Congenital Disorders

Erythroblastosis Fetalis Signs and Symptoms

- Ranges from mild anemia to jaundice to death (2nd pregnancy child is at greater risk than 1st) - Jaundice from high bilirubin - Spleen and liver may be enlarged

Cerebral Palsy Diagnosis & Treatment

- Diagnosis: Cranial MRI - Treatment: Geared toward overcoming disability

Patent Ductus Arteriosus

- Connection between pulmonary artery and aorta remains open (@ birth should close) - Frequent in premature births

Spina Bifida

- Defective closure of spinal column, associated with a mutation of *MTHFR gene* which codes for an enzyme that processes folate into methionine, can occur w/ lack of folic acid Two forms: 1). Spina Bifida Occulta 2). Spina Bifida Cystica

Osteogenesis Imperfecta

- 8 autosomal dominant and recessive forms exist - 1 in 30,000 to 1 in 60,000

Trisomy 21 (Down Syndrome)

- 95% have an extra chromosome 21 - Overall incidence is 1 in every 700 - Closely related to age of mother: In early childbearing years is 1/2000 after 40 yrs. rises to 1/40

Chromosome Disorders: Turner Syndrome XO

- Affects females: Short stature; Infertility

X-linked Disorders: Recessive

- Allele carried on the X chromosome but not the Y chromosome - Manifested in heterozygous males lacking the matching unaffected gene on the Y chromosome - Heterozygous females are carriers. - Homozygous recessive females may be affected. - Inheritance may appear to "skip generations - Ex: Duchenne muscular dystrophy; Classic hemophilia

Autosomal Recessive Disorders

- Both Parents Must Pass on the Allele for Disorder: Parents may be heterozygous and unaffected; termed carriers; Parents may be homozygous and affected - Male and female children are affected equally - Homozygous recessive child has the disorder - Heterozygous Child: No clinical signs of disease; Child is a carrier

Cerebral Palsy

- Broad term used to describe a number of motor disorders resulting from developmental abnormalities or perinatal or postnatal CNS damage - Associated with a mutation in the *AP4B1 gene* which hinders the ability of the cell to properly transport molecules from the Golgi apparatus to the correct lysosome - Also from perinatal or postnatal CNS trauma occurring before age 5, trauma during birth - It is a classification for children with nonprogressive spasticity, ataxia (defective muscle coordination), or involuntary movements - Maybe lagging motor development - Use of only one limb but not others

Cystic Fibrosis Etiology

- Carried by autosomal recessive trait - *Mutation of the CFTR gene disrupts chloride transport across plasma membrane* (lining of lungs)

Proteus Syndrome

- Caused by *mutation in AKT1 gene* in which it becomes *activated by phosphorylation and suppresses apoptosis* - Mutation occurs during embryonic growth - Probable condition of Joseph Merrick (the elephant man) - Mosaicism: Some cells have the mutation and others don't, involves atypical growth of bones and skin

Erythroblastosis Fetalis Etiology

- Caused by incompatibility between maternal mother and fetal blood - Mother is Rh- and fetus is Rh+ - Can also happen with different blood types but is usually sub-clinical - Antibody crosses placenta

Single-Gene Disorders (aka Mendelian traits)

- Classified by inheritance patterns: Recessive, dominant, X-linked recessive - Single gene controls a specific function: -e.g., color blindness - May have systemic effects: -e.g., cystic fibrosis

Examples of Multifactorial Disorders

- Cleft palate - Congenital hip dislocation - Congenital heart disease - Type 2 diabetes mellitus

Erythroblastosis Fetalis Diagnosis & Treatment

- Diagnosis: Maternal history and blood typing of mother and father; Coomb's test- detects antibodies that bind to individual's own RBC's - Treatment: Intrauterine transfusion or delivery

Hydrocephalus Diagnosis & Treatment

- Diagnosis: Measure head; Ultrasonography can determine size of ventricles - Treatment: Surgery to add shunt, or bypass around blockage

Cystic Fibrosis Diagnosis & Treatment

- Diagnosis: Suggested by clinical and laboratory signs; Confirmed by abnormally high Na and Cl levels in sweat - Treatment: No cure; Largely supportive, bronchodilators, aerosol drugs to thin secretions; Life expectancy is 37 years

Cystic Fibrosis (recessive)

- Disease of exocrine glands (mucus producing) - Most common lethal genetic disease among people of European descent - 1 in 2,400 births

Congenital Disorders

- Disorders present at birth - Include inherited or developmental disorders - a major anomaly is usually present in 3-4% of newborns

Cystic Fibrosis Pathophysiology

- Disrupts chloride transport across plasma membrane - Affected Glands Fall into 3 Categories: 1). Obstructed by thick, mucus-like material in the lumen of the gland 2). Produce an excess of normal secretions 3). Normal but secrete excessive Na and Cl in sweat

Hydrocephalus Signs and Symptoms

- Enlarged head from non-communicating - Bulging fontanelles from communicating - Often associated with projectile vomiting

Developmental Disorders

- Exposure to drugs, chemicals, or radiation during child-bearing years

Chromosome Disorders: Klinefelter Syndrome XXY

- Extra X chromosome is present; Infertility

Cleft Lip/Palate: Etiology

- Failure of palate or lip to unite - 1 in 700 to 800 births - Cleft lip causes no functional impairment - Cleft palate can interfere with feeding and speech - Sometimes caused by mutation HSX1 gene (homeobox) - Treatment: Surgically repair

X-linked Disorders: Dominant

- Heterozygous males and females are affected - Reduced penetrance in females - Fragile X Syndrome is an Example: Most common genetic cause of cognitive defects; Effects are variable and related to the extent of mutation of the allele

Autosomal Dominant Disorders

- Inheritance of one allele causes disorder, only one parent needs to carry allele - No Carriers: Unaffected persons do not transmit the disorder - Some Conditions Become Evident Later in Life: Allele for disorder may have been passed on to next generation before diagnosis of disease in parent; Termed "delayed lethal" genotype

Osteogenesis Imperfecta Etiology

- Inherited and caused by defective collagen formation from *mutation in COLIA I and COLAI II genes* (90% of cases) - Impaired ability of collagen fibers to bond together (no foundatin for bone mineral deposit) - Results in lax, stretchable connective tissue with low integrity

Cystic Fibrosis Signs and Symptoms

- Meconilum ileus is earliest sign (thick green patches) - Caused by obstruction of ileum by viscid meconium - Chronic cough and wheezing associated with recurrent or chronic pulmonary infection

Trisomy 21 (Down Syndrome) Signs and Symptoms

- Microcephaly (small head) and brachycephaly (wider head) are present - Eyes are slanted with epicanthic folds - Flattened nasal bridge - Tongue is large, furrowed, and lack central fissure - life expectancy is 40-50 yrs - no treatment; palliative- social adjustment

Proteus Syndrome Signs and Symptoms

- Multiple hyperostoses of calvaria, facial bones, and mandible - Hemihypertrophy: Overgrowth of one side of the face, body, or limbs - Tumors on skin surface may be present - Resembling lymphangioma (composed of lymph vessels) - Treatment: no known cure

Osteogenesis Imperfecta Treatment

- No effective treatment known - Directed toward preventing/controlling symptoms, maximizing independent mobility, and developing optimal bone mass and muscle strength

Osteogenesis Imperfecta Signs and Symptoms

- Numerous fractures - Easily chipped teeth - Bluish sclerae (white-part of eye is blue) - Fracture callus may be normal but remodeled bone is of poor quality

Multifactorial Disorders

- Often have pattern of familial inhertiance - Environmental component

Ventricular Septal Defect

- Part of a number of conditions grouped as *CCHD - Critical Congenital Heart Disease* -opening in septum that divides ventricles -Frequently heard as a loud, harsh murmur at lower-left sternal border - Acyanotic: Lack of bluish tint to lips, skin, and eyes - *Mutation of the GATA4 (a transcriptional activator) gene leads to VSD* but it can be caused by others - Treatment: Often closes by 1yr, can respond to anticongestive drugs, some repaired surgically

Transposition of Great Vessels

- Pulmonary artery arises from left ventricle, aorta arises from right ventricle (O2 poor blood cant get to lungs, rather carried in circulatory system) - Usually associated with patent foramen ovale - Some factors, such as rubella or other viral illnesses during pregnancy, maternal age over 40, or maternal diabetes, may increase the risk of this condition, associated with GATA4 mutation

Neural Tube Defects

- Some of the most serious defects develop during the first 2 months of gestation - Accurate in utero detection is possible through amniocentesis and ultrasonography - Folic acid supplements (4mg/day) before and during pregnancy can significantly reduce chances (allow spinal cord & brain to meet & close)

Single Gene Disorders

- Trait controlled by one set of alleles - Transmitted to subsequent generations

Chromosome Disorders: Down Syndrome

- Trisomy 21 (3 21st chromoses); May be due to non-disjunction or translocation

Chromosomal Anomalies

- Usually from an error during meiosis (sex cell division) -- Non-disjunction (when cells divide chromosome stay attached & don't seperate) -- Translocation

Patent Ductus Arteriosus Diagnosis

- by bounding pulse (rapid increase, goes away fast, then starts over again), increased pulmonary closure sound - acyanotic

Hydrocephalus Etiology: Communicating

- failure in reabsorption of CSF - Usually caused by meningeal inflammation secondary to infection or blood in subarachnoid space

TORCH: Developmental disorder

- maternal infections that result in anomalies: Toxoplasmosis, Other (Syphilis, varicella-zoster, parvovirus B19), Rubella, Cytomegalovirus (CMV), and Herpes infections. 2-3%

Teratogenic Agents

Agents that cause damage during embryonic or fetal development

Transposition of Great Vessels Diagnosis & Treatment

Chest x-ray, echocardiography - Treatment: Surgery

Non-Communicating Hydrocephalus: Etiology

Blockage most often in cerebral aqueduct but can occur almost anywhere

Erythroblastosis Fetalis (Hemolytic Disease of the Newborn): single-gene disorder

Characterized by excessive rates of RBC destruction

Spina Bifida: Cystica

Cyst produced that can contain: a). Meninges (meningocele) b). Spinal cord/nerves (myelocele) c). Both (myelomeningocele) - Most common in lower thoracic, lumbar, and/or sacral regions - If myelomeningocele, can cause paralysis of limbs and organs

Patent Ductus Arteriosus Treatment

Fluid restriction (decrease BP help closure), drugs for closure, surgery

Multifactorial Disorders

Genetic influences combined with environmental factors

Cerebral Palsy Prenatal Causes Include

Maternal rubella, maternal diabetes, toxemia -Specific cases cannot be identified until age 2, (have to positive it is cerebral palsy indefinitely)

Spina Bifida: Occulta

Only one or two verts fail to close, no protrusion of meninges

Transposition of Great Vessels Signs and Symptoms

Severe cyanosis, metabolic acidosis, possible tachypnea, tachycardia during first 3-6 weeks of life

Hydrocephalus

Ventricular enlargement with excessive CSF