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Kabuki syndrome (KS) is a genetic disorder caused mainly by de novo pathogenic variants in KMT2D or KDM6A, characterized by recognizable facial features, intellectual disability, and multi-systemic involvement, including short stature, microcephaly, hearing loss, cardiac defects, and additional congenital anomalies. While congenital anomalies of the kidneys and urinary tract (CAKUT) are known manifestations of this disorder, studies focused solely on kidney involvement are scarce, and its prevalence is most likely underestimated. This study aimed to describe the prevalence and nature of CAKUT and other renal manifestations, in a cohort of KS patients followed at a single tertiary center. All patients who were evaluated at the Sheba Medical Center and received a clinical and/or molecular diagnosis of KS, over a 16-year period (2004–2020), were included. Digital medical records, including ultrasound studies, were reviewed by a team of pediatric nephrologists. Thirteen patients were included in the study, at ages ranging from the neonatal period to 20 years. In eight patients, a pathogenic variant in KMT2D was established. CAKUT were detected in 8/13 (61.5%) of patients and varied from hypospadias, hydronephrosis, or double collecting systems to pelvic kidney, kidney asymmetry, horseshoe kidney, or kidney agenesis. One patient experienced kidney failure necessitating transplantation at 20 years of age. Our findings underscore the high prevalence of CAKUT and genitourinary involvement in patients with KS and suggest that assessment by pediatric nephrology specialists is warranted as part of the routine multidisciplinary evaluation of newly diagnosed patients. A higher resolution version of the Graphical abstract is available as Supplementary information

Background Infantile cortical hyperostosis (ICH)/Caffey disease is an inflammatory collagenopathy of infancy, manifested by subperiosteal bone hyperplasia. Genetically, ICH was linked with heterozygosity for an R836C mutation in the COL1A1 gene. Although an autosomal-recessive trait is also suspected, it has not been proven thus far. Methods A case of an infant male born to consanguineous parents is reported, presenting with classical findings, course, and clinical outcome of ICH. Whole-exome sequencing (WES) was performed in order to identify a possible underlying genetic defect. Results WES analysis revealed a novel homozygous nonsense mutation in lysine 2 of fetuin-A, encoded by the ALPHA-2-HS-GLYCOPROTEIN (AHSG) gene (c.A4T; p.K2X). Fetuin-A is an important regulator of bone remodeling and an inhibitor of ectopic mineralization. By enzyme-linked immunosorbent assay (ELISA), we show a complete deficiency of this protein in the patient’s serum, compared to controls. Conclusion A novel homozygous nonsense mutation in AHSG gene has been found in ICH patient with a typical phenotype, resulting in fetuin-A deficiency. This finding postulates an autosomal-recessive mode of inheritance in ICH, which, unlike the autosomal-dominant inheritance associated with COL1A1, is associated with AHSG and fetuin-A deficiency.

Kabuki syndrome (KS) is a genetic disorder caused mainly by de novo pathogenic variants in KMT2D or KDM6A, characterized by recognizable facial features, intellectual disability, and multi-systemic involvement, including short stature, microcephaly, hearing loss, cardiac defects, and additional congenital anomalies. While congenital anomalies of the kidneys and urinary tract (CAKUT) are known manifestations of this disorder, studies focused solely on kidney involvement are scarce, and its prevalence is most likely underestimated. This study aimed to describe the prevalence and nature of CAKUT and other renal manifestations, in a cohort of KS patients followed at a single tertiary center.All patients who were evaluated at the Sheba Medical Center and received a clinical and/or molecular diagnosis of KS, over a 16-year period (2004-2020), were included. Digital medical records, including ultrasound studies, were reviewed by a team of pediatric nephrologists.Thirteen patients were included in the study, at ages ranging from the neonatal period to 20 years. In eight patients, a pathogenic variant in KMT2D was established. CAKUT were detected in 8/13 (61.5%) of patients and varied from hypospadias, hydronephrosis, or double collecting systems to pelvic kidney, kidney asymmetry, horseshoe kidney, or kidney agenesis. One patient experienced kidney failure necessitating transplantation at 20 years of age.Our findings underscore the high prevalence of CAKUT and genitourinary involvement in patients with KS and suggest that assessment by pediatric nephrology specialists is warranted as part of the routine multidisciplinary evaluation of newly diagnosed patients. A higher resolution version of the Graphical abstract is available as Supplementary information.

Kabuki syndrome (KS) is a genetic disorder caused by pathogenic variants in KMT2D or KDM6A, and manifesting with multi-systemic involvement, including recognizable facial features, developmental delay and multiple congenital anomalies. Ophthalmological involvement has been described in varying rates in several studies. We aimed to evaluate the prevalence and nature of ophthalmological findings in a cohort of KS patients in Israel. Medical records of all patients diagnosed with KS in our tertiary center between 2004 and 2020 were retrospectively reviewed. Data collected included physical examination findings, molecular analysis as well as comprehensive ophthalmic characteristics including visual acuity, ocular alignment and motility, ocular adnexa, anterior segments and dilated fundus exams. Finally, an updated systematic review of the literature was performed. Thirteen unrelated patients were included in the study, diagnosed at an age raging from the first months of life to 20 years. Of these, three (23%) showed significant ophthalmological abnormalities, beyond the characteristic structural findings of long palpebral fissures and lower eyelid eversion. These included bilateral posterior colobomata in the first patient; bilateral ptosis, hypermetropia, esotropia, blue sclera and anisocoria in the second; and bilateral congenital cataracts in the third. To conclude, our findings underscore the importance of a comprehensive ophthalmological evaluation as part of the routine multidisciplinary assessment of children suspected/diagnosed with KS.

Background: Kawasaki disease (KD) is an acute, systemic vasculitis in children, with an etiology that is not completely understood. It is assumed that the development of KD is mediated by an immunologic response. Several reports from East Asia have found a higher prevalence of atopic diseases among patients with KD, but a large-scale study of a non-Asian population regarding this correlation is still lacking. The purpose of this article was to achieve this goal. Methods: We conducted a cross-sectional, large-scale study to estimate the correlation of KD with allergic diseases. The medical history of 1,187,757 Israeli teenagers (aged 16-20 years during the years 1998-2013) was retrieved. The study population was divided into 3 groups according to a past history of noncomplicated and complicated KD and a control group. The prevalence of allergic diseases among these groups was further investigated. Results: The prevalence of atopic diseases in the 3 study groups was presented (asthma in 11.4, 8.1 and 3.5%, respectively; angioedema/urticaria in 7.1, 0 and 0.46%, respectively; allergic rhinitis in 20, 12.1 and 6.7%, respectively). In noncomplicated KD, a statistically significant link to asthma [odds ratio (OR) 2.4; p = 0.048] and a borderline significant link to allergic rhinitis (OR 1.9; p = 0.06) were found. In KD complicated with cardiac disease, statistically significant links were found for all the allergic conditions, asthma (OR 3.5; p = 0.003), allergic rhinitis (OR 3.5; p < 0.001) and angioedema/urticaria (OR 16.48; p < 0.001). Conclusion: KD is associated with allergic diseases. This association increases with the severity of the disease.

Psychological stress is thought to play a major role in the development and exacerbation of autoimmune diseases in general, as well as in rheumatoid arthritis (RA) in particular. The aims of the current study are to compare retrospective self-reports of childhood maltreatment and lifetime major life/traumatic experiences of American and Israeli RA patients, using standardised instruments, while adjusting for concomitant mental disorders and psychological distress, in order to rule out their part in the subjective reports, thus addressing the trans-cultural robustness of the association between childhood maltreatment, traumatic experiences and RA.RA patients at the participating study centres were recruited by their physicians, both in Israel and the USA. Patients filled out questionnaires regarding demographic data, disease activity, psychological distress, potential anxiety and potential depression. In addition, patients answered questions regarding pain and childhood maltreatment.83 RA patients were recruited in the US and 23 patients in Israel. The comparison of CTQ-subscales between the US and Israeli cohorts showed significant differences between the groups only in the subscales of emotional neglect (US 10.30±5.05, Israeli 22.67±3.68, p0.05) and emotional abuse (US 10.46±5.77, Israeli 7.13±4.84, p0.05). 87% of Israeli patients had severe emotional neglect. Severe emotional abuse was associated with probable depression (OR 7.778, CI [1.907-31.716]). Using Pain Disability Index (PDI) score, Americans reported more pain during sexual activity than Israelis (US PDI Score 5.64±3.70. Israeli 3.16±3.86, p0.05). PDI score was also associated with a previous traumatic event (36.89±18.57 vs. 16.82±14.85, p0.05).A high degree of similarity was demonstrated between American and Israeli populations of RA patients, regarding psychological stressors and previous traumatic events. As expected, the results indicated a link between emotional abuse and depression in these patients. In addition, a previous traumatic event was associated with more significant pain. Physicians caring for RA patients should be vigilant regarding the possible association with childhood adversity and should consider appropriate consultations when indicated. In addition, while dealing with pain management in RA patients, physicians should keep in mind the possible contribution of distant childhood adversity.

Coexistence of rheumatoid arthritis and gout is considered to be unusual. The current study was designed as a population-based cross-sectional study, utilizing the medical database of Clalit Health Services, the largest healthcare provider organization in Israel. Data of adult patients who were previously diagnosed with rheumatoid arthritis was retrieved. For each patient, five age- and sex-matched control patients were randomly selected. Different parameters including BMI, socioeconomic status, and existence of gout as well as smoking and hypertension were examined for both groups. The study included 11,540 patients with rheumatoid arthritis and 56,763 controls. The proportion of gout in the study group was high compared to controls (1.61 vs. 0.92%, P < 0.001). In a multivariate analysis, rheumatoid arthritis was associated with gout (OR = 1.72, 95% CI 1.45–2.05, P = 0.00). The proportion of gout in rheumatoid arthritis patients is not lower than in the general population.