Nail Disorder, Nonsyndromic Congenital, 3

A number sign (#) is used with this entry because of evidence that leukonychia totalis and/or partialis, referred to here as nonsyndromic congenital nail disorder-3 (NDNC3), can be caused by homozygous or heterozygous mutation in the PLCD1 gene (602142) on chromosome 3p22-p21.3.

Description

A white appearance of the nails can result from whitening of the nail plate (true leukonychia), the nail bed (pseudoleukonychia), or neither (apparent leukonychia), and can be due to a variety of factors including infectious, metabolic, or systemic diseases, trauma, or drugs. One of the rare causes of whitening of the nail plate is hereditary leukonychia (summary by Kiuru et al., 2011). Leukonychia may involve all of the nail (leukonychia totalis) or only part of the nail (leukonychia partialis), or can appear as one or more transverse bands (leukonychia striata) or white spots (leukonychia punctata).

For a list of other nonsyndromic congenital nail disorders and a discussion of genetic heterogeneity, see NDNC1 (161050).

Clinical Features

Sibley (1922) reported a 57-year-old woman with a 13-year history of psoriasis who presented with marked white bands on most of her fingernails, especially the thumbnails where some 6 distinct bands were observed. There were no bands on her toenails. The nails were smooth on the surface and did not show any other changes, although they had been affected by psoriasis in the past. The patient stated that the bands always appeared at the base of the nail and gradually grew up to the free end. Her hair was normal, and she was edentulous, having had all teeth removed at age 21 due to dental caries. The proband's maternal grandmother had similar bands, and several other family members were likewise affected. Her daughter was said to occasionally have small white bands on her nails; at the time of examination, there were only white spots present.

Becker (1930) described a 19-year-old man who had white transverse striations on his fingernails for as long as he could remember. The stripes started at the lunula and progressed with the growth of the nail, with a new stripe starting every week or so. A varying number of nails were affected each time, but the thumbs tended to be involved most regularly. No subjective sensations had been noted, and the surface of the nails had always been smooth. Hair, skin, and teeth were normal. No other family members were affected. Examination showed broad transverse striations at various distances from the lunula on all nails, which had a normal surface. Microscopic examination of the white portion of a nail revealed an abnormal stripe about midway between the inner and outer surfaces. The cells were larger than normal, the nuclei more prominent, and both nuclei and cells took only acid stains. Staining was more intense than in other cells, and this portion appeared more opaque. In some portions, keratohyaline granules were seen in cells immediately toward the surface from this stripe. Becker (1930) concluded that the process was one of abnormal keratinization.

Kruse et al. (1951) reported a 25-year-old man of Italian descent with leukonychia totalis who had porcelain-white nails of both hands and both feet since shortly after birth. The nails were otherwise normal in shape, surface, and thickness, and he had no other physical abnormalities. His father and 2 paternal uncles were said to have the same condition of the nails, but were not available for study.. Kruse et al. (1951) commented that microscopic examination of hematoxylin and eosin-stained nail sections yielded results that were identical to those described by Becker (1930).

Medansky and Fox (1960) described white nails in 14 members of 5 generations of a family. Examination of a mother, her 4 affected sons, and an affected grandson showed that the nails of all fingers and toes were porcelain white and the lunula could not be distinguished. The nails were not brittle and the edges were not frayed; the thickness appeared to be average, and no grooves or other irregularities were observed. The white nails were present since birth in all, and no other physical abnormalities were present.

Albright and Wheeler (1964) described a mother with leukonychia totalis who had 2 daughters with leukonychia partialis. The 59-year-old mother had had white nails for as long as she could remember; all 10 fingernails were completely white with no lunula visible, and the nails were of normal thickness and texture. Four of her toenails (2 on each foot) were completely white, and the remaining toenails had the thickened, yellow-opaque appearance of mycotic infection. Her hair and teeth were normal. Her 39-year-old daughter had partially white nails all her life. Examination showed that all of her fingernails and toenails were abnormally white proximally, with a distinct sharp 2- to 4-mm transverse band of normal pink nail bed distally. The free edge of the nail was of normal white color. The lunula was faintly visible in the thumb, index, and middle fingers, and the nails were of normal texture. Her hair was normal; teeth had previously been extracted. Another daughter, 35 years old, also had partially white nails since childhood; her nails were exactly as described for her sister except for some distal onycholysis of her left index finger. She had no abnormalities of hair or teeth. The proband's 41-year-old son and a granddaughter and grandson, the children of her older daughter, were said to have normal nails.

Higashi et al. (1971) described 2 unrelated individuals who had leukonychia striata longitudinalis, in which a longitudinal white streak persisted in a fingernail for several years. One was a 29-year-old Japanese woman with a longitudinal white streak of her right middle finger for 9 years. Histologic examination of the nail plate showed abnormal cornified cells accompanied by parakeratotic hyperplasia of the nail bed epidermis. The second patient was a 31-year-old Japanese man with longitudinal leukonychia of the left thumbnail; histology showed parakeratotic hyperplasia of the nail bed epidermis upwards into the nail plate, in the absence of any abnormal cornified cells in the nail plate.

Bushkell and Gorlin (1975) found leukonychia totalis associated with multiple sebaceous cysts (see 184500) and renal calculi in grandfather, father, and son, and some of these features in 2 other relatives. Koilonychia (149300) was also found in 3 of the affected persons.

Butterworth (1982) described a 59-year-old man with phenylketonuria who was first diagnosed with leukonychia as part of a dermatologic survey of institutionalized patients in 1934. His father was said to have had similar completely white nails. Butterworth (1982) stated that in following the patient over a period of almost 5 decades, seeing him at least weekly in the institution, he noted that on some occasions the patient's nails assumed a normal color. Then, after a period of weeks or months, whiteness would appear in the nails at the cuticles and gradually spread distally until all of the nails were porcelain-like. At times, the proximal portions of the nails were white with a distal pink transverse band, 2 or 3 mm wide, at the free edge. Butterworth (1982) concluded that the 2 types of leukonychia seen in this patient were the result of 1 basic genetic defect in keratinization, stating that in patients with leukonychia totalis, the defect persists for the entire length of the nail plate, whereas in leukonychia partialis, delayed keratinization of the nail becomes complete by the time the nail plate reaches the end of the nail bed. The author noted that faulty keratinization need not be permanent, and that he had observed several patients in whom the nails at times assumed a natural pink color. In addition, Butterworth (1982) cited the patient of Harrington (1964), who was reported to have leukonychia totalis of all fingernails except for those of the right thumb and middle finger, which, along with all of the toenails, displayed leukonychia partialis with the distal third being pink.

Friedel et al. (1986) reported a 24-year-old woman who had leukonychia totalis of all 20 nails, most of which also showed koilonychia. She also had multiple trichilemmal cysts (see 609649) and short eyelashes that were irregular in size and in implantation and were associated with blepharitis, tearing, conjunctival irritation, and photophobia. Her 25-year-old sister had leukonychia totalis of all nails, occasionally sparing the distal nail, and blepharitis, but did not have trichilemmal cysts. Neither sister had palmoplantar keratoderma or anomalies of the teeth or hair. Family history revealed the presence of leukonychia totalis in 9 additional family members, segregating in an autosomal dominant fashion over 4 generations; none of these family members were reported to have blepharitis or trichilemmal cysts.

Bettoli and Tosti (1986) reported a 17-year-old boy who had leukonychia totalis at birth, but in whom several bands of normal pink color had appeared over the years. At the time of examination, the second and third fingers of both hands showed total leukonychia, whereas the first and fourth fingers showed partial leukonychia and the fifth fingernails on both hands were completely normal in color. The patient was otherwise in good health; potassium hydroxide preparations and cultures of nail scrapings were negative. His paternal grandmother and a paternal aunt were affected with the same kind of nail discoloration; the patient stated that his grandmother had leukonychia totalis at birth but that it had completely resolved by the time of her death, and that both leukonychia totalis and partialis had been present simultaneously during the course of her life. His 24-year-old affected aunt presented the same clinical picture as the proband and showed a similar progression of disease. Bettoli and Tosti (1986) stated that these findings supported the assumption of Butterworth (1982) that leukonychia partialis might be a phase of leukonychia totalis.

Mahler et al. (1987) reported a 51-year-old woman with striate leukonychia involving the entire first toenail and half of the second toenail of both feet; the fourth toenail on both feet showed minimal punctate leukonychia. No nail changes were present on the hands. The pattern of the involved nails was striking, with regular alternating transverse bands of white and normal nail, less than 1 mm wide, along the entire length of the nail. The patient stated that she became aware of the nail abnormalities sometime before the age of 5 years but was not certain whether or not they were present at birth. Microscopic examination of transverse sections of an affected nail showed a uniform band of parakeratosis on the ventral aspect of the nail plate; Mahler et al. (1987) noted that these findings were similar to those of Higashi et al. (1971). Mahler et al. (1987) further noted that the peculiar distribution of leukonychia in their patient had not previously been reported, and that the extreme regularity of the narrow white bands contrasted with the irregular appearance of the majority of cases of hereditary or acquired leukonychia striata.

Grossman and Scher (1990) provided a review and classification of leukonychia.

Kohler et al. (1998) reported 2 brothers with isolated leukonychia totalis. No other family members in 3 generations were affected; the parents were not consanguineous. The authors suggested spontaneous somatic mutation in one of the parents, which was autosomally transmitted with a gonadal mosaicism, as a possible mode of transmission. Grosshans (1998) questioned whether all the keratinizing adnexal structures had been thoroughly examined in the sibs reported by Kohler et al. (1998). Kohler et al. (1998) responded that there were no signs or symptoms of any associated ectodermal dysplasia in either brother.

Stevens et al. (1998) reported autosomal dominant inheritance of leukonychia totalis with incomplete penetrance in 5 members of a family over 3 generations. Additional reported nail findings included koilonychia of both thumbs and painful detachments at the onychodermal band on several digits in 2 of those affected. There was no evidence of systemic disease.

De and Handa (2007) reported a man with leukonychia totalis and diabetes mellitus. The man stated that his nails had been white ever since he could remember and that his maternal grandfather, mother, 2 of 4 sibs, and 2 of his 3 offspring had a similar nail condition. No other family member had diabetes.

Kiuru et al. (2011) studied 4 Pakistani families with congenital hereditary leukonychia, 2 of which were consanguineous and consistent with recessively inherited leukonychia, and 2 demonstrating dominant inheritance. All 20 nails of each affected individual were chalky white, consistent with total leukonychia, although some nails displayed incomplete leukonychia with translucency and yellowish discoloration in the distal parts of the nail plate. No other skin or hair anomalies or systemic findings were detected, and there was no family history of malignancy.

Pathogenesis

Albright and Wheeler (1964) stated that leukonychia was generally believed to be due to abnormal keratinization, which was demonstrated by the presence of large nucleated cells and keratohyaline granules in the white area of the nail plate. Thus, a severe defect could allow the persistence of a large number of immature nail cells for the entire length of the nail plate, resulting in leukonychia totalis, whereas a less severe defect could cause marked delay in maturation of keratinizing cells, so that by the time the nail plate reached the distal end of the nail bed, keratinization would be complete or nearly so, resulting in proximal leukonychia with normal appearing distal nail, as seen in leukonychia partialis. Albright and Wheeler (1964) noted that this would be in keeping with the observations of Mitchell (1953), who stated that about half of leukonychial spots he followed disappeared during their progress to the free edge of the nail.

Clinical Management

Kohler et al. (1998) stated that there is no known successful treatment for leukonychia totalis; however, they noted that the 2 brothers they reported 'were proud of their special condition; the nails were fluorescent in UV-light in discotheques, exerting a certain influence on interested women.'

Inheritance

Father-to-son transmission of leukonychia totalis (e.g., Kruse et al., 1951) indicate autosomal dominant inheritance.

Frydman and Cohen (1993) observed leukonychia totalis in a brother and sister with unaffected consanguineous Arab parents, suggesting autosomal recessive inheritance.

Both autosomal dominant and autosomal recessive forms of the disorder were confirmed by Kiuru et al. (2011).

Mapping

In a consanguineous Pakistani family segregating autosomal recessive leukonychia, Kiuru et al. (2011) performed genomewide autozygosity mapping and identified a region of excess homozygosity shared among affected individuals on chromosome 3p22-p21.3 with a lod score of 5.1. Microsatellite markers spanning the region of autozygosity were analyzed in 3 more Pakistani families with leukonychia, 1 consanguineous and 2 consistent with dominant inheritance, and all 3 showed linkage to the same location. Key recombination events narrowed the interval to 2.0 Mb flanked by markers D3S1483 and D3S1260.

Molecular Genetics

In affected members of 4 Pakistani families with leukonychia totalis mapping to chromosome 3p22-21.3, 2 of which demonstrated autosomal recessive inheritance and 2 of which were consistent with autosomal dominant inheritance, Kiuru et al. (2011) analyzed candidate genes and identified homozygosity or heterozygosity for nonsense, splice site, and missense mutations in the PLCD1 gene (602142.0001-602142.0004). None of the mutations were found in 130 unrelated population-matched controls. Kiuru et al. (2011) noted that the phenomenon of recessive and dominant mutations in the same gene resulting in a similar phenotype is rare.