Clinical Pearls: Disorders Of Cornification

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Ichthyosis Vulgaris

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This is a surprisingly difficult diagnosis to make with certainty no genetic markers, no characteristic scale, and absent granular layer in only a small minority ... Since the stratum corneum does not retain water well becaue of its inadequate endogenous humectant production, emollients containing urea or alpha hydroxy acids work best.

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X Linked Ichthyosis

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A significant number of these cases are caused by chromosomal deletions Indeed, most of my recent new cases have been referred to me after prenatal f I uorescent in situ hybridization (FISH) screening Such cases need follow up for contiguous gene syndromes ... All should be checked for undescencled testes and risk for testicular carcinoma is increased even in absence of undescencled testes ... Scaling can be quite variable, even for an individual ... Boys with extensive cradle cap at birth can have little/no scale at 1 year of age and then develop characteristic extensor scaling at 4 to 5 years of age ... Small, tightly adherent scales on flanks often give a wrinkled or pseudoatrophic
appearance ... Water is critical for these folks ... Some with marked scale in the dry winter have little or none during humid summers ... I like alphahydroxy acids for RXLI

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Epidermolytic Hyperkeratosis

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Although scale is the major manifestation of this disease, this is a disease of keratinocyte fragility ... Friction is the cause of most blisters, and repeated shear at body folds causes accentuated scale in those locations. Blisters in the absence of friction favors the diagnosis of staph aurieu…for most of my patients aquaphor is their favorite topical…strong topical keratolytics remove too much stratum corneum and leave the skin surface denuded and raw…Itching is unexplained and can be severe ... Oral retinoids are effective for many but not all…pregnancy and skeletal toxicity are ongoing concerns of oral retinoid use… Odor is a problem, somewhat reduced by hypochlorite (0.05% or 1:100 clorox) and salt (2-3% baths. Watch out for contractures, especially of palms, secondary to pain and/ r blisters ... Early referral to F.I.R.S.T., the patient support.

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Lamellar Ichthyosis

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Great variability in size and thickness of scales…Ectropion results from thick scale on the eyelids ... I've had success using topical retinoids to reduce ectropion ... but oral retinoids work better…Most patients try oral retinoids at one time or another, but retinoids unmask the underlying erythema and some patients would rather be scaly than red...Pregnancy and skeletal toxicity are ongoing concerns with retinoids ... Educate patients about heat stroke and normal activity can be pursued ... One of my pa¬tients ran crosscountry in college, another played lacrosse ... Early F.I.R.S.T referral
can be helpful.

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Congenital Ichthyosiform Erythroderma

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These patients lose considerable water and energy through their skin …Children should be encouraged to eat and drink more than their unaffected sibs.J have a low
threshold for recommending protein and calorie supplementation …Itching is usually mild; increased itching should prompt a search for chronic fungal infection. Most of my patients prefer emollients (Vaseline/aquaphor) to keratolytics/humectants. Early referral to the patient support group F.I.R.S.T. can be very helpful.

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Harlequin Fetus

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Is not the uniformly fatal disease once thought…Support in a good pediatric intensive care unit (PICU) seems most critical for survival past postnatal period ... Early intervention with oral retinoids may facilitate shedding of thick natal scale, but there are well documented cases of survival without retinoids… Barrier is extremely poor so these kids need emollients 4 5 times a day ... Call F.I.R.S.T. for names of physi¬cians with experience

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Sjogren Larsson Syndrome

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Pruritis in Sjogren Larsson syndrome (SLS) is a distinguishing feature from other Clinically similar diseases and it may respond to Zileuton therapy, which reduces leukotriene B4 levels…In some patients, the ichthyosis may wax and wane every few weeks… Photophobia is a common complaint… Retinal glistening white dots, if present in a patient with suspected SILS, is a reliable diagnostic sign, but its absence does not rule out SLS...Alopecia or nail dystrophy in not seen in this disease ... The neurologic symptoms of SLS are not typically progressive, though spasticity symptoms may worsen with age if the patient does not get regular physical therapy ... Anecdotal reports that the ichthyosis improves with administration of a low fat diet supplemented with medium chain fatty acids have not been reproduceable.

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Refsum Syndrome

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Signs and symptoms are very dependent on diet; therefore onset and severity are very variable…Neurologists usually make the diagnosis…Ichthyosis is usually mild and responsive to diet…These low vegetable/animal fat diets are tough to follow.

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Conradi-Hunermann Syndrome

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If an erythrodermic baby has hyperkeratosis in a linear or whorled pattern, look for epiphyseal stippling on x ray ... By several years of age, the epiphyseal stippling is usually gone and the erythema more limited …Severity of skin and skeletal disease varies greatly between individual adults, and there are no good early predictors yet ... Follicular atrophoderma seems to be a nearly constant finding in adults.

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Child Syndrome

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Experienced clinicians made a connection long ago between the constellation of findings in CHILD and Conradi Hbnermann, so it was satisfying to learn that their gene defects share a common biochemical pathway… In CHILD syndrome, the skin lesions can look like inflammatory linear epidermal nevi ... Excision can be curative for individuals with relatively narrow, nevoid bands.

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Netherton Syndrome

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These folks have extremely poor barrier function, so they lose lots of water and calories and absorb anything we put on their skin ...Characteristic bamboo shafts may not be seen in all hairs and may not appear until second year of life…Lateral eyebrows are a good place to look ... Characteristic scales of ILC may be fleeting and are never generalized ... Most patients look mostly like CIE ... Many develop vegetating intertriginous plaques of unknown etiology, though some may have HPV ... These patients usually have adverse reactions to topical keratolytics and oral retinoids ... Topical calcineurin inhibitors may be helpful for itch and erythema, but absorption to very high serum levels limits use ... Early referral to the patient support group F.I.R.S.T. can be very helpful.

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Erythrokeratoderma variabilis (EKV)

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usually responds exceptionally well to systemic retinoid therapy; complete clearing of hyperkeratosis and significant moderation of the erythema has been reported Systemic retinoid treatment should be considered carefully because long term therapy is required to achieve continuing results The minimal effective dose for persons with EKV is usually low ... Erythematous patches are more conspicuous during childhood and may be completely absent in adults ... Erythematous patches with pronounced, circinate or gyrate borders appear o be associated with GJB4 mutations ... Despite the finding that GJB3 (Cx31) mutations may also cause sensorineural hearing loss and peripheral neuropathy, EKV is not associated with any of these disorders ... Approximately 35% of patients report burning sensations that precede or accompany erythematous lesions

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KID

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Many of these individuals seem to have increased susceptibility to fungal (especially candida) infection and there have been several reports of squamous cell carcinomas in patients with KID (unusual in other ichthyoses) Therefore, I have a low threshold for repeated use of antifungals and biopsy of unusual looking keratotic papules ... Early reports suggest that topical calcineurin inhibitors may be valuable for erosive keratitis and that cochlear implants may improve hearing.

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Diffuse PPK

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The clinical feature that Unna, Thost, and Vorner were emphasizing in their patients a century ago was a waxy keratoderma limited to the palms and soles, without transgrediens. Vorner's patient turns out to have had epidermolytic histology and so did Thost's. At least one family with Unna type nonepidermolytic PPK has a mutation in keratin 1. Other causes for NEPPK are sure to be found. We should probably move away from using the eponyms for keratodermas, until they are genetically as well asclinically defined. Treatment is very difficult because most patients are not motivated to keep it up ... I like saltwater soaks (3% NaCl for 30 minutes) followed by 40% urea under occlusion overnight to quickly reduce hyperkeratosis and fissures ... Paring with a sharp knife is acceptable, but avoid rubbing and scraping in this disease of keratinocyte fragility.

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Howel Evans Syndrome

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The follicular and leukoplakic changes in this family have stimulated a reclassifica¬tion of this as a focal palmoplantar ectodermal defect. Feet are affected more than hands, and the hyperkeratosis is not truly diffuse, occurring mainly over points of pressure. Unfortunately, there are still no genetic or clinical clues (other than a family history) of risk for cancer in someone with acquired keratoderma. Soaking in saltwater followed by urea creams reduces hyperkeratosis; prolonged bedrest reportedly leads to great improvement.

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Vohwinkel

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Here is a good example of how genetics will help us clean up our syndromes. Vohwinkle's patient probably had a connexin mutation and clinically had honeycomb keratoderma, starfish keratoses, pseudoainhum, hearing defect, but no ichthyosis. The Vohwinkle variant described by Camisa had a loricrin mutation and clinically had no hearing defect but did have mild, generalized ichthyosis. Clearly, these are different diseases, not the same disease on a different background. I have had several cases of keratoderma with pseudoainhurn respond well to oral retinoid and avoided surgery or autoamputation

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MDM

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Erythema of palms and soles at age 1-2 years often precedes hyperkeratosis …Possibility of developing contractures and pseudoainhum encourages me to periodically use oral retinoids to control hyperkeratosis. Clinical significance of commonly positive cultures for fungi is up in the air, but I am following this association carefully

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Papillon Lefevre

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Anecdotal reports long suggested that these patients are at high risk for cutaneous bacterial and fungal infections and for unusual systemic infections, such as hepatic abscesses. The newly identified causative gene and the importance of cathepsin C in innate immunity and neutrophil function force us to rethink the real significance of those anecdotal associations. Early mechanical and antibiotic treatment for periodontal disease is reported to save adult teeth ... Keratolytics and systemic retinoids are useful for reducing keratoderma ... Maybe we should consider more aggressive cutaneous antisepsis.

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Reichner Hanhart Syndrome

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Early dietary intervention is critical. Eye findings usually precede keratoderma by several years; unfortunately diagnosis may not be considered until skin findings appear ... Tyrosine crystals in keratinocytes are thought to be important in pathogenesis.The mystery of why the cutaneous findings in this metabolic disease are mostly limited to palmar plantar epidermis is deepened by a surgical success: ten years after thigh skin was transplanted to the heel it had not become hyperkeratotic, even when surrounding heel skin was.

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Darier’s

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Establishing a routine for these patients is tough. Avoid sun, heat, occlusion, and people with chickenpox or HSV. Recurring bacterial infection (usually S. aureus but watch out for rare birds) usually require systemic antibiotics Oral retinoids are helpful, but a relative overdose can cause paradoxical worsening due to erosions. Patients with intractable disease respond to skin planning or laser ablation that removes at least some of the papillary dermis. Anecdotal reports suggest that patients with Darier disease have increased risk for depression and suicide; anyone developing a chronic disease during their teenage years deserves monitoring for psychosocial problems.

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Epidermal Nevus Syndrome

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This particular ENS (I'm a believer in many, distinct ENSs) has hypophosphaternia as its hallmark. Excision of the nevus or supplemental phosphate and calcitriol improve many of the biochemical abnormalities and may stall progression of bone and CNS changes. Therefore, I do the low yield test of checking serum P on all babies with large epidermal nevi.