Keratosis Pilaris and its Subtypes

Associations, New Molecular and Pharmacologic Etiologies, and Therapeutic Options

Jason F. Wang; Seth J. Orlow


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

In This Article

Hereditary and Syndromic Associations

Syndromes with Intellectual Disability

KP has been linked to a variety of genetic syndromes that involve intellectual disability (ID) (Table 5). Several groups have examined the rate of KP and its subtypes in patients with Down syndrome (DS).[145–151] Cabezas syndrome is a form of X-linked ID caused by a mutation in CUL4B that may be associated with KP.[152] Smith–Magenis syndrome (SMS) is a rare genetic disorder with facial and skeletal abnormalities, ID, developmental delay, and self-injurious behavior that can present with extensive KP.[153] Cornelia de Lange syndrome is a rare disorder characterized by ID, neurodevelopmental delay, congenital malformations, and growth retardation that may be associated with KPAF.[154] Rubinstein–Taybi syndrome (RTS) is a rare disorder characterized by ID, facial abnormalities, and broad thumbs and great toes also potentially associated with KPAF.[155]

Neuro-Cardio-Facial-Cutaneous Syndromes

Neuro-cardio-facial-cutaneous syndromes, also known as RASopathies, are a group of syndromes with abnormalities in the Ras signal transduction pathway (Table 5). Most RASopathies are characterized by cardiac defects, abnormal facies, ID, and dermatologic abnormalities.[156] Among the RASopathies, KP is more common in patients with SOS1, SHOC2, and BRAF mutations.[157] KP is a cardinal dermatologic feature in cardio-facio-cutaneous syndrome (CFCS).[158–164] However, histologic findings have only been reported in three cases of CFCS and one case of undifferentiated CFCS or Costello syndrome (CS).[156,161,165,166] KP also occurs in CS but less frequently than in CFCS.[167] KPAF is also very common in CFCS but not in CS.[163,167,168] In addition, KP and KPAF affect patients with Noonan syndrome (NS).[38,169–175] KP has also been reported in three family members with Noonan-like syndrome and a PTPN11 mutation.[176] However, a direct comparison of RASo-pathic patients with SOC1 and PTPN11 mutations found that SOC1 was significantly more likely to be associated with KP.[177]

Ectodermal Dysplasias

Ectodermal dysplasias (EDs) are a group of syndromes with ectodermal abnormalities, including CFCS, that have been associated with KP (Table 5). Palmoplantar keratoderma-congenital alopecia syndrome (PKCAS) is a rare genodermatosis with a mild autosomal dominant form (type 1) and a recessive form (type 2) with more severe hand involvement.[178] A total of 19 patients have been documented as having PKCAS.[178,179] Both forms include widespread and severe KP, dystrophic nails, palmoplantar keratoderma (PPK), and congenital alopecia (CA). In a report of two patients with PKCAS type 2 (PKCAS2), the main features were universal CA, diffuse KP, facial erythema, and a specific PPK that involved the fingertips and foot and hand borders with worsening sclerodactyly, contractures, and pseudoainhum.[178] The genetic basis of PKCAS2 is not yet known.

Hereditary mucoepithelial dysplasia (HMD) is a rare autosomal dominant disorder characterized by chronic mucosal lesions and is associated with non-scarring alopecia, perineal intertrigo, keratitis, and KP (Table 5).[180,181] Pachyonychia congenita (PC) is a rare genodermatosis with abnormal keratinization and dystrophic nails and has been associated with KP.[182,183] Monilethrix is rare genetic disorder of the hair shaft and may present with KP.[184–187] In addition, IFAPS, a rare X-linked congenital ectodermal dysplasia (ED), may also present with KP.[79,188]

In a previously undescribed form of ED, four family members presented with a syndrome characterized by trichodysplasia, onychodysplasia, retrognathia, abnormal dermatoglyphics, ID, and sometimes KP (Table 5).[189] In a cross-sectional study of 20 patients from seven families, an autosomal recessive syndrome was characterized by pili torti with corkscrew hairs, KP, palmoplantar keratoderma, xerosis, dental abnormalities, onychodysplasia, and facial abnormalities.[190] There has also been a report of an unnamed disorder in a family presenting as congenital hypotrichosis in all locations except the scalp hair, which appeared as coarse, tidy, and shiny, as if "auto-combed," with dystrophic nails and KP.[191] Another unnamed ectodermal dysplasia presented with KP, ID, corkscrew hairs, syndactyly, abnormal facies, dental aberrations, dermatoglyphic hypoplasia, and low numbers of epidermal ridge sweat pores.[192]

Hereditary Skin Appendage Disorders

Several hereditary skin appendage disorders are associated with KP and its subtypes (Table 5). Woolly hair (WH), a congenital structural defect of scalp hair, may present with KP either in the presence or in the absence of a neuro-cardiofacial-cutaneous syndrome.[170,193–196] KPAF and WH can also occur together,[195,196] both in the setting and in the absence of NS.[170] Hypotrichosis with KP is a rare congenital disorder with short, brittle, sparse hair and KP on the scalp. The brittleness of hair in this disorder may be due to an altered fibrous protein composition.[197] Hereditary koilonychia (HK) is a rare, hereditary nail deformity and is associated with KP both in the setting of monilethrix and in isolation.[198,199] Leukonychia totalis (LT) is a rare disorder characterized by complete white discoloration of the nails that has also been associated with KP.[200,201]

Zouboulis Syndrome and Chromosome 18 Abnormalities

Zouboulis syndrome (ZS) is an ultra-rare disorder characterized by KP, KPAF, and monosomy 18p (Table 5), suggesting that the gene for follicular keratinization is on the short arm of chromosome 18.[202–207] Laminin α1 deficiency may contribute to the pathophysiology of ZS, as patients neither have sebaceous glands nor express laminin α1 in hair follicles, dermal nerves, or skin vessels.[208] Located on chromosome 18p11.3, LAMA1 is missing in 18p monosomy, resulting in deficient laminin α1, which may lead to abnormal sebaceous glands and hair follicles.[202,208] Consideration should be given to testing children presenting with both KP and KPAF for a partial 18p monosomy.

Other Syndromes

Patients with collagen VI-related myopathies, including Ullrich congenital muscular dystrophy and Bethlem myopathy, with mutations in COL6A1, COL6A2, and COL6A3, may present with KP (Table 5).[209,210] Peeling skin syndromes are a group of genodermatoses characterized by spontaneous exfoliation and may present with KP.[211] Olmsted syndrome is a very rare disorder characterized by symmetric, mutilating PPK, symmetric hyperkeratotic plaques around body orifices, and sometimes widespread KP.[84]BTG1, a ubiquitously expressed gene that downregulates cell proliferation, may be an important contributor to the pathogenesis of KP, as interstitial deletions in 12q21-q22 comprise a very rare syndrome characterized by KP, facial dysmorphisms, growth retardation, and global developmental delay.[212] Dyschromatosis universalis hereditaria is an autosomal dominant disorder characterized by scattered hyperpigmented and hypopigmented macules and may be associated with KP.[213] There has been a report of three family members presenting with widespread KP, pediatric alopecia, premature cataracts, and psoriasis.[214] One patient presented with KP, palmoplantar keratoderma, and ainhum.[215]

Rombo syndrome is a very rare, autosomal dominant genodermatosis characterized by AV, milia, telangiectasias, hypotrichosis, trichoepitheliomas, proclivity for developing basal cell carcinomas, and peripheral vasodilation with cyanosis (Table 5).[216] Loeys–Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder caused by mutations in the TGFBR1 or TGFBR2 genes and is characterized by arterial tortuosity, hypertelorism, bifid uvula, and aortic aneurysms.[217]TGFBR2-related LDS may present with AV, suggesting a potential role for transforming growth factor β signaling in the pathogenesis of the scarring of AV.[217,218] AV has also been associated with steatocystoma multiplex.[32]