Genetic Disorders

Question 1

Definition of Critical Thinking

Answer 1

the process of tying together one’s knowledge of medicine with a specific clinical encounter to formulate a diagnostic, therapeutic or preventative strategy

Question 2

steps in clinical reasoning

Answer 2

patient's story
data acquisition
accurate "problem representation"
generation of hypothesis
search and select a "script" for the illness
diagnosis

Question 3

Congenital Malformations

Answer 3

Defined as structural defects present at birth
May not become clinically apparent for years (some cardiac and renal anomalies)
Congenital defect does not imply or exclude a genetic basis for the defect
Estimates are that approximately 3% of newborns have a major anomaly that is of functional or cosmetic significance

Question 4

causes of congenital malformations

Answer 4

about a quarter are inherited

another 10-15 environmental, including the TORCH infections, maternal disease states, drugs and chemicals.

Multifactorial is another quarter

and the rest unknown

Question 5

CHARGE syndrome findings

Answer 5

Coloboma-may involve iris and/or retina
Heart defect-occurs 75% of the time and includes Tetralogy of Fallot (33%), PDA, VSD, and others
Atresia choanae (choanal atresia)-this finding strongly suggests CHARGE syndrome
Retardation of growth and development-usually normal weight but growth falls off with time
Genitourinary problems-hypogonadism is common
Ear, olfactory and other cranial nerve problems-ear problems 80% of the time

Question 6

CHARGE syndrome diagnostic info

Answer 6

Autosomal Dominant disorder with a prevalence of 1 in 10,000
CHARGE acronym based on above findings
Newer diagnostic criteria stresses the importance of the 3C Triad (Coloboma-Choanal atresia-abnormal semicircular canals)
The major clinical findings have suggested the pathogenic mechanism may involve disturbed neural crest development

Question 7

the genes of CHARGE

Answer 7

Using a Comparative Genomic Hybridization (CGH) approach, microdeletions in the gene CHD7, located at 8q12, were identified as causative in 2/3 of the patients with a clinical diagnosis of CHARGE syndrome. A deletion of 8q12 was occasionally found.

Question 8

The CHD7 Protein

Answer 8

Function remains largely unknown
Protein is a nuclear protein and appears to be associated with nucleosome remodeling
The protein may target a set of transcriptionally active genes, including genes within the HOXA cluster, which is involved in CNS, digestive and head development

Question 9

VATER/VACTERL Association

Answer 9

First described in 1973
Acronym describes the typical components
Vertebral defects
Anal atresia
T-E fistula with esophageal atresia
Radial and Renal dysplasia

In 1975 the C for cardiac defects and L for limb defects were added to make it VACTERL association

Question 10

Syndrome verses Association

Answer 10

Syndrome has defined genetic cause

Association does not

Question 11

Inborn Errors of Metabolism

Answer 11

Individually rare but many more disorders have been identified and are being recognized much more often in the neonatal period
While newborn screening includes a growing list of conditions and should identify those early, the signs and symptoms of an error in metabolism are frequently non-specific and can begin prior to the results of screening

Question 12

Mode and Timing of IEM Presentation

Answer 12

Before birth
- Hemoglobinopathies leading to hydrops fetalis

At birth
- Congenital lactic acidosis

Sudden death usually at 2-3 days of age
- Defects in fatty acid oxidation

Deterioration after a symptom-free period
- Adrenal insufficiency

Question 13

Patterns of Deterioration

Answer 13

Unexplained hypoglycemia
Disorders of acid-base status
Neurological deterioration
Cardiac disorders: arrhythmias and cardiomyopathy
Acute parenchymal liver disease

Question 14

Causes of Hypoglycemia in Infancy

Answer 14

Endocrine:
Adrenal insufficiency
Growth hormone deficiency
Hypothyroidism
Hyperinsulinemia
Hypopituitarism

Metabolic:
	Disorders of carbohydrate metabolism
	Disorders of gluconeogenesis
	Disorders of organic acid metabolism
	Disorders of fatty acid oxidation and carnitine transport

Other:
Drugs (oral hypoglycemics/alcohol/aspirin
Sepsis

Question 15

Hypoglycemia and/or cardiac failure

Answer 15

Infants presenting with hypoglycemia associated with lethargy, hepatomegaly and liver failure, cardiomyopathy and/or dysrhythmia may have a fatty acid oxidation defect

In these infants there is no ketoacidosis, hyperammonemia may be present and uric acid levels may be high

Question 16

Hypoglycemia and/or Liver Failure

Answer 16

When evidence of liver failure remains despite correction of hypoglycemia, three disorders must be considered urgently:

• Galactosemia
• Hereditary fructose intolerance
• Tyrosinemia type I

With consideration of these orders, galactose , fructose and protein must be excluded from the diet until an exact diagnosis can be made

Question 17

Hypoglycemia With Hepatomegaly

Answer 17

Infants presenting with hypoglycemia that maintain normal glucose levels with permanent glucose provision without signs of liver failure with hepatomegaly may have glycogen storage diseases Type I and Type III or fructose-1,6-biphosphatase defects

Question 18

Recurrent Intractable Hypoglycemia

Answer 18

Infants that cannot maintain adequate glucose levels despite constant glucose provision and without evidence of ketoacidosis most likely will have hyperinsulinemia

Question 19

Neurological Deterioration

Answer 19

Most common presentation usually seizures or hypotonia
Can be caused by a variety of conditions including organic acidemias, urea cycle defects, maple syrup urine disease, fatty acid oxidation defects and congenital lactic acidosis
Rate of deterioration depends on the nature and severity of the defect

Question 20

Time to Presentation

Answer 20

Urea cycle and branched-chain organ acidemias typically appear at 12 to 72 hours of age
Maple syrup urine disease appears at 4 to 7 days of age
Hyperglycinemia appears at 48 hours of age