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IntroductionFlaviviridae family belongs to the Spondweni serocomplex, which is mainly transmitted by vectors from the Aedes genus. Zika virus (ZIKV) is part of this genus. It was initially reported in Brazil in December 2014 as an unknown acute generalized exanthematous disease and was subsequently identified as ZIKV infection. ZIKV became widespread all over Brazil and was linked with potential cases of microcephaly.Case reportWe report a case of a 28-year-old Colombian woman, who came to the Obstetric Department with an assumed conglomerate of fetal abnormalities detected via ultrasonography, which was performed at 29.5 weeks of gestation. The patient presented with multiple abnormalities, which range from a suggested Arnold–Chiari malformation, compromising the lateral and third ventricles, liver calcifications, bilateral pyelocalic dilatations, other brain anomalies, and microcephaly. At 12 weeks of gestation, the vertical transmission of ZIKV was suspected. At 38.6 weeks of gestation, the newborn was delivered, with the weight in the 10th percentile (3,180 g), height in the 10th percentile (48 cm), and cephalic circumference under the 2nd percentile (31 cm). Due to the physical findings, brain magnetic resonance imaging (MRI) was performed, revealing a small and deviated brain stem, narrowing of the posterior fossa, a giant posterior fossa cyst with ventricular dilatation, a severe cortical and white matter thinning, cerebellar vermis with hypoplasia, and superior and lateral displacement of the cerebellum. In addition, hydrocephalus was displayed by the axial sequence, and the cerebral cortex was also compromised with lissencephaly. Schizencephaly was found with left frontal open-lip, and no intracranial calcifications were found. Two novel heterozygous nonsense mutations were identified using whole-exome sequencing, and both are located in exon 8 under the affection of ZIKV congenital syndrome (CZS) that produced a premature stop codon resulting in the truncation of the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) protein.ConclusionWe used molecular and microbiological assessments to report the initial case of vertically transmitted ZIKV infection with congenital syndrome associated with a neurological syndrome, where a mutation in the CDK5RAP2 gene was also identified. The CDK5RAP2 gene encodes a pericentriolar protein that intervenes in microtubule nucleation and centriole attachment. Diallelic mutation has previously been associated with primary microcephaly.

Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterized by congenital cardiac defects and congenital deformities of the upper limbs. Herein, we report the case of a 2-year-old patient presenting with clinical diagnostic criteria of HOS with interatrial and interventricular communication associated with hip dysplasia and upper limb reduction composed of radial ray anomaly. A novel de novo, potentially pathogenic variant in the TBX5 gene at NM_181486.2:c.243-1G>C was identified.

Background Menkes disease is a congenital neurodegenerative disorder caused by ATP7A gene mutations. Clinical features include epilepsy, growth delay, reduced muscle strength, skin laxity, abnormal hair, and urologic abnormalities. Case presentation We describe an infant with developmental delay, neurologic degeneration, and kinky hair. Molecular test revealed a novel heterozygous mutation in exon 21 of the ATP7A gene. The genotype and phenotype of the patient were compared with those of the patients reported in the literature. Conclusion We propose that this mutation caused a dysfunctional protein resulting in classical Menkes disease. This case adds to the spectrum of pathogenic variants of the ATP7A gene known to cause disease.

Introduction: Microcephaly is characterized by a smaller than normal head circumference. Recently, Zika virus (ZV) has been associated with microcephaly. Objective: To describe the prevalence of microcephaly in Colombia taking as the baseline the information from the period before the Zika virus infection epidemics. Materials and methods: We reviewed Medline, Scopus, Scielo, Lilacs and annual reports of congenital malformation monitoring systems across Latin America, among others sources, for articles published before April, 2015, reporting the prevalence of microcephaly in Colombia between 1982 and 2013. Results: We identified 32 non-duplicate articles; we selected 25 articles for revision of which 12 met the criteria for inclusion in the systematic review, including 2,808,308 births. Conclusions: The prevalence of microcephaly in Colombia from 1982 to 2013, before the introduction of ZV, ranged from 0.3 to 3.1 per 10,000 births, with an average of 1.8 (95% CI 1.7-1.8) per 10,000 births. These findings are important to determine if the prevalence after the introduction of the Zika virus infection registered significant changes. Resumen Introducción. La microcefalia consiste en una circunferencia cefálica menor de la esperada. Recientemente, el virus del Zika se ha asociado con esta condición. Objetivo. Describir la prevalencia de la microcefalia en Colombia, estableciendo como línea de base el periodo anterior a la epidemia del virus del Zika. Materiales y métodos. Se revisaron las bases de datos Medline, Scopus, Scielo, Lilacs y el reporte anual de malformaciones congénitas en Latinoamérica, así como otras fuentes publicadas antes de abril de 2015 con los datos de prevalencia de la microcefalia en Colombia entre 1982 y 2013. Resultados. Se detectaron 32 artículos no duplicados, se revisaron 25 y se seleccionaron 12 que cumplían con los criterios de inclusión para la revisión sistemática, los cuales registraban 2’808.308 nacimientos. Conclusiones. La prevalencia de la microcefalia en Colombia entre 1982 y 2013, antes de la epidemia del virus del Zika, oscilaba entre 0,3 y 3,1 por 10.000 nacimientos, con un promedio de 1,8 (IC95% 1,7-1,8). Este dato es importante para determinar la diferencia en la prevalencia después de la introducción del virus del Zika en Colombia.

Pathogenic variants in WAC are uncommon causes of developmental delay and neurobehavioral phenotypes. The clinical features associated with WAC haploinsufficiency include recognizable dysmorphic facial features that were recently delineated as DeSanto-Shinawi syndrome (DESSH; OMIM 616708). Additional clinical features include hypotonia, hearing and vision abnormalities, gastrointestinal problems, and behavioral difficulties. Here, we report a case of a 4-year-old Colombian male patient with typical dysmorphic facial features, developmental delay, hyperactivity, and recurrent respiratory infections. His immune workup revealed hypogammaglobulinemia, and clinical exome sequencing revealed a novel intronic variant in WAC (c.1437+1G>A). To the best of our knowledge, this is the first case of DESSH in South America, underlining the accumulating evidence of the significant role of WAC haploinsufficiency in neurobehavioral phenotypes. Although this report suggested the potential involvement of WAC in immune regulation, additional reports are required to confirm our observations.

Los defectos congénitos de la glicosilación (CDG) son un grupo de errores innatos del metabolismo de las glicoproteínas con manifestaciones multisistémicas heterogéneas. Se han reportado más de 100 tipos diferentes de CDG. La forma que involucra el gen de la glicosilación ligada a asparagina (ALG13) comunmente ligada al X, es una enfermedad infrecuente.Objetivo: Describir las manifestaciones clínicas de un paciente con CDG relacionado con ALG13 y comparararlo con los casos reportados previamente.Caso Clínico: paciente varon de 11 años de edad, hijo de padres consanguíneos, con antecedentes de hipotonía, retardo del desarrollo psicomotor severo, déficit cognitivo y problemas de alimentación desde los 5 meses de vida. Presentaba además microcefalia, cardiopatía congénita (ductus arterioso persistente e insuficiencia mitral) sin trastorno convulsivo ni compromiso de la coagulación. Se realizaron estudios metabólicos los cuales no fueron concluyentes, incluyendo estudios de N-glicosilación en plasma normales, por lo que se decidió realizar secuenciación de Exoma completo que identificó una variante no reportada anteriormente en el gen ALG13: c.428C > T (p.P143L) en hemicigosis, confirmada por secuenciación Sanger, la madre fue portadora de la misma variante.Conclusión: Se presenta el primer paciente reportado en Colombia con CDG-Is sin epilepsia, los hallazgos amplían el espectro fenotípico de CDG-Is conocido hasta el momento y soportan que los transtornos de la N-glicosilacion pueden presentarse con estudios bioquímicos normales. Sin embargo, se necesitan estudios funcionales para demostrar estos hallazgos. La secuenciación de exoma es una tecnología costo-efectiva que permite la identificación de mutaciones responsables de los fenotipos en enfermedades con gran heterogeneidad genotípica y fenotípica.

3-Hydroxyisobutyryl-coenzyme A (CoA) hydrolase deficiency (HIBCHD; MIM: #250620) is a rare autosomal recessive inborn error of metabolism caused by a defect in the HIBCH enzyme, resulting in a deficiency of the conversion of 3-hydroxy-isobutyryl-CoA to 3-hydroxy-isobutyric acid, a critical step in valine catabolism. This neurodegenerative disease of infancy is associated with hypotonia, developmental delay, cerebral atrophy and lesions in the basal ganglia on magnetic resonance imaging (MRI). In this study, we describe two unrelated patients with infantile-onset progressive neurodegenerative disease and mutations in HIBCH identified using whole exome sequencing (WES). In Case 1, WES revealed a novel homozygous variant in the HIBCH gene: c.808A>G (p.Ser270Gly). In Case 2, a novel compound heterozygous mutation in the HIBCH gene is described: c.808A>G (p.Ser270Gly) and c.173A>G (p. Asn58Ser). Parent analysis revealed that c.808A>G (p.Ser270Gly) was inherited from the father and c.173A>G (p. Asn58Ser) from the mother. These novel mutations were predicted as a disease-causing mutation. Plasma acylcarnitine analysis was normal in both patients. Physical examination showed similar features, such as axial hypotonia and spastic hypertonia in the legs. The first patient presented with difficult-to-treat seizures, while the second patient has not yet experienced documented seizures. In conclusion, our findings would widen the mutation spectrum of HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the correct diagnosis, treatment and integral management of patients with HIBCH deficiency.

La linfohistiocitosis hemofagocítica (HLH) corresponde a una activación exagerada, primaria o secundaria, del sistema inmunológico. La linfohistiocitosis hemofagocítica familiar tipo 3 (LHF-3) es un desorden del sistema inmune severo, causado por mutaciones en el gen UNC13D, el cual codifica para una proteína esencial en la función citotóxica de los linfocitos.Objetivo: Describir la relevancia diagnóstica de la secuenciación de nueva generación (NGS) en el enfoque de un paciente con sospecha de LHF y demostrar la efectividad del trasplante de médula ósea como única medida curativa.Caso Clínico: Preescolar de 4 años masculino, previamente sano, quien debutó con un síndrome mononucleósico e IgM positiva para virus de Epstein Barr. El paciente evolucionó con hepatoesplenomegalia y deterioro clínico progresivo. Se sospechó un síndrome linfoproliferativo, el cual fue descartado por aspirado de médula ósea, encontrando evidencia de hemofagocitosis activa. El paciente cumplía criterios para síndrome hemofagocítico (por compromiso de médula ósea, pancitopenia, elevación de ferritina e hipertrigliceridemia) y ante la no respuesta al protocolo de primera línea, incluyendo terapia antiviral, se consideró la posibilidad de una etiología primaria. Se completó estudio molecular con NGS que fue positivo para LHF-3. Debido a la evolución clínica se realizó trasplante de médula ósea con resultado exitoso a los 5 años de seguimiento.Conclusión: La NGS es una herramienta indispensable en el diagnóstico de la LHF, principalmente cuando la respuesta al tratamiento estándar no es adecuada y facilita la instauración oportuna de las medidas terapéuticas necesarias.

Estephania Candelo,1,2 Gabriela Caicedo,1 Fernando Rosso,3 Adriana Ballesteros,4 Jaime Orrego,4 Luis Escobar,5 Pablo Lapunzina,6,7 Julían Nevado,6,7 Harry Pachajoa1,81Center for Research on Congenital Anomalies and Rare Diseases (CIACER), Department of Basic Medical Sciences, Universidad Icesi, Cali, Colombia; 2MSc Biomaterials and Tissues Engineering and Genetics of Human Diseases, University College London, London, UK; 3Infectology Department, Fundación Valle del Lili, Cali, Colombia; 4Neonatal Department, Fundacion Valle del Lili, Cali, Colombia; 5Pathology Department, Fundacion Valle del Lili, Cali, Colombia; 6Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario La Paz, Madrid, 28046, Spain; 7CIBER de Enfermedades Raras (CIBERER), Madrid, ISCIII, Spain; 8Genetics Department, Fundacion Valle del Lili, Cali, ColombiaIntroduction: Zika virus (ZIKV) is a little-known emerging mosquito-borne flavivirus. The perinatal ZIKV infection was associated with birth defects during the Brazilian outbreak. There was an increased risk of intrauterine transmission of the virus and a marked increase in the number of newborns with microcephaly. We report on two such cases.Case Report: The first case was a 25-year-old pregnant woman from Colombia who became acutely ill with general symptoms during the tenth week of gestation, followed by severe generalized itching and maculopapular rash for approximately five days. This case was reported during the epidemic stage of the ZIKV infection in Colombia. At 23.3 gestational weeks, ultrasonography showed abnormal intracranial anatomy with cerebral ventriculomegaly, microcephaly, and parenchymal calcification. Given the grave prognosis, the patient elected to terminate the pregnancy at 25 gestational weeks. The second case was a 24-year-old pregnant woman who became acutely ill during the 17th week of gestation, which corresponded with the ZIKV epidemic in Colombia. At 30.5 gestational weeks, ultrasonography showed isolated fetal cerebral ventriculomegaly. We detected ZIKV in the amniotic fluid; however, the virus was not detected in the urine or serum of the mother or fetus. Tests for dengue virus, chikungunya virus, Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, HIV, hepatitis B and C, and parvovirus B19 were all negative. Different samples obtained from the placenta, amniotic liquid, and cerebrospinal fluid were positive for viral isolation of ZIKV RNA using TaqMan RT-PCR. Additionally, the parents and fetuses were tested for genetic diseases using whole exome sequencing and array CGH to rule out possible genetic syndromes that produce these congenital abnormalities.Conclusion: These were the first cases in Colombia to show early vertical transmission of ZIKV and the first cases associated with congenital cerebral abnormalities in which molecular, infectious, and genomic tests were performed.Keywords: Colombia, microcephaly, whole exome sequencing, Zika virus infection, vertical transmission, brain abnormalities

Introduction Bilateral vocal folds' immobility is a challenge in laryngology. Multiple procedures have been proposed to improve breathing by statically enlarging the glottal airway, what also results in loss of voice and aspiration. We proposed a technique to enlarge the posterior glottis by rotating the arytenoids on its axis, imitating the function of the posterior cricoarytenoid muscle, with the objective of evaluating the results regarding decannulation, voice quality, and bronchoaspiration. Methods This study is a clinical case series of patients with bilateral vocal fold paralysis who underwent an arytenoid rotation surgery at a single tertiary university care institution between 2011 and 2017. Data were prospectively collected and was complemented with information from medical charts. Patients were assessed for decannulation, dyspnea, posterior glottic opening, quality of voice, and swallowing disorders. Results Nine patients were included in the study. Out of three patients who required tracheostomy, two were successfully decannulated. Six patients reported a significant improvement in their dyspnea, while four patients reported a worsening of their voice. The stroboscopy evidenced a posterior glottic opening of at least 7 mm in six patients. Eight patients had no aspiratory symptoms, and the acoustic analysis showed that only one patient has a normal voice. Conclusion The arytenoid rotation on its axis by imitating the posterior cricoarytenoid muscle preserves the physiological functions of the larynx, which allows sufficient opening of the posterior glottis for breathing, and could alter in a lesser extent the anterior glottis to maintain a good quality of voice and swallowing.

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. Clinical features are highly variable and could be developing over the life. We present a case of TSC with a molecular test that identified a novel variant in TSC2 gene. It is a sporadic missense mutation which has not been previously reported in the literature. It is caused by premature termination of protein translation and results in the production of truncated and non-functional proteins. This mutation is considered as a pathogenic variant and allows to broaden the spectrum of variants of TSC2 gene as a cause of TSC.El complejo de esclerosis tuberosa es un desorden neurocutáneo autosómico dominante causado por mutaciones en los genes TSC1 o TSC2. El diagnóstico se basa en criterios clínicos o el criterio genético. La presentación clínica es altamente variable y las manifestaciones de la enfermedad pueden desarrollarse durante toda la vida. Se reporta el caso de un niño que cumple criterios clínicos para el diagnóstico de esclerosis tuberosa y cuyo estudio molecular identificó una variante nueva del gen TSC2. Se trata de una mutación sin sentido, esporádica, no reportada previamente (c.583_586dupATCG) localizada en el exón 6, que provoca un codón de parada temprano y altera la estructura de la proteína. Puede considerarse una variante patogénica por el tipo de mutación y permite ampliar el espectro de variantes del gen TSC2 como causa del complejo de esclerosis tuberosa.