Leukonychia associated with hereditary syndromes

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Introduction 
Leukonychia is a type of dystrophy (dyschromia) of the nails, in which the appearance of areas of white color on the nail plates is noted. Leukonychia as a clinical symptom is heterogeneous and has different classifications depending on the clinical manifestations and localization of the pathological process. According to morphological classification, leukonychia is subdivided into focal, striated (longitudinal and transverse) and subtotal/total [1]. Anatomical classification distinguishes: true, apparent/false and pseudoleukonychia [2]. Syndrome-associated leukonychia is a conventional designation of nail color changes in various hereditary diseases and syndromes. These nail changes can act as one of the additional signs of the disease or be one of its obligatory components. Most often, syndrome-associated leukonychia is a true, subtotal/total leukonychia; it can occur on all or several nail plates of hands and feet. This morphologic and anatomic type of leukonychia as a manifestation of hereditary diseases and syndromes appears to be due to the influence of disease-related genetic factors that affect cell division processes in the nail matrix [3]. Diagnosis of leukonychia as a clinical symptom is not difficult due to the accessibility of the area of examination and the nature of the morphologic changes. However, if white nails are part of an inherited disease and/or syndrome, the identification of leukonychia in addition to other known criteria can significantly accelerate the diagnostic search and diagnosis. This review provides information on inherited diseases and syndromes characterized by leukonychia, and highlights the etiopathogenesis and clinical features of these disorders.

In the period from October 2024 to January 2025, we analyzed domestic and foreign databases, including Elibrary (https://elibrary.ru) and PubMed (https://pubmed.ncbi.nlm.nih.gov/) to search for information on the topic of the review. The following search queries in English and Russian were used: “leukonychia”, “heregidary leukonychia”, “syndrome-associated leukonychia”, “nails in systemic diseases”, “skin heregitary syndromes”, “inherited nail dystrophies”, “nail lesions in hereditary syndromes”, “hereditary leukonychia”. Literature reviews, descriptions of clinical cases, and original studies addressing the issues of genetic basis of diseases were analyzed. The work did not include abstracts, theses or opinions of individual authors on various aspects of the designated topic. 

Leukonychia within hereditary diseases and syndromes: generalities
The etiopathogenesis of syndrome-associated leukonychia remains incompletely understood. It should be noted that this type of onychodystrophy may be idiopathic in nature and occurs in an overwhelming number of cases in men [4]. Hereditary leukonychia can exist both in isolation and in combination with hereditary syndromes [5]. Hereditary leukonychia is known to be transmitted predominantly by autosomal dominant type, although autosomal recessive type of inheritance has also been described. This disorder is thought to be based on a mutation in the PLCD1 gene on chromosome 3p22.2, encoding phospholipase C delta-1 [6, 7]. 
As part of the clinical manifestations of hereditary syndromes, some authors consider leukonychia as one of the signs of ectodermal dysplasia with the involvement of genes responsible for keratin maturation in the pathological process [3]. Some authors also note that the GJB2 gene on chromosome 13, encoding the connexin 26 (Cx26) protein, plays a role in the development of leukonychia [8, 9, 10, 11]. 
If we consider leukonychia as one of the clinical manifestations of ectodermal dysplasia, we cannot speak about the specificity of this feature in some disorders. Leukonychia within the framework of hereditary diseases and syndromes can act both as one of the main diagnostic features and as a frequently observed symptom in combination with other types of onychodystrophies (Table 1). 

Table 1. Leukonychia as a manifestation of hereditary diseases and syndromes

Hereditary disease or syndrome (alternative name)	Disease identification number in the McCusick catalog OMIM (https://www.omim.org/)
Leukonychia as an obligatory diagnostic sign
FLOTCH syndrome (nonsyndromic congenital nail disease type 3, NDNC3)	151600
Bart-Pumphrey syndrome (BAPS)	149200
Congenital total leukonychia-black acanthosis-like rashes-hair dysplasia syndrome	*
Keratoderma-hypotrichosis-total leukonychia syndrome (palm and plantar keratoderma and congenital alopecia type 1, PPKCA1)	104100
Total leukonychia-follicular keratosis-hyperhidrosis syndrome	*
PLACK syndrome (flaking skin with leukonychia, acral pitting keratosis, cheilitis and nodules on finger joints)	616295
Guft's disease	236300
Leukonychia as a frequent diagnostic feature
Lowry-Wood syndrome (LWS)	226960
Naxos/Carvajal syndrome (NXD/ dilated cardiomyopathy with woolly-curly hair and keratoderma, DCWHK)	601214/ 605676
Trichorhinophalangeal syndrome type 1 (TRPS1)	190350
Palm and plantar keratoderma with deafness (keratoderma of the palm and plantar with deafness)	148350
POEMS syndrome	*
Haley-Haley disease (HHD)	169600
Tuberous Sclerosis (Tuberous Sclerosis Type 1, TSC1)	191100
Gopf's disease (AKV)	101900
Alagille syndrome (Alagille syndrome type 1, ALGS1)	118450
Congenital fibrosis of extraocular muscles type 1 (Congenital fibrosis of extraocular muscles type 1, CFEOM1)	135700
X-linked follicular schistose undermining keratosis of Siemens (X-linked follicular schistose undermining keratosis, KFSDX)	308800
Linear atrophoderma of Moulin	*
Sebaceous gland cyst syndrome (multiplex steatocystoma)	184500
Heimler syndrome types 1 and 2 (HMLR1, HMLR2)	234580/616617
Hypotrichosis and recurrent skin vesicles (HYPTSV)	613102
Pediatric autosomal dominant T-cell lymphopenia with or without nail dystrophy (TLIND)	618806
Ichthyosis with erythrokeratoderma (IEKD)	620507
Atrophoderma verruciformis (AVA)	209700
*- absence of nosology data in the OMIM catalog

Leukonychia as an obligatory diagnostic sign of hereditary diseases and syndromes 
FLOTCH syndrome
FLOTCH syndrome (leukonychia totalis-trichilemmal cysts-ciliary syndrome) is a rare inherited disease characterized by lesions of the skin and its appendages (total leukonychia, coilonychia, multiple sebaceous gland cysts), visual organs (ciliary dystrophy), and urolithiasis [12, 13]. The incidence of this syndrome is <1:1,000,000 [14]. The combination of sebaceous gland cysts and leukonychia was first described by Bauer in 1920. [15]. Later, the abbreviation “FLOTCH” was proposed by Friedel et al. [16] to designate a combination of different manifestations of this syndrome. The etiopathogenesis of the disease remains unknown. The autosomal dominant type of inheritance of this syndrome is assumed. Leukonychia in FLOTCH syndrome is true; its prevalence can be both total and subtotal and is one of the main diagnostic criteria for the diagnosis [13]. 

Bart-Pumphrey syndrome
Barth-Pumphrey syndrome (Schwann syndrome) is a rare genetic disorder with autosomal dominant inheritance based on a mutation in the GJB2 gene encoding the connexin 26 protein [17, 18]. The incidence of this syndrome is <1:1,000,000 [19]. Clinically, this syndrome is manifested by a combination of warty nodules on the interphalangeal joints of the feet and hands, leukonychia, palm and plantar keratoderma, and sensorineural deafness [9]. Rashes on the interphalangeal joints of the toes and fingers are the first and main complaint of patients when they see a physician. Although leukonychia is not the most common symptom of this syndrome, it represents one of its key components. Leukonychia in Bart-Pumphrey syndrome can be total or focal, involving a variable number of nail plates of the fingers and toes [20]. 

Leukonychia totalis-black acanthosis-nigricans-like lesions-abnabnabnabnabnabnabnabnabnabnabnabnabnacanthosis-nigricans-like lesions 
Leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome is a very rare inherited syndrome with unknown etiopathogenesis. The disease manifests from birth and in the first years of life [21]. The incidence of this syndrome is <1:1,000,000 [22].The disease is manifested by total nail lesions as well as black acanthosis-like rashes on the skin of the neck, axillae, and abdomen. Hair dysplasia is also noted. 

PLACK syndrome 
PLACK syndrome (acronym: Peeling, Leukonychia, Acral punctate keratoses, Cheilitis, Knuckle pads) is an autosomal recessive disorder presenting from birth. The incidence of this syndrome is <1:1,000,000 [23].The development of the disease is associated with mutations in the CAST gene. To date, six mutations have been identified that are associated with the development of this syndrome c.607dup (p.Ile203Asnfs*8), c.424A > T c.1750delG (p.Val584Trpfs*37), c.461dupGCAT (p.Ser154Cysfs*6), c.544G > T (p.Glu182*) and (c.507_508insA) [24, 25, 26, 27]. The disease manifests with generalized xerosis and desquamation of the skin, total or subtotal leukonychia, pitting keratosis of the extremities, and nodules on the pads of the fingers [24]. There is evidence of a possible genetic link between this syndrome and nested alopecia [28]. 
Also, leukonychia is a mandatory diagnostic sign of a number of extremely rare genetic syndromes, the description of clinical cases of which in the world medical literature does not exceed 10 patients. Such diseases include keratoderma-hypotrichosis-leukonychia totalis syndrome [29], leukonychia totalis-follicular keratosis-hyperhidrosis syndrome [30], and Guft's disease [31]. 

Leukonychia as a frequent diagnostic feature of hereditary diseases and syndromes
POEMS syndrome 
POEMS syndrome (acronym: Polyradiculoneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasmacell disorder, Skin changes; osteosclerotic myeloma, Takazuki syndrome, Crow-Fukas syndrome) is a rare inherited life-threatening condition characterized by neurological, endocrinological, and hematological abnormalities [32, 33]. Cases have been described in various populations including the United States, France, China and India [34, 35, 36, 37, 38] however the epidemiologic data of POEMS syndrome remains unknown. According to Nasu et al. [39], the incidence of this syndrome in the Japanese population is 0.3 per 100,000. The syndrome was first described by Bardwick in 1980, who proposed the present acronym for the clinical picture of the disease [40]. Despite the fact that changes in the skin and its appendages are small criteria for the diagnosis of this syndrome, the clinical picture of these changes is quite diverse and deserves the attention of clinicians. Patients with POEMS syndrome have hyperpigmentation foci, multiple hemangiomas, scleroderma-like skin changes in the form of atrophic foci. Hypertrichosis is also noted in patients. The most frequent nail lesions are hypertrophic osteoarthropathy and leukonychia [41-45]. 

Naxos/Carvajal syndrome
Carvajal syndrome is a rare variant of Naxos syndrome. The development of this syndrome is associated with mutation of genes encoding the functions of cell adhesion protein - plakoglobin (JUP, Naxos disease) and desmoplakin (DSP, Carvajal syndrome) [46, 47, 48]. In general, these disorders are characterized by a triad of symptoms - cardiomyopathy, palm and plantar keratosis and hair lesions. The presence of leukonychia has also been described in patients with these disorders, and in association with oligodontia [49]. 
Familial benign vesicular vesicles
Familial benign vesicular vesicles (Haley-Haley disease, Gougero-Haley-Haley disease) is an inherited skin disorder characterized by the appearance of a vesiculo-bullous rash at fold sites. The incidence of the disease is estimated at 1/50,000 cases [50]. The disease is thought to be based on a mutation in the ATP2C1 gene in chromosome 3q21-q24, which encodes isoform 1 of the Ca2+/Mn2+-ATPase of the secretory pathway of the Golgi apparatus [51, 52]. Clinically, the disease is manifested by the appearance of symmetrically arranged grouped vesicles, bullae, and erosions at sites of increased friction and folds. The rashes are usually accompanied by severe pruritus. The foci are prone to secondary infection [53]. In contrast to most of the presented disorders, in Haley-Haley bolsensis, not total but longitudinal leukonychia is noted, which is found in 70% of patients.Longitudinal leukonychia in Haley-Haley disease is considered by many authors as one of the main clinical symptoms of the disease [54, 55]. 
Tuberous sclerosis
Tuberous sclerosis (Burneyville's disease, Pringle-Burneyville disease, Focht's triad, EPILOIA) is a rare neurodermatologic disorder with an autosomal dominant type of inheritance characterized by the presence of cellular and tissue dysplasia [56]. The incidence of the disease is estimated at 1:6000-10,000 cases [57]. To date, the development of the disease has been attributed to de novo mutations in the TSC1 and TSC2 genes, encoding gamartin and tuberin proteins, respectively[58, 59]. The disease was first described by Recklinghausen and Virchow in 1862[60]. Lesions of the skin and its appendages are noted in 90% of patients with tuberous sclerosis [61]. The characteristic lesions are hyperpigmented patches resembling “ash leaves” [62] and angiofibromas of the facial skin [63]. As for nail changes, the characteristic sign of the disease is fibromas of the nail apparatus (Kennen tumor) [64]. In addition, in the work of Aldrich et al. [65] noted that the detection of longitudinal furrows, subnail hemorrhages, and longitudinal leukonychia on the nail plates are useful diagnostic findings along with nail apparatus neoplasms.  

Gopf's disease
Gopf's disease (Gopf's warty acrokeratosis) is a rare genetically determined skin disease with autosomal dominant inheritance, characterized by the appearance of hyperkeratosis foci on the dorsal surface of hands and feet. The incidence of the disease is unknown. The disease was first described by Hopf in 1931 [66]. It is assumed that the disease is based on a mutation in the ATP2A2 gene located on chromosome 12q24,[ 66]. Clinically, the disease is manifested by the appearance of hyperkeratotic papules and plaques on the back of the hands and feet, with rare cases of lesions on the elbow and knee joints, as well as the skin of the lower legs [67]. In Gopf's disease, leukonychia acts as one of the symptoms of generalized dystrophic changes of the nails, along with their thinning and the appearance of multiple longitudinal furrows [66]. 

Alagille syndrome
Alagille syndrome (arteriohepatic dysplasia, Alagille-Watson syndrome, Watson-Miller syndrome, syndromic bile duct insufficiency) is a rare genetic polysystemic disease with an autosomal dominant type of inheritance characterized by severe lesions of the liver, kidneys, visual organs, lungs, and bone system, including facial structures [68]. The incidence of the disease ranges from 1:30,000 to 1:100,000 cases [68]. Notch signaling pathways play a central role in the pathophysiology of Alagille syndrome [69], usually caused by a deletion or duplication in the JAG1 gene (chromosome 20p12.2), which encodes a protein Notch ligand and explains 94-96% of Alagille syndrome cases [69]. Leukonychia has also been described in patients with Alagille syndrome [70], but it is not the result of an inherited pathology. It can be assumed that the appearance of leukonychia in patients with Alagille syndrome is associated with severe systemic disorders, in particular liver damage, which is characterized by a change in nail color to white. 

Palmoplantar keratoderma with deafness
Palmoplantar keratoderma with deafness (palmoplantar keratoderma with deafness) is a rare genetic disorder associated with a mutation in the GJB2 gene (connexin 26) [71]. Clinically, this syndrome is manifested by the presence of palm and plantar keratoderma and bilateral sensorineural deafness. Leukonychia is common within this syndrome and appears to be a manifestation of ectodermal dysplasia [72, 73]. 
Ichthyosis with erythrokeratoderma
Ichthyosis with erythrokeratoderma is a rare genetic disease with autosomal dominant inheritance characterized by the appearance of erythematous hyperkeratotic plaques on the skin [74, 75]. The disease is based on a mutation in the KLK11 gene on chromosome 19q13, which encodes the enzyme kallikerin-related peptidase 11 (KLK11) [74]. Given that the disease is based on disorders of keratinization processes, its clinical picture is very similar to dermatoses from this group. Thus, in ichthyosis with erythrokeratoderma, erythema and itching of the skin are noted in combination with marked hyerkeratosis on the extensor surfaces of the extremities and merging hyperkeratotic plaques on the skin of the trunk. Patients also have focal or diffuse palmar and plantar keratoderma. Nail lesions in patients with this disorder include sharpened nail plate depressions and leukonychia predominantly on the toes [74, 75]. 

Cases of leukonychia have also been described in patients with Lowry-Wood syndrome[76], congenital fibrosis of the extraocular muscles type 1 [77], Simens follicular spinous undermining keratosis (keratosis follicularis spinulosa decalvans) [78], linear atrophoderma of Moulin [79], leukonychia totalis-sebaceous cysts-renal calculi syndrome [80], prichorhinophalangeal syndrome type 1 [81], Heimler syndrome types 1 and 2 [82, 83], hypotrichosis and recurrent skin vesicles [84], pediatric autosomal dominant T-cell lymphopenia with or without nail dystrophy [85], and worm-like atrophoderma [86]
Conclusion
Despite the fact that most of the described hereditary diseases and syndromes are very rare and leukonychia is by no means always their leading clinical feature, there should be increased attention to this onychodystrophy on the part of clinicians. Timely detection of a possible syndromal component of leukonychia can play an important role in the diagnosis of the underlying disease and in the choice of tactics for the management of the patient as a whole. Congenital leukonychia, as a manifestation of ectodermal dysplasia, may be one of the first and well visualized clinical signs of severe multisystem disease, which should also be taken into account by specialists of various profiles when working with this group of patients. 

 

 

About the authors

Roman Vladimirovich Saraniuk

Derma Expert” Dermatology and Venereology Clinic
KROO “Society of Integrative Dermatology”

Email: roman.saranuk@gmail.com
ORCID iD: 0000-0001-9676-1581

Doctor of dermatovenerology;

President of Kursk Regional Public Organization “Society of Integrative Dermatology”. 

Россия, Russia, 305006, Kursk region, Kursk, Anatoly Deriglazov Avenue 1, office 3.

Alexey Valerievich Polonikov

Federal State Budgetary Institution of Higher Education “Kursk State Medical University”.

Email: polonikov@rambler.ru
ORCID iD: 0000-0001-6280-247X

Director of the Research Institute of Genetic and Molecular Epidemiology of KSMU, Head of the Laboratory of Statistical Genetics and Bioinformatics, Doctor of Medical Sciences, Professor of the Department of Biology, Medical Genetics and Ecology

Россия, Russia, 305041, Kursk region, Kursk city, Karl Marx street 3.

Tatyana Alexandrovna Gosteva

LLC “Kurchatov Center of Modern Medicine”;
KROO “Society of Integrative Dermatology”.

Author for correspondence.
Email: ya-lisenok-@mail.ru
ORCID iD: 0000-0003-0059-9159

Deputy Chief Physician for clinical and expertwork, therapist, pulmonologist;

member of Kursk regional public organization "Society of Integrative Dermatology"]

Россия, Russia, 307250, Kursk region, Kurchatov, Energetikov street, 10.; Russia, 305006, Kursk region, Kursk, Anatoly Deriglazov Avenue 1, office 3.

References

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