MED 6501 CPC Case 4

Nicholas Vidor, Brock Urie, Anne Sirany, Abby Thyen, Sandi

Riggs, Chris Steevens, Mark Vukonich, Jacob Ziegler

Complaint: “What is wrong with my babies?”

• 33 y.o. woman brings in her twin babies– Vaginally delivered at 38 weeks– Apgar scores of 9 for both– Both small birth size [wt.~ 3 lbs. 16oz and 4 lbs 4

oz] [Length~ 17.5 in. and 16.9 in.]– Normal head circumference [~12.2 in. for both]– Now twins are 25 months old

Physical Exam of Twins

• Short palpebral fissures • Normal linear growth and head circumference (25th

percentile)• No significant cognitive delays• One twin had shortened forearms bilaterally, no

evidence of a constriction mark, two rudimentary fingers without nails on each forearm.

• Other twin had a cleft soft palate (has been surgically repaired)

Mother’s history

• 31 y.o. when gave birth to twins• Had normal full term delivery 13 years ago

with different partner• Her mother died of AIDS• She is a single parent working as a medical

assistant

Mother’s drug use

• Had one week ‘alcohol binge’ during time of conception

• Problems with morning sickness, took unknown drug given by her mother for 1-2 weeks

• Used crack cocaine, alcohol, and marijuana at beginning of pregnancy

• Went to chemical rehab, put on antabuse until discovered she was pregnant (~1 month)

• Has not taken any more drugs

Important Developmental Periods

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Our List

1. Congenital Abnormalities2. Viral – HIV, CMV3. Substance Abuse - Teratogenic

a) Crack cocaineb) EtOH – FASc) cigarettes

4. Antabuse5. Mysterious Drug

•Velo-cardio-Facial Syndrome (VCFS)–Most common syndrome associated with cleft palate.–Multiple anomalies including cleft palate, heart malformations, facial characteristics, and learning disabilities. –Chromosome 22q11 deletion.

•Williams Syndrome–Characterized by distinctive “elfin” facial appearance and low nasal bridge.–Deletion of elastin gene, 7q.

•De Lange Syndrome–1/3 born prematurely with facial disturbances that are present at birth and change little with age.–NIPBL gene mutations on chromosome 5p13.

Genetics

•Velo-cardio-Facial Syndrome (VCFS)–Most common syndrome associated with cleft palate.–Multiple anomalies including cleft palate, heart malformations, facial characteristics, and learning disabilities. –Chromosome 22q11 deletion

•Williams Syndrome–Characterized by distinctive “elfin” facial appearance and low nasal bridge.–Deletion of elastin gene, 7q

Genetics

Genetics

• Karyotyping

• Both twin were genetically normal

Genetics• Supportive Evidence– Twin A and B both have short palbebral fissures.– Twin B has a soft palate that was surgically

repaired.– Twin A shortened arm

• Contradicting Evidence– Karyotype was normal for both twins.

Key DevelopmentalPeriods

9WEEK 1 2 3 4 5 6 7 8

Amelia/Meromelia

UpperLimb

Conception03/04 ± 7 d

Crack Cocaine, Marijuana, EtOH

Antabuse04/02

EtOH Binge

Drug Free

Treatment03/12

Mysterious Drug? Given By Mother

Highly Sensitive Period

Less Sensitive Period

Cigarettes

Cleft Palate

Palate-16wk

Cocaine Exposure-Small for gestational age -Prematurity-Microcephaly-Urogenital abnormalities-Neuro-behavioral disturbances-Cleft palate

Cocaine ExposureEvidence for:• Cleft palate• Slightly premature • Small for gestational age

Evidence against:• No cognitive findings• Doesn’t explain other physical findings• Time of exposure: wks 1-2 (cleft palate= wks 7-8)

Alcohol Exposure

-Fetal Alcohol Spectrum Disorders (FAS)-Small for gestational age-Mental retardation-Microcephaly-Ocular abnormalities-Short palpebral fissures-Joint abnormalities

Fetal Alcohol Syndrome

Four basic findings:• growth deficiency • characteristic FAS facial phenotype • CNS damage/dysfunction• alcohol exposure in utero

Alcohol ExposureEvidence for:• Short palpebral fissures• Premature• Time frame (around wk 8)

-falls within upper limb and cleft palate development• Mom’s alcohol binge

Evidence against:• No mental retardation• Doesn’t explain degree of arm abnormalities• No delayed growth • Normal head circumferences

Antabuse (Disulfiram) • Therapy Started : April 2nd 2000• Therapy Stopped: After 1 month use ~ May 2nd

2000.• Embryonic Upper limb development: weeks

4-9

• Disulfiram exposure during this critical time of limb bud development!

Effects of Disulfiram on Upper Limb Development

• Disulfiram inhibits acetylaldehye dehydrogenase – preventing alcohol oxidation– Increased blood levels of acetylaldehye

• Animal studies have shown:– Disulfiram intoxication associated with “tibial

dyschondroplasia” and growth plate necrosis– Decreased DNA synthesis in mouse embryos

exposed to Disulfiram

Effects of Disulfiram on Upper Limb Development

• Limb abnormalities described in infants of women treated with Disulfiram during pregnancy:– Club feet– Radial aplasia– Phocomelia: very short or absent limb long bones,

fused fingers

Disulfiram’s Effect on this Pregnancy

• Therefore Disulfiram exposure during upper limb development may have contributed to Twin A’s upper limb abnormalities!!!!

Crack Cocaine, Marijuana, EtOH

Antabuse04/02

EtOH Binge

Drug Free

Conception03/04 ± 7 d

Treatment03/12

Mysterious Drug? Given By Mother

Cigarettes

Question #1

• All of the following are developmental malformations characteristic of cocaine exposure in the first trimester except:

a) Microcephalyb) Cleft palatec) Urogenital malformationsd) Hemi-penise) Neuro-behavioral disturbaces

Question Deuce

• The most critical risk of limb deformations is what period following gestation?

a) Days 14-20b) Days 3-11c) Days 28-35d) Days 21-27

Question drei

Which of the following drug abuse treatment tools are associated with absent limb long bones?

a) Nicotineb) Antabuse (disulfiram)c) Methadone (dolophine)d) Buprenorphine (buprenex)