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 Congenital Abnormalities Viral – HIV, CMV Substance Abuse - Teratogenic Crack cocaine EtOH – FAS cigarettes Antabuse Mysterious Drug

Genetics Velo-cardio-Facial Syndrome (VCFS) Williams Syndrome 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) Williams Syndrome 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 Karyotyping Both twin were genetically normal

Genetics Supportive Evidence Contradicting 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 Developmental Periods WEEK 1 2 3 4 5 6 7 8 9 Conception Treatment 03/12 Mysterious Drug? Given By Mother Cigarettes Crack Cocaine, Marijuana, EtOH Antabuse 04/02 EtOH Binge Drug Free WEEK 1 2 3 4 5 6 7 8 9 Key Developmental Periods Amelia/ Meromelia Upper Limb Cleft Palate Palate -16wk Highly Sensitive Period Less Sensitive Period

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

Cocaine Exposure Evidence for: Evidence against: 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 Exposure Evidence 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!!!!

Mysterious Drug? Given By Mother Conception 03/04 ± 7 d Treatment 03/12 Mysterious Drug? Given By Mother Cigarettes Crack Cocaine, Marijuana, EtOH Antabuse 04/02 EtOH Binge Drug Free

Question #1 All of the following are developmental malformations characteristic of cocaine exposure in the first trimester except: Microcephaly Cleft palate Urogenital malformations Hemi-penis Neuro-behavioral disturbaces

Question Deuce The most critical risk of limb deformations is what period following gestation? Days 14-20 Days 3-11 Days 28-35 Days 21-27

Question drei Which of the following drug abuse treatment tools are associated with absent limb long bones? Nicotine Antabuse (disulfiram) Methadone (dolophine) Buprenorphine (buprenex)