INTRODUCTION
Netherton syndrome (NS) is a rare autosomal recessive genodermatosis with an incidence of 1 : 200 000 [1]. The pathogenesis of NS leads to the dysfunction of the epidermal barrier. Under physiological conditions, epidermal integrity and keratinocyte turnover are regulated by a balance between the activity of serine proteases, such as kallikrein-related peptidase 5, 7 and 14 (KLK5, KLK7, KLK14), and their inhibitors, mainly by lymphoepithelial Kazal-type related inhibitor (LEKTI) [2, 3]. Serine proteases facilitate the exfoliation of mature keratinocytes through the degradation of corneodesmosomal components: desmoglein 1, desmocollin 1 and corneodesmosin. Moreover, KLK5 initiates the production of pro-inflammatory cytokines via the stimulation of protease-activated receptor 2 (PAR2). In NS, the mutation in the SPINK5 gene results in a reduction in the secretion of LEKTI. This leads to an uncontrolled and increased activation of KLK5, which causes the loss of intercellular keratinocyte connections and chronic inflammation. The dysfunctional epidermal barrier enables the penetration of pathogens and allergens deeper into the skin, which further exacerbate the cutaneous inflammatory response (fig. 1) [2, 3]. Atopic diathesis is a leading symptom of NS. Therefore, patients with severe atopic lesions and an inadequate response to the treatment, require a particularly detailed differential diagnosis. Clinically, the presence of distinctive erythematous plaques with double-edged scales, as well as thin, brittle, and sparse hair can be observed. These findings form a characteristic triad of NS, which consists of: atopic manifestations, congenital ichthyosiform erythroderma or ichthyosis linearis circumflexa, and hair shaft abnormalities (trichorrhexis invaginata) [4].
Figure 1
The pathogenesis of Netherton syndrome. A – Balance between KLKs and LEKTI facilitates physiological keratinocyte turnover and integrity of the epidermis. B – Disrupted epidermal barrier enables pathogen and allergen penetration into the skin, which aggravates cutaneous inflammatory response. C – LEKTI deficiency leads to corneodesmosomal degradation, inflammation and atopic diathesis
Due to the variable clinical manifestations and non-specific histopathological findings in NS, novel non-invasive diagnostic approaches are becoming increasingly valuable. Reflectance confocal microscopy (RCM) and line-field confocal optical coherence tomography (LC-OCT) yield high-resolution images that visualize dermal structures at the cellular level. In addition, RCM and LC-OCT enable the observation of skin lesions in a number of anatomical regions, whereas a biopsy involves a removal of a small skin sample from one or few locations. Therefore, non-invasive diagnostic techniques provide a more comprehensive presentation of the disease. LC-OCT offers both vertical and horizontal images, thus allowing a three-dimensional reconstruction of the lesions, compared to a two-dimensional histopathological examination. Moreover, real-time observation makes it possible to directly correlate the specific type of keratosis disorder with the patient’s clinical condition.
OBJECTIVE
This report presents the usefulness of non-invasive imaging in the diagnosing of NS in a 3-year-old child.
CASE REPORT
A 3-year-old girl presented with a history of recurrent eczematous rash and pruritus since the age of 6 months. Clinically, erythematous polycyclic plaques with peripheral scaling were found on the trunk, face, upper and lower extremities (fig. 2). Dermoscopy showed white-yellow double-edged scale, linear and dotted vessels (fig. 3). Additionally, a detailed physical examination revealed the hair to be noticeably short and brittle. Trichoscopy showed bamboo hairs and golf tee-like endings (fig. 4). Morphology and serum IgE levels were within the normal range. No other chronic diseases were reported by the patient’s mother, and family history was negative for dermatological conditions. RCM and LC-OCT imaging revealed scaling, parakeratosis, loosening of keratinocyte attachments, dermal papillae of varying sizes indicative of acanthosis, and sparse perivascular inflammatory infiltrates (figs. 5–7). A histopathological examination was conducted on a skin specimen taken from the trunk. The results demonstrated abnormal keratinization of the cap-like parakeratosis over a thickened granular layer. Additionally, the disintegration of intercellular junctions between keratinocytes and acanthosis were evident, supporting the observations made by LC-OCT and RCM (fig. 8). We did not perform LEKTI immunostaining, although many patients with NS exhibit an absence of LEKTI in the epidermis and hair follicles, which may facilitate the diagnosis of NS [5]. Direct immunofluorescence examination of the skin specimen revealed granular IgM deposits at the dermoepidermal junction. The indirect immunofluorescence test yielded a negative result.
Figure 2
Erythematous polycyclic plaques with peripheral scaling on the trunk (A) and lower extremities (B)
Figure 5
RCM image (horizontal view) revealing uneven stratum corneum (A) and loosened keratinocyte junctions (B)
Figure 6
LC-OCT image (horizontal view) demonstrating dermal papillae of varying sizes indicative of acanthosis (red arrows), sparse perivascular inflammatory infiltrates (white arrows) and loosening of intercellular junctions between keratinocytes (yellow arrows)
Figure 8
Histopathology of the skin specimen from the trunk shows epidermal spongiosis (orange arrows), mounds of parakeratosis (blue arrow), and thickened granular layer (green arrow) indicating disturbed keratinization
A genetic test was conducted to confirm the diagnosis of NS. It identified pathogenic and potentially pathogenic variants within the SPINK5 gene, substantiating the diagnosis of congenital ichthyosis.
Prior to the diagnosis of NS, the girl was treated ineffectively with topical corticosteroids. She did not tolerate topical calcineurin inhibitors. The current treatment plan included daily usage of emollients and syndets. She was advised to use mometasone cream on the skin lesions once a day for 3 days, followed by a twice-weekly dosage. Keratolytic gel and topical minoxidil were used on the scalp three times a week. Additionally, desloratadine was prescribed. This treatment resulted in the reduction of skin lesions, along with an improvement in hair length and density.
DISCUSSION
NS belongs to the group of congenital ichthyoses, which are manifested by abnormal keratinization. Clinical features of NS include ichthyosiform erythroderma that often evolves into ichthyosis linearis circumflexa, thin, dull, and brittle hair, atopic diathesis and recurrent infections. Trichoscopy shows unique findings – bamboo hairs (trichorrhexis invaginata) and golf tee-like endings [6]. In addition, trichorrhexis nodosa and pili torti may also be observed, however they are not exclusive to NS [7, 8]. All of these hair abnormalities can also be detected in a trichogram. However, this method is less convenient compared to the non-invasive diagnostic techniques. Since typically only a small fraction of hairs is affected, numerous samples from different parts of the scalp have to be collected and examined to detect an instance of trichorrhexis invaginata.
Topical treatment was partially effective for our patient, however there is currently no approved drug for NS. Standard therapeutic options for more severe and recalcitrant cases include narrow-band ultraviolet B (NB-UVB) phototherapy, oral retinoids and intravenous immunoglobulin treatment. A novel approach to the treatment of NS involves the use of biologics such as dupilumab, secukinumab, infliximab, spesolimab, ustekinumab and anakinra as well as Janus kinase (JAK) inhibitors mainly abrocitinib and upadacitinib. Dupilumab, an IL-4R-alpha antagonist, that selectively inhibits signalling through IL-4 and IL-13, deserves special acknowledgement. It is approved for atopic dermatitis treatment in patients aged 6 months and older. A growing number of studies show its efficacy and safety also in NS. By suppressing Th2-mediated inflammation, dupilumab reduces skin lesions and pruritus and importantly improves the quality of life. Hair growth as well as decrease in eosinophilia and serum IgE level were also observed in some patients. New therapeutic options, mainly targeting KLK5, 14, and 7 are being under development [9–15].
As presented in our case and literature data, the delay in effective symptom management in NS often results from misdiagnosis due to its high similarity to other diseases associated with hyperkeratosis, erythroderma and atopy [16, 17]. NS is repeatedly confused with other congenital ichthyoses, erythrodermic psoriasis, generalized seborrheic dermatitis, staphylococcal scalded skin syndrome, atopic dermatitis and Omenn syndrome (table 1) [4, 18–33]. Based on our experience, the utilization of non-invasive skin imaging techniques is a valuable approach in preventing such diagnostic errors.
Table 1
Differential diagnosis of Netherton syndrome
| Disease | Histopathological findings | Clinical features |
|---|---|---|
| Erythrodermic psoriasis [18–21] | ||
| Seborrheic dermatitis [22, 23] | ||
| Staphylococcal scalded skin syndrome [24] | ||
| Atopic dermatitis [25, 26] | ||
| Omenn syndrome [27–29] | ||
| Lamellar ichthyosis (LI) and congenital ichthyosiform erythroderma (CIE) [30–32] | LI:CIE: | |
| Exfoliative ichthyosis [33] |
The main non-invasive techniques currently used in clinical practice for in-depth skin imaging are RCM and OCT. RCM enables the observation of the skin structure in horizontal sections with quasi-histological resolution. The maximum imaging depth of 350 μm limits the examination to the epidermis, dermoepidermal junction and upper layers of the dermis. Confocal microscopy has proved to be effective in the diagnosis of melanocytic lesions and pigmented diseases, while increasing evidence supports its use in inflammatory and infectious diseases [34]. Compared to RCM, a greater depth of penetration into the skin tissue and lower resolution of the vertical images are characteristic features of OCT imaging. This method is employed for the diagnosis, treatment and monitoring of non-melanoma skin cancers and pre-cancerous lesions [35]. Developed in 2018 and commercialized in 2020, line-field confocal optical coherence tomography (LC-OCT) is the latest advancement in non-invasive imaging techniques that combines the properties of both previously described methods. LC-OCT imaging provides a three-dimensional visualization of the skin with a resolution close to RCM and OCT penetration depth, thus it provides the most comprehensive structural image of different diseases [36].
Although non-invasive techniques cannot yet replace the diagnostic value of classic histopathological examination with immunohistochemical staining, their advantage is painless, real-time, dynamic in vivo imaging of the skin. The implementation of these methods in clinical practice not only facilitates improved differential diagnosis but also enables the precise location of the site of surgical intervention and monitoring of the course of the disease and response to treatment. Creating and updating image databases for both common and rare dermatological diseases is important for spreading the applicability of these techniques. In the English-language literature we have not found the description of LC-OCT presentation of NS. This imaging technique revealed scale, parakeratosis, spongiosis, acanthosis and sparse perivascular inflammatory infiltrates.
CONCLUSIONS
The purpose of our report is to encourage the inclusion of NS in the differential diagnosis of recurrent erythematous lesions with co-occurring atopy. Moreover, we highlight the importance and utility of non-invasive methods such as RCM and LC-OCT in dermatological examination in order to accelerate and improve the diagnostic pathway of such diseases.
