Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

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LIPH pathogenic variants are a major cause of autosomal recessive woolly hair/hypotrichosis (ARWH; OMIM 278150/ 604379). To our knowledge, there have been no effective treatments for ARWH, although some reports have found topical minoxidil to improve hypotrichosis. 1 We report the results of a prospective nonrandomized clinical trial involving 8 Japanese patients with ARWH carrying LIPH pathogenic variants.Methods | This 1-year, single-center, 2-armed, open-label, prospective interventional study enrolled patients from the dermatology outpatient clinic of Nagoya University Hospital in Aichi, Japan (see the trial protocol in the Supplement). Eight patients in the intervention arm have LIPH pathogenic variants. One patient in the other arm has non-LIPH variations causing hypotrichosis. Written informed consent was obtained from all participants prior to participation, and this study was approved by the

A memorable patient ª

We read with great interest the recent report by Peled et al 1 on how loss-of-function mutations in CARD14 (caspase recruitment domain family, member 14) are associated with a severe variant of atopic dermatitis (AD). 1 CARD14 encodes a known regulator of nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB), and dominant gain-of-function mutations in CARD14 cause psoriasis and related disorders. 1,2 Peled et al 1 revealed that dominant negative mutations in CARD14 result in severe AD and decreased NF-kB signaling. 1 Their findings expand the spectrum of CARD14-associated phenotypes and shed light on the partially overlapping but also distinct pathophysiologic mechanisms underlying AD and psoriasis. We previously proposed that pityriasis rubra pilaris (PRP) type V, the atypical juvenile type, is a distinct variant of PRP that is caused by CARD14 mutations. 3 We had a unique case of PRP type V who showed eczematous lesions and high serum IgE and thymus and activation-regulated chemokine (TARC), which suggested defective barrier function. Our findings indicate that the pathogenesis of AD with CARD14 mutations might involve not only an imbalance of NF-kB/antimicrobial peptides but also defective skin barrier function.