Netherton Syndrome

Netherton Syndrome

Overview

Netherton syndrome is a rare genetic disorder that affects the skin, hair and immune system. The disease causes scaly skin sparse, thin, easily breakable hair and increased susceptibility to allergies and dry, flaky, red skin (atopic eczema). Symptoms appear at birth and can be severe and life-threatening; however, they tend to improve in adulthood. Netherton syndrome is caused by changes (variants) in the SPINK5 gene and is inherited in an autosomal recessive pattern.

Netherton syndrome falls within a group of skin diseases called ichthyoses. Ichthyoses cause scaling of the skin because of abnormalities with how skin cells develop and shed. The skin barrier is defective in Netherton syndrome, which can increase the risk of infection. Symptoms and their severity differ from person to person.

Genetic testing is required for diagnosis of Netherton syndrome. No specific treatment is approved for the disease in particular, but many options exist for minimizing symptoms and targeting the immune system

The characteristic symptoms of Netherton syndrome were described separately by different physicians at different time periods. Skin findings of the disease were first described by Comel in 1949 and hair findings were described by Netherton in 1958. In 1964, Wilkinson described the combination of these skin and hair findings along with an increased risk of allergies, all of which now define the collection of symptoms that are characteristic of Netherton syndrome

Symptoms

Netherton syndrome is characterized by three typical findings:2

Ichthyosis linearis circumflexa, a skin condition that includes red (erythematous), circular plaques that are scaly on their border and that spread across the body

Trichorrhexis invaginata, or bamboo hair, that refers to changes at the hair shaft that cause thin, short, fragile hair

Increased tendency to develop allergies (atopy)

Symptoms are different for each person and tend to improve with age. For instance, some people with Netherton syndrome will have only ichthyosis linearis circumflexa while others have bright red skin everywhere, as they did as a baby.2 Newborns usually do not have ichthyosis linearis circumflexa, as it often develops later in childhood or adulthood.

Skin symptoms can appear immediately after birth or take a few weeks to develop and may include:3,4

Widespread scaly, reddened skin (erythroderma) at birth or within the first few weeks after birth

Thick, waxy covering on the skin known as a collodion membrane presenting at birth

At birth, the characteristic hair defect in Netherton syndrome may not be noticeable, as all babies have sparse hair in their first months of life.4

Later, patches of hair loss may appear and the scalp hair that does grow is often dry, dull, and short

Eyebrows and eyelashes may also be affected

Additional characteristics may include: 2,4

Increased predisposition to allergies including:

Multiple food allergies

Hay fever (allergies to substances in the air)

Asthma and eczema (are also common)

Short stature

Slow growth

Pancreatic insufficiency (lack of digestive enzymes)

Intellectual disabilities

Causes

Netherton syndrome is caused by changes (variants) in the SPINK5 gene, located on the chromosome 5q32.5 The SPINK5 gene encodes an enzyme (lymphoepithelial Kazal type inhibitor [LEKTI]) that serves as the brake on the activity of certain proteases (enzymes that digest protein) in the skin.2 The impaired LEKTI enzyme of Netherton syndrome leads to overactivity of proteases called kallikreins. Increased protease action in the skin results in too few layers of the outer skin (stratum corneum) and decreased production of ceramides, which are fats that moisturize the skin and allow it to protect the body from infection.2,6 LEKTI is also normally present in hair follicles, so its impairment in Netherton syndrome accounts for hair symptoms as well. Many types of SPINK5 gene variants are associated with Netherton syndrome.2

SPINK5 gene variants also appear to affect the immune system. Most people with Netherton syndrome have increased numbers of IgE antibodies and eosinophils.2 Both IgE antibodies and eosinophils are types of immune cells involved in the immune response to allergies.

Netherton syndrome follows an autosomal recessive inheritance pattern.2 Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Affected populations

Netherton syndrome is estimated to affect 1 to 9 per 1 million people and is thought to occur in 1 out of 200,000 newborns.6,7 More females than males are affected.7 Because some patients have only mild skin findings that could be misdiagnosed as other dermatologic conditions, Netherton syndrome is suspected to be underdiagnosed. Around 20% of erythroderma (skin redness) cases in newborns are attributed to Netherton syndrome.2

Disorders with Similar Symptoms

Symptoms of the following disorders may be similar to those of Netherton syndrome. Comparisons can be useful for a differential diagnosis.

Netherton syndrome is a type of ichthyosis and can be mistaken for other ichthyoses with similar skin symptoms. Ichthyoses, a type of hereditary “epidermal differentiation disorder”, is a general term describing a group of scaly skin disorders. Ichthyoses are characterized by abnormalities in the skin growth and shedding cycle — skin cells may grow normally but shed slower, grow faster than they shed, or shed faster than they grow.8

Other ichthyoses that are inherited and present at birth (congenital) with symptoms similar to Netherton syndrome include congenital ichthyosiform erythroderma and lamellar ichthyosis. Newborns with congenital ichthyosiform erythroderma or lamellar ichthyosis are usually born with a collodion membrane that later changes to some skin reddening and thick, plate-like scale in cases of lamellar ichthyosis and widespread reddening and small, white scales in cases of congenital ichthyosiform erythroderma. The hair shaft abnormality and increased allergies of Netherton syndrome are not present with lamellar ichthyosis or congenital ichthyosiform erythroderma. The diseases are also differentiated by the genetic variants that cause their symptoms (see “Lamellar Ichthyosis” and “Congenital Ichthyosiform Erythroderma” in the Rare Disease Database).8-10

Other disorders that share similar skin symptoms with Netherton syndrome include erythrodermic psoriasis, atopic or seborrheic dermatitis and exfoliative ichthyosis; however, these conditions affect the skin and do not share hair breakage (although there may be hair loss associated with the red, scaling scalp).2 Netherton syndrome, and especially mild cases, is most often confused with atopic dermatitis or eczema, which similarly has widespread redness and scaling of skin, itch, high levels of immunoglobulin E (IgE) and increased risk of skin infections.

Acrodermatitis enteropathica and severe dermatitis, multiple allergies and metabolic wasting syndrome can present with similar skin findings, hair loss and stunted growth, but the underlying hair shaft abnormality (trichorrhexis invaginata) and the increased allergies of Netherton syndrome are not present with these disorders.2 Primary immunodeficiencies (genetic disorders that cause the immune system to malfunction), like hyperimmunoglobulin E syndrome and Omenn syndrome, have similar skin findings and increased levels of IgE antibodies, but trichorrhexis invaginata is not an associated symptom.2,11 Peeling skin syndrome type B — an inherited disorder that causes a deficiency in the protein corneodesmosin, which normally helps keep the outer layer of skin intact — shares similar skin, allergic and stunted growth symptoms with Netherton syndrome.2

Netherton syndrome can be diagnosed and differentiated from these disorders through clinical findings with the diagnosis confirmed by genetic testing.

Diagnosis

A diagnosis of Netherton syndrome may be suspected based on the presence of allergic disease and at least one of the characteristic symptoms (ichthyosis linearis circumflexa or trichorrhexis invaginata) and a family history of Netherton syndrome. Genetic testing that shows SPINK5 gene variants consistent with the disease is necessary to confirm a diagnosis of Netherton syndrome. Diagnosis before birth (prenatal diagnosis) is available to diagnose a fetus with a family history of the disease.2

In some patients, other tests may be necessary to increase suspicion for Netherton syndrome and eventually order genetic testing. Netherton syndrome should be suspected in any infant with erythroderma and in any child with skin symptoms of ichthyosis linearis circumflexa or eczema that does not improve with to treatment.2 Patients with sparse and fragile hair can be tested for trichorrhexis invaginata by having their hair examined under a microscope or dermatoscope. However, only a portion of hairs in people with Netherton syndrome may be affected by trichorrhexis invaginata. Samples should be taken from many hair strands from multiple areas of the scalp and from eyebrows, which may be more likely to show signs of the condition.2

For patients with unclear signs of ichthyosis linearis circumflexa and trichorrhexis invaginata and with skin symptoms that overlap with other diseases, examining the skin under the microscope (histology testing) and staining it for the presence of the affected enzyme in Netherton syndrome (LEKTI), if available, may help support the diagnosis if the test shows that the enzyme is lacking.2

Standard Therapies

The treatment of Netherton syndrome is based on the affected individual’s age and specific symptoms. Because of the potential for serious complications in infants with Netherton syndrome, infants with erythroderma should be monitored in the hospital and treated for dehydration, infection and malnutrition if these issues arise.2

Recommendations for children and adults include the regular use of emollients and moisturizing creams and lotions. These moisturizing agents should be applied several times a day, especially after bathing, to protect the skin barrier.12 If the skin becomes infected, topical or systemic antibiotics may be prescribed and antiseptics can be used, including diluted bleach baths. Antiseptics may also be used to prevent skin infections. Oral antihistamines, which can help control the itchy, eczematous component and topical or systemic antibiotics may also be needed occasionally.2,4

Other topical medications that may be prescribed for Netherton syndrome include topical corticosteroids, retinoids, topical keratolytics, topical protease inhibitors and topical calcineurin inhibitors (some of these medications have undergone and some are currently undergoing further investigation for their effectiveness in Netherton syndrome). The use of topical keratolytic agents that increase skin shedding, such as urea or lactic acid derivatives, may be limited by skin irritation and should be avoided, especially in infants.6 In general, topical agents should be used with caution because the skin in Netherton syndrome has a very poor barrier and may allow ingredients to be absorbed into the blood, which may pose a danger, especially to infants and children.2,6 Patients with Netherton syndrome are at risk of vitamin D deficiency and should take vitamin D supplements as well.

Phototherapy with narrow band ultraviolet light may also be recommended to treat skin symptoms by altering immune cells in the skin. A newer therapy is the use of biologics; both a biologic used for atopic dermatitis (dupilumab) and biologics used for psoriasis (secukinumab and ustekinumab) have been used with improvement in many patients, but response is unpredictable. Another treatment that improves the abnormal immune system called JAK inhibition has helped others, but should be used with caution, especially because individuals with Netherton syndrome have an increased risk of skin cancers, especially squamous cell carcinoma, and there is concern regarding safety because of the increased cancer risk. People with Netherton syndrome should have regular skin examinations to check for warts and skin cancer.2

Oral tolerance induction may be used to address food allergies. This method involves gradually introducing more and more of an allergen through the oral route to make the immune system less reactive to the allergen.6 To treat overall symptoms, including immune dysfunction, intravenous immune globulin treatment can be used in children and adults with Netherton syndrome.2 This treatment involves injecting patients with antibodies from healthy individuals to alter their immune dysfunction.

Genetic counseling is recommended for affected individuals and their families to clarify the genetic and clinical characteristics, the inheritance and the recurrence risks of the condition in their families

Type of Doctor Department : Primary care physician, dermatologist, and a geneticist