Pityriasis rubra pilaris is an uncommon skin disorder characterized by the appearance of keratotic follicular papules, well-demarcated salmon-colored erythematous plaques covered with fine powdery scales interspersed with distinct islands of uninvolved skin, and palmoplantar keratoderma. Most cases are sporadic, although up to 6.5% of PRP-affected individuals report a positive family history. The rare familial cases show autosomal dominant inheritance with incomplete penetrance and variable expression: the disorder is usually present at birth or appears during the first years of life and is characterized by prominent follicular hyperkeratosis, diffuse palmoplantar keratoderma, and erythema, with only a modest response to treatment (summary by Fuchs-Telem et al., 2012).

X-linked ichthyosis is clinically characterized by widespread, dark brown, polygonal scales and generalized dryness. Cutaneous manifestations are present soon after birth and usually do not improve with age. The histopathology of XLI typically shows compact hyperkeratosis and slight acanthosis with a normal granular layer (summary by Takeichi and Akiyama, 2016). X-linked ichthyosis is fundamentally the same disorder as placental steroid sulfatase deficiency, which is often first noted in the pregnant mother of affected males by decreased estrogen or delayed progression of parturition (Alperin and Shapiro, 1997). This is thus an example of affinity ('lumping') of phenotypes thought previously to be separate, the opposite of genetic heterogeneity. Schnyder (1970) gave a useful classification of the inherited ichthyoses. Hernandez-Martin et al. (1999) provided a comprehensive review of X-linked ichthyosis. They pointed out that among all genetic disorders X-linked ichthyosis shows one of the highest ratios of chromosomal deletions; complete deletion has been found in up to 90% of patients. Takeichi and Akiyama (2016) reviewed inherited nonsyndromic forms of ichthyosis.

Bart-Pumphrey syndrome (BAPS) is an autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, which shows considerable phenotypic variability (summary by Richard et al., 2004).

Naegeli-Franceschetti-Jadassohn syndrome (NFJS) is a rare autosomal dominant disorder of skin, hair, and teeth. It is characterized by complete absence of dermatoglyphics (fingerprint lines), a reticulate pattern of skin hyperpigmentation that tends to disappear with age, thickening of the palms and soles (palmoplantar keratoderma), and decreased sweating. Dental anomalies including enamel defects, skin blistering, and nail dystrophy have been reported in some patients. It can be distinguished from dermatopathia pigmentosa reticularis (DPR) by the latter's features of lifelong persistence of the skin hyperpigmentation, partial alopecia, and absence of dental anomalies (summary by Lugassy et al., 2006).

Complete congenital absence of dermatoglyphs is a rare syndrome characterized by autosomal dominant inheritance of the lack of ridges on palms and soles, neonatal acral blisters and facial milia, adult traumatic blistering and fissuring, absent or reduced sweating of palms and soles, and contracture of digits. Additional features may include single palmar transverse crease, palmoplantar keratoderma, and nail grooving (summary by Limova et al., 1993).

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR) is characterized by neonatal-onset ichthyotic erythroderma and profound sensorineural deafness, with failure to thrive and developmental delay in childhood. Severe corneal scarring with vision loss has been observed in adulthood. Low plasma copper and ceruloplasmin levels have been reported in some patients (Alsaif et al., 2019; Boyden et al., 2019). An autosomal dominant form of KID syndrome (KIDAD; 148210) is caused by mutation in the GJB2 gene (121011) on chromosome 13q12. Mutation in the AP1S1 gene (603531) causes a disorder with overlapping features (MEDNIK; 609313).

The TP63-related disorders comprise six overlapping phenotypes: Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome). Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome. Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Limb-mammary syndrome. Split-hand/foot malformation type 4 (SHFM4). Isolated cleft lip/cleft palate (orofacial cleft 8). Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling.

Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.

Naxos disease (NXD) is characterized by arrhythmogenic right ventricular cardiomyopathy associated with abnormalities of the skin, hair, and nails. The ectodermal features are evident from birth or early childhood, whereas the cardiac symptoms develop in young adulthood or later. Clinical variability of ectodermal features has been observed, with hair anomalies ranging from woolly hair to alopecia, and skin abnormalities ranging from mild focal palmoplantar keratoderma to generalized skin fragility or even lethal neonatal epidermolysis bullosa (Protonotarios et al., 1986; Cabral et al., 2010; Pigors et al., 2011; Erken et al., 2011; Sen-Chowdhry and McKenna, 2014). Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (DCWHK; 605676) is caused by mutation in the desmoplakin gene (DSP; 125647). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645).

Cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK) refers to a unique constellation of clinical manifestations including global developmental delay with hypotonia, roving eye movements or nystagmus, poor motor skills, and impaired intellectual development with speech delay. More variable features include microcephaly, feeding difficulties, seizures, ocular anomalies, hearing loss, and nonspecific dysmorphic facial features. Palmoplantar keratoderma and ichthyosis or neuropathy develop in some patients. Brain magnetic resonance imaging (MRI) shows varying degrees of cerebral dysgenesis, including absence of the corpus callosum and cortical dysplasia, as well as hypomyelination, white matter loss, and white matter signal anomalies suggestive of a leukodystrophy. Some patients may show developmental regression; many die in childhood (Fuchs-Telem et al., 2011; Mah-Som et al., 2021). With more patients being reported, several authors (Diggle et al., 2017; Llaci et al., 2019; Mah-Som et al., 2021) have observed that the dermatologic features and peripheral neuropathy show reduced penetrance and are more variable manifestations of this disorder, as they are not observed in all patients with biallelic SNAP29 mutations.

The Curth-Macklin type of ichthyosis hystrix (IHCM) is clinically characterized by severe fissuring and mutilating palmoplantar keratoderma. Affected individuals also exhibit extensive dark spiky or verrucous hyperkeratotic plaques over the large joints and trunk, which in some patients may cover almost the entire body. Structural and ultrastructural hallmarks include compact orthokeratotic hyperkeratosis, hypergranulosis with perinuclear edema, binucleated cells, and formation of perinuclear filamentous shells composed of feathery entangled keratin intermediate filaments (summary by Richardson et al., 2006 and Fonseca et al., 2013). The Lambert type of ichthyosis hystrix (IHL; 146600), in which palms and soles are spared, is caused by mutation in the KRT10 (148080) gene.

Woolly hair-skin fragility syndrome (WHSF) is characterized by woolly hair texture and slow hair growth, as well as superficial skin fragility which is present at birth or appears in the neonatal period and then resolves or persists only as minor palmoplantar skin peeling. The disorder appears to predominantly affect hair, and to a lesser extent skin (Jackson et al., 2023).

PPKS2 is characterized by linear hyperkeratosis of the palms, which is particularly evident in affected individuals who perform manual labor. Hyperkeratosis of the soles primarily involves pressure points, and diffuse background palmoplantar thickening may also be present. (Armstrong et al., 1999; Whittock et al., 1999). For a discussion of genetic heterogeneity of the striate form of palmoplantar keratoderma, see PPKS1 (148700).

Dilated cardiomyopathy with woolly hair and keratoderma (DCWHK) is characterized by the presence of woolly or sparse hair from birth. Some patients exhibit fragile skin with blisters/erosions after minor mechanical trauma, with hyperkeratosis and epidermolytic keratoderma developing in early childhood. Cardiomyopathy may become apparent in the first decade of life, and early death due to heart failure has been reported, but patients may remain asymptomatic into the fourth decade of life. Some patients exhibit an arrhythmogenic form of cardiomyopathy, with sudden death in early adulthood (Carvajal-Huerta, 1998; Whittock et al., 2002; Alcalai et al., 2003; Uzumcu et al., 2006). Another syndrome involving cardiomyopathy, woolly hair, and keratoderma (Naxos disease; 601214) is caused by mutation in the plakoglobin gene (JUP; 173325). Also see 610476 for a similar disorder caused by homozygous mutation in the DSC2 gene (125645). Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis (DCWHKTA; 615821) is caused by heterozygous mutation in DSP. An isolated form of striated PPK (PPKS2; 612908) is also caused by heterozygous mutation in DSP. Reviews In a review of cardiocutaneous syndromes and arrhythmogenic cardiomyopathy, Sen-Chowdhry and McKenna (2014) stated that although the cardiac component of Carvajal syndrome was originally considered dilated cardiomyopathy, many of its features resemble those of arrhythmogenic cardiomyopathy (see 607450). In addition, they noted that different disease subtypes have been found to coexist within the same kindred, suggesting a role for modifier genes and/or environmental influences.

Hereditary palmoplantar keratoderma, Gamborg-Nielsen type is characterised by the presence of diffuse palmoplantar keratoderma without associated symptoms. The syndrome has been described in multiple families from the northernmost county of Sweden (Norrbotten). The palmoplantar keratoderma found in the Gamborg-Nielsen type disease is milder than that found in Mal de Meleda but more severe than that found in Thost-Unna palmoplantar keratoderma (see these terms). Transmission is autosomal recessive.

Schopf-Schulz-Passarge syndrome (SSPS) is an autosomal recessive disorder characterized by a constellation of multiple eyelid cysts, hypodontia, hypotrichosis, palmoplantar hyperkeratosis, and onychodystrophy (summary by Mallaiah and Dickinson, 2001).

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Poikiloderma with neutropenia (PN) is characterized by an inflammatory eczematous rash (ages 6-12 months) followed by post-inflammatory poikiloderma (age >2 years) and chronic noncyclic neutropenia typically associated with recurrent sinopulmonary infections in the first two years of life and (often) bronchiectasis. There is increased risk for myelodysplastic syndrome and, rarely, acute myelogenous leukemia. Other ectodermal findings include nail dystrophy and palmar/plantar hyperkeratosis. Most affected individuals also have reactive airway disease and some have short stature, hypogonadotropic hypogonadism, midfacial retrusion, calcinosis cutis, and non-healing skin ulcers.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Hystrix-like ichthyosis with deafness (HID) is a disorder characterized by dry, scaly skin (ichthyosis) and hearing loss that is usually profound. Hystrix-like means resembling a porcupine; in this type of ichthyosis, the scales may be thick and spiky, giving the appearance of porcupine quills.\n\nNewborns with HID typically develop reddened skin. The skin abnormalities worsen over time, and the ichthyosis eventually covers most of the body, although the palms of the hands and soles of the feet are usually only mildly affected. Breaks in the skin may occur and in severe cases can lead to life-threatening infections. Affected individuals have an increased risk of developing a type of skin cancer called squamous cell carcinoma, which can also affect mucous membranes such as the inner lining of the mouth. People with HID may also have patchy hair loss caused by scarring on particular areas of skin.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) – previously referred to as arrhythmogenic right ventricular dysplasia (ARVD) – is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle, and it may also involve the left ventricle. The presentation of disease is highly variable even within families, and some affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).

Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.

Keratosis follicularis spinulosa decalvans (KFSD) is an uncommon genodermatosis characterized by follicular hyperkeratosis, progressive cicatricial alopecia, and photophobia. Most reported cases show X-linked inheritance (KFSDX; 308800) (Castori et al., 2009).

Striate palmoplantar keratoderma belongs to a group of skin diseases in which there is thickening of the skin on the palms and soles. The striate form is characterized by longitudinal hyperkeratotic lesions extending the length of each finger to the palm, and hyperkeratotic lesions are restricted to regions of the body where pressure and abrasion are greatest (summary by Hunt et al., 2001). Patients with diffuse or focal forms of keratoderma associated with mutation in the DSG1 gene have also been reported (Keren et al., 2005; Milingou et al., 2006). Genetic Heterogeneity of Keratosis Palmoplantaris Striata Type II PPKS (PPKS2; 612908) is caused by mutation in the DSP gene (125647) on chromosome 6. Type III PPKS (PPKS3; 607654) is caused by mutation in the keratin-1 gene (KRT1; 139350) on chromosome 12q. For a general phenotypic description and a discussion of genetic heterogeneity of palmoplantar keratoderma (PPK), see epidermolytic PPK (144200). Nitoiu et al. (2014) reviewed desmosome biology in cardiocutaneous syndromes and inherited skin disease, including discussion of the involvement of the DSG1 and DSP genes.

Any striate palmoplantar keratoderma in which the cause of the disease is a mutation in the KRT1 gene.

Palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome is characterised by sex reversal in males with a 46, XX (SRY-negative) karyotype, palmoplantar hyperkeratosis and a predisposition to squamous cell carcinoma. To date, five cases (four of whom were brothers) have been described. The aetiology is unknown.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a general phenotypic description and discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (summary by Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010). NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (summary by Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (summary by Lefevre et al., 2006). In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (summary by Eckl et al., 2005). For a discussion of genetic heterogeneity of autosomal recessive congenital ichthyosis, see ARCI1 (242300).

Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities.

Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities.

X-linked Olmsted syndrome (OLMSX) is a rare keratinization disorder characterized by the combination of periorificial keratotic plaques and bilateral palmoplantar transgredient keratoderma. Other clinical manifestations include diffuse alopecia, leukokeratosis of the oral mucosa, onychodystrophy, hyperkeratotic linear streaks, follicular keratosis, and constriction of the digits (summary by Yaghoobi et al., 2007). For a general phenotypic description and a discussion of genetic heterogeneity of Olmsted disease, see OLMS1 (614594).

Multiple self-healing palmoplantar carcinoma (MSPC) is characterized by recurrent keratoacanthomas in palmoplantar skin as well as in conjunctival and corneal epithelia. In addition, patients experience a high susceptibility to malignant squamous cell carcinoma (summary by Zhong et al., 2016).

A rare genetic epidermal disorder with characteristics of congenital erythroderma with severe psoriasiform dermatitis, ichthyosis, severe palmoplantar keratoderma, yellow keratosis on the hands and feet, elevated immunoglobulin E, multiple food allergies, and metabolic wasting. Other variable features may include hypotrichosis, nail dystrophy, recurrent infections, mild global developmental delay, eosinophilia, nystagmus, growth impairment and cardiac defects.

Cole disease (COLED) is a rare autosomal dominant disorder characterized by congenital or early-onset punctate keratoderma associated with irregularly shaped hypopigmented macules, which are typically found over the arms and legs but not the trunk or acral regions. Skin biopsies of palmoplantar lesions show nonspecific changes including hyperorthokeratosis, hypergranulosis, and acanthosis. Hypopigmented areas of skin, however, reveal a reduction in melanin content in keratinocytes but not in melanocytes, as well as hyperkeratosis and a normal number of melanocytes. Ultrastructurally, melanocytes show a disproportionately large number of melanosomes in the cytoplasm and dendrites, whereas keratinocytes show a paucity of these organelles, suggestive of impaired melanosome transfer (summary by Eytan et al., 2013). Some patients also exhibit calcinosis cutis or early-onset calcific tendinopathy (Eytan et al., 2013).

Pachyonychia congenita (PC) is characterized by hypertrophic nail dystrophy, painful palmoplantar keratoderma and blistering, oral leukokeratosis, pilosebaceous cysts (including steatocystoma and vellus hair cysts), palmoplantar hyperhydrosis, and follicular keratoses on the trunk and extremities.

Keratosis follicularis spinulosa decalvans is an uncommon genodermatosis chiefly characterized by widespread keratosis pilaris, progressive cicatricial alopecia of the scalp, eyebrows, and eyelashes, and an excess of affected males. Photophobia, blepharitis/conjunctivitis, and corneal dystrophy are characteristic ancillary findings. It is most often inherited as an X-linked trait (summary by Castori et al., 2009). Autosomal dominant inheritance has also been reported (KFSD; 612843). The term 'cum ophiasi' means 'with ophiasis,' i.e., baldness in 1 or more winding streaks about the head, which comes from the Greek for snake. Decalvans refers to the loss of hair.

Autosomal recessive congenital ichthyosis (ARCI) encompasses several forms of nonsyndromic ichthyosis. Although most neonates with ARCI are collodion babies, the clinical presentation and severity of ARCI may vary significantly, ranging from harlequin ichthyosis, the most severe and often fatal form, to lamellar ichthyosis (LI) and (nonbullous) congenital ichthyosiform erythroderma (CIE). These phenotypes are now recognized to fall on a continuum; however, the phenotypic descriptions are clinically useful for clarification of prognosis and management. Infants with harlequin ichthyosis are usually born prematurely and are encased in thick, hard, armor-like plates of cornified skin that severely restrict movement. Life-threatening complications in the immediate postnatal period include respiratory distress, feeding problems, and systemic infection. Collodion babies are born with a taut, shiny, translucent or opaque membrane that encases the entire body and lasts for days to weeks. LI and CIE are seemingly distinct phenotypes: classic, severe LI with dark brown, plate-like scale with no erythroderma and CIE with finer whiter scale and underlying generalized redness of the skin. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia involving the scalp and eyebrows, and palmar and plantar keratoderma. Besides these major forms of nonsyndromic ichthyosis, a few rare subtypes have been recognized, such as bathing suit ichthyosis, self-improving collodion ichthyosis, or ichthyosis-prematurity syndrome.

Keratoderma with woolly hair is a group of related conditions that affect the skin and hair and in many cases increase the risk of potentially life-threatening heart problems. People with these conditions have hair that is unusually coarse, dry, fine, and tightly curled. In some cases, the hair is also sparse. The woolly hair texture typically affects only scalp hair and is present from birth. Starting early in life, affected individuals also develop palmoplantar keratoderma, a condition that causes skin on the palms of the hands and the soles of the feet to become thick, scaly, and calloused.\n\nCardiomyopathy, which is a disease of the heart muscle, is a life-threatening health problem that can develop in people with keratoderma with woolly hair. Unlike the other features of this condition, signs and symptoms of cardiomyopathy may not appear until adolescence or later. Complications of cardiomyopathy can include an abnormal heartbeat (arrhythmia), heart failure, and sudden death.\n\nKeratoderma with woolly hair comprises several related conditions with overlapping signs and symptoms. Researchers have recently proposed classifying keratoderma with woolly hair into four types, based on the underlying genetic cause. Type I, also known as Naxos disease, is characterized by palmoplantar keratoderma, woolly hair, and a form of cardiomyopathy called arrhythmogenic right ventricular cardiomyopathy (ARVC). Type II, also known as Carvajal syndrome, has hair and skin abnormalities similar to type I but features a different form of cardiomyopathy, called dilated left ventricular cardiomyopathy. Type III also has signs and symptoms similar to those of type I, including ARVC, although the hair and skin abnormalities are often milder. Type IV is characterized by palmoplantar keratoderma and woolly and sparse hair, as well as abnormal fingernails and toenails. Type IV does not appear to cause cardiomyopathy.

A rare genetic ectodermal dysplasia syndrome characterized by short stature, nail dystrophy and/or nail loss, oral mucosa and/or tongue hyperpigmentation, dentition abnormalities (delayed teeth eruption, hypodontia, enamel hypoplasia), keratoderma on the margins of the palms and soles and focal hyperkeratosis on the dorsum of the hands and feet. Additionally, dysphagia with esophageal strictures, sensorineural deafness, bronchial asthma and severe iron-deficiency anemia have also been observed.

Palmoplantar keratoderma and woolly hair (PPKWH) is an autosomal recessive disorder characterized by the presence of these cardinal features and the absence of cardiomyopathy symptoms or findings on echocardiography and electrocardiogram. Palmoplantar keratoderma is of the striate type; hair is generally sparse; and leukonychia is present (Ramot et al., 2014).

Any peeling skin syndrome in which the cause of the disease is a mutation in the CSTA gene.

Palmoplantar keratoderma and congenital alopecia-1 (PPKCA1) is a rare autosomal dominant disorder characterized by severe hyperkeratosis and congenital alopecia. Nail changes occur in some patients (summary by Castori et al., 2010). Also see PPKCA2 (212360), an autosomal recessive disorder characterized by congenital alopecia and progressive hyperkeratosis resulting in sclerodactyly, severe contractures and tapering of the digits, and pseudoainhum formation.

Erythrokeratodermia variabilis et progressiva-2 (EKVP2) is a genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The severity and dominating features of the disease vary strikingly within families and also during an individual's course of disease. The erythematous component usually prevails in young children, whereas hyperkeratosis is the dominant or sole feature in adults. Some patients with EKVP2 display lesions resembling erythema gyratum repens (summary by Richard et al., 2003). EKVP was previously thought to be separate disorders: erythrokeratodermia variabilis (EKV) and progressive symmetric erythrokeratodermia (PSEK) (van Steensel et al., 2009). For a discussion of genetic heterogeneity of EKVP, see EKVP1 (133200).

Erythrokeratodermia variabilis et progressiva is a rare skin disease. Patients with EKVP3 have normal skin at birth but develop hyperpigmentation and scaling at sites of friction in childhood, with progression to near-confluent corrugated hyperkeratosis, palmoplantar keratoderma, and transient figurate erythema (summary by Boyden et al., 2015). For a discussion of genetic heterogeneity of EKVP, see EKVP1 (133200).

Focal nonepidermolytic palmoplantar keratoderma-1 (FNEPPK1) is an autosomal dominant skin disorder characterized by large, hard, compact, painful masses of keratin that develop at sites of recurrent friction, principally on the feet, though also on the palms and other sites, without evidence of epidermolysis (summary by Kelsell et al., 1995).

CAPOK syndrome (CAPOK) is characterized by onset of symptoms in the first year of life, with the development of progressive alopecia, hypo- and hyperpigmented macular skin lesions, palmoplantar keratoderma, and nail dystrophy. Beginning in the third decade of life, patients develop recurrent squamous cell carcinomas. Some patients may have brittle teeth resulting in tooth loss, and multinodular goiter has been observed (Courcet et al., 2015).

Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings. Ectodermal dysplasia-15 (ECTD15) is characterized by hypotrichosis that develops in early childhood and absence of sweating except with extreme exercise. Skin is dry from birth and eczematous lesions may develop in adulthood. Other features include blepharitis and photophobia (van den Bogaard et al., 2019).

Olmsted syndrome-1 (OLMS1) is a rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma (PPK) and periorificial keratotic plaques with severe pruritus of lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas (summary by Lin et al., 2012). The digital constriction ('pseudoainhum') may progress to autoamputation of fingers and toes (Olmsted, 1927). Genetic Heterogeneity of Olmsted Syndrome Olmsted syndrome-2 (OLMS2; 619208) is caused by mutation in the PERP gene (609301) on chromosome 6q23. An X-linked form of Olmsted syndrome (OLMSX; 300918) is caused by mutation in the MBTPS2 gene (300294) on chromosome Xp22.

Olmsted syndrome-2 (OLMS2) is characterized by mutilating hyperkeratotic skin lesions, primarily on the palms and soles, but also extending onto dorsal surfaces of the hands and feet and distal extremities. The lesions are progressive, becoming thicker with verrucous fissures on the palms and soles over time. In addition, affected individuals exhibit perioral hyperkeratosis, and may have lesions around other orifices as well, such as the nostrils, perineum, and anus. Most patients also have hyperkeratotic nails and light-colored woolly hair (Duchatelet et al., 2019). Some patients may experience flexion contractures of the digits due to the severity of the keratoderma, and intractable pruritus and alopecia universalis have been observed (Dai et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Olmsted disease, see OLMS1 (614594).

Annular epidermolytic ichthyosis-2 (AEI2) is characterized by erythema and blistering of skin at birth that improves without scarring, as well as palmoplantar keratoderma. Some patients experience intermittent severe flares of generalized annular and polycyclic erythematous scaling plaques (Sybert et al., 1999; Zaki et al., 2018). For a discussion of genetic heterogeneity of AEI, see AEI1 (607602).