PATIENTS AND METHODS

The family originates from a rural village in Sicily and includes 11 affected subjects in five generations (fig 1). Based on clinical and anamnestic records, III.8 was the first affected member of this family. She developed nail dystrophy, presenting with hyperkeratosis and dark and thick nails, similar to those found in other family members. IV.5, a 71 year old female, was unaffected. V.4, a 48 year old female, was a blood relative of her husband. From the age of 6 months, she was affected by onycomycosis caused by Candida involving all the nails of her hands and feet (figs 2 and 3). Caustication was followed by regeneration of the nails, manifesting similar dystrophic features and Candida infection. V.7, a 47 year old male, was affected from birth by candidiasis of the nails of hands and feet, similar to her sister, V.4 (figs 2 and 3). She was the mother of three unaffected boys. V.10 and V.14, two females aged 37 and 33 years, related to V.4 and V.7, were also affected by chronic infections of all the nails of the hands and feet with onset in early infancy (figs 2 and 3). VI.3, a 20 year old man, was the son of first cousin parents (V.1 and V.2). The first symptoms of generalised onycomycosis occurred at the age of 3 months. VI.5, the 31 year old daughter of related parents (V.3 and V.4) manifested chronic candidiasis restricted to the nails of the feet from the age of 4 months (figs 2 and 3). Her 5 year old child was unaffected. VI.7, the 27 year old daughter of related parents (V.3 and V.4), had nail lesions similar to those of her sister VI.5 (figs 2 and 3). She was the mother of a 5 year old child (VII.2), who showed candidiasis of the nails of the hands and feet from the age of 6 months (figs 2 and 3). Her 3 month old baby was unaffected. VI.9, the 14 year old son of related parents (V.3 and V.4), showed lesions in the upper and lower limb nails, similar to those of his sisters VI.5 and VI.7 (figs 2 and 3). All patients had been treated over the years by topical and systemic antimycotic drugs, which resulted in temporary recovery, while never reaching complete remission.

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Figure 1

Pedigree of the family.

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Figure 2

Lesions of the nails of the hands in seven affected family members. (A) V.4, (B) VI.5, (C) VII.2, (D) VI.9, (E) V.7, (F) V.10, (G) VI.7.

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Figure 3

Lesions of the nails of the feet in six affected family members. (A) VI.9, (B) VII.2, (C) V.4, (D) V.7, (E) VI.5, (F) VI.7.

After informed consent, a blood sample was collected from seven affected (V.4, V.7, V.10, VI.5, VI.7, VI.9, VII.2) and 15 unaffected family members (IV.1, IV.4, IV.5, IV.10, V.3, V.6, V.8, V.11, VI.4, VI.10, VI.11, VI.12, VI.13, VI.14, VII.3). Nail specimens from the affected subjects were obtained from lesional and non-lesional sites by cutting and scarifying. All subjects underwent exhaustive tests to investigate possible endocrine abnormalities.⁴ Oral and vaginal swabs were collected from all patients. In addition, the autoantibody profile was investigated. Following isolation and culture, Candida strains were characterised and virulence properties evaluated. Confirmation of species identification was performed using API products (BioMerieux, NY). The adhesion of isolates to the HeLa cells was assayed according to Samaranayake and McFarlane.⁵ Cell surface hydrophobicity (CSH) was determined by the method of Hazen and Hazen⁶ at 37°C. Secretory aspartyl proteinase production of isolates was evaluated in solid medium, as reported by De Bernardis et al.⁷ Serum ICAM-1 levels were assayed on the affected and unaffected family members, and 14 controls, sex and age matched, using anti-ICAM-1s human antibody (Biosourch International, Camarillo, CA, USA). Data, expressed as means (SD), were examined by one way analysis of variance (ANOVA) and the Student-Newman-Keults test.

RESULTS

No autoantibodies were detected in any of the subjects tested. All biochemical investigations showed unremarkable results. Oral and vaginal swabs were negative for Candida infection. Results of nail microbiological investigations and ICAM-1 assays are summarised in table 2. All patients were infected by different kinds of the genus Candida, pointing to inability of the immune system to respond to the antigenic stimulus specific against Candida. The mean ICAM-1 level and concentration (figs 4 and 5) in the affected subjects was 63.29 (SD 14.36) ng/ml, compared to 108.31 (SD 13.57) ng/ml in the unaffected relatives and 133.24 (SD 18.36) ng/ml in the controls (by ANOVA test, p<0.05). Routine testing did not show any endocrine or autoimmune disorder in the affected subjects, excluding the APECED form of CMC (table 3).

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Figure 4

Distribution of ICAM-1 serum concentration in affected subjects, their relatives, and controls.

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Figure 5

Statistical comparison of mean ICAM-1 level.

DISCUSSION

Our pedigree illustrates the vertical transmission of a form of CMC affecting only the nails of the hands and feet, associated with low serum levels of ICAM-1. The mean concentration values of ICAM-1 in the affected subjects was lower than in unaffected relatives and controls. In general, serum ICAM-1 levels are increased in chronic inflammatory conditions, in contrast to the affected subjects in the present family. Intercellular adhesion molecule-1 (ICAM-1 or CD54) is a glycoprotein membrane and a member of the immunoglobulin superfamily which plays a central role in cell to cell mediated immune response and is a ligand for leucocyte function associated antigen-1 (LFA-1).⁸ ICAM-1 can be expressed by several cell types, including most activated immunocompetent cells,^9,10 fibroblasts,¹¹ and epithelial cells.¹² Furthermore, surface ICAM-1 expression has been detected in the epithelium in several inflammatory and neoplastic diseases.^13,14 Genetic studies using different types of back cross mice, either protected or not against vaginal candidiasis, after peripheral immunisation, showed that candidate loci for the immune response to vaginal candidiasis included ICAM-1, the ICAM-1 related sequence 1, and the Fc epsilon RII.¹⁵ Genetically engineered mice, lacking ICAM-1 expression, lost more weight and had a significantly higher mortality rate following an intravenous challenge with Candida albicans compared to normal wild mice.¹⁶ Based on evidence in the murine models, we investigated ICAM-1 and found decreased values in all affected subjects. Disease inheritance, clinical expression restricted to the nails of the hands and feet, together with decreased ICAM-1 levels point to a distinct form of CMC, familial chronic nail candidiasis with ICAM-1 deficiency (FCNC). In CMCs both autosomal dominant and recessive inheritance models have been reported. Sams et al¹⁷ and Jorizzo et al¹⁸ reported autosomal dominant transmission of CMC (MIM *114580). Evidence favouring familial autosomal recessive inheritance of CMC (MIM *212050) was discussed by Wells et al¹ and Germain et al.¹⁹ We were able to trace back the origin of the family to 1689. The pedigree analysis favours autosomal dominant inheritance with incomplete penetrance, even if a few marriages between consanguineous relatives are present.

There is a clear clinical concordance between ICAM-1 serum levels and nail dystrophy. Interestingly, the only unaffected obligate carrier we analysed showed ICAM-1 serum levels (98.00 ng/ml) intermediate between those found in affected (63.29 (SD 14.36) ng/ml) and unaffected non-carrier relatives (108.31 (SD 13.57) ng/ml). However, the pathogenesis of the nail lesions in this family is unclear and the relationship with the reduced ICAM-1 expression awaits clarification.