Pachyonychia congenita (ORPHA:2309)
A rare genetic skin disease predominantly featuring painful palmoplantar keratoderma, thickened nails, cysts and white plaques affecting tongue and oral mucosa.
Epidemiology
The prevalence is not known but over a thousand patients have been registered to date worldwide in the International Pachyonychia Congenita Research Registry (IPCRR). It is estimated that there are five to ten thousand cases worldwide.
Clinical description
Pachyonychia congenita (PC) presents clinically as a spectrum of conditions. PC onset is variable with most cases manifesting soon after birth, others becoming clinically apparent only in late childhood and rarely in adulthood. The first signs of the disease usually are thickened nails or neonatal teeth. At least 3 phenotypes of hypertrophic nail dystrophy of feet and hands can be observed: nail grows to full length but a distal prominent hyperkeratosis causes an upward slant with an accentuated curvature of the nail; nail plate terminates prematurely leaving a distal region of hyperkeratosis and an exposed fingertip; or nail plate is thin with little or no hyperkeratosis. When children start walking, typically in the first years of life, a focal palmoplantar keratoderma develops, with underlying blistering causing severe pain. In some cases, the onset of keratoderma is not seen until later childhood. By about 12 years of age the majority of patients have painful plantar keratoderma. Oral leukokeratosis occurs early, may possibly cause feeding difficulties and should be distinguished from oral candidiasis in infants. Laryngeal leukokeratosis may cause hoarseness, and rarely, causes airway obstruction. Follicular keratoses on the trunk and extremities may be seen at friction points such as waist, elbows and knees. Excessive sweating of palms and soles due to palmoplantar hyperhidrosis, widespread steatocystomas appearing during or after puberty, axillary and groin cysts are other findings observed in some PC patients.
Etiology
Although historically two subtypes have been described, PC-1 and PC2, it is today recommended to classify PC patients into five subgroups based on the underlying molecular etiology: PC-K6a, PC-K6b, PC-K6c, PC-K16 and PC-K17, as PC is caused by dominant negative mutations in at least 5 genes (KRT6A, KRT6B, KRT6C, KRT16 and KRT17) encoding keratins preferentially expressed in basal and suprabasal layers of palmoplantar skin, epidermal appendages and oral mucosa.
Diagnostic methods
Diagnosis is based on clinical examination and is confirmed by molecular genetic testing.
Differential diagnosis
The differential diagnosis includes variants of PC (steatocystoma multiplex, which develops at puberty with little or no nail dystrophy) and disorders manifesting with dystrophic nails such as epidermolysis bullosa, Clouston syndrome (distinguished by the presence of alopecia or hypotrichosis), autosomal recessive nail dysplasia (only nail involvement), other disorders presenting with palmoplantar keratoderma such as palmoplantar keratoderma-esophageal carcinoma syndrome, striate palmoplantar keratoderma and acquired disorders such as psoriasis and lichen planus.
Antenatal diagnosis
Antenatal molecular diagnosis is feasible provided the causative mutation is known.
Genetic counseling
Recent data suggesting the possibility that the disease may rarely be inherited in a semi-dominant fashion emphasizes the importance of accurate molecular diagnosis for proper genetic counseling.
Management and treatment
There is no curative treatment for PC yet. Treatment of manifestations will focus primarily on grooming of nails and management of pain due to palmoplantar keratoderma: it includes the use of emollients and oral retinoids to reduce hyperkeratosis and strategies to limit frictions and trauma of the feet. Novel treatment modalities under investigation include small interfering RNA (siRNA) strategies, the use of topical rapamycin, oral and topical erlotinib and injection of botulinum toxin.
Prognosis
Complications may include secondary infection that is usually well controlled by antibiotic therapy.

                            Last update: 
                            December 2022


                            - Expert reviewer(s): 
                            Pr Edel O'TOOLE | ERN-Skin*


                                * European Reference Network