Skeletal Imaging

Definition

Skeletal dysplasia (also known as osteochondrodysplasia ) is a genetically diverse group of >450 disorders ^, of the skeleton causing abnormal bone length, shape, and density, with varying degrees of disability.

Incidence and Epidemiology

• Incidence of skeletal dysplasia is approximately 2.4–4.5:10,000 live births.

  • The most common lethal skeletal dysplasia is thanatophoric dysplasia (35%), followed by osteogenesis imperfecta type II (25%) and achondrogenesis (7%); collectively, these account for nearly half of all diagnosed skeletal dysplasias.

  • The most common nonlethal skeletal dysplasia is achondroplasia, representing approximately 10% of all skeletal dysplasias.

Etiology and Pathogenesis

• Skeletal dysplasia results from heterogeneous genetic defects ^, that affect embryonic limb development through abnormal

  • Extracellular structural proteins

  • Metabolic pathways

  • Folding and degradation of macromolecules

  • Hormone and signal transduction mechanisms

  • Nuclear proteins and transcription factors

  • Oncogenes and tumor suppressor genes

  • RNA and DNA processing and metabolism

• Most genetic defects are autosomal recessive (AR) or de novo autosomal dominant (AD) mutations, which may be associated with advanced paternal age (e.g., single nucleotide substitution c.1138G>A in FGFR3 associated with achondroplasia). ^,

Diagnostic Features

• Assessment for skeletal dysplasia is warranted if measured femur length is short (>2 SD below mean) for gestational age ( Figs. 26.1 and 26.2 ), any long bones appear angulated or bowed ( Fig. 26.3 ; Video 26.1 ), or limbs subjectively appear short compared with the fetal foot or trunk ( Fig. 26.4 ; Video 26.2 ).

  
  
  
  

• A systematic approach ( Box 26.1 ) ^, should be used to assess the fetus, with all long bone lengths compared with standard biometric tables ( Table 26.1 ). A long bone calculator using a spreadsheet is available online to calculate long bone deviations from the mean.

  Box 26.1

  Suggested Ultrasound Assessment of Fetus With Suspected Skeletal Dysplasia

  Modified from Krakow D, et al. Guidelines for the prenatal diagnosis of fetal skeletal dysplasias. Genet Med . 2009;11:127.

  • Confirm gestational age based on last menstrual period or first-trimester ultrasound.

  • Measurements

    • Record lengths of all long bones bilaterally: femur, humerus, radius, ulna, tibia, fibula, clavicle; measure foot length; assess size and shape of scapula

    • Measure circumference of head, abdomen, chest, and cardiac area

    • Measure thorax in sagittal plane; note contour for bell shape in coronal plane

  • Calculate ratios

    • Thoracic circumference-to-abdominal circumference, normal ≥0.8

    • Cardiac circumference-to-thoracic circumference, normal <0.6

    • Femur length-to-abdominal circumference, normal >0.16

    • Femur-to-foot length, normal ≥1.0

  • Note morphology of bones

    • Shape: straight, curved, fractures, absent; unilateral vs. bilateral

    • Echodensity: normal vs. poorly mineralized

    • Appearance of metaphyseal segment: premature ossification, spikes, epiphyseal calcifications

    • Abnormal posturing: clubbing, arthrogryposis

  • Assess hands for number of digits, shape of phalanges, and short fingers: polydactyly, syndactyly, brachydactyly

  • Note shape and mineralization of cranium and vertebral bodies: macrocrania, cloverleaf skull; scoliosis, platyspondyly, sacral agenesis

  • Obtain fetal profile: frontal bossing, midface hypoplasia, hypoplastic/absent nasal bone, micrognathia; assess biorbital diameter in coronal plane (hypertelorism or hypotelorism)

  • Evaluate fetus for other congenital anomalies: hydrocephalus, heart defects, hydrops fetalis

  • Amniotic fluid assessment

  • Doppler imaging to rule out growth restriction

  • Additional 3D and/or MRI may be helpful for assessing face and spine

  TABLE 26.1

  Reference Fetal Long Bone Lengths ^a

  Data from Jeanty P, et al. A longitudinal study of fetal limb growth. Am J Perinatol . 1984;1:136; and Exacoustos C, et al. Ultrasound measurements of fetal limb bones. Ultrasound Obstet Gynecol . 1991;1:325.

  GA (weeks)	Femur Percentile			Tibia Percentile			Fibula Percentile			Humerus Percentile			Ulna Percentile			Radius Percentile
  	5	50	95	5	50	95	5	50	95	5	50	95	5	50	95	5	50	95
  12	4	8	13	3	7	12				4	9	13	3	7	11
  13	6	11	16	5	10	14				7	11	15	5	10	14
  14	9	14	18	8	12	16				10	14	18	8	13	17
  15	12	17	21	10	15	19	14	15	16	13	17	21	11	15	20	13	15	17
  16	15	20	24	13	17	21	16	18	19	16	20	24	14	18	22	16	19	21
  17	18	23	27	15	20	24	19	21	22	18	22	27	16	21	25	18	19	22
  18	21	25	30	18	22	27	20	21	23	23	25	29	19	23	28	18	20	23
  19	24	28	33	21	25	29	22	25	27	24	28	32	22	26	30	20	23	24
  20	26	31	36	23	27	32	27	28	30	26	30	34	24	28	33	22	24	25
  21	29	34	38	26	30	34	30	31	33	29	33	37	26	31	35	25	27	29
  22	32	36	41	28	32	37	30	31	33	31	35	39	29	33	37	27	29	31
  23	35	39	44	31	35	39	35	36	37	33	38	42	31	35	39	30	32	34
  24	37	42	46	33	37	42	37	39	40	36	40	44	33	37	42	31	34	38
  25	40	44	49	35	40	44	38	40	41	38	42	46	35	39	44	34	36	39
  26	42	47	51	37	42	46	39	42	44	40	44	48	37	41	46	35	38	41
  27	45	49	54	40	44	48	42	44	46	42	46	50	39	43	47	37	40	42
  28	47	52	56	42	46	50	43	45	47	44	48	52	41	45	49	38	41	43
  29	50	54	59	44	48	52	44	47	49	46	50	54	43	47	51	40	42	44
  30	52	56	61	46	50	54	46	49	50	47	51	56	44	48	53	41	44	47
  31	54	59	63	47	52	56	48	49	52	49	53	57	46	50	54	43	46	48
  32	56	61	65	49	54	58	51	53	55	51	55	59	47	52	56	43	47	50
  33	58	63	67	51	55	60	52	54	58	52	56	60	49	53	57	45	48	52
  34	60	65	69	53	57	61	53	57	61	54	58	62	50	55	59	46	49	54
  35	62	67	71	54	58	63	56	59	63	55	59	63	52	56	60	47	50	54
  36	64	68	73	56	60	64	56	59	64	56	61	65	53	57	61	48	52	55
  37	65	70	74	57	61	66	57	60	64	58	62	66	54	58	63	49	52	57
  38	67	71	76	59	63	67	58	61	64	59	63	67	55	59	64	50	53	57
  39	68	73	77	60	64	69	58	62	66	61	65	69	56	60	65	50	54	58
  40	70	74	79	61	66	70	59	63	66	62	66	70	57	61	66	51	56	61

  a All long bone length measurements in millimeters. The mean SD for each measurement is approximately 2.5–3.0 mm. GA, Gestational age.

• Skeletal dysplasias are classified by site of shortened bones ( Fig. 26.5 ). ^,

  • Rhizomelia —proximal limb shortened (humerus, femur)

  • Mesomelia —intermediate limb shortened (radius, ulna, tibia, fibula)

  • Acromelia —distal limb shortened (hands, feet)

  • Micromelia —entire limb shortened

    • Micromelia is further subdivided by measured bone length: mild (>2 SD, but <3 SD below mean) or severe (>3 SD below mean).

  

• Mineralization is assessed through sonographic echogenicity of bones.

  • Normal bone is hyperechoic (brighter white) and produces acoustic shadowing.

  • Poorly mineralized bone is less echogenic (lighter gray) with less shadowing and reveals underlying structures (e.g., brain) better than expected ( Fig. 26.6 ); the poorly mineralized calvaria may be compressible with transducer pressure, distorting the normal outline ( Fig. 26.7 ; Video 26.3 ).

    
    

• Accurate prediction of lethality is an important goal of prenatal diagnosis; sonographic findings associated with lethal outcome include ^,

  • Early severe micromelia (>3 SD below mean)

  • Femur length-to-abdominal circumference ratio <0.16

  • Thoracic circumference <5th percentile

  • Thoracic circumference-to-abdominal circumference ratio <0.79 (“bell-shaped” chest) ( Fig. 26.8 ; Videos 26.4 and 26.5 )

    

  • Cardiac circumference-to-thoracic circumference >0.60 ( Video 26.6 )

  • Poor bone mineralization

  • Hydrops fetalis

  • Polyhydramnios at initial imaging suggests esophageal compression with small thorax (survival to discharge 27% versus 83%, P < .001)

• Consider 3D ultrasound imaging for face ( Fig. 26.9 ) and hand appearance.

  

• Prominent ultrasound findings and their associated conditions are presented in Box 26.2 .

  Box 26.2

  Prominent Ultrasound Findings With Skeletal Dysplasia

  Decreased Skeletal/Skull Mineralization

  • Achondrogenesis

  • Hypophosphatasia

  • Osteogenesis imperfecta

  Macrocephaly/Cloverleaf Skull (see Fig. 26.10 )

  • Achondroplasia

  • Achondrogenesis

  • Camptomelic dysplasia

  • Thanatophoric dysplasia

  Small Thorax (see Fig. 26.11 )

  • Achondrogenesis

  • Asphyxiating thoracic dysplasia

  • Camptomelic dysplasia

  • Hypophosphatasia

  • Osteogenesis imperfecta II

  • Short rib–polydactyly syndrome

  • Thanatophoric dysplasia

  Bowing of Long Bones

  • Achondrogenesis

  • Camptomelic dysplasia

  • Diastrophic dwarfism

  • Ellis–van Creveld syndrome

  • Hypophosphatasia

  • Osteogenesis imperfecta

  • Short rib–polydactyly syndrome

  • Thanatophoric dysplasia

  Fractures of Long Bones

  • Achondrogenesis

  • Hypophosphatasia

  • Osteogenesis imperfecta

• MRI may be helpful in assessing cranial sutures, intracranial anatomy, and vertebral structures in suspected nonlethal skeletal dysplasias ; 3D helical CT imaging has also been used to assess vertebral abnormalities, though its use should be limited due to risks associated with fetal radiation exposure.

• First-trimester ultrasound in patients at high risk for skeletal dysplasia (e.g., affected parent with AD disorder, both parents with skeletal dysplasia, known carrier status of AR disorder, prior affected fetus) can identify lethal skeletal dysplasias (e.g., thanatophoric dysplasia, osteogenesis imperfecta type II) by exhibiting small crown-rump length (CRL), short femur, poor mineralization, and/or increased nuchal thickness.

• Brief descriptions of common skeletal dysplasias and their associated gene defects are presented in Table 26.2 ; a comprehensive searchable genetic database containing 481 osteochondrodysplasias with over 2200 phenotypes is available at http://101.200.211.232/skeletongenetics/ .

  TABLE 26.2

  Common Skeletal Dysplasias and Gene Defects

  Skeletal Dysplasia	OMIM # a	Gene Defect	Inheritance	Features
  Achondrogenesis I	IA, 200600 IB, 600972	TRIP11 SLC26A2	AR	Severe micromelia, poorly mineralized skull and spine, bowing and numerous fractures present, polyhydramnios, hydrops; lethal
  Achondrogenesis II	200610	COL2A1	De novo AD	Severe micromelia, poorly mineralized distal spine, normally mineralized calvaria, macrocephaly, short ribs, polyhydramnios, hydrops; lethal
  Achondroplasia, heterozygous	100800	FGFR3	AD, new mutation	Rhizomelic shortening, frontal bossing with midface hypoplasia ( Fig. 26.11 ), bowed femur, brachydactyly with trident hand ( Fig. 26.12 ); most frequent form of nonlethal dwarfism
  Achondroplasia, homozygous	100800	FGFR3	AD	Appears similar to thanatophoric dysplasia type 1 (see below); lethal
  Asphyxiating thoracic dysplasia (Jeune syndrome)	208500	Unknown	AR	Mild micromelia, narrow thorax with short horizontal ribs, pulmonary insufficiency, renal abnormalities; variably lethal
  Camptomelic dysplasia	114290	SOX9	AR, de novo AD	Mild micromelia with bowed femur and tibia, macrocephaly with micrognathia, absent scapulae, clubfeet, polyhydramnios; lethal
  Chondrodysplasia punctata	215100	PEX7	AR	Rhizomelic shortening, microcephaly with frontal bossing, micrognathia, epiphyseal calcifications, mental retardation, seizures; lethal <2 years
  Diastrophic dysplasia	222600	SLC26A2	AR	Mild micromelia with thick short bones, kyphoscoliosis, “hitchhiker thumb,” clubfeet
  Ellis–van Creveld syndrome	225500	LBN, EVC	AR	Also known as chondroectodermal dysplasia; mild micromelia, narrow chest with underdeveloped ribs, heart defects, polydactyly; variably lethal
  Hypophosphatasia	241500	ALPL	AR	Severe micromelia, small thorax with rib fractures, poorly mineralized skull and bones with numerous fractures, bowed femurs; lethal
  Mesomelic dysplasia	Various	Various	AR, AD	Group of syndromes exhibiting nonlethal mesomelic shortening but otherwise generally normal phenotype
  Osteogenesis imperfecta II	166210	COL1A1, COL1A2	AR, AD	Severe micromelia, poorly mineralized skull, numerous fractures/bowing ( Fig. 26.13 ), beaded ribs, soft calvaria, platyspondyly, hydrops fetalis; lethal
  Osteogenesis imperfecta III	259420	COL1A1, COL1A2	AR, AD	Mild micromelia with poorly minimalized skull and bones, numerous fractures (see Fig. 26.14 ) and bowing, normal-sized chest, kyphoscoliosis; not lethal
  Short rib–polydactyly syndrome	263520 253530	NEK1 DYNC2H1	AR	Severe micromelia, underdeveloped ribs and small chest with pulmonary hypoplasia, polydactyly; lethal
  Thanatophoric dysplasia I	187600	FGFR3	De novo AD	Severe micromelia with “telephone receiver” femurs, macrocephaly with frontal bossing, hydrocephalus, platyspondyly, polyhydramnios; lethal
  Thanatophoric dysplasia II	187601	FGFR3	De novo AD	Severe micromelia with cloverleaf (kleeblattschädel) skull (see Fig. 26.10 ), short ribs with narrow thorax, platyspondyly, polyhydramnios; lethal

  AD, Autosomal dominant; AR, autosomal recessive; OMIM, Online Mendelian Inheritance in Man.

  a www.ncbi.nlm.nih.gov/omim .

  
  
  

Differential Diagnosis

• Fetal growth restriction (FGR)

• Aneuploidy (e.g., trisomy 21, trisomy 18, trisomy 13)

• Constitutionally small fetus (i.e., hereditary, familial short stature, ethnic variations)

• Nongenetic limb reduction conditions

  • Malformation —disordered tissue development resulting from early embryonic teratogen exposure (e.g., viral infection, radiation, medications, diabetes)

  • Disruption —breakdown of normal tissue (e.g., amniotic band sequence, vascular accident)

  • Deformation —distorted shape of normal tissue (e.g., clubfoot with prolonged premature rupture of membranes)

Associated Anomalies

• Polyhydramnios

• Hydrops fetalis

• Nonskeletal anomalies (cardiac, CNS, urogenital, and facial anomalies)

Prognosis

• Prognosis depends on which skeletal dysplasia is suspected and/or diagnosed and associated anomalies.

• The most common skeletal dysplasias with lethal outcome are listed in Box 26.3 .

  Box 26.3

  Lethal Skeletal Dysplasias

  • Achondrogenesis

  • Achondroplasia (homozygous)

  • Camptomelic dysplasia (variable)

  • Chondrodysplasia punctata (variable)

  • Hypophosphatasia

  • Osteogenesis imperfecta type II

  • Short rib–polydactyly syndrome

  • Thanatophoric dysplasia

• Long-term morbidity includes short stature with varying degrees of orthopedic complications, developmental delay, and learning disabilities.

• Long-term survivors of skeletal dysplasia may have shortened life span.

Antenatal Management

• Amniocentesis with microarray or noninvasive prenatal testing (NIPT) should be considered for karyotype and molecular testing (see Table 26.2 ).

  • Whole exome sequencing may become more generally available and offer further insight into gene mutation(s) associated with skeletal dysplasia.

• Cell-free fetal DNA (cffDNA) has been shown to detect FGFR2 and FGFR3 mutations using next-generation sequencing with 96% sensitivity (95% CI, 81%–99.3%) and 100% specificity (95% CI, 85%–100%).

• Obtain thorough patient history

  • Maternal medical history (e.g., poorly controlled diabetes, systemic lupus erythematosus, myasthenia gravis, hypothyroidism)

  • Maternal exposures (e.g., warfarin, phenytoin, methotrexate, alcohol)

  • Refer for genetic counseling and to obtain detailed family history that may reveal other affected individuals, suggesting diagnosis and/or familial short stature.

• Consider termination for suspected lethal skeletal dysplasias (see Box 26.3 ).

• Serial ultrasound examinations to monitor fetal growth, amniotic fluid, and worsening fetal condition (e.g., hydrops fetalis)

  • Continued normal progression in bone length (femur, humerus), although at a lower percentile, makes significant skeletal dysplasia less likely. ^,

  • Worsening growth (i.e., lowering percentiles or increasing SD below mean) makes skeletal dysplasia more likely.

    • Long bones of fetuses with severe micromyelia (likely lethal) exhibit little growth over time.

    • Abnormal biometric ratios suggestive of lethality become more pronounced with advancing gestation.

  • Fetal achondroplasia manifests with mild rhizomelic shortening early in pregnancy with progressive worsening of bone growth in third trimester.

• Fetal echocardiogram recommended to assess cardiac structure and function.

• Prenatal neonatology and genetics consultation to discuss postnatal management and prognosis.

• If the patient herself has a skeletal dysplasia (e.g., achondroplasia), prenatal consultation should include obstetric, neonatal, and anesthesia management plans.

• Delivery in tertiary care facility is recommended.

• Cesarean delivery should be considered for skeletal dysplasias associated with bone fractures or poor mineralization (see Box 26.2 ) and/or if the patient herself has a skeletal dysplasia.

Neonatal Management

• With lethal skeletal dysplasias, neonatal resuscitative efforts are not generally recommended.

  • Comfort care and supportive measures may be appropriate to allow parents time to accept lethal nature of the anomaly.

  • If termination or fetal/neonatal demise, offer autopsy with DNA and radiographic analysis ( Fig. 26.13 ) to further identify the skeletal dysplasia and to aid in genetic counseling for future pregnancies, if desired.

    

• Initial care of liveborn fetus should be focused on respiratory status, with attention to the trachea and larynx; need for highly aggressive ventilation due to respiratory insufficiency (e.g., small chest) may indicate a very poor prognosis for survival.

• Continuing diagnostic assessment

  • Skeletal ( Fig. 26.14 ), spinal ( Fig. 26.15 ), and cranial radiographs

    
    

  • Molecular testing

• Consultation with geneticist to help with formulating diagnosis and providing prognosis.

• UCLA International Skeletal Dysplasia Registry (ISDR), formally located at Cedars-Sinai, can be a useful resource in diagnosing less common or difficult skeletal dysplasia cases ( https://www.uclahealth.org/ortho/isdr ).

Key Points

• Short femur and/or humerus (<5th percentile) on routine biometric measurements should prompt a long bone survey to rule out skeletal dysplasia.

• A systematic approach should be used to evaluate a fetus with suspected skeletal dysplasia.

• The most common skeletal dysplasias are lethal; when skeletal dysplasia is suspected, a primary goal is to determine lethality, which may alter management of the pregnancy and delivery.

• Some cases (e.g., achondroplasia) may not become evident until the third trimester.

Definition

Arthrogryposis multiplex congenita (AMC) describes a finding of fixed joint contractures in two or more body areas resulting in limited joint movement and variable contractures. Arthrogryposis is a descriptive term of a physical characteristic, rather than a diagnosis, per se, associated with a heterogeneous group of musculoskeletal disorders. Polydactyly refers to supernumerary digits present in the hand and/or foot.

Incidence and Epidemiology

• Arthrogryposis occurs in approximately 1:3000 live births.

• Polydactyly is present in 1:3000 live births with male-to-female ratio of 2:1 ^21,22 and is classified into three types

  • Postaxial or ulnar (85%) ²³ —extra digit on ulnar or fibular side of distal extremity; 10 times more common in African Americans, occurring in 1:300 live births, and commonly bilateral (likely an autosomal dominant trait)

    • Type A—well formed digit with metacarpal present

    • Type B—poorly formed digit connected via pedunculated stalk

  • Preaxial or radial (13%) ²³ —extra digit located on radial or tibial side of distal extremity ^,

    • Type 1—Bifid distal phalanx

    • Type 2—Complete duplication of the distal phalanx

    • Type 3—Bifid proximal phalanx with duplicated distal phalanx

    • Type 4—Complete duplication of the proximal and distal phalanges

    • Type 5—Bifid first metacarpal with complete duplication of the proximal and distal phalanges

    • Type 6—Complete duplication of the entire thumb ray (metacarpal and proximal/distal phalanges)

    • Type 7—Triphalangeal

  • Mesoaxial or central (2%) ^, —extranumerary middle digit(s)

Etiology and Pathogenesis

• Arthrogryposis is caused by lack of fetal movement (akinesia) leading to abnormal periarticular connective tissue and inadequately stretched muscles and tendons with resultant low muscle mass and fibrosis resulting from several factors. ^,

  • Intrinsic factors —anomalies of fetal development (neuromuscular disorders, skeletal dysplasia, aneuploidy)

  • Extrinsic factors —compression from oligohydramnios, malpresentation, fibroids, müllerian anomalies of uterus (e.g., bicornuate uterus)

  • Environmental factors —infection, teratogen exposure

• Polydactyly results from defective embryologic differentiation of the digits with mesodermal rays that persist beyond programmed cell death, producing an extra digit or bifid digits.

  • Gene mutations associated with nonsyndromic polydactyly include ZNF141, GLI3, MIPOL1, IQCE, PITX1, GLI1, and ZRS/SHH. ^,

Diagnostic Features

• Arthrogryposis is seen as abnormal limb posturing that is fixed in an exaggerated flexed ( Figs. 26.16–26.18 ; Videos 26.7 and 26.8 ) or extended ( Fig. 26.19 ) position with persistent lack of movement and typically affects more than one joint.

  • Hands are affected with arthrogryposis more often than feet and may appear tightly clenched throughout the ultrasound examination ( Fig. 26.20 ; Video 26.9 ).

    

  • May be sonographically apparent in only 25% prior to 24 weeks ( Video 26.10 ).

  
  
  
  

• Polydactyly appears as an extra digit; the hand and/or foot should be examined in the outstretched open position with digits enumerated ( Figs. 26.21 and 26.22 ; Videos 26.11 and 26.12 ).

  • Polydactyly is more likely diagnosed in second half of pregnancy.

  
  

• Sensitivity is better for detecting arthrogryposis (81%) compared with polydactyly (19%), but the specificity for both findings is >99%.

• Consider 3D imaging ( Fig. 26.23 ; Video 26.13 ) and/or MRI to aid in diagnosis.

  

Differential Diagnosis

• Temporary unusual posturing of hand or foot

• Amniotic band sequence

• Vascular disruption

• Skeletal dysplasias (e.g., absent radius) ( Fig. 26.24 )

  

Associated Anomalies

• Arthrogryposis is an isolated finding in only one-third of cases ^, ; it may be a component of >400 specific conditions

  • Amyoplasia, a primary myopathy, accounts for one-third of all cases of AMC28

  • Other primary myopathies (myotonic dystrophy)

  • Fetal neuromuscular disorders (spinal muscular atrophy, Pena-Shokeir syndrome, cerebro-oculofacial syndrome)

  • Connective tissue disease (diastrophic dysplasia)

  • Metabolic disorders (Gaucher disease, glycogen storage disease IV, Zellweger syndrome)

  • Infection (rubella, coxsackievirus, enterovirus)

  • Maternal myasthenia gravis (transplacental passage of acetylcholine receptor antibodies)

  • Other syndromes (e.g., VACTERL association [vertebral abnormality, anal atresia, cardiac defect, tracheoesophageal fistula, renal agenesis, and radial limb abnormality])

  • Aneuploidy (e.g., trisomy 18)

  • Other findings associated with arthrogryposis include micrognathia, intrauterine growth restriction (IUGR), absent stomach bubble, short limbs, hydrops fetalis, pulmonary hypoplasia

  • Polyhydramnios (particularly with fetal akinesia)

• Polydactyly is an isolated finding (i.e., nonsyndromic polydactyly) in 85% of cases; syndromic polydactyly is more commonly seen in preaxial (20%) versus postaxial (12%) polydactyly. ^,

  • Most common associated anomaly is another limb defect (e.g., syndactyly)

  • Can be an inherited trait, the result of teratogen exposure (e.g., diabetic embryopathy, valproic acid), or a component of nearly 300 recognizable syndromes ^,

    • Aneuploidy (trisomy 13, trisomy 21)

      • Preaxial polydactyly imparts almost threefold higher risk of Down syndrome ( P < .0001)

    • Meckel-Gruber syndrome

    • Oral-facial-digital (OFD) syndrome

    • Skeletal dysplasias (e.g., Ellis–van Creveld syndrome, short rib–polydactyly syndrome)

    • VACTERL association

    • Smith-Lemli-Opitz syndrome

    • Esophageal atresia

    • Diamond-Blackfan and Fanconi anemia

Prognosis

• Prognosis of arthrogryposis and polydactyly depends on associated abnormalities and whether the finding is part of a syndrome.

• Perinatal morbidity and mortality related to isolated limb defects are low; poor prognosis with AMC if accompanying hydrops, nuchal edema, pulmonary hypoplasia, CNS malformations, scoliosis, and/or absent stomach filling. ^,

• Recurrence of limb deformity is common owing to periarticular fibrosis and thickened joint capsules.

• Long-term outcomes with AMC

  • Able to walk independently >50%

  • Scoliosis or lordosis 35%

  • Difficulty opening jaw 16%

  • Regular pain 75% (88% joint pain, 49% muscle pain)

  • Undergraduate degree 63%, graduate degree 27% (2.5 times higher than US population)

  • Quality of life comparable to the general US population

Antenatal Management

• Amniocentesis with microarray testing should be considered for karyotype and possible genetic testing, particularly if there are other associated CNS, cardiac, or renal anomalies present.

• Consider fetal echocardiogram with arthrogryposis to assess cardiac structure and function.

• Consider t oxoplasmosis, o ther agents, r ubella, c ytomegalovirus, and h erpes simplex (TORCH) testing if amniocentesis not performed. Consider Zika virus testing in endemic areas (e.g., Brazil, Paraguay, Bolivia), particularly if concomitant fetal microcephaly or brain abnormalities present.

• Serial ultrasound examinations with arthrogryposis to monitor fetal growth, thoracic development, and amniotic fluid.

• Prenatal genetic consultation to determine if syndrome likely.

• Prenatal orthopedic surgery consultation to discuss postnatal management and prognosis.

• Delivery in tertiary care facility recommended only if other anomalies or syndromes are suspected.

• Cesarean delivery should be reserved for usual obstetric indications (e.g., malpresentation, which often accompanies AMC); fractures may occur during birth with AMC even with cesarean due to osteopenia.

Neonatal Management

• Pulmonary hypoplasia and/or difficulty with airway access should be anticipated if there is global fetal akinesia, significant kyphoscoliosis, or suspected jaw involvement (e.g., micrognathia).

• Careful physical examination should be performed to assess for other anomalies, syndromes, or aneuploidy.

• Consultation with geneticist and pediatric orthopedics to establish diagnosis and plan treatment.

• Physical therapy should be initiated as soon as possible to improve range of motion in arthrogryposis cases.

• Offer autopsy if termination or perinatal demise.

• Surgical ablation of rudimentary supernumerary digits may be accomplished by suture ligation, but well-formed extra digits may require orthopedic reconstructive surgery.

Key Points

• Persistent exaggerated posturing of joints (flexed or extended) or atypical angulation of the extremities is suspicious for arthrogryposis.

• Although arthrogryposis can be isolated, it is commonly associated with other associated abnormalities and syndromes and should prompt detailed anatomic evaluation and further investigation as appropriate.

• Polydactyly is more likely to be an isolated finding, but associated abnormalities are more common with preaxial polydactyly compared with postaxial polydactyly.

Definition

Congenital clubfoot, also known as talipes equinovarus, is a malformation of the fetal ankle producing various abnormal posturing of the foot.

Incidence and Epidemiology

• Incidence of clubfoot is approximately 1–3:1000 live births; male-to-female ratio is 2:1. ^,

• Approximately two-thirds of cases are bilateral; one-third are unilateral. ^,

Etiology and Pathogenesis

• Clubfoot etiology is multifactorial and can be congenital, syndromic, or positional.

  • Intrinsic disruption of the neuromuscular unit (brain, spinal cord, nerve, muscle) and unopposed muscle activity restricting the ankle in a distorted position.

  • Extrinsic factors that restrict normal mobility of the lower extremities include oligohydramnios, malpresentation, leiomyomas, and multifetal crowding.

• Genetic factors have been implicated (25% of cases are familial), but the genetic mechanism is unclear.

  • Gene mutations associated with clubfoot include TBX4, PITX1, NAT2, RMB10, and HOXA, HOXC, and HOXD gene clusters . ^{, ,}

• Risk factors for clubfoot include positive family history of clubfoot (OR = 7.80; 95% CI, 4.04–15.04), selective serotonin reuptake inhibitor exposure (OR = 1.78; 95% CI, 1.34–2.37), maternal smoking (OR = 1.65; 95% CI, 1.54–1.78), maternal body mass index ≥30 (OR = 1.46; 95% CI, 1.29–1.65), and gestational diabetes (OR = 1.40; 95% CI, 1.13–1.72).