Pachyonychia Congenita: a Spectrum of Krt6a Mutations in Australian Patients

Pediatric Dermatology Vol. 33 No. 3 337–342, 2016

Pachyonychia Congenita: A Spectrum of KRT6a Mutations in Australian Patients

Charlotte E. Forrest, M.B.B.S.,* Genevieve Casey, M.B.B.S.,† Dylan A. Mordaunt, M.B., Ch.B.,‡,¶ Elizabeth M. Thompson, M.B.B.S., M.D.,‡,¶ and Lynne Gordon, M.B.B.S.†

*Royal Adelaide Hospital, Adelaide, South Australia, Australia, †Flinders Medical Centre, Adelaide, South Australia, Australia, ‡South Australian Clinical Genetics Service, North Adelaide, South Australia, Australia, ¶Department of Paediatrics, University of Adelaide, North Adelaide, South Australia, Australia

Abstract Background: Pachyonychia congenita (PC) is a rare inherited disorder of keratinization characterised by hypertrophic nail dystrophy, painful palmoplantar blisters, cysts, follicular hyperkeratosis and oral leukokeratosis. It is associated with mutations in five differentiation-specific keratin genes, KRT6A, KRT6B, KRT6C, KRT16,orKRT17. Objectives: Living with Pachyonychia Congenita can be isolating. The aim of this paper is to document a single patient’s experience within a national context. Method: We report the case of a 2 year old female with an atypical presentation of PC due to a mutation in KRT6A with severely hypertrophic follicular keratoses, skin fragility, relative sparing of nail hypertrophy on one hand and failure to thrive in early infancy. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), a database search was performed using Australian residency and KRT6A mutation as inclusion criteria. The IPCRR database was also searched for a matching KRT6A mutation. Six Australian patients were identified in addition to one patient with an identical mutation residing in the United States. The detailed standardized patient questionnaire data was manually collated and analysed. Results: Fingernail hypertrophy and oral leukokeratosis were the most common features. There was no recording of asymmetric distribution in any other Australian patient. Trouble nursing as an infant and follicular hyperkeratosis also occurred in the American patient, however they did not have asymmetric distribution and the oral leukokeratosis appeared later in life. Conclusion: This case has unique features. Sharing information can assist patients navigating life with this condition.

Address correspondence to Charlotte Forrest, M.B.B.S., Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000, Australia, or e-mail: [email protected].

DOI: 10.1111/pde.12841

Pachyonychia congenita (PC) is a rare inherited at 3 weeks. Her parents and three older sisters were disorder of keratinization that affects 5,000 to unaffected. 10,000 people worldwide (1). It is associated with Initial examination identified hypertrophic dystro- a mutation in one of five keratin genes (KRT6A, phy of her fingernails and toenails, markedly more KRT6B, KRT6C, KRT16, KRT17), each defined by pronounced on the right hand and foot (Figs. 1 and a constellation of clinical features. Although his- 2). Leukokeratotic plaques were identified on the torically divided into two types, classification is tongue and right buccal mucosa. The nail hypertro- now based on these genetic subtypes. The Inter- phy was unilateral, with the left hand completely national Pachyonychia Congenita Research Regis- spared and showing only mild dystrophy of the try (IPCRR) has identified more than 100 fourth, fifth, and lateral part of the second fingernails. mutations (2). Characteristic manifestations of Similarly, the left foot was relatively spared, with mild PC consist of hypertrophic nail dystrophy, painful dystrophy of only the distal part of the third and palmoplantar keratoderma, cysts, follicular hyper- fourth toenails. This distribution is difficult to appre- keratosis, and oral leukokeratosis (2). Painful ciate in the clinical photographs available. palmoplantar keratoderma is the most debilitating Hyperkeratotic papules appeared over her thighs clinical feature (1). (Fig. 3) and trunk (Fig. 4). Hyperkeratotic papules We report the case of a 2-year-old girl with an developed on the knee extensor surfaces when she unusual presentation of PC due to a mutation in started crawling at 5 months old and were exacer- KRT6A. The features of this case are compared with bated by warm weather. Painful bullae over the soles those of other Australian cases of PC with KRT6A of her feet developed upon commencement of walking defects reported to the IPCRR. at 12 months. The bullae were noted to have spread over her buttocks and thighs a few months later. This also flared during warm weather and resolved with the CASE REPORT change of seasons at 18 months. Leukokeratosis of The patient was born to Pakistani parents who were her mucous membranes fluctuated with time. Angular first cousins. She presented at 7 weeks with abnormal cheilitis (Staphylococcus aureus–positive culture) was fingernails and white spots on her buccal mucosa. She treated with a 5-day course of topical antibiotic had poor feeding from birth and was not gaining (neomycin and gramicidin); subsequent recurrences weight (failure to thrive). The parents noticed nail resolved with shorter 3-day courses of antibiotic. changes at 10 days and the leukokeratotic plaques, Treatment of the nails involved tar cream and initially thought to be secondary to candida infection, keratolytics, including 10% to 40% urea cream and

A B

C D Figure 1. Hypertrophic, elongated curved and dystrophic fingernails: (A) right hand, 2 months old; (B) right hand, 18 months old; (C) right hand, 19 months old; (D) left hand, 19 months old. Note the relative sparing of the left hand. No evidence of hypertrophy, only mild dystrophy of fourth and fifth fingernails and lateral part of second fingernail. Forrest et al: Pachyonychia Congenita in Australia 339

Figure 2. Hypertrophic toenails: (A) 2 months old, (B) 18 months old, (C) 19 months old, and (D) 2 years and 2 months old.

3% salicylic acid in aqueous cream, in combination parents elected to wait until their daughter was old with a mechanical paring device and a diamond- enough to decide for herself. tipped grinder. Aluminium chloride hexahydrate 20% Sequencing of the known pachyonychia congenita was applied to blistered areas daily for 4 weeks. A genes identiﬁed a heterozygous missense variant in short course of betamethasone valerate 0.02% and KRT6A (c.520T>A; p.Phe174Ile) (3). This variant was hydrocortisone 1% was prescribed to relieve the predicted to be pathogenic using in silico analysis irritated hyperkeratotic regions over the trunk and (p > 0.99) (4). Other disease-causing missense muta- thighs, but her parents did not start this treatment. tions in this position have previously been reported Systemic therapy with acitretin was oﬀered, but her (p.Phe174Val, p.Phe174Ser, p.Phe174Cys) (5–8). The 340 Pediatric Dermatology Vol. 33 No. 3 May/June 2016

ABC

Figure 3. (A) Hyperkeratotic papules over the legs that are worse on the right side, at 18 months old. Area of hyperkeratotic papules on the right upper thigh where blisters were previously present: (B) left leg, 18 months old; (C) 19 months old.

Figure 4. Hyperkeratotic papules over the torso, worse right of the midline: (A) 19 months old and (B) 2 years and 2 months old.

IPCRR reports that this variant has been seen in one because of incomplete data (multiple unanswered other individual in the United States (8), as mentioned in survey questions). The remaining six patients had a previous review (3). incomplete data for no more than one survey question. The IPCRR worldwide database was also searched for a matching KRT6A mutation, which METHOD identiﬁed the aforementioned patient residing in the The IPCRR collected data using their detailed stan- United States who shares the same mutation as the dardized patient questionnaire. The IPCRR per- patient described in this case. The questionnaire data formed the database search using Australian were then used to analyze the spectrum of clinical residency and KRT6A mutation as inclusion criteria, presentations in all known individuals with the which revealed seven individuals with the KRT6A KRT6A mutation in Australia in addition to the mutation registered in Australia, including our patient with the same mutation from the United patient. One of the seven patients was excluded States. Forrest et al: Pachyonychia Congenita in Australia 341

TABLE 1. Clinical Features of Individuals with Pachyonychia Congenita Due to a KRT6A Mutation

Australian patients with feature, n Clinical feature (out of a possible 6) This case US patient

Asymmetrical distribution of nail hypertrophy 1 (this case) Relative sparing of right hand All nails affected Type of mutation Familial 3 Spontaneous (F174I) Spontaneous (F174I) Spontaneous 3 Onset of nail hypertrophy Birth to 1 year 5 Birth to 1 year Birth to 1 year 1–4 years old 1 Asymmetric skin findings 1 Relative sparing of right hand Symmetrical distribution Leukokeratosis 6 Present Present Leukokeratosis onset Unknown (question not answered) 3 Birth to 1 year 3 Birth to 1 year 10–14 years old 10–14 years old Difficulty nursing or sucking as an infant Difficulty 2 Difficulty Difficulty Unknown (question not answered) 3 No difficulty 1 Skin manifestations Unknown (question not answered) 2 Follicular hyperkeratosis 2 Follicular hyperkeratosis Follicular hyperkeratosis and pilosebaceous cysts Follicular hyperkeratosis and pilosebaceous cysts 1 Follicular hyperkeratosis, 1 pilosebaceous cysts, steatocystoma Hoarseness of voice 3 Absent Absent Ear pain 0 Absent Present

RESULTS relieved their symptoms. Half of the patients The six Australian patients were from four different described their symptoms as at their best in the families and shared four different mutations (8). morning, and two-thirds reported that wearing cotton Table 1 presents the clinical features that these socks helped to maintain their feet in optimal condi- patients reported. Fingernail hypertrophy and oral tion. Factors collectively acknowledged to contribute leukokeratosis were the most common features, to deterioration in symptoms included hot weather, recorded by all six patients. In five of the six patients, walking, and hot or sweaty feet. these changes were documented to have occurred before 1 year of age. Follicular hyperkeratosis DISCUSSION occurred in four of the six patients. Hoarseness of voice was reported in half. There was no recording of PC is a rare and complex genetic disorder. The asymmetric distribution in any of the other Australian IPCRR shows that, as of October 2014, there were patients. Trouble nursing as an infant was reported in 593 genetically confirmed cases of PC, 13 of these in one other patient, but data for this survey question Australia (2). Inclusive of our patient, 7 of the 13 were missing for three patients. documented cases in Australia have a mutation in Columns 3 and 4 of Table 1 contrast our patient KRT6A, with the remainder consisting of KRT16 and with the patient from the United States. Follicular KRT17 mutations (2). hyperkeratosis was a shared clinical feature, but the The hallmark features of PC due to a KRT6A American patient also had pilosebaceous cysts. The mutation include early onset and extensive nail American patient did not have asymmetric distribution, disease, in addition to substantial disease in locations and oral leukokeratosis appeared later in life. Both of other than the palms and soles, namely oral leukok- these patients reported trouble feeding in infancy. eratosis, cysts (pilosebaceous and steatocystoma), One section of the IPCRR questionnaire focused follicular hyperkeratosis, and hoarseness of voice (8). on factors found to exacerbate and relieve symptoms. This is confirmed in the IPCRR data from the six The six Australian patients unanimously reported Australians with PC due to a KRT6A mutation that rest, reduced mobility, cool weather, and winter (Table 1). The unique aspects of our case include 342 Pediatric Dermatology Vol. 33 No. 3 May/June 2016 relative sparing of fingernail hypertrophy on one spontaneously in patients with no family history (new hand, severe follicular hyperkeratosis, and blistering mutations) (1). The history of consanguinity proved involving the proximal limbs. In the Australian to be irrelevant in this case, as this was a new mutation cohort, there are no other reports of nail hypertro- (autosomal dominant) rather than a recessive disor- phy relatively sparing one hand, although one der. Because atypical features of PC were present, we patient described skin calluses affecting the right considered the possibility of a second disorder related hand only. New dominant mutations may arise post- to consanguinity, but there were no other clinical zygotically, resulting in somatic mosaicism and features to suggest a specific second diagnosis. The asymmetric clinical features. This could be possibility of modifying factors related to consan- investigated by testing a sample of DNA taken from guinity cannot be excluded. unaffected tissue, but this was not possible in this case. Unaffected tissue might be expected to show no mutation, whereas minimally affected tissue may REFERENCES contain a smaller proportion of cells with the 1. 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