BACKGROUND: The Triggering Receptor Expressed on Myeloid Cells 2 protein (TREM2) plays a crucial role in various biological processes, including osteoclast differentiation, and disease-associated microglia (DAM) activation to regulate neuroinflammation, and phagocytosis in the brain. Genetic variations in TREM2 are implicated in neurodegenerative disorders, such as Nasu-hakola disease (NHD), characterized by bone lesions, neuropsychiatric disorders, and early-onset dementia.
METHODS: We studied 3 siblings with suspected NHD. Whole-exome sequencing was conducted on the proband to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants in the two other affected siblings, a healthy sister, and the parents.
RESULTS: We identified a novel homozygous deletion (c.549del; p.(Leu184Serfs*5)) in TREM2. Our literature review reveals 16 TREM2 mutations causing early-onset dementia and bone lesions.
CONCLUSIONS: These findings, alongside previous research, elucidate the clinical spectrum of TREM2-related diseases, aiding accurate diagnosis and patient care. This knowledge is vital for understanding TREM2-dependent DAM and its involvement in the pathogenesis of neurodevelopmental disorders which can help to develop targeted therapies and improve outcomes for TREM2-affected individuals.

BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED.
METHODS: Five-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature.
CONCLUSIONS: In this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.

UNASSIGNED: As cases of type 1 diabetes mellitus (T1DM) increase, so do their impact on sibling relationships. This literature review of four databases from 2010 to 2024 discusses findings from five studies and the themes that emerged: education needs and family functioning. Improvements in family-centered care and education are needed for siblings of children with T1DM.

UNASSIGNED: Language abilities of autistic children and children at elevated likelihood for autism (EL-siblings) are highly heterogeneous, and many of them develop language deficits. It is as of yet unclear why language abilities of autistic children and EL-siblings vary, although an interaction of multiple influential factors is likely at play. In this review, we describe research articles that identify one or multiple of such factors associated with the receptive or expressive language abilities of autistic children and EL-siblings since the introduction of the DSM-5. Our aim was to identify and summarize factors that are linked to language development in autistic children and siblings in the recent literature to ultimately gain insight into the heterogeneity of language abilities in these children.
UNASSIGNED: The search strategy of this review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following databases were consulted: Embase, MEDLINE, Web of Science Core Collection, and Scopus. Inclusion criteria for studies were the presence of a sample of autistic children no older than 7 years old who were diagnosed with autism spectrum disorder per the criteria of the DSM-5. Intervention studies and studies without an explicitly reported language measure were excluded. Risk of bias assessment was completed using the Newcastle-Ottawa Scales. Ultimately, 55 articles were included in this review.
UNASSIGNED: Fifty-six factors were identified to be related to receptive or expressive language abilities of autistic children and EL-siblings. They were grouped into three main categories: biological factors; psychosocial and environmental factors; and age-related and developmental factors, each with different subcategories. Although many of the identified variables were only examined in one article, some well-researched associated factors were reported across multiple studies and were present in both autistic children and EL-siblings, in particular joint attention, nonverbal cognitive abilities and frontal EEG power. Better insight in these factors associated with language abilities in autistic children and siblings at elevated likelihood can inform future intervention strategies to reduce language deficits and its corresponding negative consequences in these children.
UNASSIGNED: Our results confirm that multiple different factors likely underlie language deficits in autism. Important aspects that should be considered are, among others, social factors such as joint attention, child characteristics such as nonverbal cognition, and neurocognitive factors.

In typical times, adolescents\' relationships with family members influence changing cognitive, social, and physical aspects of their development. The COVID-19 pandemic, however, impacted the full family system in ways that were unprecedented. Scholars of adolescence worldwide were driven to understand how adolescents\' relationships with family members changed due to these dramatic societal shifts and the influence these relationships had on adolescents\' well-being. This systematic review examined two research questions with 189 articles published from 2020-2022: (1) How has the COVID-19 pandemic impacted families with adolescents, including broader family functioning, family relationship qualities, and parenting? and (2) How has the pandemic or pandemic-related stressors interacted with family functioning, family relationships, and parenting of adolescents to impact adolescent well-being and adjustment? Additionally, examination of the relevant studies were divided into sub-themes of pandemic influence: (a) family environment and routines, (b) family difficulties, (c) parenting and parent-adolescent relationships, and (d) sibling relationships.

The onset of deafblindness profoundly impacts both the individual with this condition and the individual\'s family, including siblings. While current studies have primarily focused on the impact felt by parents or spouses, the distinct experiences of siblings have received comparatively less attention. This systematic review addresses the existing research gap regarding the psychological and social consequences experienced by siblings of individuals with deafblindness. A comprehensive search was conducted across multiple electronic databases, including PsycINFO, PsycARTICLES, Dissertations & Theses (on ProQuest), ERIC (Education Resources Information Center), International Bibliography of the Social Sciences (IBSS), Sociological Abstracts, Google Scholar, PubMed, and Cairn Info. Seven studies were identified as meeting the eligibility criteria for inclusion. The review revealed that siblings of individuals with deafblindness face psychological and social challenges, including emotions such as feelings of neglect, resentment, embarrassment, jealousy, and anxiety. Siblings also grapple with communication difficulties, contributing to feelings of exclusion and insecurity. In addition, these siblings take on significant responsibilities within the family and encounter obstacles in forming relationships outside the family. These findings underscore the need of interventions to improve the well-being of siblings of individuals with deafblindness by addressing their psycho-emotional needs and promoting positive social interactions. These findings align with studies conducted on siblings of children with other disabilities. However, additional research is crucial to investigate overlooked dimensions, particularly positive factors like coping mechanisms and resilience, that may influence the mental health and social experiences of these siblings.

OBJECTIVE: The lives of healthy siblings living with a sibling with a long- term condition are often shaped by the family, type of illness, length of illness, age of the child, caregiver demands, and support provided to the family, ill sibling, and healthy sibling. While the experiences of healthy siblings are documented in the literature by parent proxy, literature on healthy siblings self-reported experiences of living with a sibling who has a long-term condition remains scarce.
OBJECTIVE: This umbrella review aims to synthesize reviews on the self-reported experiences of healthy siblings of children living with a sibling who has a long-term condition.
METHODS: Published peer-reviewed reviews in English language exploring the self-reported experiences of healthy siblings under 24 years old, whose siblings are diagnosed with a long-term condition.
METHODS: Using a developed search strategy, seven electronic databases (CINAHLPlus, Scopus, PubMed, PsycINFO, Cochrane Database of Systematic Reviews, Clinical Key, and Google Scholar) were searched from 2018 till December 2023. Eleven reviews met the inclusion criteria and were subjected to narrative synthesis.
RESULTS: Four themes (adjusting to changes, wanting to help, living the ups and downs, living the changes), and eight subthemes were generated from the syntheses.
CONCLUSIONS: This is the first umbrella review undertaken on healthy siblings self-reported experiences of living with a sibling who has a long-term condition. The impact of a long-term condition on healthy siblings of children with a long-term condition suggests a need for healthcare providers and organisations to provide better emotional, psychological, and informational support to healthy siblings and their families.
CONCLUSIONS: Findings from this review will inform healthcare providers, organisations, researchers, and policymakers on the development of future clinical practices and research for healthy siblings.

Netherton syndrome (NS) is a rare autosomal recessive genodermatosis. In this article, we present two siblings with NS who harbour a novel variant in the SPINK5 gene and were treated with infliximab infusions. Both patients exhibited the characteristic clinical triad of NS, and their whole exome sequencing analysis revealed a homozygous variant, c.1820+53G>A, in the SPINK5 gene. Notably, this is the first documented instance of homozygosity for this particular variant. Despite the absence of a specific treatment, both patients achieved total clearance of the skin lesions, and a significant decrease in total IgE levels was documented.

Biallelic variants in the OTUD6B gene have been reported in the literature in association with an intellectual developmental disorder featuring dysmorphic facies, seizures, and distal limb abnormalities. Physical differences described for affected individuals suggest that the disorder may be clinically recognizable, but previous publications have reported an initial clinical suspicion for Kabuki syndrome (KS) in some affected individuals. Here, we report on three siblings with biallelic variants in OTUD6B co-segregating with neurodevelopmental delay, shared physical differences, and other clinical findings similar to those of previously reported individuals. However, clinical manifestations such as long palpebral fissures, prominent and cupped ears, developmental delay, growth deficiency, persistent fetal fingertip pads, vertebral anomaly, and seizures in the proband were initially suggestive of KS. In addition, previously unreported clinical manifestations such as delayed eruption of primary dentition, soft doughy skin with reduced sweating, and mirror movements present in our patients suggest an expansion of the phenotype, and we perform a literature review to update on current information related to OTUD6B and human gene-disease association.

BACKGROUND: Severe combined immunodeficiencies (SCIDs) are hereditary disorders characterized by impaired T and B cell function, resulting in significant immune system dysfunction. Recombination-activating gene (RAG) mutations account for a substantial proportion of SCID cases. Here, we present two sibling cases of SCID caused by a novel RAG2 gene mutation.
METHODS: The index case was an 8-year-old boy who had a history of recurring infections. After a comprehensive immunological workup, the initial diagnosis of agammaglobulinemia was revised to combined immunodeficiency (CID). The patient underwent hematopoietic stem cell transplantation (HSCT) but succumbed to cytomegalovirus (CMV) infection. His brother, a 4-month-old boy, presented with CMV chorioretinitis. Leaky SCID was diagnosed based on genetic tests and immunological findings. The patient received appropriate treatment and was considered for HSCT. Both siblings had a homozygous RAG2 gene variant, with the first case classified as a variant of uncertain significance (VUS). The presence of the same mutation in the second brother, and the clinical phenotype, supports considering the mutation as likely pathogenic.
CONCLUSIONS: This case report highlights a novel RAG2 gene mutation associated with CID. The classification of a VUS may evolve with accumulating evidence, and additional studies are warranted to establish its pathogenicity. Proper communication between genetic counselors and immunologists, accurate documentation of patient information, increased public awareness, and precise utilization of genetic techniques are essential for optimal patient management.