[Multidisciplinary management with neuromuscular electrical stimulation therapy in a Goldenhar syndrome patient who presented swallowing disorder and failure to thrive.] / Manejo multidisciplinario con terapia de electroestimulación en un paciente con síndrome de Goldenhar, trastorno de la deglución y falla para crecer.

INTRODUCCIÓN: El síndrome de Goldenhar es un trastorno heterogéneo, esporádico en su mayoría o por patrón de herencia autosómico dominante o recesivo, de la morfogénesis craneofacial asociada al primero y segundo arcos faríngeos, y forma parte del espectro oculoauriculovertebral. La incidencia es de 1 por cada 3500-45,000 recién nacidos vivos, con una razón de sexo masculino/femenino de 3:2. CASO CLÍNICO: Se presenta el caso de un recién nacido con fenotipo de síndrome oculoauriculovertebral. Se abordó con radiografía de tórax, ecografía abdominal y tamizaje metabólico y auditivo, que reportaron hemivértebra torácica, fusión costal, quiste renal e hipoacusia bilateral profunda, respectivamente. Fue alimentado con lactancia mixta desde el nacimiento, sin lograr una succión adecuada y con pérdida de peso. A los 3 meses de edad recibió terapia de rehabilitación oral con electroestimulación en conjunto de 10 sesiones con 10 mA de intensidad, al igual que a los 23, 24, 25, 27, 30 y 32 meses de edad. A los 4 meses, espesamiento de fórmula con cereal; a los 7 meses, sonda de gastrostomía; a los 20 meses, cirugía de paladar y macrostomía. Mostró mejoría en intensidad de babeo en las primeras 10 sesiones y mejoría en la deglución a las 30 sesiones. A los 3 años de edad consume el 100% de los alimentos por vía oral. CONCLUSIONES: Con la escasa evidencia científica que este caso aislado aporta, el tratamiento con la terapia de rehabilitación en conjunto con la terapia convencional y la corrección anatómica dio resultados positivos para el trastorno de la deglución. BACKGROUND: Goldenhar syndrome is a heterogeneous disorder, mostly sporadic or due to a dominant autosomal or recessive pattern of inheritance, that exhibits craniofacial morphogenesis associated with the first and second pharyngeal arches and is part of the oculoauriculovertebral spectrum. Its incidence is of 1 in 3,500-45,000 live newborns, with a male to female ratio of 3:2. CASE REPORT: We describe the case of a male newborn with oculoauriculovertebral syndrome phenotype. It was approached with chest X-ray, abdominal ultrasound, metabolic and hearing screening, which reported thoracic hemivertebra, costal fusion, renal cyst, and profound bilateral hypoacusis, respectively. Although the newborn was fed with mixed lactation from birth, adequate suction and with weight loss were not achieved. At 3 months of age, as well as at 23, 24, 25, 27, 30 and 32 months of age, the infant received oral rehabilitation therapy with electrostimulation in a set of 10 sessions with 10 mA intensity. At 4 months, thickening of formula with cereal; at 7 months, gastrostomy tube; at 20 months, palate surgery and macrostomy. Improvement in drooling intensity was observed during the first 10 sessions, and improvement in swallowing after 30 sessions. At 3 years of age, the patient consumes 100% of food orally. CONCLUSIONS: According to limited scientific evidence that this isolated case provides, rehabilitation therapy together with conventional therapy coupled with anatomical correction gave positive results for swallowing disorder.

Manejo multidisciplinario con terapia de electroestimulación en un paciente con síndrome de Goldenhar, trastorno de la deglución y falla para crecer / Multidisciplinary management with neuromuscular electrical stimulation therapy in a Goldenhar syndrome patient who presented swallowing disorder and failure to thrive

Resumen Introducción: El síndrome de Goldenhar es un trastorno heterogéneo, esporádico en su mayoría o por patrón de herencia autosómico dominante o recesivo, de la morfogénesis craneofacial asociada al primero y segundo arcos faríngeos, y forma parte del espectro oculoauriculovertebral. La incidencia es de 1 por cada 3500-45,000 recién nacidos vivos, con una razón de sexo masculino/femenino de 3:2. Caso clínico: Se presenta el caso de un recién nacido con fenotipo de síndrome oculoauriculovertebral. Se abordó con radiografía de tórax, ecografía abdominal y tamizaje metabólico y auditivo, que reportaron hemivértebra torácica, fusión costal, quiste renal e hipoacusia bilateral profunda, respectivamente. Fue alimentado con lactancia mixta desde el nacimiento, sin lograr una succión adecuada y con pérdida de peso. A los 3 meses de edad recibió terapia de rehabilitación oral con electroestimulación en conjunto de 10 sesiones con 10 mA de intensidad, al igual que a los 23, 24, 25, 27, 30 y 32 meses de edad. A los 4 meses, espesamiento de fórmula con cereal; a los 7 meses, sonda de gastrostomía; a los 20 meses, cirugía de paladar y macrostomía. Mostró mejoría en intensidad de babeo en las primeras 10 sesiones y mejoría en la deglución a las 30 sesiones. A los 3 años de edad consume el 100% de los alimentos por vía oral. Conclusiones: Con la escasa evidencia científica que este caso aislado aporta, el tratamiento con la terapia de rehabilitación en conjunto con la terapia convencional y la corrección anatómica dio resultados positivos para el trastorno de la deglución.

Abstract Background: Goldenhar syndrome is a heterogeneous disorder, mostly sporadic or due to a dominant autosomal or recessive pattern of inheritance, that exhibits craniofacial morphogenesis associated with the first and second pharyngeal arches and is part of the oculoauriculovertebral spectrum. Its incidence is of 1 in 3,500-45,000 live newborns, with a male to female ratio of 3:2. Case report: We describe the case of a male newborn with oculoauriculovertebral syndrome phenotype. It was approached with chest X-ray, abdominal ultrasound, metabolic and hearing screening, which reported thoracic hemivertebra, costal fusion, renal cyst, and profound bilateral hypoacusis, respectively. Although the newborn was fed with mixed lactation from birth, adequate suction and with weight loss were not achieved. At 3 months of age, as well as at 23, 24, 25, 27, 30 and 32 months of age, the infant received oral rehabilitation therapy with electrostimulation in a set of 10 sessions with 10 mA intensity. At 4 months, thickening of formula with cereal; at 7 months, gastrostomy tube; at 20 months, palate surgery and macrostomy. Improvement in drooling intensity was observed during the first 10 sessions, and improvement in swallowing after 30 sessions. At 3 years of age, the patient consumes 100% of food orally. Conclusions: According to limited scientific evidence that this isolated case provides, rehabilitation therapy together with conventional therapy coupled with anatomical correction gave positive results for swallowing disorder.

Case Report: Congenital Arthrogryposis and Unilateral Absences of Distal Arm in Congenital Zika Syndrome.

Zika virus was recognized as a teratogen in 2015, when prenatal Zika infection was associated with neonatal microcephaly. The transmission, virulence, tropism, and consequences of Zika virus infection during pregnancy are currently studied. Decreased neural progenitor cells, arrest in neuronal migration and/or disruption of the maturation process of the fetus central nervous system have been associated. Congenital Zika Syndrome produces a fetal brain disruption sequence resulting in structural brain abnormalities, microcephaly, intracranial calcifications, fetal akinesia and arthrogryposis. Vascular abnormalities like unique umbilical artery and decreased cerebral vascular flow have been described in some patients. This article reports a Zika positive patient with sequence of fetal brain disruption, arthrogryposis and absence of distal third of the right forearm. This report expands the clinical observations of congenital Zika syndrome that may be related to disruptive vascular events.

Characterization of novel GCDH pathogenic variants causing glutaric aciduria type 1 in the southeast of Mexico.

Biallelic mutations of the GCDH gene result in Glutaric Aciduria type 1 (GA1; OMIM #231670), an uncommon autosomal recessive inborn error caused by the deficiency of glutaryl-CoA dehydrogenase (CCDH), a mitochondrial matrix protein involved in the degradation of l-lysine, L-hydroxylysine, and L-tryptophan. The enzymatic deficiency leads to the accumulation of neurotoxins causing macrocephaly at birth, hypotonia and dystonia due to bilateral striatal injury, that evolves with aging, if untreated, to fixed dystonia and akinetic-rigid parkinsonism. In this article, we describe the results of molecular studies of 5 unrelated patients with GA1 in Southern Mexico. Mutational analysis identified 2 novel likely pathogenic GCDH variants (p.Leu130Pro and p.Gly391Val), 1 pathogenic variant that is predicted to cause a premature stop codon (p.Leu370*), and 2 previously reported pathogenic variants (p.Arg294Trp and p.Arg294Gln). The recurrence of the p.Leu130Pro variant (60% of mutant alleles) suggested a possible founder mutation effect. Our results expand the mutational spectrum in GA1 patients and support the importance of early diagnosis through newborn screening that promotes early nutritional treatment and prevents metabolic crisis. TAKE HOME MESSAGE: Glutaric Aciduria type 1 has a wide mutational spectrum; the p.Leu130Pro variant may be a founder mutation in Southeast Mexico.

Zika Virus Infection in Pregnant Women, Yucatan, Mexico.

We report demographic, epidemiologic, and clinical findings for a prospective cohort of pregnant women during the initial phase of Zika virus introduction into Yucatan, Mexico. We monitored 115 pregnant women for signs of active or recent Zika virus infection. The estimated cumulative incidence of Zika virus infection was 0.31 and the ratio of symptomatic to asymptomatic cases was 1.7 (range 1.3-4.0 depending on age group). Exanthema was the most sensitive clinical sign but also the least specific. Conjunctival hyperemia, joint edema, and exanthema were the combination of signs that had the highest specificity but low sensitivity. We did not find evidence of vertical transmission or fetal anomalies, likely because of the low number of pregnant women tested. We also did not find evidence of congenital disease. Our findings emphasize the limited predictive value of clinical features in areas where Zika virus cocirculates with other flaviviruses.

Genetic variation of FTO: rs1421085 T>C, rs8057044 G>A, rs9939609 T>A, and copy number (CNV) in Mexican Mayan school-aged children with obesity/overweight and with normal weight.

OBJECTIVES: Genetic variation of the fat mass and obesity associated gene (FTO) has been identified as a risk factor for obesity and obesity traits. Distribution of FTO single nutleotide polymorphisms (SNPs) rs1421085T>C, rs9939609T>A, rs8057044G>A and copy number variation (CNV) was evaluated in association with childhood obesity or overweight status in children with Mayan ethnicity. METHODS: We included 318 school-aged children with obesity or overweight status (body mass index [BMI]: >85th percentile) and 303 children with normal weight (BMI: 15th-85th percentile). Genotyping was performed using real-time polymerase chain reaction (RT-PCR) with TaqMan probes. The cross-sectional study was carried out using univariate and multivariate logistic regression models adjusted for gender. RESULTS: FTO-SNP rs1421085 showed significant differences between children with obesity and children with normal weight for the heterozygous genotype (P = 0.003) and for allele frequencies (P = 0.023). Adjusting by gender, significant differences were found in frequencies of the hetezygous genotype of SNPs rs9939609 (P = 0.023) and rs1421085 (P = 0.003) as well as in allele frequencies (P = 0.042 and P = 0.013, respectively) between girls with obesity and girls without obesity. In contrast, SNP rs8057044 was significantly different only between heterozygous overweight versus normal weight boys (P = 0.035) and for the allele frequency of rs8057044 (P = 0.021). The mean relative CNV was significantly higher in male overweight children than in boys with normal weight (P = 0.000). CONCLUSIONS: The FTO SNP rs1421085 is a genetic factor associated with obesity in Mayan school-aged children. FTO SNPs rs1421085 and rs9939609 affect genetic susceptibility for obesity only in girls, whereas, SNP rs8057044 and CNV are associated with overweight status only in boys.

Birth Defects Associated With Congenital Zika Virus Infection in Mexico.

Part of the work agenda of international health authorities is to define the clinical spectrum of the congenital Zika syndrome (CZS) in different territories. We describe the clinical variability that gave rise to the suspicion of CZS in 3 newborn patients in the south of Mexico with active transmission of Zika. All of them presented Zika RNA by reverse transcription-polymerase chain reaction and positive antibodies for IgM by enzyme-linked immunosorbent assay. None of the mothers tested positive for active viremia, only one mother had Zika-symptoms and titers of Zika-positive IgM. Intrauterine growth restriction, brain disruption sequence, and intracranial calcifications are the clinical characteristics common in all. One patient had neural tube defect and other, arthrogryposis. Because the majority of pregnant women will be asymptomatic to Zika, we must be alert to the clinical variability of the birth defects associated to pregnancy Zika infection. Reports of clinical cases encourage the medical community to make diagnostic decisions.

Newborn cystic fibrosis screening in southeastern Mexico: Birth prevalence and novel CFTR gene variants.

OBJECTIVE: To use the results of the first five years of a cystic fibrosis newborn screening program to estimate the cystic fibrosis birth prevalence and spectrum of cystic fibrosis transmembrane conductance regulator ( CFTR) gene variants in Yucatan, Mexico. METHODS: Screening was performed from 2010 to 2015, using two-tier immunoreactive trypsinogen testing, followed by a sweat test. When sweat test values were >30 mmol/L, the CFTR gene was analyzed. RESULTS: Of 96,071 newborns screened, a second sample was requested in 119 cases. A sweat test was performed in 30 newborns, and 9 possible cases were detected (seven confirmed cystic fibrosis and two inconclusive). The most frequently detected CFTR pathogenic variant (5/14 cystic fibrosis alleles, 35.7%) was p.(Phe508del); novel p.(Ala559Pro) and p.(Thr1299Hisfs*29) pathogenic variants were found. CONCLUSIONS: Cystic fibrosis birth prevalence in southeastern Mexico is 1:13,724 newborns. Immunoreactive trypsinogen blood concentration is influenced by gestational age and by the time of sampling. The spectrum of CFTR gene variants in Yucatan is heterogeneous.

Characterization and mRNA expression analysis of a novel ARG1 splicing mutation causing hyperargininemia.

OBJECTIVES: Biallelic mutations in the ARG1 gene result in an uncommon autosomal recessive inborn defect of the urea cycle known as hyperargininemia (OMIM #207800). ARG1 splicing mutations are not reported often, and they are probably related to a more severe phenotype than missense mutations. In this article, we describe the results of molecular studies in a young hyperargininemia patient carrying a novel splicing mutation in ARG1. DESIGN AND METHODS: Molecular analyses included PCR amplification and direct nucleotide sequencing of the ARG1 gene. RT-PCR analysis was performed to investigate the effect of the mutation in mRNA splicing and in the expression of ARG1 isoforms. RESULTS: Mutational analysis identified a novel homozygous ARG1 IVS4-1G>C point mutation in the patient's DNA. Blood leukocyte mRNA was analyzed to demonstrate the splicing defect caused by this mutation. Sequencing of ARG1 RT-PCR products allowed the characterization of a mutated transcript retaining 51-bp from intron 4. In addition, two new, alternatively spliced ARG1 transcripts lacking either exon 4 or exons 4 and 5 were identified in mRNA from the patient and from controls. CONCLUSIONS: Our results expand the mutational spectrum in hyperargininemia patients and indicate that the novel splicing mutation results in an aberrant transcript retaining intronic sequences. Two novel alternatively spliced ARG1 transcripts were also recognized.

Frequency of SMN1 deletion carriers in a Mestizo population of central and northeastern Mexico: A pilot study.

Individuals who suffer from spinal muscular atrophy (SMA) exhibit progressive muscle weakness that frequently results in mortality in the most severe forms of the disease. In 98% of cases, there is a homozygous deletion of the survival of motor neuron 1 (SMN1) gene, and both parents carry the same heterozygous genetic abnormality in the majority of cases. Various population studies have been conducted to estimate the frequency of carriers and thereby identify the communities or countries in which children are at a high risk of being affected by SMA. However, the prevalence of SMA in Mexican populations has not yet been established. In the present pilot study, the frequency of the heterozygous deletion of the SMN1 gene was determined in two groups from northeastern (n=287) and central (n=133) Mexican Mestizo populations and compared with other ethnic populations. Amplification refractory mutation system polymerase chain reaction analysis yielded a disease carrier frequency of 11/420 (2.62%) healthy individuals, comprising 9/287 (3.14%) northeastern and 2/133 (1.5%) central Mexican individuals. In summary, no significant differences were identified between the northeastern and central populations of Mexico and other ethnic populations, with the exception of the general worldwide Hispanic population, which exhibited the lowest carrier frequency of 8/1,030. The results of the present study may be used to improve the evaluation procedure, and appear to justify further studies involving larger sample populations.

Focal dermal hypoplasia without focal dermal hypoplasia.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome) is an X-linked dominant disorder affecting mainly tissues of ectodermal and mesodermal origin. The phenotype is characterized by hypoplastic linear skin lesions, eye malformations, hair and teeth anomalies, and multiple limbs malformations. The disorder is caused by PORCN mutations. Here we describe a mother and daughter with FDH in whom a c.938T>G in PORCN was detected. Neither of the two had FDH, but otherwise the phenotype was classical. Focal skin hypoplasia is a hallmark of FDH but the present family indicates that FDH should also be considered in absence of this skin manifestation.