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?

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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

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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.

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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

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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.

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.

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

TO CONTACT ME

Heidi L Thorson, MD

Minnesota Perinatal Physicians 612-863-4502