Hereditary palmoplantar keratoderma associated with primary (congenital) lymphedema.

The palmoplantar keratodermas are a heterogenous group of hereditary disorders of keratinization. They are characterized by epidermal thickening and a yellow waxy appearance of the palms and soles. Genetic studies have linked various forms of palmoplantar keratoderma to markers on chromosomes one, twelve, and seventeen, and several genes have been identified. Primary lymphedema is occasionally present at birth (congenital lymphedema or Milroy's disease), but more commonly develops at puberty (lymphedema praecox). Genetic studies have linked various autosomal dominant forms of primary lymphedema (Milroy's disease and lymphedema distichiasis), to genes on chromosomes five and sixteen respectively. We report a case of palmoplantar keratoderma in a child with congenital lymphedema. To our knowledge, this has not been previously described and may represent a new phenotype for future genetic study.

[Surgical treatment of keratosis palmaris in Mal de Meleda]. / Peut-on traiter chirurgicalement le Mal de Meleda (kératodermie palmoplantaire diffuse de Siemens) ?

BACKGROUND: Mal de Meleda (MDM, OMIM #248300) is a rare congenital palmoplantar keratosis. Deep fissures cause pain and limit extension of the metacarpo-phalangeal joints. We report the case of a patient operated on both hands with a 29-year interval between each hand. OBSERVATIONS: A 53-year-old patient with MDM demonstrated severe keratosis of the left hand. The same surgeon operated on the right hand. Both hands were operated using the same technique. Skin of the palm, the palmar side of the index, and the first phalangeal of third, fourth and fifth fingers were excised with a sharp rugine. The hand was immediately covered by a full thickness-skin graft (FTSG) harvested on groin. CONCLUSIONS: The excision of all keratosis on the palm can lead to complete cure of MDM symptoms. FTSG is essential, especially on the fingers, in order to minimize secondary retraction. At the palm, FTSG offers better mechanical resistance then a split-thickness skin graft. A large groin graft, with closure of the donor site in a Y fashion, can cover the entire hand. Long term follow-up (29 years) demonstrates no recurrence of keratosis on surgically treated areas.

Palmoplantar keratoderma and skin grafting: postsurgical long-term follow-up of two cases with Olmsted syndrome.

Olmsted syndrome is a rare congenital mutilating palmoplantar keratoderma associated with periorificial keratotic plaques. Treatment options include topical keratolytics, systemic retinoids, and debulking procedures. Full-thickness excision of hyperkeratotic plaques followed by skin grafting has been reported in the medical literature, although long-term results have not been evaluated. We present two cases of Olmsted syndrome with severe palmoplantar keratoderma treated with excision and skin grafting, along with long-term clinical results 11 years (patient 1) and 6 years (patient 2) following the initial surgery.

A new cardiac manifestation associated with woolly hair: report of two cases of woolly hair, palmoplantar keratoderma, and mitral valve regurgitation.

Two siblings (a 24-year-old woman and a 14-year-old girl) with congenital woolly hair, epidermolytic palmoplantar keratoderma, and mitral valve regurgitation are described. An interesting additional feature in one of the patients (the 14-year-old girl) was posterior subcapsular cataract. The association of woolly hair and mitral valve regurgitation has not been reported previously. The occurrence of cataract in one of our patients is also a new ophthalmologic finding in this hair shaft anomaly.

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.

Naxos disease and Carvajal syndrome: cardiocutaneous disorders that highlight the pathogenesis and broaden the spectrum of arrhythmogenic right ventricular cardiomyopathy.

Naxos disease is a recessive association of arrhythmogenic right ventricular cardiomyopathy (ARVC) with wooly hair and palmoplantar keratoderma or similar skin disorder. The clinical and histopathological spectrum of heart disease, molecular genetics and genotype-phenotype correlation are reviewed in 22 affected families with this cardiocutaneous syndrome reported in the literature from Greece, Italy, India, Ecuador, Israel and Turkey. All patients had the hair and skin phenotype from infancy and developed ARVC by adolescence. Mutations in genes encoding the cell adhesion proteins piakoglobin and desmoplakin that truncate the proteins at the C-terminal domains were identified to underlie this syndrome. A particular mutation in Ecuadorian families that truncates the intermediate filament-binding site of desmoplakin results in a variant of Naxos disease with predominantly left ventricular involvement, early morbidity and clinical overlapping with dilated cardiomyopathy (Carvajal syndrome). A lethal autosomal recessive cardiocutaneous syndrome of Poll Hereford calves has been reported in Australia sharing similarities with the human syndrome reviewed here with respect to hair and cardiac phenotype. The cardiomyopathy in Naxos cardiocutaneous syndromes presents with increased arrhythmogenicity and variable left ventricular involovement and is characterized histologically by myocardial loss with fibrofatty or fibrous replacement at subepicardial and mediomural layers. The clinical heterogeneity and tissue characteristics in this cell-adhesion cardiomyopathy might be mutation specific and leads to consideration that the spectrum of ARVC should be broadened.

Olmsted syndrome--a rare syndrome with oral manifestations.

Olmsted syndrome is a rare, congenital condition characterized by severe palmo-planter keratosis, periorificial keratosis, and hypotrichosis. Though orofacial keratosis is one of the consistent findings of Olmsted syndrome, it has never been reported in the dental literature. We report a case of Olmsted syndrome in an eight-year-old boy who presented with massive and crippling palmoplanter keratosis and bilateral oral lesions in the form of keratotic plaques at the corners of the mouth, as well as on the dorsum of the tongue.

Lung carcinoma with congenital plantar keratoderma as a variant of Clarke-Howel-Evans syndrome.

A 32-year-old man was admitted to the Magdeburg University Hospital with icterus and for further diagnosis of suspected hepatitis. He also complained of generalized pruritus, abdominal pain, nausea, and diarrhea. The patient's history revealed the excision of a lymph node metastasis of the left groin showing pleomorphic macrocellular infiltrates, 2 months previously. The patient presented to our department with prominent hyperkeratosis of both feet, which had been present since early youth. The family history was negative. Both soles showed very thick, white and blackish hyperkeratosis with predominance of the heels and the forefeet (Fig. 1). The naturally occurring wrinkles of the skin of the toes were flattened. The palms were not affected, and neither was the oral mucosa. Further investigations revealed icterus of the sclera and multiple, firm tumors, which were located in the deep subcutaneous tissue, on the left hip, thigh, and buttock. From thorough clinical, laboratory and staging investigations, a non-small-cell bronchogenic carcinoma, with metastases of the liver, kidneys, adrenal glands, and several skin sites, was diagnosed. A skin biopsy specimen of the foot showed substantial acanthosis of the epidermis with hypergranulosis and excessive orthohyperkeratosis. The corneocytes were enlarged and arranged in a tile-like pattern (Fig. 2). The dermis was free of inflammatory infiltrates and human papillomavirus infection was ruled out by immunohistochemistry. Polychemotherapy was immediately started with 5-fluorouracil, mitomycin, and cisplatin, which was well tolerated. When the patient was admitted for the second cycle, however, his general health had worsened markedly. He complained of abdominal pain, severe weight loss, and nausea. Generalized metastases showed substantial progression. Chemotherapy could not be continued because of a Karnowsky index below 20%. The patient died 2 weeks later.

Olmsted syndrome: report of two new cases and literature review.

Olmsted syndrome is a rare keratinization disorder; 18 cases have been published so far. It associates a mutilating cogenital palmoplantar keratoderma with periorificial erythematokeratotic lesions. We report herein two new unrelated male children with Olmsted syndrome (OS), one of whom was studied by light and electron microscopy. Our histological, immunohistochemical, and ultrastructural findings suggest that this disease is related to epidermal hyperproliferation. We present herein a review of the twenty cases published so far and discuss the major clinicopathological and genetic features of this disease.

Eruptive vellus hair cyst in a patient with pachyonychia congenita.

Pachyonychia congenita is characterized by symmetrical nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and follicular hyperkeratosis. In addition to these features, multiple cutaneous cysts of various kinds have been described. We report a case of pachyonychia congenita associated with eruptive vellus hair cyst.

Olmsted syndrome: report of a new case.

We report the case of a 20-year-old man, who was born with an intense erythema of the genital area, unresponsive to any treatment employed. When he was 9 months old, he presented with well-defined hyperkeratotic erythematous plaques around the mouth, eyes, nose, and perianal area, with similar plaques on the lateral aspect of the neck and axillae. At the same time the erythema of the genital area became hyperkeratotic. When he was 2 years old, he presented with a disabling palmoplantar keratoderma, initially focal, and later diffuse, also unresponsive to local or systemic treatments employed. The lesions have varied during the course of the disease without ever clearing completely. The axillary and inguinal plaques have shown spontaneous resolution on occasion. Six skin biopsies have been performed with no conclusive histological diagnosis of any of the typical disorders of keratinization. All treatments, topical and systemic, including etretinate and acitretin, have failed to improve the condition. We believe that this patient has Olmsted syndrome, a rare form of palmoplantar keratoderma with periorificial keratotic plaques.