Rare primary vasculitis: update on multiple complex diseases and the new kids on the block.

Systemic vasculitis is a group of rare diseases that share an essential characteristic: inflammation of blood vessel walls. This injury occurs during the disease course, but specific features vary for each entity. In this paper, we will address relevant aspects of the newest monogenic mutation vasculitis, such as deficiency of adenosine deaminase 2 (ADA2) and VEXAS syndrome (UBA1), and other relevant vasculitis, such as Cogan syndrome and Susac syndrome that may share some similarities with them.

Dysregulation of Toll-Like Receptor Signaling-Associated Gene Expression in X-Linked Agammaglobulinemia: Implications for Correlations Genotype-Phenotype and Disease Expression.

INTRODUCTION: In X-linked agammaglobulinemia (XLA), the diversity of BTK variants complicates the study of genotype-phenotype correlations. Since BTK negatively regulates toll-like receptors (TLRs), we investigated if distinct BTK mutation types selectively modulate TLR pathways, affecting disease expression. METHODS: Using reverse transcription-quantitative polymerase chain reaction, we quantified ten TLR signaling-related genes in XLA patients with missense (n = 3) and nonsense (n = 5) BTK mutations and healthy controls (n = 17). RESULTS: BTK, IRAK2, PIK3R4, REL, TFRC, and UBE2N were predominantly downregulated, while RIPK2, TLR3, TLR10, and TLR6 showed variable regulation. The missense XLA group exhibited significant downregulation of IRAK2, PIK3R4, REL, and TFRC and upregulation of TLR3 and/or TLR6. CONCLUSION: Hypo-expression of TLR3, TLR6, and TLR10 may increase susceptibility to infections, while hyper-expression might contribute to chronic inflammatory conditions like arthritis or inflammatory bowel disease. Our findings shed light on the important inflammatory component characteristic of some XLA patients, even under optimal therapeutic conditions.

A healthcare claims analysis to identify and characterize patients with suspected X-Linked Myotubular Myopathy (XLMTM) in the Brazilian Healthcare System.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital disease, which is not well-defined. To our knowledge, no studies characterizing the XLMTM disease burden have been conducted in Brazil. We identified and described patients with suspected XLMTM using administrative claims data from the Brazilian public healthcare system. METHODS: Data from 2015 to 2019 were extracted from the DATASUS database. As no XLMTM-specific ICD-10 code was available, a stepwise algorithm was applied to identify patients with suspected XLMTM by selecting male patients with a congenital myopathies code (G71.2), aged < 18 years at index date (first claim of G71.2), with an associated diagnostic procedure (muscle biopsy/genetic test) and without spinal muscular atrophy or Duchenne muscular dystrophy. We attempted to identify patients with suspected severe XLMTM based on use of both respiratory and feeding support, which are nearly universal in the care of XLMTM patients. Analyses were performed for the overall cohort and stratified by age at index date < 5 years old and ≥ 5 years old. RESULTS: Of 173 patients with suspected XLMTM identified, 39% were < 5 years old at index date. Nearly all (N = 166) patients (96%) were diagnosed by muscle biopsy (91% of patients < 5 years old and 99% of patients ≥ 5 years old), six (3.5%) were diagnosed by clinical evaluation (8% of patients < 5 years old and 1% of patients ≥ 5 years old), and one was diagnosed by a genetic test. Most patients lived in Brasilia (n = 55), São Paulo (n = 33) and Minas Gerais (n = 27). More than 85% of patients < 5 years old and approximately 75% of patients ≥ 5 years old had physiotherapy at the index date. In both age groups, nearly 50% of patients required hospitalization at some point and 25% required mobility support. Respiratory and feeding support were required for 3% and 12% of patients, respectively, suggesting that between 5 and 21 patients may have had severe XLMTM. CONCLUSION: In this real-world study, genetic testing for XLMTM appears to be underutilized in Brazil and may contribute to underdiagnosis of the disease. Access to diagnosis and care is limited outside of specific regions with specialized clinics and hospitals. Substantial use of healthcare resources included hospitalization, physiotherapy, mobility support, and, to a lesser extent, feeding support and respiratory support.

Efficacy and safety of burosumab compared with conventional therapy in patients with X-linked hypophosphatemia: A systematic review.

Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: -1.46, 95% confidence interval [CI]: -1.76 to -1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.

Comprehensive genomic filtering algorithm to expose the cause of skewed X chromosome inactivation. The proof of concept in female haemophilia expression.

BACKGROUND: Exploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA. METHODS: A family involving three females (two symptomatic with severe/moderate HA: I.2, the mother, and II.1, the daughter; one asymptomatic: II.2) and two related affected males (I.1, the father and I.3, the maternal uncle) was studied. The genetic analysis included F8 mutational screening, multiplex ligation-dependent probe amplification, SNP microarray, whole exome sequencing (WES) and Sanger sequencing. XCI patterns were assessed in ectoderm/endoderm and mesoderm-derived tissues using AR-based and RP2-based systems. RESULTS: The comprehensive family analysis identifies I.2 female patient as a heterozygous carrier of F8:p.(Ser1414Ter) excluding copy number variations. A consistent XCI pattern of 99.5% across various tissues was observed. A comprehensive filtering algorithm for WES data was designed, developed and applied to I.2. A Gly58Arg missense variant in VMA21 was revealed as the cause for SXCI.Each step of the variant filtering system takes advantage of publicly available genomic databases, non-SXCI controls and case-specific molecular data, and aligns with established concepts in the theoretical background of SXCI. CONCLUSION: This study acts as a proof of concept for our genomic filtering algorithm's clinical utility in analysing X linked disorders. Our findings clarify the molecular aspects of SXCI and improve genetic diagnostics and counselling for families with X linked diseases like HA.

Real-world data of Brazilian adults with X-linked hypophosphatemia (XLH) treated with burosumab and comparison with other worldwide cohorts.

BACKGROUND: Disease-related variants in PHEX cause XLH by an increase of fibroblast growth factor 23 (FGF23) circulating levels, resulting in hypophosphatemia and 1,25(OH)2 vitamin D deficiency. XLH manifests in early life with rickets and persists in adulthood with osseous and extraosseous manifestations. Conventional therapy (oral phosphate and calcitriol) improves some symptoms, but evidence show that it is not completely effective, and it can lead to nephrocalcinosis (NC) and hyperparathyroidism (HPT). Burosumab (anti-FGF23 antibody) has shown to be effective and safety in the clinical trials. METHODS: The current real-world collaborative study evaluated genetic, clinical and laboratory data of XLH Brazilian adult patients treated with burosumab. RESULTS: Nineteen unrelated patients were studied. Patients reported pain, limb deformities and claudication, before burosumab initiation. 78% of them were previously treated with conventional therapy. The severity of the disease was moderate to severe (15 patients with score >5). At the baseline, 3 patients presented NC (16.7%) and 12 HPT (63%). After 16 ± 8.4 months under burosumab, we observed a significant: increase in stature (p = 0.02), in serum phosphate from 1.90 ± 0.43 to 2.67 ± 0.52 mg/dL (p = 0.02); in TmP/GFR from 1.30 ± 0.46 to 2.27 ± 0.64 mg/dL (p = 0.0001), in 1,25 (OH)2 D from 50.5 ± 23.3 to 71.1 ± 19.1 pg/mL (p = 0.03), and a decrease in iPTH from 86.8 ± 37.4 pg/mL to 66.5 ± 31.1 (p = 0.002). Nineteen variants were found (10 novel). HPT tended to develop in patients with truncated PHEX variants (p = 0.06). CONCLUSIONS: This study confirms the efficacy and safety of burosumab on XLH adult patients observed in clinical trials. Additionally, we observed a decrease in iPTH levels in patients with moderate to severe HPT at the baseline.

Incontinencia pigmenti. progresión clínica y diagnóstico de un caso / Incontinentia pigmenti. clinical progression and diagnosis of a case

Resumen La incontinencia pigmenti(IP) es una genodermatosis infrecuente ysistémica del neuroectodermo que involucra la piel, el sistema nervioso central, los ojos y los dientes, entre otros. Los signos clínicos dermatológicos constituyen el principal criterio diagnóstico, debido a que suelen ser los primeros en manifestarse. Se describen cuatro estadios característicos de la enfermedad según las lesiones cutáneas predominantes. No obstante, su pronóstico depende de los signos y síntomas extracutáneos. El diagnóstico se centra en criterios clínicos, histopatológicos y/o genéticos. Visto que no existe una terapéutica específica, la atención médica de esta enfermedad es multidisciplinaria y sintomática, y debe acompañarse del asesoramiento genético a los afectados y sus familiares. Presentamos el caso de una niña, nacida a término completo, quien presentó un cuadro clínico compatible con incontinencia pigmenti, del cual detallamos su progresión clínica, diagnóstico y seguimiento.

Abstract Incontinentiapigmenti is a rare and multisystemic,neuroectodermal genodermatosis that involves the skin, central nervous system, eyes and teeth, among others. Dermatological clinical signs are the main diagnostic criteria because they are usually the first to manifest. Four characteristic stages of the disease are described according to the predominant skin lesions. Nonetheless, prognosis depends on extracutaneous clinical signs and symptoms. Diagnosis is based on clinical, histopathological and/or genetic criteria. Considering there is no specific treatment available, the management of this disease is multidisciplinary and symptomatic, and must be accompanied by genetic counseling for those affected and their families. We present in a full-tern newborn femalethat presented with a clinical picture compatible with incontinentiapigmenti, and we will detail the clinical progression, diagnosis, and follow-up.

X-linked congenital adrenal hypoplasia: Report of long clinical follow-up and description of a new complex variant in the NR0B1 gene.

Adrenal hypoplasia congenita, attributed to NR0B1 pathogenic variants, accounts for more than 50% of the incidence of primary adrenal insufficiency in children. Although more than 250 different deleterious variations have been described, no genotype-phenotype correlation has been defined to date. We report a case of an adopted boy who reported the onset of an adrenal crisis at 2 weeks of age, requiring replacement therapy with mineralocorticoids and glucocorticoids for 4 months. For 3 years, he did well without treatment. At almost 4 years of age, the disorder was restarted. A long follow-up showed the evolution of hypogonadotropic hypogonadism. Molecular studies on NR0B1 revealed a novel and deleterious deletion-insertion-inversion-deletion complex rearrangement sorted in the 5'-3' direction, which is described as follows: (1) deletion of the intergenic region (between TASL and NR0B1 genes) and 5' region, (2) insertion of a sequence containing 37 bp at the junction of the intergenic region of the TASL gene and a part of exon 1 of the NR0B1 gene, (3) inversion of a part of exon 1, (4) deletion of the final portion of exon 1 and exon 2 and beginning of the 3'UTR region, (5) maintenance of part of the intergenic sequence (between genes MAGEB1 and NR0B1, telomeric sense), (6) large posterior deletion, in the same sense. The path to molecular diagnosis was challenging and involved several molecular biology techniques. Evaluating the breakpoints in our patient, we assumed that it was a nonrecurrent rearrangement that had not yet been described. It may involve a repair mechanism known as nonhomologous end-joining (NHEJ), which joins two ends of DNA in an imprecise manner, generating an "information scar," represented herein by the 37 bp insertion. In addition, the local Xp21 chromosome architecture with sequences capable of modifying the DNA structure could impact the formation of complex rearrangements.

Latin-American consensus on the transition into adult life of patients with X-linked hypophosphatemia.

INTRODUCTION: X-linked hypophosphatemia is an orphan disease of genetic origin and multisystem involvement. It is characterized by a mutation of the PHEX gene which results in excess FGF23 production, with abnormal renal and intestinal phosphorus metabolism, hypophosphatemia and osteomalacia secondary to chronic renal excretion of phosphate. Clinical manifestations include hypophosphatemic rickets leading to growth abnormalities and osteomalacia, myopathy, bone pain and dental abscesses. The transition of these patients to adult life continues to pose challenges to health systems, medical practitioners, patients and families. For this reason, the aim of this consensus is to provide a set of recommendations to facilitate this process and ensure adequate management and follow-up, as well as the quality of life for patients with X-linked hypophosphatemia as they transition to adult life. MATERIALS AND METHODS: Eight Latin American experts on the subject participated in the consensus and two of them were appointed as coordinators. The consensus work was done in accordance with the nominal group technique in 6 phases: (1) question standardization, (2) definition of the maximum number of choices, (3) production of individual solutions or answers, (4) individual question review, (5) analysis and synthesis of the information and (6) synchronic meetings for clarification and voting. An agreement was determined to exist with 80% votes in favor in three voting cycles. RESULTS AND DISCUSSION: Transition to adult life in patients with hypophosphatemia is a complex process that requires a comprehensive approach, taking into consideration medical interventions and associated care, but also the psychosocial components of adult life and the participation of multiple stakeholders to ensure a successful process. The consensus proposes a total of 33 recommendations based on the evidence and the knowledge and experience of the experts. The goal of the recommendations is to optimize the management of these patients during their transition to adulthood, bearing in mind the need for multidisciplinary management, as well as the most relevant medical and psychosocial factors in the region.

Efficacy and safety of burosumab compared with conventional therapy in patients with X-linked hypophosphatemia: A systematic review

ABSTRACT Burosumab, a monoclonal antibody directed against the fibroblast growth factor 23 (FGF23), has been approved for the treatment of X-linked hypophosphatemia (XLH). We conducted a systematic review to compare the efficacy and safety of burosumab versus conventional therapy (phosphorus and calcitriol) on XLH treatment. After a comprehensive literature search on MEDLINE/PubMed and Embase, we found nine studies for inclusion in the analysis. Risk of bias was assessed, and a random-effects model was used to determine the effect size. Clinical, biochemical, and radiological parameters of disease severity before and after treatment were analyzed and expressed in standardized mean difference (SMD). Burosumab resulted in normalization of phosphate homeostasis with an increase in renal tubular phosphate reabsorption and significant resolution of skeletal lesions (change in Thacher's total rickets severity score SMD: −1.46, 95% confidence interval [CI]: −1.76 to −1.17, p < 0.001, improvement in deformities, and decline in serum alkaline phosphatase levels [SMD: 130.68, 95% CI: 125.26-136.1, p < 0.001)]. Conventional therapy led to similar improvements in all these parameters but to a lower degree. In adults, burosumab normalized phosphorus levels (SMD: 1.23, 95% CI: 0.98-1.47, p < 0.001) with resultant clinical improvement. Burosumab treatment was well tolerated, with only mild treatment-related adverse effects. The present review indicates a potential role for burosumab in improving rickets, deformities, and growth in children with XLH. Given its superior efficacy and safety profile, burosumab could be an effective therapeutic option in children. We suggest further studies comparing burosumab versus conventional therapy in children and adults with XLH.

A genetic study of a Brazilian cohort of patients with X-linked hypophosphatemia reveals no correlation between genotype and phenotype.

Aim: X-linked hypophosphatemia (XLH) is the most common inherited form of rickets, and it is caused by pathogenic inactivating variants of the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. The main purpose of this study is to identify the presence of a genotype-phenotype correlation in a cohort of XLH patients. Methods: This is a retrospective study including patients diagnosed with hypophosphatemic rickets, confirmed by clinical, radiological, and laboratory findings. Medical records were reviewed for phenotypic analyses. Genomic DNA was extracted from the peripheral blood lymphocytes, and PHEX sequencing was performed by exomic NGS sequencing. The Wilcoxon rank-sum test and the two-tailed Fisher's exact test were employed for the statistical analyses of this study. Results: A total of 41 patients were included in this study, and 63.41% (26/41) of the patients were female. The mutation analyses identified 29.27% missense variants and 29.72% nonsense variants, most of them were considered deleterious (66.41%). Six novel deleterious variants in the PHEX gene were detected in seven patients. The median concentrations of pretreatment serum calcium, phosphorus, and parathyroid hormone (PTH) were not significantly different among patients with different genotypes. An orthopedic surgery due to bone deformity was required in 57.69%. Conclusions: Our analysis did not identify any specific genotype as a predictor. No significant genotype-phenotype correlation was found, suggesting that the recognition of subjacent pathogenic mutation in the PHEX gene may have limited prognostic value. Despite this finding, genetic testing may be useful for identifying affected individuals early and providing appropriate treatment.

Evaluation of the trabecular bone score in 35 children and adults with X-linked hypophosphatemic rickets.

INTRODUCTION:  The aim of this study is to evaluate and compare the trabecular bone scores (TBSs) of 11 children and 24 adults with X-linked hypophosphatemic rickets (XLH) and non-XLH subjects from a tertiary center. MATERIALS AND METHODS:  The areal bone mineral density at the lumbar spine (LS-aBMD) and LS-aBMD Z score were analyzed by dual-energy X-ray absorptiometry. The bone mineral apparent density (BMAD) and LS-aBMD Z score adjusted for height Z score (LS-aBMD-HAZ) were calculated. The TBS was determined using TBS iNsight software based on DXA images from the Hologic QDR 4500 device. RESULTS: The XLH patients exhibited a higher mean LS-aBMD Z score, BMAD, and TBS than the non-XLH subjects (p < 0.01). LS-aBMD-HAZ and BMAD were greater in the XLH children than those in their corresponding non-XLH subjects (p < 0.01 and p = 0.02), and the XLH children trended toward a greater TBS (p = 0.06). The XLH adults had a higher LS-aBMD Z score, BMAD, and TBS than the non-XLH subjects (p < 0.01). When stratified by metabolic status according to the serum values of bone formation markers, compensated adult patients had a higher LS-aBMD Z score, BMAD, and TBS than non-XLH subjects (p < 0.01). Noncompensated patients had higher LS-aBMD Z scores and BMAD results than non-XLH subjects. However, TBS values did not differ statistically significantly between those groups (p = 0.45). CONCLUSION: The higher LS-aBMD Z score, BMAD, and TBS result in the XLH patients compared to non-XLH subjects indicates an increased amount of trabecular bone within the lumbar spine, regardless of extraskeletal calcifications.

ZDHHC9 X-linked intellectual disability: Clinical and molecular characterization.

The ZDHHC9 gene encodes the Zinc Finger DHHC-Type Containing 9 protein that functions as a palmitoyltransferase. Variants in this gene have been reported as the cause of Raymond-type X-linked intellectual disability with only 16 families described in the literature. This study reviews molecular and clinical data from previously reported patients and reports the case of a 13-year-old patient with a splicing variant in ZDHHC9 presenting intellectual disability, developmental delay, facial dysmorphisms, and skeletal defects. Although intellectual disability and developmental delay with severe speech delay have been reported in all cases with available clinical data, the remaining clinical signs differ significantly between patients. Missense, nonsense, frameshift, and splicing variants, in addition to large exonic deletions, have been described suggesting a loss of function mechanism. Though variants are distributed in almost all exons, most missense and nonsense variants affect arginine residues located in the cytoplasmic domains of this transmembrane protein, suggesting possible mutational hotspots.

Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain.

For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life. Here we will review and discuss relevant data showing how particular X- and Y-linked genes and epigenetic mechanisms controlling their expression and inheritance are involved, along with or independently of gonadal hormones, in the generation of sex differences in the brain.

Clinical and genetic findings in two siblings with X-Linked agammaglobulinemia and bronchiolitis obliterans: a case report.

BACKGROUND: X-linked agammaglobulinemia (XLA) is an Inborn Errors of Immunity (IEI) characterized by pan-hypogammaglobulinemia and low numbers of B lymphocytes due to mutations in BTK gene. Usually, XLA patients are not susceptible to respiratory tract infections by viruses and do not present interstitial lung disease (ILD) such as bronchiolitis obliterans (BO) as a consequence of acute or chronic bacterial infections of the respiratory tract. Although many pathogenic variants have already been described in XLA, the heterogeneous clinical presentations in affected patients suggest a more complex genetic landscape underlying this disorder. CASE PRESENTATION: We report two pediatric cases from male siblings with X-Linked Agammaglobulinemia and bronchiolitis obliterans, a phenotype not often observed in XLA phenotype. The whole-exome sequencing (WES) analysis showed a rare hemizygous missense variant NM_000061.2(BTK):c.1751G>A(p.Gly584Glu) in BTK gene of both patients. We also identified a gain-of-function mutation in TGFß1 (rs1800471) previously associated with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. TGFß1 plays a key role in the regulation of immune processes and inflammatory response associated with pulmonary impairment. CONCLUSIONS: Our report illustrates a possible role for WES in patients with known inborn errors of immunity, but uncommon clinical presentations, providing a personalized understanding of genetic basis, with possible implications in the identification of potential treatments, and prognosis for patients and their families.

X-linked hypophosphatemic rickets: Description of seven new variants in patients followed up in reference hospitals in Rio de Janeiro.

BACKGROUND: X-linked hypophosphatemic rickets (XLHR) is a rare genetic disease, often delayed in diagnosis due to the low degree of suspicion and limited access to sophisticated diagnostic tools that confirm the diagnosis, such as genetic testing. METHODS: Through a cross-sectional and observational study, 26 patients with a previously presumptive diagnosis of X-linked hypophosphatemic rickets (based on clinical history, laboratory findings, and physical examination), were followed for approximately 12 months. During 12 months of follow-up, only 16 patients underwent genetic testing and enrolled in the study. Previous data were analyzed, such as clinical history (e.g., gender, current age, age of clinical diagnosis, age of admission to hospital, family history, and previous orthopedic surgery), physical exam, imaging tests (e.g., radiological changes) and laboratory tests (e.g., tubular maximum reabsorption rate of phosphate to glomerular filtration rate, alkaline phosphatase, and phosphate levels) at the time of the patient's admission to IEDE and UFRJ, to corroborate and substantiate our research. These data were extracted from the medical records of the patients. RESULTS: Among the 16 patients analyzed by molecular biology techniques, the new generation sequencing (NGS), using DNA samples from oral swabs, we obtained seven variants never previously described, which were verified by Sanger sequencing. Among the seven variants never previously described, the most common coding impact was the nonsense mutation. We found two frameshift, one intronic splicing variant, three nonsense, and one deletion splice junction loss. Among patients with new mutations who presented data in the medical record, 100% showed a reduction in TmP/GFR (average of 1.98 mg/dl), the most sensitive laboratory parameter at the time of diagnosis, as well as serum phosphorus (100% had hypophosphatemia on arrival at the referral hospitals--average of 2.4 mg/dl and median 2.3 mg/dl). We also performed NGS on three mothers of the patients with identified mutations. Among these mothers, only one tested negative for the mutation and no family history was reported as well. This mother had serum phosphate of 3.5 mg/dl (normal range: 2.5-4.5 mg/dl) at the time of genetic test collection. The others had a positive test, low serum phosphorus at the time of the molecular test, in addition to a positive family history. CONCLUSION: This study describes seven new variants in the PHEX gene and aims to increase the knowledge of the scientific community about the types of mutations involving this gene, increasing information on the genetic basis of this condition, enabling future considerations about genotype-phenotype correlation, in addition to diagnosis accurate and early.

NEXMIF pathogenic variants in individuals of Korean, Vietnamese, and Mexican descent.

NEXMIF pathogenic variants have been known to produce a wide spectrum of X-linked intellectual disability (ID) in both males and females. Thus far, few individuals from diverse populations have been described with NEXMIF-related disorders. Herein, we report three individuals with NEXMIF pathogenic variants, the first two are the only males of Korean and Vietnamese descent described with this disorder to our knowledge. The last patient is a Hispanic female who harbors the same pathogenic variant as a previously described Caucasian individual, but with differing clinical presentation. These patients present with many classic symptoms of NEXMIF-related disorders including ID, epilepsy, developmental delay, and dysmorphic features. In addition, they have symptoms that have not been thoroughly described in the literature, including allergies with multiple anaphylactic events and hypothyroidism. This report is intended to raise awareness and educate about the clinical signs that may prompt testing for NEXMIF-related disorders.

A patient with X-linked retinoschisis and exudative retinal detachment associated with a pathogenic hemizygous variant c.304c>T in RS1.

BACKGROUND: X-linked retinoschisis (XLRS) is a rare retinal dystrophy due to pathogenic variants in the RS1 gene. The hallmark of the disease is a foveal spoke-wheel appearance. The purpose of this report is to expand the phenotypic spectrum of XLRS reporting a patient with atypical phenotype of XLRS associated with Coats-like phenotype. MATERIALS AND METHODS: This is a case report of a patient diagnosed with XLRS who underwent ophthalmologic multimodal imaging and next-generation sequencing panel. RESULTS: The proband is a 14-year-old male patient who presented at Instituto Suel Abujamra with a history of Coats Disease in the right eye treated with retinal laser in both eyes two years ago. His best-corrected visual acuity was count finger at 1 foot in the right eye and 20/40 in the left eye. Fundus exam showed an extensive area of exudation and retinal detachment in the right eye and cystic change at the fovea in a spoke-wheel pattern in the left eye. The next-generation sequencing panel targeting inherited retinal diseases with 236 genes found a pathogenic hemizygous variant c.304C>T (p.Arg102Trp) in RS1 that has already been reported. CONCLUSIONS: The association of peripheral vascular incompetence and XLRS has already been described. Retinal exudation in the setting of XLRS is probably the result of vascular disruption and compromise. The loss of retinoschisin function that leads to foveal retinoschisis may also lead to vascular anomalies.

Alpha-Galactosidase A Levels in Colombian Males with End-Stage Renal Disease: Ten Years of Selective Screening in Dried Blood Spots

Abstract Fabry disease is a metabolic alteration linked to an enzymatic deficiency of Alpha-Galactosidase A, this disorder compromises the sphingolipid metabolism, leading to an accumulation of lysosomal globotriaosylceramide and is inherited in an X-linked recessive way. The diagnostic of this disease, in general, requires the confirmation of below-normal levels of Alpha-Galactosidase A obtained from dried blood spot (DBS) samples, followed by an assessment of the enzyme in leukocytes. We aimed to report the Alpha-Galactosidase A values obtained in Colombian males with end-stage renal disease (ESRD) screened using dried blood spot samples during ten years. This screening was performed with samples sent to the analysis center from 6156 patients between 2006- 2016. All patients with low levels in enzyme activity (compared to the control population) were sent to confirmation through enzyme analysis in isolated leukocytes. 26 males (0.42%) with low levels of Alpha-Galactosidase A were identified (Range 0.0 - 1.14 nmol/ml/hour, cut-off: 1.15), 22 patients were subsequently measured in isolated leukocytes having a confirmation of Fabry disease in 5 patients (0.08% of total male population) (Range: 0.3 -4.7 nmol/mg prot/h). These results are similar to those reported in studies with comparable characteristics being this the first reporting frequency of Fabry disease among Colombian males with end-stage renal disease.

Retinosquisis ligada al cromosoma X: presentación de un caso clínico y análisis del diagnóstico genético / X-linked Retinoschisis: a case report and genetic diagnosis analysis / Retinosquise ligada ao X: a presentação de um caso clínico e análise do diagnóstico genético

La Retinosquisis ligada al X, que se presenta fundamentalmente en varones, es una enfermedad genética caracterizada por agudeza visual reducida debido a degeneración macular. Su prevalencia es de 1/5000 varones en todo el mundo. Se manifiesta desde la primera década de la vida con pérdida de la visión que progresa hasta la adolescencia y se mantiene estable hasta la 4ta década de la vida, momento en que presenta un declive importante. El fondo de ojo suele mostrar esquisis. Las mujeres portadoras rara vez presentan síntomas. El gen involucrado es RS1, codifica para Retinosquina, proteína que participa en la integridad estructural y funcional de la retina. El mismo presenta diferentes mutaciones que generan pérdida de función de la proteína. La sospecha diagnóstica se basa en la clínica y los antecedentes familiares, y se apoya en la paraclínica confirmándose en la mayoría de los casos mediante secuenciación del gen. El tratamiento consiste en control periódico oftalmológico y cirugía de las complicaciones. Presentamos el caso de un niño de 2 años con episodios reiterados de desprendimiento de retina, con antecedentes familiares de Retinosquisis por línea materna en individuos de sexo masculino. Estos fueron estudiados demostrándose que son portadores de la variante probablemente patogénica c.466A>C (Arg156Gly) en el gen RS1 la cual había sido reportada previamente en una familia de origen chino. Se demostró que nuestro paciente presenta la mutación familiar en hemicigosis, por lo que esta es la segunda familia en que se confirma la segregación de esta variante con Retinosquisis.

X-linked Retinoschisis is a genetic disease characterized by reduced visual acuity mainly in men due to juvenile macular degeneration. Its prevalence is 1/5000 men worldwide. It manifests from the first decade of life with loss of vision that progresses to adolescence and then remains stable until the 4th decade of life, when it may present a significant decline. The fundus exam usually shows schism. Carrier women rarely have symptoms. The gene involved is RS1 (Xp22.13), which encodes for Retinoschisin, a protein that participates in the structural and functional integrity of the retina. In affected cases, mutations that generate loss of protein function were demonstrated. The diagnosis is based on the clinical and family history, and is supported by ophthalmology evaluation; in most cases it can be confirmed by sequencing of the gene. The treatment consists of periodic ophthalmological control and surgery of the complications. We describe the case of a 2 year old boy with repeated episodes of retinal detachment and who has a family history of Retinoschisis by maternal line in male individuals. These were studied, and it was shown that they are carriers of the probably pathogenic variant c.466A> C (Arg156Gly) in the RS1 gene, which had been reported previously in a family of Chinese origin. It was shown that our patient presents the family mutation in hemizygous state, so this is the second family in which the segregation of this variant with Retinoschisis is confirmed.

A retinosquise ligada ao X, que ocorre principalmente em homens, é uma doença genética caracterizada pela redução da acuidade visual devido à degeneração macular. Sua prevalência é de 1/5000 homens em todo o mundo. Manifesta-se desde a primeira década de vida com perda da visão que progride até a adolescência e permanece estável até a 4ª década de vida, época em que apresenta declínio significativo. O fundo geralmente mostra esquise. Portadoras do sexo feminino raramente apresentam sintomas. O gene envolvido é o RS1, que codifica a Retinosquina, proteína que participa da integridade estrutural e funcional da retina. Apresenta diferentes mutações que geram perda de função da proteína. A suspeita diagnóstica baseia-se na história clínica e familiar, e na paraclínica, sendo confirmada na maioria dos casos pelo sequenciamento gênico. O tratamento consiste em acompanhamento oftalmológico periódico e cirurgia para complicações. Apresentamos o caso de um menino de 2 anos com episódios repetidos de descolamento de retina, com história familiar de retinosquise materna no sexo masculino. Estes foram estudados mostrando que são portadores da variante provavelmente patogênica c.466A> C (Arg156Gly) no gene RS1, que havia sido relatado anteriormente em uma família de origem chinesa. Foi demonstrado que nosso paciente apresenta a mutação familiar em hemizigose, sendo esta a segunda família em que se confirma a segregação desta variante com Retinosquise.