Acanthosis Nigricans

This is a relatively disorder of the ski characterized by a velvety thickening, commonly occurring in the axillae, posterior neck fold, flexor skin surfaces, and umbilicus. The importance is the possible association with insulin resistance and internal malignancy.

OUTLINE

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS
INCIDENCE/ PREVALENCE
AGE
JUVENILE ACANTHOSIS NIGRICANS
Juvenile acanthosis nigricans. Sinha S, Schwartz RA. Department of Dermatology, New Jersey Medical School, Newark, New Jersey 07103, USA.	J Am Acad Dermatol. 2007 Sep;57(3):502-8. Abstract quote Acanthosis nigricans is a velvety thickening of the epidermis that primarily affects the axillae, posterior neck fold, flexor skin surfaces, and umbilicus, and infrequently is diffuse with involvement of the mucosal surfaces. It is increasingly seen in children and adolescents who are obese, and can serve as a cutaneous marker of insulin resistance and malignancy. Although malignancy-associated acanthosis nigricans is rare in the pediatric population, one need be concerned about its association with certain pediatric syndromes. More importantly, insulin resistance itself can also represent a threat to life. We review this important disorder.
SEX
GEOGRAPHY
EPIDEMIOLOGIC ASSOCIATIONS

DISEASE ASSOCIATIONS	CHARACTERIZATION
CROUZON SYNDROME
Crouzon syndrome with acanthosis nigricans: case report and mutational analysis. Nagase T, Nagase M, Hirose S, Ohmori K. Department of Plastic and Reconstructive Surgery, Tokyo Metropolitan Police Hospital, Japan.	Cleft Palate Craniofac J. 2000 Jan;37(1):78-82. Abstract quote OBJECTIVE: To describe the 22nd case of Crouzan syndrome with acanthosis nigricans, a hyperkeratotic skin disorder with hyperpigmentation. METHODS: DNA analysis and sequencing of the FGFR3 gene were performed. RESULTS: The 13-year-old Japanese boy described here also had dyspnea, facial palsy, sensorineural hearing loss, and skeletal and mental retardation. Examination of a skin biopsy specimen revealed the typical findings of acanthosis nigricans. Genetic analysis revealed the Ala391Glu mutation in one FGFR3 gene. CONCLUSIONS: Crouzon syndrome with acanthosis nigricans is a distinct clinical entity different from classic Crouzon syndrome.
MALIGNANCIES
Acanthosis nigricans: a dermatologic marker of metabolic disease. Varthakavi PK, Waingankar A, Patel KL, Wadhwa SL, Khopkar U, Sengupta RA, Merchant PC, Mehtalia SD, Nihalani KD. Dept of Endocrinology, TN Medical College & BYL Nair Ch. Hospito, Mumbai-400 008, India.	Indian J Dermatol Venereol Leprol. 2002 Mar-Apr;68(2):67-72. Abstract quote Most patients with acanthosis nigricans have either clinical or subclinical insulin resistance. We undertook a study to estimate the insulin sensitivity of a group of patients referred from the dermatologist with biopsy proven acanthosis nigricans. Thirty-six patients were evaluated in the Endocrinology clinic. Plasma glucose and serum Insulin levels were estimated after a 75 gms oral glucose load (OGTT). An intravenous Insulin Tolerance Test (ITT) was performed with measurement of Glucose Disposal Rate (GDR). There were 28 females and 8 males (M:F--3.5:1; mean age 26.3+/-1.7 years) in the study. 25/36 patients were morbidly obese (BMI--36.0 +/- 1.2 Kg/m2) with an abnormal body fat distribution (WH ratio--0.9 +/ - 0.02). One patient had generalized lipoatrophy. 16/36 patients with acanthosis nigricans had IGT or overt diabetes and all had highly significant hyperinsulinemia (AUCI = 20825 +/ 1287.7 vs. 6340.0 +/- 984.2 mIU/ml/hr in controls, p < 0.0005). The GDR in patients with acanthosis nigricans was reduced (-0.66 +/- 0.07) compared to controls (-0.39 +/- 0.08; p < 0.01). There was a significant positive correlation between indices of adiposity and insulin resistance in subjects with impaired tolerance.
POLYCYSTIC OVARY SYNDROME
Dermatologic manifestations of polycystic ovary syndrome. Lee AT, Zane LT. School of Medicine, University of California, San Francisco, California 94143-0316, USA.	Am J Clin Dermatol. 2007;8(4):201-19. Abstract quote Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women and is one of the most common endocrine disorders in women. The disorder is commonly characterized by elevated levels of androgen and insulin. Women with PCOS may present with a range of signs and symptoms, and face increased risks of reproductive, metabolic, cardiovascular, psychologic, and neoplastic sequelae, particularly if the condition is left unrecognized or untreated. The clinical definition of PCOS has changed in recent years and includes as one of its cardinal criteria the dermatologic manifestations of hyperandrogenism, chiefly hirsutism, acne vulgaris, and androgenetic alopecia. Acanthosis nigricans, a cutaneous sign of hyperinsulinemia, may also be present. These dermatologic features may provide early clinical clues to recognition of PCOS, and treatment of these cutaneous conditions may improve the patient's quality of life and psychologic well-being. The effects of androgen on pilosebaceous units in the skin can vary by anatomic location, producing pathophysiologic effects on hair growth and differentiation, sebaceous gland size and activity, and follicular keratinization. Treatment modalities may include hormonal therapy intended to modulate androgen production and action as well as non-hormonal therapies directed toward specific dermatologic conditions.

PATHOGENESIS	CHARACTERIZATION
FGFR3 (FIBROBLAST GROWTH FACTOR RECEPTOR 3 GENE) MUTATIONS
Familial Acanthosis Nigricans Due to K650T FGFR3 Mutation. Berk DR, Spector EB, Bayliss SJ. Division of Dermatology, Washington University School of Medicine, 660 S Euclid, Campus Box 8123, St Louis, MO 63110.	Arch Dermatol. 2007 Sep;143(9):1153-6. Abstract quote BACKGROUND: Acanthosis nigricans is a feature of several syndromes caused by activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3), including Crouzon syndrome with acanthosis nigricans, thanatophoric dysplasia, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN syndrome). OBSERVATIONS: We describe a healthy 4-year-old African American girl with generalized acanthosis nigricans since infancy. Her father had a history of acanthosis nigricans since childhood, in addition to Crohn disease, obesity, and adult-onset diabetes mellitus. A pedigree with numerous affected family members was constructed. Other than slightly short stature, no associated anomalies were found, including dysmorphic features or skeletal or neurologic defects. Genetic testing revealed a previously undescribed, heterozygous lysine to threonine mutation at codon 650 of the FGFR3 gene in the 4 affected family members who were tested. Conclusion Extensive acanthosis nigricans in early childhood, especially with a family history of acanthosis nigricans, may warrant testing for FGFR3 mutations.
The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Vajo Z, Francomano CA, Wilkin DJ. Department of Endocrinology and Medicine, Veterans Affairs Medical Center, Phoenix, Arizona 85012, USA.	Endocr Rev. 2000 Feb;21(1):23-39. Abstract quote Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.

LABORATORY/ RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LABORATORY MARKERS

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
VARIANTS
SADDAN (SEVERE ACHONDRODYSPLASIA WITH DEVELOPMENTAL DELAY AND ACANTHOSIS NIGRICANS)
Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3. Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA. Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.	Am J Med Genet. 1999 Jul 2;85(1):53-65 Abstract quote We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL

SPECIAL STAINS/ IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
ELECTRON MICROSCOPY

DIFFERENTIAL DIAGNOSIS

KEY DIFFERENTIATING FEATURES

PROGNOSIS

CHARACTERIZATION

TREATMENT	CHARACTERIZATION
GENERAL

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