Netherton syndrome is a severe,

autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosom ...

recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

form of

ichthyosis Ichthyosis is a family of genetic skin disorders characterized by dry, thickened, scaly skin. The more than 20 types of ichthyosis range in severity of symptoms, outward appearance, underlying genetic cause and mode of inheritance (e.g., dominant ...

associated with mutations in the ''

SPINK5 Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the ''SPINK5'' gene. Structure and function LEKTI is a large multidomain serine prot ...

'' gene. It is named after Earl W. Netherton (1910–1985), an American dermatologist who discovered it in 1958.Netherton, E. W. A unique case of trichorrhexis nodosa: 'bamboo hairs.'. Arch. Derm. 78: 483-487, 1958.

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 Trichorrhexis invaginata is a distinctive hair shaft abnormality that may occur sporadically, either in normal hair or with other hair shaft abnormalities, or regularly as a marker for Netherton's syndrome.Freedberg, et al. (2003). ''Fitzpatrick' ...

), also known as "bamboo hair". The disrupted skin barrier function in affected individuals also presents a high susceptibility to

infection An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...

and

allergy Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic derm ...

, leading to the development of scaly, reddish skin similar to atopic dermatitis. 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.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). Page 496. McGraw-Hill. . Netherton syndrome has recently been characterised as a primary immunodeficiency, which straddles the innate and acquired immune system, much as does

Wiskott–Aldrich syndrome Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive disease characterized by eczema, thrombocytopenia (low platelet count), immune deficiency, and bloody diarrhea (secondary to the thrombocytopenia). It is also sometimes called the eczem ...

. 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 Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...

. 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. 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

disorder associated with mutations in the ''SPINK5'' gene, which encodes the

serine protease Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. They are found ubiquitously in both eukaryotes and prokaryotes. Seri ...

inhibitor lympho-epithelial Kazal-type-related inhibitor (

LEKTI Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the ''SPINK5'' gene. Structure and function LEKTI is a large multidomain serine prot ...

). 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 Kallikrein-5, formerly known as stratum corneum tryptic enzyme (SCTE), is a serine protease expressed in the epidermis. In humans it is encoded by the ''KLK5'' gene. This gene is one of the fifteen kallikrein subfamily members located in a clus ...

KLK7 Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the ''KLK7'' gene. KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE). It was later identified as t ...

and

KLK14 Kallikrein-14 is a protein that in humans is encoded by the ''KLK14'' gene. Kallikreins are a subgroup of serine proteases having diverse physiological functions. Growing evidence suggests that many kallikreins are implicated in carcinogenesis an ...

. These enzymes are involved in various aspects of epidermal remodelling, including

desquamation Desquamation occurs when the outermost layer of a tissue, such as the skin, is shed. The term is . Physiologic desquamation Keratinocytes are the predominant cells of the epidermis, the outermost layer of the skin. Living keratinocytes reside in ...

PAR-2 Protease activated receptor 2 (PAR2) also known as coagulation factor II (thrombin) receptor-like 1 (F2RL1) or G-protein coupled receptor 11 (GPR11) is a protein that in humans is encoded by the ''F2RL1'' gene. PAR2 modulates inflammatory respons ...

activation and degradation of lipid hydrolases, suggesting a potential mechanism for the development of atopic manifestations characteristic of Netherton syndrome. 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 Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

or create

premature stop codon In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a ''nonsense codon'' in the transcribed mRNA, and in leading to a truncated, incomplete, and usually nonfunctional protein produc ...

s may lead to varying levels of severity. Furthermore, LEKTI-knockout mice exhibit a phenotype similar to Netherton syndrome in humans.

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. Intravenous immunoglobulin has become established as the treatment of choice in Netherton's syndrome. 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.

References

External links