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Netherton syndrome: From apex to nether

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By Warren R. Heymann, MD
March 31, 2021
Vol. 3, No. 13

Dr. Warren Heymann photo
If you are a dermatologist preparing for your board exam, I’ll wager that you can rattle off the classical features of Netherton syndrome (NS, aka Comel-Netherton syndrome) in a heartbeat. The more important question — would you recognize it in real life? I cannot recall ever rendering the diagnosis of NS, although I have considered it on occasion. Recent literature suggests how it may now be easier to diagnose NS. Additionally, novel therapies for NS are on the horizon.

NS (OMIM 256500) is a rare autosomal recessive disorder, due to germline mutation of SPINK5, affecting one in 100,000 to 200,000 live births. Congenital ichthyosiform erythroderma (CIE) and/or ichthyosis linearis circumflexa (ILC), hair shaft abnormalities (notably trichorrhexis invaginata, TI) and an atopic diathesis (elevated serum IgE) characterize the syndrome. NS is often misdiagnosed as atopic dermatitis due to the presence of eczematous skin lesions and other allergies. Neonatal cases may be complicated by hypernatremic dehydration and failure to thrive. (1)

Image for DWII on Netherton syndrome
Image for DWII on Netherton syndrome
Image from reference 6.

NS is caused by variants in the SPINK5 gene (serine protease inhibitor of kazal type 5) encoding LEKTI (lymphoepithelial kazal type‐related inhibitor), which is expressed in the stratified epithelium of the skin, mucosa, and Hassal corpuscles of the thymus. LEKTI deficiency causes a loss of inhibition of serine proteinases such as plasmin, trypsin, elastase, and others This results in unopposed activity of kallikrein‐related peptidase 5 (KLK5), which activates KLK7, KLK14, and elastase 2 (ELA2). Subsequent increased degradation of corneodesmosomal cadherins through increased degradation of desmoglein 1, increased desmosome cleavage, and reduced filaggrin proteolytic processing results. This manifests as detachment of the stratum corneum, thereby contributing to a defective skin barrier, enabling microbe and allergen penetration. (2)

Perhaps the phenotype of CIE can be explained by the finding that patients with NS display increased activity of both transglutaminase 1 (TG1) and serine proteases. Wiegmann et al demonstrated that specific LEKTI domains are crosslinked into the epidermis by TG1. (3)

Williams et al have observed that sequencing of the skin microbiome demonstrates that lesional skin of NS subjects is dominated by Staphylococcus aureus and Staphylococcus epidermidis. In mice, it has been demonstrated that these microbes promote skin inflammation in the setting of LEKTI-1 deficiency due to excess proteolytic activity promoted by S. aureus phenol-soluble modulin α as well as increased bacterial proteases staphopain A and B from S. aureus or EcpA from S. epidermidis. The authors believe these findings demonstrate the crucial need for maintaining homeostasis of host and microbial proteases for disease prevention. (4) Although an atopic diathesis is displayed, there does not appear to be any severe associated systemic immunodeficiency in patients with NS; however, there is conflicting data regarding immunological aberrations. Some of these have been attributed to the observation that IVIG has demonstrated clinical benefit in NS. (2)

Affected hair in NS appears short, dry, dull, and brittle. Trichorrhexis invaginata (TI) or “bamboo hair” is the invagination of affected hairs caused by softness of the cortex in the keratogenous zone. TI may not be obvious in infants with NS, making the diagnosis of NS difficult. Dermatoscopy and reflectance confocal microscopy may be the best way to observe TI. (5) The absence of TI does not exclude a diagnosis of NS. (1) TI often improves with age and may resolve completely. Utsumi et al described a band-like pattern in hairs with polarized light in patients with NS, which were observed more often than TI. A limitation of the study was that the procedure was not compared to other disorders of keratinization — further research will determine if this has the potential to be used as a diagnostic marker for NS. (6) Therapeutic options for NS are of relatively limited value. Topical steroids, topical calcineurin inhibitors, topical retinoids, phototherapy (narrow band UVB, PUVA), acitretin, IVIG, and TNF inhibitors have all been variably successful. (1) Volc et al reported an excellent response to ustekinumab in a 15-year-old girl, speculating that IL-17 and IL-23 inhibitors may also be of value. (7) The most intriguing therapeutic advance for NS is on the horizon. KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. White et al described how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors. (8) The prospect of a precise molecular therapy for NS is scintillating.

Point to Remember: Netherton syndrome may be easily misdiagnosed as atopic dermatitis. The diagnosis may be simplified by dermoscopy, finding either trichorrhexis invaginata or hair banding. The precise molecular treatment of NS utilizing kallikrein 5 inhibitors is currently under investigation.

Our expert’s viewpoint

Albert C. Yan, MD
Professor of Pediatrics and Dermatology
Perelman School of Medicine at the University of Pennsylvania

Our evolving understanding of Netherton syndrome exemplifies the current realization that identifying a causative gene mutation such as with SPINK5 is just one of the first steps in finding potential treatment options. It is now just as important to understand the cascade of effects that a single gene mutation has downstream which will help demonstrate potential therapeutic targets. While the importance of knowing that SPINK5 underlies Netherton syndrome cannot be understated, recently employed treatment options have exploited some of these other downstream effects. The editorial above has already highlighted new work indicating potential benefits of targeting KLK5 inhibitors. In the paper by Williams et al., Staphylococcus aureus plays a significant role in influencing the Netherton syndrome phenotype through mechanisms that increase protease activity and skin barrier disruption. Infectious organisms like Staphylococcus which may proliferate in disrupted skin are known to trigger a Th17 response and treatment of these downstream effects using medications that target IL17 and IL23 have shown some clinical benefit in patients with Netherton syndrome. Teasing out additional pathways affected by mutations in SPINK5 should help not only elucidate our understanding of the disease but also provide additional therapeutic targets for further investigation. Dr. Yan had disclosed financial relationships with the following to the AAD at the time of publication: Aclaris Therapeutics, Inc., BabyDoctor.com, Dermavant Sciences, Johnson & Johnson Consumer Products Company, Ortho Dermatologics, Pfizer Inc., Procter & Gamble Company, Regeneron Pharmaceuticals, Inc., Verrica Pharmaceuticals Inc. Full disclosure information is available.

  1. Saleem HMK, Shahid MF, Shahbaz A, Sohail A, et al. Netherton syndrome: A case report and review of literature. Cureus 2018;10:e3070. doi: 10.7759/cureus.3070.

  2. Stuvel K, Heeringa JJ, Dalm VASJ, Meijers RW, et al. Comel-Netherton syndrome: A local skin barrier defect in the absence of an underlying immunodeficiency. Allergy 2020 Jan 24. doi: 10.1111/all.14197. [Epub ahead of print]

  3. Wiegmann H, Valentin F, Tarinski E, Liebau E, et al. LEKTI domains D6, D7 and D8+9 serve as substrates for transglutaminase 1: Implications for targeted therapy of Netherton syndrome. Br J Dermatol 2019; 181: 999-1008.

  4. Williams MR, Cau L, Kaul D, Wang Y, et al. Interplay of Staphylococcal and host proteases promotes skin barrier disruption in Netherton syndrome. Cell Rep 2020 Mar 3;30(9):2923-2933.e7. doi: 10.1016/j.celrep.2020.02.021.

  5. Chen L, Yang Y, Tian X, Li D, et al. Dermatoscopy of the hair compared to three alternatives for the diagnosis of pediatric Netherton syndrome. J Dermatol 2020 Mar 15. doi: 10.1111/1346-8138.15307. [Epub ahead of print].

  6. Utsumi D, Yasuda M, Amano H, Suga Y, et al. Hair abnormality in Netherton syndrome observed under polarized light microscopy. J Am Acad Dermatol 2020 Feb 3. pii: S0190-9622(19)32571-X. doi: 10.1016/j.jaad.2019.08.024. [Epub ahead of print].

  7. Volc S, Maier I, Gritsch A, Aichelburg MC, et al. Successful treatment of Netherton syndrome with ustekinumab in a 15-year-old girl. Br J Dermatol 2020 Jan 24. doi: 10.1111/bjd.18892. [Epub ahead of print].

  8. White GV, Edgar EV, Holmes DS, Lewell XQ, et al. Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton syndrome. Bioorg Med Chem Lett 2019 Mar 15;29(6):821-825.

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