either a decreased number of insulin receptors, or insulin receptor with greatly impaired functionality. The lack and impairment of insulin receptor functionality leads to an inability to regulate blood glucose levels through severe insulin resistance. This will ultimately lead to affected development of tissues and organs throughout the body. In addition to the physical abnormalities, leprechaunism is also characterized by endocrine system abnormalities that can lead to conditions such as hyperglycemia, hypoglycemia, hyperinsulemia, and the enlargement of certain sex organs such as the penis in males, and the clitoris in females.

<span class="mw-page-title-main">HAIR-AN syndrome</span> Medical condition

The HAIR-AN syndrome is a rare subtype of polycystic ovary syndrome (PCOS) characterized by hyperandrogenism (HA), insulin resistance (IR) and acanthosis nigricans (AN). The symptoms of the HAIR-AN syndrome are largely due to severe insulin resistance, which can be secondary to blocking antibodies against the insulin receptor or genetically absent/reduced insulin receptor number/function. Insulin resistance leads to hyperinsulinemia which, in turn, leads to an excess production of androgen hormones by the ovaries. High levels of androgen hormones (hyperandrogenism) in females causes excessive hair growth, acne and irregular menstruation. Patients with both underlying mechanisms of insulin resistance may have more severe hyperandrogenism. Insulin resistance is also associated with diabetes, heart disease and excessive darkening of the skin

Diabetes mellitus (DM) is a type of metabolic disease characterized by hyperglycemia. It is caused by either defected insulin secretion or damaged biological function, or both. The high-level blood glucose for a long time will lead to dysfunction of a variety of tissues.

References

  1. 1 2 3 James, William D.; Elston, Dirk; Treat, James R.; Rosenbach, Misha A.; Neuhaus, Isaac (2020). "24. Endocrine diseases". Andrews' Diseases of the Skin: Clinical Dermatology (13th ed.). Elsevier. pp. 502–504. ISBN   978-0-323-54753-6.
  2. ↑ "acanthosis nigricans" at Dorland's Medical Dictionary
  3. 1 2 3 4 5 Higgins, SP; Freemark, M; Prose, NS (Sep 15, 2008). "Acanthosis nigricans: a practical approach to evaluation and management". Dermatology Online Journal. 14 (9): 2. doi:10.5070/D37MF6G290. PMID   19061584.
  4. ↑ "Acanthosis nigricans - Symptoms and causes". Mayo Clinic. Retrieved 2021-08-13.
  5. ↑ "What Is Acanthosis Nigricans?". WebMD. Retrieved 2021-08-13.
  6. 1 2 3 4 5 6 7 8 9 10 Thomas B. Fitzpatrick; et al. (2005). Fitzpatrick's color atlas and synopsis of clinical dermatology (5th ed.). New York: McGraw-Hill Medical Pub. Division. ISBN   978-0-07-144019-6.
  7. 1 2 3 4 James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN   0-7216-2921-0.
  8. 1 2 3 Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN   978-1-4160-2999-1.
  9. 1 2 3 4 5 6 7 8 9 Habif, Thomas P. (2009). Clinical dermatology (5th ed.). Edinburgh: Mosby. ISBN   978-0-7234-3541-9.
  10. ↑ Tamega A, Aranha AM, Guiotoku MM, Miot LD, Miot HA (1 January 2010). "[Association between skin tags and insulin resistance]". Anais Brasileiros de Dermatologia. 85 (1): 25–31. doi: 10.1590/S0365-05962010000100003 . PMID   20464083.
  11. ↑ "Nueces County Medical Society | Health Education - Insulin Resistance and Acanthosis Nigricans in Kids". www.nuecesmedsociety.org. 2018-04-12. Archived from the original on 2018-04-12. Retrieved 2020-03-01.
  12. ↑ Verma, Shyam; Vasani, Resham; Joshi, Rajiv; Phiske, Meghana; Punjabi, Pritesh; Toprani, Tushar (2016). "A descriptive study of facial acanthosis nigricans and its association with body mass index, waist circumference and insulin resistance using HOMA2 IR". Indian Dermatology Online Journal. 7 (6): 498–503. doi: 10.4103/2229-5178.193898 . ISSN   2229-5178. PMC   5134163 . PMID   27990384.
  13. ↑ Rigel DS; Jacobs MI (1980). "Malignant acanthosis nigricans:a review". The Journal of Dermatologic Surgery and Oncology. 6 (11): 923–7. doi:10.1111/j.1524-4725.1980.tb01003.x. PMID   6257767.
  14. 1 2 Ngan, Vanessa. "Acanthosis nigricans" . Retrieved 23 August 2013.
  15. ↑ Schnopp C; Baumstark J (2007). "Oral acanthosis nigricans". N Engl J Med. 357 (9): e10. doi:10.1056/NEJMicm062917. PMID   17761587.
  16. ↑ Schwartz RA (February 2007). "Acral acanthosis nigricans (acral acanthotic anomaly)". J. Am. Acad. Dermatol. 56 (2): 349–50. doi: 10.1016/j.jaad.2006.09.027 . PMID   17224380.
  17. ↑ Schwartz RA (September 1981). "Acral acanthotic anomaly (AAA)". J. Am. Acad. Dermatol. 5 (3): 345–6. doi: 10.1016/S0190-9622(81)80155-7 . PMID   7263979.
  18. ↑ Schwartz RA (July 1994). "Acanthosis nigricans". J. Am. Acad. Dermatol. 31 (1): 1–19, quiz 20–2. doi:10.1016/S0190-9622(94)70128-8. PMID   8021347.
  19. 1 2 3 Tilgen W (2009). "Benign epidermal tumors". In WHC Burgdorf; G Plewig; HH Wolff; M Landthaler; O Braun-Falco (eds.). Braun-Falco's Dermatology (3rd ed.). Heidelberg: Springer. pp. 1340–7. ISBN   978-3-540-29312-5.
  20. ↑ Garofalo, L.; A.M. Biscozzi; V. Mastrandrea; E. Bonifazi (2003). "Acanthosis nigricans vulgaris. A marker of hyperinsulinemia" (PDF). Eur. J. Pediat. Dermatol. 13: 85–8. Archived from the original (PDF) on 2011-07-09. Retrieved 2010-07-29.
  21. ↑ Schwartz, Robert A. (1994). "Acanthosis nigricans". Journal of the American Academy of Dermatology. 31 (1): 1–19. doi:10.1016/S0190-9622(94)70128-8. PMID   8021347.
  22. ↑ Brown J; Winkelmann RK (1968). "Acanthosis nigricans: study of 90 cases". Medicine. 47 (1): 33–51. doi: 10.1097/00005792-196801000-00002 . PMID   4868603. S2CID   2241453.
  23. ↑ Levine, Norman; Burk, Cynthia (2008). "50. Acquired epidermal hypermelanoses". In Nordlund, James J.; Boissy, Raymond E.; Hearing, Vincent J.; King, Richard A.; Oetting, William S.; Ortonne, Jean-Paul (eds.). The Pigmentary System: Physiology and Pathophysiology (2nd ed.). Massachusetts: Blackwell Publishing. p. 907. ISBN   978-1-4051-2034-0.
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