Keratosis Pilaris and its Subtypes

Associations, New Molecular and Pharmacologic Etiologies, and Therapeutic Options

Jason F. Wang; Seth J. Orlow

Disclosures

Am J Clin Dermatol. 2018;19(5):733-757. 

In This Article

Disease Associations

Atopy, Hereditary Ichthyoses, and Filaggrin Mutations

A history of atopy has been shown to be associated with KP (p = 0.001), with one survey reporting it in 37% of patients with KP.[7,22] The association of AD and KP may stem from abnormalities of the permeability barrier of the epidermis.[24] KP is sometimes considered a minor diagnostic criterion for AD, although there was poor diagnostic agreement on KP among physicians in a study of 14 physicians from a United Kingdom AD diagnostic criteria working party trying to correctly diagnose AD in 15 patients.[94] Studies from several groups also present conflicting information about the prevalence and diagnostic relevance of KP in AD (Table 3).[8,20,95–99] In childhood AD, the presence of KP may be associated with more severe disease.[100] Subgroups have been proposed within AD, such as intrinsic AD, which lacks allergen-specific immunoglobulin E (IgE) and is less associated with KP (p < 0.05).[101] KP in the setting of AD may differ from KP without AD, as shown by a study in which patients with AD with KP-like papules developed pustular patch test reactions to 5% nickel sulfate, but patients with KP without AD had no reaction.[102] KP is also associated with IV in the context of filaggrin mutations.[2] Like AD, the prevalence data and diagnostic value of KP in IV and other hereditary ichthyoses is conflicting among several studies (Table 3).[3,20,103–106]

Although several genomic analyses have shown that filaggrin mutations, especially R 501X and 2282del4, are associated with KP (p < 0.01 for each), they do not account for the entire KP phenotype.[4,17,24,107] For example, in a genomic analysis of 40 subjects with KP, only 35% (7/20) had filaggrin mutations.[24] Yet this is much higher than the up to 9% general prevalence rate of filaggrin variants in Caucasians.[24,108] In a genomic analysis of 459 patients, filaggrin mutations were associated with an odds ratio approaching 2 in terms of having KP (p < 0.05).[109] However, not all studies support the association of filaggrin mutations with KP.[110] Filaggrin mutations may also contribute to KP by downregulating sebocyte proliferation, causing atrophy of the sebaceous glands, and disrupting the epithelial barrier.[24,111,112] Targeted next-generation sequencing has the potential to identify specific filaggrin mutations in patients with KP, as it has already been used for this purpose in IV.[113]

Obesity, Diabetes, Pregnancy, and Related Hormonal Abnormalities

High body mass index (BMI) and related conditions, including diabetes, pregnancy, and hormonal abnormalities, are often associated with KP.[114] While several studies have found that KP is associated with high BMI and obesity, the prevalence of this phenomenon is variable (Table 4).[7,115–118] The data on whether grade of obesity is directly associated with likelihood of concomitant KP are conflicting, as one study found no correlation[118] while others showed a significant correlation.[117,119] It is suspected that obesity-related hyperinsulinemia and insulin resistance contribute to KP pathophysiology, as suggested by a case series of 13 women with acanthosis nigricans and insulin resistance, nine of whom had KP.[120]

KP is common in patients with type 1 diabetes mellitus (T1DM) and develops early in the disease course.[121] Evidence supports an association between KP and T1DM (Table 4).[121,122] Downregulation of sebocyte proliferation, a potential contributor to the pathogenesis of KP, may be due in part to low insulin-like growth factor 1 or insulin.[24,123] Peroxisome proliferator-activated receptor α, a regulator of ketogenesis, and peroxisome proliferator-activated receptor γ1, a regulator of glucose metabolism and fatty acid storage, are also expressed in sebocytes; decreased activation of these receptors downregulates sebocyte proliferation.[24,123,124] Hereditary EFFC may also be linked to diabetes.[91]

KP may be an underrecognized dermatosis of pregnancy. A case series of five women with KP demonstrated that its onset or severity may be linked to hormone changes during pregnancy.[125] In all five women, KP improved within 9 months of delivery. In addition, a 29-year-old woman developed unilateral KP during her second pregnancy.[64] This may be explained by increased androgens and insulin resistance associated with pregnancy. In addition, in a cross-sectional study of 156 women, hyperandrogenism in the setting of obesity was associated with increased incidence and severity of KP (p < 0.001).[126] After controlling for hyper-androgenism, obese women with KP were more likely to have cutaneous features of virilism than obese women without KP. This may be explained by androgen stimulation of the pilosebaceous infundibulum causing hyperkeratinization.

Primary Cicatricial Alopecias

Primary cicatricial alopecias (PCAs) are a group of hair disorders such as KFSD with permanent hair loss due to destruction of follicular structures. Graham-Little-Piccardi-Lasseur syndrome (GLPLS) is rare and characterized by KP on the trunk and extremities, cicatricial alopecia of the scalp, and non-scarring alopecia of the axillae and pubis.[127] Although KP is usually the last symptom to manifest, two cases of GLPLS in patients with androgen-insensitivity syndrome, a 40-year-old and a 29-year-old, presented with KP as the initial manifestation of GLPLS.[127,128] Without androgen-insensitivity syndrome as a comorbidity, GLPLS typically presents in postmenopausal women, as demonstrated by a case of a 75-year-old woman.[129] There are very few reports of GLPLS in men.[130] Genetics may play a role in the etiology of GLPLS.[131] These cases serve to highlight a hormone imbalance as contributory towards the pathophysiology of KP. There have been two reports of KP associated with acne keloidalis, a chronic inflammatory disorder of hair follicles on the nape and occipital scalp.[132,133] KP was found in 5.6% (1/18) of patients with frontal fibrosing alopecia (FFA) in a retrospective study of 18 patients.[134]

Other Disease Associations

There are rare reports of KP as a sign of malignancy. Acquired hypertrichosis lanuginosa, a sign of internal malignancy, appeared simultaneously with KP and furrowed tongue in a 32-year-old woman with metastatic adenocarcinoma of the liver.[135] KP appeared suddenly in a 14-year-old girl in association with stage III Hodgkin's lymphoma and resolved after chemotherapy-induced remission.[136] A possible association exists between KP and thyroid disease in children.[137,138] A cross-sectional study found KP in 27.9% of 61 children with anorexia nervosa.[139] Moderate-to-severe KP on the arms is associated with a lower prevalence and reduced severity of acne vulgaris (p < 0.01), demonstrated by a cross-sectional study of 158 patients aged 14–34 years, perhaps due to the sebaceous gland deficits in KP.[140] There has been a case of AV in association with Melkersson–Rosenthal syndrome, a rare disorder characterized by facial nerve palsy, orofacial edema, and lingua plicata.[141] KSFD has been associated with psychomotor retardation in a case report.[142] In addition, three sporadic cases of KPR have been reported in association with psychomotor retardation and precocious canities.[143] EFFC with KP has been reported in association with erythrosis pigmentosa mediofacialis in a 12-year-old girl.[144]

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....