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The Newborn Infant

See also Chapter 21 . Although the neonatal period is a highly vulnerable time as infants complete the many physiologic adjustments required for extrauterine existence, this transition is uneventful for most full-term infants. Management of the newborn should focus on parental anticipatory guidance and early detection of conditions or complications that carry risk of morbidity or even death. History in Neonatal Pediatrics Neera K. Goyal Assessment of…

Overview of Morbidity and Mortality

Infant Mortality The infant mortality rate is a metric used by public health agencies, policymakers, and governments to gauge the overall quality of pediatric and population health among a given population residing within geographically defined boundaries. The rate is stated as the number of infant deaths per 1,000 live births. Specific definitions support each variable. In the United States, an infant death is defined as mortality…

Hypoglycemia

Glucose has a central role in fuel economy and is a source of energy storage in the form of glycogen, fat, and protein (see Chapter 105 ). As an immediate source of energy, glucose provides 38 mol of adenosine triphosphate (ATP) per mole of glucose oxidized. Glucose is essential for energy metabolism in the brain, where it is usually the preferred substrate and where its utilization accounts…

The Porphyrias

Porphyrias are metabolic diseases resulting from altered activities of specific enzymes of the heme biosynthetic pathway. These enzymes are most active in bone marrow and liver. Erythropoietic porphyrias , in which overproduction of heme pathway intermediates occurs primarily in bone marrow erythroid cells, usually present at birth or in early childhood with cutaneous photosensitivity, or in the case of congenital erythropoietic porphyria, even in utero as…

Hutchinson-Gilford Progeria Syndrome (Progeria)

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is a rare, fatal, autosomal dominant segmental premature aging disease. With an estimated incidence of 1 in 4 million live births and prevalence of 1 in 20 million living individuals, there are an estimated total of 400 children living with progeria in 2018 worldwide. There is no gender, ethnic, or regional bias. Progeria is caused by a single-base mutation in…

Disorders of Purine and Pyrimidine Metabolism

The inherited disorders of purine and pyrimidine metabolism cover a broad spectrum of illnesses with various presentations. These include hyperuricemia, acute renal failure, renal stones, gout, unexplained neurologic deficits (seizures, muscle weakness, choreoathetoid and dystonic movements), intellectual and developmental disabilities, acrofacial dysostosis, compulsive self-injury and aggression, autistic-like behavior, unexplained anemia, failure to thrive, susceptibility to recurrent infection (immune deficiency), and deafness. When identified, all family members…

Mucopolysaccharidoses

Mucopolysaccharidoses are hereditary, progressive diseases caused by mutations of genes coding for lysosomal enzymes needed to degrade glycosaminoglycans (acid mucopolysaccharides). Glycosaminoglycans (GAGs) are long-chain complex carbohydrates composed of uronic acids, amino sugars, and neutral sugars. The major GAGs are chondroitin-4-sulfate, chondroitin-6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. These substances are synthesized and, with the exception of hyaluronan, linked to proteins to form proteoglycans, major…

Mitochondrial Disease Diagnosis

See also Chapter 105.4 . Overview of Mitochondrial Disease Mitochondrial diseases are multisystemic energy failure states with extensive clinical and genetic heterogeneity. Their common basis is best understood through recognition that mitochondria function as biologic “fuel cells” or “batteries,” producing chemical energy in the form of adenosine triphosphate (ATP) by aerobic metabolism of nutrient-derived reducing equivalents, through the integrated function of the 5-complex mitochondrial respiratory chain…

Defects in Metabolism of Carbohydrates

Carbohydrate synthesis and degradation provide the energy required for most metabolic processes. The important carbohydrates include 3 monosaccharides—glucose, galactose, and fructose—and a polysaccharide, glycogen. Fig. 105.1 shows the relevant biochemical pathways of these carbohydrates. Glucose is the principal substrate of energy metabolism, continuously available through dietary intake, gluconeogenesis (glucose made de novo from amino acids, primarily alanine), and glycogenolysis (breakdown of glycogen). Metabolism of glucose generates…

Defects in Metabolism of Lipids

Disorders of Mitochondrial Fatty Acid β-Oxidation Charles A. Stanley Michael J. Bennett Keywords fatty acid oxidation defects carnitine cycle newborn screening hypoglycemia medium-chain acyl-CoA dehydrogenase deficiency liver disease cardiomyopathy rhabdomyolysis fasting intolerance mitochondrial metabolism Reye syndrome Mitochondrial β-oxidation of fatty acids is an essential energy-producing pathway. It is particularly important during prolonged periods of starvation and during periods of reduced caloric intake caused by gastrointestinal illness or increased…

Defects in Metabolism of Amino Acids

Phenylalanine Oleg A. Shchelochkov Charles P. Venditti Keywords phenylalanine phenylketonuria PKU hyperphenylalaninemia phenylalanine hydroxylase tetrahydrobiopterin BH4 Phenylalanine is an essential amino acid. Dietary phenylalanine not utilized for protein synthesis is normally degraded by way of the tyrosine pathway ( Fig. 103.1 ). Deficiency of the enzyme phenylalanine hydroxylase (PAH) or of its cofactor tetrahydrobiopterin (BH 4 ) causes accumulation of phenylalanine in body fluids and in the brain.…

An Approach to Inborn Errors of Metabolism

Many childhood conditions are caused by single-gene mutations that encode specific proteins. These mutations can change primary protein structure or the amount of protein synthesized. The function of a protein, whether it is an enzyme, receptor, transport vehicle, membrane component, transcriptional co-regulator, or structural element, may be compromised or abolished. Hereditary diseases that disrupt normal biochemical processes are termed inborn errors of metabolism or inherited metabolic…

Genetic Approaches to Rare and Undiagnosed Diseases

Rare and novel disorders often present in childhood and represent a diagnostic challenge that can be addressed using advanced genetic techniques. In the United States, rare disorders are defined as those affecting <200,000 people (about 1 in 1,500 persons), but no single definition has been agreed on internationally. Scope of Genetic Disease An estimated 8000 rare disorders are recognized, and the existence of approximately 23,000 human…

Epigenome-Wide Association Studies and Disease

Pediatricians are asked to consider the possibility that certain conditions involve epigenetic mechanisms. The assumption is that epigenetic processes, generally defined as regulatory control of gene expression, are capable of overriding information encoded in the DNA sequence to increase or decrease the risk of a disease. Despite powerful genomic assays to test these regulators of gene expression, it has proved difficult to provide clear answers about…

Genetics of Common Disorders

Common pediatric diseases are usually multifactorial. The combination of many genes and environmental factors contribute to a complex sequence of events leading to disease. The complexity of the combination of contributing factors increases the challenge of finding genetic variants that cause disease. Genetic tools include the completed human genome sequence, public databases of genetic variants, and the human haplotype map. In addition to public genetic databases,…

Cytogenetics

Clinical cytogenetics is the study of chromosomes: their structure, function, inheritance, and abnormalities. Chromosome abnormalities are very common and occur in approximately 1–2% of live births, 5% of stillbirths, and 50% of early fetal losses in the 1st trimester of pregnancy ( Table 98.1 ). Chromosome abnormalities are more common among individuals with intellectual disability and play a significant role in the development of some neoplasias.…

Patterns of Genetic Transmission

Family History and Pedigree Notation The family history remains the most important screening tool for pediatricians in identifying a patient's risk for developing a wide range of diseases, from multifactorial conditions such as diabetes and attention-deficit/hyperactivity disorder, to single-gene disorders such as sickle cell anemia and cystic fibrosis. Through a detailed family history, the physician can often ascertain the mode of genetic transmission and the risks…

The Human Genome

The human genome has approximately 20,000 genes that encode the wide variety of proteins found in the human body. Reproductive or germline cells contain 1 copy (N) of this genetic complement and are haploid , whereas somatic (nongermline) cells contain 2 complete copies (2N) and are diploid . Genes are organized into long segments of deoxyribonucleic acid ( DNA ), which, during cell division, are compacted…

The Genetic Approach in Pediatric Medicine

Since the completion of the Human Genome Project, we have seen an unprecedented expansion in our understanding of how human health is impacted by variations in genomic sequence and epigenetic , non-sequence-based, changes that affect gene expression. This period has also seen the development and implementation of new clinical tests that have made it easier for physicians to detect such changes. In addition, there has been…