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[18]

ichthyosis of variable severity, often accompanied by PPK (Fig. 1B).

Skin pathology: In contrast with most ichthyoses, histopathological features of EHK are distinctive and include orthohyperkeratosis, hypergranulosis, and vacuolar degeneration confined to the upper epidermal layers. Electron microscopical examination demonstrates an increased number of clumped tonofilaments located at the periphery of suprabasal cells and poorly attached to plasma membrane desmosomes.

Molecular genetics: EHK results from mutations in K1 or K10, which are expressed in the suprabasal layers of the epidermis. As for other keratin disorders, most EHK-causing mutations affect conserved amino acid residues located at both ends of the central K1/K10 rod segment and result in aberrant KIF formation, leading to perinatal skin blistering.[2,20] Mutations in K1 or K10 genes also interfere with normal epidermal outer barrier formation, causing subsequent hyperkeratosis. Epidermolytic PPK

results from mutations in K9, a type I keratin that is specifically expressed in palmoplantar skin.[2] K9 may compensate for K10 abnormal function, explaining the fact that PPK in EHK is strongly associated with K1, but not with K10 mutations.[27] In addition, marked interfamilial and intrafamilial variations in phenotypic expression of K1/K10 mutations are typical.[27] Somatic mutations in K10 have been identified in individuals with epidermolytic epidermal nevi, manifesting with a mosaic distribution of hyperkeratotic lesions. Affected individuals are at risk for children affected with EHK; therefore, they qualify for prenatal diagnosis.[2] Finally, mutations affecting the nonhelical end domains of K1 have been shown to underlie a number of phenotypically distinct clinical entities. The pathophysiology of this group of disorders is likely to involve aberrant interactions between KIF and desmosomes.[20,22]

Differential diagnosis: Congenital ichthyosiform erythroderma (MIM242100) is characterized by erythroderma

Fig. 2 Clinical spectrum of keratin disorders. (a) Skin blister in a 1-month-old girl with EBS Dowling-Meara type. (b) Palmar hyperkeratosis in a 26-year-old individual with EHK. (c) Multiple steatocystomas and (d) nail dystrophy in a 25-year-old patient with PC-2.

and scaling at birth; however, blistering is absent and inheritance is recessive. In contrast, EBS manifests with blistering, but hyperkeratosis is usually absent. Ichthyosis bullosa of Siemens (IBS) is caused by mutations in K2e.[2] Affected individuals display mild scaling in the flexural areas, over the shins and elbows, as well as a superficial form of skin peeling, known as mauserung phenomenon. Intraepidermal separation and tonofilament clumping occur in a layer higher than that in EHK—within the granular layer.

Management: Conservative treatment measures such as lubrication, wound dressing, management of skin infections, and nutritional support are essential, especially during the first years. Satisfactory response to retinoids has been reported more often in carriers of K10 mutations than in carriers of K1 mutations.[28]

Suspected Keratin Disorder

Histology/Electron microscopy

— Screen HIM and HTM-encoding regions

Screen entire coding regions i

Confirmatory test (restriction fragment analysis, sub-cloned allele sequencing, allele-specific PCR)

Exclusion of novel mutations from a control DNA panel

Fig. 3 Diagnostic strategy for identification of mutations in keratin genes.

Fig. 4 Methods in use for prenatal testing of pregnancies at risk for keratin disorders.

ther, combined features of PC-1 and PC-2 have recently been shown to result from a deleterious mutation in K6a.[30]

Differential diagnosis: PC differential diagnosis includes toenail dermatophytic infection; psoriasis; lichen planus; dyskeratosis congenita (MIM305000), characterized by hypoplasia of the nails, oral leukokeratosis, hyperpigmentation, and hematological abnormalities; and hidrotic ectodermal dysplasia (MIM129500), manifesting with congenital nail dysplasia and focal PPK.

Management: Treatment is mainly symptomatic and involves the use of emollients or keratolytics to treat the PPK. Retinoids have been found useful in some patients. When hand or foot function is compromised by nail disease, nail matrix ablation can be considered.

Monilethrix

NAIL, HAIR, AND MUCOSAL DISORDERS Pachyonychia Congenita

Inheritance: Autosomal dominant.

Clinical description: Pachyonychia congenita (PC) type I or Jadassohn-Levandowsky syndrome (PC-1) is characterized by subungual hyperkeratosis, resulting in nail thickening and yellowish discoloration, accompanied by focal PPK, follicular hyperkeratosis, and oral leuker-atosis. In contrast, PC-2, also known as Jackson-Lawler syndrome, is accompanied by less severe nail dystrophy and milder keratoderma, and is distinguished by the presence of multiple steatocystomas, a history of neonatal teeth, and the occasional occurrence of pili torti and/or alopecia (Fig. 2c-d). Additional variants with corneal leukokeratosis (PC-3) and laryngeal lesions with mental retardation (PC-4) have been described.[2]

Molecular genetics: PC-1 is caused by mutations in K6a or K16 keratin genes, whereas PC-2 results from mutations in K6b or K17 keratin genes.[2] The pattern of expression of these two pairs of keratin underlies the specific clinical manifestations of the two PC subtypes: K6a/K16 are expressed in the nail bed and nail fold as well as in palmoplantar skin and oral mucosa; K6b/K17 are found in the nail bed, hair follicle, and selected areas of palmoplantar skin. Although most PC-causing mutations are located at both ends of the keratin central rod segment, a somatic mutation in the head domain of K16 was recently shown to cause a mosaic form of PPK.[29]

Phenotypic heterogeneity is typical of PC. Mutations in K16 have been shown to underlie keratoderma in the absence of nail changes, and mutations in K17 have been shown to cause steatocystoma multiplex with no other PC-2 manifestations.1-2-1 To complicate the picture even fur-

Inheritance: Autosomal dominant.

Clinical description: Monilethrix is characterized by the beaded appearance of hair shafts due to alternating elliptical wide (nodes) and narrow (internodes) hair segments. Hairs tend to break at the constricted sites, resulting in varying degrees of alopecia. Abnormal hair may be visible at birth or, more often, appears during the first months of life. Marked improvement is usual after puberty. Interfamilial and intrafamilial variations in disease severity have been observed.[31] In addition, patients may display additional cutaneous anomalies including follicular hyperkeratosis, and nail and tooth abnormalities.1-2-1

Molecular genetics: Pathogenic mutations have been identified in hair cortex keratin genes, hHb6 and hHb1.[2] As for most other keratin disorders, mutations are clustered at the ends of the central a-helical rod.

Differential diagnosis: Monilethrix hair has been observed in Menkes syndrome (MIM309400), an X-linked disorder characterized by neurological and hair manifestations due to deleterious mutations in the ATPA7A gene, encoding a copper-binding protein.[32] Abnormal posttranslational processing of keratin molecules due to intracellular copper deficiency may explain the occurrence of beaded hair in Menkes syndrome. Pseudo-monilethrix (MIM177750) is characterized, in contrast with monilethrix, by irregularly spaced nodes with narrow internodes representing normal hair shafts.

Management: Spontaneous improvement is frequent.

White Sponge Nevus

Inheritance: Autosomal dominant.

Clinical description: Buccal involvement is most common, although the disease also manifests in other noncornified stratified squamous epithelia, including the esophagus, nose, vagina, and rectum. Clinically, white, spongy plaques cover involved areas as a result of massive mucosal overgrowth.

Molecular genetics: The disorder is caused by mutations in two keratin genes, K4 and K13, specifically expressed in mucosal tissues.[2]

Differential diagnosis: White sponge nevus may be confused with PC-1, Darier disease (MIM124200), dyskeratosis congenita, oral lichen planus, lupus eryth-ematosus, candidiasis, and precancerous leukoplakia and oral florid papillomatosis.

Management: Antibiotics, including topical tetracy-clines, have been shown to provide significant improvement. In most cases, no treatment is necessary.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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