Netherton Syndrome with a Novel Likely Pathogenic Variant c.420del (p.Ser141ProfsTer5) in SPINK5 Gene: A Case Report

Netherton syndrome (NS) is a rare autosomal recessive genodermatosis with an estimated incidence of 1:200,000 newborns, predominantly affecting females. It is characterized by congenital ichthyosiform erythroderma, atopic diathesis (including food allergies and asthma), recurrent skin infections, elevated serum IgE levels, and delayed physical development. The pathognomonic feature is trichorrhexis invaginata (TI), a hair shaft abnormality also known as "bamboo hair." NS is caused by mutations in the SPINK5 gene on chromosome 5q32, which encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI). LEKTI regulates proteolytic enzymes (kallikreins) and profilaggrin processing; its deficiency leads to premature corneodesmosome degradation, impaired skin barrier function, and chronic inflammation. Clinical severity varies from mild ichthyosis linearis circumflexa to severe exfoliative erythroderma, which can be fatal in neonates due to dehydration, hypothermia, and sepsis.

This case report describes a 6-year-old boy with NS. He was born at 37 weeks of gestation (birth weight 3,350 g, height 53 cm) after a second normal pregnancy. At birth, he was diagnosed with congenital ichthyosiform erythroderma and admitted to the neonatal intensive care unit on day 5 for neonatal infection and poor general health, presenting with severe erythema, edema, and serous exudate. He was treated with intravenous antibiotics, human albumin, systemic antihistamines, and topical corticosteroids and emollients. Despite treatment, his skin remained red, dry, and covered with erosions and yellowish foul-smelling scales. At age 6, he was in good general health with normal neuropsychological development but slightly delayed physical development: height 109.5 cm (10th percentile), weight 19 kg (25th percentile), BMI 17. Dermatological examination revealed diffuse erythema and lamellar desquamation on the scalp, face, thorax, and extremities, with well-contoured erythematosquamous plaques covered by large yellowish scales on extensor surfaces of upper limbs, thighs, and posterior lower legs. Squamous crust plugs were present in the external auditory canals. Trichoscopy of the scalp demonstrated TI. The child had fragile, brittle hair; eyebrows and some eyelashes were missing. Ophthalmological evaluation identified ectropion of both eyes with lagophthalmos, slight ptosis of the right upper eyelid, and retraction of the lower eyelid. Fluorescein staining revealed keratitis with two paracentral corneal defects in each eye; lenses and fundi were normal. Histopathological examination of skin showed hyperkeratosis with parakeratosis and psoriasiform epidermal hyperplasia. Laboratory tests were normal except for 25-OH vitamin D deficiency (39.99 nmol/L) and elevated IgE (173 IU/mL; normal <90 IU/mL for ages 6–9). Microbiological skin culture grew Proteus mirabilis. Radiographs showed delayed ossification in the right palm and wrist, and bone age corresponded to 4 years. Genetic testing was performed using next-generation sequencing with the TruSight One Expanded Sequencing Panel (Illumina) targeting exons and exon-intron boundaries of 6,699 clinically relevant genes. Variants were interpreted using the ACMG five-tier classification. Two variants in the SPINK5 gene were identified: a pathogenic nonsense mutation c.1530C>A (p.Cys510Ter) inherited from the mother, and a likely pathogenic frameshift mutation c.420del (p.Ser141ProfsTer5) inherited from the father. The paternal variant is novel and has not been previously reported. Segregation analysis confirmed that the proband's elder brother was a heterozygous carrier of the paternal variant only. The patient was treated with acitretin 0.5 mg/kg/day for 3 months, but this led to worsening of skin condition with severe thinning and erosion due to persistent erythroderma, necessitating discontinuation. Other treatments included gentamycin 40 mg i.m. daily for 7 days, levocetirizine dihydrochloride solution, cholecalciferol 2,000 IU daily, topical emollients (white soft paraffin/liquid paraffin 50:50), and ophthalmological care with tobramycin eye drops, dexpanthenol 5% eye gel, and artificial tears.

This case underscores the critical role of genetic testing in confirming NS diagnosis, particularly when clinical features are atypical. The novel frameshift variant expands the mutation spectrum of SPINK5 and correlates with a severe phenotype. Acitretin therapy was ineffective and exacerbated skin lesions, consistent with some previous reports. Alternative treatments, such as biologics (e.g., anti-TNF-α inhibitors, dupilumab, ixekizumab, anakinra), have shown promise in severe NS and may be considered. Multidisciplinary management involving dermatology, ophthalmology, endocrinology, and genetics is essential for addressing the diverse manifestations of NS, including growth retardation, vitamin D deficiency, and ocular complications. Early diagnosis and tailored therapeutic strategies can improve quality of life and prevent complications.