OBJECTIVE: Deficiency of adenosine deaminase-2 (DADA2) is a monogenic disorder closely resembling polyarteritis nodosa (PAN) and can present to physicians across various specialties. Through this case series, we aim to describe the clinical spectrum and outcome of Indian children with DADA2. We aimed to study the clinical spectrum and outcome of Indian children with DADA-2.
METHODS: The deidentified data from all participating centres were entered in an excel sheet, and the coordinating centre (All India Institute of Medical Sciences, New Delhi) screened the data for accuracy and completeness.
RESULTS: We enrolled 16 children (11 females) in the study; the mean (SD) age at the time of onset of symptoms for males and females was 46.2 (47) and 73.6 (50.4) months, respectively. The most common clinical feature in this cohort was fever and rash in 80% of patients. More than half of children n, (%) [8, (53%)] had a CNS stroke. The other clinical features were hypertension [5(33%)], anaemia [3 (20%)] and arthralgia/arthritis in 4 (26%). These children were managed with various immunomodulators: steroids [13, (86%)], anti-TNF agents [(12, (80%)], cyclophosphamide [2 (13%)] and mycophenolate mofetil [3 (20%)]. The median (IQR) duration of follow-up for this cohort was 17 (10, 29) months. Fourteen children achieved remission and none had recurrent strokes after the initiation of anti-TNF drugs.
CONCLUSIONS: DADA-2 closely resembles PAN; early age of onset and CNS stroke are striking differentiating features from classic PAN. Most children respond well to anti-TNF agents without serious adverse events during short-term follow-up.

Systemic autoinflammatory diseases (SAIDs) arise from dysregulated innate immune system activity, which leads to systemic inflammation. These disorders, encompassing a diverse array of genetic defects classified as inborn errors of immunity, are significant diagnostic challenges due to their genetic heterogeneity and varied clinical presentations. Although recent advances in genetic sequencing have facilitated pathogenic gene discovery, approximately 40% of SAIDs patients lack molecular diagnoses. SAIDs have distinct clinical phenotypes, and targeted therapeutic approaches are needed. This review aims to underscore the complexity and clinical significance of SAIDs, focusing on prototypical disorders grouped according to their pathophysiology as follows: (i) inflammasomopathies, characterized by excessive activation of inflammasomes, which induces notable IL-1β release; (ii) relopathies, which are monogenic disorders characterized by dysregulation within the NF-κB signaling pathway; (iii) IL-18/IL-36 signaling pathway defect-induced SAIDs, autoinflammatory conditions defined by a dysregulated balance of IL-18/IL-36 cytokine signaling, leading to uncontrolled inflammation and tissue damage, mainly in the skin; (iv) type I interferonopathies, a diverse group of disorders characterized by uncontrolled production of type I interferons (IFNs), notably interferon α, β, and ε; (v) anti-inflammatory signaling pathway impairment-induced SAIDs, a spectrum of conditions characterized by IL-10 and TGFβ anti-inflammatory pathway disruption; and (vi) miscellaneous and polygenic SAIDs. The latter group includes VEXAS syndrome, chronic recurrent multifocal osteomyelitis/chronic nonbacterial osteomyelitis, Schnitzler syndrome, and Still\'s disease, among others, illustrating the heterogeneity of SAIDs and the difficulty in creating a comprehensive classification. Therapeutic strategies involving targeted agents, such as JAK inhibitors, IL-1 blockers, and TNF inhibitors, are tailored to the specific disease phenotypes.

About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.

BACKGROUND: Monogenic lupus is defined as systemic lupus erythematosus (SLE)/SLE-like patients with either dominantly or recessively inherited pathogenic variants in a single gene with high penetrance. However, because the clinical phenotype of monogenic SLE is extensive and overlaps with that of classical SLE, it causes a delay in diagnosis and treatment. Currently, there is a lack of early identification models for clinical practitioners to provide early clues for recognition. Our goal was to create a clinical model for the early identification of pediatric monogenic lupus, thereby facilitating early and precise diagnosis and treatment for patients.
METHODS: This retrospective cohort study consisted of 41 cases of monogenic lupus treated at the Department of Pediatrics at Peking Union Medical College Hospital from June 2012 to December 2022. The control group consisted of classical SLE patients recruited at a 1:2 ratio. Patients were randomly divided into a training group and a validation group at a 7:3 ratio. A logistic regression model was established based on the least absolute shrinkage and selection operator to generate the coefficient plot. The predictive ability of the model was evaluated using receiver operator characteristic curves and the area under the curve (AUC) index.
RESULTS: A total of 41 cases of monogenic lupus patients and 82 cases of classical SLE patients were included. Among the monogenic lupus cases (with a male-to-female ratio of 1:1.05 and ages of onset ranging from birth to 15 years), a total of 18 gene mutations were identified. The variables included in the coefficient plot were age of onset, recurrent infections, intracranial calcifications, growth and developmental delay, abnormal muscle tone, lymphadenopathy/hepatosplenomegaly, and chilblain-like skin rash. Our model demonstrated satisfactory diagnostic performance through internal validation, with an AUC value of 0.97 (95% confidence interval = 0.92-0.97).
CONCLUSIONS: We summarized and analyzed the clinical characteristics of pediatric monogenic lupus and developed a predictive model for early identification by clinicians. Clinicians should exercise high vigilance for monogenic lupus when the score exceeds - 9.032299.

The demarcation between monogenic and polygenic type 2 diabetes (T2D) is less distinct than previously believed. Notably, recent research has highlighted a new entity, that we suggest calling oligogenic forms of T2D, serving as a genetic link between these two forms. In this opinion article, we have reviewed scientific advances that suggest categorizing genes involved in oligogenic T2D. Research focused on polygenic T2D has faced challenges in deepening our comprehension of the pathophysiology of T2D due to the inability to directly establish causal links between a signal and the molecular mechanisms underlying the disease. However, the study of oligogenic forms of T2D has illuminated distinct causal connections between genes and disease risk, thereby indicating potential new drug targets.

Kidney stones are becoming increasingly common, affecting up to 10% of adults. A small percentage are of monogenic origin, such as Dent\'s disease (DD). DD is a syndrome that causes low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, and nephrocalcinosis. It is X-linked, and most patients have mutations in the CLCN5 gene. We performed a review of the literature and evaluated the case series (n = 6) of a single center in Spain, reviewing the natural evolution of kidney stones, clinical implications, laboratory analyses, radiological development, and treatment. All patients had a genetically confirmed diagnosis, with the CLCN5 mutation being the most frequent (66%). All patients had proteinuria and albuminuria, while only two and three presented hypercalciuria and phosphate abnormalities, respectively. Only one patient did not develop lithiasis, with most (60%) requiring extracorporeal shock wave lithotripsy or surgery during follow-up. Most of the patients are under nephrological follow-up, and two have either received a renal transplant or are awaiting one. The management of these patients is similar to that with lithiasis of non-monogenic origin, with the difference that early genetic diagnosis can help avoid unnecessary treatments, genetic counseling can be provided, and some monogenic kidney stones may benefit from targeted treatments.

Pesticides remain a cornerstone in pest control, yet their extensive and irrational use also fuel the evolution of resistance. This review analyzes globally published experimental data spanning from the 1970s to 2023 to focus on how phenotypic and underlying genotypic variations are shaped during the selective response. The discussion commences with an examination of sex-linked/maternal resistance. Observations related to maternal inheritance have enriched our understanding of pesticide mode of action, notably exemplified by bifenazate. However, the predominant control of the resistant phenotype is attributed to autosomal traits, with a high prevalence of dominance and monogenic inheritance observed, also evident in field strains. This observation raises concerns regarding resistance management strategies due to their potential to accelerate the spread of resistance. The interplay between dominance levels and monogenic inheritance is further explored, with dominant traits being significantly more prevalent in polygenic inheritance. This observation may be attributed to the accumulation of enhanced metabolism. Notably, further analysis indicated that field strains exhibit a higher incidence of monogenic inheritance compared to other selected strains, aligning with established theoretical frameworks. In conclusion, the genetic architecture of resistance warrants increased research focus for its pivotal role in guiding resistance management strategies and advancing fundamental research.

When stroke occurs in pediatric age, it might be mistakenly interpreted as non-accidental head injury (NAHI). In these situations, a multidisciplinary approach is fundamental, including a thorough personal and familial history, along with accurate physical examination and additional investigations. Especially when the clinical picture is uncertain, it is important to remember that certain genetic conditions can cause bleeding inside the brain, which may resemble NAHI. Pediatric strokes occurring around the time of birth can also be an initial sign of undiagnosed genetic disorders. Hence, it is crucial to conduct a thorough evaluation, including genetic testing, when there is a suspicion of NAHI but the symptoms are unclear. In these cases, a characteristic set of symptoms is often observed. This study aims to summarize some of the genetic causes of hemorrhagic stroke in the pediatric population, thus mimicking non-accidental head injury, considering elements that can be useful in characterizing pathologies. A systematic review of genetic disorders that may cause ICH in children was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We selected 10 articles regarding the main genetic diseases in stroke; we additionally selected 11 papers concerning patients with pediatric stroke and genetic diseases, or studies outlining the characteristics of stroke in these patients. The disorders we identified were Moyamoya disease (MMD), COL4A1, COL4A2 pathogenic variant, Ehlers-Danlos syndrome (E-D), neurofibromatosis type 1 (Nf1), sickle cell disease (SCD), cerebral cavernous malformations (CCM), hereditary hemorrhagic telangiectasia (HHT) and Marfan syndrome. In conclusion, this paper provides a comprehensive overview of the genetic disorders that could be tested in children when there is a suspicion of NAHI but an unclear picture.

The etiologies of podocyte dysfunction that lead to pediatric nephrotic syndrome (NS) are vast and vary with age at presentation. The discovery of numerous novel genetic podocytopathies and the evolution of diagnostic technologies has transformed the investigation of steroid-resistant NS while simultaneously promoting the replacement of traditional morphology-based disease classifications with a mechanistic approach. Podocytopathies associated with primary and secondary steroid-resistant NS manifest as diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Molecular testing, once an ancillary option, has become a vital component of the clinical investigation and when paired with kidney biopsy findings, provides data that can optimize treatment and prognosis. This review focuses on the causes including selected monogenic defects, clinical phenotypes, histopathologic findings, and age-appropriate differential diagnoses of nephrotic syndrome in the pediatric population with an emphasis on podocytopathies.

Hypertension is a heritable disease that affects one-fourth of the population and accounts for about 50% of cardiovascular deaths. The genetic basis of hypertension is multifaceted, involving both monogenic and most commonly complex polygenic forms. With the advent of the human genome project, genome-wide association studies (GWAS) have identified a plethora of loci linked to hypertension by examining common genetic variations. It\'s notable, however, that the majority of these genetic variants do not affect the protein-coding sequences, posing a considerable obstacle in pinpointing the actual genes responsible for hypertension. Despite these challenges, precise mapping of GWAS-identified loci is emerging as a promising strategy to reveal novel genes and potential targets for the pharmacological management of blood pressure. This review provides insight into the monogenic and polygenic causes of hypertension. Special attention is given to PRDM6, among the earliest functionally characterized GWAS-identified genes. Moreover, this review delves into the roles of genes contributing to renal and vascular forms of hypertension, offering insights into their genetic and epigenetic mechanisms of action.