Identification of a pathogenic CARD14 mutation in a 70-year-old woman with pityriasis rubra pilaris: when genetic diagnosis influences choice of treatment strategy

Abstract

Pityriasis rubra pilaris (PRP) is a rare dermatosis characterised by hyperkeratotic follicular papules, orange-red scaly plaques and palmoplantar keratoderma. The aetiology of the disease is in most cases unclear and treatment can be challenging. Familial cases of PRP may result from pathogenic variants in the caspase recruitment domain family member 14 (CARD14). We present a case of lifelong PRP in a 70-year-old woman, where genetic testing revealed a heterozygote missense variant c.412G>A, p.(Glu138Lys) in CARD14. Therapy with ustekinumab was initiated with remarkable effect, which improved the patient’s quality of life significantly.

Background

Pityriasis rubra pilaris (PRP) is a rare, chronic, papulosquamous dermatosis. The disease is characterised by hyperkeratotic follicular papules, which merge into orange-red scaly, well-demarcated plaques with islands of sparing or involving the whole skin. Often the patients have palmoplantar hyperkeratosis.¹ Histopathology shows typically ‘checkerboard pattern’ with othokeratosis and parakeratosis seen in a vertical and horizontal pattern together with hypergranulosis, broad rete ridges, thickened suprapapillary plates, follicular plugs and sparse superficial perivascular infiltrates.²

The aetiology of the disease is in most cases still unclear. Because of the rarity of the disease, the prevalence is uncertain but has been estimated to be approximately 2.5 patients per million in the population with an equal sex ratio.^{1 3}

In 1980, Griffiths classified PRP into five different subtypes based on age and morphology.⁴ Later, a sixth HIV-related type was added. The fifth type is classified as atypical juvenile type, which accounts for about 5% of all cases.⁴ Most familial cases of PRP belong to type V, which usually is inherited in an autosomal dominant manner.⁵ In the atypical juvenile type, the disease usually presents early in childhood and shows a more chronic progression.

Treatment of PRP can be challenging. Phototherapy and topical application of corticosteroids can be used as treatment but is often without satisfying results.⁶ Best clinical response is seen with immunosuppressive drugs, retinoids and biologic therapies such as tumour necrosis factor-α inhibitors (adalimumab, infliximab, etanercept) or interleukin (IL) inhibitors (ustekinumab (IL-12/IL-23), secukinumab (IL-17A)).^6–8

In 2012, Fuchs-Telem et al demonstrated that familial cases of PRP may result from pathogenic variants in the caspase recruitment domain family member 14 (CARD14) gene.⁹ This hereditary variant of PRP should be considered in subjects with a papulosquamous eruption including the face, family history of PRP or psoriasis, early onset of disease and insufficient response to conventional treatments.¹⁰

Case presentation

A 70-year-old woman had a history of severe skin disease. The symptoms debuted before the age of one with generalised, confluent eruption of red, scaly plaques. Throughout her life, she suffered severely from her skin disease, which involved primarily the face, arms and legs with few islands of sparing (figures 1–3). She had a family history without specifically diagnosed skin disorders, although her grandfather’s skin was described as kind of special, her mother developed a scaly, localised rash at the age of 75 years and her older sister seemingly had a transient bullous eruption in infancy. She had a healthy twin brother. As an adult, our patient decided not to have children because of the fear of passing on the disease. She had been followed by dermatologists throughout her life and different diagnoses were considered, including Netherton’s syndrome and congenital ichthyosiform erythroderma, which were disproved by biopsies and immunostaining. Different traditional treatment strategies had been tried, including acitretin, methotrexate and alitretinoin, all with minimal response. At the age of 70 years, she was referred to genetic counselling based on a suspicion of PRP. DNA was extracted from peripheral blood and next-generation sequencing of CARD14 was performed. A heterozygote missense variant c.412G>A, p.(Glu138Lys) was identified. The variant had been reported as pathogenic in at least three other patients with PRP.^{5 10 11} Family testing was offered, and the variant was not detected in her two siblings. The parents were deceased, and it was not possible to perform further segregation analysis.

Figure 1.

Left: redness and scaling of face, neck and upper trunk before treatment with ustekinumab (October 2017). Right: after ustekinumab, note improvement of redness and no longer scaling (August 2019).

Figure 2.

Generalised, red, scaly plaques with islands of sparring (back). Photo from 2009 (before ustekinumab).

Figure 3.

Generalised, red, scaly plaques with islands of sparring (front). Photo from 2009 (before ustekinumab).

After the genetic diagnosis was made, biological therapy with ustekinumab was initiated with a dosis regimen as in psoriasis (45 mg on weeks 0 and 4 and thereafter 45 mg every 12th week). Remarkable effect was seen within 3 weeks (figures 1, 4 and 5) and the patient’s quality of life was significantly improved.

Figure 4.

Body (back) 2019 illustrating the treatment response.

Figure 5.

Body (front) 2019 illustrating the treatment response.

Investigations

She was referred to genetic counselling based on a suspicion of PRP. DNA was extracted from peripheral blood and next generation sequencing of CARD14 was performed. A heterozygote missense variant c.412G>A, p.(Glu138Lys) was identified.

Treatment

After the genetic diagnosis was made, biological therapy with ustekinumab was initiated with a dose regimen as in psoriasis (45 mg on weeks 0 and 4 and thereafter 45 mg every 12th week).

Outcome and follow-up

Remarkable effect was seen within 3 weeks and the patient’s quality of life was significantly improved.

Discussion

CARD14 is highly expressed in the skin, and pathogenic variants of the gene are identified in both PRP and psoriasis patients.¹² Typical features of patients with pathogenic variants in CARD14 are early onset of disease, prominent involvement of the face and good response to therapy with ustekinumab.^{10 13} Ustekinumab is a human monoclonal antibody directed against the p40 subunit shared by IL-12 and IL-23—ILs known to cause activation of the nuclear factor kappa B pathway, which in familial PRP is inappropriately active.^{9 14 15}

Craiglow et al made a study of 15 families with CARD14 mutation and with features of both psoriasis and PRP.¹⁰ Topical therapy had been unsatisfying in all cases. Variable response was seen with systemic treatments such as methotrexate, cyclosporine, oral retinoids and biological agents (adalimumab, guselkumab, ixekizumab or etanercept). However, five out of six patients treated with ustekinumab showed near-complete response, the sixth patient showed partial response. The patient had the same mutation as our case (c.412G>A, p.E138K).

A few other reports of patients with familial PRP and CARD14 mutations with response to treatment with ustekinumab have been described.^{13 16 17} This is an example of personalised medicine, which illustrates that genetic testing can work as a helpful tool in choice of treatment. Furthermore, molecular genetic diagnostics in similar cases can also be relevant if patients, like in our case, have fear of passing on the disease, since a molecular diagnosis gives the possibility to offer prenatal diagnostics or preimplantation genetic testing.

Our case represented a woman with lifelong, chronic PRP with early onset and with poor response on therapy, which should lead to consideration of a genetic disorder. Genetic testing identified a pathogenic variant in CARD14, which lead to initiation of ustekinumab with remarkable response in this 70-year-old woman, who has suffered from severe lifelong skin disease. Our case therefore illustrates how genetic diagnostics can influence treatment strategy.

Patient’s perspective.

During my life with juvenile PRP I have tried countless treatments with no effect but with side effects. After acitretin I gave up treatment completely until I found a facebook group and read about a possible good effect of stelara in juvenile PRP.

Stelara is the first medication that has decreased the formation of scaling in my skin that could form in just 4 days. With telara, it is now up to 20 days before the scaling looks like before. The injection interval is 10 weeks and the effect is best from weeks 2 to 8. Although my PRP is not completely cured, as the skin is still a little red and scaly, stelara has reduced my consistent treatments with hour-long baths and the constant use of topical ointments.

Along with stelara I was genetically tested and they found a rare mutation ‘CARD14 c.412>A, p. (Glu138Lys)’. Hereby my fear/inner beliefs are confirmed; that my PRP was a congenital genetic disease either inherited or via a new mutation. In my youth, genetics could not be tested and no one in my family had similar skin problems, but I chose not to have children as not to risk passing on PRP. Today, when I am aware of the mutation in CARD14, I am happy with that decision, as a life with severe PRP involves a lot of special care, distress and opt-outs.

Learning points.

• Chronic pityriasis rubra pilaris is often with poor response on therapy, which should lead to consideration of a genetic disorder.

• Genetic diagnostics can influence treatment strategy.

• Patients with pathogenic variants in CARD14 often show good response to therapy with ustekinumab.