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Netherton Syndrome - Causes, Symptoms, Diagnosis, and Treatment

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Netherton syndrome is an extremely rare condition affecting hair, skin, and immune systems. Read the article to know more.

Written by

Dr. Sameeha M S

Medically reviewed by

Dr. Dhepe Snehal Madhav

Published At March 8, 2023
Reviewed AtJanuary 4, 2024

Introduction

Netherton syndrome (NS) is a rare autosomal recessive illness marked by congenital ichthyosis linearis circumflexa (ILC) or ichthyosiform erythroderma (CIE), hair shaft anomalies, and elevated serum IgE (immunoglobulin E) levels (atopic diathesis). It was named after Earl W. Netherton, an American dermatologist who found it in 1958. Netherton syndrome causes red, scaly skin in newborns, and the skin may leak fluid. Some affected babies are born with a collodion membrane, a tight, clear sheath covering their skin. The majority of Netherton syndrome patients have immune-related issues such as asthma, food allergies, hay fever, or eczema, an inflammatory skin illness. Affected individuals may also have delicate hair that breaks readily. Netherton syndrome affects one in every 200,000 births.

What Is Netherton Syndrome?

Netherton syndrome is a rare hereditary illness characterized by three main symptoms. Individuals with Netherton syndrome may exhibit some or all of these characteristics, depending on the severity of their symptoms.

  • Ichthyosiform Erythroderma (CIE) - It is characterized by inflamed, red, scaly skin.

  • Trichorrhexis Invaginata - Hair that is short, brittle, and lacks luster.

  • Atopic Diathesis - It is a tendency to have allergic reactions.

As neonates with Netherton syndrome lack the protection given by normal skin, they are at risk of dehydration and acquiring skin infections or infections throughout the body (sepsis), which can be fatal. Affected babies may also fail to gain weight and grow at the expected rate. People with Netherton syndrome normally improve health with age; however, they frequently stay underweight and low in stature. Some affected individuals exhibit periodic redness or breakouts of ichthyosis linearis circumflexa, a specific skin condition characterized by regions of numerous ring-like lesions. The causes of the outbreaks are unknown, although researchers believe they may be related to stress or infections.

What Are the Causes of Netherton Syndrome?

Mutations in the gene SPINK5 (a tumor suppressor gene) on the long arm of chromosome 5 have been identified as the cause of Netherton syndrome. As Netherton syndrome is an autosomal recessive condition, individuals must inherit two recessive genes from each parent to have this condition. The SPINK5 gene encodes instructions for the production of a protein known as LEKT1 (lymphoepithelial Kazal-type-related inhibitor). LEKT1 functions as a serine peptidase inhibitor. Serine peptidase inhibitors regulate the activity of serine peptidases, enzymes that break down other proteins. LEKT1 is present in the thymus and the skin. LEKT1 regulates the activity of specific serine peptidases in the skin's outer layer (epidermis), which serves as a strong barrier between the body and the surrounding. Serine peptidase enzymes aid natural skin shedding by breaking the connections between stratum corneum cells. LEKT1 is also involved in hair growth, lymphocyte formation in the thymus, and peptidase regulation that activates immune system function.

SPINK5 gene mutations result in a LEKT1 protein that cannot modulate serine peptidase activity. The absence of LEKT1 function permits serine peptidase overactivity and breaks too many proteins in the stratum corneum. As a result, there is excessive skin shedding, and the stratum corneum is excessively thin and readily breaks down, resulting in skin abnormalities associated with Netherton syndrome. Loss of LEKT1 function also causes atypical hair growth and immunological malfunction, which can lead to asthma, allergies, and eczema.

What Are the Clinical Features of Netherton Syndrome?

Netherton syndrome can be identified at birth or in the first few weeks of life. The clinical symptoms associated with Netherton syndrome are the following.

  • Skin inflammation.

  • Bamboo hair (hair shaft defect).

  • Severe dehydration.

  • Susceptibility to infection.

  • Ichthyosis.

  • Reddish, scaly skin.

  • Fragile hair.

  • Premature birth.

  • Trouble gaining weight.

  • Atopic dermatitis.

  • Food allergy.

  • Urticaria.

  • Circular scaling of the skin.

How Is Netherton Syndrome Diagnosed?

The diagnosis of Netherton syndrome is based on clinical suspicion and findings. The presence of scaling erythroderma, anomalies in the hair shaft, a history of Netherton syndrome in a sibling, and the detection of a germline SPINK5 mutation by DNA sequencing are the findings used for diagnosing Netherton syndrome. The identification of SPINK5 mutation by DNA sequencing supports the diagnosis of Netherton syndrome. However, the cost of doing DNA sequencing analysis restricts its application in diagnosis. Skin biopsy and microscopic examination of abnormal hair follicles can also be used as diagnostic tools for Netherton syndrome.

What Are the Treatment Options for Netherton Syndrome?

There is no recognized treatment for Netherton syndrome; however, several things can be done to reduce the symptoms. Moisturizers are particularly effective in Netherton syndrome for reducing skin scaling or cracking. Anti-infective medications are also useful for the skin vulnerable to infection. Netherton syndrome treatment is symptomatic, often challenging, and should be personalized to the patient's unique needs. Regular use of moisturizing creams, emollients, and lotions is advised. Other topical medicines should be used with caution since the skin in Netherton syndrome may allow some topically applied pharmaceuticals to be absorbed into the blood, posing a risk to the patient.

Oral antihistamines are also used in Netherton syndrome patients to manage itchy and eczematous skin. Mild dandruff shampoos and topical steroids may be useful in treating scalp scaling. Both oral and topical steroids can help reduce skin inflammation and eczema. Oral retinoids like Acitretin, Isotretinoin, and photochemotherapy (PUVA) have also been tried for Netherton syndrome; however, these may aggravate skin issues in some patients. Treatment options for severe sickness include anti-TNF (tumor necrosis factor) and intravenous immunoglobulin. Intravenous immunoglobulin therapy significantly improves patients' quality of life by reducing infection. It also enables improvement and even resolution of skin and hair problems.

Conclusion

Netherton syndrome is a rare inherited disorder characterized by scaling skin, hair anomalies, greater susceptibility to atopic dermatitis (dry, red, and flaky skin), raised IgE levels, chronic skin inflammation, stunted growth, and other symptoms. It is an autosomal recessive disorder. This syndrome is related to mutations in the SPINK5 gene. This gene encodes LEKTI protein, a serine protease inhibitor. Mutations in the SPINK5 gene increase protease enzyme activity and skin defects. The affected individuals are more susceptible than healthy people to infections of various kinds, including recurring staphylococcus skin infections and other severe infections.

Dr. Dhepe Snehal Madhav
Dr. Dhepe Snehal Madhav

Venereology

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