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Ichthyotic disorders
Published in Biju Vasudevan, Rajesh Verma, Dermatological Emergencies, 2019
Netherton syndrome (NS) is a rare autosomal recessive disorder characterized by erythroderma, ichthyosis, hair shaft defects, and atopy. NS is caused by mutations in the SPINK 5 gene which encodes lymphoepithelial Kazal-type-related inhibitor (LETK1). NS manifests at birth as generalized scaling and erythroderma at birth or during the early infantile period but not with collodion baby phenotype (Figure 22.6) [10]. After 2 years, they develop characteristic ichthyosis called ichthyosis linearis circumflexa (ILC). ILC presents as migratory, polycyclic scaly lesions with a peripheral double-edged scale (Figure 22.7). Associated features include failure to thrive, hypernatremic dehydration secondary to excess fluid loss from the defective skin barrier, delayed growth, short stature, and recurrent infections. Approximately 75% of those with NS develop atopic manifestations with increased serum IgE levels. The pathognomic feature of NS is the hair shaft defect called trichorrhexis invaginata (TI) or a ball-and-socket defect (Figure 22.8). Trichorrhexis nodosa and pili torti can also be seen in NS [11]. Examining eyebrow hairs is more informative for diagnosing hair shaft defects. Histology shows psoriasiform dermatitis. Any child presenting with neonatal erythroderma should be investigated for hair shaft defects to rule out NS.
Hair dysplasias
Published in Pierre Bouhanna, Eric Bouhanna, The Alopecias, 2015
Juan Ferrando, L. Alheli Niebla, Gerardo A. Moreno-Arias
Netherton syndrome is an autosomal recessive geno-dermatosis that is more frequently observed in females and may be associated with trichorrhexis invaginata, atopy, ichthyosis linearis circumflexa, erythroderma ichthyosiformis, and ichthyosis vulgaris.4,40–42
Clinical Aspects and Differential Diagnosis of Atopic Dermatitis
Published in Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld, Atopic Dermatitis and Eczematous Disorders, 2014
Donald Rudikoff, Diana Lee, Steven R. Cohen
Hair-shaft defects and atopic manifestations, such as elevated IgE levels, food allergy, allergic rhinitis, asthma, and eosinophilia can occur concomitantly in Netherton syndrome. The range of hair and scalp abnormalities includes short, brittle hairs, scaly scalp, and a pathognomonic defect termed ‘trichorrhexis invaginata.’ Descriptively, trichorrhexis invaginata occurs when the proximal portion of the hair overlaps the distal portion, creating a likeness to intussusception of the bowel or the stalk of bamboo (known as bamboo hair) (Burk et al. 2008) (Fig 3.62). Dermatoscopic examination of the hair shaft can facilitate early diagnosis (Fig 3.63). Powell (2000) has observed that the density of nodes per unit length of hair is 10 times greater in eyebrow hairs than in scalp hairs; eyebrow hairs should be cut, not plucked. Therefore, examining the eyebrows will offer the highest yield of bamboo hairs. Children with Netherton syndrome typically have sparse hair (Fig 3.64) but this can be seen as well in some patients with AD. Other hair defects such as trichorrhexis nodosa and pili torti have also been described in these patients. Generalized erythroderma in the first months postpartum can make the diagnosis of Netherton syndrome an enormous challenge. However, within the first year of life, classic lesions of ichthyosis linearis circumflexa appear as distinctive, migratory, polycyclic, erythematous plaques with a double-edged scale (Fig 3.65 and see Fig 3.61b).
The role of kallikreins in inflammatory skin disorders and their potential as therapeutic targets
Published in Critical Reviews in Clinical Laboratory Sciences, 2021
Caitlin T. Di Paolo, Eleftherios P. Diamandis, Ioannis Prassas
Netherton syndrome (NS) is a rare hereditary autosomal recessive disorder characterized by congenital ichthyosiform erythroderma, hair abnormality (often described as “bamboo hair”), and continuous peeling of the skin [82]. Excessive TH2 cell signaling and immunoglobin E (IgE) production also play key roles in the pathogenesis of this skin disease [83]. NS has an estimated incidence of 1/100,000–200,000 and the disease manifestations are variable between patients [84]. Mutations in the SPINK5 gene, which encodes the protease inhibitor LEKTI, is responsible for the disease pathophysiology [85]. Elevated SC proteolytic activity has been observed in NS and SPINK5-deficient mice mimic NS in displaying skin protease hyperactivity [86,87]. KLK5 and KLK7 were found to be the main players responsible for the increased desquamation and PAR2-mediated inflammation observed in NS with the lack of functional LEKTI resulting in uncontrolled KLK activity [62,88]. This was further confirmed in mouse-modeling experiments where KLK5 overexpressing mice were found to display all phenotypic hallmarks of NS symptoms and inactivation of KLK5 was seen to delay disease manifestation [89,90]. Notably, it was recently found that the concurrent ablation of KLK5 and KLK7 is both necessary and sufficient to rescue disease phenotype in models of NS [91,92]. Disease severity and phenotype are seen to depend on the degree of serine protease activity and residual skin LEKTI expression [93,94].
Advances in understanding of Netherton syndrome and therapeutic implications
Published in Expert Opinion on Orphan Drugs, 2020
Evgeniya Petrova, Alain Hovnanian
Since the first description in 1949, the understanding of the clinical and biological manifestations of Netherton syndrome and its underlying pathogenesis have considerably improved. It is now clear that this rare and severe genetic skin disease with life-threatening complications in the neonatal period results from defective inhibition of several epidermal proteases, at the forefront of which are KLK5, 7 and 14. Loss of proteolytic regulation results in a profound skin barrier defect leading to skin inflammation, multiple organ allergy and recurrent skin infections where Staphylococcus aureus predominates. Patients’ peripheral lymphocytes display a Th17/Th22 skewing, with debated features of immune deficiency. Murine models have been instrumental to decipher the biological cascades involved, especially constitutive and conditional Spink5 knock-out mice which closely recapitulate the disease phenotype. Patient investigations and murine model characterization have allowed to identify therapeutic targets, involving deregulated proteases and pro-inflammatory cytokines. This has led to the development of different molecules aiming at inhibiting KLK5 and/or KLK7 proteolytic activities and the use of biologics blocking pro-inflammatory cytokines showing significantly increased expression profiles. Several case studies have reported clinical improvement in a small number of NS patients, including intravenous immunoglobulins and diverse biologics such as anti-IL-17A. Clinical trials using existing biologics as well as new molecules under development targeting KLK5 and/or KLK7 hold promise for improved treatment.
Asthma: An Undermined State of Immunodeficiency
Published in International Reviews of Immunology, 2019
Evangelos A. A. Christou, Giuliana Giardino, Evangelia Stefanaki, Fani Ladomenou
The genes ORMDL3 and GSDMB, both encoded in the 17q21 locus, are differentially expressed in asthmatic patients as compared to healthy individuals [4]. Although the function of ORMDL3 is not yet fully described, this gene has been reported to be involved in lung epithelial secretory and stem cell proliferation pathways [15,16]. GSDMB is involved in the unfolded-protein response, which is a cellular mechanism triggered by a variety of stressful events such as infection, as well as in the function of the epithelial barrier [15]. HRV infections have been shown to increase ORMDL3 expression, which in turn increases viral replication and decreases repair capacity [16]. SPINK5 is another gene involved in the maintenance and repair of the epithelia [17,72]. Polymorphisms in SPINK5 gene have been associated with atopy and asthma development [17]. Following a lung infection, SPINK5 expression is downregulated in asthmatic patients compared to healthy individuals [17]. Of importance, loss-of-function mutations in SPINK5 gene cause the Netherton syndrome, which is a rare autosomal recessive disorder that affects the skin and the hair, and causes immune dysfunction [9,73].