SLOS? (Smith-Lemli-Opitz Syndrome) Dr E. P. Frohlich Sunninghill Hospital, Private Practice

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1 SLOS? (Smith-Lemli-Opitz Syndrome) Dr E. P. Frohlich Sunninghill Hospital, Private Practice

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3 Introduction SLOS is part of a heterogenic group of monogenically (AR, AD, XD) determined syndrome of multiple malformations VACTERL, Zellweger, Ehlers-Danlos, Kartagener, Meckel and Pierre Robin are some of the more common similar syndromes. 25% recurrence, severe, highly variable

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6 Case Report 39 years old P1G3, on 10mg Stilnox PREM 34w Forceps 2620 healthy M Ectopic pregnancy L/S S/Stomy wrong dates, EDD st visit at 4w+6d, GS intrauterine 7w+6d YS+, FHS 11w+4d NT=1mm, NB+, FB=2mm

7 Case Report -cont First Trimester DS Biochemistry Report -DS risk: by maternal age 1:94 biochemistry 1: 3 biochemistry+nt 1:14 13w+5d Counseled regarding management: -normal US findings, AC more accurate than CVB and less invasive, -15w+5d FU normal US, not sure -Feto Maternal consultation requested

8 Feto Maternal Consultation 19w+6d US examination: normal, no US markers for chromosomal anomalies, except for tricuspid valve thickening but no regurgitation. Fetal ECHO recommended; -after counseling the patient declined it CNS: BPD, HC, Ventricles, TCD, CM normal, FH 4ch, outflow tracks normal NB, AC, FL, Humerus and EBW normal

9 Invasive Testing After further discussions it was decided to perform an AC 19w+6d AC performed: transplacental, 1 attempt 18ml clear AF AC results: FISH NM and cytogenetic analysis 46 XY, AFAFP normal 1w Post AC US normal AF volume, FHS

10 Routine AN Visits Since all investigations proved negative, routine AN visits were planned 23w+5d US ambiguous genitalia, counseling, Long lapse in ANC visits 31w+2d APH Low Lying Placenta, Steroids given, Ambiguous genitalia and IUGR, counseled again 31w+6d Feto Maternal Consultation

11 Feto Maternal Consultation 31w+6d: BPD, OFD and HC are >-2SD TCD 31w+6d AC, FL and Humerus >-2SD SUA Fetal head, brain, face, spine, neck and skin, chest, abdominal wall, GIT, kidneys and bladder, extremities and skeleton normal

12 Feto Maternal Consultation 31w+6d: continued Sex: male. Micropenis, bifid scrotum and hypospadias Fetal heart: normal except right ventricle larger than left ventricle. Likely rare genetic syndrome such as SLOS Patient counseled, fetal ECHO requested

13 Fetal Echocardiography 35w Fetal genitalia: normal male Fetal heart basically normal, slightly larger right side MV and TV normal Both arches normal PFO, no pericardial effusion Immediate post partum assessment

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45 Congenital Anomaly, IUGR 32w+4d IUGR and oligohydramnios 34w+6d severe IUGR and severe OH 36w EFW 1798gm, FMC 37w EFW 1770gm, FMC 37w+1d massive APH, Emergency C/S -1850gm Male fetus, vigorous -Hypospadias and bifid scrotum -Low set ears, FLK

46 Post Natal Pediatric Evaluation SGA Dysmorphic,? Syndromic Male geniatalia with severe hypospadias Right inguinal hernia Low set ears, facial asymetry Low fetal cholesterol levels

47 Post Natal Echocadiography Dysmorphic newborn Normal LV function Dilated RA and RV Normal P and Systemic V Drainage PDA with R to L shunting, normal 6.2mm ASD

48 SLOS Disorder of cholesterol biosynthesis gene mutation of the DHCR7 reductase Blockage at 7DHC reduction to C The pathway starts with 2 AcetylCoA and ends in the synthesis of Cholesterol The Fetus has high 7DHC tissue levels and low circulating Cholesterol levels

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50 Androgen Biosynthesis The Testosterone and 5a HydroT pathway starts with Cholesterol > Pregnenolone > Progesterone > 17a hydroxyp > AD and finally Testosterone T is peripherally converted by 5a- Reductase to the active form of 5a HT Defects at this level can cause ambiguous genitalia

51 Androgen Biosynthesis

52 Metabolism of Testosterone

53 Sumary Until 23 weeks gestation, besides the false positive FTDS biochemical test there were no signs of congenital anomaly Ambiguous genitalia could have been pseudohermaphroditism, Morris S or SLOS The 6.2mm ASD was missed antenatally

54 Sumary The IUGR started at 23w and accelerated between 31 and 34 weeks gestation Post partum there were three vessels in the umbilical cord

55 SLOS Pathology and Variable Clinical Features IUGR and post natal growth restriction Limb anomalies: Poly/Sin/Clin dact CNS: ACC, Hydroceph, Holopros, Cardiac: AVSD, VSD, HPLV, ASD Genitourinary: ambig Pulmonary: abnormal lobation ambig, hyposp,, renal, Craniofacial: microceph, cleft, nose,, NF

56 New Begining