Nail changes in genodermatoses

ARTICLE

Diseases of the nails can be inherited or acquired, local or systemic. Congenital and/or hereditary abnormalities of the nails may be isolated or more often combined with developmental changes of other organs, especially the skin, the skeletal system, the teeth and the central nervous system. In many cases of ectodermal and/or mesodermal disorders the developmental anomalies of the other organs predominate those of the nails. But sometimes nail changes are the initial presentation and the clue to the diagnosis of a hidden systemic disorder or a syndrome. Considering that approximately 10% of dermatologic patients have nail alterations [1, 2], this article aims to show the most common and most important nail changes in genodermatoses and draw the physician's attention to a careful clinical inspection of the nail apparatus.

The most common cause of nail abnormalities is a defect in the nail matrix. The matrix can have an abnormal form, position or function. In some nail disorders nail matrix and nail bed are involved and the disorder is then called nail field defect [3]. Such defects may result in alterations of the nail plate relief, consistence, form and color [4].

Anatomy and physiology of the nail apparatus

The nail apparatus consists of the nail plate with the lunula, the nail matrix, the nail bed, the lateral and proximal nail folds with the cuticle and the hyponychium. The close spatial relationship of the nail unit to the underlying bone of the distal phalanx with the dermis of the nailbed closely attached to the periosteum of the distal phalanx leads to the frequent concurrence of nail changes and bone alterations. The nails serve for protection of the distal phalanx, they enhance the tactile capacity and deftness and not least they are of high cosmetic significance.

The nail plate is a keratinized structure which is continuously growing throughout life. The nail plate results from maturation and keratinization of the nail matrix epithelium [5]. It is closely attached to the nail bed which contributes partially to its formation [6, 7]. The nail growth, depending on the age of the individual, the vascular and neurologic supply, the mechanical demand and the nutrition, is about 0.5-1.2 mm a week for the fingernails and 0.2-0.5 mm for the toenails. The complete replacement of a fingernail requires therefore about 6 months, the replacement of a toenail 12-18 months. For these reasons injuries to the nail matrix become apparent only after a considerable delay. The thickness of the nail plate increases with age. The mean thickness at the distal part of fingernails is approximately 0.5 mm and of toenails 1.5 mm. The nail thickens from the central lunula to the distal margin of the lunula and to the distal free edge of the nail [6]. Thinning of the nail plate is usually a sign of a nail matrix disorder, nail thickening a sign of a nail bed disorder [5]. The nail plate consists of a dorsal, an intermediate and a ventral portion. The dorsal and the intermediate portion are produced by the nail matrix, the ventral portion by the nail bed [6, 8]. The nail plate is proximally and laterally surrounded by the nail folds. The proximal nail fold overlies the proximal part of the nail matrix and is continous with the horny cuticle. The cuticle is an important anatomic barrier that protects the space between the proximal nail fold and the nail plate. The dermis of the proximal nail fold contains numerous capillaries which are easily visible by capillary microscopy. The arterious and the venous limbs of the capillaries run in parallel rows forming loops, typically altered in collagenoses. The lunula is the visible halfmoon portion of the nail matrix. In this area the nail plate is only loosely attached to the underlying tissue and therefore the lunula appears whitish in contrast to the firmly attached nail plate which appears pink. Above the lunula the nail plate consists only of the dorsal and the intermediate portion. At the tip of the digit the nail plate separates from the nail bed at the hyponychium. The nail bed is highly vascular, supplied by the two lateral digital arteries. The epidermis and the dermis of the nail bed are arranged in longitudinal ridges and grooves extending from the lunula to the hyponychium. Fine capillaries run in these parallel ridges and explain the linear pattern of splinter hemorrhages. The nail bed is rich in glomus bodies, neurovascular structures containing arteriovenous anastomoses and nerve endings, responsible for the temperature dependent regulation of blood supply. Melanin is usually not present in the nail matrix nor in the nail bed. But trauma to the proximal nail fold may activate the melanocytes and result in transient pigmented longitudinal bands especially in dark skinned people.

Biochemical properties of the nail plate

The nail plate consists of low sulphur keratins embedded in an amorphous interfilamentous matrix of high sulphur proteins and high glycine/tyrosine proteins [9]. Keratins are intermediate filamentous proteins with a 7-11 nm diameter [10]. Intermediate filament proteins consist of a structurally conserved alpha-helical rod domain flanked by tissue-specific non-helical head and tail domains. Keratins form the cytoskeleton of epithelial cells. The major function of keratin filaments in the nail is to impart mechanical stability to make the nail plate resistent to trauma and physical stress. Keratins are grouped into acidic proteins (type I keratins) and basic proteins (type II keratins) and are expressed as obligate heterodimers of specific type I and type II keratin pairs [11]. Mutations in either protein of a keratin expression pair may lead to very similar disease phenotypes [12]. The epithelial keratins K9-K20 and the hair keratins Ha1-Ha5 and HRa1 are acidic type I keratins. The epithelial keratins K1-K8 and the hair keratins Hb1, Hb3, Hb5 and Hb6 are basic type II keratins. Type I keratin genes are clustered on chromosome 17 while type II keratin genes are located on chromosome 12 [13]. Different keratin pairs are found in different epithelial tissues and in different stages of development [14]. Nail keratins consist of 80-90% hard "hair-type'' keratins and 10-20% soft "epithelial-type'' keratins. In nail material Heid et al. [15] identified 8 major trichocytic hard cytokeratins Ha1-4 and Hb1-4 together with 2 minor cytokeratin polypeptides Hax and Hbx. In addition to the hard keratins they isolated significant amounts of the epithelial keratins K5, K6, K14, K16 and K17 from the nail apparatus. Moreover they localized epithelial cytokeratin K19 in suprabasally located cells of the nail bed and the nail fold in fetal fingernails. De Berker et al. [14] detected K1 and K10 on both the ventral and dorsal aspect of the nail fold, on the digit pulp and to a lesser extent in the nail matrix, but not in the nail bed. Keratin 17 is remarkable since it is normally expressed in the basal cells of complex epithelia as in the nail bed, hair follicle, sebacous glands and eccrine sweat glands, but not in stratified or simple epithelia. K17-positive keratinocytes are also located at the base of primary epidermal ridges of palmoplantar epidermis [16]. K6b (type II keratin) is the expression partner of K17 (type I keratin). Keratin 6a (type II keratin) forms a keratin pair with K16 (type I keratin). Keratins K6a/K16 are expressed in palmoplantar skin [16], oral mucosa and epidermal appendages including the nail bed, the proximal nail fold and the digit pulp [14, 17]. Keratins K6, K16 and K17 are typically expressed in hyperproliferative epidermis as in psoriasis or wound healing [18].

Further nail constituents are water, lipids and minerals. The normal water content of the nail plate varies at around 18%. The lipid content of the nail plate is 0.1-1%, the main lipid being cholesterol. Traces of minerals such as calcium, iron, aluminium, copper and sulphur can be identified in the nail plate. They do not seem to contribute to the hardness of the nail plate.

Nail embryology

The human nail apparatus starts to develop in the 9th week of gestation and is completed by the 20th week of intrauterine life [9, 19]. Congenital nail defects occurring in this time period are called embryopathies, those appearing after the 20th week of gestation are called fetopathies. Embryopathies are often inherited, while fetopathies are usually caused by vascular and/or mechanical injuries [9]. Some of these defects become apparent only later in life because of the increased susceptibility of the abnormal nail to trauma and infection. A further group of the inherited nail changes appearing after birth develops secondary to an inherited ectodermal disorder.

At 10 weeks the nail field becomes visible, a rectangular area overlying the dorsal tip of the terminal digit, the area in which the entire nail apparatus will develop. The nail field is delineated by a continous shallow proximal, lateral and distal groove [9, 19]. Immediately proximally to the distal groove the distal ridge develops and will later become the hyponychium. The distal groove will later disappear. The nail matrix grows at the proximal part of the nail field by a wedge of germinative epithelial cells extending downward and proximally into the dermis. At 11 weeks the proximal and lateral nail folds have emerged. The area between distal ridge, lateral nail folds and the nail matrix will become the nail bed. At the same time the nail bed begins to keratinize from the distal ridge. At 14 weeks the whole nail bed has developed a granular layer. The nail plate, an accumulation of flattened keratinocytes, emerges from the nail matrix beneath the proximal nail fold and grows distally. The granular layer of the nail bed gradually disappears and keratinocytes of the nail bed are integrated into the underside of the nail plate. At 17 weeks the nail plate covers most of the nail bed and at 22 weeks it grows over the distal ridge, now called the hyponychium [3].

Embryologic development of nails may be subjected to homeobox genes, transcription factors highly conserved in evolution, crucial for adult eukariotic cell function and human diseases [20]. Proper limb growth and patterning requires signals from the zone of polarizing activity (ZPA) in the posterior mesoderm, from the overlying apical ectodermal ridge (AER) [21] and from the dorsal limb ectoderm [22]. ZPA controls limb patterning across the anterior-posterior axis via the Sonic hedgehog gene (Shh). Shh (MIM 600725) as a homeobox gene is the molecule responsible for the morphogenetic properties of the ZPA. So Shh is required for early limb development, for anterior-posterior limb patterning and for distal limb outgrowth. Shh binds to the transmembrane receptor protein Patched-1 (MIM 6012309) and Patched-2 (MIM 603673). Patched-1 and Patched-2 interact via another transmembrane protein, Smoothened (MIM 601500), with Gli-signaling [23]. Mutations in the Sonic hedgehog-patched-gli-pathway (Shh-Ptch-Gli) are implicated in several human birth defects and cancers. Dysregulation of this signaling cascade may also affect development of nails as in Smith-Lemli-Opitz-syndrome (#MIM 270400), Greig syndrome (#MIM 175700), Pallister-Hall-syndrome (#MIM 146510), postaxial and preaxial polydactyly (#MIM 174200 and 172700) or Rubinstein-Taybi-syndrome (#MIM 180849) [23].

Congenital and hereditary nail disorders

Nail changes may be the earliest signs by which a hereditary ectodermal syndrome can be recognized. Telfer et al. [3] proposed a simplistic but useful classification of congenital and hereditary nail disorders based on embryologic and pathophysiologic considerations. They distinguished between nail matrix defects, nail field defects, nail bed defects and combined ectodermal-mesodermal defects. It would be impossible and beyond the scope of this article to discuss each known congenital and hereditary nail disorder. We will summarize selected nail diseases in Table I based on the classical classification of Telfer et al. [3]. We will then try to explain the embryology of nail disorders by representative disorders from each group, disorders with known genetic background.

Nail-Patella Syndrome (NPS), Hereditary osteo-onychodysplasia (HOOD), Turner-Kieser syndrome (#MIM 161200)

Anonychia/Hyponychia - change in matrix size

NPS is an autosomal dominant disorder characterized by dysplasia of nails, patellae and elbow joints, exostoses of iliac crest, and, in some cases nephropathy.

NPS is the best-known syndrome where nails may be absent. Nails are abnormal from birth. In 98% of patients fingernails may be absent or hypoplastic, fragile, split and longitudinally ridged. Triangular or V-shaped lunules are particularly characteristic. The nail abnormalities are most severe on the ulnar side of the thumbs, decreasing to the little finger [24]. Toenails are rarely involved [25].

Absence or hypoplasia with luxation of the patellae is an essential feature of the syndrome. Deformation with (sub)luxation of the head of the radius and defects of the humerus may result in impaired mobility of the elbow with decreased extension and pronation/supination. Iliac horns, exostoses of the iliac crests, present in 70% of patients, are pathognomonic for NPS. Digital, popliteal and antecubital webs have been reported [25].

The most serious feature of NPS, nephropathy, is described in 40 to 60% of cases [26, 27]. Nephropathy manifests with chronic benign proteinuria. In 15% patients will develop end-stage renal failure [27, 28]. Ultrastructurally, glomeruli show irregular thickening of the glomerular basement membrane (GBM), inappropriate deposition of fibrillar collagen within the GBM and the mesangium and fused podocyte foot processes [26-29]. In the mouse model Morello et al. [28] showed that the renal pathology is in part due to dysregulation of GBM-specific alpha3(IV) and alpha4(IV) collagen.

Other abnormalities occasionally seen are heterochromia of the iris with hyperpigmentation of the papillary margin, glaucoma [30], palmoplantar hyperhidrosis and various bone abnormalities such as thickened scapulae, dislocated hips, pes equinovarus and scoliosis [24, 31].

The gene for NPS has been mapped to the long arm of chromosome 9 by the establishment of linkage of NPS to the AB0 blood group and the adenylate kinase 1 gene. Campeau et al. [32] localized the NPS gene to an interval on 9q34.1. This was confirmed and refined later by McIntosh et al. [33]. In 1998 Chen et al. [34] demonstrated an essential function for the LIM-homeodomain protein Lmx1b in mouse limb and kidney development. Mice ablated for Lmx1b exhibited hypoplastic nails and the skeletal and renal pathology of NPS patients. At the same time Dreyer et al. [35] showed that LMX1B maps to 9q34 and that NPS is the result of mutations within the LMX1B gene. Lmx1b encodes a LIM homeodomain transcription factor and plays a central role in dorso-ventral patterning of the vertebrate limb [36]. Vollrath et al. [37] demonstrated mutations of LMX1B in 4 families with combined NPS and open angle glaucoma. Morello et al. [28] showed that LMX1B directly regulates expression of alpha3(IV) and alpha4(IV) collagen required for normal GBM morphogenesis and that its dysregulation contributes to the renal pathology in NPS. These findings indicate that the observed skeletal, renal and ophthalmic abnormalities in NPS result from mutations in a single gene, LMX1B.

Trichorhinophalangeal syndrome (TRPS)

Hypoplastic nails - change in nail matrix size

Trichorhinophalangeal syndrome (TRPS), first described by Giedion in 1966 [38], is characterized by the triad of fine, sparse, slowly growing scalp hair, a pear-shaped bulbous nose, and brachyphalangia with radiologically cone-shaped epiphyses of hands and feet (Fig. 1). Nails have been described as dystrophic, hypoplastic, brittle, slow-growing, koilonychotic and leuconychotic [39, 40]. Many other clinical features have been reported in patients with TRPS [39-42]. Three subtypes with considerable clinical overlap can be distinguished:

Type I (TRPS1) (#MIM 190350)

Type I may, in addition to the above mentioned characteristics, feature moderate postnatal growth retardation, occasionally mental retardation [43] and moderate brachydactyly with shortened phalanges and metacarpals [44, 45]. Eyebrows are generally sparse or may be medially thick and laterally thin [46]. Type I is inherited in an autosomal dominant pattern [45]. Several sporadic and rare recessive cases have been reported. In 1986 Fryns and Van den Berghe [47] presented for the first time a small interstitial 8q24.12 deletion in a patient with TRPS1.

Type II (TRPS2) Langer-Giedion syndrome (LGS) (#MIM 150230)

Type II is characterized by the presence of multiple cartilaginous exostoses which clearly distinguishes it from type I and type III [48]. Mental retardation and microcephaly are typical features of TRPS2. Eyebrows are generally thick, broad and bushy [48]. Redundant and loose skin in infancy, disappearing during childhood, has been reported in TRPS2 [46]. Moderate growth retardation and mild brachydactyly may be present. Inheritance is most often sporadic. Chromosomal deletions extend from 8q22.2 to 8q24.2 [49]. In a patient with multiple exostoses Hou et al. [50] found a deletion overlapping the distal end of the LGS deletion region. A patient with TRPS1 was found to have a chromosome 8 breakpoint just at the proximal end point of the LGS deletion region, so that Hou et al. hypothesized that Langer-Giedion syndrome is a true contigous gene syndrome due to loss of functional copies of both the genes for TRPS I and for the Hereditary Multiple Exostoses (EXT1).

Type III (TRPS3) Sugio-Kajii syndrome (#MIM 190351)

TRPS3 is the rarest form. It is characterized by marked short stature, severe brachydacytyly due to shortening of phalanges and metacarpals and pronounced cone-shaped epiphyses. Eyebrows are normal. Exostoses and mental deficiency are absent. Inheritance is autosomal dominant [41, 51]. Sporadic cases have been reported [24]. Ludecke et al. [52] performed extensive mutation analysis and concluded that TRPS3 is at the severe end of the TRPS spectrum and that TRPS3 is caused by a mutation in the TRPS1 gene.

Rubinstein-Taybi syndrome (RSTS) (#MIM 180849)

Broad nails - change in nail matrix size/form

RSTS originally described in 1963 by Rubinstein and Taybi [53] is now a well defined complex of multiple congenital anomalies with mental retardation. In 1990 Rubinstein [54] reviewed 571 patients with RSTS and defined as major diagnostic criteria broad short terminal phalanges of the thumbs and halluces, a characteristic facial appearance with beaked or straight nose, antimongoloid slant of palpebral fissures, hypertelorism and grimacing smile, stature and head circumference below the 50th percentile, mental, motor, social and language retardation, stiff awkward gait and incomplete or delayed descent of testes in males (Fig. 2). Many other facial abnormalities have been associated with RSTS such as epicanthic folds, ptosis, heavy arched eyebrows, long eyelashes, frontal bossing, broad nasal bridge, nasal septum below alae, small-appearing mouth, high arched palate, micro- and retrognathia, ear abnormalities and puffy face in infancy [55-57].

On the hands and feet broad and radially deviated thumbs, broad terminal phalanges of other fingers, broad halluces with or without varus/valgus angulation with broad and sometimes duplicated nails, polydactyly, syndactyly and clinodactyly, have been found in RSTS [54].

Additional characteristics are congenital heart defects including atrial and ventricular septal defects, patent ductus arteriosus, coarctation of the aorta, pulmonic stenosis, mitral valve regurgitation and bicuspid aortic valve [58]; orthopaedic problems such as scoliosis, kyphosis, sternal changes and joint laxity [54]; ocular anomalies as strabismus, coloboma, congenital glaucoma and cataracts; neurological anomalies as hypotonia and seizures; dermatological anomalies as dermatoglyphic changes, keloid formation, hypertrichosis, port-wine stains and epidermal nevus [59]; dental changes [60]; kidney abnormalities; recurrent respiratory infections [55, 56], and increased risk of tumors. Miller and Rubinstein [61] reviewed the tumors occurring in 724 patients with RSTS and found a pattern of neural and developmental tumors, especially of the head, among others oligodendrogliomas, medulloblastomas, neuroblastomas [62], meningeomas, pilomatricomas and nasopharyngeal rhabdomyosarcomas.

A breakthrough in the search for a specific gene locus for RSTS occurred in 1991 with the detection of chromosomal translocations and inversions involving chromosome band 16p13.3 [63-65]. Subsequently submicroscopic deletions within 16p13.3 could be identified as the cause for RSTS [55, 66, 67]. In 1995 Petrji et al. [68] found that all the breakpoints reported in patients with RSTS are restricted to a region that contains the gene for the human CREB binding protein (CREBBP or CBP), a ubiquitously expressed nuclear protein participating as a transcriptional coactivator in cyclic-AMP-regulated gene expression. CBP is central to a variety of signal transduction pathways regulating the expression of many genes. Petrij et al. [69] recently analyzed CBP in 194 RSTS patients and found only 20% CBP mutations in this large series suggesting that mutations in other genes might also play a role in the etiology of RSTS.

X-Linked dyskeratosis congenita (DC), Zinsser-Cole-Engman syndrome (#MIM 305000)

Change in nail matrix function

X-linked recessive dyskeratosis congenita is a genodermatosis characterized by the triad of reticulated skin hyper- and hypopigmentation, nail dystrophy and mucosal leukoplakia (Fig. 3). Bone marrow failure, predisposition to malignancy, and pulmonary complications are causes for early mortality of DC patients. Systemic findings may additionally involve eyes, teeth, bones, central nervous system, genitourinary and gastrointestinal tract.

The mucocutaneous features, skin pigmentation, nail changes and leukoplakia usually appear first, between the ages of 5 and 10 years [70, 71]. The reticulate skin pigmentation commonly affects the upper trunk, neck, shoulders and thighs. It typically shows a tan-gray hue with telangiectasias and atrophy. Additional skin findings include hyperkeratosis, hyperhidrosis and trauma-induced bullae of the palms and soles. Nail changes are progressive and range from pitting, ridging, fissuring, thinning, splitting and pterygia formation to complete nail loss [72]. Nonscarring diffuse alopecia with premature greying and sparse eyelashes have been observed [73]. Leukoplakia occurs in 78% [70] and is seen most commonly on the oral mucous membranes, but can also be found on the genital, urethral, anal and conjunctival mucosa. These leukoplakias may progress to invasive squamous cell carcinoma.

Bone marrow failure and complications of its treatment are the principal causes of early mortality. 67% of deaths are due to pancytopenia-induced opportunistic infections or bleeding [70]. Cytopenia of one or more lineages are described in 83 to 93% of cases [70, 71], 76% having pancytopenia, in most cases before the age of 20 years [70]. There is a predisposition for DC patients to myelodysplasia and acute myeloid leukemia. Other reported malignancies are carcinomas of the bronchus, colon, larynx, oesophagus, pancreas, skin and tongue and Hodgkin's lymphoma [70]. Eye findings include blepharitis, conjunctivitis, ectropion, and epiphora secondary to lacrimal duct obstruction. Dental abnormalities include alveolar bone loss, periodontal disease and dental caries. Mild mental retardation is reported in up to 25% of patients. Pulmonary disease with reduced diffusion capacity and/or restrictive disease is seen in 20%. Skeletal manifestations consist of osteoporosis, aseptic necrosis and abnormal bone trabeculation. Genito-urinary abnormalities include urethral strictures, phimosis, hypogonadism and undescended testes. Gastrointestinal fndings are oesophageal strictures and liver cirrhosis.

The gene locus has been mapped to chromosome Xq28 [74, 75]. Dokal et al. [76] showed that primary skin fibroblast cultures were abnormal both in morphology and in growth rate. The finding of unbalanced chromosomal re-arrangements in the peripheral blood, the bone marrow and fibroblasts in the absence of any clastogenic effects has led them to conclude that DC is a chromosomal instability disorder [76]. Knight et al. [75] further refined the DKC1 locus on Xq28. Several authors observed skewed X-inactivation patterns in female carriers of DC families [77-79]. Heiss et al. [80] identified the gene responsible for X-linked DC. He designated the gene and the corresponding protein DKC1 respectively dyskerin. Both DKC1 transcript and dyskerin are highly conserved in eukaryotes and prokaryotes. Studies of the rat and yeast orhologue led them to suggest that DKC1 encodes a multifunctional protein involved in rRNA biosynthesis, ribosomal subunit assembly and centromer/microtubule binding. Knight et al. [81] found mutations in DKC1 in two families with Hoyeraal-Hreidarsson syndrome (HH), a multisystem disorder characterized by aplastic anemia, immunodeficiency, microcephaly, cerebellar hypoplasia and growth retardation, and demonstrated with this finding that HH is a severe variant of DC. Mitchell et al. [82] showed that DC is rather caused by a defect in the maintenance of telomeres, the repeat DNA sequences at the ends of chromosomes. They showed that DC cells have a lower level of telomerase RNA, produce lower levels of telomerase activity and have shorter telomeres then matched normal cells, which may limit the proliferative capacity of human somatic cells. Telomerase activity is normally present in the cells of the early mammalian embryo, in germ line cells, in proliferating stem cells like those of the hematopoetic system and in cancer cells [83]. The hallmarks of DC, epithelial abnormalities and deficiencies of the hematopoetic stemm cells, defects in highly proliferative tissues, could be a consequence of a telomere maintenance disorder.

Pachyonychia congenita (PC)

Hypertrophic nails - nail field defect

PC is a group of autosomal dominant inherited disorders characterized by symmetrical hypertrophic nail dystrophy associated with other ectodermal dyskeratotic features as palmoplantar keratoderma, follicular hyperkeratosis and oral leucokeratosis (Fig. 4). Epidermal cysts, natal teeth, hairshaft abnormalities, palmoplantar hyperhidrosis and blister formation [84, 85] are more inconstant features [86]. Occasionally corneal dystrophy and cataract, laryngeal leukokeratosis with hoarseness [87], angular cheilitis, congenital alopecia and mental retardation are observed [85, 87].

Usually all 20 nails are affected with subungual hyperkeratosis, increased transverse curvature with distal elevation of the nail plate and a brownish-yellow discoloration. Pachyonychia is usually present at birth or develops in the neonatal period. But delayed-onset PC beginning as late as in the 2nd to 3rd decade has been reported [87-90]. PC has been shown to be caused by mutations in keratin K16 [12, 91, 92] or its expression partner K6a [93-95] respectively in either K17 [90, 92, 96-99] or K6b [100] genes. Gene locus has been mapped to 17q12-q21 for keratins K16 and K17 respectively to 12q13 for keratin K6. All reported mutations have affected either end of the alpha-helical rod domain of keratin genes, also known as the helix initiation peptide (HIP) respectively the helix termination peptide (HTP). The HIP/HTP sequence is an evolutionary highly conserved structure common to all intermediate filamentous molecules. HIP/HTP are critical for molecular overlap interactions, heterodimer formation and further polymerization of keratin molecules. Mutations in this region lead to defective intermediate filament assembly, to pathologic aggregation of the keratin cytoskeleton and clumping of keratin filaments resulting in decreased mechanical stability of keratinocytes and fragility of epithelial structures. The cytoplasmatic keratin clumping is visible by electron microscopy. Mutations outside these regions generally do not cause filament aggregation and lead to milder disease phenotype [101]. However only recently Connors et al. [88] have described a novel mutation in a girl with late onset PC exceptionally located in the central portion of the K16 rod domain.

Clinically two major subtypes of PC are distinguished [102].

Pachyonychia congenita type 1 (PC1), Jadassohn-Lewandowsky syndrome (MIM #167200)

PC1 is clinically characterized by onychogryposis, palmoplantar keratoderma with or without hyperhidrosis, follicular keratoses of knees and elbows and leukoplakia of the oral mucous membranes. Oral leucokeratosis is the distinguishing feature of PC1 from PC2. Hyperkeratotic whitish plaques may present on the tongue and less frequently on the buccal and palatal mucosa. Palmoplantar keratoderma is patchy, particularly manifesting on the pressure bearing forefoot and heel and to a milder extent on the palms. Sometimes palmoplantar blistering is observed [84]. PC1 has been shown to be caused by mutation in the keratin K16 [12, 91, 92] or in the keratin K6a gene [93-95]. The clinical manifestations of PC1 correspond to the expression pattern of keratins K6a/16 in palmoplantar epidermis [16], oral mucous membranes and nail bed. Mutations in the K16 gene have also been found in nonepidermolytic palmoplantar keratoderm (NEPPK) without associated nail changes [103]. The heterogenous phenotypic expression related to mutations in this particular keratin gene remains to be cleared.

Pachyonychia congenita type 2 (PC2), Jackson-Lawler syndrome (MIM #167210)

PC2 is associated with focal palmoplantar keratoderma with or without hyperhidrosis, follicular keratoses, natal teeth, multiple pilosebaceous cysts resembling steatocystoma multiplex, bushy eyebrows and pili torti [90]. Leukokeratosis is usually not seen in PC2. Palmoplantar keratoderma is milder than in PC1 reflecting the minor expression of keratin K17 in palmoplantar skin compared to K16 [16]. Premature dentition and multiple epidermal cysts distinguish PC2 from PC1. The cysts develop postpubertally particularly on the trunk, axillae, head and neck. Histologically they may manifest as eruptive vellus hair cysts as well as as steatocystoma [104]. Keratin 17 is expressed in the medulla compartment of human hair from eyebrows and beard, the major sites for occurrence of pili torti in PC2 [11]. McGowan et al. [11] observed that the K17 positive cell population displays a similar polarized expression pattern in the hair follicle matrix as has been reported for the sonic hedgehog molecule. Disrupting the polarization of the sonic hedgehog molecule in the matrix impacts the orientation of the hair follicle relative to the skin surface. Mutations of K17 in the matrix might play a similar role in the twisted hair phenotype. Involvement of the larynx with leukokeratosis of the vocal cords may cause constant or transient hoarseness [87, 105]. PC2 is caused by mutations in keratin K6b [100] or K17 gene [90, 92, 96-99]. Mutations in K17 gene may also cause steatocystoma multiplex (SM), without associated features such as nail dystrophy or palmoplantar keratoderma [90]. Covello et al. [98] described two families, one manifesting the clinical features of PC2 with epidermal cysts, the other manifesting the clinical picture of SM without nail changes or palmoplantar keratoderma. The two families had the identical pyrimidine transition mutation of the K17 gene. This observation shows that mutations of the K17 gene underlie both phenotypes, PC2 and SM, and that the phenotype expressed is independent of the specific mutation involved. The variable phenotype expression must be due to an additional environmental factor.

Schönfeld [106] proposed distinguishing a type 3 of PC consisting of the symptoms of type 1, associated with leukokeratosis of the cornea. In a literature survey from 1904 to 1985 Feinstein et al. [107] reviewed 168 PC cases and based on these data they added a type 4 of PC with all clinical signs of PC1, 2 and 3 plus laryngeal lesions, mental retardation, hair abnormalities and alopecia.

Familial incontinentia pigmenti (IP), Bloch-Sulzberger syndrome (#MIM 308300)

Secondary nail changes

Familial incontinentia pigmenti, also known as Bloch-Sulzberger syndrome, is an X-linked dominant multiorgan disorder with dermatological, dental and ocular features [108], with anomalies of the central nervous system, hair, and nails and less common with skeletal and cardiovascular defects [109].

The skin findings are the most characteristic clinical features in IP. They usually pass through four consecutive and sometimes overlapping stages. The first, vesiculobullous stage is most often present at birth or will develop shortly after. Erythematous macules, papules and vesicles occur in swirls and streaks following Blaschko lines. They gradually resolve over the following weeks and months. The second, verrucous stage is characterized by papular, warty, hyperkeratotic plaques arising in the first few months of life. The third, pigmentary stage usually presents within the first year of life and is characterized by macular hyperpigmentation arranged in streaks and whorls. The fourth stage presents with atrophic, hypopigmented or depigmented scarring skin lesions, which persist and may be the only sign in adults with IP [110, 111]. The name of the disorder derives from incontinence of melanin from the epidermal melanocytes into the corium where many melanophages are deposited particularly in the third stage.

The nails in IP may be involved in up to 40% of cases [112]. The nail changes range from pitting, transverse and longitudinal ridging, koilonychia to severe dystrophy with marked thickening of the nail plate (Fig. 5). The cause of this nail disruption is unknown. After puberty painful subungual hyperkeratotic tumors [113] may arise. As a consequence the subungual tumors can lead to nail dystrophy with onycholysis and lytic deformities of the underlying terminal bony phalanges [114]. The tumors may disappear spontaneously after several months. But sometimes electrodessication, curettage or surgical excision is necessary because of pain. Retinoids may lead to resolution of the tumors [9]. The tumors have the histological appearance of the second stage skin lesions. They present with verrucous or pseudoepitheliomatous hyperplasia of the epidermis and focal dermal dyskeratosis [112]. Hair anomalies have been observed in up to 50% including vertex alopecia, hypoplasia of eyebrows and eyelashes and woolly hair nevus [111, 112, 115].

Dental anomalies include pegged and conical shaped teeth, hypodontia and adontia and delayed eruption of deciduous and permanent teeth. 30% of IP patients have severe visual impairment. The most common eye abnormality is strabismus [109]. Most characteristic are various retinal lesions ranging from retinal ischemia with proliferation of new vessels to retinal detachment resulting in blindness. Other ocular manifestations are phtisis bulbi, microphtalmy, cataract, corneal changes, optic atrophy and severe myopia [109]. Various neurological features such as seizures, cerebral palsy and mental retardation, motor retardation and microcepaly may occur in up to 30% of cases [116].

Familial IP segregates as an X-linked dominant disorder and is usually lethal prenatally in males [117]. Cells expressing the mutated X-chromosome are eliminated selectively around the time of birth, so females with IP exhibit extremely skewed X-inactivation [117]. Familial IP is caused by mutations in the NEMO (NFkappa-essential modulator) gene, which maps to Xq28 [117]. NEMO (IKK-gamma) is essential for the activation and subsequent translocation to the nucleus of the transcription factor NF-kappaB (nuclear factor kappaB). Activated NF-kappaB protects against apoptosis, especially that induced by tumor necrosis factor (TNF)-alpha. It could be shown that embryonic fibroblasts from IP patients lack NF-kappaB activation and are therefore highly sensitive to proapoptotic signals. Enhanced sensitivity to apoptosis may cause the typical skewing of X inactivation in females and lethality in males [118]. Interestingly the gene for dyskeratosis congenita (DC) maps to the same region Xp28 as IP. DC and IP show phenotypic overlap, sharing clinical abnormalities such as nail dystrophy, alopecia, hypodontia and skin manifestations. But Heiss et al. [119] could not find any mutations in the DKC1 gene in IP patients and concluded that the two diseases are not allelic.

Article accepted on 03/12/01

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