Clinical and pathological features of pachyonychia congenita.

Pachyonychia congenita (PC) is a rare genodermatosis affecting the nails, skin, oral mucosae, larynx, hair, and teeth. Pathogenic mutations in keratins K6a or K16 are associated with the PC-1 phenotype whereas K6b and K17 mutations are associated with the PC-2 phenotype. Analysis of clinical, pathological, and genetic data from the literature and two research registries reveal that >97% of PC cases exhibit fingernail and toenail thickening, and painful plantar keratoderma. Prospective evaluation of 57 PC patients from 41 families revealed variable clinical findings: hyperhidrosis (79%), oral leukokeratosis (75%), follicular keratosis (65%), palmar keratoderma (60%), cutaneous cysts (35%), hoarseness or laryngeal involvement (16%), coarse or twisted hair (26%), early primary tooth loss (14%), and presence of natal or prenatal teeth (2%). Stratification of these data by keratin mutation confirmed the increased incidence of cyst formation and natal teeth among PC-2 patients, although cysts were more commonly seen in PC-1 than previously reported (25%-33%). Previously unreported clinical features of PC include development of painful oral and nipple lesions during breastfeeding, copious production of waxy material in ears, and inability to walk without an ambulatory aid (50%). Possible pathogenic mechanisms are discussed with respect to the clinicopathologic and genetic correlations observed.

Treatment of pachyonychia congenita.

There are currently no specific treatments for pachyonychia congenita (PC). Available treatments generally are directed at specific manifestations of the disorder, and an effective treatment plan must recognize that different patients are more or less troubled by different manifestations of the disease. Treatment for all aspects of PC has been less than completely satisfactory. Very few studies have compared different approaches to treatment, and fewer still have given longitudinal follow-up of efficacy and patient acceptance. This review is essentially a compilation of anecdotes. It was collected from physicians' reports in the literature, from direct communication with physicians currently following patients with PC and from patients who answered a questionnaire on the Pachyonychia Congenita Project web page (http://www.pachyonychia.org/Registry.html).

Insights into genotype-phenotype correlation in pachyonychia congenita from the human intermediate filament mutation database.

Keratins are the intermediate filament proteins specifically expressed by epithelial cells. The Human Genome Project has uncovered a total of 54 functional keratin genes that are differentially expressed in specific epithelial structures of the body, many of which involve the epidermis and its appendages. Pachyonychia congenita (PC) is a group of autosomal dominant genodermatoses affecting the nails, thick skin and other ectodermal structures, according to specific sub-type. The major clinical variants of the disorder (PC-1 and PC-2) are known to be caused by dominant-negative mutations in one of four differentiation-specific keratins: K6a, K6b, K16, and K17. A total of 20 human keratin genes are currently linked to single-gene disorders or are predisposing factors in complex traits. In addition, a further six intermediate filament genes have been linked to other non-epithelial genetic disorders. We have established a comprehensive mutation database that catalogs all published independent occurrences of intermediate filament mutations (http://www.interfil.org), with details of phenotypes, published papers, patient support groups and other information. Here, we review the genotype-phenotype trends emerging from the spectrum of mutations in these genes and apply these correlations to make predictions about PC phenotypes based on the site of mutation and keratin pair involved.

The genetic basis of pachyonychia congenita.

In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 2B domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.

Congenital acantholytic dyskeratotic dermatosis: localized Darier disease or disseminated benign papular acantholytic dermatosis?

Acantholytic dyskeratosis is a histopathologic pattern defined by a hyperkeratotic and parakeratotic epidermis with intraepidermal clefts containing acantholytic and dyskeratotic keratinocytes. These typical features are distinctive but not entirely pathognomonic of Darier disease, since they may occur at cutaneous and mucocutaneous sites in other conditions such as Grover disease, acantholytic and dyskeratotic epidermal nevus (nevus of Starink), warty dyskeratoma, or acantholytic papular dermatosis localized to the vulvocrural area. We report a newborn girl who had congenital erosive papules and plaques located on the left thigh, left ankle, and right side of the neck. Histopathologic examination of a punch biopsy specimen disclosed findings typical of acantholytic dyskeratosis. In the absence of any family history or other manifestations of Darier disease, we propose the descriptive term "congenital acantholytic dyskeratotic dermatosis." This descriptor characterizes our patient's disease on the basis of the clinical and histopathologic findings and facilitates recognition of this condition until a putative genetic mutation can be demonstrated or ruled out.

Dermatoglyphics in Darier's disease.

BACKGROUND: Darier's disease is an acantholytic dyskeratotic genodermatosis with autosomal dominant inheritance. A predictive diagnostic marker for this disorder would be beneficial because of the relatively late onset and the large number of sporadic cases of the disease. The dermatoglyphic features of patients with Darier's disease were examined to determine whether they have a common pattern. METHODS: Ink prints of fingers and palms obtained from 11 patients of both sexes with sporadic and familial Darier's disease were analyzed and compared with those of normal subjects. RESULTS: No significant quantitative or qualitative differences were found between the dermatoglyphic features of our patients and those of a healthy population, except for punctate interruptions of the skin ridges that indicate pitting, a well-known manifestation of Darier's disease. CONCLUSIONS: These results refute the conclusions of a previous publication claiming that there is a common characteristic dermatoglyphic feature in patients with this dermatosis.

Keratosis follicularis spinulosa decalvans: report of a case with ultrastructural study and unsuccessful trial of retinoids.

Keratosis follicularis spinulosa decalvans (KFSD) is a genetic disorder characterized by disseminated follicular hyperkeratosis, especially localizated to scalp and face. We report the case of a new patient displaying typical features of KFSD. Ultrastructural study was performed and displayed round keratohyalin granules in follicular keratinocytes. Trial with etretinate, which has not been reported before in this disease, proved to be ineffective.

Follicular ichthyosis.

We describe four patients with congenital follicular hyperkeratosis, of whom three also had pseudoacanthosis nigricans and two had facial abnormalities. Skin specimens were studied by light microscopy, autoradiography, histochemistry and scanning electron microscopy, and the results were compared with those from patients with keratosis pilaris. The condition appears to constitute a distinctive form of ichthyosis in which the abnormal epidermal differentiation occurs mainly within the hair follicles.

Oral retinoid (Tigason R etretinate) therapy in congenital disorders of keratinisation.

We report our experience in Singapore with the use of the new oral Retinoid-etretinate (Tigason RO 10-9359) in 23 patients suffering from various congenital disorders of keratinisation. In this study the drug was administered to 8 patients with Darier's disease, 7 patients with congenital ichthyosis, 4 patients with palmar plantar keratoderma, 2 patients with systematised epidermal naevus and 2 patients with progressive symmetrical erythrokeratoderma. The best results were obtained in patients with ichthyosis where complete clearance was possible. All patients with Darier's except one showed significant improvement. Palmar plantar keratoderma except for one patient gave only fair to minimal improvement. Etretinate was useful in systematised epidermal naevus and progressive symmetrical erythrokeratoderma. Pruritus and cheilitis were the commonest side effect. In two patients (both with Darier's disease) treatment was stopped because of side effects. The side effects were dose related. The histology showed a reduction of the keratin layer but remnants of the original features of the pathology were still present.