Epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma (bullous CIE), is a rare autosomal dominant genodermatosis

, although up to 50% of cases represent new mutations. EHK presents as a bullous disease in newborns, followed by a lifelong ichthyotic skin disorder. In 1902, Brocq first described it as bullous ichthyotic erythroderma to distinguish the entity from congenital ichthyotic erythroderma.

Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) results from mutations in the keratin 1 and keratin 10 genes. Many different mutation sites in the genes have been reported. Keratins are divided into 2 classes: basic type II keratins and acidic type I keratins. Keratin 1 is one of the basic type II keratins found on chromosome 12; keratin 10 is one of the acidic type I keratins found on chromosome 17. Keratins form intermediate filaments when both type I and type II keratins are present. Intermediate filaments provide structural stability to keratinocytes. Keratins 1 and 10 are coexpressed and are involved in the suprabasilar differentiation of keratinocytes. Mutations in these keratin genes lead to the formation of defective keratin proteins, which, although still able to incorporate into intermediate filaments, function poorly. This leads to skin cell collapse and clinical blistering. The thickening of the skin is thought to be compensatory to protect against blistering. United States The incidence of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) is 1 case per 200,000-300,000 persons. International The incidence of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) internationally is the same as it is in United States.

Mortality and morbidities of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) include recurrent infection, sepsis, and electrolyte imbalance, which are possible during the neonatal period.

No racial predilection is apparent for epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]).

Symptoms in some patients may ameliorate over time. 2] Epidermolytic hyperkeratosis (EHK. The ichthyosis is typically generalized and is often more prominent at flexures and overlying joints. Palms and soles have varying degrees of hyperkeratosis. and/or peeling. nails.Sex No sex predilection is recognized for epidermolytic hyperkeratosis (EHK. Epidermolytic hyperkeratosis (EHK. rare autosomal recessive cases have also been reported. so patients may have a family history of a similar condition. bullous congenital ichthyosiform erythroderma [bullous CIE]) is a lifelong condition with an onset at birth or in the neonatal period. bullous congenital ichthyosiform erythroderma [bullous CIE]). As patients age. Pungent body odor may often be associated. leave raw denuded areas. Ectropion does not occur. The scale is classically described as “corrugated cardboard”–like. However. Age Epidermolytic hyperkeratosis (EHK. bullous congenital ichthyosiform erythroderma [bullous CIE]) presents at birth or shortly thereafter with erythema. as many as half the cases are a result of sporadic mutations. blistering. Note the images below. Moreover. bullous congenital ichthyosiform erythroderma [bullous CIE]) presents in neonates as widespread superficial blisters. which.[1. Hyperkeratosis appears from the third month on. the scaling becomes thicker and the propensity to blister decreases. but subtle skin thickening or scaling may be apparent during the first month of life. when ruptured. and the hair. and teeth are normal. . EHK is inherited in an autosomal dominant fashion.

• NPS epidermolytic hyperkeratosis subtypes do not have severe palmoplantar involvement. while others are localized only. and is generalized in skin distribution. In contrast. the palmoplantar surface in NPS-3 epidermolytic hyperkeratosis is hyperlinear. Erythroderma is mild to moderate. a generalized skin distribution. Palms and soles may have varying In 1994. including NPS (without severe palm/sole hyperkeratosis) and PS (with severe palm/sole hyperkeratosis) based on the presence or absence of severe palmoplantar hyperkeratosis. no digital contractures. a positive history of blistering. Distinctions between the 3 NPS epidermolytic hyperkeratosis subtypes are based on different clinical presentations. a hystrix scale. The only differences are a brown scale instead of a hystrix scale and a lack of gait abnormalities. . degrees of hyperkeratosis.[3] The 2 primary types were subdivided further into 3 subtypes each depending on the clinical presentations. and a thin white scale is most prominent on the trunk. no digital contractures. similar to NPS-1 epidermolytic hyperkeratosis and NPS-2 epidermolytic hyperkeratosis. o NPS-1 epidermolytic hyperkeratosis has normal palmoplantar surfaces.The scale in epidermolytic hyperkeratosis is classically described as "corrugated cardboard"-like. Some of the subtypes have general involvement. o NPS-3 epidermolytic hyperkeratosis has no palmoplantar hyperkeratosis. no history of erythroderma. DiGiovanna and Bale separated the various clinical presentations of epidermolytic hyperkeratosis into 2 primary types. and patients may have abnormal gait. o NPS-2 epidermolytic hyperkeratosis is similar to NPS-1 epidermolytic hyperkeratosis. NPS-3 epidermolytic hyperkeratosis may have associated gait abnormalities similar to NPS-1 epidermolytic hyperkeratosis. has minimal scale.

12.• PS epidermolytic hyperkeratosis subtypes have severe palmoplantar involvement. Close-up view of ankle. there has been a report of epidermolytic hyperkeratosis and congenital platelike osteoma cutis in a child. and no gait abnormalities.[4. o PS-2 epidermolytic hyperkeratosis has smooth palmoplantar hyperkeratotic surfaces but has digital contractures. have been reported. no erythroderma. a localized blistering. no digital contractures. Rare cases of patients with epidermolytic hyperkeratosis and hypocalcemic rickets.[9. these mutations are missense substitutions into the highly conserved alpha-helical rod . generalized skin involvement. 5] A case of epidermolytic hyperkeratosis with no facial involvement has also been reported. 11. bullous congenital ichthyosiform erythroderma [bullous CIE]). Causes Defects in genes for keratin 1 (KRT1) and 10 (KRT10) are the cause of epidermolytic hyperkeratosis (EHK. truncal sparing). a localized distribution of skin involvement (limited flexural involvement.[7] as well as epidermolytic hyperkeratosis localized to the vulva. with or without vitamin D resistance. neonatal blistering. mild-to-moderate erythroderma. no digital contractures. generalized skin involvement with hyperkeratosis most severe over the joints at both flexor and extensor surfaces. Epidermolytic hyperkeratosis has been infrequently found to be associated with other clinical findings. no erythroderma. and may have gait abnormalities.[8] The following are clinical images of epidermolytic hyperkeratosis lesions of the ankles: Anterior ankles. a tan scale. positive blistering. 10. 13] Usually. and no gait abnormalities. The 3 subtypes are differentiated based on clinical presentations.[6] More recently. o PS-1 epidermolytic hyperkeratosis has smooth palmoplantar hyperkeratotic surfaces. o PS-3 epidermolytic hyperkeratosis has cerebriform palmoplantar surfaces.

skin biopsy can be helpful. bullous congenital ichthyosiform erythroderma [bullous CIE]).[15] In the medical literature.[14] Defects in keratin 1 are associated with the PS epidermolytic hyperkeratosis variants. Occasionally. X-Linked Staphylococcal Scalded Skin Syndrome Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Laboratory Studies • • • No general laboratory studies are needed for epidermolytic hyperkeratosis (EHK. Procedures • • Along with clinical presentation and history. Lamellar Ichthyosis. however. a thick granular layer. bullous congenital ichthyosiform erythroderma [bullous CIE]). defects in keratin 10 are associated with the NPS epidermolytic hyperkeratosis variants. bullous congenital ichthyosiform erythroderma [bullous CIE]). mutation-specific testing for relatives and prenatal diagnosis is available. deeper . with the histologic findings confirming a diagnosis of epidermolytic hyperkeratosis (EHK. or fetal skin biopsies.[17] An epidermal nevus with histologic changes of epidermolytic hyperkeratosis is a mosaic condition in which the affected skin carries a mutation in keratin 1 or keratin 10. except if necessary to follow chosen therapy or bacterial culture for suspected infection. Differential Diagnoses • • • • • Epidermolysis Bullosa Ichthyosis. Keratin defect studies can be performed on buccal swabs or blood. Typical findings include marked hyperkeratosis. Individuals with more extensive forms can have offspring with generalized epidermolytic hyperkeratosis. analysis of amniotic cells. hematoxylin and eosin findings are distinctive but not unique to epidermolytic hyperkeratosis. Palmoplantar keratoderma is usually associated with KRT1 mutations. Once a mutation is identified in an affected individual. and vacuolar degeneration of the upper dermis. Histologic Findings In epidermolytic hyperkeratosis (EHK. due to germline mutations in keratin 1 or keratin 10. a girl with epidermolytic hyperkeratosis and palmoplantar keratoderma with the KRT10 mutation has been reported.and the nonhelical H1 domains of the keratin proteins. Patients with generalized EHK may be born to parents with epidermolytic epidermal nevi[16] or linear epidermolytic hyperkeratosis. Prenatal diagnosis can be made through chorionic villus sampling. coarse keratohyaline granules. new mutations in both genes continue to be reported.

granular cells become dense. Medical Care Accurate diagnosis of epidermolytic hyperkeratosis (EHK. round-to-oval. They should be handled gently to avoid further trauma to the skin. In older children. enlarged. bullous congenital ichthyosiform erythroderma [bullous CIE]) is important in order to properly inform and counsel parents. and electrolyte imbalance. mosaic form of epidermolytic hyperkeratosis. secondary sepsis.[20] Newborns with epidermolytic hyperkeratosis who have denuded skin are at increased risk for infection. topical emollients continue to be the mainstay of treatment. and an odor. Hematoxylin and eosin staining of epidermolytic hyperkeratosis is shown in the images below. dense clumps of keratin tonofilaments can be seen in the lower epidermal layers. These newborns should be transferred to the neonatal ICU to be monitored and treated as needed. Pathology of epidermolytic hyperkeratosis (hematoxylin and eosin stain). those with focal involvement revealing skip areas of normal epidermis are more likely to have a sporadic. and irregular. Pathology of epidermolytic hyperkeratosis (hematoxylin and eosin stain). dyskeratosis is frequently present to varying degrees. The accumulation of scale predisposes to overgrowth of bacteria. in particular with Staphylococcus aureus. Genetic counseling and prenatal diagnosis also can be offered. Patients may benefit from the use of mild antibacterial soaps or chlorhexidine-containing . In addition. and the shaped masses appear to be keratohyaline granules. large.[18] Patients whose pathologic slides demonstrate continuous involvement of the entire horizontal epidermis with these distinctive findings are more likely to have generalized disease.[19] On electron microscopy. Wound care for blistering and moisturization/emollients are important in the newborn period.

Chorionic villus sampling can diagnose epidermolytic hyperkeratosis earlier by direct gene sequencing if the familial mutation is known. 23] . Keratolytic agents are poorly tolerated by these patients.cleansers. 22. resulting in sloughing of large plates of scale. Prenatal diagnosis can be made by ultrastructural analysis and by direct gene sequencing. bullous congenital ichthyosiform erythroderma [bullous CIE]). calcipotriol. antibacterial soap. systemic retinoids. and urea. Epidermolytic hyperkeratosis tends to improve with increasing age. lactic acid. Consultations Refer patients who are considering conceiving children to a geneticist for reproductive concerns and assistance. Diet No special diet is needed for patients with epidermolytic hyperkeratosis (EHK. topical retinoids. however. bullous congenital ichthyosiform erythroderma [bullous CIE]).[21. bullous congenital ichthyosiform erythroderma [bullous CIE]) Medication Summary No reported cure or specific therapy is available for epidermolytic hyperkeratosis (EHK. • • Prenatal diagnosis of epidermolytic hyperkeratosis can be performed by ultrastructural analysis of fetal skin biopsy specimens and amniotic fluid cells. 10% glycerin. Keratin 1 and keratin 10 are expressed suprabasally as early as week 14 of gestation. normal fetal keratinization does not begin until the 24th week. but the chorionic villus sampling theoretically can be tested as early as the eighth week of gestation. Surgical Care No surgical care is needed or recommended for epidermolytic hyperkeratosis (EHK. keratin filament aggregates have been detected for diagnostic purposes in the 19th week of gestation. alpha-hydroxy acid. The earliest documented diagnosis by this method is at the 15th week of gestation. To date. Activity Activity restrictions are not necessary for patients with epidermolytic hyperkeratosis (EHK. bullous congenital ichthyosiform erythroderma [bullous CIE]). reports of improvement have been noted with high-dose beta-carotene.

bullous congenital ichthyosiform erythroderma [bullous CIE]) patients may need to be transferred to the neonatal ICU for monitoring of infection. bullous congenital ichthyosiform erythroderma [bullous CIE]) to the neonatal ICU to monitor for sepsis and electrolyte imbalance may be necessary. Transfer Transfer of infants with epidermolytic hyperkeratosis (EHK. bullous congenital ichthyosiform erythroderma [bullous CIE]) are at an increased risk for recurrent infections. bullous congenital ichthyosiform erythroderma [bullous CIE]).[26] A patient with the mosaic-type disease was successfully treated with topical maxacalcitol. then tapered down to a dose of acitretin 30 mg/d and erythromycin 500 mg/d. a vitamin D3 analogue. sepsis. electrolyte imbalance).[27] Further Inpatient Care Neonatal epidermolytic hyperkeratosis (EHK. Further Outpatient Care Schedule routine follow-up visits as needed for symptomatic relief or to follow laboratory studies during systemic therapies for epidermolytic hyperkeratosis (EHK.[24] Another patient had complete clearing of her lesions after 2 months of acitretin (35 mg/day. sepsis. but the lesions recurred 3 months after discontinuation of acitretin. . and a pungent smell can be noted.[25] Acitretin at 25 mg/day may significantly improve a patient’s quality of life and skin condition. bullous congenital ichthyosiform erythroderma [bullous CIE]) are determined by clinical need to treat secondary effects of this condition (eg. Complications Patients with epidermolytic hyperkeratosis (EHK. and administration of intravenous fluids or antibiotics.5 mg/kg/day). electrolyte imbalance.Improvement has been reported with topical retinoid therapy. Outpatient medications for epidermolytic hyperkeratosis are determined by what works best with each individual patient (see Medication). Inpatient & Outpatient Medications Inpatient medications for epidermolytic hyperkeratosis (EHK. 0. although widespread application should be avoided because of the risk of systemic absorption. One patient had significant improvement in clinical disease on a combination therapy of acitretin 40 mg/d and erythromycin 500 mg twice daily.

Chief Editor: Dirk M Elston. University of California. Society for Pediatric Dermatology. MD embryology gut ganglion formation-hirschsprung disease Contributor Information and Disclosures Author Tina S Chen. Some patients may experience amelioration of symptoms as they age. MD Pediatric Dermatology Fellow. MD is a member of the following medical societies: American Academy of Dermatology. University of California. San Diego Tina S Chen. MD Assistant Clinical Professor of Dermatology and Pediatrics. Chief of Pediatric Dermatology. California Society of Dermatology and Dermatologic Surgery. Rady Children's Hospital. Diseases & Prosedures Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma) • Author: Tina S Chen. Patient Education Educate patients with epidermolytic hyperkeratosis (EHK. Irvine. MD is a member of the following medical societies: American Academy of Dermatology. Department of Dermatology. bullous congenital ichthyosiform erythroderma [bullous CIE]) about the potential of passing the chromosomal defect on to offspring.Prognosis Epidermolytic hyperkeratosis (EHK. Coauthor(s) Brandie J Metz. School of Medicine Brandie J Metz. and Women's Dermatologic Society . bullous congenital ichthyosiform erythroderma [bullous CIE]) is a lifelong condition. Medscapa REFERENCE Drugs. MD. and Society for Pediatric Dermatology Disclosure: Nothing to disclose.

Genentech Grant/research funds investigator. Association of Professors of Dermatology. Ackerman Academy of Dermatopathology. MD is a member of the following medical societies: Alpha Omega Alpha. Specialty Editor Board Marjan Garmyn. and Society for Investigative Dermatology Disclosure: Nothing to disclose. New York . Department of Dermatology. Department of Dermatology. MD. Abbott Grant/research funds investigator. Belgium Disclosure: Nothing to disclose. MD Associate Professor of Dermatology. Chair and Adjunct Head. Assistant Professor. Center for Clinical Epidemiology and Biostatistics. Pennsylvania State University College of Medicine. Pennsylvania State Milton S Hershey Medical Center Jeffrey J Miller.Disclosure: Nothing to disclose. North American Hair Research Society. Mountain View Dermatology. Staff Dermatologist. Katholieke Universiteit Leuven. MD Assistant Clinical Professor. Department of Dermatology. Richard P Vinson. PA Richard P Vinson. Associate Scholar. NIAMS and NHLBI Grant/research funds investigator Chief Editor Dirk M Elston. American Academy of Dermatology. MD is a member of the following medical societies: American Academy of Dermatology. Novartis investigator. MD. University of Leuven. University of Pennsylvania Joel M Gelfand. Texas Tech University Health Sciences Center. AMGEN Grant/research funds Investigator. Centocor Consulting fee Consulting. Texas Dermatological Society. Celgene Consulting fee DMC Chair. Joel M Gelfand. PhD Professor. Pfizer Grant/research funds investigator. MD Director. Belgium. Paul L Foster School of Medicine. Association of Military Dermatologists. Jeffrey J Miller. MSCE is a member of the following medical societies: Society for Investigative Dermatology Disclosure: AMGEN Consulting fee Consulting. Clinical Studies Unit. and Texas Medical Association Disclosure: Nothing to disclose. Consulting Staff. Abbott Consulting fee Consulting. MSCE Medical Director. Faculty of Medicine. MD.

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