What is Netherton syndrome

Netherton syndrome is a rare hereditary disorder that affects the skin, hair, and immune system. Netherton syndrome is inherited as an autosomal recessive trait. Netherton syndrome is characterized by scaling skin, hair anomalies, increased susceptibility to atopic eczema (a skin condition that can result in dry, red and flaky skin), elevated IgE levels, and other related symptoms. Newborns with Netherton syndrome have skin that is red and scaly (ichthyosiform erythroderma), and the skin may leak fluid. Some affected infants are born with a tight, clear sheath covering their skin called a collodion membrane. This membrane is usually shed during the first few weeks of life. Because newborns with this disorder are missing the protection provided by normal skin, they are at risk of becoming dehydrated and developing infections in the skin or throughout the body (sepsis), which can be life-threatening. Affected babies may also fail to grow and gain weight at the expected rate (failure to thrive). The health of older children and adults with Netherton syndrome usually improves, although they often remain underweight and of short stature.

Netherton syndrome is estimated to affect 1 in 200,000 newborns. There are approximately 150 cases reported in the medical literature, but the true number of affected individuals may be much higher due to diagnostic difficulties and overlapping symptoms with common atopic dermatitis and other congenital ichthyoses.

After infancy, the severity of the skin abnormalities varies among people with Netherton syndrome and can fluctuate over time. The skin may continue to be red and scaly, especially during the first few years of life. Some affected individuals have intermittent redness or experience outbreaks of a distinctive skin abnormality called ichthyosis linearis circumflexa, involving patches of multiple ring-like lesions. The triggers for the outbreaks are not known, but researchers suggest that stress or infections may be involved.

Itchiness is a common problem for affected individuals, and scratching can lead to frequent infections. Dead skin cells are shed at an abnormal rate and often accumulate in the ear canals, which can affect hearing if not removed regularly. The skin is abnormally absorbent of substances such as lotions and ointments, which can result in excessive blood levels of some topical medications. Because the ability of the skin to protect against heat and cold is impaired, affected individuals may have difficulty regulating their body temperature.

People with Netherton syndrome have hair that is fragile and breaks easily. Some strands of hair vary in diameter, with thicker and thinner spots. This feature is known as bamboo hair, trichorrhexis nodosa, or trichorrhexis invaginata. In addition to the hair on the scalp, the eyelashes and eyebrows may be affected. The hair abnormality in Netherton syndrome may not be noticed in infancy because babies often have sparse hair.

Most people with Netherton syndrome have immune system-related problems such as food allergies, hay fever, asthma, or an inflammatory skin disorder called eczema.

The treatment of Netherton syndrome is symptomatic, often difficult, and should be tailored to the patient’s specific needs. Recommendations include the regular use of emollients and moisturizing creams and lotions. Other topical agents should be used with caution because the skin in Netherton syndrome may allow ingredients from some topically applied medications to be absorbed into the blood, which may pose a danger to the child. Topical keratolytic agents such as urea or lactic acid derivatives may be limited by skin irritation and should generally be reserved for older children. The base line treatment also includes oral antihistamines, which can help to control the itchy, eczematous component, and topical or systemic antibiotics as needed. To treat the scaling of the scalp, mild dandruff shampoos and topical steroids might be helpful. Oral and topical steroids are beneficial in reducing inflammation and the eczematous component of the disease. However, the well-documented side effects of long-term steroid use need to be considered. Oral retinoids have been used with varying success, leading to dramatic improvement in some patients and severe worsening of the disease in others.

Figure 1. Netherton syndrome

Footnote: Clinical aspects of Netherton syndrome. a) Congenital erythroderma with scaling. b) Erythroderma with transient alopecia and absence of eyebrows. c) Eczematous-like lesions with fine scaling. d) Severe skin inflammation with superficial desquamation. e) Abnormal hair shaft showing protrusion of its distal part into its proximal part

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Netherton syndrome causes

Netherton syndrome is inherited as an autosomal recessive trait. Netherton syndrome is caused by mutations in the SPINK5 gene. This gene provides instructions for making a protein called LEKT1. LEKT1 is a type of serine peptidase inhibitor. Serine peptidase inhibitors control the activity of enzymes called serine peptidases, which break down other proteins. LEKT1 is found in the skin and in the thymus, which is a gland located behind the breastbone that plays an important role in the immune system by producing white blood cells called lymphocytes. LEKT1 controls the activity of certain serine peptidases in the outer layer of skin (the epidermis), especially the tough outer surface known as the stratum corneum, which provides a sturdy barrier between the body and its environment. Serine peptidase enzymes are involved in normal skin shedding by helping to break the connections between cells of the stratum corneum. LEKT1 is also involved in normal hair growth, the development of lymphocytes in the thymus, and the control of peptidases that trigger immune system function.

Mutations in the SPINK5 gene result in a LEKT1 protein that is unable to control serine peptidase activity. The lack of LEKT1 function allows the serine peptidases to be abnormally active and break down too many proteins in the stratum corneum. As a result, too much skin shedding takes place, and the stratum corneum is too thin and breaks down easily, resulting in the skin abnormalities that occur in Netherton syndrome. Loss of LEKT1 function also results in abnormal hair growth and immune dysfunction that leads to allergies, asthma, and eczema.

Netherton syndrome inheritance pattern

Netherton syndrome is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

• If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
• Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
• This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
• There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
• Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 2 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 2. Netherton syndrome autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Netherton syndrome symptoms

Netherton syndrome presents with the three following characteristics:

1. Ichthyosiform erythroderma – inflamed, red, scaly skin
2. Trichorrhexis invaginata (“bamboo hair”) – short, brittle, lustreless hair
3. Atopic diathesis – predisposition to allergy problems

Individuals with Netherton syndrome may show some or all of these features with varying degrees of severity of their symptoms.

Netherton syndrome may be evident at birth or during the first weeks of life. There is widespread reddening (erythroderma) and the skin is covered in dry fine scales (ichthyosis). An itchy eczematous rash may be present, especially later in childhood. The skin defect causes the skin to be “leaky” and the newborn infant loses heat, water and proteins, which are all essential for normal growth and development. In addition, babies are more at risk of infection, which can be life- threatening in some cases. Newborns with severe symptoms often have a poor prognosis.

For infants with less severe symptoms, many will suffer from a failure to thrive in the first year of life and by the second year of life although the health of most children will start to improve, most will remain underweight and of short stature. Other signs a patient may develop sometime throughout their lifetime include:

• Ichthyosis linearis circumflexa – development of a distinctive circular scaling on the skin. This condition usually occurs after 2 years of age and tends to go through bouts of flaring followed by months of no skin symptoms. The rash is circular and has a thickened horny margin with a slowly changing pattern.
• “Bamboo hair” – a ball-and-socket-type hair-shaft deformity. Most patients will grow sparse, abnormal hair that is short, spiky, lustreless and brittle. Older patients may lose eyebrows and eyelashes altogether. Some patients may appear to have normal-looking hair but the hair shaft is abnormal under the microscope (subclinical trichorrhexis invaginata).
• Allergic manifestations – many patients are prone to develop food allergy, especially to nuts. Most will have a greater likelihood of developing hay fever, asthma and atopic eczema. Patients have high levels of IgE (allergy antibody) in their blood and may suffer attacks of angioedema (severe allergic skin reaction) and urticaria.

Netherton syndrome diagnosis

Netherton syndrome should be at the top of the differential diagnosis list in a newborn with erythroderma and abnormal-looking scalp hair, or in an older child with ichthyosis linearis circumflexa and sparse lustreless hair.

Examination of abnormal hair under microscope shows trichorrhexis invaginata (defects of the hair shafts). This does not usually develop until after 2 years of age but may occur earlier.

Skin biopsy and DNA testing may also be performed to confirm diagnosis.

Netherton syndrome treatment

There is no specific treatment for Netherton syndrome. The goals of treatment are to manage the symptoms and prevent skin infections and other complications.

• Emollients and keratolytics (for example, creams containing urea, lactic acid or salicylic acid) should be applied to keep the skin moist and hydrated
• Antibiotics may be used for skin infections
• Topical steroids may be helpful in older children with eczema but can be absorbed too much in infants with erythroderma causing complications such as pituitary adrenal axis suppression
• Other treatments that have been tried include photochemotherapy (PUVA) and oral retinoids (acitretin and isotretinoin) but these may aggravate the skin problem

Symptoms of Netherton syndrome tend to improve with age. Periods of little or no disease symptoms are interspersed with intermittent exacerbations. Netherton syndrome may increase the risk of skin cancer developing.

Netherton syndrome life expectancy

Netherton syndrome have normal life expectancy. Netherton syndrome erythroderma and hair fragility tends to improve as patients age, but the course can be punctuated by intermittent exacerbations. The erythroderma can change to ichthyosis linearis circumflexa periodically.

Skin colonization and cutaneous infections are common. Cutaneous and systemic infections are common and disturbing consequences in almost all patients with Netherton syndrome.

References

1. Hovnanian, Alain. “Netherton syndrome: skin inflammation and allergy by loss of protease inhibition.” Cell and Tissue Research 351 (2013): 289-300.