Genetic and pediatrics disorders PDF

CHAPTER 7 GENETIC DISEASES CONTENTS : – INTRODUCTION – MUTATIONS – MENDELIAN DISORDERS (DISEASES CAUSED BY SINGLE-GENE DEFECTS) – DISORDERS WITH MULTIFACTORIAL INHERITANCE – CYTOGENETIC DISORDERS – SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE...

CHAPTER 7 GENETIC DISEASES CONTENTS : – INTRODUCTION – MUTATIONS – MENDELIAN DISORDERS (DISEASES CAUSED BY SINGLE-GENE DEFECTS) – DISORDERS WITH MULTIFACTORIAL INHERITANCE – CYTOGENETIC DISORDERS – SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE 1 Genetic disorders 2 …cont 3 4 5 6  INTRODUCTION Genetic disorders are far more common than is widely appreciated. The life time frequency of genetic diseases is estimated to be 670/ 1000. It is estimated that 50% of spontaneous abortions during the early months of gestation are due to chromosomal abnormalities. About 1% of new born infants posses a gross chromosomal abnormality. 7  Genetic information is stored in DNA. The typical normal human cell contains 46 chromosomes (i.e. 23 pairs of chromosomes: 22 homologous pairs of autosomes & 1 pair of sex chromosomes (xx or xy). Members of a pair carry matching genetic information though they may have slightly different forms, which are called alleles. 8  One member of each pair of chromosome is inherited from the mother & the other from the father. Each chromosome is in turn composed of a very long unbranched molecule of DNA bound to histones & other proteins. In turn DNA is composed of 2 very long complementary chains of deoxy nucleotides. 9  The two strands of DNA twist around each other to form a double helix “twisted ladder model”. Each deoxynucleotide is in turn composed of a nitrogenous base (i.e. adenine (A), guanine (G), cytosine (C), or thymine (T) bound to deoxyribose & phosphate. 10 …cont 11  DNA has 2 basic functions: 1. It provides the genetic information for protein synthesis 2. It transmits the genetic information to the daughter cells & to the offspring of the individual. 12  The portion of DNA that is required for production of a protein is called a GENE. The transcription of a gene is regulated by a promoter region or enhancer region. 3 consecutive nucleotides form a code word or codon. Each codon signifies a single amino acid. 13 Transmission of genetic information DNA → RNA → protein Codon, a triplet of bases that specify a particular aminoacid The central dogma of molecular biology is: 15  Therefore, the sequence of amino acids in the protein is determined by the sequence of codon in the mRNA which in turn is determined by the sequence of nucleotides in the DNA. 16  Genetic information is transmitted to daughter cells under 2 circumstances: 1. Somatic cells divide by mitosis 2. Germ cells (sperm & ova ) undergo meiosis 17  Terminology  Hereditary disorders – disorders derived from one’s parents. Congenital disorders-means ‘born with’ Genotype- the genetic constitution (genome) Phenotype- the observed biochemical, physiological & morphological characteristics of an individual as determined by the genotype & the environment in which it is expressed. Allele- one of the alternative versions of a gene that may occupy a given locus. 18 MUTATION Permanent change in the primary nucleotide sequence of DNA. Occur spontaneously during cell division or caused environmentally by mutagens such as radiation, viruses & chemicals. Mutation in germ cells cause hereditary diseases There are 3 categories of mutation: 19 1. Genome mutations – Is loss or gain of the whole chromosome. – Are exemplified by aneuploidy & polyploidy. – Are often incompatible with survival. 20 2. Chromosomal mutations – Are due to rearrangement of genetic material in a chromosome which results in structural change in the chromosome. – Are exemplified by translocations. – Are infrequently transmitted because most are incompatible with survival. 21 3. Gene mutations – Single base mutations (more common) or they may affect a large portion of a gene. – Cause most of the hereditary diseases – Have the following types: A. Point mutations (single base pair changes) B. Deletions & insertions C. Expansion of repeat sequences (trinucleotide repeat mutations) 22 A. Point mutation Single base substitution. Types include: – I. Silent mutation – ll. Missense mutation – lll. Nonsense mutation 23  I. Silent mutation The genetic code is redundant (i.e. there is more than 1 codon for most amino acids). There fore, a change in one base may result in no change in the amino acid sequence of the protein. E.g. the change of the codon UUU which codes for phenylalanine to UUC (I.e. the replacement of U by C) is a silent mutation b/c the new codon (UUC) also codes the same amino acid (phenylalanine). 24 ll. Missense mutation Changes the codon for one amino acid to the codon for another amino acid. E.g. sickle – cell anemia – Glutamic acid (GAG) in the β – globin chain of Hgb is substituted by valine (GUG). 25 lll. Nonsense mutation Changes the codon for an amino acid to a stop codon, leading to termination of translation of the mRNA. E.g. β – thalassemia – A substitution of U for C in the codon 39 of the β – globin chain of Hgb (i.e. the change of CAG to UAG) converts the codon for glutamine to a stop codon. 26 B. Deletions or insertions – Can occur within coding or non – coding sequences: 1. Deletions or insertions of 1 or 2 bases within the coding sequence – Lead to frame shift mutation b/c they alter the reading frame of the triplet genetic code in the mRNA so that every codon distal to the mutation in the same gene is read in the wrong frame. – This leads to altered amino acid sequence & usually premature termination of the peptide chain. 28 2. Deletions or insertions of 3 or a multiple of 3 base pairs within coding sequence – Doesn’t cause frame shift mutation, instead it results in abnormal protein missing 1 or more amino acid. 3. Deletions within the non – coding sequence – Leads to promoter\ enhancer mutations. 29 C. Expansion of repeat sequences (trinucleotide repeat mutations) Show amplification or expansion of a sequence of 3 nucleotides. Normally 3 nucleotides are repeated 20 – 30X. Trinucleotide repeat mutation is when there is expansion of these normally repeated sequences to more than 100 repeats. 31  The mechanism leading to an increase in the number of repeats & how the increase leads to disease is not clear. E.g. Huntington’s disease, fragile x – syndrome. 32  CATEGORIES OF GENETIC DISEASE Genetic diseases generally fall into one of the following 4 categories: 1. Mendelian disorders 2. Chromosomal disorders 3. Multifactorial disorders 4. Single gene disease with non – classic patterns of Inheritance 33 1. MENDELIAN DISORDERS Single-gene defects (mutations) follow the well- known mendelian patterns of inheritance. Thus, the conditions they produce are often called mendelian disorders Based on their patterns of inheritance mendelian disorders are classified in to the following: – Autosomal dominant inheritance – Autosomal recessive inheritance – X – linked recessive inheritance 34 I. Autosomal dominant disorders Autosomal dominant disorders are manifested in the heterozygous state In the mating of an affected heterozygote to a normal homozygote, each child has a 50% chance to inherit the abnormal allele and be affected & a 50% chance to inherit the normal allele. Every child affected will have an affected parent. Some patients do not have affected parents b/c the disease in such cases is due to new mutations in the sperm\ ovum. 35 Autosomal dominant… The two sexes are affected in equal numbers (b/c the defective gene resides on one of the two autosomes. Autosomal dominant disorders can show reduced penetrance (i.e. some individuals’ inherit the mutant gene but are phenotypically normal). Autosomal dominant disorders commonly show variable expressivity. Variable expressivity is the ability of the same genetic mutation to express differently among individuals. 36 Autosomal dominant…  Pathogenesis – Caused by 2 types of mutations: A. Loss of function mutations –  They result in inactive or decreased amount of regulatory proteins. B. Gain of function mutations – less common. The mutant gene produces toxic protein. 37 Autosomal dominant… In many conditions the age at onset is delayed and symptoms and signs do not appear until adulthood. In autosomal dominant disorders, a 50% reduction in the normal gene product is associated with clinical symptoms. Because a 50% loss of enzyme activity can usually be compensated for, involved genes usually do not encode enzyme proteins. Two categories of nonenzyme proteins affected in autosomal dominant disorders: – Those involved in regulation of complex metabolic pathways, often subject to feedback control – Structural proteins, such as collagen 38 Autosomal dominant…. Clinical examples: Marfan syndrome Neurofibromatosis Achondroplasia Osteogenesis imperfecta 39  II. Autosomal recessive disorders Largest group among Mendelian disorder. The phenotype is usually observed only in the homozygote. Affect male & female siblings with normal parents. In the mating of the phenotypically normal heterozygotes, each pregnancy is 25% homozygous normal, 50% heterozygous normal & 25% homozygous affected. 40  Unlike autosomal dominant disorders they show uniform expression of the trait. Show complete penetrance. Unlike autosomal dominant disorders which have delayed onset, they have early onset. 41 Pathogenesis – Loss of function mutation which results in decreased enzyme proteins. Clinical examples : Sickle cell anemia Thalessemia Hemochromatosis Congenital adrenal hyperplasia 42 III. X- Linked disorders All sex- linked disorders are x- linked & almost all are recessive. No Y- linked diseases are as yet known. In heterozygous female (Xx), there is some chance of random inactivation of one of the X- Chromosome, so that there will be some cells affected & the female will express partially. 43  There are a very few X-linked dominant diseases and they are much less common than disorders arising from autosomal mutations. Their inheritance pattern is characterized by transmission of the disease to 50% of the sons and daughters of an affected heterozygous female. An affected male cannot transmit the disease to his sons, but all daughters are affected. 44  BIOCHEMICAL AND MOLECULAR BASIS OF SINGLE-GENE (MENDELIAN) DISORDERS The genetic defect may lead to – Formation of an abnormal protein or a – Reduction in the output of the gene product. The phenotypic effects of a mutation may result – Directly from abnormalities in the protein encoded by the mutant gene, or – Indirectly owing to interactions of the mutant protein with other normal proteins.  The mechanisms involved in single-gene disorders can be classified into four categories: 1) Enzyme defects and their consequences; 2) Defects in membrane receptors and transport systems 3) Alterations in the structure, function, or quantity of nonenzyme proteins; and 4) Mutations resulting in unusual reactions to drugs.  Enzyme Defects and Their Consequences Mutations may result in the synthesis of a defective enzyme or in a reduced amount of a normal enzyme which results in a metabolic block Consequences of an enzyme defect in such a reaction may lead to three major consequences:  Accumulation of the substrate  Excessive accumulation of complex substrates within the lysosomes as a result of deficiency of degradative enzymes is responsible for a group of diseases generally referred to as lysosomal storage diseases  A metabolic block and a decreased amount of end product that may be necessary for normal function  eg absence of melanin due to defect in tyrosinase  Failure to inactivate a tissue-damaging substrate  eg. α1-antitrypsin deficiency  Defects in Receptors and Transport Systems A genetic defect in a receptor-mediated transport system  Examples Familial hypercholesterolemia, in which reduced synthesis or function of low-density lipoprotein (LDL) receptors leads to defective transport of LDL into the cells and secondarily to excessive cholesterol synthesis. In cystic fibrosis, the transport system for chloride ions in exocrine glands, sweat ducts, lungs, and pancreas is defective.  Alterations in Structure, Function, or Quantity of Nonenzyme Proteins Typical examples includes Hemoglobinopathies such as sickle cell disease Thalassemias Osteogenesis imperfecta Hereditary spherocytosis Muscular dystrophies  DISORDERS ASSOCIATED WITH DEFECTS IN STRUCTURAL PROTEINS 1. Marfan Syndrome – It is autosomal dominant disorder of connective tissues – The basic biochemical abnormality affects fibrillin 1. – Fibrillin 1 are considered integral components of elastic fibers. – Fibrillin 1 is encoded by the FBN1 gene. – Mutations in the FBN1 gene are found in all patients with Marfan syndrome. – The mutant fibrillin 1 protein act as a dominant negative by preventing the assembly of normal microfibrils. – With deficiency of fibrillin-1 there is increased TGF-β production resulting in overgrowth of bones … 52  Clinical manifestations Skeletal abnormalities – – The patient is unusually tall with exceptionally long extremities and long, tapering fingers and toes. – The joint ligaments in the hands and feet are lax. – The head is commonly dolichocephalic (long-headed) with bossing of the frontal eminences and prominent supraorbital ridges. – Spinal deformities such as kyphosis, scoliosis, or rotation or slipping of the dorsal or lumbar vertebrae. – Chest is deformed (either pectus excavatum or pigeon breast deformity)  Ocular changes – – Bilateral subluxation or dislocation of the lens ( ectopia lentis ) Cardiovascular lesions – Are the most life-threatening features of this disorder. – The commonest lesions are MVP( mitral valve prolapse ) & dilation of the ascending aorta owing to fragmentation of the elastic fibers in the tunica media  2. Ehlers-Danlos Syndromes – Comprise a clinically and genetically heterogeneous group of disorders that result from some defect in the synthesis or structure of fibrillar collagen. – The mode of inheritance of EDS encompasses all three mendelian patterns but all single gene disorders – At least six clinical and genetic variants of EDS are recognized. – Because defective collagen is present in all the variants, certain clinical features are common to all. – Tissues rich in collagen, such as skin, ligaments, and joints, are frequently involved in most variants of EDS.  The molecular bases of EDS are varied and include the following: Deficiency of the enzyme lysyl hydroxylase. Deficient synthesis of type III collagen Defective conversion of procollagen type I to collagen  Deficient synthesis of type III collagen resulting from mutations affecting the COL3A1 gene. – This variant, vascular EDS, is inherited as an autosomal dominant disorder. – It is characterized by weakness of tissues rich in type III collagen (e.g., blood vessels, bowel wall), predisposing them to rupture. 57  Deficiency of the enzyme lysyl hydroxylase – Decreased hydroxylation of lysyl residues in types I and III collagen interferes with the formation of crosslinks among collagen molecules. – This variant (kyphoscoliotic EDS) is inherited as an autosomal recessive disorder. – Patients typically manifest with congenital scoliosis and ocular fragility. 58  Deficient synthesis of type V collagen resulting from mutations in COL5A1 and COL5A2 – It is inherited as an autosomal dominant disorder and – It results in classical EDS. 59  Diseases Caused by Mutations in Genes Encoding Receptor Proteins or Channels Familial Hypercholesterolemia Cystic Fibrosis 60  Familial Hypercholesterolemia Familial hypercholesterolemia is a “receptor disease” caused by – Loss-of-function mutations in the gene encoding the LDL receptor, which is involved in the transport and metabolism of cholesterol 61  Normal Cholesterol Metabolism – Cholesterol may be derived from the diet or from endogenous synthesis. – Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal mucosa and travel by way of the gut lymphatics to the blood. – These chylomicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat. – The chylomicron remnants, rich in cholesterol, are then delivered to the liver. – Some of the cholesterol enters the metabolic pool and some is excreted as free cholesterol or as bile acids into the biliary tract. 62  The endogenous synthesis of cholesterol and LDL begins in the liver. The first step in the synthesis is the secretion of triglyceride-rich very-low- density lipoprotein (VLDL) by the liver into the blood. In the capillaries of adipose tissue and muscle, the VLDL particle undergoes lipolysis and is converted to (IDL). In comparison with VLDL, the content of triglyceride is reduced and that of cholesteryl esters is enriched in IDL. IDL retains on its surface the VLDL-associated apolipoproteins B-100 and E. Further metabolism of IDL occurs along two pathways: – Most of the IDL particles are directly taken up by the liver through the LDL receptor. – Others are converted to cholesterol-rich LDL by a further loss of triglycerides and the loss of apolipoprotein E. In the liver cells, IDL is recycled to generate VLDL. 63 64  The LDL receptor pathway metabolizes two- thirds of the resultant LDL particles. The rest is metabolized by a receptor for oxidized LDL (scavenger receptor). The LDL receptor binds to apolipoproteins B- 100 and E and thus is involved in the transport of both LDL and IDL. Approximately 75% of the LDL receptors are located on hepatocytes of the liver. 65 66  The cholesterol in the cell is – Used for membrane synthesis – Takes part in intracellular cholesterol homeostasis by a feedback control 67  cholesterol homeostasis feedback control – Intracellular cholesterol suppresses cholesterol synthesis by inhibiting the activity of the enzyme 3-hydroxy-3-methylglutaryl– coenzyme A reductase (HMG-CoA reductase). – It stimulates the formation of cholesterol esters for storage of excess cholesterol. – It down regulates the synthesis of cell surface LDL receptors, thus preventing excessive accumulation of cholesterol inside cells. 68  The transport of LDL by the scavenger receptors, seems to occur in cells of the mononuclear- phagocyte system and possibly in other cells as well. Monocytes and macrophages have receptors for chemically modified (e.g., acetylated or oxidized) LDLs. The amount catabolized by this scavenger receptor pathway is directly related to the plasma cholesterol level. 69  Pathogenesis In familial hypercholesterolemia, mutations in the LDL receptor protein impair the intracellular transport and catabolism of LDL, resulting in accumulation of LDL cholesterol in the plasma. It also impairs the transport of IDL into the liver, so a greater proportion of plasma IDL is converted into LDL. Thus, patients develop excessive levels of serum cholesterol as a result of the combined effects of reduced catabolism and excessive biosynthesis. This leads to a marked increase of cholesterol uptake by the monocyte-macrophages and vascular walls through the scavenger receptor. This accounts for the appearance of skin xanthomas and premature atherosclerosis. 70  Familial hypercholesterolemia is an autosomal dominant disease. Heterozygotes – Although their cholesterol levels are elevated from birth, they remain asymptomatic until adult life. Homozygotes – Develop cutaneous xanthomas in childhood and often dye of myocardial infarction before the age of 20 years. 71  More than 900 different mutations can give rise to familial hypercholesterolemia. These can be divided into five categories. – Class I mutations are associated with complete loss of receptor synthesis. – Class II mutations, the receptor protein transport from the endoplasmic reticulum to the Golgi apparatus is impaired because of defects in protein folding. – Class III mutations produce receptors that are transported to the cell surface but fail to bind LDL normally. – Class IV mutations give rise to receptors that fail to internalize within clathrin pits after binding to LDL – Class V mutations encode receptors that can bind LDL and are internalized but are trapped in endosomes because dissociation of receptor and bound LDL does not occur. 72  The transport of LDL by the scavenger receptors takes place in cells of the mononuclear phagocyte system and possibly in other cells as well. Monocytes and macrophages have receptors for chemically modified (e.g., acetylated or oxidized) LDLs. The amount catabolized by this "scavenger receptor" pathway is directly related to the plasma cholesterol level. 73  Cystic Fibrosis Cystic fibrosis (CF) is a disorder of epithelial ion transport affecting fluid secretion in exocrine glands and the epithelial linings of the respiratory, gastrointestinal, and reproductive tracts. The ion transport defects lead to abnormally viscid mucous secretions. This blocks the airways and the pancreatic ducts which in turn are responsible for the two most important clinical manifestations of CF: – Recurrent and chronic pulmonary infections and – Pancreatic insufficiency A high level of sodium chloride in the sweat is a consistent and characteristic biochemical abnormality in CF. 74  CF can present with variable set of clinical findings. This variation in phenotype results from – diverse mutations in the CF-associated gene, – tissue-specific effects of loss of the CF gene’s function, and – the influence of disease modifier genes. 75  CF follows simple autosomal recessive transmission. Heterozygous carriers have a predisposition toward pulmonary and pancreatic disease at higher rates than the general population. 76  Pathogenesis The primary defect in CF is reduced production, or abnormal function of an epithelial chloride channel protein encoded by the CF transmembrane conductance regulator (CFTR) gene. Disruptive mutations in CFTR render the epithelial membranes relatively impermeable to chloride ions. The impact of this defect on transport function is tissue specific. – CFTR protein in the sweat gland ducts VS – CFTR in the respiratory and intestinal epithelium 77 78  Respiratory and intestinal complications in CF stem from dehydration of surface fluid layer. In the lungs, this dehydration leads to – Defective mucociliary action and – Accumulation of viscid secretions obstruct the air passages & predispose it to recurrent infections. 79  More than 1800 CF-causing mutations have been identified. They may result in: – Reduced quantity of functional CFTR or – Reduced function of CFTR They can also be classified as severe or mild, depending on the clinical phenotype. 80  Since CF is an autosomal recessive disease, affected persons harbor mutations on both alleles. As discussed later, the nature of mutations on the two alleles influences the overall phenotype, as well as organ-specific manifestations. There is increasing evidence that other genes modify the frequency and severity of organ- specific manifestations. 81  MORPHOLOGY of CF Pancreatic abnormalities – the ducts are plugged, causing atrophy of the exocrine glands and progressive fibrosis. Small intestine of infants – Thick viscid plugs of mucus cause small bowel obstruction, known as meconium ileus. pulmonary changes – Obstruction of the air passages by the viscous mucus secretions – Development of lung abscesses is common Liver involvement follows the same basic pattern. Azoospermia and infertility are found in 95% of the affected males 82 83 84 DISORDERS ASSOCIATED WITH DEFECTS IN ENZYMES Phenylketonuria (PKU) Galactosemia Lysosomal Storage Diseases 85  PHENYLKETONURIA (PKU) PKU results from mutations that cause lack of the enzyme phenylalanine hydroxylase (PAH). It is autosomal recessive disorder with several variants. Homozygotes have a severe lack of PAH, leading to hyperphenylalaninemia and PKU. By 6 months of life, severe mental retardation becomes too evident. 86  Seizures, decreased pigmentation, & eczema often accompany the mental retardation. Hyperphenylalaninemia can be avoided by restricting phenylalanine intake early in life. Maternal PKU, results from the teratogenic effects of phenylalanine that cross the placenta & affect fetal organs. 87  The biochemical abnormality in PKU is an inability to convert phenylalanine into tyrosine. – Less than 50% of the dietary intake of phenylalanine is necessary for protein synthesis. – The remainder is converted to tyrosine by the phenylalanine hydroxylase system. 88 89  When phenylalanine metabolism is blocked shunt pathways yield several intermediates that are excreted in the urine and sweat. These impart a strong musty or mousy odor to affected infants. Concomitant lack of tyrosine a precursor of melanin, is responsible for the light color of hair and skin. 90  Approximately 500 mutant alleles of the PAH gene have been identified. – Some of them cause a severe deficiency of the enzyme. – Those with some residual activity may be asymptomatic, a condition referred to as benign hyperphenylalaninemia. 91  Enzyme replacement with phenylalanine ammonia lyase (PAL) therapy is being tried. 2% of hyperphenylalaninemia arise from abnormalities in synthesis or recycling of the cofactor tetrahydrobiopterin. – In this case treatment requires supplementation with tetrahydrobiopterin. 92  Galactosemia – Galactosemia is an autosomal recessive disorder of galactose metabolism. – Lactase splits lactose into glucose and galactose – Galactose is then converted to glucose in several steps, in one of which the enzyme galactose-1- phosphate uridyltransferase (GALT) is required. – Lack of this enzyme is responsible for galactosemia. – As a result of GALT deficiency, galactose 1-phosphate and other metabolites, including galactitol, accumulate in tissues including: the liver, spleen, lens, kidney, and cerebral cortex. 93  The early-onset hepatomegaly results largely from fatty change, but in time widespread scarring supervene. Opacification of the lens (cataract) develops, because the lens absorbs water and swells as galactitol accumulates and increases its tonicity. Nonspecific alterations appear in the central nervous system (CNS), including loss of nerve cells, gliosis, and edema. 94  Almost from birth, affected infants fail to thrive. Vomiting and diarrhea appear within a few days of milk ingestion. Jaundice and hepatomegaly usually become evident during the first week of life. Accumulation of galactose and galactose-1- phosphate in the kidney impairs amino acid transport, resulting in aminoaciduria. 95  Many of the clinical and morphologic changes of galactosemia can be prevented or ameliorated by removal of galactose from the diet. Even with dietary restrictions, older patients frequently are affected by a speech disorder and gonadal failure and, less commonly, by an ataxic condition. 96 2. Lysosomal Storage Diseases Lysosomes contain a variety of hydrolytic enzymes that are involved in the breakdown of complex substrates into soluble end products. These large molecules may be derived from the turnover of intracellular organelles that enter the lysosomes by autophagocytosis, or they may be acquired from outside the cells by phagocytosis. 97  With an inherited lack of a lysosomal enzyme, catabolism of its substrate remains incomplete, leading to accumulation of the partially degraded insoluble metabolites within the lysosomes, this is called primary storage. Because lysosomal function is essential for autophagy, impaired autophagy gives rise to secondary storage of autophagic substrates such as polyubiquinated proteins and old and effete mitochondria. 98 99  The combined frequency of lysosomal storage disorders (LSDs) is about 1 in 5000 live births. But lysosomal dysfunction may be involved in the etiology of several more-common diseases. Examples: – An important genetic risk factor for developing Parkinson disease is the carrier state for Gaucher disease, and – Virtually all Gaucher disease patients develop Parkinson disease. Lysosomes play critical roles in: – (i) autophagy – (ii) immunity – (iii) membrane repair 100  Certain features are common to most diseases in this group: – Autosomal recessive transmission – Commonly affect infants and young children – Storage of insoluble intermediates in the mononuclear phagocyte system, giving rise to hepatosplenomegaly – Frequent CNS involvement with associated neuronal damage – Cellular dysfunctions caused by storage of undigested material & by secondary events, such as macrophage activation and release of cytokines. 101  Tay-Sachs Disease (GM2 Gangliosidosis: Deficiency in Hexosaminidase β Subunit) Gangliosidoses are characterized by accumulation of gangliosides, principally in the brain, as a result of a deficiency of one of the lysosomal enzymes that catabolize these glycolipids. Depending on the ganglioside involved, these disorders are subclassified into GM1 and GM2 categories. Tay-Sachs disease is caused by loss-of-function mutations of the β subunit of the enzyme hexosaminidase A, which is necessary for the degradation of GM2. More than 100 mutations have been described; most disrupt protein folding or intracellular transport. 102  In the absence of hexosaminidase A, GM2 ganglioside accumulates in many tissues (heart, liver, spleen, nervous system) but the involvement of neurons in the central & autonomic nervous systems and retina dominates the clinical picture. 103 104  The molecular basis for neuronal injury is not fully understood. Because in many cases the mutant protein is misfolded, it induces the so-called “unfolded protein” response. Misfolded enzymes undergo proteasomal degradation, leading to accumulation of toxic substrates and intermediates within neurons. 105 Niemann-Pick Disease Types A and B Type A and type B Niemann-Pick diseases are related entities characterized by a primary deficiency of acid sphingomyelinase and the resultant accumulation of sphingomyelin. As with Tay-Sachs disease, Niemann-Pick disease types A and B are common in ?Ashkenazi Jews?. 106  Type A Niemann-Pick diseases, is characterized by a severe deficiency of sphingomyelinase. The breakdown of sphingomyelin into ceramide and phosphorylcholine is impaired, and excess sphingomyelin accumulates in phagocytes & neurons. The affected neurons are enlarged and vacuolated. This variant manifests in infancy with massive organomegaly and severe neurologic deterioration. Death usually occurs within the first 3 years of life. 107  Patients with the type B variant, which is associated with mutant sphigomyelinase with some residual activity, have organomegaly but no neurologic manifestations. 108  Niemann-Pick Disease Type C NPC is quite distinct at the biochemical and molecular levels and is more common than types A and B combined. Mutation is in two related genes, NPC1 and NPC2, that involved in the transport of free cholesterol from the lysosomes to the cytoplasm. Unlike most other lysosomal storage diseases, NPC results from a primary defect in lipid transport. Affected cells accumulate cholesterol as well as gangliosides such as GM1 and GM2. The most common form manifests in childhood and is marked by ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria, and psychomotor regression. 109 110  Gaucher Disease Gaucher disease results from mutation in the gene that encodes glucocerebrosidase. It leads to an accumulation of glucocerebroside in the mononuclear phagocytic cells. Macrophages in the liver, spleen, and bone marrow, sequentially degrade glycolipids derived from the breakdown of senescent blood cells. In Gaucher disease, the degradation stops at the level of glucocerebrosides, which accumulate in macrophages. Gaucher disease is caused not just by the burden of storage material but also by activation of the macrophages. 111  Gaucher Disease There are three autosomal recessive variants of Gaucher disease. Type 1, also called the chronic nonneuronopathic form, accounts for 99% cases of Gaucher disease. It is characterized by bone involvement, hepatosplenomegaly, and absence of CNS involvement. Gaucher cells are found in the liver, spleen, lymph nodes, and bone marrow. 112 113  Gaucher Disease Neurologic signs and symptoms characterize types 2 and 3 variants. In type 2, these manifestations appear during infancy (acute infantile neuronopathic form) and are more severe. In type 3 they emerge later and are milder (chronic neuronopathic form). The neurologic disturbances include convulsions and progressive mental deterioration. Patients with Gaucher disease have a 20 fold higher risk of developing Parkinson disease. 114  Currently, there are two approved therapies for type I Gaucher disease. – The first is lifelong enzyme replacement therapy via infusion of recombinant glucocerebrosidase. – The second is substrate reduction therapy 115  Mucopolysaccharidoses Mucopolysaccharidoses (MPSs) are characterized by defective degradation and excessive storage of mucopolysaccharides in various tissues. 116  Mucopolysaccharides are part of the extracellular matrix and are synthesized by connective tissue fibroblasts. Most mucopolysaccharide is secreted, but a certain fraction is degraded within lysosome involving multiple enzymes. Several clinical variants of MPS, classified numerically from MPS I to MPS VII, have been described, each resulting from the deficiency of one specific enzyme in this pathway. 117  The mucopolysaccharides that accumulate within the tissues include: – dermatan sulfate, heparan sulfate, keratan sulfate, and chondroitin sulfate. Features that are seen in all of the MPSs – Hepatosplenomegaly, skeletal deformities, lesions of heart valves, subendothelial arterial deposits. Of the seven recognized variants, the two well- characterized syndromes are: – MPS type I, also known as Hurler syndrome – MPS type II or Hunter syndrome 118  MPS type I, also known as Hurler syndrome, is caused by a deficiency of α-L-iduronidase. Accumulation of dermatan sulfate and heparan sulfate is seen: – in cells of the mononuclear phagocyte system, – in fibroblasts, and – within endothelium and smooth muscle cells of the vascular wall. In Hurler syndrome, affected children have a life expectancy of 6 to 10 years, and death is often a result of cardiac complications. 119  MPS type II or Hunter syndrome, differs from Hurler syndrome in: – its mode of inheritance (X-linked), – the absence of corneal clouding, – and often its milder clinical course. As in Hurler syndrome, the accumulated mucopolysaccharides in Hunter syndrome are heparan sulfate and dermatan sulfate, But this results from a deficiency of L-iduronate sulfatase. 120  Glycogen Storage Diseases (Glycogenoses) An inherited deficiency of any one of the enzymes involved in glycogen synthesis or degradation can result in excessive accumulation of glycogen or some abnormal form of glycogen in various tissues. The type of glycogen stored, its intracellular location, and the tissue distribution of the affected cells vary depending on the specific enzyme deficiency. The glycogen most often is stored within – cytoplasm, or – sometimes within nuclei. – Pompe disease, is a form of lysosomal storage Disease 121  Approximately a dozen forms of glycogenoses have been described in association with specific enzyme deficiencies. Based on pathophysiologic findings, they can be grouped into three categories: – Hepatic type – Myopathic type – Type II glycogenosis (Pompe disease) 122  Hepatic type. – Liver contains several enzymes that synthesize glycogen for storage and also break it down into free glucose. – Deficiency of these hepatic enzymes is associated with Enlargement of the liver due to storage of glycogen and Hypoglycemia due to a failure of glucose production 123  Myopathic type. In striated muscle, glycogen is an important source of energy. When enzymes that are involved in glycolysis are deficient, glycogen storage & muscle weakness occurs due to impaired energy production. Myopathic forms of glycogen storage diseases are marked by : – muscle cramps after exercise – myoglobinuria, and – failure of exercise to induce an elevation in blood lactate levels because of a block in glycolysis. 124  Type II glycogenosis (Pompe disease) – is caused by a deficiency of lysosomal acid maltase – It is associated with deposition of glycogen in virtually every organ, but cardiomegaly is most prominent. Most affected patients die within 2 years of onset of cardiorespiratory failure. 125 126  Crystal-Induced Arthritis Endogenous crystals shown to be pathogenic include: – monosodium urate (MSU) (gout), – calciumpyrophosphate dehydrate (pseudogout), and – basic calcium phosphate. 127  Gout Gout is marked by transient attacks of acute arthritis initiated by urate crystals deposited within and around joints. 128  Pathogenesis Hyperuricemia (plasma urate level above 6.8 mg/dL) is necessary, but not sufficient, for the development of gout. Uric acid metabolism can be summarized as follows: – Synthesis. Uric acid is the end product of purine catabolism. – Excretion. Uric acid is filtered from the circulation by the glomerulus and virtually completely resorbed by the proximal tubule of the kidney. 129  In primary gout, elevated uric acid most commonly results from reduced excretion, the basis of which is unknown in most patients. A small minority of primary gout is caused by uric acid overproduction as a result of identifiable enzymatic defects. – For example, partial deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT) interrupts the salvage pathway, so purine metabolites degraded into uric acid. – Complete absence of HGPRT also results in hyperuricemia, but neurologic manifestations (Lesch-Nyhan syndrome) dominate the clinical picture. 130  Secondary gout can also be caused by increased production: – rapid cell lysis during chemotherapy for leukemia, so-called tumor lysis syndrome or – decreased excretion (chronic renal disease). 131  The inflammation in gout is triggered by precipitation of urate crystals in the joints, stimulating the production of cytokines that recruit leukocytes. Macrophages and neutrophils phagocytose the crystals, which activates a cytosolic sensor, the inflammasome. The inflammasome activates caspase-1 which is involved in the production of active IL-1β. 132  The result is an acute arthritis, which typically remits spontaneously in days to weeks. Repeated attacks of acute arthritis lead eventually to the formation of tophi, aggregates of urate crystals and inflammatory tissue, in the inflamed synovial membranes and periarticular tissue. 134  MORPHOLOGY The distinctive morphologic changes in gout are 4: Acute arthritis is characterized by – a dense inflammatory infiltrate that permeates the synovium and synovial fluid. – Urate crystals are frequently found in the cytoplasm of the neutrophils and are arranged in small clusters in the synovium. – They are long, slender, and needle-shaped, and are negatively birefringent. Chronic tophaceous arthritis – evolves from the repetitive precipitation of urate crystals during acute attacks. – The crystals encrust the articular surface and form visible chalky deposits in the synovium. – The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells and forms a pannus that destroys the underlying cartilage. 135  Tophi in the articular cartilage, ligaments, tendons, and bursae are pathognomonic of gout. – They are formed by large aggregations of urate crystals surrounded by an intense foreign body giant cell reaction. Gouty nephropathy – refers to the renal complications caused by urate crystals or tophi in the renal medullary interstitium or tubules. – Complications include uric acid nephrolithiasis and pyelonephritis. 136  Clinical Course Gout is associated with male sex, obesity, metabolic syndrome, excess alchohol intake, renal failure, and age greater than 30 years. Four clinical stages are recognized: Asymptomatic hyperuricemia appears around puberty in men and after menopause in women. Acute arthritis – presents as sudden onset excruciating joint pain, localized hyperemia, and warmth. – Most first attacks are monoarticular; 50% occur in the first metatarsophalangeal joint. 138  Asymptomatic intercritical period: – Resolution of the acute arthritis leads to a symptom- free interval. – In the absence of appropriate therapy, the attacks recur at decreasing intervals and frequently become polyarticular. Chronic tophaceous gout develops on average about 12 years after the initial acute attack. – At this stage, radiographs show characteristic juxtaarticular bone and loss of the joint space. 139  Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout) 140  DISORDERS WITH MULTIFACTORIAL INHERITANCE A multifactorial physiologic or pathologic trait may be defined as one governed by the additive effect of two or more genes of small effect, conditioned by environmental, nongenetic influences The genetic component exerts a dosage effect Environmental influences, however, significantly modify the phenotypic expression of multifactorial traits  The following features characterize multifactorial inheritance The risk of expressing a multifactorial disorder is conditioned by the number of mutant genes inherited. The rate of recurrence of the disorder (in the range of 2% to 7%) is the same for all first-degree relatives (i.e., parents, siblings, and offspring) of the affected individual. The likelihood that both identical twins will be affected is significantly less than 100% but is much greater than the chance that both nonidentical twins will be affected.  CYTOGENETIC DISORDERS The study of chromosomes—karyotyping—is the basic tool of the cytogeneticist A karyotype is a standard arrangement of a photographed or imaged stained metaphase spread in which chromosome pairs are arranged in order of decreasing length. A variety of staining methods but the one most commonly employed uses a Giemsa stain and is hence called G banding The use of these banding techniques permits certain identification of each chromosome  Cytogenetic disorders may result from alterations in – Numeric abnormalities or – Structure abnormalities of chromosomes and may affect autosomes or sex chromosomes. Numeric Abnormalities – Any exact multiple of the haploid number(n=23) is called polyploid. – If an error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not an exact multiple of 23, it is referred to as aneuploidy – The chief cause of aneuploidy is nondisjunction of a homologous pair of chromosomes during meiotic division – When nondisjunction occurs during gametogenesis, the gametes formed have either an extra chromosome (n+1) or one less chromosome (n-1) – Fertilization of such gametes by normal gametes results in—trisomic (2n+1) or monosomic (2n-1) zygotes – Monosomy or trisomy involving the sex chromosomes are compatible with life – Monosomy involving an autosome don’t permit live birth or even embryogenesis – but a number of autosomal trisomies do permit survival. – With the exception of trisomy 21, all yield severely handicapped infants who almost invariably die at an early age. – Occasionally, mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement, in the same individual, a condition referred to as mosaicism – Mosaicism can result from mitotic errors during the cleavage of the fertilized ovum or in somatic cells. – Mosaicism affecting the sex chromosomes is relatively common.eg 45,X/47,XXX mosaic Structural Abnormalities Usually result from chromosomal breakage followed by loss or rearrangement of material. The patterns of chromosomal rearrangement after breakage are: – Translocation or – Deletion Short hand writing eg. 2q34 indicates chromosome 2, long arm, region 3, band 4. 47xy 21 Xp21.2 46,XY, del(16) (p11.2) Structural Abnormalities….  Translocation –  Is transfer of a part of one chromosome to another chromosome( usually reciprocal) In genetic shorthand, translocations are indicated by t followed by the involved chromosomes in numeric order. E.g. 46,XX,t(2;5)(q31;p14). Because there has been no loss of genetic material, the individual is likely to be phenotypically normal A balanced translocation carrier, however, is at increased risk for producing abnormal gametes. A special pattern of translocation involving two acrocentric chromosomes is called centric fusion type, or robertsonian translocation. Isochromosomes result when the centromere divides horizontally rather than vertically. Structural Abnormalities…. Deletion – Refers to loss of a portion of a chromosome. – Most deletions are interstitial, but rarely terminal deletions may occur. – Inversions occur when there are two interstitial breaks in a chromosome, and the segment reunites after a complete turnaround. – Ring chromosome: after loss of segments from each end of the chromosome, the arms unite to form a ring.  Chromosomal disorders may be associated with absence (deletion, monosomy), excess (trisomy), or abnormal rearrangements (translocations) of chromosomes. In general, loss of chromosomal material produces more severe defects than does gain of chromosomal material Imbalances of sex chromosomes (excess or loss) are tolerated much better than are similar imbalances of autosomes. Cytogenetic Disorders Involving Autosomes 1.Trisomy 21 (Down Syndrome) - most common of the chromosomal disorders 1 in 700 The most common cause of trisomy is meiotic nondisjunction Maternal age has a strong influence In about 4% of all patients with trisomy 21 the extra chromosomal material is due to translocation The parents of such children have a normal karyotype and are normal in all respects. Approximately 1% of trisomy 21 patients are mosaics  Clinical manifestation – Most common genetic cause of mental retardation – Epicanthic folds, flat facial profile, macroglossia – Simian crease Heart cushion defects Increased risk of Hirschsprung's disease and duodenal atresia Increased risk for leukemia ----- Alzheimer's disease by 35 years of age in most cases Females have a 50% chance of having a child with Down syndrome. Sterility in all males 2.Edwards' syndrome – Trisomy 18 – Clinical findings Mental retardation Clenched hands with overlapping fingers Ventricular septal defect (VSD) Early death 2.Patau's syndrome – Trisomy 13 – Clinical findings Mental retardation Cleft lip and palate Polydactyly, VSD, cystic kidneys Early death Cytogenetic Disorders Involving Sex Chromosomes Genetic diseases associated with changes involving the sex chromosomes are far more common than those related to autosomal aberrations. Furthermore imbalances (excess or loss) of sex chromosomes are much better tolerated than are similar imbalances of autosomes A number of abnormal karyotypes involving the sex chromosomes, ranging from 45,X to 49,XXXXY, are compatible with life Features that are common to all sex chromosome disorders. In general, they cause subtle, chronic problems relating to sexual development and fertility. They are often difficult to diagnose at birth, and many are first recognized at the time of puberty. In general, the higher the number of X chromosomes, in both male and female, the greater the likelihood of mental retardation Klinefelter Syndrome male hypogonadism that develops when there are at least two X chromosomes and one or more Y chromosomes Most patients are 47,XXY nondisjunction of sex chromosomes during meiosis Advanced maternal age and hx of irradiation of either parents Klinefelter syndrome is the most common cause of hypogonadism in males. Only rarely are patients fertile, and these are presumably mosaics with a large proportion of 46,XY cells  Approximately 15% of patients show mosaic patterns, including 46,XY /47,XXY,or 47,XXY /48,XXXY, Clinical features Female secondary sex characteristics at puberty such as gynecomastia, female type hair distribution and soft skin Delayed sexual maturation (hypogonadism), testicular atrophy Disproportionately long legs, learning disabilities Decreased testosterone  higher risk for breast cancer (20 times more common than in normal males), extragonadal germ cell tumors, and autoimmune diseases such as systemic lupus erythematosus. Turner Syndroame primary hypogonadism in phenotypic females partial or complete monosomy of the short arm of the X chromosome the entire X chromosome is missing in 57% of patients(45X) & they are most severly affected including  significant growth retardation(short stature)  Lymphedema in hands and feet in infancy with webbed neck  low posterior hairline; cubitus valgus, shieldlike chest with widely spaced nipples; high-arched palate  congenital malformations such as horseshoe kidney, bicuspid aortic valve, and coarctation of the aorta  In adolescence, affected girls fail to develop normal secondary sex characteristics and Most have primary amenorrhea  Streak gonads  Mental status usually normal Approximately 43% of patients either are mosaics or have structural abnormalities of the X chromosome. have an almost normal appearance and may present only with primary amenorrhea SINGLE-GENE DISORDERS WITH ATYPICAL PATTERNS OF INHERITANCE Three groups of diseases resulting from mutations affecting single genes do not follow the mendelian rules of inheritance: – Diseases caused by triplet repeat mutations – Diseases caused by mutations in mitochondrial genes – Diseases associated with alteration of imprinted regions of the genome 168  1.Triplet-Repeat Mutations Fragile X Syndrome - Fragile X syndrome is the prototype of diseases in which the mutation is characterized by a long repeating sequence of 3 nucleotides Huntington disease and myotonic dystrophy are other examples associated with trinucleotide repeat mutations. All disorders with such mutation discovered so far are associated with neurodegenerative changes. It is characterized by mental retardation, macroorchidism, and abnormal facial structures.  Like all X-linked recessive disorders, this disease affects males. However, unlike patients with other X-linked recessive disorders, approximately 20% of males who are known to carry the fragile X mutation may be clinically and cytogenetically normal. These "carrier males" can transmit the disease to their grandsons through their phenotypically normal daughters.  As with all X-linked diseases, fragile X syndrome predominantly affects males. But it shows some patterns of transmission not typically associated with other X-linked recessive disorders. These include the following: – Carrier males, approximately 20% – Affected females, 30% to 50% of carrier women might show features of mild cognitive impairment – Anticipation, clinical features of fragile X syndrome worsen with each successive generation 171  In the normal population, the number of repeats of the sequence CGG in the FMR1 gene is small, averaging around 29, whereas affected persons have 200 to 4000 repeats. The molecular basis for fragile X syndrome is related to silencing of the product of the FMR1 gene, familial mental retardation protein (FMRP). When the number of trinucleotide repeats exceeds 230, the DNA region of the gene & the promoter region of the gene become abnormally methylated resulting in transcriptional suppression of FMR1. FMRP is expressed in higher levels in the brain and the testis. 172 173  2. Fragile X Tremor/Ataxia CGG premutations in the FMR1 gene can cause a disease that is phenotypically different from fragile X syndrome through a distinct mechanism involving a toxic “gain-of function. ” This syndrome is characterized by intention tremors and cerebellar ataxia and may progress to parkinsonism. In these patients, the FMR1 gene instead of being methylated and silenced continues to be transcribed. CGG-containing FMR1 mRNAs so formed are “toxic.” 174  Triplet-Repeat Mutations Some general principles are: – gene functions are altered by an expansion of the repeats. – the expansion in fragile X syndrome occurs during oogenesis, in others premutations are converted to full mutations during spermatogenesis. – The expansion may involve untranslated regions or coding regions. – When mutations affect noncoding regions, there is “loss of function’’ – Mutations involving translated parts of the gene give rise to misfolded proteins. Involve CAG repeats that encode polyglutamine tracts. 175  2.Diseases Caused By Mutations in Mitochondrial Genes Mitochondria contain several genes that encode enzymes involved in oxidative phosphorylation. Inheritance of mitochondrial DNA is associated with maternal inheritance Diseases caused by mutations in such genes affect organs most dependent on oxidative phosphorylation (skeletal muscle, heart, brain). Leber hereditary optic neuropathy is the prototypical disorder in this group Progressive loss of central vision.  Diseases Caused by Alterations of Imprinted Regions: Prader-Willi and Angelman Syndromes All humans inherit two copies of each gene (except sex chromosome genes in males), carried on homologous maternal and paternal chromosomes. Functional differences exist between paternal and maternal copies of some genes. The differences arise from an epigenetic process called genomic imprinting, whereby certain homologous genes are differentially “inactivated” during paternal and maternal gametogenesis. Thus, maternal imprinting refers to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated. 177  Imprinting occurs in ova or sperm and is then stably transmitted to all somatic cells derived from the zygote. Prader-Willi syndrome characterize by – Mental retardation, short stature, hypotonia, obesity, small hands and feet, and hypogonadism. – an interstitial deletion of band in the long arm of paternally derived chromosome 15— del(15)(q11;q13)—can be detected. 178  Patients with the phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers. Patients with Angelman syndrome also are mentally retarded, but in addition they present with ataxic gait, seizures, and inappropriate laughter. Because of the laughter and ataxia, this syndrome has been called the happy puppet syndrome. A comparison of these two syndromes clearly demonstrates the “parent-of origin” effects on gene function. 179 180  The molecular basis of these two syndromes can be understood in the context of imprinting. A set of genes on the maternal chromosome at 15q12 is imprinted (and hence silenced), so the paternal chromosome provides the only functional alleles. When these are lost as a result of a deletion (in the paternal chromosome), the patient develops Prader-Willi syndrome. Conversely, a distinct gene, UBE3A, that also maps to the same region of chromosome 15 is imprinted on the paternal chromosome. Deletion of this maternal gene on chromosome 15 gives rise to the Angelman syndrome. 181  Molecular studies of cytogenetically normal patients with Prader-Willi syndrome have shown that in some cases, both of the structurally normal copies of chromosome 15 are derived from the mother. Inheritance of both chromosomes of a pair from one parent is called uniparental disomy. 182  Pediatric Diseases Many diseases of infancy and childhood are of genetic origin. Others, although not genetic, either are unique to children or take distinctive forms in this patient population and thus merit the designation pediatric diseases.  CONGENITAL ANOMALIES – Congenital anomalies are structural defects that are present at birth. – The term congenital does not imply or exclude a genetic basis.  CONGENITAL ANOMALIES…. Definition of some terms – Malformations are primary errors of morphogenesis, usually are multifactorial. – Disruptions result from secondary destruction of body region that was previously normal in development. – Deformations represent an extrinsic disturbance of development. – Sequence refers to multiple congenital anomalies that result from secondary effects of a single localized aberration in organogenesis. – Malformation syndrome refers to the presence of several defects that cannot be explained on the basis of a single localizing initiating error in morphogenesis. Syndromes most often arise from a single causative condition (e.g., viral infection or a specific chromosomal abnormality). – Some general terms are applied to organ-specific malformations. Agenesis refers complete absence of an organ Aplasia and hypoplasia indicate incomplete development and underdevelopment, respectively. Atresia describes the absence of an opening.  Etiology : causes of malformations can be grouped into 3 categories: – Genetic – Environmental and – Multifactorial  Pathogenesis – 1. The timing of the prenatal teratogenic insult has an important impact on the occurrence and the type of anomaly produced. – 2. The complex interplay between environmental teratogens and intrinsic genetic defects is exemplified by the fact that features of dysmorphogenesis caused by environmental insults often can be recapitulated by genetic defects.  PERINATAL INFECTIONS Infections of the fetus and neonate may be acquired : – Transcervically (ascending infections) or – Transplacentally (hematologic infections).  PREMATURITY AND FETAL GROWTH RESTRICTION Prematurity is defined by a gestational age less than 37 weeks and is the second most common cause of neonatal mortality.  RESPIRATORY DISTRESS SYNDROME OF THE NEWBORN The most common cause of respiratory distress in the newborn is respiratory distress syndrome (RDS), also know as hyaline membrane disease because of the formation of “membranes” in the peripheral air spaces. The fundamental defect in RDS is insufficient surfactant.  NECROTIZING ENTEROCOLITIS Necrotizing enterocolitis (NEC) most commonly occurs in premature infants. The involved segment typically is distended, friable, and congested or gangrenous; intestinal perforation with accompanying peritonitis may be seen.  SUDDEN INFANT DEATH SYNDROME (SIDS) SIDS is defined as “the sudden death of an infant under 1 year of age which remains unexplained after a thorough case investigation.’’ SIDS is multifactorial condition. Three interacting variables have been proposed: – (1) a vulnerable infant – (2) a critical developmental period in homeostatic control, and – (3) one or more exogenous stressors.  Vulnerable infant, the most compelling hypothesis is that SIDS reflects a delayed development of arousal and cardiorespiratory control. Among the potential environmental causes, prone sleeping position, sleeping on soft surfaces, and thermal stress.  FETAL HYDROPS Fetal hydrops refers to the accumulation of edema fluid in the fetus during intrauterine growth.  Immune Hydrops results from an antibody- induced hemolytic disease in the newborn that is caused by blood group incompatibility between mother and fetus. The most common antigens to result in clinically significant hemolysis are the Rh and ABO blood group antigens.  Nonimmune Hydrops – The major causes of nonimmune hydrops include those disorders associated with cardiovascular defects, chromosomal anomalies, and fetal anemia.  TUMORS AND TUMORLIKE LESIONS OF INFANCY AND CHILDHOOD Malignant neoplasms constitute the second most common cause of death in children between the ages of 4 and 14 years; next to accidents. Benign tumors are even more common than cancers. Two special categories of tumorlike lesions should be recognized: – Heterotopia or choristoma – Hamartoma refers to an excessive but focal overgrowth of cells and tissues.  Benign Neoplasms – Hemangiomas are the most common neoplasms of infancy. – Both cavernous and capillary hemangiomas may be encountered.  Lymphangiomas represent the lymphatic counterpart of hemangiomas.  Teratomas may occur as : – Benign, well-differentiated cystic lesions (mature teratomas) – Lesions of indeterminate potential (immature teratomas), or – Unequivocally malignant teratomas. Sacrococcygeal teratomas are the most common teratomas of childhood, accounting for 40% or more of cases.  Malignant Neoplasms The organ systems involved most commonly by malignant neoplasms in infancy and childhood are the hematopoietic system, neural tissue, and soft tissues.  Malignant neoplasms of infancy and childhood differ biologically and histologically from those in adults : – Frequent demonstration of a close relationship between teratogenesis and oncogenesis, suggesting a common stem cell defect. – Prevalence of familial syndromes that predispose to cancer. – Tendency to regress spontaneously or “differentiation” into mature elements. – Better survival or cure of many childhood tumors.  Many malignant pediatric neoplasms tend to exhibit a primitive (embryonal) microscopic appearance, and frequently they exhibit features of organogenesis. Because of their primitive histologic appearance, many childhood tumors have been collectively referred to as small, round, blue-cell tumors.  Neuroblastoma – The term neuroblastic includes tumors of the sympathetic ganglia and adrenal medulla that are derived from primordial neural crest cells; neuroblastoma is the most important member of this family. 40% of neuroblastomas arise in the adrenal medulla.  Many factors influence prognosis, but the most important are the stage of the tumor and the age of the patient.  Retinoblastoma – Retinoblastoma is the most common primary intraocular malignancy of children.  Clinical Features – The presenting findings include poor vision, strabismus, a whitish hue to the pupil (“cat’s eye reflex”), and pain and tenderness in the eye. – The median age at presentation is 2 years, although the tumor may be present at birth. – Untreated, the tumors usually are fatal, but when treated survival is the rule.  Wilms Tumor – Wilms tumor, or nephroblastoma, is the most common primary tumor of the kidney in children, with most cases occurring between 2 and 5 years of age.  WAGR syndrome (i.e., Wilms tumor, aniridia, genital abnormalities, and mental retardation); Denys-Drash syndrome (DDS), and Beckwith-Wiedemann syndrome (BWS) are congenital malformations associated with wilms tumor.  On microscopic examination, Wilms tumors are characterized by recognizable attempts to recapitulate different stages of nephrogenesis. The classic triphasic combination of blastemal, stromal, and epithelial cell types is observed in most lesions, although the percentage of each component is variable.  Clinical Course – Patients typically present with a palpable abdominal mass. The prognosis for Wilms tumor generally is very good, and excellent results are obtained with a combination of nephrectomy and chemotherapy.  THANK YOU 227