Rasopathies case report: concurrence of two pathogenic variations de novo in NF1 and KRAS genes in a patient.

BACKGROUND: Rasopathies are a group of genetic malformative syndromes including neurofibromatosis 1, Noonan, LEOPARD, Costello, cardio-facio-cutaneous, Legius, and capillary malformation-arteriovenous malformation syndromes. CASE PRESENTATION: We present a female newborn that consulted at the emergency department with refusal to eat and sleepiness. A shortened femur, thickened nucal fold and suspect for agenesis of the corpus callosum were observed in prenatal ultrasound. Her phenotype included hypertelorism, antimongoloid obliquity of the palpebral fissure, prominent forehead, long filtrum, thickened nucal fold, separated nipples, widespread thickened skinfolds and café-au-lait spots. She had a systolic murmur due to pulmonary valve stenosis. The NF1 gene testing found the pathogenic variant p.E2586X (c.7756G > T) in exon 53, not described in any international database or scientific publications yet. Also, a mutation in the Kras gene was detected (p.Val14lle), which is associated with mild Noonan phenotype. Both variations were de novo. CONCLUSIONS: Not all genes and mutations have already been discovered, so it's important to document new findings, like our patient's, to enrich and update the international database and broaden all possible knowledge about rasopathies. This is the first case to be described presenting simultaneously two mutations in Kras and NF1 genes, whose possible synergic effect regarding its pathogenicity is unknown, but could be interesting towards therapeutic alternatives.

[Risk factors and biochemical markers in metabolic bone disease of premature newborns]. / Factores de riesgo y marcadores bioquímicos de la enfermedad metabólica ósea del recién nacido prematuro.

BACKGROUND: Metabolic bone disease (MBD) of prematurity is a complication of multifactorial aetiology, which has been increasing, due to progressive decrease in mortality of preterm newborns. The aim of the study was to analyze risk factors of severe MBD and its analytical markers. PATIENTS AND METHOD: Retrospective study involving preterm infants less than 32 weeks gestational age and/or weight less tan 1,500 g born between january 2012 and december 2014. Comparison was made according to the presence of severe MBD. RESULTS: 139 patients were recruited. Mean value of 25(OH)D3 was 70.68 ± 25.20 nmol/L, being higher in patients born in spring-summer than in autumn-winter (80.94 ± 25.33 vs 61.13 ± 21.07; p = 0.000). Levels of 25(OH)D3 were similar in patients with severe MBD compared with the rest of patients (65.61 ± 26.49 vs 72.07 ± 24.89, P = 0.283). Higher levels of alkaline phosphatase (AP, IU/L ) (1314.19 ± 506.67 vs 476.56 ± 188.85; p = 0.000) were found in these patients. Cutoff point of AP 796.5 IU/L (S 95.2%, specificity 92.4%) was calculated by ROC curve. The risk factors most associated to severe EMO were restricted fetal growth, birth weight, duration of ventilation therapy and parenteral nutrition. CONCLUSIONS: AP levels were the best marker of severe MBD development. EMO risk increases with the number of risk factors and lower levels of 25(OH)D3. Levels of 25(OH)D3 higher than 70nmol/L appear to protect from the development of severe MBD, even in patients with multiple risk factors.

Factores de riesgo y marcadores bioquímicos de la enfermedad metabólica ósea del recién nacido prematuro / Risk factors and biochemical markers in metabolic bone disease of premature newborns

Introducción: La enfermedad metabólica ósea (EMO) del recién nacido prematuro (RNPT) es una complicación de origen multifactorial, que ha ido en aumento, consecuencia de la disminución progresiva de la mortalidad. El objetivo del estudio fue analizar los factores de riesgo (FR) pre y postnatales relacionados con la EMO severa y sus marcadores analíticos. Pacientes y Métodos: Estudio retrospectivo observacional, descriptivo y analítico, que incluyó RNPT nacidos con menos de 32 semanas y/o peso menor de 1.500 g entre enero de 2012 y diciembre de 2014. Se analizó la muestra en función del desarrollo de EMO severa. Resultados: 139 pacientes, con 25(OH)D3 media de 70,68 ± 25,20 nmol/l, mayor en los nacidos en primavera-verano que en otoño-invierno (80,94 ± 25,33 vs 61,13±21,07; p = 0,000). Los pacientes con EMO severa presentaron valores de 25(OH)D3 similares al resto de pacientes (65,61 ± 26,49 vs 72,07 ± 24,89; p = 0,283), y superiores de fosfatasa alcalina (FA) (1314,19 ± 506,67 vs 476,56 ± 188,85; p = 0,000). Mediante curva ROC se calculó un punto de corte de FA de 796,5 IU/l (S 95,2%, E 92,4%). Los FR más asociados al desarrollo de EMO severa fueron el crecimiento intrauterino restringido, el peso al nacimiento y la duración de ventiloterapia y nutrición parenteral. Conclusiones: Las cifras de FA son las que mejor se relacionan con el desarrollo de EMO severa. El riesgo de ésta aumenta a mayor número de factores de riesgo y menores cifras de vitamina D3. Niveles de 25(OH)D3 por encima de 70 nmol/l parecen proteger del desarrollo de EMO, incluso en pacientes con múltiples factores de riesgo.

Background: Metabolic bone disease (MBD) of prematurity is a complication of multifactorial aetiology, which has been increasing, due to progressive decrease in mortality of preterm newborns. The aim of the study was to analyze risk factors of severe MBD and its analytical markers. Patients and Method: Retrospective study involving preterm infants less than 32 weeks gestational age and/or weight less tan 1,500 g born between january 2012 and december 2014. Comparison was made according to the presence of severe MBD. Results: 139 patients were recruited. Mean value of 25(OH)D3 was 70.68 ± 25.20 nmol/L, being higher in patients born in spring-summer than in autumn-winter (80.94 ± 25.33 vs 61.13 ± 21.07; p = 0.000). Levels of 25(OH)D3 were similar in patients with severe MBD compared with the rest of patients (65.61 ± 26.49 vs 72.07 ± 24.89, P = 0.283). Higher levels of alkaline phosphatase (AP, IU/L ) (1314.19 ± 506.67 vs 476.56 ± 188.85; p = 0.000) were found in these patients. Cutoff point of AP 796.5 IU/L (S 95.2%, specificity 92.4%) was calculated by ROC curve. The risk factors most associated to severe EMO were restricted fetal growth, birth weight, duration of ventilation therapy and parenteral nutrition. Conclusions: AP levels were the best marker of severe MBD development. EMO risk increases with the number of risk factors and lower levels of 25(OH)D3. Levels of 25(OH)D3 higher than 70nmol/L appear to protect from the development of severe MBD, even in patients with multiple risk factors.

Deposiciones sanguinolentas iniciadas en los primeros días de vida / Bloody stools started in the first days of life

La proctocolitis alérgica del lactante es un trastorno caracterizado por la presencia de deposiciones mucosanguinolentas en los dos primeros meses de vida, pudiendo aparecer en los primeros días de vida. Anteriormente, relacionado con niños alimentados con lactancia artificial, en los últimos años se observa un aumento de la incidencia en niños alimentados con lactancia materna exclusiva debido al paso de proteínas de leche de vaca a la leche de la madre. Recién nacido a término, alimentado con lactancia materna exclusiva inicia a los dos días de vida deposiciones con hebras de sangre de forma intermitente. Todos los estudios realizados resultan normales. La clínica mejora progresivamente tras la eliminación de las proteínas de leche de vaca de la dieta de la madre, por lo que se diagnostica de proctocolitis alérgica. El diagnóstico se basa en la clínica, la desaparición de los síntomas al retirar las proteínas de leche de vaca de la dieta, y en la reaparición de éstos al reintroducirla. Los niños mantienen buen estado general en todo momento, siendo la gran mayoría tolerantes a la leche de vaca al año de vida, por lo que se considera una patología de buen pronóstico.

Allergic colitis is a pathology characterized by blood in faeces, appeared in first two months of life, but it can also appear during the first days of life. Previously it was related with children with non breastfeeding, however in the last years incidence is increasing in children with breastfeeding. This is explained with the presence of cow’s milk proteins in human’s milk. Newborn term, fed with exclusive breastfeeding, starts at second day of life blood in faeces, intermittently. The studies done are normal. The symptoms improve progressively after removing the cow’s milk proteins of the mother’s diet, so the child is diagnosed with allergic protocolitis. Diagnosis is based on the symptoms, the improvement with the removal of the cow’s milk protein of the diet, and the worsening when they are reintroduced. The children conserve good general condition every moment, almost all of them tolerate cow’s milk when they are one year old, and so it is considered pathology of well prognosis.