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Last updated: 10/7/2024
Years published: 1988, 1989, 1993, 1997, 1999, 2004, 2005, 2024
NORD gratefully acknowledges Amy S. Paller, MD, Walter J. Hamlin Professor and Chair of Dermatology, Professor of Pediatrics, Northwestern University, Feinberg School of Medicine, for assistance in the preparation of this report.
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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.
Introduction
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.1
Netherton syndrome is characterized by three typical findings:2
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
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
Additional characteristics may include: 2,4
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.
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
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
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.6
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.12
In adults with Netherton syndrome, biologics can also treat overall symptoms. Biologics are medications that target specific functions of the immune system. Biologics prescribed for Netherton syndrome include infliximab, anakinra, ixekizumab, secukinumab, ustekinumab and dupilumab.2,4,14 Studies are underway to investigate how well some of these biologics treat Netherton syndrome.
A treatment under investigation for Netherton syndrome based on understanding its cause is kallikrein inhibition (a type of protease inhibitor). Because skin abnormalities in Netherton syndrome are linked to overactivity of kallikrein, kallikrein inhibitors may be able to improve skin symptoms.6 Both topicals and injections are being investigated.
Topical gene therapies that deliver the enzyme LEKTI (the enzyme that is impaired in Netherton syndrome) through bacteria packaged into a skin ointment are also being investigated. This type of therapy is meant to be applied to only affected skin areas.15
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Study information is also posted at the Porphyrias Consortium website:
https://rarediseasesnetwork.epi.usf.edu/porphyrias/index.htm
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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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