A loss-of-function mutation in a gene known as ADAM17 is likely to be the cause of neonatal inflammatory skin and bowel lesions in two children born to consanguineous parents, researchers reported.
This gene, located on chromosome 2, encodes a protein that cleaves membrane-bound tumor necrosis factor (TNF)-α, converting it to soluble TNF-α, according to David P. Kelsell, PhD, of the London School of Medicine and Dentistry, and colleagues.
The two out of three affected siblings, one boy and one girl, both developed severe erythema and pustular rashes within two days of birth, and later showed abnormalities of the hair and nails.
They also were susceptible to skin infections throughout childhood.
In addition, within a week of birth, both children developed bloody diarrhea suggestive of malabsorption, which in the girl was associated with failure to thrive.
She died at age 12 from myocarditis associated with parvovirus B19 infection.
Subsequent evaluation of her affected brother revealed the presence of mild left ventricular abnormalities.
To identify the genetic basis of this disorder, Kelsell and colleagues obtained biopsy specimens from the skin and intestines of the family members and age-matched controls.
Genetic analysis identified a deletion in exon 5 of ADAM17 in the two affected children that was not present in the unaffected sibling. Both affected children were homozygous for the mutation.
Histochemical analysis then revealed a lack of expression of ADAM17 in biopsy specimens and peripheral blood mononuclear cells in the affected children, which was not the case in unaffected family members or controls.
Because of the inflammatory nature of the disorder, the researchers also examined cytokine production in peripheral blood mononuclear cells.
Stimulation with lipopolysaccharide or anti-CD3 and anti-CD28 antibodies led to robust production of TNF-α in samples from controls and the mother, but only weak production in samples from the affected boy.
Other cytokines, including interleukin-1β, interleukin-6, and interferon-γ, were secreted in all samples, including those from the affected boy.
A knockout mouse model lacking ADAM17 exhibits a severe phenotype with a lack of development of epithelial cells in various organs including the intestine, and few mice carrying the mutation survive long after birth.
The mutant mice typically also have abnormalities of the skin and hair.
The researchers noted that there were phenotypic similarities between the knockout mice and the affected children, but there also were differences.
Although the children manifested skin and gut abnormalities soon after birth, intestinal biopsies done later in childhood found few abnormalities.
This, according to the researchers, suggests "the presence in humans of compensatory mechanisms" for epithelial repair even when ADAM17 is lacking.
"The cause of the gut problems in both children has never been satisfactorily resolved and requires more investigation," they noted.
A possible explanation for the attenuated phenotype in humans compared with the mice is that the expression of ADAM10 was retained, and there is some overlap in the activity of that enzyme and ADAM17, such as in targeting desmoglein 2 in the skin and hair follicles.
Desmoglein 2 is known to be expressed in myocytes in the heart, which may help explain the cardiac abnormalities in the affected children, they suggested.
Moreover, the lack of TNF-α, which has cardioprotective properties as well as immune-regulating activity, may have played a role in the affected girl's death at age 12.
The inadequate levels of TNF-α also may have contributed to the children's susceptibility to opportunistic skin infections. "Given the redundancy in the immune system, however, other pathways were probably operating in the patient's skin and gut to limit infection and inflammation," the researchers hypothesized.
ADAM17 has previously been considered a potential pharmacologic target in diseases characterized by chronic inflammation and overproduction of TNF-α, but the severe phenotype seen in the knockout mice suggested that blocking this target could be lethal in humans as well.
These researchers' findings suggest that such a concern may be unwarranted, and they noted that reconsideration of targeting ADAM17 might be useful for patients with conditions such as rheumatoid arthritis and psoriasis, although the possibility for adverse cardiac effects exists.
Source reference:
Blaydon D, et al "Inflammatory skin and bowel disease linked to ADAM17 deletion" N Engl J Med 2011; 365: 1502-1508.
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