The diagnosis of NS is often difficult in early infancy because the clinical presentation of erythroderma with failure to thrive is common with other conditions, such as immune deficiency syndromes.

Histology and molecular analyses are frequently used to confirm the diagnosis.

Histological examination of a skin biopsy shows the followings: –

• Marked epidermal hyperplasia with elongated and enlarged rete ridges.
• Stratum corneum detachment.
• Lack of or reduced granular layer.
• Variable cell infiltrates in the papillary dermis.

Confirmation of the diagnosis relies on the demonstration by immunostaining of complete absence, or more rarely marked reduction, of LEKTI expression in the granular layer of the epidermis and in the inner root sheath of hair follicles.

The finding of bi-allelic loss-of-function mutations in SPINK5, the majority of which result in premature termination codons, is the definitive proof of NS.

The Human Gene Mutation Database currently lists more than 85 different disease-causing SPINK5 mutations.

At present, there is no curative nor specific therapy targeting NS pathophysiology, and most NS treatments are palliative.

The majority of currently approved NS therapies are also used to treat other dermatological conditions like psoriasis and/or atopic dermatitis.

Topical emollients, keratolytics, tretinoin, and corticosteroids can be used alone or in combination to treat symptoms.

Phototherapy and psoralen-UVA (PUVA) have produced variable results.