A New Case Report of Traboulsi Syndrome: A Literature Review and Insights Into Genotype-Phenotype Correlations.

Traboulsi syndrome is a rare genetic disorder characterized by facial dysmorphism, lens subluxation, anterior segment anomalies, and spontaneous filtering blebs. The syndrome is due to mutations in the ASPH gene, which plays a crucial role in the development and maintenance of the lens. This case report describes the clinical and genetic findings in a Mexican male with Traboulsi syndrome, highlighting the identification of a novel ASPH variant. A 21-year-old male presented with trauma to the right eye while playing soccer. He had a history of lens subluxation and dysmorphic facial features. Ophthalmic examination revealed right eye lens subluxation into the anterior chamber (with signs of a previous episode of acute angle closure) and left eye posterior and inferior lens subluxation with sectorial iris atrophy. Genetic analysis identified a pathogenic ASPH variant (NM_004318.3:c.1892G>A, p.Trp631*) and a novel likely pathogenic variant (deletion of exons 20-21), confirming Traboulsi syndrome. This is the first instance of Traboulsi syndrome in the Mexican population. The absence of spontaneous filtering blebs in this patient supports previous reports of the wide phenotypic variability that could be related to the type of mutation. This novel ASPH variant expands the known genetic heterogeneity of Traboulsi syndrome.

Optic nerve abnormalities in female-restricted Wieacker-Wolff syndrome by a novel variant in the ZC4H2 gene.

BACKGROUND: Wieacker-Wolff syndrome is an ultra-rare disease with X-linked inheritance characterized by arthrogryposis, intellectual disability, microcephaly, and distal limb muscle atrophy. Ophthalmic abnormalities such as ptosis, strabismus, and oculomotor apraxia have been reported in half of the patients. Wieacker-Wolff syndrome female-restricted (WRWFFR) is an even rarer disease recently used for females with a more severe phenotype. MATERIALS AND METHODS: Clinical geneticist and ophthalmic examination, neuroimaging, and exome sequencing. RESULTS: A 4 years-old girl with developmental and language delay, microcephaly, camptodactyly, digital pads, and arthrogryposis was identified by the clinical geneticist. Ophthalmic examination revealed deep-set eyes, high hyperopic astigmatism in both eyes, and reduced retinal nerve fiber layer thickness measured by optical coherence tomography. Exome sequencing identified a novel, probably pathogenic variant in the ZC4H2 gene NM_018684.3:c.145A>T p. (Lys49*) in heterozygosis. DISCUSSION: WRWFFR is an ultra-rare disease with X-linked inheritance by variants in the ZC4H2 gene. This case reports a girl with a novel nonsense variant in the ZC4H2 gene and a severe phenotype; previous reports have identified WRWFFR in females with large deletions and nonsense mutations which could explain the manifestations in the current case report. A complete ophthalmic examination should be considered in patients with WRWFFR to detect the possibly associated optic nerve involvement and other previously described manifestations such as ptosis and strabismus.

Prevalence of Glucose-6-Phosphate Dehydrogenase Deficiency in Newborns in Northeast Mexico.

OBJECTIVE: Glucose-6-phosphate dehydrogenase deficiency (G6PDd) is the most common enzymatic disease worldwide and the prevalence is not well established because of the lack of screening. This study aimed to estimate the prevalence of G6PDd in a Hispanic population from Northeast Mexico. STUDY DESIGN: In this retrospective study, a database was used to analyze the G6PDd in neonates included in the expanded newborn metabolic screening of inherited metabolic disorders during a period of 4 years through the GSP Neonatal G6 kit (PerkinElmer). RESULTS: Among 96,152 (48,462 male) neonates screened for G6PD enzyme activity, a total of 566 (0.58%) cases were deficient for G6PD. Of those 566 patients, 469 (82.8%) attended the second test and the other 97 (17.2%) patients were lost. Of those 469 who did attend, 384 (81.9%) neonates were deficient in the second test and 85 (18.1%) were normal. With the data collected, 384 neonates were confirmed with G6PDd, 348 (88.6%) were male and 36 (11.4%) patients were female. The calculated prevalence for this population was 0.72 cases per 100 male newborns. CONCLUSION: The prevalence of G6PDd in the Northeastern Mexican population is high. Since migration is increasing in the United States, pediatricians should be aware of the need to search for G6PDd in newborns and the wide clinical manifestations they can present. KEY POINTS: · The calculated prevalence of glucose-6-phosphate dehydrogenase deficiency in Northeast Mexico is 3.99 cases per 1,000 newborns.. · Glucose-6-phosphate dehydrogenase deficiency screenings should be included in all newborn metabolic screenings.. · Glucose-6-phosphate dehydrogenase deficiency is a common erythroenzymopathy that must be addressed as a public health concern. To anticipate clinical complications, target population monitoring is required..

Molecular Characterization of Associated Pathogens in Febrile Patients during Inter-Epidemic Periods of Urban Arboviral Diseases in Tapachula Southern Mexico.

Emerging and re-emerging vector-borne infections are a global public health threat. In endemic regions, fever is the main reason for medical attention, and the etiological agent of such fever is not usually identified. In this study, non-specific febrile pathogens were molecularly characterized in serum samples from 253 patients suspected of arbovirus infection. The samples were collected in the southern border region of Mexico from April to June 2015, and February to March 2016. ZIKV, CHIKV, DENV, leptospirosis, and rickettsiosis were detected by qPCR and nested PCR to identify flavivirus and alphavirus genera. The results indicated that 71.93% of the samples were positive for CHIKV, 0.79% for ZIKV, and 0.39% for DENV, with the number positive for CHIKV increasing to 76.67% and those positive for ZIKV increasing to 15.41% under the nested PCR technique. Leptospira Kmetyi was identified for the first time in Mexico, with a prevalence of 3.16%. This is the first report of ZIKV in Mexico, as well the first detection of the virus in early 2015. In conclusion, the etiological agent of fever was determined in 94% of the analyzed samples.

Whole-Exome Sequencing, Proteome Landscape, and Immune Cell Migration Patterns in a Clinical Context of Menkes Disease.

Menkes disease (MD) is a rare and often lethal X-linked recessive syndrome, characterized by generalized alterations in copper transport and metabolism, linked to mutations in the ATPase copper transporting α (ATP7A) gene. Our objective was to identify genomic alterations and circulating proteomic profiles related to MD assessing their potential roles in the clinical features of the disease. We describe the case of a male patient of 8 months of age with silvery hair, tan skin color, hypotonia, alterations in neurodevelopment, presence of seizures, and low values of plasma ceruloplasmin. Trio-whole-exome sequencing (Trio-WES) analysis, plasma proteome screening, and blood cell migration assays were carried out. Trio-WES revealed a hemizygous change c.4190C > T (p.S1397F) in exon 22 of the ATP7A gene. Compared with his parents and with child controls, 11 plasma proteins were upregulated and 59 downregulated in the patient. According to their biological processes, 42 (71.2%) of downregulated proteins had a participation in cellular transport. The immune system process was represented by 35 (59.3%) downregulated proteins (p = 9.44 × 10-11). Additional studies are necessary to validate these findings as hallmarks of MD.

The Latin American network for congenital malformation surveillance: ReLAMC.

The early detection of congenital anomaly epidemics occurs when comparing current with previous frequencies in the same population. The success of epidemiologic surveillance depends on numerous factors, including the accuracy of the rates available in the base period, wide population coverage, and short periodicity of analysis. This study aims to describe the Latin American network of congenital malformation surveillance: ReLAMC, created to increase epidemiologic surveillance in Latin America. We describe the main steps, tasks, strategies used, and preliminary results. From 2017 to 2019, five national registries (Argentina [RENAC], Brazil [SINASC/SIM-BRS], Chile [RENACH], Costa Rica [CREC], Paraguay [RENADECOPY-PNPDC]), six regional registries (Bogotá [PVSDC-Bogota], Cali [PVSDC-Cali], Maule [RRMC SSM], Nicaragua [SVDC], Nuevo-León [ReDeCon HU], São Paulo [SINASC/SIM-MSP]) and the ECLAMC hospital network sent data to ReLAMC on a total population of 9,152,674 births, with a total of 101,749 malformed newborns (1.1%; 95% CI 1.10-1.12). Of the 9,000,651 births in countries covering both live and stillbirths, 88,881 were stillborn (0.99%; 95% CI 0.98-0.99), and among stillborns, 6,755 were malformed (7.61%; 95% CI 7.44-7.79). The microcephaly rate was 2.45 per 10,000 births (95% CI 2.35-2.55), hydrocephaly 3.03 (2.92-3.14), spina bifida 2.89 (2.78-3.00), congenital heart defects 15.53 (15.27-15.79), cleft lip 2.02 (1.93-2.11), cleft palate and lip 2.77 (2.66-2.88), talipes 2.56 (2.46-2.67), conjoined twins 0.16 (0.14-0.19), and Down syndrome 5.33 (5.18-5.48). Each congenital anomaly showed heterogeneity in prevalence rates among registries. The harmonization of data in relation to operational differences between registries is the next step in developing the common ReLAMC database.

A case series of infants with increased VAMP7 gene dosage at birth and virilization defects.

BACKGROUND: Genitourinary disorders are the most frequent congenital defects in newborns; however, little is known about their etiology. Several studies have been carried out to find genetic risk factors in the development of these malformations. The expression of VAMP7 is found in testes, epididymis, seminal vesicles, prostatic tissues, penis, and urethra. Alterations in gene dose of VAMP7 were recently reported in a subset of male patients initially identified clinically by the presence of congenital genitourinary disorders. In 2016, the authors developed a diagnostic algorithm for early detection of sex chromosome aneuploidies by quantifying the SHOX, VAMP7, and SRY gene dose in newborns by qPCR using dried blood spot (DBS) samples. OBJECTIVE: Correlate the increased gene dose of VAMP7, obtained by qPCR using DBS, with genitourinary congenital defects attributable to disorders in virilization and verify the increased gene dose by microarrays. STUDY DESIGN: Samples that only presented increased VAMP7 gene dosage were selected from a previously analyzed group of 5088 males in which the early detection of sex chromosomes aneuploidies was performed. Eight males were found with an increased gene dose of VAMP7 (relative quantitation > 1.3) and were called in for a complete clinical evaluation aimed at the identification of genitourinary anomalies, qPCR and microarrays. RESULTS: Eight males from 5088 samples were identified with increased VAMP7 gene dosage of which six patients were clinically evaluated, of which 50% were identified with alterations in genital development (bilateral cryptorchidism, unilateral cryptorchidism, and glandular hypospadias) and speech delay, while the rest presented different types of atopy. DISCUSSION: Tannour-Louet et al. postulated on 2014 that the duplication of the Xq28 region, specifically of VAMP7, plays a role in the human masculinization disorders of the urogenital tract. The study was based on array comparative genomic hybridization (aCGH) results performed to 116 males with disorders of sexual differentiation. In the present study, the patients were initially selected due to an increased gene dose of VAMP7 detected by qPCR, then the clinical evaluation and the aCGH were performed, inverse to what was reported previously but with similar percentages between both studies. CONCLUSION: In this work, the authors report cases of cryptorchidism, hypospadias, language delay and atopy in male preschoolers initially identified because they have an increased gene dose of VAMP7.

Gene Copy Number Quantification of SHOX, VAMP7, and SRY for the Detection of Sex Chromosome Aneuploidies in Neonates.

Aims: To explore the feasibility of detecting sex chromosome aneuploidies (SCAs) by means of gene copy number quantification of short stature homeobox (SHOX), vesicle-associated membrane protein 7 (VAMP7), and SRY in newborns. Materials and Methods: Gene doses of SHOX, VAMP7, and SRY were determined by quantitative polymerase chain reaction (qPCR) using DNA obtained from dried blood samples from newborns. Relative quantification values were obtained. An aneuploidy profile was established according to cutoff values. Samples with ≥2 gene doses (out of range) were reanalyzed, and those with aneuploidy profiles were confirmed by karyotyping. Sensitivity, specificity, and positive and negative predictive values were obtained. Results: A total of 10,033 samples were collected (4945 females and 5088 males). Of 244 (2.43%) samples with ≥2 gene doses that were retested, 20 cases were confirmed. The overall incidence of SCAs was 1 in 500 live newborns. There were six cases of Turner syndrome (1/824), 3 cases of XXX (1/1648), 7 cases of Klinefelter syndrome (1/726), and 4 cases of of XYY (1/1272). The sensitivity was 0.952 (95.42%); the specificity was 0.975 (97.56%); the positive predictive value was 0.909 (90.91%) and the negative predictive value was 0.987 (98.77%). Conclusions: Gene copy number analyses of the VAMP7, SHOX, and SRY genes by qPCR from blood samples spotted onto filter paper is a highly reliable method for the early detection of male and female SCAs.

Molecular genetic diagnosis by next-generation sequencing in a cohort of Mexican patients with haemophilia and report of novel variants.

INTRODUCTION: Molecular analysis in haemophilia is currently used in the diagnosis, treatment and prognosis of this disease. Hispanic populations in Latin America have been of interest to researchers due to the reportedly high prevalence of inhibitors in these patients. AIM: To perform next-generation sequencing (NGS) in a cohort of Mexican patients with HA and HB and correlate with clinical phenotypes. METHODS: Patients with Haemophilia A (HA) or haemophilia B (HB), were evaluated using NGS with an Ion AmpliSeq Custom Panel. Odds ratios (ORs) for associations between F8 variants and inhibitors were obtained. RESULTS: A total of 85 patients (60 with HA and 25 with HB) were included. Pathogenic variants in F8 were found in 93.3% of HA patients and in F9 in 96% of HB patients. Twelve novel potentially pathogenic variants were found. Inhibitors were observed in 20% of patients with severe HA. Four patients clinically diagnosed with HA were negative for F8 variants. CONCLUSION: Overall detection rate of pathogenic variants in F8 and F9 genes was 94.6%. We identified 12 non previously reported variants and pathogenic variants in other coagulation related genes. Molecular diagnosis of HA and HB permits better options for management, assessment and genetic counseling.

Proteomic tools and new insights for the study of B-cell precursor acute lymphoblastic leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a hematological malignancy of immature B-cell precursors, affecting children more often than adults. The etiology of BCP-ALL is still unknown, but environmental factors, sex, race or ethnicity, and genomic alterations influence the development of the disease. Tools based on protein detection, such as flow cytometry, mass spectrometry, mass cytometry and reverse phase protein array, represent an opportunity to investigate BCP-ALL pathogenesis and to identify new biomarkers of disease. This review aims to document the recent advancements with respect to applications of proteomic technologies to study mechanisms of leukemogenesis, how this information could be used in the discovery of biological targets, and finally we describe the challenges of application of proteomic tools for the approach of BCP-ALL.

How Does Comprehensive Care Impact Life of Pediatric Patients With Hemophilia? Results From a Center in a Developing Country.

BACKGROUND: Quality of life (QoL) has been included as a marker of treatment effectiveness in pediatric patients with chronic diseases. We believe that frequent multidisciplinary interventions and patient education could lead to an improvement in QoL. AIMS: Determine the QoL and economic impact of monthly interventions in multidisciplinary treatment. MATERIALS AND METHODS: The Haemo-QoL questionnaire was applied to patients who attended the hemophilia center of the University Hospital "Dr. José Eleuterio González," Monterrey, Mexico, at the time of enrollment and 1 year later. RESULTS: Male patients between 4 and 16 years diagnosed with hemophilia were included. The score results presented are based on Haemo-QoL versions that classify patients by their age group: group 1 (4 to 7 y) and group 2 (8 to 12 y). Statistical significant improvement was observed in the overall score (sociodemographic, psychosocial, etc.) after 1 year of follow-up in both groups (P<0.05). CONCLUSIONS: Impact on the QoL of patients receiving this approach was favorable. Improvement was observed regardless of severity and in those who were already in prophylaxis, suggesting that this type of approach could be causing the improvement. Results support the application of multidisciplinary treatment as the gold standard, and it should be considered in all centers including those with limited resources.

Phenotypic Variation in Patients with Homozygous c.1678G>T Mutation in EVC Gene: Report of Two Mexican Families with Ellis-van Creveld Syndrome.

BACKGROUND Ellis-van Creveld syndrome is an autosomal recessive chondro-ectodermal dysplasia characterized by disproportionate short stature, limb shortening, narrow chest, postaxial polydactyly and dysplastic nails and teeth. In addition, 60% of cases present congenital heart defects. Ellis-van Creveld syndrome is predominantly caused by mutations in the EVC or EVC2 (4p16) genes, with only a few cases caused by mutations in WDR35.  CASE REPORT Here, we report on two Mexican families with patients diagnosed with Ellis-van Creveld syndrome. Family 1 includes four patients: three females of 15, 18, and 23 years of age and a 7-year old male. Family 2 has only one affected newborn male. All patients exhibited multiple features including hypodontia, dysplastic teeth, extra frenula, mild short stature, distal limb shortening, postaxial polydactyly of hands and feet, nail dystrophy, and knee joint abnormalities. Only two patients had an atrial septal defect. In all cases, molecular analysis by Sanger sequencing identified the same homozygous mutation in exon 12 of EVC, c.1678G>T, which leads to a premature stop codon.  CONCLUSIONS The mutation c.1678G>T has been previously reported in another Mexican patient and it appears to be a recurrent mutation in Mexico which could represent a founder mutation. The large number of patients in this case allows the clinical variability and spectrum of manifestations present in individuals with Ellis-van Creveld syndrome even if they carry the same homozygous mutation in a same family.

Detection of Turner Syndrome by quantitative PCR of SHOX and VAMP7 genes.

Turner Syndrome (TS) is an unfavorable genetic condition with a prevalence of 1:2500 in newborn girls. Prompt and effective diagnosis is very important to appropriately monitor the comorbidities. The aim of the present study was to propose a feasible and practical molecular diagnostic tool for newborn screening by quantifying the gene dosage of the SHOX, VAMP7, XIST, UBA1, and SRY genes by quantitative polymerase chain reaction (qPCR) in individuals with a diagnosis of complete X monosomy, as well as those with TS variants, and then compare the results to controls without chromosomal abnormalities. According to our results, the most useful markers for these chromosomal variants were the genes found in the pseudoautosomic regions 1 and 2 (PAR1 and PAR2), because differences in gene dosage (relative quantification) between groups were more evident in SHOX and VAMP7 gene expression. Therefore, we conclude that these markers are useful for early detection in aneuploidies involving sex chromosomes.