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/Morbidity
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.

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

Sex
No sex predilection is recognized for epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]).

Age
Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) is a lifelong condition with an onset at birth or in the neonatal period. Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) presents at birth or shortly thereafter with erythema, blistering, and/or peeling. Symptoms in some patients may ameliorate over time. EHK is inherited in an autosomal dominant fashion, so patients may have a family history of a similar condition. However, as many as half the cases are a result of sporadic mutations. Moreover, rare autosomal recessive cases have also been reported.[1, 2] Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) presents in neonates as widespread superficial blisters, which, when ruptured, leave raw denuded areas. Hyperkeratosis appears from the third month on, but subtle skin thickening or scaling may be apparent during the first month of life. As patients age, the scaling becomes thicker and the propensity to blister decreases. The ichthyosis is typically generalized and is often more prominent at flexures and overlying joints. The scale is classically described as corrugated cardboardlike. Palms and soles have varying degrees of hyperkeratosis. Note the images below. Ectropion does not occur, and the hair, nails, and teeth are normal. Pungent body odor may often be associated.

The scale in epidermolytic hyperkeratosis is classically described as

"corrugated cardboard"-like. degrees of hyperkeratosis.

Palms and soles may have varying

In 1994, DiGiovanna and Bale separated the various clinical presentations of epidermolytic hyperkeratosis into 2 primary types, including NPS (without severe palm/sole hyperkeratosis) and PS (with severe palm/sole hyperkeratosis) based on the presence or absence of severe palmoplantar hyperkeratosis.[3] The 2 primary types were subdivided further into 3 subtypes each depending on the clinical presentations. Some of the subtypes have general involvement, while others are localized only.

NPS epidermolytic hyperkeratosis subtypes do not have severe palmoplantar involvement. Distinctions between the 3 NPS epidermolytic hyperkeratosis subtypes are based on different clinical presentations. o NPS-1 epidermolytic hyperkeratosis has normal palmoplantar surfaces, no digital contractures, a hystrix scale, a generalized skin distribution, no history of erythroderma, a positive history of blistering, and patients may have abnormal gait. o NPS-2 epidermolytic hyperkeratosis is similar to NPS-1 epidermolytic hyperkeratosis. The only differences are a brown scale instead of a hystrix scale and a lack of gait abnormalities. o NPS-3 epidermolytic hyperkeratosis has no palmoplantar hyperkeratosis, no digital contractures, and is generalized in skin distribution, similar to NPS-1 epidermolytic hyperkeratosis and NPS-2 epidermolytic hyperkeratosis. In contrast, the palmoplantar surface in NPS-3 epidermolytic hyperkeratosis is hyperlinear, has minimal scale, and a thin white scale is most prominent on the trunk. Erythroderma is mild to moderate. NPS-3 epidermolytic hyperkeratosis may have associated gait abnormalities similar to NPS-1 epidermolytic hyperkeratosis.

PS epidermolytic hyperkeratosis subtypes have severe palmoplantar involvement. The 3 subtypes are differentiated based on clinical presentations. o PS-1 epidermolytic hyperkeratosis has smooth palmoplantar hyperkeratotic surfaces, no digital contractures, a localized distribution of skin involvement (limited flexural involvement, truncal sparing), no erythroderma, a localized blistering, and no gait abnormalities. o PS-2 epidermolytic hyperkeratosis has smooth palmoplantar hyperkeratotic surfaces but has digital contractures, generalized skin involvement with hyperkeratosis most severe over the joints at both flexor and extensor surfaces, mild-to-moderate erythroderma, positive blistering, and may have gait abnormalities. o PS-3 epidermolytic hyperkeratosis has cerebriform palmoplantar surfaces, no digital contractures, a tan scale, generalized skin involvement, no erythroderma, neonatal blistering, and no gait abnormalities.

Epidermolytic hyperkeratosis has been infrequently found to be associated with other clinical findings. Rare cases of patients with epidermolytic hyperkeratosis and hypocalcemic rickets, with or without vitamin D resistance, have been reported.[4, 5] A case of epidermolytic hyperkeratosis with no facial involvement has also been reported.[6] More recently, there has been a report of epidermolytic hyperkeratosis and congenital platelike osteoma cutis in a child,[7] as well as epidermolytic hyperkeratosis localized to the vulva.[8] The following are clinical images of epidermolytic hyperkeratosis lesions of the ankles:

Anterior ankles.

Close-up view of ankle.

Causes
Defects in genes for keratin 1 (KRT1) and 10 (KRT10) are the cause of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]).[9, 10, 11, 12, 13] Usually, these mutations are missense substitutions into the highly conserved alpha-helical rod

and the nonhelical H1 domains of the keratin proteins.[14] Defects in keratin 1 are associated with the PS epidermolytic hyperkeratosis variants; defects in keratin 10 are associated with the NPS epidermolytic hyperkeratosis variants. Palmoplantar keratoderma is usually associated with KRT1 mutations; however, a girl with epidermolytic hyperkeratosis and palmoplantar keratoderma with the KRT10 mutation has been reported.[15] In the medical literature, new mutations in both genes continue to be reported. Patients with generalized EHK may be born to parents with epidermolytic epidermal nevi[16] or linear epidermolytic hyperkeratosis.[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. Individuals with more extensive forms can have offspring with generalized epidermolytic hyperkeratosis, due to germline mutations in keratin 1 or keratin 10.

Differential Diagnoses

Epidermolysis Bullosa Ichthyosis, Lamellar Ichthyosis, 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, bullous congenital ichthyosiform erythroderma [bullous CIE]), except if necessary to follow chosen therapy or bacterial culture for suspected infection. Keratin defect studies can be performed on buccal swabs or blood. Once a mutation is identified in an affected individual, mutation-specific testing for relatives and prenatal diagnosis is available.

Procedures

Along with clinical presentation and history, skin biopsy can be helpful, with the histologic findings confirming a diagnosis of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]). Prenatal diagnosis can be made through chorionic villus sampling, analysis of amniotic cells, or fetal skin biopsies.

Histologic Findings
In epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]), hematoxylin and eosin findings are distinctive but not unique to epidermolytic hyperkeratosis. Typical findings include marked hyperkeratosis, a thick granular layer, coarse keratohyaline granules, and vacuolar degeneration of the upper dermis. Occasionally, deeper

granular cells become dense, enlarged, and irregular, and the shaped masses appear to be keratohyaline granules. In addition, dyskeratosis is frequently present to varying degrees.[18] Patients whose pathologic slides demonstrate continuous involvement of the entire horizontal epidermis with these distinctive findings are more likely to have generalized disease; those with focal involvement revealing skip areas of normal epidermis are more likely to have a sporadic, mosaic form of epidermolytic hyperkeratosis.[19] On electron microscopy, large, round-to-oval, dense clumps of keratin tonofilaments can be seen in the lower epidermal layers. Hematoxylin and eosin staining of epidermolytic hyperkeratosis is shown in the images below.

Pathology of epidermolytic hyperkeratosis (hematoxylin

and eosin stain). Pathology of epidermolytic hyperkeratosis (hematoxylin and eosin stain).

Medical Care
Accurate diagnosis of epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) is important in order to properly inform and counsel parents. Genetic counseling and prenatal diagnosis also can be offered.[20] Newborns with epidermolytic hyperkeratosis who have denuded skin are at increased risk for infection, secondary sepsis, and electrolyte imbalance. These newborns should be transferred to the neonatal ICU to be monitored and treated as needed. They should be handled gently to avoid further trauma to the skin. Wound care for blistering and moisturization/emollients are important in the newborn period. In older children, topical emollients continue to be the mainstay of treatment. The accumulation of scale predisposes to overgrowth of bacteria, in particular with Staphylococcus aureus, and an odor. Patients may benefit from the use of mild antibacterial soaps or chlorhexidine-containing

cleansers. Keratolytic agents are poorly tolerated by these patients, resulting in sloughing of large plates of scale. Epidermolytic hyperkeratosis tends to improve with increasing age.

Surgical Care
No surgical care is needed or recommended for epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]).

Consultations
Refer patients who are considering conceiving children to a geneticist for reproductive concerns and assistance. Prenatal diagnosis can be made by ultrastructural analysis and by direct gene sequencing.

Prenatal diagnosis of epidermolytic hyperkeratosis can be performed by ultrastructural analysis of fetal skin biopsy specimens and amniotic fluid cells. 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. To date, keratin filament aggregates have been detected for diagnostic purposes in the 19th week of gestation. Chorionic villus sampling can diagnose epidermolytic hyperkeratosis earlier by direct gene sequencing if the familial mutation is known. The earliest documented diagnosis by this method is at the 15th week of gestation, but the chorionic villus sampling theoretically can be tested as early as the eighth week of gestation.

Diet
No special diet is needed for patients with epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]).

Activity
Activity restrictions are not necessary for patients with epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE])

Medication Summary
No reported cure or specific therapy is available for epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]); however, reports of improvement have been noted with high-dose beta-carotene, systemic retinoids, topical retinoids, 10% glycerin, lactic acid, alpha-hydroxy acid, calcipotriol, antibacterial soap, and urea.[21, 22, 23]

Improvement has been reported with topical retinoid therapy, 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, then tapered down to a dose of acitretin 30 mg/d and erythromycin 500 mg/d.[24] Another patient had complete clearing of her lesions after 2 months of acitretin (35 mg/day; 0.5 mg/kg/day), but the lesions recurred 3 months after discontinuation of acitretin.[25] Acitretin at 25 mg/day may significantly improve a patients quality of life and skin condition.[26] A patient with the mosaic-type disease was successfully treated with topical maxacalcitol, a vitamin D3 analogue.[27]

Further Inpatient Care

Neonatal epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) patients may need to be transferred to the neonatal ICU for monitoring of infection, sepsis, electrolyte imbalance, and administration of intravenous fluids or antibiotics.

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, bullous congenital ichthyosiform erythroderma [bullous CIE]).

Inpatient & Outpatient Medications

Inpatient medications for epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) are determined by clinical need to treat secondary effects of this condition (eg, sepsis, electrolyte imbalance). Outpatient medications for epidermolytic hyperkeratosis are determined by what works best with each individual patient (see Medication).

Transfer
Transfer of infants with epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) to the neonatal ICU to monitor for sepsis and electrolyte imbalance may be necessary.

Complications
Patients with epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) are at an increased risk for recurrent infections, and a pungent smell can be noted.

Prognosis
Epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) is a lifelong condition. Some patients may experience amelioration of symptoms as they age.

Patient Education
Educate patients with epidermolytic hyperkeratosis (EHK, bullous congenital ichthyosiform erythroderma [bullous CIE]) about the potential of passing the chromosomal defect on to offspring.

Medscapa REFERENCE Drugs, Diseases & Prosedures

Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma)

Author: Tina S Chen, MD; Chief Editor: Dirk M Elston, MD

embryology gut ganglion formation-hirschsprung disease

Contributor Information and Disclosures Author Tina S Chen, MD Pediatric Dermatology Fellow, Rady Children's Hospital, Department of Dermatology, University of California, San Diego Tina S Chen, MD is a member of the following medical societies: American Academy of Dermatology, California Society of Dermatology and Dermatologic Surgery, and Society for Pediatric Dermatology Disclosure: Nothing to disclose. Coauthor(s) Brandie J Metz, MD Assistant Clinical Professor of Dermatology and Pediatrics, Chief of Pediatric Dermatology, University of California, Irvine, School of Medicine Brandie J Metz, MD is a member of the following medical societies: American Academy of Dermatology, Society for Pediatric Dermatology, and Women's Dermatologic Society

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

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology Disclosure: Nothing to disclose. Additional Contributors The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Sidney B. Smith, MD, and Jeffrey Smith, MD, to the development and writing of this article.

References
1. Terheyden P, Grimberg G, Hausser I, et al. Recessive epidermolytic hyperkeratosis

caused by a previously unreported termination codon mutation in the keratin 10 gene. J Invest Dermatol. Nov 2009;129(11):2721-3. [Medline]. 2. Tsubota A, Akiyama M, Kanitakis J, et al. Mild recessive bullous congenital ichthyosiform erythroderma due to a previously unidentified homozygous keratin 10 nonsense mutation. J Invest Dermatol. Jul 2008;128(7):1648-52. [Medline]. 3. DiGiovanna JJ, Bale SJ. Clinical heterogeneity in epidermolytic hyperkeratosis. Arch Dermatol. Aug 1994;130(8):1026-35. [Medline]. 4. el-Khateeb EA. Bullous congenital ichthyosiform erythroderma associated with hypocalcemic vitamin D-resistant rickets. Pediatr Dermatol. Mar-Apr 2008;25(2):27982. [Medline]. 5. Bhat YJ, Baba AN, Manzoor S, Qayoom S, Ahmed SM. Bullous icthyosiform erythroderma with rickets in child of a parent with naevus unius lateralis. Indian J Dermatol Venereol Leprol. Mar-Apr 2010;76(2):192-4. [Medline]. 6. Ishii N, Hamada T, Yasumoto S, Hashimoto T. A case of epidermolytic hyperkeratosis with no facial involvement associated with mutation in keratin 10. Clin Exp Dermatol. May 2008;33(3):353-4. [Medline]. 7. Blalock TW, Teague D, Sheehan DJ. Epidermolytic hyperkeratosis and congenital platelike osteoma cutis in a child. Cutis. Jun 2011;87(6):278-80. [Medline]. 8. Russell P, Valmadre S, Howard V. Localised epidermolytic hyperkeratosis of the vulva: a case of mistaken identity. Pathology. 2010;42(5):483-5. [Medline]. 9. Lacz NL, Schwartz RA, Kihiczak G. Epidermolytic hyperkeratosis: a keratin 1 or 10 mutational event. Int J Dermatol. Jan 2005;44(1):1-6. [Medline]. 10. Math A, Frank J, Handisurya A, et al. Identification of a de novo keratin 1 mutation in epidermolytic hyperkeratosis with palmoplantar involvement. Eur J Dermatol. Sep-Oct 2006;16(5):507-10. [Medline].

11. McGowan KA, Aradhya S, Fuchs H, de Angelis MH, Barsh GS. A mouse keratin 1

mutation causes dark skin and epidermolytic hyperkeratosis. J Invest Dermatol. May 2006;126(5):1013-6. [Medline]. 12. Muller FB, Huber M, Kinaciyan T, et al. A human keratin 10 knockout causes recessive epidermolytic hyperkeratosis. Hum Mol Genet. Apr 1 2006;15(7):1133-41. [Medline]. 13. Betlloch I, Lucas Costa A, Mataix J, Prez-Crespo M, Ballester I. Bullous congenital ichthyosiform erythroderma: a sporadic case produced by a new KRT10 gene mutation. Pediatr Dermatol. Jul-Aug 2009;26(4):489-91. [Medline]. 14. Chamcheu JC, Siddiqui IA, Syed DN, Adhami VM, Liovic M, Mukhtar H. Keratin gene mutations in disorders of human skin and its appendages. Arch Biochem Biophys. Apr 15 2011;508(2):123-37. [Medline]. [Full Text]. 15. Morais P, Mota A, Baudrier T, et al. Epidermolytic hyperkeratosis with palmoplantar keratoderma in a patient with KRT10 mutation. Eur J Dermatol. Jul-Aug 2009;19(4):333-6. [Medline]. 16. Chassaing N, Kanitakis J, Sportich S, et al. Generalized epidermolytic hyperkeratosis in two unrelated children from parents with localized linear form, and prenatal diagnosis. J Invest Dermatol. Dec 2006;126(12):2715-7. [Medline]. 17. Akhyani M, Kiavash K, Kamyab K. Bullous ichthyosiform erythroderma in a child born to a parent with systematized linear epidermolytic hyperkeratosis. Int J Dermatol. Feb 2009;48(2):215-7. [Medline]. 18. Bergman R, Khamaysi Z, Sprecher E. A unique pattern of dyskeratosis characterizes epidermolytic hyperkeratosis and epidermolytic palmoplantar keratoderma. Am J Dermatopathol. Apr 2008;30(2):101-5. [Medline]. 19. Ross R, DiGiovanna JJ, Capaldi L, Argenyi Z, Fleckman P, Robinson-Bostom L. Histopathologic characterization of epidermolytic hyperkeratosis: a systematic review of histology from the National Registry for Ichthyosis and Related Skin Disorders. J Am Acad Dermatol. Jul 2008;59(1):86-90. [Medline]. 20. Rothnagel JA, Lin MT, Longley MA, et al. Prenatal diagnosis for keratin mutations to exclude transmission of epidermolytic hyperkeratosis. Prenat Diagn. Aug 1998;18(8):826-30. [Medline]. 21. Kragballe K, Steijlen PM, Ibsen HH, et al. Efficacy, tolerability, and safety of calcipotriol ointment in disorders of keratinization. Results of a randomized, double-blind, vehiclecontrolled, right/left comparative study. Arch Dermatol. May 1995;131(5):556-60. [Medline]. 22. Kwak J, Maverakis E. Epidermolytic hyperkeratosis. Dermatol Online J. Sep 8 2006;12(5):6. [Medline]. 23. Achar A, Naskar B, Laha R, Ray S. Epidcermolytic hyperkeratosis: a case report. J Indian Med Assoc. Mar 2009;107(3):171-2. [Medline]. 24. ten Freyhaus K, Kaiser HW, Proelss J, Tuting T, Bieber T, Wenzel J. Successful treatment of bullous congenital ichthyosiform erythroderma with erythromycin. Dermatology. 2007;215(1):81-3. [Medline]. 25. Kocaturk E, Zemheri E, Kavala M, Aktas S, Sarigul S, Sudogan S. Two cases of linear epidermolytic hyperkeratosis: therapeutic challenge with acitretin. Eur J Dermatol. MayJun 2010;20(3):404-5. [Medline].

26. Nassif PW, Nakandakari S, Fogagnolo L, Contin LA, Alves CJ. Epidermolytic

hyperkeratosis: a follow-up of 23 years of use of systemic retinoids. An Bras Dermatol. Jul-Aug 2011;86(4 Suppl 1):S72-5. [Medline]. 27. Umekoji A, Fukai K, Ishii M. A case of mosaic-type bullous congenital ichthyosiform erythroderma successfully treated with topical maxacalcitol, a vitamin D3 analogue. Clin Exp Dermatol. Jul 2008;33(4):501-2. [Medline].