Dominant negative variants in IKZF2 cause ICHAD syndrome, a new disorder characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

BACKGROUND: Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and immune function. Although predominantly recognised for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. METHODS: We performed detailed phenotypic, genomic and functional investigations on two unrelated individuals with a phenotype of immune dysregulation combined with syndromic features including craniofacial differences, sensorineural hearing loss and congenital abnormalities. RESULTS: Genome sequencing revealed de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZFs) of Helios. Proband 1 had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios (p.Gly136_Ser191dup) and Proband 2 had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios (p.Gly153Arg). Functional studies confirmed that both these variant proteins are expressed and that they interfere with the ability of the wild-type Helios protein to perform its canonical function-repressing IL2 transcription activity-in a dominant negative manner. CONCLUSION: This study is the first to describe dominant negative IKZF2 variants. These variants cause a novel genetic syndrome characterised by immunodysregulation, craniofacial anomalies, hearing impairment, athelia and developmental delay.

Topical skin adhesives for laceration repair in children.

QUESTION: A 4-year-old child presented to my office recently with a 2-cm forehead laceration. The child had needle phobia and was very upset, so suturing in the office might have been very challenging. The parents were also concerned about the use of suture. Can topical skin adhesives (TSAs) be used instead of sutures, and what factors should be considered? ANSWER: Lacerations in children are common and TSAs are useful alternatives to sutures. They achieve comparable outcomes to suturing in appropriately selected wounds. Appropriate lacerations are small, superficial, appropriately cleaned, and have well approximated edges that are not under tension. Complications such as wound dehiscence and infection are rare and cosmetic outcomes are comparable to sutures. Using TSAs can also save time, minimize patient anxiety, and eliminate the need for suture removal.

Online Cleft Educational Videos: Parent Preferences.

OBJECTIVE: Determine what parents of children with cleft lip and palate value in online educational videos and evaluate whether their needs are currently being met. DESIGN: Focus groups and telephone interviews were used to define parent information needs, followed by an evaluation of whether currently available YouTube videos meet these needs. SETTING: British Columbia Children's Hospital multidisciplinary cleft clinic. PARTICIPANTS: Twenty-four parents of children with nonsyndromic cleft lip and palate. RESULTS: Parents desired videos that are accessible, trustworthy, relatable, and positive. Parents preferred a series of short videos addressing relevant topics as their child grows. Currently available YouTube videos only partially met these needs, with underrepresented topics including hearing, dentition, and surgeries for older children. CONCLUSIONS: While access and validity of video resources can be improved by directing patients and families to appropriate videos, some parent needs remain unmet.

Nodular fasciitis: A rapidly enlarging destructive periorbital mass in an infant.

PURPOSE: To review the clinical and histopathological features of nodular fasciitis, a rare benign periorbital tumor that mimics orbital malignancy, by presenting a case involving an infant with marked orbital wall erosion requiring repair. OBSERVATIONS: A 9-month-old boy developed a rapidly growing periorbital mass concerning for a soft tissue malignancy. Computerized tomography (CT) scans showed bony erosion of the lateral orbital wall. Incisional biopsy revealed nodular fasciitis. USP6 gene rearrangement was negative. The tumor was completely excised and the underlying orbital wall defect was repaired with polydioxanone (PDS) plate. CONCLUSIONS AND IMPORTANCE: Nodular fasciitis is a benign periorbital tumor that presents like malignancies and warrants prompt investigations, especially in children. Orbital wall erosion is rare and can be repaired to yield good functional and cosmetic outcome.

Aging increases the susceptibility of skeletal muscle derived satellite cells to apoptosis.

The mechanisms causing the impaired regenerative response to injury observed in skeletal muscle of old animals are unknown. Satellite cells, stem cell descendants within adult skeletal muscle, are the primary source of regenerating muscle fibers. Apoptosis may be a mechanism responsible for the depletion of satellite cells in old animals. This work tested the hypothesis that aging increases the susceptibility of satellite cells to apoptosis. Satellite cells were cultured from the extensor digitorum longus muscles of young (3-month-old), adult (9-month-old), and old (31-month-old) Brown Norway rats. Satellite cells were treated for 24h with the pro-apoptotic agents TNF-alpha (20 ng/mL) and Actinomycin D (250 ng/mL). Immunostaining for activated caspases and terminal deoxynucleotydil transferase-mediated dutp nick-end labeling (TUNEL) was performed to identify apoptotic satellite cells. Quantity of the anti-apoptotic protein bcl-2 was determined by Western blot analysis. Satellite cells from old animals demonstrated significantly higher percentages of cells with activated caspases and TUNEL-positive cells, and significantly lower amounts of bcl-2 compared to young and adult animals. These data support the hypothesis that aging increases satellite cell susceptibility to apoptosis. In old muscle, apoptosis may play a causative role in the depletion of satellite cells, impairing the regenerative response to injury.