Natural history and life-threatening complications in Myhre syndrome and review of the literature.

Myhre syndrome is a rare multisystem genetic disorder that is caused by de novo heterozygous gain-of-function variants in SMAD4. Patients with Myhre syndrome exhibit several phenotypes at different ages such as small size, autism, developmental delay, left-sided heart defects, and hearing loss and often have a characteristic facial appearance. The early clinical diagnosis of Myhre syndrome remains a major challenge, particularly in the first year of life. A Chinese male infant with syndactyly of fingers, hypertelorism, short palpebral fissures, and short philtrum was enrolled into the ENT department of the Chinese PLA General Hospital. Whole exome sequencing analysis was used to detect the disease-causing variant. A literature review of Myhre syndrome was also performed. A recurrent de novo missense variant c.1498A > G p.I500V(p. Ile500Val) in SMAD4 was detected confirming the clinical diagnosis of Myhre syndrome at the age of 38 days. The infant appears to be the youngest reported case of Myhre syndrome. At 23-month follow-up, the affected infant has dysmorphic facial features, growth retardation, and previously undescribed complete syndactyly. Review the literatures noted several common features in Myhre syndrome patients including hearing loss (72.7%), characteristic facial features (26.0%-54.5%), finger and toe abnormalities (3.9%-48.1%), short stature (45.5%), and respiratory (30.0%) and cardiovascular problems (65.0%). Clinicians should have a low threshold to perform genetic testing on patients with features suggesting Myhre syndrome even in the first year of life. Although some individuals with Myhre syndrome have normal hearing, early onset or progressive hearing loss usually occur in one or both ears in most patients, with remarkable phenotypic heterogeneity. Syndactyly may be minor such as typical 2-3 toe involvement, or more complicated as was observed in our patient.

Myhre syndrome (MIM 139210) is a rare autosomal‐dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life‐threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011, SMAD4 (SMAD family member 4) has been identified as the disease‐causing gene. All mutations identified so far are de novo heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF‐β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of SMAD4 mutations during development will decipher new regulatory network related to TGF‐β/BMP signalling. Key Concepts Myhre syndrome is a rare genetic condition of autosomal‐dominant inheritance due to SMAD4 mutations affecting Arg496 or Ile500 residues. Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Myhre syndrome is associated to a risk of early death due to possibly life‐threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis). Similar to mothers against decapentaplegic family member 4 ( SMAD4 ) encodes the common partner SMAD of the eight‐member family of SMAD proteins. SMAD4 aggregates into heterotrimer with the receptor‐regulated SMADs (R‐SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF‐β, activin or BMP receptor pathways. The SMAD4 mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes. Germline heterozygous mutations in SMAD4 are known to cause juvenile polyposis syndrome (JPS) and JPS‐hereditary hemorrhagic telangiectasia. The SMAD4 mutations observed in JPS and JPS‐HHT include nonsense, missense, splice‐site changes and deletions, consistent with a loss‐of‐function mechanism. Increased tumoural risk has not been observed so far in Myhre syndrome. The development of tissue‐specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes.

Myhre syndrome is a rare autosomal dominant disorder caused by a narrow spectrum of missense mutations in the SMAD4 gene. Typical features of this disorder are distinctive facial appearance, deafness, intellectual disability, cardiovascular abnormalities, short stature, short hands and feet, compact build, joint stiffness, and skeletal anomalies. The clinical features generally appear during childhood and become more evident in older patients. Therefore, the diagnosis of this syndrome in the first years of life is challenging. We report a 2‐year‐old girl diagnosed with Myhre syndrome by whole exome sequencing (WES) that revealed the recurrent p.Ile500Val mutation in the SMAD4 gene. Our patient presented with growth deficiency, dysmorphic features, tetralogy of Fallot, and corectopia (also known as ectopia pupillae). The girl we described is the youngest patient with Myhre syndrome. Moreover, corectopia and tetralogy of Fallot have not been previously reported in this disorder.

Objective To test the hypothesis that consuming Mediterranean diet and using olive oil for cooking/dressing salads during pregnancy might be associated with less wheezing during the first year of the offspring's life. Methods A study was conducted in 1,409 infants (mean age, 16.6 ± 2.5 months) attending healthy infant clinics in Spain. Dietary data of mothers' intake during pregnancy was collected by means of a parental food frequency questionnaire. Demographic information and data on wheezing during the first year of the offspring's life were also recorded. Infants were stratified according to any wheezing (42.2%) during the first year of life. Results In the univariate analysis, adherence to a Mediterranean diet and using olive oil for cooking/dressing salads during pregnancy were both significantly associated with less wheezing during the first year of life. However, after multivariate analysis, only olive oil consumption during pregnancy remained associated with less wheezing in the studied period (aOR = 0.57 [95% CI = 0.4–0.9]); whereas male gender (1.8 [1.4–2.3]), day care attendance (2.15 [1.5–3.1]), maternal asthma (2.16 [1.3–3.6]), maternal smoking during pregnancy (1.83 [1.3–2.2]), infant eczema (1.95 [1.3–2.9]), and mould stains on the household walls (1.72 [1.2–2.5]) remained associated with wheezing. Conclusion Our findings suggest a protective effect (primary prevention) of olive oil use during pregnancy on wheezing during the first year of the offspring's life. Pediatr Pulmonol. 2010; 45:395–402. © 2010 Wiley-Liss, Inc.

Effective monitoring throughout pregnancy and the first year of life is a crucial factor in achieving lower rates of maternal and infant mortality. Currently, research on socioeconomic factors that influence the lack of adherence to preventive and control measures during pregnancy and the first year of life is limited. The objective of this review is to examine the available evidence on social determinants that influence participation in health promotion and preventive activities throughout the pregnancy journey and in infants during their first year of life. We performed a systematic review of the literature searching in the major scientific databases (PubMed, Scopus, EMBASE, WOS, and Cochrane Library) for articles from February 2017 to May 2023 containing information on health inequities that impact participation in health promotion and preventive measures from pregnancy through the first year of an infant's life. A total of 12 studies were selected; these studies were performed in ten different countries on five different continents. The selected studies cover preventive measures during maternal care, vaccination, and immunization during pregnancy and the first year of life, newborn screening, and follow-up of the first 12 months of life. The social factors associated with low adherence to health promotion activities during pregnancy and the first year of life include education, income, ethnicity, place of residence, and family characteristics. Despite the diverse geographical distribution, it is observed that there are common social factors linked to a decrease in the adherence to preventive measures during pregnancy and in the early years of life.

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Dietary prevention of allergy, atopy, and allergic diseases

Background. Currently, therapeutic hypothermia (TH) is the only approved method for treating hypoxic-ischemic encephalopathy (HIE) that helps improve outcomes. However, it also has significant drawbacks, including the necessity for expensive equipment and treatment technologies, poorly understood pathophysiological mechanisms, and, most importantly, not always well-understood long-term results. Numerous scientific studies report the potential benefits of TH, but the actual risk/benefit ratio is still unknown. The results of long-term follow-up of children who underwent TH and did not have serious neuromotor or intellectual disorders are variable. It is believed that the correlation between neonatal neuroimaging and the degree of nervous system impairment remains poorly defined. Chronic brain injuries diagnosed after the neonatal period, such as parenchymal volume loss, appear to be more prognostically significant, which may be reflected by moderate enlargement of the ventricular system of the brain. The method for determining the size of the ventricular system using ultrasound can be accessible for infants of the first year of life who had HIE but do not have direct indications for magne­tic resonance imaging. Therefore, this study aimed to explore the characteristics of the cerebral ventricular system in infants of the first year of life who suffered severe asphyxia at birth, depen­ding on the method of post-resuscitation care (with or without TH). Materials and ­methods. The study examined the results of neurosonographic examinations of 309 infants during their first year of life. Inclusion criteria were gestational age at birth ≥ 36 weeks and birth weight ≥ 2000 g, manifestations of HIE in the early neonatal period without adverse short-term outcomes (at the time of discharge from the neonatal hospital, the children showed no signs of destructive hypoxic-ischemic lesions of the central nervous system (CNS), seizures, or pathological muscle tone, and had full oral feeding). Exclusion criteria were diagnosed congenital CNS abnormalities, neuroinfections, psychomotor development delay of more than 3 months during the first years of life, progressive obstructive ventriculomegaly or ventriculomegaly associated with non-atrophic subarachnomegaly. The children were divided into three groups: hypothermia group — 19 infants who underwent TH after birth; normothermia group — 14 children who conditio­nally had indications for TH but did not undergo it; comparison group — 276 children in their first year of life who did not require TH (Apgar score > 5 at 10 minutes of life, manifestations of mild or moderate HIE (according to the Sarnat scale) during the first days of life). Neurosonographic examinations were conducted at the age of 2–7 months (mean of 2.12 ± 0.07 months). The sizes of the lateral ventricles were assessed in comparison with the results from the control group of infants of the same age (34 healthy children with no recorded factors of complicated perinatal period, no signs of neurological dysfunction during the neonatal period, and the seven-month observation). Enlargement of the lateral ventricles was recorded when the size of the anterior horn or body of the ventricle in the parasagittal projection exceeded the 95th percentile of the corresponding measurements from the control group. Results. Enlargement of the lateral ventricles during the neurosonographic examination was detected in 36.8 % of children in the hypothermia group, 14.3 % in the normothermia group, and 8.0 % of children in the comparison group. Significant differences were registered only when comparing the results of the hypothermia group with the comparison group (p < 0.05, Fisher’s exact test). Significant correlations (p < 0.05) were found between the size of the lateral ventricles and clinical signs such as sleep disturbances, decreased muscle tone in the arms, increased tendon reflexes, delayed motor development, increased muscle tone in a pyramidal pattern, and diffuse muscle hypotonia. Conclusions. Thus, infants who had severe asphyxia at birth and underwent TH significantly more often had enlargement of the cerebral ventri­cular system (versus the comparison group). Therefore, although therapeutic hypothermia improves outcomes for the development of the nervous system in children who have moderate and severe hypoxic-ischemic encephalopathy, brain morphology (particularly the state of the ventricular system) may still be altered in infants during the first year of life. And the presence of significant correlations between the size of the lateral ventricles and clinical signs of neurological dysfunction argues for further clinical monitoring of children after therapeutic hypothermia throughout the first years of life and in the absence of short-term adverse outcomes of HIE or significant delays in psychomotor development during the first year of life.

To test the hypothesis that consuming Mediterranean diet and using olive oil for cooking/dressing salads during pregnancy might be associated with less wheezing during the first year of the offspring's life. A study was conducted in 1,409 infants (mean age, 16.6 +/- 2.5 months) attending healthy infant clinics in Spain. Dietary data of mothers' intake during pregnancy was collected by means of a parental food frequency questionnaire. Demographic information and data on wheezing during the first year of the offspring's life were also recorded. Infants were stratified according to any wheezing (42.2%) during the first year of life. In the univariate analysis, adherence to a Mediterranean diet and using olive oil for cooking/dressing salads during pregnancy were both significantly associated with less wheezing during the first year of life. However, after multivariate analysis, only olive oil consumption during pregnancy remained associated with less wheezing in the studied period (aOR = 0.57 [95% CI = 0.4-0.9]); whereas male gender (1.8 [1.4-2.3]), day care attendance (2.15 [1.5-3.1]), maternal asthma (2.16 [1.3-3.6]), maternal smoking during pregnancy (1.83 [1.3-2.2]), infant eczema (1.95 [1.3-2.9]), and mould stains on the household walls (1.72 [1.2-2.5]) remained associated with wheezing. Our findings suggest a protective effect (primary prevention) of olive oil use during pregnancy on wheezing during the first year of the offspring's life.

To test how prenatal participation in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) impacts health care utilization and immunizations within the first year of an infant's life. We utilize comprehensive South Carolina Medicaid claims data from 2004 to 2013 linked with birth certificates data from 2004 to 2012. These data contain information on WIC participation and all health care utilization within the first year of an infant's life. We employ a maternal fixed-effects empirical design to control for unobserved factors that influence WIC participation and health care utilization. We estimate that WIC participation increases infant health care utilization within the first year of life by 0.20 well-child visits (95 percent CI 0.16-0.23), by 0.22 vaccinations (95 percent CI 0.17-0.27), and by increasing the probability of receiving care in an emergency room by 2.9 percentage points (95 percent CI 2.0-3.8). Additionally, our results show that WIC participation decreases the average number of days an infant spends in the hospital within his or her first year of life by 0.41days (95 percent CI 0.22-0.60). These findings suggest that WIC may increase health care costs in some dimensions while reducing it in others, and more work is needed to fully evaluate the impact of the program on future expenditures.

The lessons of noninterventional and interventional prospective studies on the development of atopic disease during childhood.

Myhre syndrome (MS) is a rare autosomal-dominant disorder characterized by short stature, intellectual disability, skeletal anomalies, restricted joint mobility, distinctive facial dysmorphism, and deafness. Early diagnosis of MS is difficult because its features progress and become noticeable at school age. Recently, the SMAD4 gene was identified as the major gene responsible for MS. Herein, we report the first Korean case of MS after identification of a SMAD4 mutation by clinical exome sequencing. The patient was born small for gestational age, and she had the typical clinical features of MS, including short stature, characteristic facial appearance, developmental delay, and selective mutism. She was diagnosed with central precocious puberty. Because of the patient’s precocious puberty and short stature, we administered combined recombinant human growth hormone and gonadotropin-releasing hormone agonist treatments, which resulted in improved height. While there have been 79 cases of MS reported worldwide, to our knowledge, this is the first case of genetically-confirmed MS in Korea.

Reverse causation and confounding‐by‐indication: do they or do they not explain the association between childhood antibiotic treatment and subsequent development of respiratory illness?

In Brief Objective To assess additional risk of newborn death owing to early discharge. Methods This was a historical cohort study using Washington State linked birth certificates, death certificates, and hospital discharge records that covered 47,879 live births in 1989 and 1990. Logistic regression was used to assess risk of death within the first year of life after early discharge (less than 30 hours after birth) compared with later discharge (30–78 hours after birth). Results Newborns discharged early were more likely to die within 28 days of birth (odds ratio [OR] 3.65; 95% confidence interval [CI] 1.56, 8.54), between 29 days and 1 year (OR 1.61; 95% CI 1.10, 2.36), and any time within the first year (OR 1.84; 95% CI, 1.31, 2.60) of life than newborns sent home later. Newborns discharged early also were more likely to die of heart-related problems (OR 3.72; CI 1.25, 11.04) and infections (OR 4.72; CI 1.13, 19.67) within 1 year of birth than newborns discharged later. Conclusion Newborns discharged within 30 hours of birth are at increased risk of death within the first year of life. Newborns discharged early are at increased risk of death within the first year of life.