Clinical and genetic characterization of Netherton syndrome due to SPINK5 founder variant in Latvian population.

OBJECTIVE: Netherton syndrome (NS) (OMIM:256500) is a very rare autosomal recessive multisystem disorder mostly affecting ectodermal derivatives (skin and hair) and immune system. It is caused by biallelic loss-of-function variants in the SPINK5 gene, encoding the protease inhibitor lymphoepithelial Kazal-type-related inhibitor (LEKTI). MATERIAL, METHODS AND RESULTS: Here, we describe NS clinical and genetic features of homogenous patient group: 9 individuals from 7 families with similar ethnic background and who have the same SPINK5 variant (NM_006846.4: c.1048C > T, p.(Arg350*)) in homozygous or compound heterozygous states, suggesting that it is a common founder variant in Latvian population. Indeed, we were able to show that the variant is common in general Latvian population, and it shares the same haplotype among the NS individual. It is estimated that the variant arose >1000 years ago. Clinically, all nine patients exhibited typical NS skin changes (scaly erythroderma, ichthyosis linearis circumflexa, itchy skin), except for one patient who has a different skin manifestation-epidermodysplasia. Additionally, we show that developmental delay, previously underrecognized in NS, is a common feature among these patients. CONCLUSIONS: This study shows that the phenotype of NS individuals with the same genotype is highly homogeneous.

The pharmacokinetics of tacrolimus after first and repeated dosing with 0.03% ointment in infants with atopic dermatitis.

BACKGROUND: In adults and children aged > 2 years, systemic absorption of tacrolimus from tacrolimus ointment is very low. In this study, the pharmacokinetics of tacrolimus 0.03% ointment were investigated in infants aged 3-24 months. METHODS: The pharmacokinetics of tacrolimus after first and repeated topical application of tacrolimus 0.03% ointment were evaluated in 53 infants (age, 3-24 month) with atopic dermatitis requiring treatment with mid-potency topical corticosteroids. Patients were grouped according to percentage of body surface area affected (Group 1: 5-20%; Group 2: > 20-40%; Group 3: > 40%). After stratification, patients were randomized (double-blind) to receive once-daily or twice-daily tacrolimus 0.03% ointment. RESULTS: Blood samples taken on days 1 and 14 (first and last application) showed minimal systemic tacrolimus exposure. Overall, 97% of blood samples assayed contained tacrolimus concentrations < 1 ng/ml, and 20% were below the lower limit of quantification (0.025 ng/ml). Systemic tacrolimus exposure was variable, but tended to increase as the treated body surface area increased. Mean apparent half-life of tacrolimus was 80 +/- 35 h (range: 25-175 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically significant changes in laboratory values, and the most frequently reported adverse events were minor infections and local skin irritations. CONCLUSIONS: Tacrolimus 0.03% ointment in infants is associated with very low systemic exposure to tacrolimus. Treatment was well tolerated and led to considerable clinical improvement.

A multicenter study of the pharmacokinetics of tacrolimus ointment after first and repeated application to children with atopic dermatitis.

The pharmacokinetics of tacrolimus after first and repeated application of 0.1% tacrolimus ointment were evaluated in 39 children, aged 6-12 y, with moderate to severe atopic dermatitis. The patients were grouped according to the size of the affected body surface area to be treated: Group 1< or =1500 cm(2); Group 2 >1500 cm(2) < or =3000 cm(2); Group 3 >3000 cm(2) < or =5000 cm(2). Serial blood samples to calculate pharmacokinetic parameters taken on Day 1 (first ointment application) and Day 14 (last application) showed minimal systemic exposure to tacrolimus. Overall, 92% of the blood samples assayed contained tacrolimus concentrations below 1 ng per mL and 17% of samples were below 0.025 ng per mL, the lower limit of quantification. Systemic exposure to tacrolimus varied between patients and tended to increase proportionally as the size of the treated body surface area increased. Absorption decreased with time as the skin lesions healed and there was no evidence of systemic accumulation. The mean apparent half-life of tacrolimus (t(1/2, z)) was 66+/-27 h (range 19-125 h). Most patients experienced substantial clinical improvement in their atopic dermatitis. There were no clinically relevant changes in laboratory values, and the most frequently reported adverse event was skin burning, which resolved quickly as the skin condition improved.