MICHAEL Mcnamara, DO Kristen de Berg, ms, cgc Mother to Baby: Hereditary causes for congenital heart defects in the newborn MICHAEL Mcnamara, DO Kristen de Berg, ms, cgc

OBjectives Review early heart development Overview of congenital heart disease (CHD) Genetic causes for congenital heart disease Case presentations

Fetal Heart First major organ system to function Nutritional and oxygen requirements not being met by diffusion alone More than 500 genes involved with developing the fetal heart Progenitor cells for the heart come from several sources Heart first begins to beat at day 22-23 Blood flow at four weeks and heart beat visualized by ultrasound

Congenital heart defects How did this happen? Why did this happen? Is it familial/genetic? Will other family members need screening? Can it happen again?

Risk Factors Influencing heart development Fetal Maternal Familial Most cases without risk factor

Risk Factors - Fetal Abnormal visceral / cardiac situs Abnormal 4 chamber view, outflow tracts, three vessel Arrhythmia Aneuploidy Two vessel umbilical cord, other fetal malformation IUGR / polyhydramnios Hydrops Twins Increased nuchal translucency

Fetal abnormalities Central Nervous System Thoracic Skeletal Gastrointestinal Urogenital

Risk factors - maternal Systemic lupus, Sjogrens syndrome Diabetes Phenylketonuria Viral syndromes Maternal congenital heart disease Teratogen exposure In vitro fertilization

Teratogens Anticonvulsants Warfarin Aspirin / NSAIDs Valproic acid, carbamazepine, phenytoin, phenobarbital Warfarin Aspirin / NSAIDs Tricyclic antidepressants Lithium Alcohol Recreational drugs (cocaine) Isoretinoin

Risk factors - familial First degree relative with CHD DiGeorge syndrome Long QT syndrome Noonan syndrome Marfan syndrome Tuberous sclerosis Williams syndrome Tetrology of Fallot repair

CHD overview Congenital heart disease: Structural malformation of the heart present at birth 0.5-1% of all births 25-40% of cases are syndromic ~2% have a first degree relative with CHD Oyen et al. 2009

Septal LVOT Conotruncal Other

Condition Cardiac finding % with CHD Trisomy 21 ASD, VSD, AVSD, TOF 40-50% Trisomy 18 ASD, VSD, PAD, TOF, DORV, CoA, BAV 90-100% Trisomy 13 ASD, VSD, PDA, HLHS 80% Monosomy X CoA, BAV, AS, HLHS 25-35% 22q11.2 deletion Aortic arch, TOF, truncus 75% Williams Supravalvar AS, PPS 50-85% Holt-Oram ASD, VSD, AVSD, AV conduction Noonan PS, AVSD, HCM, CoA 50-80% CHARGE conotruncal defects, VSD, ASD 74% Kabuki CoA, other left-sided obstruction, VSD 90%: Sotos ASD, VSD 25%

Case #1 31 year old G2P0 at 12+3 weeks gestation referred for enlarged nuchal translucency vs cystic hygroma seen on 1st trimester U/S. Both parents are known carriers for cystic fibrosis

Case #1 31 year old G2P0 at 12+3 weeks gestation referred for enlarged nuchal translucency vs cystic hygroma seen on 1st trimester U/S. Turner syndrome? Cardiac defect? Trisomy 21? Patient offered diagnostic testing or NIPS (non invasive prenatal screening) for chromosome abnormalities (trisomies 13, 18, 21 and XY). Elected to proceed with NIPS.

Case #1 Patient presents at 19+5 days for detailed anatomy scan Suspected fetal heart defect: VSD vs AV canal, possible coarctation of aorta. Dilated fetal kidneys

Case #1 Upon closer examination, the mother had some subtle physical traits suspicious of an underlying genetic condition.

Noonan syndrome

Case #1 The mother had been evaluated as a child by genetics for these “phenotypic” changes At that time, her genetic testing was normal for Noonan syndrome. Fast forward 20+ years, we discussed discussed changes in testing She RE-tested for Noonans syndrome

Case #1 results

Noonan syndrome

Case #1 Amniocentesis for diagnosis Autosomal dominant for Noonan’s (50% chance) Cystic fibrosis (25% chance, 50% chance for carrier) Results SOS1 - postitive Cystic fibrosis - negative

Case #1 management Now that we know why there’s a fetal heart defect, how do we take care of baby AND mom? Prenatal/postnatal care: Edema? Cardiac consults? (mom and baby?) Peds Cardiology consult Maternal echocardiogram negative previously

Management for noonan syndrome Multi-system evaluations Cardiac evaluations (echo & EKG) Ophthalmologic evaluation Hearing evaluation Renal ultrasound Clinical and x-rays assessment of spine and rib cage Brain and spine MRI if neuro symptoms present Developmental evaluation Consult with genetics

Case #1 management Spontaneous labor at term Vaginal delivery with forceps Baby to the NICU Transferred to University of Michigan Ann Arbor for repair Maternal condition diagnosed with fetal findings!

Case #2 23-year-old gravida 3, para 1 at 20 weeks +1 day Maternal history of Holt-Oram syndrome with a previously affected child

Holt Oram syndrome aka “heart-hand syndrome” Autosomal dominant Abnormalities associated with: Bone of the hand and arm Cardiac defects TBX5 pathogenic variants

Management for Holt-oram System/Concern Evaluation Comment Musculoskeletal Physical exam for limb involvement Hand & upper-limb radiographs Cardiac Chest radiograph Identify enlarged pulmonary arteries caused by pulmonary HTN or cardiomegaly Echo Identify septal defects or other CHD EKG Identify cardiac conduction disease Other Consult w/ genetics regarding recurrence Refer family members for examination

Case #2 Management Ultrasound findings at 20 weeks Triphalangeal thumb Congenital heart defect, AV canal defect Peds Cardiology consult Delivery at tertiary care center Maternal condition helped with fetal diagnosis and management!

Case #3 27yr-old female presents at 20w6d due to previous IUFD and family history of heart defects Previous 16 week loss of unknown etiology, normal aCGH. Spouse with heart surgery as baby Family history of trisomy 21 (patient’s sibling)

Case #3 Double-outlet right ventricle with d-transposition of the great arteries and large muscular ventricular septal defect Patient’s partner: d-transposition of great arteries, ventricular septal defect, atrial septal defect, and straddling mitral valve

Case #3 Patient elected to proceed with amniocentesis

Case #3 Peds Cardiology consult Term delivery Transferred to University of Michigan Ann Arbor for repair

So why does CHD occur more in some families? + Genetic variants Epigenetic factors Environmental factors Hemodynamic factors

Counseling for Congenital heart defects How did this happen? Why did this happen? Is it familial/genetic? Will other family members need screening? Can it happen again?

Conclusion - CHD Most common birth defect 3-4/1000 needing surgical repair in first year of life Many different risk factors though most without a risk factor Diagnosis and post delivery counseling Genetic counseling for recurrence in future pregnancies and possibly with other family members

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