Angela Hernández-Martín, Rebeca Kennedy-Batalla, Elvira Cañedo, Esther Bernaldo-de-Quirós, Begoña Carazo-Gallego, Angel Vera, Antonio Torrelo, Lucero Noguera-Morel, Rogelio González-Sarmiento, Marieke Bolling, Marta Martínez-Bonet, Marjorie Pion, Rafael Correa-Rocha.
N Engl J Med 2019 Nov 28;381(22):2176-2178.
The SAM syndrome, which is characterized by severe dermatitis, multiple allergies, and metabolic wasting (Online Mendelian Inheritance in Man number, 615508), is a congenital skin disease caused by mutations in the genes encoding either desmoglein-1 (DSG1) or desmoplakin (DSP).
These mutations result in reduced epidermal integrity, which may be lethal in children because of recurrent sepsis and extreme undernourishment. The immunopathogenic mechanisms remain uncertain, and no treatments have been available.
A 9-month-old girl was referred to our practice because of severe erythroderma and failure to thrive. The infant had a clinical presentation of a SAM-like syndrome, but the genetic analysis was not conclusive (see the Results section in the Supplementary Appendix, available with the full text of this letter at NEJM.org). In addition to the erythroderma, the infant had hypotrichosis (lack of hair growth), diffuse yellowish hyperkeratotic plaques, warty palmoplantar hyperkeratosis, and onychodystrophy affecting all the nails on the hands and feet (Figure 1A). Refractory pruritus prevented the infant from sleeping despite high doses of antihistamines. Her risk of death was increased by recurrent episodes of sepsis and the presence of severe growth retardation, with a weight of 4.6 kg (z score, –4.8 SD), a length of 59 cm (z score, –5.0 SD), and a weight-for-height z score of –2.3 SD.
Available treatments targeting Th17 cells include biologic drugs that are currently licensed for psoriasis therapy, such as ustekinumab and secukinumab.4 Ustekinumab was recently evaluated, with encouraging results, in two patients with DSP mutations,5 but we had obtained little cutaneous improvement in another patient with SAM syndrome who had DSG1 mutations. Because 99% of the Th17 cells in our patient had a memory phenotype, we hypothesized that long-survival memory Th17 cells would not be vulnerable to the neutralization of interleukin-23 (as with ustekinumab), whereas secukinumab could neutralize the effect of the preformed Th17 pool by blocking the action of interleukin-17A on the skin.
We initiated therapy with 75 mg of secukinumab subcutaneously at weeks 0, 1, 2, 3, and 4 and then monthly on a compassionate-use basis when our patient was 18 months of age. The improvement was evident 3 weeks after treatment initiation (Fig. S3). At week 35, the patient showed a marked cutaneous improvement (Figure 1B), the pruritus had almost disappeared, her weight and length charts had improved dramatically (Figure 1F and 1G), and the weight-for-height z score had increased from −2.3 SD to +1.9 SD (Table S3).
The major effect of secukinumab on our patient’s quality of life supports interleukin-17A as a new target to treat patients with serious skin disorders, such as SAM syndrome. Furthermore, our study proposes an innovative strategy to identify individualized immune biomarkers to exploit with precision the biologic therapeutic arsenal.
Imbalance in T-Helper 17 Cells and Targeted Therapy in an Infant with SAM-like Syndrome – PubMed (nih.gov)