Version July 2025
INTRODUCTION —
Skeletal dysplasias (also called osteochondrodysplasia) are a large, heterogeneous group of disorders involving development of some segments of bone and cartilage. Affected bones are shorter, their growth over time is slower than expected, and their morphology and mineralization are usually abnormal. A specific skeletal dysplasia can have considerable phenotypic variability and often has overlapping features with other skeletal dysplasias. Thus, determining the specific dysplasia prenatally can be challenging. When a specific skeletal dysplasia cannot be diagnosed prenatally, the immediate prenatal goal is to determine whether the dysplasia will be life-limiting or life-altering postnatally. Although most infants with a life-limiting skeletal dysplasia are stillborn or die within the first week of life, some survive for months or even years with aggressive medical therapy [1]. This is the basis of using the term "life-limiting" rather than "lethal," as the latter does not fully encompass the potential postnatal clinical course with aggressive medical support [2].
In pregnancies that undergo an early ultrasound, fetal skeletal dysplasia may be first suspected at an 11- to 14-week examination. More commonly, it is first suspected when a short femur length (FL) or other bony abnormalities are noted at the routine fetal anatomic survey at 18 to 22 weeks of gestation. Typically, an early prenatal presentation is associated with more severe skeletal dysplasias, ie, those with a life-limiting prognosis because the small thorax results in pulmonary hypoplasia and respiratory failure after birth. In contrast, the skeletal abnormalities of the life-altering skeletal dysplasias may not be evident until the third trimester or at any time from birth to adult life. Thus, a normal second-trimester fetal skeletal examination does not exclude a potentially life-altering skeletal dysplasia. The commonest life-altering skeletal dysplasia is the heterozygous form of achondroplasia.
This topic will focus on the life-limiting skeletal dysplasias that present prenatally and will offer a systematic detailed approach to predicting a life-limiting prognosis. Postnatal evaluation, clinical findings, and diagnosis of skeletal dysplasias are reviewed separately. (See "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders".)
CLASSIFICATION —
The Nosology Committee of the International Skeletal Dysplasia Society created a system that includes 771 different disorders associated with 552 genes classified into 41 major groups based on their clinical, radiographic, and/or molecular phenotype [3,4]. (See "Skeletal dysplasias: Approach to evaluation", section on 'Classification of skeletal dysplasias'.)
PREVALENCE
●Skeletal dysplasia – The overall birth prevalence of skeletal dysplasias is estimated to be 1.1 to 4.5 per 10,000 births [5-7]. Each of the known 771 individual skeletal dysplasia is rare [3,6,8,9].
●Life-limiting skeletal dysplasias – The prevalence of the life-limiting skeletal dysplasias ranges from 0.95 to 1.5 per 10,000 live births, accounting for approximately 50 percent of skeletal dysplasias [6,9,10]. Death usually occurs in utero, at birth, or within the first week of life [9,11,12]. The four most common life-limiting skeletal dysplasias, which account for 40 to 60 percent of all life-limiting skeletal dysplasias, are [7,9,13-16]:
•Thanatophoric dysplasia (TD)
•Achondrogenesis
•Homozygous achondroplasia
•Osteogenesis imperfecta type 2
Characteristics of these and additional, rarer life-limiting skeletal dysplasias are described below. (See 'Examples of life-limiting skeletal dysplasias' below.)
INITIAL IDENTIFICATION OF SKELETAL DYSPLASIA
Gestational age — The long bones and many other skeletal components are ossified by 12 weeks of gestation, thus the 11- to 14-week ultrasound examination is an appropriate time for initial assessment of these structures. A first-trimester examination in addition to the routine second-trimester fetal anatomic survey is becoming more common in the general obstetric population, and is often desired by patients with a personal or family history of skeletal dysplasia. The routine second-trimester fetal anatomic survey is performed between 18 and 22 weeks of gestation.
Procedure
●11- to 14-week scan – The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) updated practice guideline for the performance of 11- to 14-week ultrasound scan recommends visualizing all four extremities and including all three segments of the upper and lower limbs [17].
●≥14-week scan
•Femur length – At a minimum, femur length (FL) is measured on all ultrasounds performed ≥14 weeks [18]. The FL is imaged with both ends of the ossified diaphysis visible (image 1). The calipers are placed on the ends of the ossified diaphysis without including the distal femoral epiphysis. There is a trend to call this measurement a femur diaphysis length rather than a FL to more accurately reflect the actual measurement obtained. A perpendicular angle of insonation is preferred; however, typically an angle between 45 to 90 degrees is considered acceptable. The same technique may be applied to the other long bones, including the humerus, radius, ulna, tibia and fibula. The longest axis of the ossified diaphysis is measured. Several longitudinal measurements should be obtained, and the longest is recorded.
•Other bones – At the midtrimester scan at 18 to 22 weeks, many guidelines, such as the ISUOG practice guideline, recommend a systematic evaluation to assess the presence of all long bones and evaluate their symmetry, length, shape alignment, joint position, and movement [17]. Presence of hands and feet should be assessed, but counting fingers and toes is not required on a routine mid-trimester scan. If this routine evaluation detects possible abnormalities, then all long bones are measured and a detailed anatomic examination is performed, with consideration of referral for expert evaluation and genetic consultation.
When to suspect skeletal dysplasia — Fetal skeletal dysplasia should be suspected when either, and especially when both, of the following findings is observed:
●Femur length shorter than expected for gestational age – Typically, this is defined as below the 5th percentile for gestational age, although some use two standard deviations (SDs) from the mean for the gestational age to define a short femur. In a prospective Danish population study, the 5th percentile corresponded to the mean minus 1.645 SD, leading the authors to suggest that a cutoff value closer to -2 SD instead of the 5th percentile should be considered to minimize overdiagnosis [19].
●Qualitative bony abnormalities associated with skeletal dysplasia – These include bowing, angulation, fracture of long bones; short ribs; bell shaped thorax; metaphyseal irregularities; club foot; and abnormal spine, scapula, or calvarium. (See 'Qualitative assessment of long bones' below and 'Qualitative assessment of other bones' below.)
Differential diagnosis of causes of the mildly short femur — An isolated mildly short fetal femur is not uncommon. Differential diagnosis includes [20,21]:
●Normal variation – The majority of isolated mildly short femurs represent normal variation or constitutional short stature, and has been termed "constitutional short femur." If interim FL growth over three to four weeks is normal and along the same growth curve below the normal centiles, a short-limb skeletal dysplasia is unlikely. If FL over this interval falls further from the mean, then skeletal dysplasia or severe fetal growth restriction (FGR) becomes more likely [22].
Parental ancestry impacts height and should be considered in interpretation of the FL percentile. Mean FL is shorter in Asian populations compared with White populations and shorter in White populations compared with Black populations [23,24]. However, they are all above -2 SDs.
●Measurement error – As many as 13 percent of isolated mildly short femurs diagnosed at 18 to 24 weeks are reclassified as normal on follow-up [25]. This suggests the original value was a measurement error rather than an interim catch-up growth spurt.
●Skeletal dysplasia – Findings most predictive of skeletal dysplasia include:
•FL more than 5 mm below the -2 SD value for gestational age (which is approximately the equivalent of more than 4 SD below the mean at the time of the fetal anatomic survey between 18 and 22 weeks) [22].
•Femur-to-foot length ratio <0.9 [26]. The normal femur-to-foot length ratio is 1.0 throughout pregnancy; when it falls below 0.9, the likelihood of a skeletal dysplasia is increased relative to other causes of short femur, such as FGR or chromosome abnormality, as the majority of prenatally diagnosed skeletal dysplasias are associated with severe micromelia, but the foot length typically is near normal for gestational age.
•FL to abdominal circumference (AC) ratio <0.16 [27,28]
Associated skeletal or anatomic abnormalities support this diagnosis as opposed to normal variation or measurement error. (See 'Detailed ultrasound evaluation' below.)
The differential diagnosis of skeletal dysplasia is lengthy, often not possible prenatally, and beyond the scope of this review. This review will focus on the life-limiting skeletal dysplasia that can be predicted with reasonable accuracy. (See 'Predicting potential life-limiting skeletal dysplasias based on pulmonary hypoplasia' below.)
●Aneuploidy – The possibility of aneuploidy, in particular trisomy 21, should be considered as a mildly short femur and/or a mildly short humerus is a soft marker for fetal aneuploidy, albeit the predictive value is low when this is an isolated finding [19]. Other findings associated with trisomy 21 include cardiovascular anomalies (eg, endocardial cushion defects, tetralogy of Fallot, ventricular septal defects), central nervous system anomalies (eg, mild ventriculomegaly), gastrointestinal anomalies (eg, duodenal atresia [after 22 weeks]), increased nuchal translucency, and absent/hypoplastic nasal bone; the latter is considered a specific marker for midtrimester diagnosis of trisomy 21. (See "Sonographic findings associated with fetal aneuploidy", section on 'Trisomy 21 (Down syndrome)'.)
In patients with prior negative aneuploidy screening by cell-free DNA (cfDNA) testing, no further aneuploidy testing is indicated as the risk of trisomy 21 is not increased in the setting of an isolated mildly short femur. Patients without prior aneuploidy screening should be offered screening, preferably by cell-free fetal DNA. (See "Sonographic findings associated with fetal aneuploidy", section on 'Slightly short long bones'.)
●Fetal growth restriction – An isolated short FL at the midtrimester scan is a risk factor for subsequent diagnosis of FGR [29]. Additional findings that support the diagnosis of FGR include small AC, abnormal placental morphology, abnormal Doppler parameters on ultrasound and, if available, low pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) in maternal blood. Even if none of these findings are present when the short femur is detected, over time, the AC, humerus length, and sometimes head circumference will also begin to drop below the normal growth curves for gestational age in FGR. (See "Fetal growth restriction: Screening and diagnosis".)
DIAGNOSTIC EVALUATION OF SUSPECTED SKELETAL DYSPLASIA
Refer to an expert — When a short femur is identified, we recommend referral to a center with expertise in skeletal dysplasias to perform a detailed ultrasound examination and determine the etiology of the short femur (skeletal dysplasia versus another etiology). When skeletal dysplasia is strongly suspected, experts in pediatric imaging, maternal-fetal medicine, and genetics can attempt to diagnose the specific skeletal dysplasia through specific imaging findings and molecular testing, and provide counseling [30]. Prenatal screening using cell-free fetal DNA in maternal blood is becoming available for some single gene disorders, including several of the life-limiting skeletal dysplasia. (See 'Role of molecular diagnostic testing' below.)
We also recommend that patients with a family history of skeletal dysplasia who are planning to conceive or who are in early pregnancy undergo a detailed evaluation at a center with expertise in skeletal dysplasias. The assessment should include reanalysis of prior diagnostic genetic studies, and prenatal ultrasound imaging. For some skeletal dysplasias, ultrasound evaluation at 11 to 14 weeks or even earlier may be of value in determining potential occurrence/recurrence of a known skeletal dysplasia. When the genetic etiology has been determined, prenatal diagnosis via chorionic villus sampling (CVS) or amniocentesis can be performed for definitive diagnosis.
Detailed ultrasound evaluation — The components of detailed ultrasound assessment in cases of suspected skeletal dysplasia are listed in the table (table 1) and discussed in the following sections.
Quantitative assessment of long bone length
●All long bones (ie, each femur, humerus, radius, ulna, tibia, and fibula) should be measured to determine the relative shortening against normative values. For best practice, the most appropriate chart to use is one that has been validated in the population of interest. These charts may be incorporated into the onsite ultrasound equipment [31].
Pattern of limb shortening — Limb shortening is described by the affected segment. The four main patterns are:
●Rhizomelia, proximal segment shortening (eg, femur, humerus).
●Mesomelia, middle segment shortening of the (eg, radius, ulna, tibia, fibula).
●Acromelia, distal segment shortening (eg, hands, feet).
●Micromelia, shortening of all segments. Micromelia can be subdivided into mild, mild and bowed, or severe (image 2).
Qualitative assessment of long bones — Evaluation of the long bones includes the following assessments:
●Presence – Is each femur, humerus, fibula, tibia, radius, and ulna present?
●Shape – Is there bowing, angulation, metaphyseal flaring (dumbbell-shaped bones) or bone irregularities suggesting fractures?
Bowing or angulation of the femurs is a finding in most skeletal dysplasias; the four most common are campomelic dysplasia, achondroplasia, thanatophoric dysplasia (TD), and osteogenesis imperfecta type II. Non-life-limiting disorders associated with isolated bowed femurs include osteogenesis imperfecta type I and IV, Stuve-Wiedemann [32] and Schwartz-Jampel [33] syndromes, among others. Metaphyseal flaring is associated with Kniest syndrome, which is also non-life-limiting.
●Mineralization – Are there fractures?
Decreased mineralization of the long bones is most reliably diagnosed by fractures; decreased or absent acoustic shadowing is a less reliable marker. Bone fractures may appear as angulations or interruptions in the bone contour or as thick, wrinkled contours corresponding to repetitive cycles of fracture and callus formation. These findings are common in osteogenesis imperfecta, achondrogenesis, and hypophosphatasia congenita.
●Position – Are joint deformities present? Joint contractures suggest skeletal dysplasias associated with arthrogryposis multiplex congenita and fetal akinesia syndromes. Multiple joint contractures associated with kyphoscoliosis and micromelia are typical of diastrophic dysplasia.
●Epiphyses – Premature ossification of the epiphysis associated with multiple ossification centers ("stippled epiphysis") is characteristic of chondrodysplasia punctata (CDP), but may also be associated with warfarin embryopathy and maternal systemic lupus erythematosus and other autoimmune diseases [34].
Qualitative assessment of other bones — Specific dysmorphic features of other bones (eg, clavicular or scapular hypoplasia; platyspondyly [flattened vertebral bodies]) can be helpful to further define a specific skeletal dysplasia.
●Spine – Short-trunk/short stature is mainly caused by changes in the spine. The spine is assessed for segmentation anomalies, kyphoscoliosis, platyspondyly (flattened vertebral body), demineralization, myelodysplasia, and caudal regression. Although platyspondyly is the most common spine abnormality, it may be difficult to diagnose on prenatal ultrasound [35]. Severe platyspondyly is present in TD and osteogenesis imperfecta type II. Milder degrees of platyspondyly may be present in conditions such as fibrochondrogenesis, de la Chapelle dysplasia, and Kniest syndrome, among others.
Vertebral disorganization with secondary kyphoscoliosis may be associated with syndromes such as dyssegmental dysplasia and costovertebral dysplasia (Jarcho-Levin syndrome) [36].
Under-ossification of the spine is seen in conditions such as atelosteogenesis, achondrogenesis, and hypophosphatasia.
Disproportionately short-trunk/short stature is a type of skeletal dysplasia that is not associated with shortened limb length. It can occur in spondyloepiphyseal dysplasia or secondary to lysosomal storage disorders with bone involvement, such as mucolipidosis type 2.
●Hands and feet – Common deformities of the hands and feet include clubfoot, rocker bottom foot, clubhand, short fingers (brachydactyly), or an abnormal number of digits. The position of the thumbs and toes can provide a clue to the diagnosis; a hitchhiker thumb or abducted thumb/first toe is present in diastrophic dwarfism.
Polydactyly (extra digits) suggests a group of conditions known as short-rib polydactyly syndromes (SRPS; eg, Ellis-van Creveld syndrome, Jeune asphyxiating thoracic dystrophy, Saldino-Noonan, etc) and some chromosomal abnormalities (trisomy 13). It may also be a familial condition (Grieg syndrome) and associated with ancestry (about 1.5 percent of all African American peoples are born with postaxial polydactyly), thus family history and ancestry are important.
Syndactyly is associated with Apert syndrome, and oligodactyly is associated with De Lange and Roberts syndromes.
●Calvarium – In most skeletal dysplasias with prenatal onset, the long bones are disproportionately short. The calvarium may be normal, large for dates (macrocephaly), or small for dates (microcephaly) and have associated findings such as frontal bossing or cloverleaf skull. Some skeletal dysplasia are also associated with underlying structural brain abnormalities. In particular, temporal lobe dysplasia is associated with TD, achondroplasia, and hypochondroplasia and all are associated with pathogenic variants in the fibroblast growth factor receptor 3 (FGFR3) group of genetic disorders [37-39]. An abnormal cranial contour and cloverleaf skull may indicate premature fusion of the sutures (craniosynostosis). Common craniosynostosis syndromes, such as Apert, Crouzon, Carpenter, Muenke, and Pfeiffer syndromes, manifest with craniosynostosis in association with limb anomalies such as syndactyly ("mitten hands"), abducted thumbs, and polydactyly. Macrocephaly is associated with TD, achondroplasia, and achondrogenesis but can also be constitutional. (See "Overview of craniosynostosis" and "Craniosynostosis syndromes".)
Decreased mineralization of the calvarium may present with a range of sonographic findings from enlarged fontanelles to extreme demineralization where the midline falx appears more echogenic than the calvarium itself. Abnormal compressibility of the cranial vault with normal transducer pressure is considered a reliable finding in cranial vault demineralization. These findings may be associated with osteogenesis imperfecta type 2, achondrogenesis, or hypophosphatasia congenita. Absent calvarial ossification/very large fontanelles can also be seen in cleidocranial dysplasia and renal tubular dysgenesis, as well as in prenatal exposure to angiotensin-converting enzyme inhibitors [40].
●Face – Common facial abnormalities include midface hypoplasia, saddle nose deformity, hypertelorism, cleft lip and palate, frontal bossing, micrognathia (mandibular hypoplasia), and retrognathia (abnormal posterior positioning of the mandible) (image 3). The bi-orbital diameter should be measured to assess for hypotelorism or hypertelorism. TD is characterized by the combination of midface hypoplasia, saddle nose deformity, and high forehead with frontal bossing.
Osteogenesis imperfecta type 2, the life-limiting variant, is usually caused by an autosomal dominant de novo genetic variant in COL1A1 or COL1A2 (coding for the type I collagen) and typically presents with facial dysmorphism including a triangular face with prominent eyes and retrognathia/micrognathia. Variants in the COL2A1 gene, coding for type II collagen and associated with a variety of conditions including Kniest syndrome and Stickler syndrome type 1, also present with micrognathia/retrognathia but usually with cleft palate (Robin sequence) and prominent eyes with severe myopia and retinal detachment.
●Ribs – Ribs are assessed for abnormal appearance or number. Short ribs, encircling less than 70 percent of the thorax, are associated with life-limiting skeletal dysplasias. This will result in a narrow anteroposterior diameter of the thorax, a flared appearance to the lower thorax, and a reduced thoracic circumference. Rib fractures may result in angulation or, when numerous, in a beaded appearance.
Associated syndromes with abnormal appearance/number of ribs include costovertebral dysplasia (Jarcho-Levin syndrome), Poland anomaly, VACTERL association (vertebral abnormalities, anal atresia, cardiac abnormalities, tracheoesophageal fistula, kidney abnormalities, limb abnormalities), campomelic dysplasia, and chromosome abnormalities.
●Scapula – Hypoplastic or absent scapula is commonly noted in campomelic dysplasia but may also occur in Cousin syndrome, Kosenow syndrome, and Antley-Bixler syndrome [41]. Within the platyspondylic life-limiting skeletal dysplasias, the presence of two inferior spikes suggests the Luton variety. One review includes an excellent schematic demonstration of the various scapular anomalies and the associated syndromes (figure 1) [42].
●Pelvic bones – Although important to evaluate, the pelvic bones are difficult to assess on conventional two-dimensional (2D) ultrasound; additional three-dimensional (3D) techniques may be required to appreciate the shape of the iliac bones and the sacrosciatic notches.
Achondrogenesis, which is a relatively common life-limiting musculoskeletal dysplasia, presents with multiple abnormalities including abnormal decreased mineralization in the ischium and pubic bones. "Squared" iliac bones are features of both TD and achondroplasia.
Survey of nonskeletal anatomy — A detailed evaluation of the cardiovascular, genitourinary, gastrointestinal, and central nervous systems should be performed concurrently with the skeletal evaluation. The composite findings may point to a specific skeletal dysplasia. Detection of associated anomalies may suggest a more specific diagnosis and thus help direct counseling and management. In many fetal skeletal dysplasias, the skin and subcutaneous layers continue to grow at a faster rate than the long bones, resulting in relatively thickened skin folds that may be mistaken for skin edema. Polyhydramnios is common and may be related to a combination of factors, including esophageal compression (by a small chest), micrognathia (which interferes with normal swallowing), associated gastrointestinal abnormalities, and hypotonia-related reduction in swallowing.
Role of specialized imaging techniques
●Three-dimensional (3D) ultrasound – 3D ultrasound is becoming an increasingly useful complement to 2D ultrasound in diagnosis of skeletal dysplasia and pulmonary hypoplasia [43-46]. However, studies defining the role of 3D ultrasound as compared with 2D ultrasound in skeletal dysplasias are limited [47].
High-contrast structures such as the fetal skeleton are especially amenable to 3D ultrasound rendering software. Coronal multiplanar reformation (MPR; ie, the process of using the data from axial computed tomography [CT] images to create nonaxial 2D images) appears to be particularly helpful in defining segmentation vertebral anomalies or helping to define the type of scapular anomaly. Surface rendering capabilities are particularly useful to visualize subtle facial dysmorphism, such as low set or deformed ears, micrognathia, flattening of the facial profile associated with midface hypoplasia as in chondrodysplasia punctata (CDP), cranial distortion due to craniosynostosis, or assessing hand/foot abnormalities [43]. However, available data are insufficient to gauge the diagnostic performance of this modality.
●Magnetic resonance imaging – After 20 weeks of gestation, magnetic resonance imaging (MRI) may play a complementary role to ultrasound in diagnosis of specific skeletal dysplasias because it can identify and better define some abnormalities, particularly of the brain. Additionally, it can be used to calculate lung volumes, albeit data are limited on the reliability for life-limiting pulmonary hypoplasia in the setting of skeletal dysplasia.
Unenhanced MRI, which is typical for skeletal dysplasia imaging, has no known harmful fetal effects. Postnatally, MRI can be useful in the context of "virtual autopsy" when autopsy is declined [48]. However, skeletal radiographs and molecular genetics using whole exome sequencing (WES)/whole genome sequencing (WGS) or a comprehensive gene panel enables more precise diagnosis in skeletal dysplasias and would typically provide sufficient information in this setting [49]. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Magnetic resonance imaging' and "Skeletal dysplasias: Approach to evaluation", section on 'Imaging'.)
●Low-dose computed tomography – The key benefit of low-dose CT with 3D reconstruction is that it provides detailed images of the entire skeleton with 3D-rendered images. The fetal radiation exposure is in the 3 mGy range when technical factors are optimized to minimize radiation dose [43,50-52]. In 2009, the International Commission on Radiological Protection concluded that in utero dose exposure less than 100 mGy is below the threshold for induction of malformations and that the lifetime risk of childhood cancer would be similar to that following irradiation in early childhood [53]. The Fetal Imaging Task Force of the European Society of Paediatric Radiology have published guidelines regarding the use of ultra-low-dose CT prenatally [52]. (See "Diagnostic imaging in pregnant and lactating patients", section on 'Fetal risks'.)
This modality should be considered if pregnancy termination (also called pregnancy interruption) is being planned by dilation and extraction since the procedure is likely to result in fetal fragmentation which limits the utility of post-mortem radiographs. It should also be considered after 20 weeks of gestation in the diagnostic evaluation of some cases of suspected skeletal dysplasia when the diagnosis remains uncertain and additional information may affect pregnancy management.
In one study, the diagnostic utility of low-dose fetal CT was similar to a postnatal radiographic skeletal survey and, in 59 percent of their cases, the findings changed the ultrasound-provided diagnosis to the correct one, thus permitting more accurate management and counseling in the prenatal period [54]. In another study, low-dose fetal CT revealed additional findings in up to 81 percent of cases, which sometimes led to a more specific diagnosis [55]. It should be noted that studies have not compared 3D-CT with state-of-the-art 3D-ultrasound skeletal bony rendering; thus, its potential benefits compared with contemporary 3D-ultrasound are unclear and evolving.
As with postnatal MRI, 3D-CT can be useful postnatally in the context of "virtual autopsy" when autopsy is declined; however, skeletal radiographs and molecular genetics using WES/WGS or a comprehensive gene panel enables more precise diagnosis in skeletal dysplasias [49]. (See "Skeletal dysplasias: Approach to evaluation", section on 'Imaging'.)
●Radiography – Prenatal radiography has a limited role in prenatal diagnosis of skeletal disorders because the superimposition of fetal and maternal bones makes interpretation difficult.
Postnatal radiography (skeletal survey), however, plays a critical role in defining the characteristic skeletal features present in many skeletal dysplasias. (See "Skeletal dysplasias: Approach to evaluation", section on 'Imaging'.)
Role of molecular diagnostic testing — Diagnosis of skeletal dysplasia is usually based on a combination of imaging, clinical, and molecular testing. Karyotype/chromosome microarray analysis is usually normal as most skeletal dysplasias result from single gene pathogenic variants with autosomal dominant, autosomal recessive, or X-linked mode of inheritance. A significant portion of the dominant conditions are the result of a "de novo" pathogenic variant in the sperm or egg resulting in an affected fetus (without evidence of the pathogenic variant in either parent) and thus carry a low recurrence risk.
Identifying a specific single gene disorder on molecular analysis in an affected fetus with a skeletal dysplasia is important for genetic counseling regarding the prognosis and recurrence risk, patient counseling about options for managing the current pregnancy, counseling regarding their future reproductive plans, and counseling about the impact the diagnosis may have on the family [56,57]. The utility of next-generation sequencing has not yet been characterized in an unselected population with skeletal dysplasia; however, WES/WGS as well as gene panel testing can provide diagnostic information, particularly in the setting where the radiological phenotype is nonspecific or overlaps with several conditions [49,58]. Despite phenotypic variability, detailed phenotyping by imaging may supplement the molecular diagnosis, particularly in life-limiting conditions with findings on second-trimester imaging.
Fetal DNA analysis can be performed via chorionic villus sampling (CVS; performed transcervically at 11 to 14 weeks of gestation or transabdominally after 11 weeks of gestation) or amniocentesis (performed at ≥15 weeks of gestation) (see "Chorionic villus sampling" and "Diagnostic amniocentesis"). Cell-free DNA (cfDNA) testing of maternal blood has been used to identify single gene disorders such as achondroplasia and TD, thus providing a noninvasive tool for supporting the sonographic diagnosis [59]; however, cfDNA for single gene disorders is a screening test and not a diagnostic test as false-positive and false-negative results may occur. (See "Cell-free DNA screening for fetal conditions other than the common aneuploidies".)
Shared decision-making should guide choice of further diagnostic testing [60]. Decision-making depends, in part, by the clinical setting:
●No prior personal or family history of skeletal dysplasia – The role of molecular studies for diagnosis of a specific life-limiting skeletal dysplasia in an ongoing pregnancy with no personal or family history is controversial for several reasons. A genetic variant has not been determined for all skeletal dysplasias, thus a negative result or failure to identify a specific genetic variant may not change the clinical implications based on the ultrasound findings. Furthermore, variants in the same gene can cause different forms of skeletal dysplasia and variants in different genes can cause similar skeletal abnormalities [61]. Lastly, WES/WGS is costly and may require several weeks for results, thus it may not be amenable with the timeline for important management deadlines. Nevertheless, molecular analysis (gene panel or WES/WGS) can be an important diagnostic tool in cases of suspected skeletal dysplasia when there is no family history of a specific condition and when no specific diagnosis can be made based on fetal imaging [62]. Narrowing down the possibilities based on the constellation of ultrasound findings can help in choosing an appropriate gene panel if WES/WGS is not available.
Since prenatal sonographic findings of life-limiting skeletal dysplasia are prognostically reliable, prenatal or postnatal molecular analysis in these cases is most useful for planning future pregnancies rather than for predicting the outcome of the affected pregnancy. When a de novo causative fetal pathogenic gene variant is identified (eg, as in TD), the patient is usually given a recurrence risk in the range of 1 percent. Preimplantation genetic testing in future pregnancies is not useful in these cases, but prenatal diagnosis using CVS/amniocentesis and fetal ultrasound can be offered. When a familial genetic condition is the cause, options for future pregnancies include either preimplantation genetic testing or prenatal diagnosis using CVS/amniocentesis and fetal ultrasound.
●Parent is affected or a known carrier – If a parent is affected (in autosomal dominant conditions such as achondroplasia) or the mother is a carrier for an X-linked condition (as in X-linked spondyloepiphyseal dysplasia tarda), fetal DNA can be analyzed for specific variants. Pathogenic variants have been identified for approximately 70 percent of skeletal dysplasias [11,63] and can be used to provide early prenatal diagnosis (before diagnostic findings are seen on ultrasound) or to confirm the presumptive diagnosis on imaging performed later in pregnancy, as well as for preimplantation genetic testing in at-risk couples. A microarray analysis is usually performed at the same time.
When both parents are affected with the same or different autosomal dominant skeletal disorders, the fetus is at high risk of life-limiting skeletal dysplasia because of homozygosity or compound heterozygosity for the same condition, or heterozygosity for two dominant conditions (double heterozygote) [64]. For example, when both parents are affected with achondroplasia, the most common skeletal dysplasia, the likelihood of having a fetus who is homozygous or compound heterozygous for the FGFR3 variant associated with achondroplasia, and thus with the life-limiting form, is 25 percent, while the risk for having a fetus with achondroplasia is 50 percent. In such cases, molecular diagnosis is useful to distinguish between a fetal heterozygote, homozygote, and compound heterozygote [65]. When one parent has an autosomal recessive skeletal dysplasia, the risk of having an affected fetus is low if the other parent does not carry a pathogenic variant in the same gene.
DIAGNOSIS
Prenatal diagnosis — The prenatal diagnosis of skeletal dysplasia is based on the characteristic appearance of the fetal skeleton on imaging (primarily ultrasound): limb and/or spine shortening and a spectrum of accompanying bone abnormalities (eg, absence, decreased mineralization, fracture, abnormal curvature, abnormal shape, abnormal angulation of joints, metaphyseal flaring) that may involve the face, hands/feet, calvarium, ribs, and scapula. Magnetic resonance imaging (MRI), computed tomography (CT), or radiography may be used to support the presumptive sonographic diagnosis. A specific skeletal dysplasia may be suspected based on family history or the constellation of findings and may be confirmed by molecular testing, if available. (See 'Diagnostic evaluation of suspected skeletal dysplasia' above and 'Examples of life-limiting skeletal dysplasias' below.)
The accuracy of prenatal ultrasound for diagnosis of skeletal dysplasia has improved significantly in the past 20 years: 68 percent for correct prenatal diagnosis and 31 percent for partially correct diagnosis, with 0.07 percent false positives [14,15,27,66-70]. Despite the rare occurrence of any specific dysplasia, a combination of imaging, molecular analysis of fetal DNA, and postnatal radiographs and physical examination can allow classification to a specific group in up to 99 percent of cases and a specific diagnosis within the group in 86 percent of cases, using the Nosology and Classification of Genetic Skeletal Disorders [4,5]. A family history of consanguinity, a sibling or a parent affected with a skeletal dysplasia, or a prior affected fetus can help in diagnosing a specific skeletal dysplasia; however, the low incidence, phenotypic variability, overlapping features, and lack of family history in most cases make diagnosis of a specific dysplasia difficult.
The immediate prenatal goal is to determine whether the dysplasia is life-limiting or life-altering even if a specific skeletal dysplasia cannot be identified. Diagnostic accuracy is critical, as the patient may choose to terminate the pregnancy or avoid cesarean birth if the skeletal dysplasia is life-limiting or associated with high morbidity and quality-of-life factors that are unacceptable to the parents.
After birth, postnatal radiographs, autopsy (in life-limiting cases and/or terminated pregnancies), and molecular testing are crucial for making an accurate diagnosis [67,71]. Overlapping features and phenotypic variability of the skeletal dysplasias limit the accuracy of diagnosis based on physical examination alone. (See 'Postnatal/post-termination evaluation' below and "Skeletal dysplasias: Approach to evaluation".)
Predicting potential life-limiting skeletal dysplasias based on pulmonary hypoplasia — One of the most important determinations that needs to be made prenatally is whether the condition is potentially life-limiting because of pulmonary hypoplasia (image 4). This prediction is usually based on ultrasound evidence of changes correlating with pulmonary hypoplasia, which are described below. Molecular diagnosis for known life-limiting skeletal dysplasias can be performed using gene panels or whole exome sequencing (WES)/whole genome sequencing (WGS) but prompt fetal sample acquisition by CVS/amniocentesis and DNA analysis is required to obtain a timely result. (See 'Role of molecular diagnostic testing' above.)
Prediction of life-limiting pulmonary hypoplasia by prenatal ultrasound is accurate, ranging from 81 to more than 99 percent in various studies [14,15,66,72]. In the largest prospective study using a standardized ultrasound approach to the evaluation of these disorders, a life-limiting condition was accurately predicted in 96.8 percent of 500 cases in the International Skeletal Dysplasia Registry [14]. Review of the literature indicates that death occurs in this group before or during the neonatal period, typically due to respiratory failure; however, in one study of a cohort of 38 infants with typically life-limiting skeletal dysplasias, including thanatophoric dysplasia (TD), achondrogenesis, and osteogenesis imperfecta type II, the survival rate was 50 percent in the neonatal period and 28.9 percent at one year of life [73]. This group of infants required aggressive medical intervention, including intubation in 78.9 percent, mechanical ventilation in 92.1 percent, and tracheostomy placement in 23.7 percent. Contemporary data should be considered when counseling parents about the most common of the so-called "lethal" skeletal dysplasias, acknowledging some limitations of the diagnosis of "lethality." As part of this counseling, the clinician should discuss with parents whether they would like the medical staff to carry out every heroic measure to treat the newborn and their decision should be respected.
●First-trimester prognostic findings – In general, the earlier in gestation a skeletal dysplasia is detected, the more likely a life-limiting condition is present, thus the majority of cases identified in the first trimester represent life-limiting skeletal dysplasias [74]. The combination of shortened long bones and a small chest is predictive of a life-limiting condition. Additional findings may include abnormal skull shape, abnormal joint position, bone demineralization, fractures, and abnormal vertebral development.
Increased nuchal translucency is a marker for several fetal disorders and commonly associated with skeletal dysplasia [74,75]. (See "Enlarged nuchal translucency and cystic hygroma".)
●Second- and third-trimester prognostic findings – The following second-trimester findings are suggestive of pulmonary hypoplasia (image 4). Presence of multiple sonographic parameters improves accurate prediction of lethality [76].
•Thoracic circumference <5th percentile, measured at the level of the four-chamber heart view
•Thoracic to abdominal circumference (AC) ratio <0.6 [8,70]
•Short thoracic length (from the neck to the diaphragm compared with nomograms)
•Ribs that encircle less than 70 percent of the thoracic circumference at the level of the four-chamber cardiac view [77]
•Markedly narrowed anteroposterior diameter (sagittal view)
•Concave or bell-shaped contour of the thorax (coronal view)
•Heart to chest circumference ratio >50 percent [70]
•Femur length (FL) to AC ratio <0.16; this ratio is even more predictive when associated with polyhydramnios [8,28,70]
A comparative study of eight different methods for the prediction of fetal lung hypoplasia determined that the lung volumes and the thoracic circumference to AC ratios performed best [78]; however, the majority of these studies were performed in the congenital diaphragmatic hernia population and may not be generalizable to this population [79,80].
Role of ancillary imaging — Three-dimensional (3D) ultrasound and MRI may be used to support the two-dimensional (2D) ultrasound prognosis; however, data on lung volumes measured by ultrasound and MRI specifically in fetuses with musculoskeletal disorders are limited [81]. One study showed the feasibility of 3D ultrasound for measuring lung volumes in fetuses with skeletal dysplasia and found that it could accurately predict life-limiting pulmonary hypoplasia in these cases [82]. It should be noted that measurements after 32 weeks were not performed due to technical limitations. Another study found that the FL:AC ratio correlated best with low lung weight [83].
In a MRI study of a cohort of 23 patients with skeletal dysplasia, an observed/expected total fetal lung volume less than 47.9 percent on MRI was a predictor of a life-limiting skeletal dysplasia [81]. This value is larger than that for life-limiting pulmonary hypoplasia in congenital diaphragmatic hernia, thus reinforcing the concept that larger studies need to be performed in the skeletal dysplasia population since results in the congenital diaphragmatic hernia population may not be generalizable to this population [78-80]. Several reviews have demonstrated high variability in lung volume nomograms in different studies due to differing methodologies [84-86]. This suggests MRI should be reserved for borderline cases of pulmonary hypoplasia and difficult diagnostic scenarios.
PREGNANCY MANAGEMENT
Counseling — The finding of a skeletal dysplasia and the subsequent communication of this news are difficult tasks, which require empathy and support. Referral to a clinician with expertise in clinical genetics to discuss possible phenotypes and genotypes in offspring, prognosis, options for prenatal diagnosis, and preimplantation genetic testing in future pregnancies, can be very helpful.
When ultrasound and any additional diagnostic evaluations lead to the diagnosis of a specific skeletal dysplasia, the patient can be given prognostic information (see 'Diagnosis' above). However, for many patients, the diagnosis of a skeletal dysplasia is sufficient for making a decision regarding pregnancy management. In many cases, the exact diagnosis is not known, but the prognosis is evident based on the ultrasound findings and/or the findings on molecular analysis.
The fetal findings and the implications should be explained in language that is simple to understand so that the patient can make an informed decision regarding the management of the pregnancy and possible delivery and postnatal care. Cultural differences need to be respected and taken into consideration during the counseling process. For some patients, any type of skeletal dysplasia is unacceptable and the option of pregnancy termination should be discussed.
After the initial detailed ultrasound evaluation and maternal-fetal medicine consultation, options include:
●Obtain further information prior to making a decision, with repeated fetal ultrasound, fetal echocardiography, fetal magnetic resonance imaging (MRI), and further counseling by specialists from other disciplines, such as medical geneticists, neonatologists, orthopedic surgeons, palliative treatment groups, social workers, organizations/support groups of other affected families, and the parents' religious or community sources of support. (See 'Role of specialized imaging techniques' above.)
Fetal DNA analysis using skeletal dysplasia gene panel or whole exome sequencing (WES)/whole genome sequencing (WGS) or targeted gene sequencing when the gene is strongly suspected based on the fetal ultrasound findings or based on a known familial gene variant identified in a previous pregnancy, provides substantial additional diagnostic information. WES/WGS is the preferred study since it provides a better detection rate in fetuses with skeletal dysplasia [87]. Gene panels are less useful because the number of genes associated with skeletal dysplasia is constantly increasing and the number of genes included in gene panels for fetuses with skeletal dysplasia is limited and controlled by the companies providing the test. (See 'Role of molecular diagnostic testing' above.)
●Continue the pregnancy with repeated fetal ultrasound examinations and counseling by specialists from other disciplines, as appropriate, regarding the management of delivery and postnatal care. The route of delivery, especially in cases with fetal macrocrania (which may preclude vaginal birth), and the extent of postnatal treatment should be discussed, and the poor prognosis should be kept in mind.
●Pregnancy termination.
Postnatal/post-termination evaluation — Despite the rare occurrence of individual skeletal dysplasias, assessment of radiographic findings, molecular analysis, and pathology specimens enables postnatal assignment to a specific group within the 2015 and 2023 Nosology and Classification of Genetic Skeletal Disorders system in up to 99 percent of cases [4,5,63].
Fetal autopsy should be offered to identify the etiology of the skeletal dysplasia, especially if the diagnosis is uncertain or the results will affect future reproductive plans [88]. For example, if the risk of recurrence is increased, some parents may choose to have preimplantation genetic testing to transfer unaffected embryos, egg/sperm or embryo donation in cases of inherited autosomal recessive or X-linked conditions, early prenatal diagnosis, or avoid subsequent pregnancy.
It is preferable for the autopsy to be performed by a perinatal pathologist. If the patient declines a full postmortem evaluation, then a minimally invasive evaluation including external evaluation and imaging (X-ray and computed tomography [89]) as well as DNA/fibroblasts/tissue banking may be of value.
With parental consent, external and internal examinations are performed, and skeletal radiographs and photographs are taken. Histopathologic examination of bones, relevant tissue, and the placenta should be performed. The femur is the most useful bone for examination, as it offers bone and cartilaginous tissue in addition to two large growth plates. Bone and cartilage may be kept deeply frozen for later studies. Tissue should be referred for DNA extraction and banking, as well as fibroblast banking for further studies, including microarray analysis, genetic variant analysis for a specific gene disorder when a specific diagnosis is suspected, or a gene panel or WES/WGS when no specific diagnosis is suspected [90]. If WES is used, parental DNA should also be obtained to improve the diagnostic yield. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers", section on 'Advanced testing options'.)
Resources — When local expertise is unavailable and/or the diagnosis cannot be determined, resources such as the International Skeletal Dysplasia Registry or the European Skeletal Dysplasia Network should be consulted. Detailed and up-to-date information regarding the molecular tests available for the diagnosis of skeletal dysplasias is available at:
●European Skeletal Dysplasia Network
●Division of Molecular Pediatrics
●International Skeletal Dysplasia Registry
●On-line Inheritance of Man (OMIM)
EXAMPLES OF LIFE-LIMITING SKELETAL DYSPLASIAS —
The diagnostic features of the hundreds of specific skeletal dysplasias is beyond the scope of this review; common skeletal dysplasia are described separately (see "Skeletal dysplasias: Specific disorders"), and a comprehensive list can be found in the 2023 Nosology and Classification of Genetic Skeletal Disorders [4,63].
Life-limiting skeletal dysplasias are described below. When a life-limiting skeletal dysplasia is suspected because of severe micromelia, early onset, and/or a small chest, the more common types can be distinguished from one another by four key features: bone mineralization, fractures, macrocranium (disproportionately large head), and short trunk (table 2) [91]. The most important determinant of life-limitation is the degree of pulmonary hypoplasia.
Thanatophoric dysplasia — Thanatophoric dysplasia (TD) is the most common life-limiting skeletal dysplasia, with a prevalence of 0.24 to 0.69 per 10,000 births. Some characteristic features are (table 2):
●Severe micromelia with rhizomelic predominance; typically, the extremities are so foreshortened that they protrude at right angles to the body
●Small thoracic circumference
●Macrocrania or cloverleaf skull deformity
●Normal trunk length
●Normal mineralization
●No fractures
●Thickened, redundant skin folds
●Platyspondyly (flattened vertebral bodies)
●Temporal lobe dysplasia
Type 1 TD (TD1) is the more common form of TD [44,56,92] and is usually caused by R248C and Y373C variants in the fibroblast growth factor receptor 3 gene (FGFR3). The appearance of TD1 includes the typical bowed "telephone receiver" shape of the femur [44,56], along with frontal bossing and midface hypoplasia, but no cloverleaf skull deformity (image 5).
Type 2 TD (TD2) is usually caused by the K650E variant in FGFR3 and is less common than TD1. The femurs are typically straight with flared metaphyses. The most specific feature of TD2 is the cloverleaf skull: a trilobed appearance of the skull in the coronal plane that results from premature craniosynostosis of the lambdoid and coronal sutures.
Both TD1 and TD2 are autosomal dominant conditions, with all cases caused by new dominant variants in the FGFR3 gene. TD has many phenotypic similarities to homozygous achondroplasia, but the latter is distinguished by the positive family history [65,91] in which both parents have achondroplasia (heterozygous for the specific FGFR3 mutations associated with achondroplasia).
Polyhydramnios is present in approximately 50 percent of affected fetuses [93].
TD is associated with brain abnormalities, specifically temporal lobe dysplasia (deep and transverse temporal sulci, which can be seen on brain autopsy at 18 weeks of gestation) and polymicrogyria. The abnormal deep transverse sulci in the temporal lobes can be visualized on fetal ultrasound at the time of routine second mid-trimester fetal anatomic evaluation, and thus may help in confirming the diagnosis if the patient decides not to have amniocentesis [37,94].
Achondrogenesis — Achondrogenesis is the second most common life-limiting skeletal dysplasia, with a prevalence of 0.09 to 0.23 per 10,000 births. Although a phenotypically and genetically diverse group of chondrodysplasias, it shares the following characteristic ultrasound features (table 2) [71,95-97]:
●Severe micromelia
●Small thoracic circumference
●Macrocrania
●Short trunk length
●Decreased mineralization, most marked in the vertebral bodies, ischium, and pubic bones
●Occasional fractures
Type 1 achondrogenesis (20 percent of cases) has autosomal recessive inheritance and thus has a 25 percent recurrence risk. In addition to decreased mineralization of the vertebral column, sacrum and pubic bones, type 1 achondrogenesis is also associated with calvarial demineralization. Type 1A is caused by a variant in TRIP11 (Golgi-microtubule-associated protein, 210-kDa, GMAP210) and type 1B is associated with a variant in the DTDST gene (SLC26A2 sulfate transporter) [98].
Type 2 achondrogenesis (80 percent of cases) is an autosomal dominant condition caused by a new dominant variant in COL2A1, which encodes type 2 collagen and carries a low recurrence risk.
Polyhydramnios is present in approximately 25 percent of affected fetuses [93].
Osteogenesis imperfecta type 2 — Osteogenesis imperfecta is a clinically and genetically heterogeneous group of collagen disorders characterized by brittle bones that are prone to fracture. It has been classified into four major subtypes based on genetic, radiographic, and clinical considerations, but additional, less common types also exist [99,100]. (See "Osteogenesis imperfecta: An overview".)
Individuals with type 2 osteogenesis imperfecta usually die in utero or in early infancy due to severe fractures and pulmonary hypoplasia (table 2). The key ultrasound features are [101]:
●Severe micromelia, with femur length (FL) more than 3 standard deviations (SDs) below the mean for gestational age
●Small thoracic circumference
●Normal cranial size
●Short trunk length
●Decreased mineralization
●Multiple bone fractures, including multiple fractures within a single bone and fractured ribs
The demineralized bones have multiple angulations and thickening due to innumerable fractures and repetitive callus formation. Multiple rib fractures result in a concave thoracic contour, most evident at the lateral thorax where the elbows "bash" in the fragile rib cage (image 6). Demineralization of the cranium causes it to deform upon gentle pressure with the ultrasound transducer (image 7). Platyspondyly and micrognathia are commonly present.
The diagnosis may be made sonographically as early as 13 to 15 weeks of gestational age. A normal ultrasound examination after 17 weeks essentially excludes this diagnosis.
Hypophosphatasia congenita — Hypophosphatasia congenita is an autosomal recessive skeletal dysplasia mapped to 1p36.1-p34 and caused by a homozygous or compound heterozygote variant in the ALPL gene [102] and associated with low levels of alkaline phosphatase (see "Skeletal dysplasias: Specific disorders", section on 'Hypophosphatasia'). The key ultrasound features are:
●Severe micromelia
●Small thoracic circumference
●Normal cranial size
●Normal trunk length
●Decreased mineralization
●Occasional fractures
The cranium is demineralized and compressible. The bones appear thin, delicate, or entirely absent, with occasional fractures.
Homozygous achondroplasia — The homozygous form of achondroplasia occurs when both parents are affected with achondroplasia, the most common skeletal dysplasia. The homozygous form is phenotypically similar to TD and usually life-limiting because of early postnatal death from respiratory insufficiency due to a small chest cage and neurologic dysfunction with recurrent seizures and cervicomedullary stenosis [103]. The heterozygous form is life-altering. When both parents are affected heterozygotes, 25 percent of their offspring will have the homozygous form and 50 percent will have the heterozygous form achondroplasia. Molecular diagnosis is useful to distinguish between a fetal heterozygote, homozygote, and compound heterozygote.
Although this topic is not focused on the large group of life-altering but not typically life-limiting skeletal dysplasia, heterozygous achondroplasia is discussed because it is the commonest skeletal dysplasia. It accounts for 90 percent of cases of disproportionate short stature and has an incidence of 1 in 10,000 to 26,000 births. The mode of inheritance is autosomal dominant and is typically fully penetrant. In 98 percent of the individuals with achondroplasia, a pathogenic variant (c.1138G>A [p.Gly380Arg]) is identified and in 1 percent of individuals with achondroplasia, a (c.1138G>C [p.Gly380Arg]) is identified [104].
The majority of pathogenic variants arise in the sperm and are associated with advanced paternal age. The pathogenic variant is in the fibroblast growth reception-3 gene (FGFR3) mapped to band 4p16.3. Hypochondroplasia is also associated with a pathogenic variant in the FGFR3 gene and presents with a similar but less severe phenotype. Molecular testing and preimplantation genetic testing play an important role in diagnosis. As heterozygous achondroplasia is the most common skeletal dysplasia, there is a concern for "assertive mating" or partnering with individuals with a similar phenotype, which may result in offspring affected by more a severe phenotype.
The key ultrasound features of heterozygous achondroplasia are:
●Mild-moderate rhizomelic limb shortening, typically affecting the upper limb more than the lower limb.
●FL that begins to fall off the growth curve after 24 to 26 weeks.
●Biparietal diameter (BPD) is typically >90 percent of expected while FL is less than expected and the AC is normal or slightly increased. Thus, BPD/FL discrepancy charts can be useful.
●Additional ultrasound signs which are variably present prenatally include: frontal bossing (67 percent), macrocephaly (17 percent), midface hypoplasia with depressed nasal bridge, brachydactyly, trident hand configuration. These features may progressively present in the third trimester.
The proximal femur diaphysis-metaphysis angle (DMA) >130 degrees [105] is a relatively new sign, present in up to 83 percent of affected fetuses in third trimester; however, its specificity has not been determined. At 20 to 23 weeks, the DMA potentially may be wider than in unaffected fetuses, thus offering an opportunity for earlier diagnosis as there is a linear relationship between gestational age and the femur DMA.
Campomelic dysplasia or bent-limb dysplasia — Campomelic dysplasia or bent-limb dysplasia is a rare autosomal dominant condition, usually the result of a new dominant variant in SOX9 (sex-determining protein homeobox 9 mapped to 17q24.3); however, some of the cases are the result of a variant upstream of the SOX9 gene [106]. Most cases (77 percent) are life-limiting because of respiratory insufficiency from laryngotracheomalacia in combination with a mildly narrowed thorax. In one series, all 46 cases of campomelic dysplasia demonstrated severe hypoplasia of the scapulae, irrespective of campomelia of the femora [42]. Similar, less severe hypoplasia of the scapulae may be present in Antley-Bixler syndrome (multisynostotic osteodysgenesis).
Ultrasound features may include [107,108]:
●Hypoplastic scapula and cervical vertebrae (present in at least 63 percent of cases)
●Short femur and tibia that are ventrally bowed. Bowing may also occur in the upper extremities
●Hypoplastic or absent fibula
●Talipes equinovarus (clubfoot)
●Late ossification of midthoracic pedicles
●Dislocated hips
●11 rib pairs
●Facial abnormalities, including micrognathia and cleft palate (Robin sequence)
●Congenital heart disease (present in 33 percent of cases)
●Brain abnormalities
●Renal abnormalities
●Cutaneous skin dimpling along the ventral lower limb may be identified with surface rendered three-dimensional (3D) ultrasound
Phenotypic sex reversal can be observed in approximately 75 percent of affected genotypic males (46,XY), with a gradation of defects ranging from ambiguous genitalia to normal female external genitalia [109].
Skeletal ciliopathies — Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies [110]. A subset of these disorders is associated with skeletal abnormalities that include a narrow chest with markedly short ribs, micromelia, and polydactyly. These include the short-rib polydactyly syndromes (SRPS), which are life-limiting, and the less severe asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, and cranioectodermal dysplasia phenotypes, which may be either life-limiting or life-altering.
Short-rib polydactyly syndromes — SRPS are a heterogeneous group of rare and life-limiting skeletal dysplasias with an autosomal recessive inheritance. They are subdivided into four groups: type 1 (Saldino-Noonan), type 2 (Majewski), type 3 (Verma-Naumoff), and type 4 (Beemer-Langer) (which can occur without polydactyly) [102,111]. Radiographic and clinical features can distinguish them. However, there is a substantial clinical and radiological overlap between type 1 and 3 and between these and asphyxiated thoracic dystrophy [112]. A few genes associated with this group of conditions have been identified. Type 2 is associated with variants in the genes DYNC2H1 and NEK1, and type 4 has not yet been associated with a specific gene. Thus, prenatal diagnosis using DNA analysis is possible in some of the cases.
Ultrasound features may include (table 2):
●Severe micromelia (present in 100 percent of cases)
●Small thoracic circumference (present in 100 percent of cases)
●Normal cranial size
●Normal bone mineralization
●Polydactyly
●Cardiac abnormalities
●Genitourinary and gastrointestinal abnormalities
Chondroectodermal dysplasia (Ellis-van Creveld syndrome) and asphyxiating thoracic dystrophy (Jeune syndrome) have features similar to SRPS but less severe micromelia and thoracic narrowing and they are not typically associated with fetal/neonatal lethality. Chondroectodermal dysplasia is associated with postaxial polydactyly and congenital cardiac disease, typically an atrial septal defect. The condition is autosomal recessive and is caused by homozygous or compound heterozygous variants in the EVC1 and EVC2 genes. (See "Skeletal dysplasias: Specific disorders", section on 'Chondroectodermal dysplasia (Ellis-van Creveld syndrome)'.)
Asphyxiating thoracic dystrophy is a genetically heterogeneous autosomal recessive condition and is caused by homozygous or compound heterozygous variants in the DYNC2H1, IFT80, WDR34, TTC21B, WDR19 WD, IFT172, and IFT140 genes. It can be associated with cystic disease of the kidney. Variants in KIAA0753 were found to be associated with SRPS and Joubert syndrome, thus expanding the phenotype of skeletal ciliopathy [113]. (See "Chest wall diseases and restrictive physiology", section on 'Asphyxiating thoracic dystrophy'.)
Fibrochondrogenesis — Fibrochondrogenesis is a rare life-limiting osteochondrodysplasia with an autosomal recessive inheritance. Ultrasound features include [114,115]:
●Micromelia with metaphyseal flaring
●Small thoracic circumference
●Normal cranial size
●Flat facies
●Decreased mineralization of the skull
●Vertebrae display platyspondyly and midline clefts
The short long bones have irregular metaphyses with peripheral spurs and extra-articular calcifications, giving the appearance of stippling. The condition is caused by homozygous or compound heterozygous variants in COL11A1 and COL11A2.
Atelosteogenesis — Atelosteogenesis is a rare life-limiting osteochondrodysplasia and represents a heterogeneous group of disorders. The incidence of all types of atelosteogenesis is estimated to be 1 in one million. Ultrasound features include [116]:
●Severe micromelia associated with hypoplasia of the distal femur and humerus resulting in a characteristic distal long bone tapering
●Bowed long bones
●Flat facies, micrognathia
●Narrow chest with short ribs
●Delayed segments of spine ossification
●Hands/feet may demonstrate abducted (hitch-hiker) thumb/toe and deficient ossification of the metacarpals, proximal, and middle phalanges with preservation of distal phalangeal ossification
Facial clefts and dislocations of the hip, knee, and elbow can occur.
Atelosteogenesis type 1 and 3 have an autosomal dominant inheritance and are caused by pathogenic variants in the filamin B gene and atelosteogenesis type 2 is autosomal recessive and is caused by homozygous or compound heterozygous pathogenic variants in DTDST.
Chondrodysplasia punctata or stippled epiphyses — Chondrodysplasia punctata (CDP) or stippled epiphyses is etiologically a heterogeneous group of disorders with many small calcifications (ossification centers) in the cartilage, the ends of bones, and around the spine [117,118].
The rhizomelic form of CDP appears as severe, symmetrical, predominantly rhizomelic limb shortening [102,119]. It is associated with severe intellectual disability and is generally lethal before the second year of life. The condition is the result of peroxisomal dysfunction caused by homozygous or compound heterozygous variants in PEX7. It can be associated with low unconjugated estriol concentration on second-trimester screening for Down syndrome. The enlarged epiphyses with characteristic stippling may be identified on ultrasound in the third trimester. The humeri tend to be relatively shorter than the femurs and have metaphyseal cupping. Other abnormalities include dysmorphic facial features, joint contractures, coronal clefting of the vertebral bodies, and brain abnormalities.
Another nonrhizomelic form of CDP, the Conradi-Hünermann type, has X-linked dominant inheritance. This syndrome is usually life-limiting in hemizygous males. Affected females have a variable phenotype; severe prenatal ultrasonography findings are rare and include precocious asymmetric shortening and bowing of the long bones, stippled epiphysis on second-trimester ultrasound, and vertebral irregularity [120]. The possibility of maternal autoimmune disease and vitamin K deficiency due to malabsorption should be considered when the etiology of the CDP cannot be identified [34].
Other life-limiting skeletal dysplasias — Other life-limiting skeletal dysplasias include Boomerang dysplasia, de la Chapelle dysplasia, and Schneckenbecken dysplasia. These are rare and difficult to diagnose accurately on prenatal ultrasound.
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ultrasound imaging in pregnancy" and "Society guideline links: Non-ultrasound imaging in pregnancy".)
SUMMARY AND RECOMMENDATIONS
●Background – Skeletal dysplasias are a large, heterogeneous group of disorders involving development of some segments of bone and cartilage, and affecting bone length, shape, and mineralization. The clinical phenotype ranges from mild to severe abnormality. A minority of skeletal dysplasias are life-limiting (eg, thanatophoric dysplasia [TD], osteogenesis imperfecta type 2, achondrogenesis) because of pulmonary hypoplasia resulting in respiratory failure and death soon after birth. (See 'Introduction' above and 'Classification' above and 'Prevalence' above.)
●Identification
•When to suspect skeletal dysplasia – Skeletal dysplasia should be suspected in fetuses with a short femur (below the 5th percentile for gestational age, or less commonly below two standard deviations [SDs] from the mean for the gestational age) or qualitative bony abnormalities (eg, bowing, bending, angulation, fracture) at the routine anatomic survey at 18 to 22 weeks of gestation. The diagnosis may be suspected as early as the first trimester, particularly if the dysplasia is life-limiting. Skeletal dysplasias detected only in the third trimester are less likely to be life-limiting, but can be life-altering.
Pregnancies with suspected skeletal dysplasia should be referred promptly to a tertiary center for specialized fetal evaluation (table 1 and table 2). (See 'When to suspect skeletal dysplasia' above and 'Differential diagnosis of causes of the mildly short femur' above and 'Diagnostic evaluation of suspected skeletal dysplasia' above.)
•Prenatal diagnosis – Prenatal diagnosis of skeletal dysplasia is based on the characteristic appearance of the fetal skeleton on imaging: limb and/or spine shortening and a spectrum of accompanying bone abnormalities (eg, absence, decreased mineralization, fracture, abnormal curvature, abnormal shape, abnormal angulation of joints, metaphyseal flaring) that may involve the face, hands/feet, calvarium, ribs, and scapula. Magnetic resonance imaging (MRI), computed tomography (CT), or radiography may be used to support the presumptive sonographic diagnosis. (See 'Prenatal diagnosis' above.)
A specific skeletal dysplasia may be suspected based on family history or the constellation of findings.
•Predicting prognosis – The immediate prenatal goal is to determine whether the dysplasia is life-limiting or life-altering. A life-limiting prognosis can be predicted based on ultrasound evidence of a small chest circumference with consequent pulmonary hypoplasia (table 2). Molecular diagnosis of a known skeletal dysplasia is conclusive, and should be initiated early in the prenatal evaluation. (See 'Predicting potential life-limiting skeletal dysplasias based on pulmonary hypoplasia' above.)
Many life-altering skeletal dysplasias (eg, heterozygous achondroplasia) have unremarkable fetal surveys in the second trimester, but significant limb dysplasia is noted on third-trimester ultrasound. This limits the utility of imaging when the fetus is at 50 percent risk of achondroplasia in the setting of a parent with achondroplasia. The homozygous form of achondroplasia is phenotypically similar to TD and usually life-limiting. (See 'Homozygous achondroplasia' above.)
●Pregnancy management
•Counseling – Once a determination regarding the life-limiting or life-altering potential of findings and a possible diagnosis is made, the patient should be counseled and provided with the options of continuing or terminating the pregnancy. The counselling should be provided by a team that includes perinatal imaging specialists, medical geneticists, maternal-fetal medicine specialists, genetic counselors, and neonatologists. If one of the parents or both parents have skeletal dysplasia, their diagnoses should be determined and the implications of these diagnoses on their pregnancy should be discussed, including the mode of delivery and the postnatal management. (See 'Pregnancy management' above.)
•Genetic testing – Most skeletal dysplasias result from single gene pathogenic variants with autosomal dominant, autosomal recessive, or X-linked mode of inheritance. A significant portion of the dominant conditions are the result of a "de novo" pathogenic variant in the sperm or egg resulting in an affected fetus (without evidence of the pathogenic variant in either parent) and thus carry a low recurrence risk.
When both parents are affected with the same or different autosomal dominant skeletal disorders, the fetus is at high risk of a life-limiting condition because of homozygosity or compound heterozygosity (for the same condition) or heterozygosity for two dominant conditions (double heterozygosity). In such cases, it is useful to identify the parental genetic variants before pregnancy and offer preimplantation genetic testing or early prenatal diagnosis (before diagnostic findings are seen on ultrasound) or later prenatal diagnosis to confirm the presumptive diagnosis on imaging performed later in pregnancy.
When neither parent is affected but the fetus is suspected to have a life-limiting skeletal dysplasia, prenatal or postnatal molecular analysis is most useful for planning future pregnancies rather than for predicting the outcome of the affected pregnancy since prenatal sonographic findings of life-limiting skeletal dysplasia are prognostically reliable. (See 'Role of molecular diagnostic testing' above.)
●Postnatal evaluation/counseling – Following the delivery or pregnancy termination, the diagnosis should be determined/confirmed using clinical, radiographic, autopsy findings, and DNA analysis. Cell culture and DNA should be banked and used for further investigation including microarray and molecular analysis, if not done during the pregnancy.
The results and their implications on future reproductive plans should be discussed with the patient and their partner. If the diagnosis has an impact on other family members, further counselling and investigation should be offered and done with the couple's permission. (See 'Postnatal/post-termination evaluation' above.)
