Diseases of Infancy and Childhood

Congenital Anomalies Causes of death by age groups – Table 10-1 Definitions Causes of anomalies Pathogenesis of anomalies

Congenital Anomalies Definitions: – Malformation – intrinsically abnormal developmental process – Disruption – extrinsic disturbance in morphogenesis, secondary destruction of a previously normal organ or region – Deformation – abnormal biomechanical force leading to a structural abnormality – Sequence – cascade of anomalies triggered by one initiating aberrration – Syndrome – constellation of anomalies, usually a single etiologic agent that simultaneously affects several tissues

Congenital Anomalies Causes: – Genetic – Environmental – infections, maternal disease states, drugs and other chemicals, irradiations – Multifactorial – Unknown – 40-60% – Table 10-3

Congenital Anomalies Pathogenesis – The timing of the prenatal teratogenic insult has an important impact on the occurrence and the type of anomaly produced – The complex interplay between environmental teratogens and intrinsic genetic defects is underscored by the fact that features of dysmorphogenesis caused by environmental insults can often be recapitulated by genetic defects in the pathways targeted by these teratogens

Disorders of Prematurity Causes of prematurity and fetal growth restriction Neonatal respiratory distress syndrome Necrotizing enterocolitis

Disorders of Prematurity Appropriate for gestational age – 10 th -90 th percentile Small for gestational age - <10 th percentile Large for gestational age - > 90 th percentile Pre-term – before 37 weeks Post-term – after 42 weeks

Disorders of Prematurity Causes of prematurity and growth restriction – Preterm premature rupture of membranes – Intrauterine infection – Uterine, cervical, and placental structural abnormalities – Multiple gestation – Fetal conditions – Placental insufficiency – Maternal conditions

Disorders of Prematurity Hyaline membrane disease (neonatal RDS) Necrotizing enterocolitis Sepsis Intraventricular hemorrhage Patent ductus arteriosus Long-term complications

Disorders of Prematurity Neonatal RDS – Immaturity of the lungs is the most important substrate upon which this condition develops – The fundamental defect in RDS is the deficiency of pulmonary surfactant – Role of glucocorticoids is particularly important – Figure Pathophysiology of RDS – Retinopathy of prematurity – Bronchopulmonary dysplasia

Perinatal Infections Transcervical ( Ascending) infections – most bacterial and a few viral ( herpes simplex) Transplacental (Hematologic) infections – most parasitic and viral and a few bacterial, TORCH Sepsis – Group B streptococcus

Fetal Hydrops Immune hydrops – – Blood group incompatibility between mother and fetus – Anemia and jaundice – Pathogenesis – Figure Nonimmune hydrops – Cardiovascular defects – Chromosomal anomalies – Fetal anemia

Inborn Errors of Metabolism PKU Galactosemia Cystic Fibrosis

Phenylketonuria (PKU) Biochemical abnormality: – Inability to convert phenylalanine into tyrosine – Hepatic PAH system BH4, DHPR – Important to recognize PKU variants – Severe mental retardation, seizures, decreased pigmentation of hair and skin, eczema – Maternal PKU

Galactosemia Two variants – More common – lack of GALT ( galactose-1- phospahte uridyl transferase) – Rare – deficiency of galactokinase FTT, vomiting and diarrhea, jaundice, hepatomegaly, E. coli sepsis, cataracts, mental retardation

Cystic Fibrosis Also called mucoviscidosis Disorder of ion transport in epithelial cells that affects fluid secretion in exocrine glands and the epithelial lining of the respiratory, GI, and reproductive tracts Primary defect – Abnormal function of an epithelial chloride channel protein encoded by the CFTR gene Functions of CFTR – Regulates multiple ion channels and cellular processes – Functions are tissue-specific: sweat glands vs resp and GI tracts – Mediates transport of bicarbonate ions

Cystic Fibrosis CFTR gene mutations – Class I: defective protein synthesis – Class II : abnormal protein folding, processing, and trafficking – Class III: defective regulation – Class IV: decreased conductance – Class V: reduced abundance – Class VI: altered regulation of separate ion channels

Cystic Fibrosis NB screening – controversial Clinical features and diagnostic criteria – Table 10-6

SIDS The sudden death if an infant under one year of age which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history. Risk factors and postmortem findings- Table 10-7 ALTE – apparent life-threatening event Back to Sleep campaign “Triple-risk” model – Vulnerable infant, critical developmental period of homeostatic control, exogenous stressor

Tumors and Tumor-Like Lesions of Infancy and Childhood Benign and tumor-like lesions Malignant tumors – Incidence and types – Neuroblastic Tumors – Wilms Tumors

Benign Tumors and Tumor-like Lesions Hemangioma Lymphatic tumors Fibrous tumors Teratomas

Malignant Tumors Incidence and types – Table blastomas Small round cell tumors

Neuroblastic Tumors Spontaneous or therapy-induced differentiation of primitive neuroblasts into mature elements, spontaneous tumor regression, wide range of clinical behaviour and prognosis ALK gene Homer-Wright pseudorosettes, ganglioneuroma, Schwann cells Staging Prognostic factors – Table 10-9 Clinical features – Abdominal masses, fevers, weight loss – “blueberry muffin” – Proptosis and periorbital echymosis – Catecholamine production – Bone pain, respiratory complaints, GI complaints

Wilms Tumor Biology of tumor illustrates important aspects of childhood tumors – Relationship between malformations and neoplasia – Organogenesis and oncogenesis – Two-hit theory of recessive tumor suppressive genes – Role of premalignant lesions – Potential for judicious treatment modalities to dramatically affect prognosis and outcome

Wilms Tumor Nephrogenic rests Large abdominal mass, hematuria, abdominal pain, intestinal obstruction, hypertension Syndromic tumor – WAGR syndrome – aniridia, genital abnormalities, mental retardation – Denys-Drash syndrome – gonadal dysgenesis, nephropathy – Beckwith-Wiedermann syndrome – enlargement of body organs, genomic imprinting – WT1 and WT2 – Beta-catenin