Mal de Meleda (MDM) is a rare autosomal recessive skin disorder characterized by transgressive palmoplantar keratoderma (PPK), keratotic skin lesions, perioral erythema, brachydactyly, and nail abnormalities (summary by Fischer et al., 2001). The PPK in MDM is often accompanied by hyperhidrosis, maceration, fetid odor, and painful fissures (Ward et al., 2003). Some patients exhibiting similar but less severe features of MDM, with milder hyperkeratosis and no nail dystrophy, lichenoid plaques, pachydermia, or distant keratosis, were previously designated as having 'Gamborg Nielsen (Norrbotten) PPK' (see NOMENCLATURE).

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

Sjogren-Larsson syndrome (SLS) is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, impaired intellectual development, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (summary by Lossos et al., 2006).

The phenotypic characteristics of ichthyosis vulgaris include palmar hyperlinearity, keratosis pilaris, and a fine scale that is most prominent over the lower abdomen, arms, and legs. Marked presentation includes prominent scaling, whereas mild presentation consists of palmar hyperlinearity, keratosis pilaris, and, in some cases, fine scaling (summary by Smith et al., 2006).

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.

Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia characterized by sensorineural hearing loss, photophobia and corneal vascularization, hyperkeratosis of the palms and soles, erythrokeratoderma, follicular hyperkeratosis, and recurrent bacterial and fungal infections. A subset of patients with KID may develop multiple cystic pilar tumors, which are prone to malignant transformation and metastasis (Nyquist et al., 2007). Vohwinkel syndrome (124500) is an allelic disorder involving congenital deafness with keratopachydermia and constrictions of fingers and toes. Another similar disorder caused by mutation in GJB2 is palmoplantar keratoderma with deafness (148350). Genetic Heterogeneity of Keratitis-Ichthyosis-Deafness Syndrome An autosomal recessive form of KID syndrome (KIDAR; 242150) is caused by mutation in the AP1B1 gene (600157) on chromosome 22q12.

Initial symptoms of multiple sulfatase deficiency (MSD) can develop from infancy through early childhood, and presentation is widely variable. Some individuals display the multisystemic features characteristic of mucopolysaccharidosis disorders (e.g., developmental regression, organomegaly, skeletal deformities) while other individuals present primarily with neurologic regression (associated with leukodystrophy). Based on age of onset, rate of progression, and disease severity, several different clinical subtypes of MSD have been described: Neonatal MSD is the most severe with presentation in the prenatal period or at birth with rapid progression and death occurring within the first two years of life. Infantile MSD is the most common variant and may be characterized as attenuated (slower clinical course with cognitive disability and neurodegeneration identified in the 2nd year of life) or severe (loss of the majority of developmental milestones by age 5 years). Juvenile MSD is the rarest subtype with later onset of symptoms and subacute clinical presentation. Many of the features found in MSD are progressive, including neurologic deterioration, heart disease, hearing loss, and airway compromise.

Cardiofaciocutaneous (CFC) syndrome is characterized by cardiac abnormalities (pulmonic stenosis and other valve dysplasias, septal defects, hypertrophic cardiomyopathy, rhythm disturbances), distinctive craniofacial appearance, and cutaneous abnormalities (including xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis). The hair is typically sparse, curly, fine or thick, woolly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Some form of neurologic and/or cognitive delay (ranging from mild to severe) is seen in all affected individuals. Neoplasia, mostly acute lymphoblastic leukemia, has been reported in some individuals.

Ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome is characterised by ichthyosis, hepatosplenomegaly and late-onset cerebellar ataxia. It has been described in two brothers. Transmission is either autosomal recessive or X-linked.

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).

Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features, microcephaly, seizures, and developmental delay / intellectual disability. Seizures are of various types and can be difficult to manage. Developmental delay / intellectual disability (ID) is severe in nearly a half, moderate in a third, and mild in the remainder. Nearly a third never develop speech or language skills.

DOLK-congenital disorder of glycosylation (DOLK-CDG, formerly known as congenital disorder of glycosylation type Im) is an inherited condition that often affects the heart but can also involve other body systems. The pattern and severity of this disorder's signs and symptoms vary among affected individuals.\n\nIndividuals with DOLK-CDG typically develop signs and symptoms of the condition during infancy or early childhood. Nearly all individuals with DOLK-CDG develop a weakened and enlarged heart (dilated cardiomyopathy). Other frequent signs and symptoms include recurrent seizures; developmental delay; poor muscle tone (hypotonia); and dry, scaly skin (ichthyosis). Less commonly, affected individuals can have distinctive facial features, kidney disease, hormonal abnormalities, or eye problems.\n\nIndividuals with DOLK-CDG typically do not survive into adulthood, often because of complications related to dilated cardiomyopathy, and some do not survive past infancy.

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.

MEDNIK syndrome is a severe multisystem disorder characterized by impaired intellectual development, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (summary by Montpetit et al., 2008). Patients with MEDNIK exhibit distinct dysmorphic features, including high forehead, upslanting palpebral fissures, depressed nasal bridge, and low-set ears, as well as growth retardation and moderate to severe intellectual disability, with brain atrophy on imaging. Other features include sensorineural deafness, enteropathy with congenital diarrhea, abnormalities of copper metabolism associated with liver disease, and ichthyosis, hyperkeratosis, and erythroderma. Peripheral neuropathy has also been observed in adult patients (Martinelli et al., 2013). MEDNIK syndrome shows phenotypic similarities to CEDNIK syndrome (609528).

Ichthyosis-cheek-eyebrow syndrome is characterized by ichthyosis, prominent full cheeks and sparse lateral eyebrows. It has been described in several individuals from four generations of one family. Transmission is autosomal dominant.

Gaucher disease (GD) encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. The identification of three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular) is useful in determining prognosis and management. GD type 1 is characterized by the presence of clinical or radiographic evidence of bone disease (osteopenia, focal lytic or sclerotic lesions, and osteonecrosis), hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease; in the past, they were distinguished by age of onset and rate of disease progression, but these distinctions are not absolute. Disease with onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years is classified as GD type 2. Individuals with GD type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity.

Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) is a rare autosomal recessive syndrome characterized by scalp hypotrichosis, scarring alopecia, ichthyosis, and sclerosing cholangitis (summary by Feldmeyer et al., 2006).

A rare clinical variant of epidermolytic ichthyosis, with manifestations of blistering phenotype at birth and the development from early infancy of annular polycyclic erythematous scales on the trunk and extremities. It has been reported in less than 10 families. The disease is caused by mutations in the KRT1 (12q11-q13) and KRT10 (17q21-q23) genes, encoding keratins 1 and 10 respectively. These mutations impair keratin filament formation and weaken the structural stability of the keratinocyte cytoskeleton. Transmission is autosomal dominant.

CHIME syndrome, also known as Zunich neuroectodermal syndrome, is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (summary by Ng et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Neutral lipid storage disease with myopathy (NLSDM) is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (summary by Reilich et al., 2011). Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; 275630) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (summary by Fischer et al., 2007).

Retinitis pigmentosa with or without skeletal anomalies (RPSKA) is characterized by retinal degeneration, brachydactyly, craniofacial abnormalities, short stature, and neurologic defects. Night blindness occurs around 10 years of age, followed by restriction of visual fields. Brachydactyly affects primarily the distal phalanges. Craniofacial abnormalities include frontal bossing, downslanting palpebral fissures, large columella, hypoplastic nares, micrognathia, and large low-set ears (summary by Xu et al., 2017).

An ectodermal dysplasia syndrome characterized by severe generalized lamellar icthyosis at birth with alopecia, eclabium, ectropion and intellectual disability. Although similar to Sjogren-Larsson syndrome, this syndrome lacks the presence of neurologic or macular changes. There have been no further descriptions in the literature since 1987.

Rhizomelic chondrodysplasia punctata type 1 (RCDP1), a peroxisome biogenesis disorder (PBD) has a classic (severe) form and a nonclassic (mild) form. Classic (severe) RCDP1 is characterized by proximal shortening of the humerus (rhizomelia) and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata, or CDP), coronal clefts of the vertebral bodies, and cataracts that are usually present at birth or appear in the first few months of life. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period. Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, CDP or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1.

Any arthrogryposis-renal dysfunction-cholestasis syndrome in which the cause of the disease is a mutation in the VPS33B gene.

Stormorken syndrome is an autosomal dominant disorder characterized by mild bleeding tendency due to platelet dysfunction, thrombocytopenia, anemia, asplenia, tubular aggregate myopathy, congenital miosis, and ichthyosis. Additional features may include headache or recurrent stroke-like episodes (summary by Misceo et al., 2014).

A rare genetic disease characterized by sclerosing dysplasia affecting the diaphyseal and metaphyseal regions of the long bones, as well as the skull and metacarpals, in association with skin changes like those seen in ichthyosis vulgaris and premature ovarian failure with bilateral hypoplasia of the ovaries. Patients present in adulthood, primarily with swelling of the extremities and occasional mild pain in the legs.

Megaconial-type congenital muscular dystrophy (MDCMC) is an autosomal recessive disorder characterized by early-onset muscle wasting and impaired intellectual development. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (summary by Mitsuhashi et al., 2011).

Hystrix-like ichthyosis with deafness (HID) syndrome is an autosomal dominant keratinizing disorder characterized by sensorineural deafness and spiky hyperkeratosis affecting the entire skin. Erythroderma appears shortly after birth. After the first year of life, spiky and cobblestone-like hyperkeratosis develops, covering the entire skin surface. Palms and soles are only mildly affected. Scarring alopecia may be present (summary by Van Geel et al., 2002).

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) is an autosomal recessive disorder of keratinization characterized by ichthyosis, palmoplantar keratoderma with constricting bands around fingers, flexural deformities of fingers, and keratotic papules in a linear distribution on the flexural side of large joints. Histologic examination shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers, with abundant abnormal keratohyaline granules in differentiated keratinocytes (summary by Dahlqvist et al., 2010).

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

A very rare inherited connective tissue disorder with characteristics of macrocephaly, sparse scalp hair, soft redundant and hyperextensible skin, joint hypermobility, and scoliosis. Patients have progressive facial coarsening with downslanted palpebral fissures, upper eyelid fullness/infraorbital folds, thick/everted vermillion, gingival overgrowth and abnormal position of the teeth. Rare manifestations such as abnormal high-pitched voice, bronchiectasis, hypergonadotropic hypergonadism and brachydactyly have also been reported. Caused by homozygous mutation in the RIN2 gene on chromosome 20p11.

Arthrogryposis, renal dysfunction, and cholestasis-2 (ARCS2) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells (Qiu et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of ARCS, see ARCS1 (208085).

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

ISQMR is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (summary by Aldahmesh et al., 2011).

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) 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.

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).

Ichthyosis with confetti (IWC), also known as congenital reticular ichthyosiform erythroderma (CRIE), is a rare skin condition characterized by slowly enlarging islands of normal skin surrounded by erythematous ichthyotic patches in a reticulated pattern. The condition starts in infancy as a lamellar ichthyosis, with small islands of normal skin resembling confetti appearing in late childhood and at puberty. Histopathologic findings include band-like parakeratosis, psoriasiform acanthosis, and vacuolization of keratinocytes with binucleated cells in the upper epidermis, sometimes associated with amyloid deposition in the dermis. Ultrastructural abnormalities include perinuclear shells formed from a network of fine filaments in the upper epidermis (summary by Krunic et al., 2003).

X-linked chondrodysplasia punctata 1 (CDPX1) is characterized by chondrodysplasia punctata (stippled epiphyses), brachytelephalangy (shortening of the distal phalanges), and nasomaxillary hypoplasia. Although most affected males have minimal morbidity and skeletal findings that improve by adulthood, some have significant medical problems including respiratory involvement, cervical spine stenosis and instability, mixed conductive and sensorineural hearing loss, and intellectual disability.

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.

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.

Neu-Laxova syndrome-2 (NLS2) is a rare autosomal recessive disorder characterized by a recognizable pattern of severe congenital malformations leading to prenatal or early postnatal lethality. Affected individuals have abnormal craniofacial features, microcephaly, intrauterine growth retardation, ichthyosis, flexion deformities, limb malformations, and edema of the hands and feet. Some patients have malformations of the central nervous system, such as abnormal gyration (summary by Acuna-Hidalgo et al., 2014). For a discussion of genetic heterogeneity of Neu-Laxova syndrome, see NLS1 (256520).

Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675.

Male EBP disorder with neurologic defects (MEND) is an X-linked recessive disorder representing a continuous phenotypic spectrum with variable manifestations associated with a defect in sterol biosynthesis. Features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. Not all patients show all features, and the severity is highly variable. Molecular studies indicate that affected males are hemizygous for a nonmosaic hypomorphic EBP allele. Carrier females are generally clinically asymptomatic, but may show biochemical abnormalities (summary by Arnold et al., 2012 and Barboza-Cerda et al., 2014).

Trichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008). For a discussion of genetic heterogeneity of TTD, see 601675.

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

About half of all people with trichothiodystrophy have a photosensitive form of the disorder, which causes them to be extremely sensitive to ultraviolet (UV) rays from sunlight. They develop a severe sunburn after spending just a few minutes in the sun. However, for reasons that are unclear, they do not develop other sun-related problems such as excessive freckling of the skin or an increased risk of skin cancer. Many people with trichothiodystrophy report that they do not sweat.\n\nTrichothiodystrophy is also associated with recurrent infections, particularly respiratory infections, which can be life-threatening. People with trichothiodystrophy may have abnormal red blood cells, including red blood cells that are smaller than normal. They may also have elevated levels of a type of hemoglobin called A2, which is a protein found in red blood cells. Other features of trichothiodystrophy can include dry, scaly skin (ichthyosis); abnormalities of the fingernails and toenails; clouding of the lens in both eyes from birth (congenital cataracts); poor coordination; and skeletal abnormalities including degeneration of both hips at an early age.\n\nIntellectual disability and delayed development are common in people with trichothiodystrophy, although most affected individuals are highly social with an outgoing and engaging personality. Some people with trichothiodystrophy have brain abnormalities that can be seen with imaging tests. A common neurological feature of this disorder is impaired myelin production (dysmyelination). Myelin is a fatty substance that insulates nerve cells and promotes the rapid transmission of nerve impulses.\n\nMothers of children with trichothiodystrophy may experience problems during pregnancy including pregnancy-induced high blood pressure (preeclampsia) and a related condition called HELLP syndrome that can damage the liver. Babies with trichothiodystrophy are at increased risk of premature birth, low birth weight, and slow growth. Most children with trichothiodystrophy have short stature compared to others their age. \n\nThe signs and symptoms of trichothiodystrophy vary widely. Mild cases may involve only the hair. More severe cases also cause delayed development, significant intellectual disability, and recurrent infections; severely affected individuals may survive only into infancy or early childhood.\n\nIn people with trichothiodystrophy, tests show that the hair is lacking sulfur-containing proteins that normally gives hair its strength. A cross section of a cut hair shows alternating light and dark banding that has been described as a "tiger tail."\n\nTrichothiodystrophy, commonly called TTD, is a rare inherited condition that affects many parts of the body. The hallmark of this condition is hair that is sparse and easily broken. 

SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG, formerly known as congenital disorder of glycosylation type Iq) is an inherited condition that causes neurological and vision problems and other signs and symptoms. The pattern and severity of this condition's features vary widely among affected individuals.\n\nIndividuals with SRD5A3-CDG typically develop signs and symptoms of the condition during infancy or early childhood. Most individuals with SRD5A3-CDG have intellectual disability, vision problems, unusual facial features,low muscle tone (hypotonia), and problems with coordination and balance (ataxia). \n\nVision problems in SRD5A3-CDG often include involuntary side-side movements of the eyes (nystagmus), a gap or hole in one of the structures of the eye (coloboma), underdevelopment of the nerves that carry signals between the eyes and the brain(optic nerve hypoplasia), or vision loss early in life (early-onset severe retinal dystrophy). Over time, affected individuals may develop clouding of the lenses of the eyes (cataracts) or increased pressure in the eyes (glaucoma).\n\nOther features of SRD5A3-CDG can include skin rash, unusually small red blood cells (microcytic anemia),and liver problems.

Noonan syndrome-like disorder with loose anagen hair is characterized by facial features similar to those observed in Noonan syndrome (163950), including hypertelorism, ptosis, downslanting palpebral fissures, low-set posteriorly angulated ears, and overfolded pinnae. In addition, patients display short stature, frequently with growth hormone (GH; see 139250) deficiency; cognitive deficits; relative macrocephaly; small posterior fossa resulting in Chiari I malformation; hypernasal voice; cardiac defects, especially dysplasia of the mitral valve and septal defects; and ectodermal abnormalities, in which the most characteristic feature is the hair anomaly, including easily pluckable, sparse, thin, slow-growing hair (summary by Bertola et al., 2017). Reviews Komatsuzaki et al. (2010) reviewed the clinical manifestations of patients with Noonan syndrome, Costello syndrome (218040), and cardiofaciocutaneous syndrome (CFC; see 115150) compared to patients with mutations in the SHOC2 gene. They noted that although there is phenotypic overlap among the disorders, loose anagen/easily pluckable hair had not been reported in mutation-positive patients with Noonan, CFC, or Costello syndrome, and appeared to be a distinctive feature of SHOC2 mutation-positive patients. Genetic Heterogeneity of Noonan Syndrome-Like Disorder with Loose Anagen Hair NSLH2 (617506) is caused by mutation in the PPP1CB gene (600590) on chromosome 2p23.

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset), primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia/immunodeficiency, and neurologic abnormalities that can include developmental delay, regression / progressive neurologic involvement, cranial nerve deficits, and peripheral motor and sensory neuropathy.

Any Neu-Laxova syndrome in which the cause of the disease is a mutation in the PHGDH gene.

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.

Schimmelpenning-Feuerstein-Mims syndrome, also known as linear sebaceous nevus syndrome, is characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects (summary by Happle, 1991 and Ernst et al., 2007). The linear sebaceous nevi follow the lines of Blaschko (Hornstein and Knickenberg, 1974; Bouwes Bavinck and van de Kamp, 1985). All cases are sporadic. The syndrome is believed to be caused by an autosomal dominant lethal mutation that survives by somatic mosaicism (Gorlin et al., 2001).

In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare.

Immunodeficiency-58 is an autosomal recessive primary immunologic disorder characterized by early-onset skin lesions, including eczematous dermatitis, infectious abscesses, and warts, recurrent respiratory infections or allergies, and chronic persistent infections with candida, Molluscum contagiosum, mycobacteria, EBV, bacteria, and viruses. Some patients may have gastrointestinal involvement, including inflammatory bowel disease, EBV+ smooth muscle tumors, and esophagitis. Immunologic analysis shows defective T-cell function with decreased Treg cells and deficient CD3/CD28 costimulation responses in both CD4+ and CD8+ T cells. B-cell function may also be impaired (summary by Wang et al., 2016 and Alazami et al., 2018).

A rare genetic metabolic liver disease with characteristics of progressive neurodegeneration, cutaneous abnormalities including varying degrees of ichthyosis or seborrheic dermatitis, and systemic iron overload. Patients manifest with infantile-onset seizures, encephalopathy, abnormal eye movements, axial hypotonia with peripheral hypertonia, brisk reflexes, cortical blindness and deafness, myoclonus and hepato/splenomegaly, as well as oral manifestations including microdontia, widely spaced and pointed teeth with delayed eruption and gingival overgrowth.

Immunodeficiency-63 with lymphoproliferation and autoimmunity (IMD63) is an autosomal recessive disorder characterized by immune dysregulation. Affected individuals present in infancy with features of both abnormal activation of certain immune signaling pathways, resulting in lymphoid proliferation, dermatitis, enteropathy, and hypergammaglobulinemia, as well as features of immunodeficiency, such as recurrent infections and increased susceptibility to viral infections, especially CMV. Laboratory studies show increased NK cells that show impaired differentiation, as well as abnormal T cell populations or responses. Some patients may die in childhood; hematopoietic bone marrow transplantation is curative (summary by Zhang et al., 2019).

Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (Mueller et al., 2019). In addition, patients exhibit mild facial dysmorphism (Kutkowska-Kazmierczak et al., 2018).

Nonphotosensitive trichothiodystrophy-7 (TTD7) is an autosomal recessive disorder characterized by cysteine- and threonine-deficient hair that displays a diagnostic alternating light and dark 'tiger-tail' banding pattern under polarization microscopy, as well as ichthyosis (Theil et al., 2019). For a discussion of genetic heterogeneity of trichothiodystrophy, see 601675.

Siddiqi syndrome (SIDDIS) is an autosomal recessive disorder characterized by global developmental delay, early-onset progressive sensorineural hearing impairment, regression of motor skills, dystonia, poor overall growth, and low body mass index (BMI). More variable features may include ichthyosis-like skin abnormalities or sensory neuropathy (summary by Zazo Seco et al., 2017).

Alopecia-intellectual disability syndrome-4 (APMR4) is characterized by alopecia universalis, scaly skin, and psychomotor retardation of varying degrees (Besnard et al., 2019). For a discussion of genetic heterogeneity of alopecia-intellectual disability syndrome, see APMR1 (203650).

Neurodevelopmental disorder with hypotonia and dysmorphic facies (NEDHYDF) is characterized by global developmental delay and hypotonia apparent from birth. Affected individuals have variably impaired intellectual development, often with speech delay and delayed walking. Seizures are generally not observed, although some patients may have single seizures or late-onset epilepsy. Most patients have prominent dysmorphic facial features. Additional features may include congenital cardiac defects (without arrhythmia), nonspecific renal anomalies, joint contractures or joint hyperextensibility, dry skin, and cryptorchidism. There is significant phenotypic variability in both the neurologic and extraneurologic manifestations (summary by Tan et al., 2022).

Nonphotosensitive trichothiodystrophy-9 (TTD9) is characterized by brittle hair and nails and scaly skin, accompanied by failure to thrive, microcephaly, and neuromotor developmental delay. Hair analysis shows low sulfur content, and skin fibroblasts demonstrate normal DNA repair efficiency after UV irradiation (Botta et al., 2021). For a general phenotypic description and discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (601675).

Microcephaly, congenital cataract, and psoriasiform dermatitis (MCCPD) represents an inborn error of cholesterol metabolism that is characterized by accumulation of a large amount of methylsterols, particularly dimethylsterols, in affected patients. The associated features of immune dysregulation, skin disease, and growth delay can be at least partially corrected with cholesterol and statin supplements (He et al., 2014).

Immunodeficiency-55 is an autosomal recessive primary immunodeficiency characterized by intrauterine growth retardation, natural killer (NK) cell deficiency, and chronic neutropenia. Most patients also have postnatal growth retardation. Other clinical manifestations include mild facial dysmorphism, dry or eczematous skin, and recurrent infections with both viruses and bacteria. The disorder appears to result from a defect in DNA replication causing blockade of immune cell differentiation in the bone marrow, particularly affecting NK cells (summary by Cottineau et al., 2017).

Autosomal recessive keratoderma-ichthyosis-deafness syndrome (KDIDAR) is characterized by severe palmoplantar keratoderma, mild generalized ichthyosis, and progressive sensorineural deafness. Other variable features include contractures, mild bleeding diathesis, and psychomotor retardation (Gruber et al., 2017).

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).

Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities (ARCME) is characterized by severe dilated cardiomyopathy resulting in death or cardiac transplantation in childhood. Ventricular tachycardia, sustained or nonsustained, has been reported. In addition, some patients exhibit ectodermal manifestations including woolly or wiry hair, dental anomalies, dry skin, and/or dystrophic nails. Cleft lip and palate and corneal abnormalities have also been observed (Robinson et al., 2020; Henry et al., 2022).