Nail disorder, nonsyndromic congenital 1-10

A very rare and heterogeneous group of ectodermal dysplasias is summarized under the term "congenital non-syndromic nail changes" . These ectodermal dysplasias occur as "non-syndromic" disorders in which single but also all nails (see also twenty-nail dystrophy) as well as other ectodermal appendages (e.g.hair) may be affected (Saygı C et al. 2019).

The congenital nonsyndromic nail disorders are divided into 10 different subtypes,6 of which are inherited in an autosomal dominant manner (Nail disorder, nonsyndromic congenital 1-10).

To date, 6 genes have been associated with nail dysplasia:

• HPGD gene (mutations of the gene is associated with Primary Hypertrophic Osteoarthropathy ).
• SLCO2A1 gene (mutation of the gene is also associated with Primary hypertrophic osteoarthropathy - encodes for a prostaglandin transporter)
• RSPO4 gene (mutations of the gene are associated with the clinical picture of anonychia congenita )
• PLCD1 gene (mutations of the gene are associated with Leukonychia partialis/punctata/striata)
• COL7A1 gene (mutations of the gene are associated with epidermolysis bullosa dystrophica, recessive with congenital absence of skin and nail dystrophy (historically: Bart syndrome)
• FZD6 gene (mutations of the gene are associated with 20-nail dysplasia - Khan S et al. 2015).

The HPGD gene is associated with isolated congenital nail dystrophy (clumped nails/OMIM 119900) and is responsible for the metabolism of prostaglandins. Following irritation or injury, arachidonic acid (AA) is released and oxygenated by calcium-dependent enzyme systems, leading to the formation of prostaglandins. In addition, both the influx of extracellular calcium and the mobilization of intracellular calcium are very important in the process of prostaglandin formation (Taylor SM et al (1990). Mutations of the gene is associated with Primary Hypertrophic Osteoarthropathy.

The RSPO4 gene is another gene associated with nonsyndromic congenital nail disease (NCDC4; OMIM 206800). It is a secreted protein known to play a role in embryonic development and homeostatic self-renewal in adult tissues; it also plays a role in Wnt signaling, which has both anti-inflammatory and pro-inflammatory functions.

The PLCD1 gene is associated with congenital nonsyndromic nail alteration 3 (NDNC3/OMIM 151600), a member of the phospholipase C family that regulates immune homeostasis in the skin. The absence of PLCD1 protein leads to dermatitic reactions. Moreover, exogenously expressed PLCD1 attenuates LPS-induced expression of IL-1b (COL7A1Nakamura Y et al (2007). Mutations of the PLCD1 gene cause nail changes of varying severity in humans (Nail disorder, non-syndromic congenital, 3; Leukonychia partialis also known as Leukonychia punctata, Leukonychia striatus, Leukonychia totalis, Leukonychia totalis and/or partialis, Porcelain nails). The clinical picture is characterized by a varying degree of white coloration of the nail plate, which otherwise appears unchanged (true leukonychia). Leukonychia can affect the entire nail (Leukonychia totalis) or only a part of the nail (Leukonychia partialis, Leukonychia punctata, Leukonychia striata).

COL7A1 is another gene associated with nail diseases. COL7A1 encodes the alpha chain of type VII collagen. Mutations in COL7A are associated with congenital nonsyndromic nail disorder (NDNC8/ OMIM 607523). Mutations in COL7A1 result in lifelong severe blistering of the skin and mucous membranes, followed by scarring caused by loss of adhesion between the epidermis and dermis.

The FZD6 gene functions as a negative regulator of canonical Wnt/beta-catenin signaling via the encoded FZD6 protein. In a study of patients affected by nail dysplasia, FZD6 signaling was observed to activate beta-catenin. In this study, the Wnt3a pathway was reported to cause the accumulation of beta-catenin in healthy but not in FZD6-mutated fibroblasts, indicating a canonical role of FZD6 in this context. Furthermore, Kilander et al. showed that recombinant WNT-1, - 2, 3A, - 4, -5A, -7A, -9B, and -10B affect the surface mobility of FZD6 and thus act directly on FZD6 (Kilander MB et al. (2014). Accordingly, there is an interaction between the WNT signaling network, inflammatory cytokines, and innate immunity signaling pathways. Individual WNT proteins have been shown to have pro- or anti-inflammatory functions. The common intersection of all known NDNC genes is their association with the immune system, particularly innate immunity (Saygı C et al. 2019). In this respect, the associated occurrence of autoimmune diseases or chronic infectious diseases is not surprising (Saygı C et al. 2019).

The SLCO2A1 gene (SLCO2A1 stands for Solute Carrier Organic Anion Transporter Family Member 2A1) is a protein-coding gene located on chromosome 3q22.1-q22.2. The SLCO2A1 gene encodes a prostaglandin transporter that belongs to the 12-membrane spanning superfamily of transporters. The encoded protein may be involved in mediating the uptake and excretion of prostaglandins in numerous tissues. Associated metabolic pathways include transport of vitamins, nucleosides, and related molecules, and disruption of transmembrane transporters. Diseases associated with SLCO2A1 include Primary hypertrophic osteoarthropathy, autosomal recessive (OMIM: 259100).

Human nail development begins around the ninth week of gestation and is completed by the fifth month of pregnancy (Saygı C et al. (2019).

1. Cong F et al.(2004) Wnt signals across the plasma membrane to activate the beta-catenin pathway by forming oligomers containing its receptors, frizzled and LRP. Development 131:5103-5115.
2. Fröjmark AS et al (2011) Mutations in frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet 88:852-860.
3. Khan S et al (2015) Genetics of human isolated hereditary nail disorders. Br J Dermatol 173:922-929.
4. Kilander MB et al. (2014) Assessment of frizzled 6 membrane mobility by FRAP supports G protein coupling and reveals WNT-frizzled selectivity. Cell Signal 26:1943-1949
5. Nakamura Y et al (2007) Lack of phospholipase C-delta1 induces skin inflammation. Biochem Biophys Res Commun 356:912-918.
6. Saygı C et al. (2019) A possible founder mutation in FZD6 gene in a Turkish family with autosomal recessive nail dysplasia. BMC Medical Genetics 20: https://doi.org/10.1186/s12881-019-0746-6.
7. Taylor SM et al (1990) Influence of extracellular calcium on the me- tabolism of arachidonic acid in alveolar macrophages. J Leukoc Biol 48:502-511.
8. Wilson NJ et al (2013) Recessive mutations in the gene encoding frizzled 6 cause twenty nail dystrophy - expanding the differential diagnosis for pachyonychia congenita. J Dermatol Sci 70:58-60.