Approach to the patient with a possible genetic disorder

Question 1

What is shown in the attached picture? Describe it!

Answer 1

Coloboma-an absence or defect in tissue

Question 2

What is the definition of a congenital malformation?

Answer 2

Structural defect present at birth

Question 3

Are congenital malformations always present at birth?

Answer 3

Yes, but they may not become apparent for many years, such as in cardiac and renal anomalies

Question 4

What are the main causes of congenital malformations?

Answer 4

Genetic

Environmental

Multifactorial

Unknown

Question 5

What are the genetic types of congenital malformation inheritance mechanisms?

Answer 5

Chromosomal Aberrations

Mendelian Inheritance

Question 6

What are the types of environmental factors that can contribute to congenital malformations?

Answer 6

Maternal/placental infections

• TORCH organisms

Maternal disease states

• DM
• PKU
• Endocrinopathies

Drugs and chemicals

• ETOH
• Folic acid antagonists
• Androgens
• phenytoin
• Thalidomide
• Warfarin
• 13-cis-retinoic acid

Irradiation

Question 7

What are the steps in clinical reasoning on cases like this?

Answer 7

1. Patient story
2. Data gathering
3. accurate representation of problem
4. Hypothesis
5. Search and select a “script” for the illness
6. Diagnosis

Question 8

You are called to the NICU to evaluate a male term infant. Physical exam reveals a right retinal coloboma, right choanal atresia, square face, micrognathia, malformed, low set ears and shallow orbital ridges. A large systolic murmur is heard. Cardiovascular workup shows a ventricular septal defect. Auditory evoked potentials reveal bilateral deafness.

What is this most likely?

Answer 8

Charge Syndrome

Question 9

What are the components of charge syndrome? (hint, charge is the acronym)

Answer 9

• *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 10

What is choanal atresia?

Answer 10

The passageway from the pharynx to back of nose is closed off.

Question 11

Which image is normal? What is being visualized here? What is going on in the abnormal one?

Answer 11

Semicircular Canals, Left is normal.

On the right we see radioopaque mass in place of canals. This absence of canals is typical of CHARGE syndrome.

Question 12

What is the inheritance pattern for CHARGE syndrome? Prevalence?

Answer 12

Autosomal dominant

1/10,000

Question 13

What do the most recent diagnostic criteria stress in diagnosis of CHARGE syndrome?

Answer 13

3C Triad

Coloboma

Choanal Atresia

Abnl. Semicircular Canals

Question 14

What do the clinical findings in CHARGE syndrome suggest the pathogenic mechanism involves?

Answer 14

Disturbed neural crest development

Question 15

What is the gene that takes damage in CHARGE Syndrome? What sorts of events occur at this gene?

Answer 15

CHD7 gene located at 8q12 may suffer microdeletions (67%) or a total deletion of 8q12 may occur

Question 16

The function of the CHD7 protien is mostly unknown. What does it appear to do though?

Answer 16

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

Question 17

What is this?

Answer 17

Lobster-claw malformation of the right foot

Question 18

• A 32 year old para 2, gravida 3woman had and eventful pregnancy up to 29 weeks when she began to have vaginal spotting. Family and personal histories were unremarkable. No medication was taken during the pregnancy. Previous ultrasound exams at 8 and 29 weeks were reported as normal. At 31 weeks she was admitted to the hospital fully dilated and 45 minutes later delivered a male infant who cried weakly and had a gasping respiratory effort. Despite rescuitation efforts the baby died 30 minutes later.
• Necropsy was performed within 10 hours of death.

What happened here?

Answer 18

VATER/VACTERL Association

Question 19

What does the acronym for VATER/VACTERL Association stand for?

Answer 19

• *V**ertebral defects
• *A**nal atresia
• *T-E** fistula with esophageal atresia
• *R**adial and Renal dysplasia

Cardiac defects

Limb defects

Question 20

On external exam what might we find in a baby with VATER Association?

Answer 20

1. Bilateral cleft lip and palate
2. Dysplastic low set ears
3. Absence of penis with rudimentary scrotum
4. Imperforate anus
5. Right “lobster claw” foot

Question 21

What might we see as far as pathological and radiographic exam findings of a VATER association?

Answer 21

1. T-E fistula with proximal esophageal atresia
2. Hypoplastic lungs
3. Bilateral renal dysplasia
4. Agenesis of the bladder and urethra
5. Right hemivertebra
6. Partial fusion of cervical vertebrae

Question 22

What is the difference between syndrome and association?

Answer 22

Syndrome has a defined genetic cause