Severe Congenital Neutropenia Type 4: A Rare Disease Harboring a G6pc3 Gene Pathogenic Variant Particular to the Mexican Population

ABSTRACT Background: Severe congenital neutropenia type 4 (SCN4) is a rare autosomal recessive granulopoiesis disorder caused by G6PC3 gene pathogenic variants. The estimated prevalence is 1/10,000,000 people. Over 90% of patients present a syndromic form with variable multisystemic involvement, including congenital heart defects, increased visibility of superficial veins (IVSV), inflammatory bowel disease, and congenital urogenital defects as prominent symptoms. Objectives: The objective of the study was to study non-hematological phenotypic findings that suggest a clinical diagnosis of SCN4. Methods: We examined medical records of patients diagnosed with neutropenia from January 2000 to December 2020, selecting cases with non-hematologic manifestations for phenotypic description and G6PC3 gene sequencing. Results: We found 11 cases with non-hematologic features: congenital heart defects in 8, IVSV in 6, inflammatory bowel disease in 4, urogenital defects in 4, and similar facial appearance. In addition, Sanger sequencing confirmed 3 homozygous cases for the c.210delC variant, a compound heterozygous harboring this variant, and a c.199_218+1 deletion. Conclusions: Our findings of the c.210delC variant in very close geographical settings, to date, have only been reported among Mexicans, and a mutual uncommon surname in two families strongly supports a founder effect for the variant in the studied population. Furthermore, the described non-hematologic symptoms in patients with severe primary neutropenia should be explored, confirming SCN4 by investigating G6PC3 gene mutations.

Telomeres Length Variations in a Rheumatoid Arthritis Patients Cohort at Early Disease Onset and after Follow-Up

ABSTRACT Background: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic synovial joint inflammation, progressive disability, premature immune aging, and telomere length (TL) shortening. Objective: The objective of the study was to study TL changes in patients at early disease onset and after follow-up. Methods: Relative leukocyte TL (rLTL) was measured by quantitative polymerase chain reaction (qPCR) in 88 at-admission patients (AAP) with < 1 year of symptoms onset, self-compared after follow-up, and a reference group of sex- and age-matched healthy individuals. Correlations between rLTL percentage change after variable disease exposure time (DET) and clinical laboratory disease activity markers and treatments were assessed. Non-parametrical statistics were applied, considering < 0.05 p-value significant. Results: The median (p25, p75) rLTL was lower in patients after DET (0.61, 0.49-0.70) than in AAP (0.64, 0.50-0.77), p = 0.017. Furthermore, telomeres at early stages of RA were shorter than in the reference group (0.77, 0.59-0.92; p = 0.003). HLA-DRB1*04 allele carrier status did not significantly affect rLTL at an early stage and after follow-up. The patients' rLTL shortening was mainly associated with longer at-admission telomeres (OR 16.2, 95%CI: 3.5-74.4; p < 0.0001). Conclusion: At follow-up, RA patients showed significantly shorter rLTL than AAP, particularly in those AAP with longer telomeres, disregarding disease activity and treatments, denoting an rLTL shortening effect influenced by age, DET, and native rLTL.

Malformaciones congénitas en hijos de madres epilépticas con y sin tratamiento con anticonvulsivantes / Congenital malformations in the offspring of epileptic mothers with and without anticonvulsant treatment

OBJETIVO: Determinar la frecuencia y tipo de malformaciones congénitas (MC) en hijos de madres epilépticas (HME) tratadas y no tratadas con anticonvulsivantes, la posible correlación anticonvulsivante/MC y la asociación con otras alteraciones del desarrollo. MATERIAL Y MÉTODOS: Estudio multicéntrico de casos y controles en 166 recién nacidos vivos HME identificados en 21 501 recién nacidos con MC y respectivos controles del Registro y Vigilancia Epidemiológica de Malformaciones Congénitas (RYVEMCE). RESULTADOS: La frecuencia de MC en HME tratadas fue mayor, (48.3%) que en HME no tratadas (28.3%); (RM= 2.37 IC95% 1.08-5.40), p=0.03. Las MC más frecuentes fueron espina bífida, anomalías en reducción de miembros, labio/paladar hendido, microcefalia, anotia/microtia, hipospadias, paladar hendido, polidactilia, anoftalmia/microftalmia y onfalocele. No hubo diferencias entre uso de mono o politerapia. La difenilhidantoína, carbamazepina y ácido valproico fueron los anticonvulsivantes más utilizados. CONCLUSIONES: Los resultados confirman la teratogenicidad propia de la epilepsia y el efecto sinérgico de ciertos anticonvulsivantes, lo que evidencia la necesidad de un apropiado control periconcepcional de esta enfermedad y su tratamiento.

OBJECTIVE: To determine the prevalence at birth and type of congenital malformations (CM) in newborns of epileptic mothers (NEM) treated and not treated with anticonvulsants, the correlation anticonvulsant/CM and other developmental disorders. MATERIALS AND METHODS: Multicenter case-control study, in 166 live births NEM diagnosed in 21 501 newborns with CM and respective controls from the Registro y Vigilancia Epidemiológica de Malformaciones Congénitas (RYVEMCE). RESULTS: The frequency of CM in NEM treated with anticonvulsants was higher (48.3%) than in NEM of untreated mothers (28.3%), (OR= 2.37 IC95% 1.08-5.40), p=0.03. CMs most frequently found were: spina bifida, limb reduction defects, cleft lip palate, microcephaly, anotia/microtia, hypospadias, polydactyly, cleft palate, anophthalmia/ microphthalmia and omphalocele. No differences among monotherapy and polytherapy were observed. Diphenyl-hydantoin, carbamazepine and valproic acid were the most frequently anticonvulsants used. CONCLUSIONS: Our results show the teratogenicity of epilepsy by itself, the synergistic effect of some anticonvulsants, and the need of an appropriate periconceptional control of the disease and treatment.