Pachyonychia congenita type 1 with skeletal abnormalities

ARTICLE

Auteur(s) : Jaap JAJ van der Velden, Maurice AM van Steensel

Department of Dermatology, Maastricht University Medical Center+, P. Debijelaan 25, 6202AZ Maastricht, the Netherlands

Pachyonychia congenita (PC) is characterized by hyperkeratosis of the nail bed with thickening and distortion or curvature of the nail plate [1]. There are two types of PC: Jadassohn-Lewandowsky syndrome (PC1) and Jackson-Lawler syndrome (PC2). The PC1 phenotype is associated with mutations in KRT6A or KRT16, whereas PC2 is associated with mutations in KRT17 or KRT6B [1]. Although sometimes difficult, it is possible to distinguish both subtypes clinically. Oral leukokeratosis is seen in PC1. Steatocystomas/pilosebaceous cysts, vellus hair cysts, hair abnormalities and natal teeth are features of PC2. There can be considerable overlap, however [1]. Pachyonychia congenita usually begins in infancy. A late-onset subtype seems to exist but is rare [2]. Associated skeletal abnormalities such as acro-osteolysis [3] have been described, but abnormal skeletal patterning has not yet been reported in the context of PC.

Recently, a 1-year-old boy of Dutch origin was referred to our outpatient clinic because of skeletal abnormalities of both feet since birth and nail abnormalities that appeared later. After 42 weeks of gestation, following an uncomplicated pregnancy, he was born with absence of one ray of both feet, an accessory phalanx at the most lateral digit of the left foot and complete fusion of the tibial metatarsals of the right foot (figures 1A,B). The hands showed no skeletal defects (figure 1C). Growth and development were normal. He was able to sweat and shed tears. At the age of 7 months he developed thickening of the nails of both hands and feet. His non-consanguineous Dutch parents and other family members were not affected. Physical examination revealed dystrophic nails with subungual hyperkeratosis and distal onycholysis (figure 1D). A solitary, oval, tender, yellowish, hyperkeratotic plaque was present at the plantar side of the right foot (figure 1D). Hair and teeth appeared normal. Apart from the oligodactyly, the accessory phalanx of the left foot, a marked hypoplasia of the middle phalanges and the complete fusion of the tibial metatarsalia of the right foot (figures 1E,F), radiological examination revealed no other skeletal abnormalities. There were no other dysmorphic traits. Based on these clinical features the diagnosis pachyonychia congenita type I with unclassifiable skeletal malformations was made.

Mutation analysis was performed through the International Pachyonychia Congenita Consortium (by GeneDx, Gaithersburg, MD, USA) and demonstrated a known heterozygous trinucleotide deletion c.389_391delCCT (causing p.Ser130del) in exon 1 of the KRT16 gene.

The combination of pachyonychia congenita type I and the above-mentioned unusual skeletal malformation has not been previously described. It is tempting to speculate that the abnormalities are not coincidental. As it seems biologically implausible that a KRT16 mutation could affect skeletal development, one might assume the existence of a contiguous gene syndrome. However, that is unlikely as we found a trinucleotide deletion in the KRT16 gene for which the patient is clearly heterozygous, thus ruling out microdeletions encompassing all or part of KRT16. It is therefore more prudent to assume that there is no causal relationship. It is even debatable whether the skeletal abnormality is genetically determined, as it cannot be classified into one of the known categories of acral developmental abnormalities. Thus, we think that the concurrence we describe is a coincidental one. It is, however, quite possible that the abnormal skeleton can contribute to the pachyonychia and concomitant keratoderma by altering pressure distribution.

We also suggest that the other skeletal defects that have been reported in association with pachyonychia type I were not causally related. The relatively high frequency in the literature may be due to an ascertainment bias.

Acknowledgements

References

2 Connors JB, Rahil AK, Smith FJ, McLean WH, Milstone LM. Delayed-onset pachyonychia congenita associated with a novel mutation in the central 2B domain of keratin 16. Br J Dermatol 2001; 144: 1058-62.

3 Murugesh SB, Reddy S, Ragunatha S, Mohammed Faizal MM, Shashikala P. Acro-osteolysis: a complication of Jadassohn-Lewandowsky syndrome. Int J Dermatol 2007; 46: 202-5.