Facial Dysmorphic Features in a Patient With Nonketotic Hypoglycemia and a Pathogenic Variant in the AKT2 Gene.

Background/Objective: AKT2 is a serine/threonine kinase that plays a key role in regulating insulin signaling. The phenotype related to the gain-of-function alteration in the AKT2 gene (c.49G>A, p.Glu17Lys) has been described in 5 patients with clinical findings that mimic hyperinsulinemic hypoglycemia but with undetectable levels of insulin and C-peptide. One of the reports highlights the facial dysmorphic features. We report the case of a new patient with the same activating AKT2 alteration leading to autonomous activation of the insulin signaling pathway and dysmorphic features. Moreover, to our knowledge, this is the first report using waxy maize heat-modified starch (WMHMS) in this condition. Case Report: A previously healthy child was evaluated at 6 months of age for episodes of hypoglycemia. The laboratory test results for the critical samples showed hypoketotic hypoglycemia (glucose level, 2.16 mmol/L [38 mg/dL]) with undetectable levels of insulin (<0.2 mU/L) and C-peptide (<0.033 nmol/L [reference range, 0.37-1.47 nmol/L]). Physical examination revealed hypertelorism, prominent proptosis of the eyes, a flat nasal bridge, delayed psychomotor development, and postnatal symmetrical overgrowth. The genetic study of AKT2 showed a pathogenic variant (c.49G>A, p.Glu17Lys). To achieve euglycemia, a diet of regular uncooked cornstarch (UCCS) carbohydrate was started. Subsequently, waxy maize heat-modified starch (WMHMS; Glycosade Vitaflo) was used to increase the fasting period to 4 hours. However, we did not find any advantages in comparison with UCCS. Discussion: The range of phenotypes of this gain-of-function alteration in AKT2 may be broad, including dysmorphic features, although the patients harbor the same pathogenic variant. Conclusion: Regarding the treatment, we observed a similar response with WMHMS compared with UCCS, with no adverse effects.

Insulin resistance parameters in children born very preterm and adequate for gestational age.

BACKGROUND: Preterm neonates are at risk for metabolic syndrome later in life. Whether prematurity constitutes an independent risk factor for the development of cardiovascular disease and metabolic syndrome remains controversial. OBJECTIVE: To compare anthropometric measures, cardiometabolic risk factors and insulin resistance variables between children who were born very preterm (VPT, <32 gestational weeks) and at term (Term, >37 gestational weeks) and adequate for gestational age (AGA). METHODS: We designed a cross-sectional cohort study, recruiting 120 children (5.0-8.5 years old) from the preterm clinic at Red de Salud UC-Christus and Complejo Asistencial Dr. Sótero del Río, and term children from the community. We excluded children born small for gestational age, based on INTERGROWTH21. Anthropometrics data were classified using WHO reference standards. The homeostasis model assessment insulin resistance (HOMA-IR) index, quantitative insulin sensitivity check index (QUICKI), triglyceride-to-HDL-C ratio (TG/HDL-C) and Pediatric Score Index for Metabolic Syndrome (PsiMS) were calculated. RESULTS: VPT children born AGA had lower HDL cholesterol levels (p = .019) and a higher PsiMS score than those born at term (p = .043). We observed a higher percentage of children with HDL cholesterol ≤40 mg/dl (13.0% vs. 2.3%, p = .026) and BP ≥90th percentile among the VPT children than among the Term children (26.0% vs. 11.6%, p = .031). CONCLUSIONS: At school age, blood pressure was higher, and HDL-C was lower among VPT children born AGA, suggesting a potential metabolic risk; therefore, it is essential to follow this group throughout their lives.

Quality of Life in Chilean Transgender Children and Adolescents.

INTRODUCTION: Transgender (TG) children and adolescents experience problems in school as well as with family and social relationships that can adversely affect their physical and psychosocial health and impair their quality of life (QoL). This study aimed to assess health-related quality of life (HRQoL) in TG children. METHODS: We performed a cross-sectional study comparing HRQoL in gender non-conforming (Trans) and gender-conforming (CIS) children and adolescents using the Spanish version of KIDSCREEN-52 in 120 Chilean Trans and CIS children (aged 8-18 years) and their parents. All scores were standardized according to the KIDSCREEN manual. RESULTS: Among the 100 questionnaires answered, 38 corresponded to children and adolescents aged 8.4-18 years. Twenty-one of them were TG (71% trans males) and 17 were CIS (76% females). Sixty-two parents answered the questionnaires: 33 from families of TG children (PTrans) and 29 from families of CIS children (PCis). Trans children had lower HRQoL scores in all domains than CIS children. The lowest-scoring domains for TG children were "Moods and Emotions," "Psychological Well-Being" and "Social Acceptance," and the highest-scoring domain was "School Environment." The PTrans group had significantly higher scores than the Trans group for 3 of the 10 domains: "Psychological Well-Being," "Moods and Emotions," and "Parent Relations and Home Life." CONCLUSION: Our results revealed that TG children and adolescents have lower QoL than their CIS counterparts, especially regarding items related to mental health. Furthermore, their parents may underestimate their well-being, confirming the vulnerability of the TG population. This finding underlies the need to perform early assessments of QoL for early detection and intervention in aspects that could deteriorate their quality of life.

Different Clinical Manifestations Related to Subvirilization in Three XY Patients With the Same Pathogenic Variant of Steroidogenic Factor 1.

OBJECTIVE: During the prenatal period, steroidogenic factor 1 is required for the development of the adrenal glands and for gonadal determination and differentiation, and after birth, it regulates gonadal progenitor cell formation and their survival. Here, we describe the clinical phenotype of three 46,XY patients (2 brothers and an unrelated subject) with disorder of sex development due to the same genetic variant. METHODS: All patients underwent hormonal and pelvic ultrasound studies. Sequence analysis and deletion/duplication testing of a panel encompassing 8 genes (AR, DHH, MAP3K1, NROB1, SRD5A2, SRY, WT1, and nuclear receptor subfamily 5, group A, member 1 [NR5A1]) were performed in the index cases. All family members were tested for the presence of the NR5A1 variant. RESULTS: A variant previously described as likely pathogenic in NR5A1 (c.251G>A, p.Arg84His) that segregated in 1 family with different degrees of under-virilization was found. The family 1 index case (IV2) and his brother (IV3) had an external masculinization scale score of 5/12, but only the index case had Müllerian remnants; however, the family 2 patient had a milder score of 9/12. The older female relatives of family 1 who harbor this variant experienced premature menopause. CONCLUSION: To our knowledge, this is the first report where the c.251G>A (p.Arg84His) variant is associated with the presence of Müllerian remnants in 46,XY subjects and primary ovarian insufficiency in 46,XX individuals. The segregation of this variant with clinical manifestations provides further evidence for considering it as pathogenic.

Variación estacional de 25-hidroxi-vitamina D3, hormona paratiroidea y fosfatasa alcalina en niños escolares / Seasonal variations in 25-hydroxy vitamin D3, parathormone and alkaline phosphatase in school-aged children

INTRODUCCIÓN: El principal rol de la vitamina D es la regulación del metabolismo del calcio, cuya principal fuen te es la vitamina D3 que se obtiene principalmente por la acción de la luz ultravioleta (UV) en la piel. OBJETIVO: Evaluar las diferencias estacionales en las concentraciones de 25-hidroxi-vitamina D3 (25OHVitD3), hormona paratiroidea (PTH), fosfatasa alcalina (FA) y calcio en niños en edad esco lar. SUJETOS Y MÉTODO: Se midieron las concentraciones de 25OHVitD3, PTH, FA y calcio en niños de 5 a 8 años, sin suplementación de Vitamina D, reclutados en Santiago de Chile (latitud -33.4372) en distintas estaciones del año. El estatus de VitD fue definido como suficiente con concentraciones de 25OHVitD3 > 20 ng/mL (50 nmol/L), insuficiente 12-20 ng/mL (30-50 nmol/L) y deficiente 20 ng/mL) en verano, lo que disminuyó significativamente en invierno (54,3%, p < 0,0001). CONCLUSIONES: Las concentraciones de 25OHVitD3 disminuyeron en aproximadamente la mitad de los niños durante el invierno, lo que se vio acompañado de un aumento de la PTH y FA, asociado a concentraciones normales de calcio. De acuerdo a nuestros resultados, la suplementación con VitD en niños podría ser necesaria durante otoño e invierno.

INTRODUCTION: The main role of Vitamin D is to regulate calcium metabolism, whose main source is vitamin D3 ob tained mostly from the action of ultraviolet (UV) light on the skin. OBJECTIVE: To evaluate the seaso nal differences in the concentrations of 25-hydroxy-vitamin D3 (25OHVitD3), parathyroid hormone (PTH), alkaline phosphatase (ALP), and calcium in school-age children. SUBJECTS AND METHOD: The concentrations of 25OHVitD3, PTH, ALP, and calcium were measured in children from Santiago, Chile (latitude -33.4372), aged 5 to 8 years, without Vitamin D supplementation, in different seasons of the year. VitD status was defined as sufficient with concentrations of 25OHVitD3 >20 ng/mL (50 nmol/L), insufficient 12-20 ng/mL (30-50 nmol/L) and deficient 20 ng/mL), which decreased significantly in winter to 54.3% (p <0.0001). CONCLUSIONS: In winter, 25OHVitD3 concentrations decreased in approximately half of the children, which was associated with an increase in PTH and ALP, and normal calcium concentrations. According to our results, children may need VitD supple mentation during fall and winter.

Perinatal antecedents of sleep disturbances in schoolchildren.

STUDY OBJECTIVES: Prematurity has been associated with an increased risk for sleep apnea. However, sleep disturbances in children born preterm have not been extensively investigated. Considering that determinants of sleep may originate early in life, the potential impact of prematurity on sleep disturbances later in life could be important. To establish the role of prematurity on sleep disturbances in a cohort of schoolchildren that were born preterm and compare them with healthy controls. METHODS: A cohort of 147 schoolchildren, 45 born at term (≥37 weeks) and 102 very preterm (<32 weeks), was recruited and evaluated at school age (5-9 years). The Pediatric Sleep Questionnaire (PSQ) and the Sleep Disturbance Scale for Children (SDSC) were used to assess sleep disturbances in different domains. RESULTS: PSQ score was significantly higher in former preterm children (0.26 ± 0.18 vs. 0.18 ± 0.14 in controls; p = 0.004), and SDSC total score was also significantly different among groups (21.7 ± 11.6 vs. 14.1 ± 12.6; p < 0.001). Regression models showed significant mean differences in PSQ score, total SDSC score, and two SDSC subscale scores (i.e. sleep-wake transition disorders, sleep-breathing disorders, and sleep hyperhidrosis) even after adjustment for confounders. Maternal age and type of delivery were not significantly associated with total PSQ scores. CONCLUSIONS: Sleep disturbances may originate early in life since children born preterm exhibit an increased risk for developing long-term sleep problems. These findings may have important implications for management of preterm children and for implementation of early interventions focused on optimizing sleep habits.

[Seasonal variations in 25-hydroxy vitamin D3, parathormone and alkaline phosphatase in school-aged children]. / Variación estacional de 25-hidroxi-vitamina D3, hormona paratiroidea y fosfatasa alcalina en niños escolares.

INTRODUCTION: The main role of Vitamin D is to regulate calcium metabolism, whose main source is vitamin D3 ob tained mostly from the action of ultraviolet (UV) light on the skin. OBJECTIVE: To evaluate the seaso nal differences in the concentrations of 25-hydroxy-vitamin D3 (25OHVitD3), parathyroid hormone (PTH), alkaline phosphatase (ALP), and calcium in school-age children. SUBJECTS AND METHOD: The concentrations of 25OHVitD3, PTH, ALP, and calcium were measured in children from Santiago, Chile (latitude -33.4372), aged 5 to 8 years, without Vitamin D supplementation, in different seasons of the year. VitD status was defined as sufficient with concentrations of 25OHVitD3 >20 ng/mL (50 nmol/L), insufficient 12-20 ng/mL (30-50 nmol/L) and deficient <12 ng/mL (30 nmol/L) based on the recommendations of the expert group of the "Global Consensus for the Prevention and Mana gement of Nutritional Rickets". RESULTS: 133 children participated (89 preterms under or equal to 32 weeks), 41 during summer, 28 in fall, 35 in winter, and 29 in spring. The difference of means between summer and winter was 9.6 ng/mL for 25OHVitD3 (p <0.0001), -11.1 pg/mL for PTH (p <0.0001), and -47.5 IU/mL for ALP (p= 0.01). There were no differences in calcium concentrations. In sum mer, 97.6% of the subjects were classified with sufficiency status (> 20 ng/mL), which decreased significantly in winter to 54.3% (p <0.0001). CONCLUSIONS: In winter, 25OHVitD3 concentrations decreased in approximately half of the children, which was associated with an increase in PTH and ALP, and normal calcium concentrations. According to our results, children may need VitD supple mentation during fall and winter.

Diabetes mellitus por mutación en el gen de glucokinasa: caso clínico / Diabetes mellitus caused by a mutation of glucokinase gene: report of an affected family

Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.

[Diabetes mellitus caused by a mutation of glucokinase gene. Report of an affected family]. / Diabetes mellitus por mutación en el gen de glucokinasa. Caso clínico.

Maturity-Onset Diabetes of the Young (MODY) refers to a heterogeneous group of monogenic diabetes. Unlike other types of MODY characterized by genetic defects in transcription factors, MODY 2 is triggered by metabolic alterations caused by mutations of glucokinase (GCK), the first enzyme of the glycolytic pathway. We report a three-generation Chilean family with multiple cases affected with this disease. The index case is a patient who presented severe neonatal hyperglycemia (831 mg/dl, without ketosis) requiring continuous infusion of insulin, which was suspended after 48 hours with normalization of blood glucose. Subsequently, continuous glucose monitoring at 4 months of age revealed 47% of tissue glucose levels above 140 mg/dl, with fasting glucose levels between 120 and 166 mg/dl. The genetic analysis revealed a previously reported mutation in heterozygous state of the GCK gene (c.148C>T; p.His50Tyr). This mutation was also identified in more than one affected relative in the last two generations, with a transmission pattern suggestive of dominant inheritance. GCK gene sequencing led to a correct molecular diagnosis of MODY 2 while bioinformatic analysis indicated the possible molecular causes of the enzyme dysfunction. The knowledge of the molecular diagnosis allowed an adequate medical treatment for this disease.

[Persistent elevation of aspartate aminotransferase (AST) due to the presence of macro-AST: Report of one case]. / Aumento aislado y sostenido de aspartato aminotransferasa por presencia de macroenzimas: Caso clínico.

We report an asymptomatic 23-year-old woman with an isolated and persistent increase in serum levels of aspartate aminotransferase (AST). An extensive work up including laboratory and image testing revealed no abnormalities thus suggesting the presence of macro-AST. A polyethylene glycol (PEG) precipitation assay was performed and confirmed the presence of macro-AST.

Aumento aislado y sostenido de aspartato aminotransferasa por presencia de macroenzimas: caso clínico / Persistent elevation of aspartate aminotransferase (AST) due to the presence of macro-AST: report of one case

We report an asymptomatic 23-year-old woman with an isolated and persistent increase in serum levels of aspartate aminotransferase (AST). An extensive work up including laboratory and image testing revealed no abnormalities thus suggesting the presence of macro-AST. A polyethylene glycol (PEG) precipitation assay was performed and confirmed the presence of macro-AST.

HPV16/18 genotyping for the triage of HPV positive women in primary cervical cancer screening in Chile.

BACKGROUND: We previously conducted a population-based screening trial of high-risk human papillomavirus (hrHPV) testing and conventional cytology, demonstrating higher sensitivity (92.7 % vs 22.1 % for CIN2+) but lower positive predictive value (10.5 % vs 23.9 %) of hrHPV testing. Here we report the performance of HPV16/18 genotyping to triage the hrHPV positive participants. METHODS: Women aged 25 years and older received hrHPV (Hybrid Capture 2) and Papanicolaou testing; positives by either test underwent colposcopy and directed biopsy, as did a sample of double-negatives. hrHPV positive women were reflex-tested with HPV16/18 genotyping (Digene HPV Genotyping PS Test). RESULTS: Among the 8,265 participants, 10.7 % were hrHPV positive, 1.7 % had ASCUS+ cytology, 1.2 % had CIN2+; 776 (88 %) hrHPV positive women had complete results, of whom 38.8 % were positive for HPV16 (24.0 %), HPV18 (9.7 %) or both (5.1 %). CIN2+ prevalence in HPV16/18 positive women (16.3 %, 95 % CI 12.3-20.9) was twice that of HPV16/18 negative women (8.0 %, 95 % CI 5.7-10.8). HPV16/18 genotyping identified 40.5 % of CIN2, 66.7 % of CIN3 and 75.0 % of cancers. Compared to hrHPV screening alone, HPV16/18 triage significantly reduced the referral rate (10.7 % vs 3.7 %) and the number of colposcopies required to detect one CIN2+ (9 vs 6). When HPV16/18 negative women with baseline ASCUS+ cytology were also colposcopied, an additional 14 % of CIN2+ was identified; referral increased slightly to 4.2 %. CONCLUSIONS: HPV16/18 triage effectively stratified hrHPV positive women by their risk of high-grade lesions. HPV16/18 positive women must be referred immediately; referral could be deferred in HPV16/18 negative women given the slower progression of non-HPV16/18 lesions, however, they will require active follow-up.

Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos / Effect of VKORC1 and CYP2C9 variants on dosage of oral anticoagulants in Chilean individuals

Background: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. Aim: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. Material and Methods: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. Results: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. Conclusions: There is an association between VKORC1-1639A variant and anticoagulant doses.

A Deletion of More than 800 kb Is the Most Recurrent Mutation in Chilean Patients with SHOX Gene Defects.

BACKGROUND: Deletions in the SHOX gene are the most frequent genetic cause of Leri-Weill syndrome and Langer mesomelic dysplasia, which are also present in idiopathic short stature. AIM: To describe the molecular and clinical findings observed in 23 of 45 non-consanguineous Chilean patients with different phenotypes related to SHOX deficiency. METHODS: Multiplex ligation-dependent probe amplification was used to detect the deletions; the SHOX coding region and deletion-flanking areas were sequenced to identify point mutations and single-nucleotide polymorphisms (SNPs). RESULTS: The main genetic defects identified in 21 patients consisted of deletions; one of them, a large deletion of >800 kb, was found in 8 patients. Also, a smaller deletion of >350 kb was observed in 4 patients. Although we could not precisely determine the deletion breakpoint, we were able to identify a common haplotype in 7 of the 8 patients with the larger deletion based on 22 informative SNPs. CONCLUSION: These results suggest that the large deletion-bearing allele has a common ancestor and was either introduced by European immigrants or had originated in our Amerindian population. This study allowed us to identify one recurrent deletion in Chilean patients; also, it contributed to expanding our knowledge about the genetic background of our population.

[Human papillomavirus testing in cervical cancer screening at a public health service of Santiago, Chile]. / Examen de detección de virus papiloma humano en el tamizaje de cáncer cervicouterino en un Servicio de Salud de Santiago, Chile.

BACKGROUND: Molecular techniques for human papillomavirus (HPV) detection have a good performance as screening tests and could be included in cervical cancer early detection programs. We conducted a population-based trial comparing HPV detection and Papanicolaou as primary screening tests, in a public health service in Santiago, Chile. AIM: To describe the experience of implementing this new molecular test and present the main results of the study. MATERIAL AND METHODS: Women aged 25 to 64 enrolled in three public health centers were invited to participate. In all women, samples were collected for Papanicolaou and HPV DNA testing, and naked-eye visual inspection of the cervix with acetic acid was performed. Women with any positive screening test were referred to the local area hospital for diagnostic confirmation with colposcopy and biopsy of suspicious lesions. RESULTS: Screening results were obtained for 8265 women, of whom 931 (11.3%) were positive to any test. The prevalence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was 1.1%; nine women had invasive cervical cancer. Sensitivities for the detection of CIN2+ were 22.1% (95% confidence interval (CI) 16.4-29.2) for Papanicolaou and 92.7% (95% CI 84.4-96.8) for HPV testing; specificities were 98.9% (95% CI 98.7-99.0) and 92.0% (95% CI 91.4-92.6) respectively. CONCLUSION: This experience showed that the implementation of a molecular test for cervical cancer screening is not a major challenge in Chile: it was well accepted by both the health team and the participants, and it may improve the effectiveness of the screening program.

Examen de detección de virus papiloma humano en el tamizaje de cáncer cervicouterino en un Servicio de Salud de Santiago, Chile / Human papillomavirus testing in cervical cancer screening at a public health service of Santiago, Chile

Background: Molecular techniques for human papillomavirus (HPV) detection have a good performance as screening tests and could be included in cervical cancer early detection programs. We conducted a population-based trial comparing HPV detection and Papanicolaou as primary screening tests, in a public health service in Santiago, Chile. Aim: To describe the experience of implementing this new molecular test and present the main results of the study. Material and Methods: Women aged 25 to 64 enrolled in three public health centers were invited to participate. In all women, samples were collected for Papanicolaou and HPV DNA testing, and naked-eye visual inspection of the cervix with acetic acid was performed. Women with any positive screening test were referred to the local area hospital for diagnostic confirmation with colposcopy and biopsy of suspicious lesions. Results: Screening results were obtained for 8265 women, of whom 931 (11.3%) were positive to any test. The prevalence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was 1.1%; nine women had invasive cervical cancer. Sensitivities for the detection of CIN2+ were 22.1% (95% confidence interval (CI) 16.4-29.2) for Papanicolaou and 92.7% (95% CI 84.4-96.8) for HPV testing; specificities were 98.9% (95% CI 98.7-99.0) and 92.0% (95% CI 91.4-92.6) respectively. Conclusion: This experience showed that the implementation of a molecular test for cervical cancer screening is not a major challenge in Chile: it was well accepted by both the health team and the participants, and it may improve the effectiveness of the screening program.

[Effect of VKORC1 and CYP2C9 variants on dosage of oral anticoagulants in Chilean individuals]. / Efecto de las variantes de VKORC1 y CYP2C9 sobre la dosis de anticoagulantes orales en individuos chilenos.

BACKGROUND: The dose of oral anticoagulants (OAC) shows great variability among patients. Pharmacogenetic studies have shown that common variants in genes CYP2C9 (*2 and *3) and VKORC1 (-1639G>A) are associated with lower requirements of OAC. AIM: To study the association between average maintenance doses of oral anticoagulant therapy required to maintain a stable INR and CYP2C9 and VKORC1 gene variants in Chilean adults. MATERIAL AND METHODS: Prospective study of patients on anticoagulant treatment and with a stable international normalized ratio (INR) for prothrombin time for at least three months. Patients were classified as having high or low acenocoumarol or warfarin requirements. Peripheral blood DNA genotyping was performed by polymerase chain reaction and restriction fragment polymorphism or sequencing and electrophoresis. RESULTS: The study included 185 patients, 125 on acenocoumarol and 60 on warfarin. Patients with VKORC1-1639A allele were more likely to require lower doses of both drugs than patients with the G allele (Odds ratio [OR] for acenocoumarol 9.06, and OR for warfarin = 18.7). There was no association between CYP2C9*2 and*3 and acenocoumarol or warfarin requirements. CONCLUSIONS: There is an association between VKORC1-1639A variant and anticoagulant doses.

A novel insertion in the FOXL2 gene in a Chilean patient with blepharophimosis ptosis epicanthus inversus syndrome type I.

OBJECTIVE: A novel insertion in the forkhead transcription factor 2 (FOXL2) was identified in a Chilean patient with blepharophimosis, ptosis, and epicanthus inversus syndrome associated with premature ovarian failure (BPES type I). A clinical and molecular characterization of a patient with BPES type I was performed. METHOD: We present a 16-year-old adolescent girl with surgically treated blepharophimosis, ptosis, and epicanthus inversus that was associated with delayed puberty and secondary amenorrhea at the age of 15, indicators that suggested that the patient had BPES type I. The FOXL2 gene was analyzed by sequencing its coding region. RESULTS: The sequence analysis of the FOXL2 gene revealed a novel heterozygous mutation: an 11 bp duplication (c.901_911dup11) that was predicted to encode a truncated protein (p.Pro305Argfs*54). CONCLUSIONS: A novel out-of-frame duplication following the polyalanine domain in the FOXL2 gene was identified in a Chilean patient with BPES type I. This study characterized the molecular alterations in FOXL2 and confirmed the diagnosis, thereby providing information to allow for improved genetic counseling for the patient and her family.

Screening trial of human papillomavirus for early detection of cervical cancer in Santiago, Chile.

Cervical cancer mortality in Chile is four times higher than in developed countries. We compared the accuracy of human papillomavirus (HPV) DNA testing and conventional Papanicolaou (Pap) testing to detect prevalent precancerous and cancerous lesions in the routine clinical practice of the public health system. Women aged 25 years and older residing in the area covered by three primary care centers of Santiago, Chile, were invited to participate. Eligible women received both HPV DNA (Hybrid Capture 2) and Pap testing. Women positive by either test (Pap: ASCUS+, HC2: RLU/CO ≥ 1.0) underwent colposcopy and biopsy, as did a sample of double-negative women with an abnormal cervix at visual inspection or with risk factors for cervical lesions. Crude and verification bias-corrected sensitivities and specificities were estimated. In total, 8,265 women (98.8% of eligible) had complete screening results. Of these, 10.7% were HPV positive, 1.7% were Pap positive and 1.1% were positive by both tests. In all, 931 (11.3%) women were screen-positive, of whom 94.3% attended colposcopy. Additionally, 295 control women were invited for colposcopy, of whom 78% attended. In all, 42 CIN2, 45 CIN3 and 9 cancers were identified. Verification bias-corrected sensitivity for CIN2+ (95% confidence interval) was 92.7% (84.4-96.8) for HPV and 22.1% (16.4-29.2) for Pap; corresponding specificities were 92.0% (91.4-92.6) and 98.9% (98.7-99.0). In conclusion, in routine clinical practice in a developing country, HPV testing was four times more sensitive for CIN2+ than Pap testing, identifying three times more CIN2+ lesions; HPV testing was easily implemented in our established cervical cancer prevention program.

The first case of tinea faciei caused by Trichophyton mentagrophytes var. erinacei isolated in Chile.

BACKGROUND: Trichophyton mentagrophytes var. erinacei is a zoophilic dermatophyte transmitted by hedgehogs which human infections manifest as highly inflammatory and pruritic eruptions. METHODS: We report a 21-year-old woman who presented with a two-week history of a pruritic scaly erythematous plaque on the nose. The patient had kept hedgehogs as pets, and one had bitten her on the tip of the nose two months prior to the appearance of the nasal lesion. RESULTS: Fungal culture from the scales on the tip of the patient's nose was compatible with T. mentagrophytes var. erinacei. The strains isolated from cultures made from samples taken from the noses and ears of the pet hedgehogs were morphologically similar to the strain isolated from the patient. Morphological identification was confirmed by sequencing the internal transcribed spacer. The lesion was diagnosed as tinea faciei, and therapy was initiated with topical and systemic terbinafine 250mg/day for eight weeks, which resulted in complete improvement. CONCLUSIONS: Trichophyton mentagrophytes var. erinacei is the most common dermatophyte isolated in hedgehogs. Usually T. mentagrophytes var. erinacei infection manifests as an extremely inflammatory and pruritic eruption that is confined to the site of contact with the hedgehog. Although the identification of T. mentagrophytes by traditional methods is possible, identification by ITS region analysis is a fast, simple, and increasingly available method. The increasing frequency of the practice of keeping exotic animals as pets has resulted in the emergence of several zoonotic diseases that can potentially be transmitted to humans.