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 – 10th-90th percentile

• Small for gestational age - <10th percentile• Large for gestational age - > 90th 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 10-7- 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 10-11

• 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 10-8• -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