Netherton syndrome

Netherton syndrome
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Synonyms	Comèl-Netherton syndrome
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Netherton syndrome is a severe, autosomal recessive<ref name="ns05">,

 Netherton syndrome: report of two Taiwanese siblings with staphylococcal scalded skin syndrome and mutation of SPINK5, 
 Br J Dermatol, 
 2005,
 Vol. 152(Issue: 1),
 pp. 159–165,
 DOI: 10.1111/j.1365-2133.2005.06337.x,
 PMID: 15656819,</ref> form of ichthyosis associated with mutations in the SPINK5 gene.<ref name="pmid10835624">, 
 Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome, 
 Nat. Genet., 
 
 Vol. 25(Issue: 2),
 pp. 141–142,
 DOI: 10.1038/75977,
 PMID: 10835624,</ref><ref name="Fitz2"/> It is named after Earl W. Netherton (1910–1985), an American dermatologist who discovered it in 1958.<ref>Netherton, E. W. A unique case of trichorrhexis nodosa: 'bamboo hairs.'. Arch. Derm. 78: 483-487, 1958.</ref>

Signs and symptoms

Netherton syndrome is characterized by chronic skin inflammation, universal pruritus (itch), severe dehydration, and stunted growth. Patients with this disorder tend to have a hair shaft defect (trichorrhexis invaginata), also known as "bamboo hair". The disrupted skin barrier function in affected individuals also presents a high susceptibility to infection and allergy, leading to the development of scaly, reddish skin similar to atopic dermatitis.<ref name="descargues"> ,

 Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity., 
 Nat Genet, 
 
 Vol. 37(Issue: 1),
 pp. 56–65,
 DOI: 10.1038/ng1493,
 PMID: 15619623,</ref> In severe cases, these atopic manifestations persist throughout the individual's life, and consequently post-natal mortality rates are high. In less severe cases, this develops into the milder ichthyosis linearis circumflexa.<ref name="Fitz2">Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). Page 496. McGraw-Hill. ISBN 0-07-138076-0.</ref>

Netherton syndrome has recently been characterised as a primary immunodeficiency, which straddles the innate and acquired immune system, much as does Wiskott–Aldrich syndrome. A group of Netherton patients have been demonstrated to have altered immunoglobulin levels (typically high IgE and low to normal IgG) and immature natural killer cells. These Natural Killer cells have a reduced lytic function; which can be improved with regular infusions of immunoglobulin (see 'Treatment'); although the mechanism for this is not clear.<ref name="Renner">,

 Comel-Netherton syndrome defined as primary immunodeficiency., 
 The Journal of Allergy and Clinical Immunology, 
 
 Vol. 124(Issue: 3),
 pp. 536–543,
 DOI: 10.1016/j.jaci.2009.06.009,
 PMID: 19683336,
 PMC: 3685174,</ref>

Patients are more prone than healthy people to infections of all types, especially recurrent skin infections with staphylococcus. They may have more severe infections; but are not as vulnerable to opportunistic pathogens as patients with true Natural Killer cell deficiency-type SCID.

Cause

Netherton syndrome is an autosomal recessive disorder associated with mutations in the SPINK5 gene, which encodes the serine protease inhibitor lympho-epithelial Kazal-type-related inhibitor (LEKTI).<ref name="pmid10835624"/> These mutations result in a dysfunctional protein that has a reduced capacity to inhibit serine proteases expressed in the skin. Potential endogenous targets of LEKTI include KLK5, KLK7 and KLK14.<ref name="Ovaere2009"> ,

 The emerging roles of serine protease cascades in the epidermis, 
 Trends Biochem Sci, 
 
 Vol. 34(Issue: 9),
 pp. 453–63,
 DOI: 10.1016/j.tibs.2009.08.001,
 PMID: 19726197,

</ref> These enzymes are involved in various aspects of epidermal remodelling, including desquamation, PAR-2 activation and degradation of lipid hydrolases, suggesting a potential mechanism for the development of atopic manifestations characteristic of Netherton syndrome.<ref name="pmid16601670"> ,

 Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome, 
 J Invest Dermatol, 
 
 Vol. 126(Issue: 7),
 pp. 1609–21,
 DOI: 10.1038/sj.jid.5700288,
 PMID: 16601670,

</ref>

Disease severity is determined by the level of LEKTI expression and, consequently, serine protease activity. Complete SPINK5 gene deletions have been linked to severe cases, while mutations which induce alternate splicing or create premature stop codons may lead to varying levels of severity.<ref name="pmid16601670" /> Furthermore, LEKTI-knockout mice exhibit a phenotype similar to Netherton syndrome in humans.<ref name="descargues" />

Diagnosis

• Netherton syndrome is diagnosed based on the symptoms and confirmed by genetic testing for changes in the SPINK5 gene.
• Other types of testing, such as close examination of the hair and a skin biopsy to obtain a small skin sample for examining under the microscope can also be helpful for diagnosis.

Treatment

There is no known cure at the moment but there are several things that can be done to relieve the symptoms. Moisturising products are very helpful to minimize the scaling/cracking, and anti-infective treatments are useful when appropriate because the skin is very susceptible to infection. Extra protein in the diet during childhood is also beneficial, to replace that which is lost through the previously mentioned "leaky" skin.

Steroid and retinoid products have been proven ineffective against Netherton syndrome, and may in fact make things worse for the affected individual. ^{(June 2010)}

Intravenous immunoglobulin has become established as the treatment of choice in Netherton's syndrome.<ref name="Renner"/> This therapy reduces infection; enables improvement and even resolution of the skin and hair abnormalities, and dramatically improves quality of life of the patients; although exactly how it achieves this is not known. Given this; it is possible that the reason Netherton's usually is not very severe at or shortly after birth is due to a protective effect of maternal antibodies; which cross the placenta but wane by four to six months.

See also

• List of skin conditions

References

• Yang T, Liang D, Koch PJ, Hohl D, Kheradmand F, Overbeek PA,

 Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice, 
 Genes Dev., 
 
 Vol. 18(Issue: 19),
 pp. 2354–8,
 DOI: 10.1101/gad.1232104,
 PMID: 15466487,
 PMC: 522985,

External links

• Template:DermAtlas