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Skeletal Dysplasia: When to Be Concerned Heidi L Thorson, MD Minnesota Perinatal Physicians Maternal-Fetal Medicine Clinical Genetics

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Skeletal Dysplasia: When to Be Concerned Heidi L Thorson, MD Minnesota Perinatal Physicians Maternal-Fetal Medicine Clinical Genetics 9/7/2018 DISCLOSURE None Skeletal Dysplasia: When to be concerned Heidi L Thorson, MD Minnesota Perinatal Physicians Maternal-Fetal Medicine Clinical Genetics September 7, 2018 OBJECTIVES Skeletal Dysplasia - Incidence Understand normal skeletal growth Over 400 unique skeletal dysplasias To recognize skeletal dysplasias >50 can be diagnosed prenatally To recognize indications for referral 1:3000-1:5000 live births To recognize concerns for lethal vs nonlethal Lethal skeletal dysplasias 1:10,000 Specific key measurements, ratios, landmarks help identify skeletal dysplasias, differentiate from normal variation, fetal growth restriction and help determine lethality Bone formation Femur Length Membranous ossification – mesenchymal cells transform into bone with cartilage stage • Measurement of the Calvarium, portions of clavical femur length alone Endochondral ossification – will detect most Cartilaginous model of bone differentiation skeletal dysplasias Appendicular and axial skeleton (long bones) • What is to short? ©AllinaHealthSystems 1 9/7/2018 Femur discrepancy Referral for skeletal dysplasia 28 year old G1P0 32 weeks by excellent dates Parameter Weeks BPD 30.0 HC 30.2 AC 29.1 FL 29.0 Referred for possible skeletal dysplasia Femur Length Femur Length < 5th %, 18-24 weeks 129 cases • Differential diagnosis for FL < 2SD or <5th centile 83 cases (isolated) • Normal physiologic variation 33/83 (40%) • IUGR Severe IUGR • Abnormal Karyotype Abnormal umbilical Doppler • Genetic Syndromes Abnormal uterine Doppler • Skeletal Dysplasia 36% preeclampsia 33% intra-uterine demise __________ Papageorghiou AT et al. US OB Gyn 2008;31:507. Femur Length Femur Length • < 5th %, 18-24 weeks • Measurement of the FL alone will detect most skeletal dysplasias • 129 cases • But what is too short? • 46 (36%) associated • ≥5mm below the 2 SD for Age/Size • abnormalities • ≥10 mm below the mean for Age/Size • Skeletal dysplasia • <5th centile but within 2-3SD is typically constitutional or normal • Chromosomal variation abnormalities • <4 SD or >5mm below 2SD likely to be associated with skeletal • Genetic syndromes dysplasia • FL/AC ratio is normally between 0.2-0.24. <0.16 suggests _________ severe skeletal dysplasia Papageorghiou AT et al. • FL/Foot ratio <0.87 discriminates between IUGR and severe US OB Gyn 2008;31:507. skeletal dysplasia ©AllinaHealthSystems 2 9/7/2018 Femur Length Percentile Skeletal Dysplasias Centile • Sonographic assessment Week 3 10 50 • Femur 15 13.6* 14.7 17.2 • Length/growth 16 16.5 17.7 20.3 • Bone curvature 17 19.4 20.7 23.3 • Fractures 18 22.3 23.6 26.3 • Cranium 19 25.1 26.4 29.2 • Shape/mineralization 20 27.9 29.2 32.1 • Spine *mm • Thorax __________ Chitty LS et al. Br J Obstet Gynaecol 2002;109:919. • Hands/feet Skeletal dysplasia Short Femur Degree of Bone Curvature Interval Long Bone Growth OI, Type II 15 weeks Campomelic Anterior bowing of femur and • Femur grows: tibia 2.5 mm/week between Achondroplasia 21-27 weeks Osteogenesis Imperfecta, I & II 16-22 weeks Thanatophoric dysplasia • Assess specific Hypophosphatasia skeletal dysplasia in mind Kurtz AB et al. J Ultrasound Med 1986;5:137 Valcamonico A et al. Fetus 1992;2:7544 Campomelic Dysplasia Long Bone Fractures Associated anomalies Micrognathia Osteogenesis Imprefecta, II 11 pair ribs Long bone fractures Hypoplastic scapula Rib fractures (string of pearls) Ventriculomegaly Severe micromelia _______ Jones KL. Recognizable Patterns of Human Malformations. Phila PA. Elsevier Saunders 2006. ©AllinaHealthSystems 3 9/7/2018 Bone Mineralization Bone Mineralization Poorly ossified skull Poorly ossified skull intracranial anatomy flatten calvarium visible in near field with transducer Cranium Cranium Macrocephaly Cloverleaf skull Frontal bossing Premature closure of sutures Thanatophoric 14% of thanatophorics1 OI (amost exclusively in type Achondroplasia II) Homozygous achondropasia ___________ 1Mahony BS et al. J Ultrasound Med 1985;4:151. Apert Syndrome Spine Bilateral coronal suture synostosis Hemivertebrae Conical “tower” skull Complex syndactyly of hands and Scoliosis feet Vertebral disorganization Mitten hands Platyspondyly (flat spine) Decreased mineralization Achondrogesis ©AllinaHealthSystems 4 9/7/2018 Evaluation of Thorax Evaluation of Thorax Cardio-thoracic ratio • Is the chest bell shaped? Circumference 0.4-0.55 normal • Thoracic circumference >0.6 indicating cardiomegaly • <5% increases Area likelihood of pulmonary hypoplasia 0.25-0.35 Rib length at 4 chamber view • Beware of IUGR Do they encircle 70% ______________ Abuhamad AZ et al. Ultrasound Obstet Gynecol 1996;7:193 Paladina D. Arch Dis child 1990;65:20 ____________ Chaoi R. Fetal Dx Ther 1994;9:92 Nimrod C et al. Am J Obstet Gynecol 1988;158:277. Huhta JC. Sem Fetal Neonatal Med 2005;10:542. Hands and Feet Hands and Feet Fingers of equal length – 3rd and 4th do not Club foot approximate (“Trident”) Polydactyly § achondroplasia1 short rib polydactyly asphyxiating thoracic • Abnormal thumb position dystrophy (“hitchhiker”) Syndactyly – diastrophic2 _________________ 2Tongsong T et al. J Clin Ultrasound 2002;30:103. 1Guzman ER et al. J Ultrasound Med 1994;13:63. ©AllinaHealthSystems 5 9/7/2018 Fetal Ratios Extra-Skeletal Findings • Polydramnios1 • Femur = foot • 3rd trimester • Thanatophoric: 58% • FL/foot ≤ 0.84 = dysplasia1 • Achondroplasia: 27% • Femur/AC x 100 • Normal: 22 ± 22 • Hydrops 2 • < 16.0 suggests lethal • Short-rib polydactyly skeletal dysplasia3 • Achondrogenesis3 • Inaccurate with FL bowing • Congenital heart disease ____________ 1Brons JTJ et al. Eur J Obstet Gynecol Reprod Biol 1990;34:37 _______________________ 2Hadlock FP et al. AJR 1983;141:979 1 3Ramus RM et al. Am J Obstet Gynecol 1998;179:1348 Thomas RL et al. Am J Perinatol 1987;4:293. 2Meizner I et al. J Clin Ultrasound 1985;13:284. 3Soothill PW et al. Prenat Diagn 1993;13:523. First Trimester Detection of Severe Skeletal 3-D Ultrasound Dysplasia • Charts for 1st trimester limb length available1 • Limited application – better views: • face, ribs, and digits chest volume • nuchal translucency with skeletal anomalies2 ____________ 1Gabrielli S et al. Ultrasound Obstet Gynecol 1999;13:107. __________ 2 Hill LM et al. Prenat Diagn 1998;18:1198. Garjian KV et al. Radiology 2000;214:717. Heterozygous Achondroplasia Heterozygous Achondroplasia • Incidence: 1/30,000 births • Autosomal dominant • 80% of cases are new mutations • Paternal age effect • Fibroblast growth factor receptor 3 (FGFR3) mutation • Homozygous – lethal ______________ Torvormina PL et al. Am J Hum Genet 1999;64:722. Seino Y et al. Acta Pediatr 1999;88 (Suppl):118. ©AllinaHealthSystems 6 9/7/2018 Heterozygous Achondroplasia Thanatophoric Dysplasia • G, thantos. death • Incidence: 1 – 3/100,000 births Features: • Autosomal dominant • FGFR 3 mutation • Proximal shortening of long bones • APA 50% occur with paternal age>35 • Frontal bossing • TYPE I 85% • Mid-face hypoplasia • Normal ossification • Long bones severely effected • Megalencephaly • Prominent bowing • Brachydactyly – small hands and feet • “telephone receiver” femur • No fractures • Trident hand • Macrocephaly – relatively normal skull • Normal intelligence • TYPE II 15% • Kleeblattshadel “cloverleaf” skull • Femurs longer, less curved Thanatophoric Dysplasia Thanatophoric Dysplasia • Features Features • markedly shortened/bowed limbs • Redudant skin • Decreased limb movement • femur = “telephone receiver” • Positioned at right angles to body • Brachydactyly – trident hand • Polyhydramnios – severe 2nd/3rd • Platyspondyly • Frontal bossing • Chest circumference <5th centile Osteogenesis Imprefecta Osteogenesis Imperfecta Type II • Incidence: 1/50,000 births • 90% due to mutations in COL1A1/COL1A2 • Autosomal dominant • Highly variable • Mutations in collagen gene • Type I –classic –moderate fractures, blue sclera, hearing loss, • Perinatal lethal “child abuse” • Features: • Type II – neonatal lethal – severe, multiple fractures • Hypomineralization of the skull • Type III – progressively deforming with severe disability by • Extremely short/thick bones early adulthood • In utero fractures • Ribs short, beaded • Narrow chest • Protuberant abdomen ©AllinaHealthSystems 7 9/7/2018 TO CONTACT ME Heidi L Thorson, MD Minnesota Perinatal Physicians 612-863-4502 ©AllinaHealthSystems 8.
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