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Inherited Disorders of Cornification
Abstract
The majority of keratinization disorders are referred to as Mendelian disorders of cornification. This is a very broad group, clinically characterized by hyperkeratosis or visible scaling or both. This chapter deals with the ichthyoses, palmoplantar keratodermas (PPKs) and miscellaneous cornification disorders such as porokeratoses. It is aimed primarily at dermatologists and physician scientists who have to make a clinical diagnosis and provide adequate management for their patients. Therefore a nosology and classification scheme has been chosen that is based on clinicogenetic and morphological features. Clinical diagnoses are then discussed with their molecular pathology. Part of the chapter addresses the management of congenital ichthyoses. Various tables provide an overview on clinical and/or pathophysiologically related groups of diseases. Finally, several cornification disorders are discussed that do not have a genetic basis, but are acquired or are of unknown aetiology (e.g. acquired ichthyoses/PPKs or perforating keratotic disorders).
... The distinctive triad of IHS patients includes mild to moderate ichthyosis, severe hypotrichosis, lacking eyebrows and eyelashes at birth onset which is reported to be improved with disease course. As patient grows, they harbour hypotrichosis, follicular atrophoderma, spares and curly eyebrows, photophobia and pingueculum [2,58]. Trichoscopic analysis of patient's hairs presents dysplastic hairs and pilitorti [58,59] (Fig. 1c; Table 1). ...
... As patient grows, they harbour hypotrichosis, follicular atrophoderma, spares and curly eyebrows, photophobia and pingueculum [2,58]. Trichoscopic analysis of patient's hairs presents dysplastic hairs and pilitorti [58,59] (Fig. 1c; Table 1). IHS is further classified into allelic variants: (1) autosomal recessive ichthyosis (ARIH) with hypohidrosis manifesting all characteristic described above except atrophoderma [4,7]. ...
... (2) Congenital ichthyosis follicular atrophoderma hypotrichosis-hypohydrosis (IFAH) exhibits similar phenotype assisted with follicular atrophoderma [41]. Both these phenotypes are linked with autosomal recessive variations in ST14 gene [41,58]. ...
Syndromic ichthyosis is rare inherited disorders of cornification with varied disease complications. This disorder appears in seventeen subtypes associated with severe systematic manifestations along with medical, cosmetic and social problems. Syndromic ichthyosis with prominent hair abnormalities covers five major subtypes: Netherton syndrome, trichothiodystrophy, ichthyosis hypotrichosis syndrome, ichthyosis hypotrichosis sclerosing cholangitis and ichthyosis follicularis atrichia photophobia syndrome. These syndromes mostly prevail in high consanguinity states, with distinctive clinical features. The known pathogenic molecules involved in ichthyosis syndromes with prominent hair abnormalities include SPINK5, ERCC2, ERCC3, GTF2H5, MPLKIP, ST14, CLDN1 and MBTPS2. Despite underlying genetic origin, most of the health professionals solely rely on phenotypic expression of these disorders that leads to improper management of patients, hence making these patients living an orphanage life. After dermal features, association of other systems such as nervous system, skeletal system, hair abnormalities or liver problems may sometimes give clues for diagnosis but still leaving place for molecular screening for efficient diagnosis. In this paper, we have presented a review of ichthyosis syndrome with prominent hair abnormalities, with special emphasis on their updated genetic consequences and disease management. Additionally, we aim to update health professionals about the practice of molecular screening in ichthyosis syndromes for appropriate diagnosis and treatment.
... Affected patients are characterized by patchy or generalized scaling that evolves into large scaly plaques and erythema. Netherton syndrome (NS), a syndromic form of ichthyosis, is caused by loss of function mutation in the serine protease inhibitor of Kazal type 5-gene (SPINK5, OMIM #256500) [13]. Functional loss of the SPINK5-encoded serine protease inhibitor lympho-epithelial Kazal type related inhibitor (LEKTI) leads to a compromised inhibition of kallikreins. ...
... Functional loss of the SPINK5-encoded serine protease inhibitor lympho-epithelial Kazal type related inhibitor (LEKTI) leads to a compromised inhibition of kallikreins. The balance between protease activity and inhibition is shifted towards excessive proteolytic activity, leading to premature degradation of corneodesmosomes, impaired skin barrier integrity and skin inflammation [13]. ...
Ichthyoses comprise a broad spectrum of keratinization disorders due to hereditary defects of cornification. Until now, mutations in more than 50 genes, mostly coding for structural proteins involved in epidermal barrier formation, have been identified as causes for different types of these keratinization disorders. However, due to the high heterogeneity and difficulties in the establishment of valid experimental models, research in this field remains challenging and translation of novel findings to clinical practice is difficult. In this review, we provide an overview of existing models to study hereditary cornification defects with focus on ichthyoses and palmoplantar keratodermas.
... Harlequin ichthyosis (HI) is the most severe type of autosomal recessive congenital ichthyosis causing abnormalities in the expression of epidermal keratin and in the structure of lamellar granules in the stratum granulosum that results in unformed extracellular lipid lamellar [1], [2], [3], [4]. There is no predilection for race or sex, and inbreeding increases the incidence [1], [2], [5]. ...
Harlequin ichthyosis (HI) is a rare genetic disease caused by the lipid transporter gene ABCA12 mutation. The incidence is 1 in 300,000 live births. Clinically, the skin's keratin layer thickens to form a geometric pattern resembling a Harlequin clown costume. The mortality rate was high, mainly caused by infections and metabolic abnormalities. We report a case of HI in a preterm baby girl with signs of respiratory distress and sepsis that can survive for 4 months.
... Inherited palmoplantar keratodermas (PPKs) are a heterogeneous group of disorders characterized by hyperkeratosis of the palms and soles and categorized into different syndromes based on associated clinical findings. [1] The Papillon-Lefèvre syndrome (PLS) was first described by French physicians Papillon and Lefevre in 1924 with the incidence of one to four cases per million population having onset between the ages of 1 and 4 years with no racial or sexual predilection. [2] It is characterized by diffuse PPK, premature loss of deciduous and permanent teeth, and a tendency to recurrent pyogenic infections of the skin and internal organs. ...
Papillon–Lefevre (PLS) is a rare autosomal recessive disorder of keratinization characterized by symmetric, trans-gradient type palmoplantar keratoderma (PPK), rapidly progressive periodontopathy, and precocious loss of dentition. The management of this condition is difficult and needs a combined approach of both dermatologist and periodontologist. Different treatment options tried previously include keratolytic agents such as salicylic acid, urea, topical steroids in combination with keratolytic, propylene glycol, and systemic retinoids such as etretinate, isotretinoin, and acitretin. Both skin and dental manifestations show good therapeutic responses to systemic retinoids. Thereby, we report a case of PLS in a young female child who showed an excellent response to oral acitretin therapy.
... In addition to their use to study the inflammasome, our CRISPR/Cas9 targeted HPKs were able to differentiate in vitro, thus opening application possibilities such as the generation of skin substitutes (Biedermann et al., 2013). Skin diseases such as epidermolysis bullosa simplex and epidermolytic hyperkeratosis are linked to mutations in either of the keratin 5 or keratin 14 genes and keratin 1 or keratin 10, respectively (Oji et al., 2016). Clinical features include skin blistering due to the fragility of the basal layer cells or skin thickening due to cellular hyperproliferation and accumulation of corneocytes (Rothnagel et al., 1992;McLean and Moore, 2011). ...
... Transgrediens et progrediens palmoplantar keratoderma or Greither's disease is a rare type of inherited non-epidermolytic palmoplantar keratoderma characterized by diffuse involvement of palms and soles with an erythematous border that usually presents after 2 years of age and gradually resolves in later life [1]. We present a case of Greither's disease in a male child with classical features but without family history. ...
Transgrediens et progrediens palmoplantar keratoderma or Greither’s disease is a rare type of inherited non-epidermolytic palmoplantar keratoderma characterized by diffuse involvement of palms and soles with an erythematous border that usually presents after 2 years of age and gradually resolves in later life [1]. We present a case of Greither’s disease in a male child with classical features but without family history.
Background
Palmoplantar keratoderma (PPK) is a heterogeneous group of hereditary or acquired disorders characterised by excessive epidermal thickening of the palms and soles. Proper knowledge about the aetiology of the disease and clinico-demographic profile helps in planning management and predicting outcomes.
Aims and Objective
To determine the prevalence of different dermatoses and describe their clinico-histological correlation in acquired palmoplantar keratoderma.
Materials and Methods
An institution-based cross-sectional study conducted after obtaining Ethics-Committee permission and consent from participants. Patients of any age or gender presenting with acquired PPK were recruited. The calculated sample size was 67 by using the prevalence rate (p) of 22.2%, allowable error (L) of 10%, the confidence level of 95% ( z = 1.96 ), and an infinite population size of 20,000. Patients were evaluated by taking demographic and clinical data in a pre-designed case record form, necessary laboratory investigations and histopathological examination that wereevaluated by three blinded experts. The pooled data were analysed with statistical software.
Results
Among the 67 participants, Psoriasis was diagnosed clinically in 39 (58.2%) and histologically in 7 (10.4%), Lichen planus (LP) clinically in 16 (23.9%) and histologically in 9 (13.4%), Pityriasis rubra pilaris (PRP) in 8 (11.9%) patients clinically and 7 (10.4%) histologically and Hyperkeratotic eczema (HKE) in 4 (6%) clinically and 43 (64.2%) histopathologically. There was very poor inter-rater agreement (Kappa = 0.148, SE 0.0047, 95% CI 0.057 to 0.24). The clinico-pathological correlation was found to be agreeable in 17.9% Psoriasis, 56.2% LP and 87.5% PRP. HKE was commonly misdiagnosed as Psoriasis in 65.1% of patients.
Conclusion
Hyperkeratotic lesions of the palm and sole often present with overlapping clinical features and a skin biopsy has to be done to aid in diagnosis.
Limitation
Stratification of the clinical expertise of clinicians was done during the analysis.
Inherited palmoplantar keratodermas (PPKs) have onset in the late infancy or early childhood and have a positive family history. Sporadic cases and cases with onset in adulthood have been rarely reported. We describe two female cases with transgradiens and progradiens PPK, with onset in adulthood having clinical and histological features of Greither's disease (GD). Only a single report of adult-onset GD has been reported in the literature. All patients presenting with palmoplantar keratoderma should be thoroughly evaluated, as it may be a late-onset inherited disorder, it adds to the spectrum of conditions to presenting with PPKs of late-onset.
Hereditary ichthyoses are Mendelian disorders of cornification that affect the entire skin and are characterized by thickening of the corneal layer and scaling. Functionally, ichthyoses may be regarded as disorders of the epidermal barrier. Clinical diagnostics and management of the multitude of extremely rare diseases are challenging. Therefore, classification is based on a clinico-genetic algorithm that distinguishes between non-syndromal and syndromal forms. The differentiation of more common ichthyoses, i.e., ichthyosis vulgaris and/or X-chromosomal ichthyosis, from rare congenital types is of practical importance. In general, acquired ichthyosiform skin conditions should be excluded. In this chapter, the complex genetic background of the ichthyoses is explained. To clarify the clinical view it is emphasized with detailed pictorial material. Therapeutic recommendations follow the maxim that much can be achieved for the patients by symptomatic therapy measures.
We include in this chapter a number of interesting cases that fall outside of the previous chapters. Still, they should be of interest to all those who are interested in dermatology on black skin and so we present them here.
Ichthyoses are inborn keratinization disorders affecting the skin only (non-syndromic) or are associated with diseases of internal organs (syndromic). In newborns, they can be life-threatening. The identification of the gene defects resulted in reclassification and a better understanding of the pathophysiology. Histopathologic patterns include orthohyperkeratosis with a reduced or well-developed stratum granulosum, hyperkeratosis with ortho- and parakeratosis with preserved or prominent stratum granulosum, and epidermolytic ichthyosis. Another pattern features “perinuclear vacuoles and binucleated keratinocytes”, which is associated with keratin mutations. Some ichthyoses are histologically defined by psoriasis-like features, and distinct subtypes show follicular hyperkeratosis. In addition to histological and immunohistochemical methods, these patterns allow a better histopathologic diagnosis.
Disorders of keratinization are those group of diseases in which there is abnormal differentiation and desquamation of the epidermis resulting in a defective cutaneous barrier. It includes ichthyosis, palmoplantar keratoderma, porokeratoses and a perforating group of disorders.
Genodermatoses are heritable skin diseases that can cause significant morbidity and mortality. Most of them show characteristic cutaneous findings. Genodermatoses can be associated with extracutaneous system abnormalities. Diagnosing hereditary skin disorders is still a challenging task due to their rarity and diversity, due to diseases evolving over many years and the initial manifestations not always beingdiagnostic; therefore, on-going evaluation and surveillance is often required to make the accurate diagnosis. The algorithm for the diagnosis depends on a combination of thorough clinical and family history clinical examination, laboratory findings, consultation of multiple medical specialists and molecular analysis. Diagnostic testing targeted at differentiation of similar genodermatoses may be required. Recognition is crucial for the initiation of the treatment for skin manifestations and detection of other extracutaneous abnormalities, including malignancy. Diagnostic accuracy and molecular diagnosis may help in providing a template for on-going management, testing and education and prognostication for families of children with genodermatoses.
Inherited monogenic palmoplantar keratodermas are a heterogeneous group of conditions characterised by persistent epidermal thickening of the palmoplantar skin. Palmoplantar keratodermas are grouped depending on the morphology of the keratoderma into diffuse, focal/striate or papular/punctate. Some palmoplantar keratodermas just affect the skin of the palms and soles and others have associated syndromic features which include changes in hair, teeth, nails, hearing loss or cardiomyopathy. Next generation sequencing has helped discover genes involved in many of these conditions and has led to reclassification of some palmoplantar keratodermas. In this review, we discuss the diagnostic features of palmoplantar keratodermas and management options.
Pachyonychia congenital (PC) is a rare genetic disorder of cornification and is classified into five types on the basis of keratin gene involved. There are no established treatment options available for PC. Sirolimus in both topical and oral form has been studied in management of PC. We report a young female with a novel genetic mutation in KRT6A gene who presented with painful palmoplantar hyperkeratosis and onychogryphosis, which was cosmetically disfiguring. She was prescribed oral sirolimus after all investigations. There was significant improvement in pain within a week. Pain relief was sustained at 1 year follow‐up with topical treatment only. Serial nail avulsion surgeries were also done with showed significant cosmetic improvement in the nails. Medical therapies can be combined with surgery for a better cosmetic outcome and improvement in patient quality of life.
Hereditäre Ichthyosen sind erbliche Verhornungsstörungen, die sich auf die gesamte Haut beziehen und durch Verdickung der Hornhaut und Schuppung gekennzeichnet sind. Pathophysiologisch gesehen handelt es sich primär um Störungen der epidermalen Barriere. Die Vielzahl der äußerst seltenen Erkrankungen zu überblicken, ist eine Herausforderung: Die Klassifikation erfolgt auf klinisch-genetischer Basis und nach nichtsyndromalen oder syndromalen Formen. Die diagnostische Abgrenzung der Ichthyosis vulgaris und der X-chromosomal-rezessiven Ichthyose von den seltenen kongenitalen Ichthyosen ist von großer praktischer Bedeutung. Zu unterscheiden sind zudem erworbene ichthyosiforme Hautzustände. In diesem Kapitel werden die faszinierenden einzelnen genetischen Störungen erklärt. Zur Schärfung des klinischen Blicks ist es mit ausführlichem Bildmaterial unterlegt. Die Therapiehinweise folgen der Maxime, dass mittels symptomatischer Therapiemaßnahmen viel für die Patienten erreicht werden kann.
Since its description in 1995, porokeratosis ptychotropica (PP) has remained a less-recognized variant of porokeratosis (PK). The term porokeratosis ptychotropica was coined in reference to its characteristic of affecting body folds. It mimics many other dermatological diseases and is therefore often misdiagnosed. We report a patient with multiple hyperkeratotic, warty lesions across the buttocks that mimicked cutaneous tuberculosis (CTB), but histological examination confirmed the correct diagnosis of PP.
Porokeratosis is a specific keratinization disorder that manifests clinically as well-demarcated annular or linear keratotic plaques of various sizes and forms and with distinguished histology showing cornoid lamella, which is a column of closely packed par-akeratotic cells extending through the stratum corneum. Nail changes secondary to porokeratotic lesions involving digits are quite uncommon and rarely reported in the porokeratosis of Mibelli (PM) subtype. Here we report the case of a young girl with a PM lesion over the hand along with nail dystrophy of the involved digit.
We evaluated a female patient with an unusual form of Naxos disease, who presented with central cyanosis and clubbing, simulating congenital heart disease. Adjuvant low-dose colchicine therapy (0.5 mg once daily) showed positive eff ects and has been continued for six months. Colchicine has anti-infl ammatory and anti-fi brotic properties. It inhibits mitosis by disrupting tubulin assembly and enhances cellular apoptosis. Follow-up showed improvement in the patient’s clinical status, with a dramatic disappearance of the electrical storm and reductions in cyanosis and palmoplantar hyperkeratosis. Low-dose colchicine may be safe and eff ective in patients with Naxos disease and may reduce related complications.
The BIDS syndrome comprises brittle hair, intellectual impairment, decreased fertility and short stature. Hair from patients with the BIDS syndrome shows disordered cuticular scales on scanning electronmicroscopy, alternate bright and dark banding on polarizing microscopy and low sulphur content. This report describes a case in which ichthyosis occurred in combination with the other features of the BIDS syndrome.
Background
Olmsted syndrome is a rare congenital disorder with mutilating palmoplantar keratoderma, periorificial keratotic plaques, and other variable features.
Objective
We describe a 65-year-old woman with Olmsted syndrome complicated by the occurrence of a malignant melanoma inside the plantar keratoderma. To our knowledge, this is the first reported case of such an occurrence in Olmsted syndrome. The published cases of this rare disorder are reviewed.
Conclusion
An association between malignant epithelial tumors and Olmsted syndrome has already been reported. The association of malignant melanoma with other types of palmoplantar keratodermas has been reported. This may suggest a predisposition to melanocytic as well as squamous cell malignancies in congenital keratodermas. Oral retinoids appear to be the most promising treatment for Olmsted syndrome and for other symptomatic keratodermas.
Background
Keratoelastoidosis marginalis is a rare disease that is a variant of solar elastosis. Long-term ultraviolet radiation exposure and chronic trauma secondary to manual labor are considered to be inciting factors.
Objective
To outline the clinical and histological features of this disorder.
Methods
We report two cases and review the literature.
Results
Both patients had persistence of their disease despite multiple topical treatment regimens.
Conclusion
Keratoelastoidosis marginalis is a chronic and progressive disease that is difficult to treat. The differential includes focal acral hyperkeratosis and acrokeratoelastoidosis.
BACKGROUND: Striated palmoplantar keratoderma or Brunauer-Fohs-Siemens syndrome is a very rare, focal, nonepidermolytic palmoplantar keratoderma with autosomal inheritance. Unlike other palmoplantar keratodermas, no association with visceral or skin cancer has ever been reported.
OBJECTIVE: We report a case of malignant melanoma arising in the hyperkeratotic lesions on the right heel of a patient with striated palmoplantar keratoderma. The lesion was completely excised; our patient also underwent sentinel lymph node biopsy and then was treated with high-dose interferon adjuvant therapy.
METHODS: Sentinel lymph node biopsy incision was made in elliptical fashion, long enough to harvest a full-thickness skin graft to cover the wide local excision defect. The skin graft was defatted by sharp dissection. Several perforations were made in graft and it was secured in place with sutures and bolster dressing.
RESULTS: At follow-up, the grafted skin showed hyperkeratotic changes but no local or systemic signs of the disease was observed.
CONCLUSION: The association between striated palmoplantar keratoderma and acral melanoma is discussed.
The inherited nature of many of the ichthyotic disorders has been clear since their original clinical recognition, and the early genetic studies of Cockayne1 and others provided some of the most conclusive examples of simple Mendelian inheritance in human disease. During subsequent years an almost universal finding in genetic disorders has been the phenomenon of genetic heterogeneity; this has proved particularly widespread in the ichthyoses, so that a considerable number of distinct inherited disorders can now be recognized, in addition to others whose separate identity is less secure. The major forms are summarized in Table 14.1. The accurate recognition of this heterogeneity is fundamental to our understanding of the underlying molecular basis of this group of conditions, particularly as their investigation is now moving from a purely descriptive phase to a study of their biochemical nature. In this paper the ways in which genetic heterogeneity may be suspected and established are outlined, together with the consequences resulting from it.
Follicular atrophoderma is a rare anomaly observed mainly in the X-dominant form of chondrodysplasia punctata (Conradi-Hunermann-Happle syndrome) and in the X-linked dominant Bazex syndrome, We report on five Emirati sibs (three girls and two boys), 4-18 years old, with normal stature, diffuse congenital ichthyosis, patchy follicular atrophoderma, generalized and diffuse non-scarring hypotrichosis, and marked hypohidrosis. Steroid sulfatase activity, assessed in the two boys, was found to be normal, Electron microscopic studies of ichthyotic skin did not show any specific abnormality, The association of congenital diffuse ichthyosis with follicular atrophoderma and hypotrichosis has not been reported before, The patients were reminiscent of Bazex syndrome; however, ichthyosis is not a component of Bazex syndrome. We conclude that this syndrome of congenital ichthyosis with follicular atrophoderma represents a new autosomal recessive genodermatosis. (C) 1998 Wiley-Liss, Inc.
Ectodermal dysplasias form a heterogeneous group of clinically and genetically distinct syndromes. The case of a 50-year-old-woman with unusual hydrotic ectodermal dysplasia (HED) of the Clouston type, associated with numerous anomalies is described. Prominent findings of the disease included diffuse hypotrichosis, with absent eyebrows and eyelashes and onychodysplasia; normal sweating and palmoplantar keratoderma. This patient also shows other anomalies including deafness, strabismus, congenital nystagmus. A pattern of minor defects includes brachydactyly, pes cavus, mallet 2(nd) toe, os tibiale externum, multiple melanocytic nevi, oligoamenorrhoea, slight mental retardation, glossitis, fibrocystic mastopathy, low stature. Keratosis palmaris et plantaris began at the age of 17 and steadily became more striated. Teeth developed normally but were affected with caries. During the last few years she developed two well differentiated keratoblastic squamous cell carcinoma on her right hand and a bilateral leukoplakia of the mouth. Her karyotipe and tumour-marker studies were normal. No hair anomalies were found under scanning electron microscopy and using X-ray microanalysis. Plasma levels of amino acid were within the normal range. In our knowledge, this is the first report of a new variant of HED distinct from previously described cases.
A 5 yr old girl is presented with a linear arranged eruption on the right leg. Clinically and histologically the lesion proved to be porokeratosis (Mibelli). Therapy with topical 5% 5 fluorouracil applied once daily has resulted in 50% resolution of the lesions in areas selected for treatment after 6 wk. Porokeratosis is probably more common than reported and consideration should be given to this disorder in the differential diagnosis of hyperkeratotic or atrophic linear lesions of childhood. Treatment with topical 5 fluorouracil may offer a new effective therapeutic approach.
• We present two cases of asymptomatic, widespread keratotic eruptions in young female patients. Clinically, the lesions are well-demarcated, small, hypopigmented, flattopped papules occurring on the trunk and extremities in a uniform distribution. Skin biopsy specimens from one patient revealed hyperorthokeratosis, papillomatosis, and a normal amount of melanin. We suggest that this is a newly recognized dermatologic entity that may be descriptively termed disseminated hypopigmented keratoses. Disseminated hypopigmented keratoses may be distinguished by clinical and histologic criteria from similar keratotic eruptions. Since the lesions of disseminated hypopigmented keratoses are both inconspicuous and asymptomatic, it is likely that the disorder is more prevalent than our two cases would suggest.
(Arch Dermatol. 1991;127:848-850)
In 1921, Fox [4] very briefly reported a case of life-long, noninflammatory skin shedding under the label “keratolysis exfoliativa congenita”. Three years later, Wile [11] described an unusual type of congenital ichthyotic erythroderma occuring in three family members. He emphasized consanguinity, peeling of areas of skin, and pruritis as cardinal features of this condition. In 1982, Levy and Goldsmith [8] reported a further case and reinvestigated one of the original patients studied by Wile. They affirmed that this disease is a distinct type of congenital ichthyosis and introduced the name “peeling-skin syndrome”. It is quite obvious that the condition Wile [11] and Levy and Goldsmith [8] delineated is different from that of Fox. Unfortunately, the designation Levy and Goldsmith chose had already been used by Kurban and Azar [7], who referred to four cases similar to those of Fox as “continual skin peeling”. In the past few years both conditions have been reported as “peeling-skin syndrome” [3, 5, 9] or as “continual peeling-skin syndrome” [1, 10]. To complicate things further, both conditions are regarded as ichthyosis, and both are probably inherited as autosomal recessive traits. Therefore, I suggest distinguishing between the peeling-skin syndrome, type A (cases similar to that of Fox) and the peeling-skin syndrome, type B (cases similar to those of Wile).
Background and Design:
Epidermolytic hyperkeratosis (EHK) is a rare autosomal dominant disorder of cornification. While different clinical presentations of EHK have been described, the distinctions have not been clear. We have examined 52 patients with EHK from 21 families in an effort to define and characterize the specific clinical features of this disorder.Results:
We found that several features were useful for separating patients with EHK into clinical groups. The most distinctive characteristic was presence vs absence of severe palmoplantar hyperkeratosis. Twenty-nine patients in six families had this finding and were grouped into ''PS types'' (those with severe palm/sole hyperkeratosis). The remaining 23 patients (from 15 families) were classified as ''NPS types'' (those without severe palm/ sole hyperkeratosis). We identified three distinct PS types and three distinct NPS types. The classification was always found to be consistent in all affected family members. In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types.Conclusions:
We were able to classify our cohort of 52 patients with EHK from 21 families into distinct types. There was a correlation between presence or absence of severe palm/sole hyperkeratosis and the specific keratin involved.(Arch Dermatol. 1994;130:1026-1035)
In 1949, the Italian dermatologist Comèl [7] from Pisa delineated a new type of congenital ichthyosis. He reported on a 23-year-old woman suffering from an ichthyosis-like dermatosis characterized by migratory, serpiginous skin lesions showing double-edged scales. Comèl recognized that this was a new skin disorder and coined the term “ichthyosis linearis circumflexa”. Nine years later, Netherton [22] described a 4-year-old girl suffering from congenital ichthyotic erythroderma and a characteristic hair shaft abnormality which he called “bamboo hair”. In 1964 Wilkinson and his associates [30] reported a similar case and introduced the term “trichorrhexis invaginata” for the peculiar hair shaft abnormality. Furthermore, they suggested that atopic diathesis is an additional symptom and referred to the association of congenital ichthyosis, trichorrhexis invaginata, and atopic diathesis as “Netherton’s syndrome”. In 1968, Schnyder and Wiegand [23] first described trichorrhexis invaginata in two patients suffering from ichthyosis linearis circumflexa. Over the next few years, it became obvious that in most cases reported as Netherton’s syndrome the ichthyosis corresponded to ichthyosis linearis circumflexa (ILC) as described by Comèl, while only a very few cases showed generalized involvement with congenital ichthyotic erythroderma (CIE) [19]. For historical reasons, I think it most appropriate to refer to the syndrome of congenital ichthyosis with trichorrhexis invaginata as the “Comèl-Netherton syndrome”. The nature of the ichthyosis in this syndrome has been the subject of a considerable debate, raising the question of whether the Comèl-Netherton syndrome is a heterogeneous condition [1, 15, 19]. We recently argued that the Comèl-Netherton syndrome can encompass a broad clinical spectrum and should be viewed as a singular disease [27, 28]. Moreover, I strongly suspect that the peeling-skin syndrome type B is identical with the Comèl-Netherton syndrome. This issue is discussed below in Sect. 6.5.4.
The various manifestations of ichthyoses are classified either by their appearance or their molecular genetics. This volume focuses on generalized, inherited disorders of cornification, which constitute an ever-enlarging group of monogenic diseases caused by a large number of genes that affect a broad array of cellular functions. The authors' overview reflects their unique perspective that the clinical phenotype in the inherited ichthyoses mirrors a 'best attempt' by a metabolically compromised epidermis to maintain a barrier sufficiently impermeable for survival in a desiccating external environment. The basis for threats to survival is illuminated, and the systemic problems, including growth failure, also reflect a compromised barrier. A new consensus classification of these disorders is provided, and the distinguishing clinical features of each disorder are described. Further, the latest molecular genetic information is succinctly reviewed with up-to-date and comprehensive references. Yet, the major emphases of this volume are on disease pathogenesis and on the identification of key ultrastructural features. This publication will prove an invaluable aid to dermatologists, pediatric dermatologists and pediatricians dealing with patients with inherited ichthyoses. In addition, clinical geneticists and dermatopathologists will find it interesting reading.
This rare condition of the hands and feet, although in the past studied chiefly by dermatologists, should interest pediatricians as well, on account of its hereditary nature and its tendency to appear in early life. Then, too, it must be considered in differential diagnosis with a number of cutaneous disorders of childhood.
First described by Krost,¹ in 1880, and by Unna.¹ in 1883, the hereditary character of this form of keratodermia was emphasized by the earliest authors. Vörner recorded its existence in four generations of one family, sixteen out of forty members being affected. Cases have been reported from time to time in Europe, North and South America and Japan. The high incidence of the disease among the natives of the small island of Meleda in the Adriatic Sea off the coast of Dalmatia led early observers in this locality to attach to it the name of mal
To the Editor.—
There have been some reports of internal malignancy associated with nonfamilial palmoplantar keratoderma of late onset,1-4 as well as of esophageal squamous cell carcinoma in association with familial keratosis palmaris et plantaris of early onset.5 We describe a patient who had developed nonfamilial, acquired diffuse palmoplantar keratoderma of late onset as a cutaneous manifestation of primary bronchial carcinoma. A review of the literature on similar cases1-4 disclosed a possible relationship between late-onset, nonfamilial palmoplantar keratoderma and intrathoracic squamous cell carcinoma.
Report of a Case.—
A 49-year-old man presented to our clinic in June 1985, with a three-month history of progressive thickening of his palms and soles. Physical examination revealed diffuse keratoderma of both palms and soles with dry, thick, and yellowish scales (Figure). Repeated microscopic examinations and cultures of scales for fungi gave negative findings. A skin biopsy specimen obtained from the palmar skin
Porokeratosis of Mibelli is an uncommon dermatosis, which may be associated with immunosuppression and may undergo malignant transformation. Due to the wide range of clinical presentations, numerous classifications have evolved, resulting in some confusion. This article examines the classification and presentation of porokeratosis and, in particular, reviews the association with immunosuppression.
Nine cases of Olmsted syndrome have been reported in the world literature. In this syndrome, keratoderma usually starts during infancy on the palms and soles when the baby starts to use the feet for walking and the hands for grasping. Within weeks or months, there is progressive spread of solid, symmetrical, thick hyperkeratotic keratoderma to both palms and soles, surrounded by erythematous margins. Contraction of fingers and deep fissuring of the feet are common complications. Symmetrical, yellow-brown hyperkeratotic plaques and papules are also observed around body orifices such as the mouth, nares, inguinal region, and perianal and gluteal areas. Other clinical manifestations have been reported, including diffuse alopecia, thin nails, leukokeratosis of the oral mucosa, onychodystrophy, hyperkeratotic linear streaks, exaggerated keratosis pilaris, and large verrucous plaques in the axillae. In the differential diagnosis, other keratoderma and hyperkeratotic syndromes should be considered.
A clinical picture of familial continual peeling of the skin is described and discussed together with light and ultramicroscopic manifestations in one of the probands. The pattern of splitting distinguishes this condition from keratolysis exfoliativa. The ultramicroscopy exhibited mainly predominance of low-density keratocytes in the corneal layer, abnormalities in distribution of lamellar granules and disrupted coating of the cells in the intercellular spaces of the corneal layer.
Palmar and plantar keratoses developed in seven patients many years after ingeston of trivalent inorganic arsenic. Six had basal cell carcinoma (superficial multicentric type in five), carcinoma "in situ" or squamous cell carcinoma of the skin. Two had systemic carcinoma--one, bilateral breast adenocarcinoma and one, carcinoma of the colon. From these observations and from the findings of a review of the literature, there seems no question that long-term arsenic ingestion can cause palmar and plantar keratoses and skin cancer, particularly basal cell carcinoma of the superficial multicentric type, usually on the torso. It is suspected but not proved to cause other cancers. Although over the last 50 years general exposure to arsenic has greatly decreased, particularly that from insecticides, this element is still found occasionally in drinking water (naturally or as a smelter byproduct), in certain foods and in cigarette smoke.
Dorfman-Chanarin syndrome is a rare, autosomal recessive inherited lipid storage disease with congenital ichthyotic erythroderma due to an acylglycerol recycling defect. Demonstration of lipid vacuoles in neutrophils from peripheral blood smears (Jordans’ anomaly) in patients with ichthyotic erythroderma leads to the diagnosis. In spite of frequent liver, muscle, ear, eye and central nervous system involvement, DorfmanChanarin syndrome may present clinically as monosymptomatic ichthyosis. Here, we report clinical and laboratory investigations in a consanguineous family from Turkey with 3 affected family members, and demonstrate the lipid vacuoles in epidermal Langerhans’ cells for the first time. Langerhans’ cell phenotyping suggests that the skin inflammation is due to the gene defect and not to underlying atopic dermatitis. Microscopic examination of eosinophils for lipid vacuoles to identify conductors revealed variable percentages of normal and vacuolized eosinophils in conductors, suggesting the microscopic analysis of at least 10 eosinophils for conductor identification.
Refsum's disease (RD) is an inherited neurological syndrome biochemically characterized by the accumulation of phytanic acid in plasma and tissues. Patients with RD are unable to degrade phytanic acid due to a deficient activity of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalysing the first step of phytanic acid α-oxidation. To enable mutation analysis of RD at the genome level, we have elucidated the genomic organization of the PHYH gene. The gene is ∼21 kb and contains nine exons and eight introns. Mutation analysis of PHYH cDNA from 22 patients with RD revealed 14 different missense mutations, a 3 bp insertion, and a 1 bp deletion, which were all confirmed at the genome level. A 111 bp deletion identified in the PHYH cDNA of several patients with RD was due to either one of two different mutations in the same splice acceptor site, which result in skipping of exon 3. Six mutations, including a large in-frame deletion and five missense mutations, were expressed in the yeast Saccharomyces cerevisiae to study their effect on PhyH activity. The results showed that all these mutations lead to an enzymatically inactive PhyH protein.
An apparently new neurocutaneous syndrome was observed in 25 members from over five generations in a family of French Canadian ethnic background. The syndrome is characterized by the appearance soon after birth, of papulosquamous erythematous plaques which have mild variations in intensity and which tend to subside during the summer months. In most cases, the cutaneous manifestations almost disappear near the age of 25, sometimes to reappear after the age of 40. At that time, a slowly progressive neurological syndrome, with decreased tendon reflexes, nystagmus, dysarthria, and severe gait ataxia, becomes the predominant feature. The syndrome is inherited in an autosomal dominant fashion.
Punctate palmoplantar keratodermas (PPKPs) are rare autosomal-dominant inherited skin diseases that are characterized by multiple hyperkeratotic plaques distributed on the palms and soles. To date, two different loci in chromosomal regions 15q22-15q24 and 8q24.13-8q24.21 have been reported. Pathogenic mutations, however, have yet to be identified. In order to elucidate the genetic cause of PPKP type Buschke-Fischer-Brauer (PPKP1), we performed exome sequencing in five affected individuals from three families, and we identified in chromosomal region 15q22.33-q23 two heterozygous nonsense mutations—c.370C>T (p.Arg124∗) and c.481C>T (p.Arg161∗)—in AAGAB in all affected individuals. Using immunoblot analysis, we showed that both mutations result in premature termination of translation and truncated protein products. Analyses of mRNA of affected individuals revealed that the disease allele is either not detectable or only detectable at low levels. To assess the consequences of the mutations in skin, we performed immunofluorescence analyses. Notably, the amount of granular staining in the keratinocytes of affected individuals was lower in the cytoplasm but higher around the nucleus than it was in the keratinocytes of control individuals. AAGAB encodes the alpha-and gamma-adaptin-binding protein p34 and might play a role in membrane traffic as a chaperone. The identification of mutations, along with the results from additional studies, defines the genetic basis of PPKP1 and provides evidence that AAGAB plays an important role in skin integrity.
Desmosomes are major cell adhesion junctions, particularly prominent in the epidermis and cardiac tissue and are important for the rigidity and strength of the cells. The desmosome consists of several proteins, of which desmoplakin is the most abundant. Here, we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy. A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity. All tested affected members of three families from Ecuador were homozygous for this mutation which produces a premature stop codon leading to a truncated desmoplakin protein missing the C domain of the tail region. Histology of the skin revealed large intercellular spaces and clustering of desmosomes at the infrequent sites of keratinocyte adhesion. Immunohistochemistry of skin from the patients showed a perinuclear localization of keratin in suprabasal keratinocytes, suggesting a collapsed intermediate filament network. This study demonstrates the importance of desmoplakin in the attachment of intermediate filaments to the desmosome. In contrast to null Desmoplakin mice which die in early development, the truncated protein due to the homozygous 7901delG mutation in humans is not embryonic lethal. This suggests that the tail domain of desmoplakin is not required for establishing tissue architecture during development.
Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features of PPK and severe periodontitis, a number of additional findings are reported in HMS including arachnodactyly, acro-osteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers. While PLS cases have been identified throughout the world, HMS has only been described among descendants of a religious isolate originally from Cochin, India. Parental consanguinity is a characteristic of many cases of both conditions. Although autosomal recessive transmission of PLS is evident, a more “complex” autosomal recessive pattern of inheritance with phenotypic influences from a closely linked modifying locus has been hypothesised for HMS. Recently, mutations of the cathepsin C gene have been identified as the underlying genetic defect in PLS. To determine if a cathepsin C mutation is also responsible for HMS, we sequenced the gene in affected and unaffected subjects from the Cochin isolate in which both the PLS and HMS phenotypes appear. Here we report identification of a mutation of cathepsin C (exon 6, 2127A→ G) that changes a highly conserved amino acid in the cathepsin C peptide. This mutation segregates with HMS in four nuclear families. Additionally, the existence of a shared common haplotype for genetic loci flanking the cathepsin C gene suggests that affected subjects descended from the Cochin isolate are homozygous for a mutation inherited “identical by descent” from a common ancestor. This finding supports simple autosomal recessive inheritance for HMS in these families. We also report a mutation of the same exon 6CTSC codon (2126C→T) in a Turkish family with classical PLS. These findings provide evidence that PLS and HMS are allelic variants of cathepsin C gene mutations.
The epidermis functions as a barrier against the environment by means of several layers of terminally differentiated, dead keratinocytes - the cornified layer, which forms the endpoint of epidermal differentiation and death. The cornified envelope replaces the plasma membrane of differentiating keratinocytes and consists of keratins that are enclosed within an insoluble amalgam of proteins, which are crosslinked by transglutaminases and surrounded by a lipid envelope. New insights into the molecular mechanisms and the physiological endpoints of cornification are increasing our understanding of the pathological defects of this unique form of programmed cell death, which is associated with barrier malfunctions and ichthyosis.
Plantar epidermis of the bovine heel pad as well as human plantar and palmar epidermis contain large amounts of an acidic (type I) keratin polypeptide (No. 9) of Mr 64,000 which so far has not been found in epidermis of other sites of the body. We present evidence for the keratinous nature of this protein, including its ability to form cytokeratin complexes and intermediate-sized filaments in vitro. We have isolated RNA from plantar epidermis of both species and show, using translation in vitro, that these polypeptides are genuine products of distinct mRNAs. Using immunofluorescence microscopy with specific antibodies against this protein, we demonstrate its location in most cells of suprabasal layers of plantar epidermis as well as in sparse keratinocytes which occur, individually or in small clusters, in upper layers of epidermis of other body locations. We conclude that cytokeratin No. 9 is characteristic of a special program of keratinocyte differentiation which during morphogenesis is expressed in most epidermal keratinocytes of soles and palms but only in a few keratinocytes at other body sites. This example of cell type-specific expression of a member of a multigene family in relation to a body site-related program of tissue differentiation raises important biological questions concerning the regulation of keratinocyte differentiation and morphogenesis as well as the function of such topological heterogeneity within a given type of tissue.
Five patients with varying severities of hyperkeratotic verrucous thickening at the skin illustrate that the condition may occasionally become elephantoid and occurs in some cases of long-standing lymphedema regardless of its cause. The morphologic term “elephantiasis” has been as sociated with the end of lymphedema, but his been used by different authors to mean different things and has, therefore, became imprecise. The noun “lymphedema” modified by the appropriate adjective is more accurate in describing these skin changes. Under the beading-“elephantiasis”–Index Medicus now states–“see lymphedema”
Olmsted syndrome is a rare disorder that consists of sharply marginated keratoderma of the palms and soles, constriction of digits and toes that may result in spontaneous amputation of the distal phalanges, hyperkeratotic plaques around the body orifices, onychodystrophy, and other less common cutaneous and extracutaneous anomalies. Although some patients had other affected family members, most cases of Olmsted syndrome seem to be of sporadic occurrence. We describe a patient with the characteristic features of Olmsted syndrome. The symptoms consisted of diffuse transgrediens palmoplantar keratoderma and keratotic plaques around the mouth and nose. Our patient also had the associated anomalies of hyperhidrosis of the palms and soles and congenital deaf-mutism. Histopathologic study of the keratoderma demonstrated epidermal hyperplasia with acanthosis, papillomatosis, and orthokeratotic hyperkeratosis.
Immunohistochemical study showed more basal and suprabasal keratinocytes of the epidermis with immunoreactivity for Ki-67 marker when compared with the keratinocytes of the epidermis of the adjacent non-involved skin. These results support the notion that Olmsted syndrome is a hyperproliferative disorder of the epidermis.
Olmsted syndrome is a rare disorder of keratinization appearing at birth or in early infancy that is characterized by the unusual association of palmoplantar keratoderma and periorificial hyperkeratosis, with possible involvement of other ectodermal derivatives.1-6 We report the second familial case, showing a progressive course unresponsive to conventional treatment.Report of a Case.
The patients are monozygotic male twins, born at term to nonconsanguineous parents, aged 29 (father) and 25 (mother) years. At 4 months of age, both children developed bilateral palmoplantar keratoderma and keratotic lesions at the external acoustic meatus. Familial history was negative for any related skin disorders.Examination at age 15 months showed symmetrical, thick, sharply marginated, and yellowish areas of hyperkeratosis affecting the plantar surface of the forefeet and of the first and fifth toes. The lesions were surrounded by an erythematous border and extended onto the lateral aspects of the toes. A periodic complete
The histopathologic features of degenerative collagenous plaques of the hands, brought out in the study of six cases, are those of senile degeneration (senile elastosis) of the skin.
Nutritional rickets has occasionally been described in children with lamellar ichthyosis, but their vitamin D endocrine status has not been described. We report 3 cases of vitamin D-deficiency rickets associated with ichthyosis in African children.
A 13-month-old Nigerian boy with lamellar ichthyosis had rib beading, elevated alkaline phosphatase, and rachitic changes on radiographs. His rickets did not resolve with calcium therapy, and his 25-hydroxyvitamin D level was low. His rickets resolved with parenteral vitamin D treatment, but his skin did not improve. Topical 0.005% calcipotriene (an analog of 1,25-dihydroxyvitamin D that has been useful in treating adults with psoriasis) was similarly ineffective in improving the child's skin condition.
An 8-year-old Nigerian boy with life-long skin findings consistent with lamellar ichthyosis had windswept deformity of the legs with rib beading and enlargement of the wrists and ankles. Radiographs showed active rickets, and the boy had an elevated alkaline phosphatase level and a decreased calcium level. Before knowing that his 25-hydroxyvitamin D level was low, he was treated with calcium and showed radiologic improvement. The skin did not improve with resolution of the rickets but did improve with unilateral topical application of 0.005% calcipotriene.
A 7-year-old South African girl presented with progressive windswept deformities of the legs and a 4-year history of skin disease (and a skin biopsy consistent with X-linked ichthyosis). Radiographs and biochemical data confirmed active rickets. Her rickets improved dramatically with vitamin D treatment.
Thus, 3 African children with ichthyosis developed vitamin D-deficiency rickets, probably because of a combination of impaired skin production and sunlight avoidance. This is consistent with previous findings of hypovitaminosis D in adults with ichthyosis and other disorders of keratinization. Measurement of 25-hydroxyvitamin D may be indicated in children with ichthyosis to identify those at risk for vitamin D-deficiency rickets, because it is possible that the cutaneous synthesis of vitamin D in such children is impaired.
Although the ichthyosis did not improve with resolution of vitamin D deficiency and rickets, 1 of 2 children treated with topical calcipotriene showed improvement in the treated areas of skin. Calcipotriene does not seem to be effective in reversing systemic vitamin D deficiency but can be effective in improving the severity of skin disease in children with ichthyosis.
This report describes the clinical and pathologic features of a series of patients we have observed with linear, firm plaques of the medial and lateral aspects of the hands. Five illustrative cases are presented. The lesions are bilateral and symmetrical and are situated at the juncture of the palmar and dorsal skin. Histologically, the process is characterized by a rather distinctive deposition of dense collagen and elastic tissue, involving most of the reticular dermis but usually sparing the papillary dermis and subcutis.
The condition is chronic, essentially asymptomatic, and slowly progressive. Our patients could not date the exact onset of their lesions but had noticed slow development over a 5- to 15-year period. The only symptom mentioned by any of the patients has been stiffness resulting from advanced involvement of the flexor creases. In the fully developed case, both hands are symmetrically involved. A firm plaque extends from near the
This rare condition has been previously described in Japan. The disease is manifested by strictly circular scaly brownish patches, darker or lighter than the surrounding skin, of variable number and diameter. This report is the first in the United Arab Republic, North Africa, and the Middle East areas. It is not related to any diagnosable internal disorder. The surrounding ichthyotic skin, freedom of flexures, winter exacerbations and summer remissions, and the histopathologic picture support the idea that this disease is a special type of acquired ichthyosis.
We report a missense mutation in the connexin 26 gene (GJB2) in a family with an autosomal dominant syndrome of hearing loss and hyperkeratosis. The affected family members have high frequency, slowly progressive, bilateral, sensorineural hearing loss and palmoplantar hyperkeratosis. The mutation causes an amino acid substitution (G59A), which may disrupt a reverse turn in the first extracellular loop of connexin 26. Connexin 26 mutations have been reported in syndromes of deafness and palmoplantar keratoderma. These data provide additional evidence for the role of connexin 26 in syndromes of this type.
Apart from nonspecific inflammatory markers and a persistently high leukocyte count, the main laboratory abnormalities were secondary electrolyte disorders, with severe hypernatremia (sodium, >160 mmol/L) without complications in 9 cases, or with major hypoalbuminemia (< 30 g/L) in 3 cases (Table 3). The eosinophil count was high (>0.5 × 10⁹/L) in 28 cases (55%), and the IgE level was elevated in 22 cases (59%) (Table 3). Laboratory tests of cellular and humoral immune functions were carried out in 35 patients (68%), demonstrating abnormalities in 18 cases. An immunodeficiency disease was identified in 15 cases, including 7 cases of Omenn syndrome, 1 case of severe combined immunodeficiency, 5 cases of graft-vs-host disease, 1 case of IgA deficiency, and 1 case of Wiskott-Aldrich syndrome (Table 1). In 3 cases of atopic dermatitis, moderate abnormalities were noted: 1 demonstrated transient lymphopenia with a reversed CD4/CD8 ratio, and the other 2 showed low levels of IgA and IgG, respectively. After several immune function tests, the results of which were considered normal, 1 of the 5 patients with no diagnosis developed severe CD3 lymphopenia (CD3, 10%) and 1 developed CD8 lymphopenia (CD8, 4%). Reduction of the activity of the fatty oxidoreductase enzyme was found in 2 patients, both of whom had a typical evolution of Sjögren-Larsson syndrome with spastic paraplegia. No other metabolic abnormalities were noted.