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Evaluation and Diagnosis of the Dysmorphic Infant
Abstract
Neonatologists have a unique opportunity to be the first to identify abnormalities in a neonate. In this review, multiple anomalies and physical features are discussed along with the potential associated genetic syndromes. The anomalies and physical features that are discussed include birth parameters, aplasia cutis congenita, holoprosencephaly, asymmetric crying facies, preauricular ear tags and pits, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, congenital heart defects, ventral wall defects, and polydactyly.
Copyright © 2015 Elsevier Inc. All rights reserved.
... Neonatologists frequently encounter newborns with dysmorphic features. They are often the first physicians to evaluate these appearances (9). Auricular anomalies are frequently implicated in genetic pathology, and even minor variants may be an important indicator for the detection of some genetic syndromes (5,8). ...
... Auricular anomalies are frequently implicated in genetic pathology, and even minor variants may be an important indicator for the detection of some genetic syndromes (5,8). Neonatologists need to be familiar with this common finding so that they can perform further testing for occult malformations as needed and collaborate with the medical geneticist to perform diagnostic testing thoroughly and counsel families appropriately (9). ...
... Preauricular tags are small non-cartilaginous skin-colored protrusions that can be found anterior to the insertion of the ear usually hairless and containing no striated muscle (9,11). Preauricular pits are small skin openings of variable locations. ...
Preauricular skin tags represent a commonly seen minor congenital anomaly of the auricle that may occur either in isolation or together with other dysmorphic features or malformations as part of a syndrome. Even minor dysmorphic features can lead to a genetic diagnosis with far-reaching, systemic implications. Neonatologists must be familiar with this common presentation and have good communication with the medical geneticist to identify a possible underlying genetic condition early and manage each case appropriately. Ear abnormalities such as preauricular tags and pits may be associated with additional specific abnormalities such as hearing loss or renal malformations that need to be considered and further investigated. This article aims to provide data and guidance for the management of neonates with preauricular tags or preauricular pits, a minor congenital anomaly of the ear, where early recognition of syndromes based on minor anomalies is ideal.
... In fact, vaccinations are quite useful considering the high risk of respiratory infections in children with congenital heart disease, dysphagia/gastroribs abnormalities (17). The pediatrician must constantly follow in which way the family tackles the problem and the 2 When the newborn arrives without a diagnosis, but instead with one or more major malformations (18)(19)(20). The pediatri-tion of the disease, knowing that even without a diagnostic label, the single problems can be faced in the same way. ...
... He should also document the clinical problems and his own diagnostic suspicion, directing the child to the geneticist. Apart from this he should explain why is sending the child to the geneticist and the possible diagnostic process (18,20,(22)(23)(24)(25)(26). At this point the pediatrician should inform the parents about the limits of the diagnostic process, in fact his suspicion could be erroneous or else it isn't possible to draw up a perfect diagnosis (13). ...
... The clinical approach to the malformation syndromes presents peculiarities because of the clinical, etiological and pathosuspicion which precedes the clinical analysis, but demands especially attention on the part of the pediatrician (18). ...
... Aplasia cutis congenita (ACC) is the congenital absence of the skin, and may occur on any part of the body. It afects the scalp in 70-80% of the cases (Figure 1), either as solitary lesions or associated with skull and dura mater defects [2,7]. Aplasia cutis congenita is a rare anomaly in neonates. ...
... These patients should be examined for any other malformations in an atempt to include the anomaly in a genetic syndrome such as [2,[26][27][28][29]: ...
... When auricular istulae and nodules are isolated, no further evaluation is required for these children [2]. ...
... El síndrome dismórfico hace referencia a los pacientes que presentan al nacer alguna anormalidad física, estructural y/o funcional. También se le conoce con el nombre de anomalías congénitas (1). Se estima que anualmente el 6 % de los niños a nivel mundial nacen con una anomalía congénita (2) y más de 300,000 mueren durante el primer mes de vida (3). ...
... Esto puede deberse a diferentes factores, como la presencia de variaciones fenotípicas entre los pacientes con la misma enfermedad (7), diferentes grados de severidad y comorbilidades asociadas (8,9), así como también patologías maternas no evaluadas adecuadamente ni tratadas de manera oportuna (10,11). A esto se suma la necesidad de realizar pruebas genéticas (1,12), necesidad usualmente insatisfecha por cuestiones de acceso, disponibilidad y costos. ...
Introducción: El síndrome dismórfico hace referencia a los pacientes que presenten al nacer alguna anormalidad física, estructural y/o funcional. Se estima que anualmente el 6% de niños a nivel mundial nacen con una anomalía congénita y más de 300 000 mueren durante su primer mes de vida. Su diagnóstico puede llegar a ser complicado e incluso subjetivo, sobre todo cuando existen variaciones fenotípicas, diferentes grados de severidad y comorbilidades asociadas, y patologías maternas no evaluadas de manera adecuada ni oportuna. A esto se le suma que es necesario el uso de pruebas genéticas que en muchas ocasiones no son de fácil acceso. Objetivo: Informar sobre las manifestaciones clínicas y complicaciones del síndrome dismórfico. Presentación del caso: Se presenta el caso de un recién nacido de 30 semanas según Capurro, cuya madre tenía antecedente de diabetes e inadecuado control prenatal. El neonato presenta múltiples rasgos dismórficos, además de atresia de esófago. Se plantean como posibles diagnósticos una asociación VACTERL (defectos vertebrales, malformaciones anales, cardiopatías congénitas, alteraciones traqueo-esofágicas, malformaciones renales y alteración en extremidades) o una trisomía 18. Este último llegó a confirmarse mediante pruebas genéticas, pero posterior a la defunción del paciente, ocurrida al final de la tercera semana de vida. Conclusiones: El abordaje del neonato con síndrome dismórfico representa un verdadero desafío diagnóstico, terapéutico y social. La falta de recursos y deficiencias en el sistema de salud hacen difícil un diagnóstico precoz, más aún en estas patologías infrecuentes.
... This patient had presented with meso and postaxial polydactyly as well as syndactyly of the 3rd and 4th metacarpals at birth. Polydactyly is relatively common in infants [13]. Although typically of the sporadic, isolated form [13], polydactyly can also be a feature of about 300 well-characterized syndromic malformations [14]. ...
... Polydactyly is relatively common in infants [13]. Although typically of the sporadic, isolated form [13], polydactyly can also be a feature of about 300 well-characterized syndromic malformations [14]. Clinically, there are no typical features of the polydactyly to suggest that it forms part of a specific syndrome including PHS. ...
Pallister-Hall syndrome (PHS) is an extremely rare syndrome of unknown prevalence with autosomal dominant inheritance due to GLI3 gene mutations classically characterized by the presence of a hypothalamic hamartoma and polydactyly. Additional diagnostic criteria include bifid epiglottis, imperforate anus, small nails, hypopituitarism, growth hormone deficiency, and genital hypoplasia. It is typically diagnosed in infancy and early childhood, presenting with seizures and/or precocious puberty due to the hypothalamic hamartoma, and with limb anomalies due to central polydactyly. Our patient had presented with polysyndactyly at birth. However, as this is not uncommon in infants and is usually as part of the sporadic, isolated form of polydactyly, no further work up was done. He then presented at age 16 years with a headache and subjective visual changes, with brain imaging revealing a hypothalamic hamartoma. He did not have a history of seizures or central precocious puberty. Genotyping revealed a pathogenic variant affecting the GLI3 gene. We encourage all clinicians to consider PHS or an associated syndrome with a clinical finding of polydactyly. Further, as the natural history continues to reveal itself, this patient’s presentation provides important new data to the broad phenotypic spectrum of PHS.
... To date, no unifying etiology for VACTERL/VATER association has been established, and there is strong evidence for causal heterogeneity [8,9,10]. The genetic etiology of VACTERL has not been elucidated and it is thought to be multifactorial, although some cases may be due to teratogenic exposure, such as maternal diabetes [11]. Some of the malformations make their appearance early in the embryological period; 23-30 days post conception, while others occur later in embryogenesis. ...
... Nonetheless, even with optimal surgical management of cardiac defects, tracheaesophageal fistula, and limb abnormalities patients can face considerable medical challenges throughout life. Finally, despite significant morbidity associated with the component congenital malformations, it is also important to note that these patients do not typically display neurocognitive impairment [11,39]. The prognosis for growth and development in newborns who survive infancy is good. ...
... The rest of the physical examination was normal with no dysmorphic features. 12 He was intubated and was easily managed with low ventilatory settings. Venous blood gas, chest X-rays (CXRs), and 2D echocardiography were normal. ...
... This was based on dichotomization of the number of dysmorphisms ascertained at examination (0 vs. ≥ 1). ECA status and dysmorphology were distinguished based on guidelines for defining minor versus major anomalies in the literature and using the Elements of Morphology to distinguish dysmorphisms/minor anomalies (Jones and Adam 2015;Adam and Hudgins 2003). Otherwise, we also varied the thresholds of the number of dysmorphisms for defining dysmorphology status at ≥ 1 to ≥ 5 dysmorphisms and investigated associations with genetic diagnoses identified. ...
Background
Dysmorphology evaluation is important for congenital heart disease (CHD) assessment, but there are no prior investigations quantifying the screening performance compared to standardized genetics evaluations. We investigated this through systematic dysmorphology assessment in CHD patients with standardized genetic testing in primarily pediatric patients with CHD.
Methods
Dysmorphology evaluations preceding genetic testing results allowed us to test for associations between dysmorphic status and genetic diagnoses while adjusting for extracardiac anomalies (ECAs). We use a test‐negative case–control design on a pediatric inpatient CHD cohort for our study.
Results
Of 568 patients, nearly 96% of patients completed genetic testing, primarily chromosome microarray (CMA) ± exome sequencing‐based genetic testing (493/568, 86.8%). Overall, 115 patients (20.2%) were found to have genetic diagnoses, and dysmorphic patients had doubled risk of genetic diagnoses, after ECA adjustment (OR = 2.10, p = 0.0030). We found that 7.9% (14/178) of ECA−/nondysmorphic patients had genetic diagnoses, which increased to 13.5% (26/192) in the ECA−/dysmorphic patients. Nearly 43% of ECA+/dysmorphic patients had genetic diagnoses (63/147). The positive predictive value of dysmorphic status was only 26.3%, and the negative predictive value of nondysmorphic status was 88.7%.
Conclusions
Dysmorphology‐based prediction of genetic disorders is limited because of diagnoses found in apparently isolated CHD. Our findings represent one of the only assessments of phenotype‐based screening for genetic disorders in CHD and should inform clinical genetics evaluation practices for pediatric CHD.
... Independently of age, chronic airway diseases such as asthma, COPD, or cystic fibrosis are associated with recurrent RTIs (rRTIs), with worsening of their conditions [16][17][18][19][20]. Active and passive smoking [21,22], low serum vitamin D levels [22,23], a lack of physical activity [24], sudden changes in temperature at work [25], occupational exposure to various physical, chemical, and other hazards [26,27], obesity, and Type 2 diabetes [22,28,29] are reported as risk factors for RTIs. Moreover, immunocompromised individuals (including those with immunodeficiency, cystic fibrosis, and HIV, as well as the use of corticosteroids, transplantation, and postsplenectomy) [30][31][32][33][34][35][36][37][38][39][40] and those with anatomical anomalies including facial dysmorphic changes [41] or nasal polyposis [42] are also at high risk for RTI. ...
Bacterial Lysates are immunostimulants clinically prescribed for the prevention of respiratory tract infections (RTIs). It has been shown that Bacterial Lysates upregulate the immune system, acting both on innate and adaptive reactions. In fact, there are demonstrations of their efficacy in restoring the integrity and immune function of epithelial barriers, activating ILC3 and dendritic cells with an enhanced Th1 response, and producing serum IgG and serum and salivary IgA specific to the administered bacterial antigens. The activated immune system also protects against other bacteria and viruses due to a trained immunity effect. Most studies show that the number of RTIs and their severity decrease in Bacterial Lysates-pretreated patients, without relevant side effects. The Bacterial Lysates treatment, in addition to reducing the number of RTIs, also prevents the deterioration of the underlying disease (i.e., COPD) induced by repeated infections. Despite these positive data, the most recent meta-analyses evidence the weakness of the studies performed, which are of low quality and have an inadequate number of patients, some of which were non-randomized while others were without a control group or were performed contemporarily in different clinical conditions or with different ages. The high heterogeneity of the studies does not allow us to state Bacterial Lysates’ effectiveness in preventing RTIs with sufficient certainty. To completely define their indications, double-blind, placebo-controlled, multicenter, randomized clinical trials should be performed for each product and for each indication. The study population should be adequate for each indication. For this purpose, an adequate run-in phase will be necessary.
... ECA status was defined dichotomously (absent/present) to include any noncardiac major anomalies, including structural anomalies/malformations as well as medically significant functional anomalies (e.g., seizures, dystonia, growth restriction, immunodeficiency, and hypo/hypercalcemia). ECAs are defined as major anomalies with medical/cosmetic significance and differentiated from minor anomalies (dysmorphisms) using previous guidelines [27,28]. We also classified each ECA occurring in patients as representing specific body systems or organs. ...
Extracardiac anomalies (ECAs) are strong predictors of genetic disorders in infants with congenital heart disease (CHD), but there are no prior studies assessing performance of ECA status as a screen for genetic diagnoses in CHD patients. This retrospective cohort study assessed this in our comprehensive inpatient CHD genetics service focusing on neonates and infants admitted to the intensive care unit (ICU). The performance and diagnostic utility of using ECA status to screen for genetic disorders was assessed using decision curve analysis, a statistical tool to assess clinical utility, determining the threshold of phenotypic screening by ECA versus a Test-All approach. Over 24% of infants had genetic diagnoses identified (n = 244/1013), and ECA-positive status indicated a 4-fold increased risk of having a genetic disorder. However, ECA status had low–moderate screening performance based on predictive summary index, a compositive measure of positive and negative predictive values. For those with genetic diagnoses, nearly one-third (32%, 78/244) were ECA-negative but had cytogenetic and/or monogenic disorders identified by genetic testing. Thus, if the presence of multiple congenital anomalies is the phenotypic driver to initiate genetic testing, 13.4% (78/580) of infants with isolated CHD with identifiable genetic causes will be missed. Given the prevalence of genetic disorders and limited screening performance of ECA status, this analysis supports genetic testing in all CHD infants in intensive care settings rather than screening based on ECA.
... Urođene anomalije predstavljaju bilo koju patoanatomsku karakteristiku prisutnu na rođenju koja je nastala kao posledica morfoloških poremećaja u procesu humane ontogeneze. Genetički uzrokovane kongenitalne anomalije mogu biti hereditarne ili nastale kao posledica de novo oštećenja genetičkog materijala u germinativnim ćelijama jednog od roditelja (1,2). Smatra se da su za pojavu razvojnog kašnjenja i urođenih anomalija kod približno polovine slučajeva odgovorni genetički faktori (3). ...
Introduction: Global developmental delay (GDD) and congenital anomalies represent a heterogeneous group of medical conditions that may have a known genetic etiology. Molecular karyotyping is the gold standard for detecting copy number variations (CNV), and the first-line test in patients with GDD and congenital anomalies, with an average diagnostic yield of 15%. Chromosome 15 (C15) is one of the chromosomes on which CNV occurs most frequently. Aim: To analyze all detected (significant) CNVs on C15 in patients with GKR and/or congenital anomalies, estimate their share in the overall CNV detection rate of different pathogenicity classes, and present several illustrative cases. Material and methods: In the total sample of 350 patients analyzed by molecular karyotyping technique, 92 with detected significant CNV were singled out. All patients with variants on C15 were then analyzed and further classified according to type, size, and clinical significance. Results: In 11 patients, at least one significant CNV was detected on chromosome 15, which is 3.15% of the total sample and 11.96% of a sample of patients with significant CNV of any localization. In 72.7% cases, CNV was described as pathogenic or likely pathogenic and in 27.3% as a variant of unknown significance. In the total detection rate of csCNV from all chromosomes 15.4%, the percentage of variations from C15 was 17.2%. Conclusion: The detection rate of csCNVs on C15 in the diagnostic yield of the molecular karyotypisation of patients with GDD and congenital anomalies is 17.2%, which confirms that they make up a significant portion of the GDD etiology.
... Noncardiac congenital anomalies comprise $10% of NICU admissions and can be categorized as malformations, deformations, and disruptions. 133 Patients with congenital anomalies represent a subgroup with high rate of morbidity and mortality. 51 There is increasing evidence that patients with CDH, occurring in approximately 1 in 3,000 live births, may have a variable underlying phenotype that affects morbidity and mortality; specifically, pulmonary hypoplasia with varying degrees of PH and RV dysfunction or LV hypoplasia leading to pulmonary venous hypertension have both been reported. ...
... Children under the age of 5 years are categorized as individuals with global developmental delay (DD) if they present with slow performance in reaching at least two of the following milestones: gross or fine motor activity, speech or language, cognition or mental activity, and social or personal activities of daily living [1,2]. Individuals with congenital malformations (CM) had a problem in the heart, kidney, brain, muscles, or skeleton since birth, and individuals with intellectual disability (ID) had problems with general mental abilities: (i) intellectual functioning (such as learning, reasoning, problem-solving) and/or (ii) adaptive functioning (such as language, number concept, time calculation, memory, social responsibility, communication, and independent living) [3,4]. The Saudi Population Registry (statistics authority) reported a combined disabilities population of around discuss the characteristic features and clinical significance of the detected CNVs including pathogenic and VUS and compare the diagnostic yields of array CGH with previous reports. ...
Chromosomal imbalance is implicated in developmental delay (DD), congenital malformations (CM), and intellectual disability (ID), and, thus, precise identification of copy number variations (CNVs) is essential. We therefore aimed to investigate the genetic heterogeneity in Saudi children with DD/CM/ID. High-resolution array comparative genomic hybridization (array CGH) was used to detect disease-associated CNVs in 63 patients. Quantitative PCR was done to confirm the detected CNVs. Giemsa banding-based karyotyping was also performed. Array CGH identified chromosomal abnormalities in 24 patients; distinct pathogenic and/or variants of uncertain significance CNVs were found in 19 patients, and aneuploidy was found in 5 patients including 47,XXY (n = 2), 45,X (n = 2) and a patient with trisomy 18 who carried a balanced Robertsonian translocation. CNVs including 9p24p13, 16p13p11, 18p11 had gains/duplications and CNVs, including 3p23p14, 10q26, 11p15, 11q24q25, 13q21.1q32.1, 16p13.3p11.2, and 20q11.1q13.2, had losses/deletions only, while CNVs including 8q24, 11q12, 15q25q26, 16q21q23, and 22q11q13 were found with both gains or losses in different individuals. In contrast, standard karyotyping detected chromosomal abnormalities in ten patients. The diagnosis rate of array CGH (28%, 18/63 patients) was around two-fold higher than that of conventional karyotyping (15.87%, 10/63 patients). We herein report, for the first time, the extremely rare pathogenic CNVs in Saudi children with DD/CM/ID. The reported prevalence of CNVs in Saudi Arabia adds value to clinical cytogenetics.
... As more symptoms and comorbidities of ARTHS are discovered each time a new case is reported, it will be important to verify the genetic background of each case and to rule out the existence of other mild causal variants. The salient features of this case included dysmorphic facial appearance, cleft palate, and congenital heart disease, which are major features that strongly suggest multiple congenital abnormalities [23][24][25][26]. As WES successfully identifies de novo, rare, and truncating genomic variants of several genes in undiagnosed cases with neurodevelopmental disorders or multiple congenital anomalies [21,24,27,28]. ...
Background
Arboleda-Tham syndrome (ARTHS), caused by a pathogenic variant of KAT6A , is an autosomal dominant inherited genetic disorder characterized by various degrees of developmental delay, dysmorphic facial appearance, cardiac anomalies, and gastrointestinal problems.
Case presentation
A baby presented multiple facial deformities including a high arched and cleft palate, with philtral ridge and vermilion indentation, a prominent nasal bridge, a thin upper lip, low-set ears, an epicanthal fold, and cardiac malformations. Whole exome sequencing (WES) revealed a heterozygous nonsense mutation in exon 8 of the KAT6A gene (c.1312C>T, p.[Arg438*]) at 2 months of age. After a diagnosis of ARTHS, an expressive language delay was observed during serial assessments of developmental milestones.
Conclusions
In this study, we describe a case with a novel KAT6A variant first identified in Korea. This case broadens the scope of clinical features of ARTHS and emphasizes that WES is necessary for early diagnosis in patients with dysmorphic facial appearances, developmental delay, and other congenital abnormalities.
... For this study, ECAs were defined as (1) presence of any noncardiac organ malformation(s) and/or major anomalies and/or (2) any constellation of anatomical dysmorphisms not considered normal population variation and deemed minor anomalies. These were determined by medical geneticists who followed guidelines for defining minor vs. major anomalies in the literature [21,22]. Other clinically significant medical issues indicative of a possible syndrome such as hypo-or hypercalcemia, immunodeficiency, or seizures were noted. ...
The use of clinical genetics evaluations and testing for infants with congenital heart defects (CHDs) is subject to practice variation. This single-institution cross-sectional study of all inpatient infants with severe CHDs evaluated 440 patients using a cardiovascular genetics service (2014–2019). In total, 376 (85.5%) had chromosome microarray (CMA), of which 55 (14.6%) were diagnostic in syndromic (N = 35) or isolated (N = 20) presentations. Genetic diagnoses were made in all CHD classes. Diagnostic yield was higher in syndromic appearing infants, but geneticists’ dysmorphology exams lacked complete sensitivity and 6.5% of isolated CHD cases had diagnostic CMA. Interestingly, diagnostic results (15.8%) in left ventricular outflow tract obstruction (LVOTO) defects occurred most often in patients with isolated CHD. Geneticists’ evaluations were particularly important for second-tier molecular testing (10.5% test-specific yield), bringing the overall genetic testing yield to 17%. We assess these results in the context of previous studies. Cumulative evidence provides a rationale for comprehensive, standardized genetic evaluation in infants with severe CHDs regardless of lesion or extracardiac anomalies because genetic diagnoses that impact care are easily missed. These findings support routine CMA testing in infants with severe CHDs and underscore the importance of copy-number analysis with newer testing strategies such as exome and genome sequencing.
... Minor anomalies are subtle differences that are in and of themselves cosmetically or medically insignificant, and are not associated with functional impairment. However, a pattern of three or more specific minor anomalies is a potential "red flag" for the presence of an associated major malformation, which can be occultsuch as a defect in brain development [16,17]. Four of the nine children who received a dysmorphology exam in this case series were found to have three or more minor malformations, but no consistent pattern was identified, and only one of these children was also found to have a major birth defect (multiple hemangiomas). ...
Objective
Rituximab is a CD20-directed cytolytic antibody used for non-Hodgkin lymphoma, chronic lymphocytic leukaemia, and rheumatoid arthritis, and off-label for juvenile idiopathic arthritis, multiple sclerosis and lupus. Due to concerns about infant B cell depletion, the manufacturer recommends avoiding rituximab throughout pregnancy and for 12 months prior to conception. This study aims to add to the limited data on pregnancy outcomes in women with exposure to rituximab.
Methods
Data were obtained from MotherToBaby Pregnancy Studies. Participants were prospectively enrolled into this observational study between 2007 and 2019. Pregnancy exposure and outcome data were collected from medical records, telephone interviews, and dysmorphology examinations. Outcomes examined include spontaneous abortion, stillbirth, premature delivery, pregnancy complications, major and minor anomalies, small for gestational age, neonatal complications, and serious infections.
Results
We classified 19 women with exposure to rituximab into three groups. Group A included three women who received rituximab during pregnancy. Group B included three women who received their last infusion before conception, but had assumed pregnancy exposure due to the drug’s long half-life. Group C included 13 women who used rituximab in the two years prior to pregnancy, with the last infusion given no sooner than five half-lives prior to conception. Three children had a major structural defect. Preterm delivery occurred in two pregnancies, and two infants were small for gestational age on birth weight. No cases of B cell depletion were reported.
Conclusion
No pattern of major structural anomalies or other adverse outcomes were reported in this case series.
... Namely, the autism group was significantly enriched for the presence of CFD (61% vs. 37-40%) (Fig. 1A), suggesting many rare autism syndromes may be dysplastic in nature (χ 2 = 5.42-6.38, p = 0.03) [13][14][15]. Meanwhile, the epilepsy group was similarly enriched for NLF (68% vs. 31-39%), indicating some form of cell stress involvement in these IDs (χ 2 = 11.18-19.63, ...
Background
Linking genotype to phenotype is a major aim of genetics research, yet many complex conditions continue to hide their underlying biochemical mechanisms. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.
Methods
Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical symptoms of complex versus simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered using via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment modules within the full ID network.
Results
Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to module.
Conclusions
These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.
... Most anomalies are found in the head/neck and cardiovascular systems but they can also involve the skeletal, genitourinary, and gastrointestinal systems. In particular, ACF has been associated with the 22q11 deletion syndrome (4,5). ...
BACKGROUND
Genetic disorders are prevalent in patients with congenital heart disease (CHD), but genetic evaluations are underutilized and nonstandardized. We sought to quantify a dysmorphology score and develop phenotype-based prediction models for genetic diagnoses in CHD.
METHODS
We used a test-negative case-control study of inpatient infants (<1 year) with CHD undergoing standardized genetic evaluations. We quantified a novel dysmorphology score and combined it with other clinical variables used in multivariable logistic regression models to predict genetic diagnoses identified by genetic testing.
RESULTS
Of 1008 patients, 24.1% (243/1008) had genetic diagnoses identified. About half of the cohort were either nondysmorphic or mildly dysmorphic with dysmorphology scores ≤2. There were higher dysmorphology scores according to CHD class ( P =0.0007), extracardiac anomaly-positive status ( P <0.0001), female sex ( P =0.05), and genetic diagnosis identified ( P <0.0001). Multivariable logistic regression models quantified this effect further: each +1 increase in the dysmorphology score was associated with a 17% to 20% increased risk of genetic diagnoses (odds ratios, 1.17–1.20, P <0.0001). Extracardiac anomaly-positive status remained a stronger predictor of genetic diagnoses (odds ratios, 2.81–3.39). Nonetheless, about 10% of the cohort were minimally dysmorphic (dysmorphology scores ≤2), had isolated CHD, and were found to have genetic diagnoses, indicating that dysmorphology-based screening can be used to risk-stratify but not exclude genetic diagnoses.
CONCLUSIONS
The dysmorphology score is a novel screen for patients with CHD at high risk of having genetic diagnoses identified by genetic testing, including disorders not easily recognized by clinicians. We used these results to develop predicted probability plots for genetic diagnoses in patients with CHD.
Dysmorphisms, or physical abnormalities in appearance, can vary in frequency and severity among individuals with inherited metabolic disorders (IMD). The prevalence of dysmorphisms in these disorders can range from rare occurrences to more common features, depending on the specific disorder and its genetic characteristics. It is important to note that not all individuals with IMDs will exhibit dysmorphic features, and the presence of such features may vary widely among different types of metabolic disorders. The data presented in this study, which includes a detailed list of 374 IMDs with dysmorphic characteristics categorized by affected organs (such as head and face, nose, mouth and tongue, eye, ear, hands and feet, and others), as well as an overview of important clinical features and recommended diagnostic strategies, could be valuable for professionals in the field of healthcare. This information may be particularly useful for healthcare providers who treat individuals with metabolic disorders or those who care for individuals exhibiting dysmorphic features that could indicate the presence of an inherited metabolic disorder.
Congenital anomalies contribute significantly to perinatal, neonatal, and infant morbidity and mortality. The causes of these anomalies vary, ranging from teratogen exposure to genetic disorders. A high suspicion for a genetic condition is especially important because a genetic diagnosis carries a risk of recurrence in future pregnancies. Various methods are available for genetic testing, and each plays a role in establishing a genetic diagnosis. This review summarizes a practical, systematic approach to a fetus or neonate with congenital anomalies.
To investigate the differences of the nasal soft and hard tissue asymmetry in postoperative patients with unilateral cleft lip and palate (UCLP) between adolescence and adulthood, and to explore the correlation of nasal soft and hard tissue asymmetry.
CT data from 47 repaired UCLP patients were included and divided into two groups:1. adolescent group: 23 patients (15 males, 8 females; age: 10–12 years old). 2. adult group: 24 patients (16 males, 8 females; age:18–32 years old). The three-dimensional asymmetry in nasal soft and hard tissues was analyzed. Additionally, the correlation between nasal soft and hard tissue asymmetry was also analyzed.
Both the adolescent group and adult group showed asymmetries in nasal soft and hard tissues. Compared to the adolescent group, the adult group had a significantly increased horizontal asymmetry of nasal soft tissues Sbal (P < 0.05). Furthermore, the sagittal asymmetry of soft tissue Glat (P < 0.05), Sbal (P < 0.001), Sni (P < 0.001) and hard tissue LPA (P < 0.05) also increased significantly. In the adult group, there were more landmarks with a correlation between the asymmetry of nasal hard tissue and soft tissue compared to the adolescent group. There were moderate to strong correlations between nasal hard and soft tissue symmetries in the horizontal and sagittal directions (0.444 < r < 764), but no correlation in the vertical direction in the adult group (P > 0.05).
The asymmetry of nasal soft and hard tissues in patients with repaired UCLP becomes more apparent in the horizontal and sagittal dimensions from adolescence to adulthood. The correlation between the asymmetry of nasal hard tissue and soft tissue becomes stronger in the horizontal and sagittal dimensions. These factors should be taken into account when performing treatment for repaired UCLP patients in adolescence and adulthood.
Approaching discussions and introducing the idea of dysmorphology to parents and families can be perceived as difficult and even daunting by health professionals resulting in uneasiness in how best to initiate important dialogues sensitively and accessibly.
Here, we offer a structured approach to the assessment of, and subsequent initial discussion around, dysmorphism and potential syndromic features in babies and children.
EEC syndrome is an autosomal dominant genetic disease with incomplete penetrance characterized by ectrodactyly, ectodermal dysplasia, and cleft lip/palate; these manifestations can differently occur in the affected subjects and can also be associated with other anomalies, such as in the urogenital tract. We reported the case of a newborn with prenatal diagnosis of EEC type 3 associated with severe cardiac abnormalities (Tetralogy of Fallot), high esophageal atresia with fistula and penoscrotal hypospadias.
The diagnostic approach to pediatric hypotonia and weakness should be logical, systematic, and based on localization of symptoms along the neural axis. Distinguishing features on history and physical examination can help differentiate the underlying cause. A practical algorithm is provided for the hypotonic infant and the weak child. Common conditions causing hypotonia and weakness are featured, in addition to uncommon conditions and mimics.
Intellectual disability is the impairment of cognitive, linguistic, motor and social skills that contribute to the global level of intelligence that occurs in the pediatric age, and now comprises also the term “mental retardation” used in the past to describe the same impairments under 5 years of age. Intellectual disability involves 3% of the general population, also due to a genetic cause including chromosome aberrations to account for the 3–28% of intellectual disability. Between people with intellectual disabilities, the cause of the disorders was identified as a single gene disorder up to 12%, as multifactorial disorders up to 4%, and as genetic disorders up to 8.5%. Children affected by a malformation syndrome associated with mental retardation or intellectual disability represent a care challenge for the pediatrician. The presence of a multidisciplinary team is essential to manage the patient, trying to control the complications of the syndrome for promoting the correct psychophysical development. This encourages continuous follow-up of these children since the pediatrician is essential both in the clinical management of the syndrome and in facilitating the social integration of these children.
Prenatal genetic screening, including evaluation for inherited genetic disorders, aneuploidy risk assessment, and sonographic assessment, combined with a thorough newborn examination and standard newborn screening, including blood, hearing, and congenital heart disease screening, can reveal conditions requiring further evaluation after delivery. Abnormal prenatal or newborn screening results should prompt additional diagnostic testing guided by maternal fetal medicine, perinatal genetics, or pediatric specialists.
Congenital heart disease (CHD), the most common major congenital anomaly, is associated with a genetic syndrome (chromosomal anomalies, genomic disorders, or monogenic disease) in 30% of patients. The aim of this systematic review is to evaluate if, in the neonatal setting, clinical clues that orient the diagnostic path can be identified. For this purpose, we revised the most frequent dysmorphic features described in newborns with CHD, comparing those associated with monogenic syndromes (MSG) with the ones reported in newborns with genomic disorders. For this systematic review according to PRISMA statement, we used PubMed, Medline, Google Scholar, Scopus database, and search terms related to CHD and syndrome. We found a wide range of dysmorphisms (ocular region, ears, mouth, and/or palate and phalangeal anomalies) detected in more than half of MSGs were found to be associated with CHDs, but those anomalies are also described in genomic rearrangements syndromes with equal prevalence. These findings confirm that etiological diagnosis in newborns is challenging, and only the prompt and expert recognition of features suggestive of genetic conditions can improve the selection of appropriate, cost-effective diagnostic tests. However, in general practice, it is crucial to recognize clues that can suggest the presence of a genetic syndrome, and neonatologists often have the unique opportunity to be the first to identify abnormalities in the neonate.
'Snow White and the Seven Dwarfs', a fairytale that is widely known across the Western world, was originally written by the Brothers Grimm, and published in 1812. Though each dwarf was first given an individual name in the 1912 Broadway play by the same title, in Walt Disney's 1937 film 'Snow White and the Seven Dwarfs', they were renamed, and their names have become household words. As it is well known, myths, fables, and fairytales, though appearing to be merely children’s tales about made-up and magical beings and places, have, more often than not, originated from real facts. Therefore, the presence in the story of seven brothers with short stature is, from an endocrinological point of view, highly intriguing, in fact, thrilling. The diversity of the phenotypes among the seven dwarfs is also stimulating , although puzzling. We undertook a differential diagnosis of their common underlying disorder based on the original Disney production drawings and the unique characteristics of these little gentlemen, while we additionally evaluated several causes of short stature and, focusing on endocrine disorders that could lead to these clinical features among siblings, and we have, we believe, been able to reveal the underlying disease depicted in this archetypal tale.
BMR 29, 2018, several Review articles....
Background: Linking genotype to phenotype is a major aim of genetics research, yet the underlying biochemical mechanisms of many complex conditions continue to remain elusive. Recent research provides evidence that relevant gene-phenotype associations are discoverable in the study of intellectual disability (ID). Here we expand on that work, identifying distinctive gene interaction modules with unique enrichment patterns reflective of associated clinical features in ID.
Methods: Two hundred twelve forms of monogenic ID were curated according to comorbidities with autism and epilepsy. These groups were further subdivided according to secondary clinical manifestations of complex vs. simple facial dysmorphia and neurodegenerative-like features due to their clinical prominence, modest symptom overlap, and probable etiological divergence. An aggregate gene interaction ID network for these phenotype subgroups was discovered via a public database of known gene interactions: protein-protein, genetic, and mRNA coexpression. Additional annotation resources (Gene Ontology, Human Phenotype Ontology, TRANSFAC/JASPAR, and KEGG/WikiPathways) were utilized to assess functional and phenotypic enrichment patterns within subgroups.
Results: Phenotypic analysis revealed high rates of complex facial dysmorphia in ID with comorbid autism. In contrast, neurodegenerative-like features were overrepresented in ID with epilepsy. Network analysis subsequently showed that gene groups divided according to clinical features of interest resulted in distinctive interaction clusters, with unique functional enrichments according to gene set.
Conclusions: These data suggest that specific comorbid and secondary clinical features in ID are predictive of underlying genotype. In summary, ID form unique clusters, which are comprised of individual conditions with remarkable genotypic and phenotypic overlap.
The evaluation of the neonate with congenital anomalies has always been a vital and challenging task. In recent years, many advances and challenges have complicated the process, including noninvasive prenatal screening, Zika virus, assisted reproductive technology, and rapid exome sequencing. This review will provide a context for the general evaluation of a neonate with congenital anomalies, including adaptation of the most precise terminology, definition of major and minor anomalies, and the determination of whether the anomalies are the result of a sequence, deformation, disruption, or malformation. Practical tools, including a concise family history, nutritional implication, pregnancy history, and the effects of assisted reproductive technologies are also presented. With the advent of Zika virus-associated congenital anomalies, emphasis has also been placed on travel and infection exposures. A particular challenge has been the incorporation of both pre- and postnatal genetic screening and testing into a diagnostic framework. The most common tests will be reviewed, including the practical applications of both a positive and negative result in varying contexts. It has become clear that noninvasive prenatal screening and rapid exome sequencing are having an increasing impact on the evaluation of children with congenital anomalies, and their application and evaluation of their results will be reviewed in detail. The overarching goal of this review is to provide neonatal clinicians the tools to assess, contextualize, and discuss congenital anomalies in neonates to improve communication and the diagnostic process.
VATER association was first described in the early 1970s as the non-random co-occurrence of congenital malformations including: Vertebral defects, Anal atresia, Tracheo-Esophageal fistula (TEF) with or without esophageal atresia (EA), and Radial and Renal dysplasia.1 Following initial reports, it was suggested that “V” should include Vascular anomalies (including single umbilical artery). Cardiac malformations (“C”) and Limb (“L”) anomalies other than radial anomalies were also added, such that the term “VACTERL” became the most common descriptor, despite variable evidence for the inclusion of features such as cardiac or renal anomalies.2–6 The presence of VACTERL association, which usually requires at least 3 component features and the absence of evidence for an overlapping condition, is estimated to occur in approximately 1/10,000–1/40,000 live births.7, 8
Just as there are challenges in defining the condition, there is no standard approach for the initial diagnostic work-up of a neonate with identified or suspected VACTERL association. This can be problematic: missed manifestations may obfuscate the etiological work-up8; delay medical interventions, potentially contributing to higher morbidity and mortality9; result in less informed and effective counseling.
To attempt to address these issues, we assembled a multi-disciplinary group of clinicians and researchers whose expertise focuses on VACTERL association and/or its individual component features. Following review of the literature, and based upon our collective experience, we offer suggestions for the evaluation of individuals identified or suspected to have VACTERL association.
Literature Search
We conducted a PubMed-based literature search for case reports and collections of patients identified or suspected of having VACTERL association and/or associated component features. Search terms included the following: Anal atresia; Anorectal malformations; Cardiac anomalies; Cardiac malformations; Cardiovascular anomalies; Cardiovascular malformations; Esophageal atresia; Genitourinary anomalies; Genitourinary malformations; Imperforate anus; Limb anomalies; Limb malformations; Radial anomalies; Radial dysplasia; Renal anomalies; Renal malformations; TEF; Tracheo-esophageal fistula; VACTERL; VATER; Vertebral anomalies; Vertebral malformations. Only articles describing human patients were considered, and articles were excluded if they did not pertain to component features specifically seen in VACTERL association.
Autosomal recessive Adams-Oliver syndrome was diagnosed in three remotely related Bedouin consanguineous families. Genome-wide linkage analysis ruled out association with known Adams-Oliver syndrome genes, identifying a single-homozygosity ∼1.8-Mb novel locus common to affected individuals (LOD score 3.37). Whole-exome sequencing followed by Sanger sequencing identified only a single mutation within this locus, shared by all affected individuals and found in patients from five additional apparently unrelated Bedouin families: a 1-bp deletion mutation in a predicted alternative splice variant of EOGT, leading to a putative truncated protein. RT-PCR demonstrated that the EOGT-predicted alternative splice variant is ubiquitously expressed. EOGT encodes EGF-domain-specific O-linked N-acetylglucosamine transferase, responsible for extracellular O-GlcNAcylation of epidermal growth factor-like domain-containing proteins, and is essential for epithelial cell-matrix interactions. F-actin staining in diseased fibroblasts showed apparently intact cell cytoskeleton and morphology, suggesting the EOGT mutation acts not through perturbation of cytoskeleton but through other mechanisms yet to be elucidated.European Journal of Human Genetics advance online publication, 17 July 2013; doi:10.1038/ejhg.2013.159.
CHARGE syndrome is a highly variable, multiple congenital anomaly syndrome, of which the complete phenotypic spectrum was only revealed after identification of the causative gene in 2004. CHARGE is an acronym for ocular coloboma, congenital heart defects, choanal atresia, retardation of growth and development, genital hypoplasia, and ear anomalies associated with deafness. This typical combination of clinical features is caused by autosomal dominant mutations in the CHD7 gene.
To explore the emerging phenotypic spectrum of CHD7 mutations, with a special focus on the mild end of the spectrum.
We evaluated the clinical characteristics in our own cohort of 280 CHD7 positive patients and in previously reported patients with CHD7 mutations and compared these with previously reported patients with CHARGE syndrome but an unknown CHD7 status. We then further explored the mild end of the phenotypic spectrum of CHD7 mutations.
We discuss that CHARGE syndrome is primarily a clinical diagnosis. In addition, we propose guidelines for CHD7 analysis and indicate when evaluation of the semicircular canals is helpful in the diagnostic process. Finally, we give updated recommendations for clinical surveillance of patients with a CHD7 mutation, based on our exploration of the phenotypic spectrum and on our experience in a multidisciplinary outpatient clinic for CHARGE syndrome.
CHARGE syndrome is an extremely variable clinical syndrome. CHD7 analysis can be helpful in the diagnostic process, but the phenotype cannot be predicted from the genotype.
Clefts of the lip and/or palate (CLP) are common birth defects of complex aetiology. CLP can occur in isolation or as part of a broad range of chromosomal, Mendelian or teratogenic syndromes. Although there has been marked progress in identifying genetic and environmental triggers for syndromic CLP, the aetiology of the more common non-syndromic (isolated) forms remains poorly characterized. Recently, using a combination of epidemiology, careful phenotyping, genome-wide association studies and analysis of animal models, several distinct genetic and environmental risk factors have been identified and confirmed for non-syndromic CLP. These findings have advanced our understanding of developmental biology and created new opportunities for clinical translational research.
Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages.
Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.
Although many pediatricians pursue renal ultrasonography when patients are noted to have external ear malformations, there is much confusion over which specific ear malformations do and do not require imaging. The objective of this study was to delineate characteristics of a child with external ear malformations that suggest a greater risk of renal anomalies. We highlight several multiple congenital anomaly (MCA) syndromes that should be considered in a patient who has both ear and renal anomalies.
Charts of patients who had ear anomalies and were seen for clinical genetics evaluations between 1981 and 2000 at Cedars-Sinai Medical Center in Los Angeles and Dartmouth-Hitchcock Medical Center in New Hampshire were reviewed retrospectively. Only patients who underwent renal ultrasound were included in the chart review. The literature was reviewed for the epidemiology of renal anomalies in the general population and in MCA syndromes with external ear anomalies. We defined a child as having an external ear anomaly when he or she had any of the following: preauricular pits and tags; microtia; anotia; or cup, lop, and other forms of dysplastic ears. A child was defined as having a renal anomaly if an ultrasound revealed any of the following: unilateral or bilateral renal agenesis; hypoplasia; crossed ectopia; horseshoe, pelvic, cystic kidney; hydronephrosis; duplicated ureters; megaureter; or vesicoureteric reflux.
Because clinical genetics assessments were made by the same clinician at both sites (J.M.G.), data were combined. A total of 42 patients with ear anomalies received renal ultrasound; 12 (29%) of them displayed renal anomalies. Of the 12 patients with renal anomalies, 11 (92%) also received a diagnosis of MCA syndrome. Eleven of 33 patients (33%) with MCA syndromes had renal anomalies, whereas 1 of 9 patients (11%) with isolated ear anomalies had renal anomalies. Specific disorders seen were CHARGE association, Townes-Brocks syndrome, branchio-oto-renal syndrome, Nager syndrome, and diabetic embryopathy.
We conclude that ear malformations are associated with an increased frequency of clinically significant structural renal anomalies compared with the general population. This is due to the observation that auricular malformations often are associated with specific MCA syndromes that have high incidences of renal anomalies. These include CHARGE association, Townes-Brocks syndrome, branchio-oto-renal syndrome, Nager syndrome, Miller syndrome, and diabetic embryopathy. Patients with auricular anomalies should be assessed carefully for accompanying dysmorphic features, including facial asymmetry; colobomas of the lid, iris, and retina; choanal atresia; jaw hypoplasia; branchial cysts or sinuses; cardiac murmurs; distal limb anomalies; and imperforate or anteriorly placed anus. If any of these features are present, then a renal ultrasound is useful not only in discovering renal anomalies but also in the diagnosis and management of MCA syndromes themselves. A renal ultrasound should be performed in patients with isolated preauricular pits, cup ears, or any other ear anomaly accompanied by 1 or more of the following: other malformations or dysmorphic features, a family history of deafness, auricular and/or renal malformations, or a maternal history of gestational diabetes. In the absence of these findings, renal ultrasonography is not indicated.
Fetal growth restriction, also known as intrauterine growth restriction, is a common complication of pregnancy that has been associated with a variety of adverse perinatal outcomes. There is a lack of consensus regarding terminology, etiology, and diagnostic criteria for fetal growth restriction, with uncertainty surrounding the optimal management and timing of delivery for the growth-restricted fetus. An additional challenge is the difficulty in differentiating between the fetus that is constitutionally small and fulfilling its growth potential and the small fetus that is not fulfilling its growth potential because of an underlying pathologic condition. The purpose of this document is to review the topic of fetal growth restriction with a focus on terminology, etiology, diagnostic and surveillance tools, and guidance for management and timing of delivery.
Polydactyly of the hand is a difficult problem and poses a unique challenge for the hand surgeon. The embryology of limb development is complex, leading to a host of different phenotypes of polydactyly. Polydactyly can occur in any digit and is described as preaxial, postaxial, and central, based on location. Classification systems exist for each of these locations, which guide treatment options. Surgical treatment needs to address the aesthetic and functional aspect of hand reconstruction. Careful consideration and planning of surgical treatment individualized to each patient is required to obtain the best possible outcome.
IntroductionTrisomy 18Trisomy 13Manifestations and ManagementResources
Asymmetric crying facies (ACF) refers to a neonate or infant whose face appears symmetric at rest and asymmetric during crying as the mouth is pulled downward on one side while not moving on the other side. It is a minor anomaly found in 1 per 160 live births and is caused by hypoplasia or agenesis of the depressor anguli oris muscle (DAOM) or compression of one of the branches of the facial nerve. Associated major and minor malformations as well as deformations have been described. The risk of associated major anomalies with ACF is 3.5-fold higher compared with the general population. Such anomalies are most common in the cardiovascular system and cervicofacial region. Certain clinical signs may differentiate ACF from true facial paralysis. Physical findings, electromyography, and ultrasonography studies can help differentiate between the two causes of ACF. An approach to the diagnostic evaluation is suggested, both for initial evaluation and for decisions about subsequent treatment of ACF.
This article reviews clefts involving the lip with or without the palate (CLP±P) and isolated clefts of the palate (CP) from genetic and epidemiologic perspectives. Particular attention is given to management strategies to address issues arising in the neonatal period before the deformity is treated. The multidisciplinary team is especially important in tailoring care to the needs of the child. Regional specialist services are recommended during early childhood for infants who have CLP±P or CP.
Aplasia cutis congenita (ACC) is a rare disorder that is estimated to affect approximately three newborns in every 10,000 live births. It is usually detected at birth and most commonly affects the scalp as a solitary lesion. The type of lesion may be classified into one of nine groups. Membranous types and those with a "hair collar" are at highest risk to be associated with underlying neurodevelopmental abnormalities. In rare cases, associated abnormalities and syndromes may also be seen. Appropriate evaluation can be undertaken depending on clinical signs and symptoms. Treatment is often conservative, but more aggressive treatment may be indicated for some larger scalp lesions. © 2012 by the American Academy of Pediatrics. All rights reserved.
Esophageal Atresia (EA) is a severe developmental defect of the foregut that presents with or without a Tracheo-Esophageal Fistula (TEF). The prevalence of EA/TEF over time and around the world has been relatively stable. EA/TEF is manifested in a broad spectrum of anomalies: in some patients it manifests as an isolated atresia or fistula, but in over half it affects several organ systems. While the associated malformations are often those of the VACTERL spectrum (Vertebral, Anorectal, Cardiac, Tracheo-Esophageal, Renal and Limb), many patients are affected by other malformations, such as microcephaly, micrognathia, pyloric stenosis, duodenal atresia, a single umbilical artery, and anomalies of the genitourinary, respiratory and gastrointestinal systems. Though EA/TEF is a genetically heterogeneous condition, recurrent genes and loci are sometimes affected. Tracheo-Esophageal (TE) defects are in fact a variable feature in several known single gene disorders and in patients with specific recurrent Copy Number Variations and structural chromosomal aberrations.
The increasing prevalence of abdominal wall defects prompted analysis of anomalies associated with gastroschisis and omphalocele in the Texas Birth Defects Registry (TDBR).
Cases of gastroschisis (ICD9 code 756.71), omphalocele (756.70), and/or unspecified anomalies of the abdominal wall (756.79) were obtained from the TDBR after IRB approval and analyzed using Microsoft Access© and Excel© databases.
Analysis began with 2825 cases including 1831 of gastroschisis, 814 of omphalocele, and 180 of unspecified abdominal wall defects plus 9680 associated anomalies that were classified according to system. The overall prevalence of abdominal wall defects among 3,806,299 Texas births from 1999 to 2008 was 7.4 per 10,000 with 4.8 per 10,000 for gastroschisis and 2.1 for omphalocele. After excluding ambiguous cases (8.5% possibly misclassified), anomaly spectra were similar for the two AWD with musculoskeletal (limb contractures or defects), cardiovascular, gastrointestinal, urogenital, and central nervous system defects being most common. Of 1831 cases with gastroschisis, 594 (32%) had associated anomalies compared to 654 (80%) of 814 omphalocele cases.
Gastroschisis as well as omphalocele has significant associated anomalies that are important to appreciate during pre- and postnatal management.
Hypospadias is one of the most common congenital malformations, affecting about 4-6 males per 1,000 male births, and ranging in severity from a urethral meatus that is slightly off-center to a meatus in the perineal area. Over the past three decades its prevalence may have increased due to changes in reporting of mild cases and/or increased survival of low birth weight infants due to improved neonatal care. However, despite the increasing numbers of males with hypospadias, the overall etiology remains unclear and likely multifactorial in nature. The purpose of this review article is to provide a comprehensive overview of the various factors implicated in hypospadias etiology, including genetic and environmental factors. In addition, we list syndromes in which hypospadias is a relatively common association and delineate the areas that require further investigation in an effort to understand this condition.
Background/Purpose
Ulnar polydactylies present with a wide variation in the size and appearance of the affected finger, ranging from small cutaneous appendages to fully formed additional fingers. Since ulnar polydactyly is rarely associated with functional disabilities, psychological and cosmetic reasons are the main rationale for surgical treatment. The aim of this study was to present the appearance, treatment regimen, and outcome of a series of children treated with ulnar polydactylies.
Methods
Data of all pediatric patients treated between 2000 and 2010 were included. For assessing long-term outcome, patients were contacted via mail and asked to complete a questionnaire concerning location and appearance of the scar as well as functional and cosmetic satisfaction (VAS 0–100).
Results
In that period, 32 patients (20 male, 12 female) with 53 ulnar polydactylies were treated. In 20 patients the polydactyly occurred bilaterally (63%), in 10 patients on the left side (31%), and 2 patients presented with right-sided ulnar polydactyly (6%). The vast majority of ulnar polydactylies were floating cutaneous appendages. The mean age of the patients at operation was 8.6 months (range 0 to 10 years). 20 patients (63%) responded to the postal questionnaire. Follow-up time was 4.9 years (range 2.1 to 10 years). The majority of patients reported a flat scar (n = 18, 90%). Mean overall satisfaction with the postoperative result using a VAS 0–100 score was 89.
Conclusion
We were able to report a good postoperative outcome of a series of patients suffering from ulnar polydactylies.
The inherited bone marrow failure syndromes (IBMFS) are a set of clinically related yet heterogeneous disorders in which at least one hematopoietic cell lineage is significantly reduced. Many of the IBMFS have notably increased cancer risks, as well as other physical findings. Highly penetrant germline mutations in key pathways, such as DNA repair, telomere biology, or ribosomal biogenesis, are causative of Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond-Blackfan anemia (DBA), respectively. Next-generation sequencing (NGS) generally refers to high-throughput, large-scale sequencing technologies and is being used more frequently to understand disease etiology. In the IBMFS, NGS has facilitated the discovery of germline mutations that cause thombocytopenia absent radii syndrome (TAR), a subset of DC and DBA, and other uncharacterized, but related, disorders. Panels of large numbers of genes are being used to molecularly characterize patients with IBMFS, such as FA and DBA. NGS is also accelerating the discovery of the genetic etiology of previously unclassified IBMFS. In this review, we will highlight recent studies that have employed NGS to ascertain the genetic etiology of IBMFS, namely, FA, DC, DBA, and TAR, and discuss the translational utility of these findings.
Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM. © 2013 Wiley Periodicals, Inc.
Objective: To determine the role of renal ultrasonography in the evaluation of healthy newborn infants with isolated pre-auricular tags and pits. Study design: During the 4 years of prospective study, 108 of 17,286 infants were born with isolated pre-auricular tags or pits (6.2 per 1000 live births): 92 were assessed for urinary tract abnormalities by performing renal ultrasonography at 1 to 3 months of age. The study group was compared with a control group of 95 consecutive healthy infants without pre-auricular tags or pits born during the same period who underwent renal ultrasonography on the second day of life. Results: The study and control groups were comparable in birth weight, gestational age, and sex ratio. Renal ultrasonography was abnormal only in 2 infants with pre-auricular tags (2.2%); both had mild left pyelectasis. The prevalence did not differ significantly from that in the control group, in which 3 infants had mild pyelectasis (3.1%, P = 1.0) and 1 infant had a renal calculus. The prevalence of renal abnormalities in infants with isolated pre-auricular tags or pits in our study (2.2%) was also comparable to the prevalence in the general population (all abnormalities 0.2%-8.1%; significant abnormalities 0.2%-1.4%). Conclusions: We conclude that renal ultrasonography is not indicated in the routine evaluation of the newborn infant with isolated pre-auricular tags or pits. (J Pediatr 2002;141:388-91)
Noonan syndrome is a genetic multisystem disorder characterised by distinctive facial features, developmental delay, learning difficulties, short stature, congenital heart disease, renal anomalies, lymphatic malformations, and bleeding difficulties. Mutations that cause Noonan syndrome alter genes encoding proteins with roles in the RAS-MAPK pathway, leading to pathway dysregulation. Management guidelines have been developed. Several clinically relevant genotype-phenotype correlations aid risk assessment and patient management. Increased understanding of the pathophysiology of the disease could help development of pharmacogenetic treatments.
The trisomy 18 and trisomy 13 syndromes represent important and common conditions of human aneusomy. Together, their combined prevalence in live-born infants approaches 1 in 4000 births. These syndromes are unique among chromosome disorders as well as the other conditions described in this text since about 90% of children with trisomies 18 and 13 die before their first birthday. Because of this high infant mortality rate, the conditions are sometimes labeled simplistically as “lethal.” However, about 10% of infants do indeed survive. Regardless of the figures for survival, the parents of the child and the practitioners caring for the family seek an approach to management and health supervision as in any other serious medical disorder. Ongoing support and care by professionals are crucial to a family whose child has an uncertain prognosis. This chapter will provide a concise review of the literature of the syndromes and a plan of management for the primary care of children with trisomies 18 and 13.
IntroductionManifestations and ManagementResources
Several reports have suggested that propylthiouracil (PTU) may be safer than methimazole (MMI) for treating thyrotoxicosis during pregnancy because congenital malformations have been associated with the use of MMI during pregnancy.
We investigated whether in utero exposure to antithyroid drugs resulted in a higher rate of major malformations than among the infants born to a control group of pregnant women.
We reviewed the cases of women with Graves' disease who became pregnant. The pregnancy outcomes of 6744 women were known, and there were 5967 live births. MMI alone had been used to treat 1426 of the women, and 1578 women had been treated with PTU alone. The 2065 women who had received no medication for the treatment of Graves' disease during the first trimester served as the control group. The remaining women had been treated with potassium iodide, levothyroxine, or more than one drug during the first trimester. The antithyroid drugs were evaluated for associations with congenital malformations.
The overall rate of major anomalies in the MMI group was 4.1% (50 of 1231), and it was significantly higher than the 2.1% (40 of 1906) in the control group (P = 0.002), but there was no increase in the overall rate of major anomalies in the PTU group in comparison with the control group (1.9%; 21 of 1399; P = 0.709). Seven of the 1231 newborns in the MMI group had aplasia cutis congenita, six had an omphalocele, seven had a symptomatic omphalomesenteric duct anomaly, and one had esophageal atresia. Hyperthyroidism in the first trimester of pregnancy did not increase the rate of congenital malformation.
In utero exposure to MMI during the first trimester of pregnancy increased the rate of congenital malformations, and it significantly increased the rate of aplasia cutis congenita, omphalocele, and a symptomatic omphalomesenteric duct anomaly.
Gestational diabetes mellitus (GDM) from all causes of diabetes is the most common medical complication of pregnancy and is increasing in incidence, particularly as type 2 diabetes continues to increase worldwide. Despite advances in perinatal care, infants of diabetic mothers (IDMs) remain at risk for a multitude of physiologic, metabolic, and congenital complications such as preterm birth, macrosomia, asphyxia, respiratory distress, hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia and hyperviscosity, hypertrophic cardiomyopathy, and congenital anomalies, particularly of the central nervous system. Overt type 1 diabetes around conception produces marked risk of embryopathy (neural tube defects, cardiac defects, caudal regression syndrome), whereas later in gestation, severe and unstable type 1 maternal diabetes carries a higher risk of intrauterine growth restriction, asphyxia, and fetal death. IDMs born to mothers with type 2 diabetes are more commonly obese (macrosomic) with milder conditions of the common problems found in IDMs. IDMs from all causes of GDM also are predisposed to later-life risk of obesity, diabetes, and cardiovascular disease. Care of the IDM neonate needs to focus on ensuring adequate cardiorespiratory adaptation at birth, possible birth injuries, maintenance of normal glucose metabolism, and close observation for polycythemia, hyperbilirubinemia, and feeding intolerance.
This Clinical Report was revised. See https://doi.org/10.1542/peds.2022-057010
These guidelines are designed to assist the pediatrician in caring for the child in whom a diagnosis of Down syndrome has been confirmed by chromosome analysis. Although a pediatrician's initial contact with the child is usually during infancy, occasionally the pregnant woman who has been given a prenatal diagnosis of Down syndrome will be referred for review of the condition and the genetic counseling provided. Therefore, this report offers guidance for this situation as well.
Laboratory evaluation of patients with developmental delay/intellectual disability, congenital anomalies, and dysmorphic features has changed significantly in the last several years with the introduction of microarray technologies. Using these techniques, a patient's genome can be examined for gains or losses of genetic material too small to be detected by standard G-banded chromosome studies. This increased resolution of microarray technology over conventional cytogenetic analysis allows for identification of chromosomal imbalances with greater precision, accuracy, and technical sensitivity. A variety of array-based platforms are now available for use in clinical practice, and utilization strategies are evolving. Thus, a review of the utility and limitations of these techniques and recommendations regarding present and future application in the clinical setting are presented in this study.
Omphalocele is a congenital malformation that involves protrusion of abdominal contents into the umbilicus. Though omphalocele may present as a manifestation of several chromosomal and Mendelian syndromes, the etiology for nonsyndromic omphalocele is unknown. The present study sought to estimate the birth prevalence of nonsyndromic omphalocele in offspring of women residing in Texas from 1999 to 2004, and to describe prevalence as a function of parental and infant demographic characteristics. Data on 325 cases with nonsyndromic omphalocele and 2,208,758 live births delivered during 1999-2004 were obtained from the Texas Birth Defects Registry. These data were used to estimate omphalocele birth prevalence and obtain both crude and adjusted prevalence ratios for the association of nonsyndromic omphalocele with parental and infant demographic characteristics. Nonsyndromic omphaloceles were significantly more common among the offspring of women without previous live births (adjusted prevalence ratio: 1.80, 95% CI: 1.41-2.30), compared to the offspring of women with previous live births. The prevalence of nonsyndromic omphalocele was also increased among women aged 25-29 (adjusted prevalence ratio: 1.68, 95% CI: 1.12-2.50) and women aged 40 and older (adjusted prevalence ratio: 4.83, 95% CI: 2.63-8.86) compared to the offspring of women age <20, and in infants of multiple gestation pregnancies compared to singleton infants (adjusted prevalence ratio: 2.03, 95% CI: 1.22-3.37). In addition, among Hispanic women, the prevalence of nonsyndromic omphalocele was higher in the offspring of those born in the U.S. as compared to those born elsewhere (adjusted prevalence ratio: 1.50, 95% CI: 1.12-2.00). These findings augment the existing omphalocele literature.
Primary prevention efforts for both gastroschisis and omphalocele are limited by the lack of known risk factors. Our objective was to investigate associations between potential maternal risk factors and gastroschisis and omphalocele within a large population-based sample of participants enrolled in the National Birth Defects Prevention Study (NBDPS).
Demographic, health-related, and environmental exposure data from the NBDPS were collected from women with expected delivery dates between October 1997 and December 2003. Data were collected on 485 cases of gastroschisis, 168 cases of omphalocele, and 4967 controls.
Women who had offspring with gastroschisis were younger (adjusted odds ratio [AOR], 0.84; 95% confidence interval [CI], 0.81-0.86) and less likely to be black (AOR, 0.54; 95% CI, 0.34-0.85) than controls. They also were more likely to have smoked (AOR, 1.51; 95% CI, 1.12-2.03), taken ibuprofen (AOR, 1.61; 95% CI, 1.23-2.10), and consumed alcohol (AOR, 1.38; 95% CI, 1.06-1.79) than controls. Women who had offspring with omphaloceles were more likely to have consumed alcohol (AOR, 1.53; 95% CI, 1.04-2.25) and be heavy smokers (AOR, 4.26; 95% CI, 1.58-11.52) than controls.
Our results suggest a moderately increased risk of gastroschisis among women who used tobacco, alcohol, and ibuprofen during early pregnancy. A modestly elevated risk was observed for omphaloceles among women who used alcohol during the first trimester and among women who were heavy smokers.
Diabetes is the most common endocrinologic complication during pregnancy, and poor control can lead to a variety of congenital anomalies in the fetus. However, it is often difficult to differentiate between diabetes-related anomalies and an underlying genetic syndrome. In the 1990s it was proposed that preaxial hallucal polydactyly, particularly when proximally placed, was a distinguishing feature of diabetic embryopathy.
We summarize the clinical findings in 18 patients (five previously reported in abstract form) with diabetic embryopathy and preaxial hallucal polydactyly to determine which features are most suggestive of diabetic embryopathy.
All 18 patients had preaxial hallucal polydactyly (seven bilateral, 11 unilateral), of which 15 patients had proximal implantation of the extra hallux. Further skeletal findings included the following: segmentation anomalies of the spine, equinovarus deformity of the feet, tibial hemimelia, hip dysplasia, and femoral hypoplasia. Upper limb malformations were rare. Eleven of the 18 mothers had prepregnancy insulin-dependent diabetes, while one mother had prepregnancy type 2 diabetes that required insulin therapy in the 3(rd) trimester. Five mothers had gestational diabetes that required insulin and one mother had gestational diabetes that was controlled by diet. The majority of mothers had poorly controlled diabetes during the pregnancy.
Proximally placed preaxial hallucal polydactyly, particularly when coupled with segmentation anomalies of the spine and tibial hemimelia, is highly suggestive of diabetic embryopathy. Varying degrees of diabetes in the mothers point to a possible genetic predisposition interacting with the teratogenic effects of poor glycemic control leading to specific limb anomalies.
The main features of Wiedemann-Beckwith syndrome (WBS) include macroglossia, abdominal wall defects, visceromegaly, gigantism, hypoglycemia, ear creases, nevus flammeus, and mid-face hypoplasia. Twenty-two cases of WBS were examined clinically and cytogenetically, and compared to 226 previously reported cases. Aspects of the clinical evaluations are discussed. All individuals examined were chromosomally normal with no evidence of 11p abnormality as has been reported recently. The relevance of a possible relationship between clinical findings, chromosome abnormalities, and genes present on 11p is discussed. Transmission of this condition is most consistent with autosomal dominant inheritance with incomplete penetrance.
Polydactyly was observed as the single diagnosed malformation in 188 of 185,704 (0.101%) consecutive live births examined at 47 hospitals in Argentina, Chile, and Uruguay. The observed incidence was significantly higher in Uruguay (0.172%) where there also was a higher frequency of Negro ancestors (12.85%). For the other geographic areas the incidence of polydactyly was 0.091% and that of Negro ancestors, 0.49%. Postaxial B polydactyly was the type responsible for the observed differential frequency. There was a higher frequency of affected males for preaxial 1, which involved upper limbs more frequently than lower ones as did the postaxial B type. The inverse was seen for postaxial A. Postaxial B preferentially affected the left side. The estimated penetrance of postaxial polydactylies was 0.68 for type A and 0.43 for type B under an autosomal dominant hypothesis. Gene frequencies and mutation rates were estimated under the same hypothesis; values were not corrected for incomplete penetrance. The observed differences between A and B types of postaxial polydactylies suggest the involvement of different loci and the high estimated mutation rate for type B (1.4 x 10 -4) suggests genetic heterogeneity.
Holoprosencephaly is a congenital defect of the median structures of the brain and face. The epidemiology is poorly known due to the paucity of population-based studies. This study describes the epidemiology of holoprosencephaly in a large population, using cases identified through the New York State Congenital Malformations Registry, and born in 1984-1989. We describe the craniofacial abnormalities present, their frequency, and their cooccurrence, and we examine the correspondence between the severity of craniofacial abnormalities, chromosomal abnormalities, and severity of the brain defect. Liveborn cases totaled 78, yielding a prevalence of 4.8 per 100,000 live births. Prevalence among girls was nearly double that in boys, and was 4.2 times higher among infants of mothers under age 18 compared to infants of older mothers. Only 9.8% of all cases had no craniofacial abnormalities other than the brain defect. Eye malformations were present in 76.8%, nose malformations in 69.5%, ear malformations in 50%, and oral clefts in 41.5%. These malformations arise at different times during gestation. The variability in patterns of cooccurrence suggests variability in the developmental pathways and/or timing of developmental derangements which result in holoprosencephaly. This, in turn, is consistent with a model of multiple causes. Children with alobar holoprosencephaly tended to have the most severe craniofacial anomalies, but the correspondence was not 100%. Craniofacial phenotype does not consistently discriminate between cytogenetically normal and abnormal cases.
Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase (DHCR7). Clinical signs vary in severity, ranging from fetal loss to holoprosencephaly with multiple malformations to isolated syndactyly. The biochemical defect in SLOS is a deficiency of DHCR7, which results in an abnormally low cholesterol level, and increased amounts of intermediates of sterol biosynthesis. Animal models currently exist through the use of cholesterol biosynthesis inhibitors, from which a great deal has been learned. Pregnant rats treated with inhibitors of DHCR7 yield pups that have abnormal sterol profiles and craniofacial abnormalities characteristic of severe SLOS. Biochemical testing of human patients can be performed using gas chromatography/mass spectroscopy (GC/MS) to analyze the sterol content of tissues, amniotic fluid, or cell culture lysate. Numerous mutations have been identified in DHCR7 but seven individual mutations account for 67% of the total mutations reported in the literature. Clinical trials with SLOS are underway, with the goal of increasing the cholesterol concentration in the plasma and tissues through the administration of dietary cholesterol. Thus far, this approach has shown limited efficacy. Nevertheless, the recent identification of the biochemical and molecular genetic basis for SLOS is reason for optimism that the condition may one day yield to treatment.
To determine the role of renal ultrasonography in the evaluation of healthy newborn infants with isolated pre-auricular tags and pits. Study design: During the 4 years of prospective study, 108 of 17,286 infants were born with isolated pre-auricular tags or pits (6.2 per 1000 live births): 92 were assessed for urinary tract abnormalities by performing renal ultrasonography at 1 to 3 months of age. The study group was compared with a control group of 95 consecutive healthy infants without pre-auricular tags or pits born during the same period who underwent renal ultrasonography on the second day of life.
The study and control groups were comparable in birth weight, gestational age, and sex ratio. Renal ultrasonography was abnormal only in 2 infants with pre-auricular tags (2.2%); both had mild left pyelectasis. The prevalence did not differ significantly from that in the control group, in which 3 infants had mild pyelectasis (3.1%, P = 1.0) and 1 infant had a renal calculus. The prevalence of renal abnormalities in infants with isolated pre-auricular tags or pits in our study (2.2%) was also comparable to the prevalence in the general population (all abnormalities 0.2%-8.1%; significant abnormalities 0.2%-1.4%).
We conclude that renal ultrasonography is not indicated in the routine evaluation of the newborn infant with isolated pre-auricular tags or pits.
The objective of this study was to describe the congenital anomalies in 17 Canadian neonatal intensive care units (NICUs) and their impact on mortality, morbidity, and resource utilization. This study was performed using a database analysis of 19,507 consecutive admissions. Results show that 13.7% of admissions had one or more anomalies. There was wide variation in incidence between NICUs (4.4 to 36.6%). Congenital anomalies were associated with increased severity of illness, and higher mortality, morbidity, and resource use. Inclusion of congenital anomalies improves mortality prediction in regression analyses models. Congenital anomalies have a significant impact on NICU outcomes and resource use.
Most children with Turner's syndrome are under the care of specialists. It has been proposed that adults should also be followed in multidisciplinary specialty clinics. We believe, on the basis of our own experience, that most affected women can best be served by their primary care practitioners, with the use of informed judgment about the need for referral to specialists. Although these women have substantial health concerns, their care for the most part falls under the standard repertoire of primary care, and continued follow-up in specialty care centers may inhibit their integration into society and foster a sense of ill-being. Support groups for patients with Turner's syndrome and their families (listed in the Appendix) can be a source of valuable information.
Beckwith-Wiedemann syndrome (BWS) is a clinically heterogeneous overgrowth syndrome associated with an increased risk for embryonal tumor development. BWS provides an ideal model system to study epigenetic mechanisms. This condition is caused by a variety of genetic or epigenetic alterations within two domains of imprinted growth regulatory genes on human chromosome 11p15. Molecular studies of BWS have provided important data with respect to epigenotype/genotype-phenotype correlations; for example, alterations of Domain 1 are associated with the highest risk for tumor development, specifically Wilms' tumor. Further, the elucidation of the molecular basis for monozygotic twinning in BWS defined a critical period for imprint maintenance during pre-implantation embryonic development. In the future, such molecular studies in BWS will permit enhanced medical management and targeted genetic counseling.
The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.
Prevention of congenital cardiovascular defects has been hampered by a lack of information about modifiable risk factors for abnormalities in cardiac development. Over the past decade, there have been major breakthroughs in the understanding of inherited causes of congenital heart disease, including the identification of specific genetic abnormalities for some types of malformations. Although relatively less information has been available on noninherited modifiable factors that may have an adverse effect on the fetal heart, there is a growing body of epidemiological literature on this topic. This statement summarizes the currently available literature on potential fetal exposures that might alter risk for cardiovascular defects. Information is summarized for periconceptional multivitamin or folic acid intake, which may reduce the risk of cardiac disease in the fetus, and for additional types of potential exposures that may increase the risk, including maternal illnesses, maternal therapeutic and nontherapeutic drug exposures, environmental exposures, and paternal exposures. Information is highlighted regarding definitive risk factors such as maternal rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide, vitamin A cogeners, or retinoids; and indomethacin tocolysis. Caveats regarding interpretation of possible exposure-outcome relationships from case-control studies are given because this type of study has provided most of the available information. Guidelines for prospective parents that could reduce the likelihood that their child will have a major cardiac malformation are given. Issues related to pregnancy monitoring are discussed. Knowledge gaps and future sources of new information on risk factors are described.
The VACTERL association is the nonrandom co-occurrence of Vertebral anomalies, Anal atresia, Cardiovascular malformations, Tracheo-esophageal fistula (TEF) and/or Esophageal atresia (EA), Renal anomalies, and/or Limb-anomalies. The full phenotype of patients with EA/TEF and other anomalies of the VACTERL spectrum of defects association is not well described in the literature.
Data on patients with EA/TEF seen in two pediatric surgical centers in the Netherlands between January 1988 and August 2006 were evaluated for defects of the VACTERL spectrum as well as non-VACTERL-type defects. The presence of two or more defects of the VACTERL spectrum in addition to EA/TEF was the criterion for inclusion in this study. A detailed description was made of all defects.
Of 463 patients with EA and/or TEF, 107 (23.1%) fulfilled the inclusion criterion, of which seventeen cases had a recognized etiology and were excluded, leaving 90 cases (19.4%) for analysis. Other than the esophagus and the trachea, the vertebrae/ribs and the cardiovascular system were most commonly affected (68.9 and 65.6%, respectively). Interestingly, 70% of cases had additional non-VACTERL-type defects, with high occurrences for single umbilical artery (20%), genital defects (23.3%), and respiratory tract anomalies (13.3%).
Many patients with EA/TEF and at least two other defects of the VACTERL spectrum also display non-VACTERL-type congenital anomalies.
American College of Obstetricians and Gynecologists. ACOG Practice bulletin no. 134: fetal growth restriction
American College of Obstetricians and Gynecologists. ACOG Practice bulletin no. 134: fetal growth
restriction. Obstet Gynecol. 2013; 121:1122-33. [PubMed: 23635765]
- M M Tollefson
Tollefson MM. Aplasia cutis congenita. Neoreviews. 2012; 13:e285-e292.