Direct testing by polymerase chain reaction revealed 2 compound heterozygous mutations of the serine protease inhibitor Kazal-type 5 gene (SPINK5) in the proband, one present in his mother and the other in his father. A diagnosis of Comèl-Netherton syndrome was made.
Comèl-Netherton syndrome (OMIM #256500) is an autosomal recessive disease caused by mutations of the SPINK5 gene1 and characterized by the triad of ichthyosis linearis circumflexa, trichorrhexis invaginata, and atopic diathesis. The incidence of Comèl-Netherton syndrome is approximately 1 in 200 000 persons per year. Comèl-Netherton syndrome is also thought to be the cause of up to 18% of congenital erythrodermas2; mortality, mostly due to infections or electrolyte imbalance, is highest during the first year of life. Most patients have mutations in the SPINK5 gene, located on chromosome 5q32, resulting in a loss or reduced expression of the multidomain serine protease inhibitor lymphoepithelial Kazal-type 5 related inhibitor (LEKTI). LEKTI has been proposed to downregulate desquamation and matrix maturation. LEKTI is expressed by epithelial cells of skin, mucosa, and Hassall corpuscles, raising the possibility that LEKTI affects T-cell maturation.3 Although generally not listed among primary immunodeficiencies, a recent study strongly suggests that Comèl-Netherton syndrome is a multisystem disorder associated with dysfunctional innate and cognate immunity.3
The extent of early skin findings of Comèl-Netherton syndrome can vary greatly. Patients with more severe cases are born with collodion membrane or congenital ichthyosiform erythroderma.2 The initial eruption usually evolves over time into ichthyosis linearis circumflexa, which consists of migratory polycyclic erythematous patches surrounded by a serpiginous overlying double-edged scale.
Trichorrhexis invaginata (also called bamboo hair) is a focal defect of the hair shaft that produces development of torsion nodules and invaginated nodules. The proximal element of the node overlaps the distal portion, causing an intussusception.2 If hair is pulled distally from this focal defect, a golf tee–like deformity is left. Hence, any hairs examined should be cut rather than plucked. The hair shaft nodules caused by this defect are sometimes seen by the naked eye. These hair defects can be found on the scalp but are most common on the eyebrows or eyelashes. Grossly, scalp hair is described as sparse and brittle with patchy thinning. Hair growth often improves with age, and the hair defects can completely resolve. The presence of trichorrhexis invaginata is required to make the diagnosis. However, the manifestations of the disorder are quite protean even in the same patient over time. Neither the skin nor the hair may have a characteristic appearance at birth, and with age the hair defects may disappear.
Besides an atopic dermatitis–like picture, atopic diathesis can include asthma, allergic rhinitis, food allergy, urticaria or angioedema, and anaphylactoid reactions. Other clinical features include mental deficiency, neurologic deficits (either seizure disorders or spastic diplegia), failure to thrive, delayed growth and body development, short stature, recurrent infections (skin, eye, upper or lower respiratory tract), aminoaciduria, heat intolerance, hypogammaglobulinemia, or hypergammaglobulinemia.
The main differential diagnosis is with atopic dermatitis (mainly severe, long-lasting, and/or treatment-resistant forms). Ichthyosis linearis circumflexa and/or trichorrhexis invaginata allow a high index of suspicion when present. Genetic testing is usually required to confirm the diagnosis. Other entities to consider are neonatal and childhood erythrodermas (including seborrheic dermatitis and congenital ichthyoses) and immunodeficiency-associated dermatitis or erythroderma (such as in common variable immunodeficiency and hyper-IgE syndromes).
Many treatments have been attempted for skin manifestations of Comèl-Netherton syndrome. Topical corticosteroids are inconsistently successful. Other treatments include lactate lotion, 12%,4 calcineurin inhibitors (tacrolimus and pimecrolimus),5 and isotretinoin.6 Patients with Comèl-Netherton syndrome are likely more susceptible to systemic absorption of medication and are potentially at increased risk to experience adverse reactions to topical therapies. Oral treatments include low-dose oral corticosteroids, etretinate, and psoralen UV-A therapy.2
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Correspondence: Daniele Torchia, MD, PhD, University of Miami Hospital, 1295 NW 14th St, Ste K, Miami, FL 33125 (firstname.lastname@example.org).
Accepted for Publication: October 13, 2010.
Author Contributions:Study concept and design: Torchia and Schachner. Acquisition of data: Torchia and Schachner. Analysis and interpretation of data: Torchia and Schachner. Drafting of the manuscript: Torchia. Critical revision of the manuscript for important intellectual content: Torchia and Schachner. Study supervision: Schachner.
Financial Disclosure: None reported.
Picture of the Month—Diagnosis. Arch Pediatr Adolesc Med. 2011;165(8):764. doi:10.1001/archpediatrics.2011.120-b