Netherton syndrome
Last Updated: 2023-10-12
Author(s): Lindemann H.
ICD11: Q80.8
Last Updated: 2023-10-12
Author(s): Lindemann H.
ICD11: Q80.8
Comel, 1949; Netherton, 1958
Comel-Netherton syndrome, Ichtyosis linearis circumflexa (Rille-Comel) and trichorrhexis invaginata, Erythroderma ichtyoseform congenitum, Bamboo hair syndrome, Tichorrhexis syndrome, SPINK disease, OMIM: 256500
Netherton syndrome is a rare autosomal recessive genodermatosis characterised by a combination of ichthyosis linearis circumflexa, structural hair shaft abnormalities, failure to thrive, immunodeficiency and elevated IgE levels. Cerebral seizures and oligophrenia may occur
The incidence is 1:200,000.
To date, about 150 patients have been described with Netherton syndrome worldwide.
It is estimated that the prevalence of Netherton syndrome may be as high as 1:100,000 or 1:50,000. This is thought to be due to low diagnostic sensitivity resulting from variable phenotypes and overlap with various ichthyoses and atopic dermatitis.
The prevalence of Netherton's syndrome is estimated to be as high as 1:100,000 or 1:000
Biallelic mutations have been detected in the gene of the serine protease inhibitor Kazal type 5 (SPINK5), which encodes the multidomain serine protease inhibitor LEKTI. Premature termination of mRNA translation or missense mutations lead to impairments of the LEKTI protein. LEKTI deficiency causes excessive serine protease function.
LEKTI could be detected in epithelia, thymus, trachea, tonsils, parathyroid gland, stratum corneum and stratum granulosum, but also in skin appendages.
The mutation of the SPINK5 gene causes accelerated degradation of desmoglein 1 and desmosomes in the skin. Horn cells detach. This causes cracks in the stratum corneum and allergens can penetrate more easily through the disturbed skin barrier.
The thymus shows defective T-cell differentiation, resulting in an unbalanced Th2 response and a greatly increased IgE concentration.
Histochemically, a reduced number of disulphide bonds in hair shafts could be determined, resulting in defective hair structures.
Often, congenital ichtyotic erythroderma is seen shortly after birth.
In the majority of cases, the symptoms regress with age and are clinically described as ichthyosis linearis circumflexa. Annular scaling and erythematous plaques are seen on the trunk and extremities, typically fringed by a double-edged scale bar. Scalp involvement is common.
Obligate conditions include rhagades at the corner of the mouth, papillomas in the genital area, alopecia and hair shaft abnormalities (trichorrhexis invaginata (bamboo hair), trichorrhexis nodosa, pili torti). Hair structure damage can vary in severity and often improves with age.
Due to pronounced itching, many patients develop lichenifications in the bending sides and eczematous plaques.
Often there is type I sensitisation to environmental allergens and foods.
Immunohistological staining with LEKTI antibodies.
Molecular genetic tests of the SPINK5 gene.
Prenatal diagnosis in families with known SPINK5 mutations can be done by chorionic villus sampling (from the 10th week of pregnancy).
Children show pronounced skin changes that can affect the entire body.
As they get older, the trunk and extremities are predominantly affected. The scalp may be involved.
An abnormal cleavage is seen in the superficial stratum corneum in the absence of stratum grangulosum. Typically, a psoriasiform epitehl reaction with parakeratosis can be detected.
In the upper dermis, there may be perivascular infiltrates with single neutrophil and eosinophil granulocytes.
Transmission electron microscopy of the hair shafts shows clefts and defective keratinisation, as well as electron-dense deposits in the cortex.
Complications result in particular from a disturbed skin barrier and the frequent congenital immunodeficiency.
About 20% of newborns develop potentially life-threatening complications such as dehydration, electrolyte disturbances, failure to thrive, impaired thermoregulation, pneumonia or sepsis.
In the course, recurrent superinfections may occur.
The majority of patients experience a decrease in clinical symptoms with increasing age.
Newborns with marked skin findings have a high risk of experiencing serious complications due to the impaired skin barrier and should be able to receive intensive care as needed. Failure to thrive and enteropathies may require nutritional support.
Urea/polidocanol/lactic acid/ammonium lactate-containing creams, ointments or lotions have proven effective as external keratolytic therapeutics.
Local therapies with retinoids (e.g. tayarotene) or tacrolimus (Protopic) can be tried.
Systemically, retinoids (e.g. acitretin) have a positive effect on skin and hair changes.
PUVA, UVA1 or balneophototherapy can achieve therapeutic success.
Oral antihistamines help to alleviate pruritus
In off-label use, single case reports show good efficacy of dupilumab. Here, the dosage is the same as the approved dosage for atopic dermatitis (initially 600mg s.c., followed by 300mg every 14 days). Secukinumab has also been used successfully.
