INTRODUCTION — Skeletal dysplasias (also called osteochondrodysplasia) are a large, heterogeneous group of conditions involving the formation and growth of bone and include osteodysplasia, chondrodysplasia, and dysostosis. Although more than 450 skeletal dysplasias have been identified, only a few are lethal in the prenatal/postnatal period. Typically, fetuses with lethal skeletal dysplasias have a reduction in bone length accompanied by a decrease in the bone growth trajectory. Assessment of fetal rib and lung growth are also critical in distinguishing lethal from nonlethal skeletal dysplasias.
This topic will focus on the lethal skeletal dysplasias that present prenatally and will offer a systematic detailed approach to enable evaluation of lethality and help the practitioner determine a specific diagnosis. The majority of skeletal dysplasias will ultimately present postnatally either in the neonatal period or over time. Postnatal evaluation, clinical findings, and diagnosis of skeletal dysplasias are reviewed separately. (See "Skeletal dysplasias: Approach to evaluation" and "Skeletal dysplasias: Specific disorders".)
BACKGROUND
●Etiology – Skeletal dysplasias are primarily caused by genetic variants, but they may also be related to extrinsic causes, including maternal exposure to drugs (eg, thalidomide) [1] and maternal diseases (eg, diabetes mellitus with poor glycemic control, autoimmune diseases) [2,3].
●Classification system – A nosology and classification system categorizes genetic bone disorders into 461 different diseases classified into 42 major groups based on their clinical, radiographic, and/or molecular phenotype [4]. Pathogenetic variants affecting 437 genes have been identified in 425 of the 461 (92 percent) disorders. (See "Skeletal dysplasias: Approach to evaluation", section on 'Classification of skeletal dysplasias'.)
●Prevalence – Overall, skeletal dysplasias account for approximately 5 percent of genetic disorders identified in the newborn period [5].
The overall birth prevalence of skeletal dysplasias is estimated to be 2.4 to 4.5 per 10,000 births [6]. The overall prevalence during pregnancy appears to be slightly higher at 7.5 per 10,000 ultrasound-screened pregnancies [7]. Each individual skeletal dysplasia is very rare, given that there are 461 different skeletal dysplasias currently published [1,4,8,9].
The prevalence of the lethal skeletal dysplasias ranges from 0.95 to 1.5 per 10,000 live births [8-10]. The three most common lethal skeletal dysplasias are thanatophoric dysplasia (29 percent) [11], osteogenesis imperfecta type 2 (14 percent), and achondrogenesis (9 percent) [12], which account for 40 to 60 percent of all lethal skeletal dysplasias [9,13-15]. Chondroectodermal dysplasia, campomelic dysplasia, and Jeune asphyxiating thoracic dysplasia are also among the more common lethal skeletal dysplasias, although it should be noted that this latter group is variably lethal depending on the severity of phenotypic expression [16]. The percentages cited are from specific tertiary centers and reflect the rate of consanguinity and the specific ethnic background of the population served by the tertiary center.
●Prenatal identification – The fetal skeleton has a high level of intrinsic contrast, which permits early evaluation of the skeleton by ultrasound. Skeletal dysplasias begin to manifest in the early stages of fetal development. The lethal group typically has an earlier onset with more severe phenotypic features than the nonlethal group; thus, lethal skeletal dysplasias are potentially more amenable to prenatal diagnosis [17].
●Perinatal mortality – Approximately 50 percent of skeletal dysplasias are lethal perinatally [18]. The overall frequency of perinatal deaths due to skeletal dysplasias is approximately 9 per 1000 births, with 23 percent stillborn and an additional 32 percent who do not survive beyond the first week of life [9,19].
OVERVIEW OF PRENATAL DIAGNOSIS
●Prenatal diagnostic accuracy is critical, as it will significantly affect parental counseling and decision-making regarding the pregnancy management as well as the patient's reproductive options, including preimplantation or prenatal genetic testing in future pregnancies.
●Prenatal diagnosis is based primarily upon fetal ultrasound findings, but magnetic resonance imaging (MRI), computed tomography (CT), radiography, and molecular analysis may be used to support the presumptive diagnosis. (See 'Initial ultrasound evaluation' below and 'Role of specialized imaging techniques' below and 'Role of molecular diagnostic testing' below.)
●Prenatal screening and diagnosis are primarily performed in the second trimester, but late-first-trimester fetal structural assessment is becoming more common with advances in transvaginal ultrasound imaging and the widespread use of first-trimester nuchal translucency evaluation.
●Fetal skeletal dysplasias may be suspected because the femur is found to be short for gestational age or qualitative bony abnormalities are observed during a fetal anatomic survey. In some cases, the initial fetal ultrasound is performed because of a family history of skeletal dysplasia, although most cases have no family history of the disorder.
A comprehensive assessment of the fetal skeleton is necessary to determine which bones are affected and the type and severity of the abnormalities. Concurrently, a comprehensive evaluation of all fetal organ systems is performed. The composite findings may or may not point to a specific skeletal dysplasia.
●Over the past decade, the accuracy of prenatal ultrasound for diagnosis of skeletal dysplasia has improved significantly: 68 percent for correct prenatal diagnosis and 31 percent for partially correct diagnosis, with 0.07 percent false positives [13,14,16,20-24]. Accurate prediction of lethality is considered to be extremely high (see 'Predicting lethality' below). A family history of consanguinity, a sibling or a parent affected with a skeletal dysplasia, or a prior affected fetus can help in making a specific diagnosis. However, the low incidence, phenotypic variability, overlapping features, and lack of family history in most cases make a specific diagnosis, and thus prognostic counseling, difficult.
●Invasive procedures to obtain fetal DNA for a specific molecular analysis can confirm the diagnosis in some cases (see 'Role of molecular diagnostic testing' below). Despite the rare occurrence of any specific dysplasia, a combination of radiology, pathology, and molecular analysis can allow classification to a specific group in up to 99 percent of cases, using the Nosology and Classification of Genetic Skeletal Disorders [6,25]. (See 'Postnatal/post-termination evaluation' below.)
●When a specific skeletal dysplasia cannot be identified, the immediate prenatal goal is to determine whether the dysplasia is lethal or nonlethal (see 'Predicting lethality' below). Diagnostic accuracy is critical, as the patient may choose to terminate the pregnancy or avoid cesarean delivery if the skeletal dysplasia is lethal or associated with high morbidity and quality of life that are unacceptable to the parents.
●After birth, postnatal radiographs, autopsy (in lethal cases and/or terminated pregnancies), and molecular testing are crucial for making an accurate diagnosis [20,26]. (See "Skeletal dysplasias: Approach to evaluation".)
INITIAL ULTRASOUND EVALUATION
Screening — The ultrasound evaluation of the bones includes assessing their presence or absence, length, shape (curvature), and whether any fractures are present. These features can be visualized well at ≥14 weeks of gestation, as much of the skeleton begins to ossify early in development: the clavicle, mandible, ileum, scapula, and long bones ossify by 12 weeks of gestation and the metacarpals and metatarsals are ossified by 12 to 16 weeks [27]. However, the talus and calcaneus ossify at weeks 22 to 24, epiphyseal ossification centers are seen on radiographs at approximately 20 weeks of gestation, and the carpal bones ossify after birth.
International Society of Ultrasound in Obstetrics & Gynecology (ISUOG) practice guidelines state that femur length (FL) should be measured on ultrasound examinations performed at ≥14 weeks [28]. The femur is generally the only long bone routinely measured at the second-trimester ultrasound evaluation, although many scanning guidelines recommend the systematic documentation of the presence and symmetry of all extremities.
The FL is imaged such that both ends of the ossified metaphysis are visible, and then the longest length of the femur diaphysis is measured (image 1). Several longitudinal measurements should be obtained, and the longest is recorded. There is a trend to call this measurement a femur diaphysis length (FDL) rather than a FL in order to more accurately reflect the actual measurement obtained.
Definition of short femur — A short femur is typically defined as below the 5th percentile for gestational age, or less commonly below two standard deviations (SD) from the mean for the gestational age.
●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 [29]. In this study, an isolated short FL at the second-trimester anatomic scan was associated with a higher risk of chromosomal anomalies, in particular trisomy 21, and a higher risk for delivery of a small for gestational age infant and early preterm birth.
●In another study of 27 fetuses with shortened femurs, a markedly short FL (≥5 mm below the -2 SD line [equivalent to >-4.3 SD]) was associated with a high likelihood of a skeletal dysplasia, whereas a mildly shortened femur (within 4 mm of the -2 SD line [between -2 and -4 SD below the mean]) in combination with normal interval growth was unlikely to be associated with skeletal dysplasia [30].
Evaluation of the fetus with a mildly shortened femur — The differential diagnosis for a mildly shortened FL includes normal variation, constitutional short limb, a false-positive measurement, fetal growth restriction (FGR) [31], and aneuploidy (primarily trisomy 21). The following key points help in differential diagnosis when a short femur is detected on ultrasound:
●The majority of isolated mildly short femurs represent normal variation or constitutional short stature, and has been termed "constitutional short femur." Over time, children with constitutional short stature will demonstrate normal interval growth of the long bones, but along a line below the normal centiles.
●As many as 13 percent of isolated mildly short femurs diagnosed at 18 to 24 weeks are reclassified as normal on follow-up [32]. This suggests the original value was a measurement error rather than an interim catch up growth spurt.
●Parental ethnicity impacts height and should be considered in interpretation of FL percentile. Mean FL is shorter in Asian populations compared with White populations and shorter in White populations compared with Black populations [33,34].
●The possibility of aneuploidy, in particular trisomy 21, should be considered as a mildly short femur is a soft marker of fetal aneuploidy, although the predictive value is low when this is an isolated finding and the patient is otherwise at low risk for fetal aneuploidy. The high detection rate for trisomy 21, using noninvasive prenatal screening (NIPS) by analyzing cell-free DNA, should be offered to rule out this possibility when amniocentesis is declined. (See "Prenatal screening for common aneuploidies using cell-free DNA" and "Sonographic findings associated with fetal aneuploidy", section on 'Slightly short long bones'.)
●The possibility of FGR should be considered. The diagnosis of FGR is supported by other sonographic evidence of growth restriction (eg, small abdominal circumference, abnormal placental morphology, abnormal Doppler parameters) and low pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF). An isolated short femur may be the presenting sign of FGR, but over time, other measurements, such as abdominal circumference and sometimes the head circumference, will also begin to drop below the normal growth curves for gestational age. (See "Fetal growth restriction: Screening and diagnosis".)
●Further sonographic evaluation of the fetus and serial examinations can help point to the correct diagnosis.
•All long bones should be measured. The combination of a mildly short femur and mildly short humerus can be related to trisomy 21, FGR, or skeletal dysplasia [31,35].
•If interim growth over three to four weeks is normal, and along the same growth curve, a short-limb skeletal dysplasia is unlikely. If FL over this interval falls further from the mean, skeletal dysplasia or severe FGR becomes more likely [30].
•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) [30]
-Femur to foot length ratio <0.9 [36]
-FL to abdominal circumference ratio <0.16 [22,37]
ESTABLISHING A DIAGNOSIS
Refer to an expert — When a short femur is identified in a fetus, we recommend referral to a center with expertise in skeletal dysplasias to perform a detailed ultrasound examination, determine the etiology of the short femur, make a specific diagnosis (if possible), and provide counseling [38].
Components of a comprehensive ultrasound evaluation for skeletal dysplasia — The components of detailed ultrasound assessment are listed in the table (table 1) and discussed below.
Pattern of limb shortening — All long bones (ie, each femur, humerus, radius, ulna, tibia, and fibula) should be measured to determine the relative shortening against normative values. There are four main patterns of limb shortening:
●Rhizomelia, shortening of the proximal segment (femur and humerus)
●Mesomelia, shortening of the middle segment (radius, ulna, tibia, and fibula)
●Acromelia, shortening of the distal segment (hands and feet)
●Micromelia, shortening of all parts of the limb. Micromelia is further subdivided into mild, mild and bowed, or severe (image 2)
The majority of prenatally diagnosed skeletal dysplasias are associated with severe micromelia, but the foot length typically is relatively maintained. The femur to foot length ratio is normally 1.0 throughout the pregnancy; thus, a ratio <1.0 is useful to instigate a systematic evaluation in order to distinguish skeletal dysplasia from other causes of short femur, such as fetal growth restriction (FGR) or aneuploidy [36]. When the ratio falls below 0.9, the likelihood of a skeletal dysplasia is increased relative to these other diagnoses.
Timing of onset of limb shortening — In general, the earlier the onset of documented limb shortening, the graver the prognosis. The most common nonlethal skeletal dysplasia is the heterozygous form of achondroplasia and demonstrates a later onset, where limb length is typically preserved until around 22 weeks of gestation with a subsequent progressive drop below the normal percentiles with a rhizomelic pattern.
Qualitative assessment of long bones — Assessment of long bones includes:
●Shape (bowing, angulation, contour, metaphyseal flaring)
Bowing/bending/angulation of the femurs is a finding in most skeletal dysplasias, but the four most common are campomelic dysplasia, thanatophoric dysplasia (TD), achondroplasia, and osteogenesis imperfecta. Conditions that are associated with isolated bowed femurs include Stuve-Wiedemann [39] and Schwartz-Jampel [40] syndromes, amongst others.
Metaphyseal flaring is associated with Kniest syndrome.
●Mineralization and presence of fractures
Decreased mineralization of the long bones is most reliably diagnosed by the presence of 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.
●Absence of individual long bones (fibula, tibia, radius)
●Joint deformities. Multiple joint contractures in association with kyphoscoliosis and micromelia are typical of diastrophic dysplasia.
●Premature ossification of the epiphysis in association with multiple ossification centers ("stippled epiphysis") is characteristic of chondrodysplasia punctata but may also be associated with warfarin embryopathy and maternal systemic lupus erythematosus and other autoimmune diseases [3].
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 — The spine is assessed for segmentation anomalies, kyphoscoliosis, platyspondyly, demineralization, myelodysplasia, and caudal regression. Although platyspondyly is the most common spine abnormality, it may be difficult to diagnose on prenatal ultrasound [41]. Severe platyspondyly is present in TD and lethal variants of osteogenesis imperfecta. Milder degrees of platyspondyly may be present in conditions such as fibrochondrogenesis, de la Chapelle dysplasia, and Kniest syndrome, amongst others. Vertebral disorganization with secondary kyphoscoliosis may be associated with syndromes such as dyssegmental dysplasia and costovertebral dysplasia (Jarcho-Levin syndrome) [42]. Under-ossification of the spine is seen in conditions such as atelosteogenesis, achondrogenesis, and hypophosphatasia. Disproportionate short-trunk skeletal dysplasia with absent limb length shortening can occur in spondyloepiphyseal dysplasia or secondary to lysosomal storage disorders with bone involvement.
●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 (eg, Ellis-van Creveld syndrome, Jeune asphyxiating thoracic dystrophy, Saldino-Noonan, etc) and some chromosomal abnormalities. Joint contractures suggest skeletal dysplasias associated with arthrogryposis multiplex congenita and fetal akinesia syndromes. 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, and the calvarium is normal or large. The cranium is also evaluated for macrocephaly or microcephaly, frontal bossing, cloverleaf skull deformity, and underlying brain abnormalities. Of particular note, temporal lobe dysplasia is associated with TD, achondroplasia, and hypochondroplasia associated with variants in the fibroblast growth factor receptor 3 (FGFR3) gene group of genetic disorders [43-45]. 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 [46].
●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 or maxilla) (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 and frontal bossing.
Osteogenesis imperfecta type 2, the lethal 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 lethal 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, renal 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 [47]. Within the platyspondylic lethal skeletal dysplasias, the presence of two inferior spikes suggests the Luton variety. A review by Mortier et al [48] includes an excellent schematic demonstrating the various scapular anomalies and the associated syndromes (figure 1) [48].
●Pelvic bones — Although important to evaluate, the pelvic bones are difficult to assess on conventional two-dimensional (2D) ultrasound and additional three-dimensional (3D) techniques may be required to appreciate the shape of the iliac bones and the sacrosciatic notches.
Achondrogenesis, a relatively common lethal 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.
Nonskeletal anatomic survey — A detailed evaluation of the cardiovascular, genitourinary, gastrointestinal, and central nervous system should be done concurrently with the skeletal evaluation. The composite findings may or may not point to a specific skeletal dysplasia.
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, which 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, associated gastrointestinal abnormalities, and hypotonia with decreased swallowing.
Role of specialized imaging techniques
Three-dimensional ultrasound — 3D ultrasound is becoming an increasingly useful complement to 2D ultrasound in diagnosis of skeletal dysplasia and pulmonary hypoplasia [49-52]. However, studies defining the role of 3D ultrasound as compared with 2D ultrasound in skeletal dysplasias are limited [53].
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, cranial distortion due to craniostenosis, or assessing hand/foot abnormalities [49]. However, there are insufficient published data to gauge the diagnostic performance of this modality. (See 'Computed tomography' below.)
Magnetic resonance imaging — After 20 weeks of gestation, magnetic resonance imaging (MRI) may play a complementary role to ultrasound because it can identify and better define some abnormalities, particularly of the brain. There are no known deleterious effects of fetal unenhanced MRI on the developing fetus. Postnatally, MRI can be useful in the context of "virtual autopsy" in families who have declined autopsy [54]. (See "Diagnostic imaging in pregnant and nursing patients", section on 'Fetal risks from magnetic resonance imaging'.)
Computed tomography — Prenatal low-dose 3D-CT can provide detailed images of bone morphology with complete 3D rendering of the fetal skeleton with fetal radiation exposure in the 3 mGy range when technical factors are optimized to minimize radiation dose [49,55,56]. In 2009, the International Commission on Radiological Protection concluded that in utero dose exposures 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 [57]. (See "Diagnostic imaging in pregnant and nursing patients", section on 'Fetal risks from ionizing radiation'.)
This modality should be considered if dilation and extraction is planned for pregnancy termination since it is likely to result in fetal fragmentation. 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 after other imaging modalities have been performed 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 [58]. 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 [59]. 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.
Postnatally, 3D-CT can be useful in the context of "virtual autopsy" in families who have declined autopsy. Postnatal 2D CT is not performed routinely, but sometimes used in specific clinical settings. (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 — The molecular diagnosis of a specific skeletal dysplasia is useful in predicting the prognosis [60,61]. Fetal DNA for molecular diagnostic testing can be performed via chorionic villus sampling (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".) Circulating cell-free DNA in 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 [62]. However, as in all cases with major fetal abnormalities identified on ultrasound, cell-free DNA analysis for single gene disorders has limited availability and generally not recommended since a negative result can provide false assurance.
The role of molecular studies for diagnosis of a specific skeletal dysplasia in an ongoing pregnancy with no personal or family history is controversial since the time necessary for DNA analysis can be lengthy and a negative result or failure to identify a specific genetic variant does not change the clinical implications derived from 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 [63]. Nevertheless, molecular analysis (gene panels, exome sequencing [ES], genome sequencing [GS]) 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 [64]. Since detailed fetal ultrasound has a high detection rate for lethal skeletal dysplasia, molecular analysis in these cases is mainly needed for prenatal and preimplantation genetic testing for future pregnancies rather than for prognostication in the affected pregnancy.
●Prior affected fetus – For parents with a prior affected fetus due to a new dominant disorder, there is no consensus whether molecular diagnosis should be performed for a relatively low risk of germline mosaicism. In most of these cases, the risk for a miscarriage associated with the prenatal invasive procedures is probably higher than the risk that the fetus will be affected [65]; furthermore, fetal ultrasound is reliable in making a relatively early diagnosis. Likewise, the role of molecular diagnosis for a skeletal dysplasia in an ongoing pregnancy is controversial since the time necessary for DNA analysis can be lengthy and a negative result or failure to identify a specific condition does not change the clinical implications derived from the ultrasound findings.
●Parent is affected or a known carrier – Fetal DNA is analyzed for specific variants when the fetus is known to be at risk for having skeletal dysplasia because of an affected parent (in autosomal dominant conditions), a carrier mother (for an X-linked condition), or parents identified as being carriers of an autosomal recessive skeletal dysplasia (due to a personal or family history of an affected child/fetus). Genetic variants have been identified for approximately 70 percent of skeletal dysplasias [18,66] and can be used to provide early prenatal diagnosis (before diagnostic findings are seen on ultrasound), preimplantation diagnosis in at-risk families, or to confirm the presumptive diagnosis on imaging performed later in pregnancy. A microarray analysis is usually performed at the same time and can provide diagnostic information. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray".)
When both parents are affected with the same or different autosomal dominant skeletal disorders, the fetus is at high risk of lethality because of homozygosity or compound heterozygosity for the same condition, or heterozygosity for two dominant conditions (double heterozygote) [67]. For example, when both parents are affected with achondroplasia, the most common skeletal dysplasia, the likelihood of having a fetus with homozygote or compound heterozygote variant in the FGFR3 gene associated with achondroplasia, and thus with the lethal 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 [68]
When one parent has an autosomal recessive skeletal dysplasia, the risk of an affected fetus is relatively low and the appropriateness of molecular diagnosis is less clear.
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/genotypes in offspring, options for prenatal diagnosis, prognosis, and reproductive options, can be very helpful.
When ultrasound and any additional diagnostic evaluations lead to the diagnosis of a specific skeletal dysplasia, parents can be given prognostic information (see 'Predicting lethality' below). However, for many parents, 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 parents 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.
Pregnancy 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/groups of other affected families, and the parents' religious or community sources of support.
Results from amniocentesis for DNA analysis for a specific condition or exome sequencing (ES)/genome sequencing (GS) when no specific condition is suspected may aid in decision making. For fetal skeletal anomalies overall, exome sequencing increased diagnostic yield by about 50 percent over microarray in a systematic review (pooled increased diagnostic yield: 53 percent, 95% CI 42-63 percent) [69].
●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 delivery), and the extent of postnatal treatment should be discussed, and the poor prognosis should be kept in mind.
●Pregnancy termination.
Predicting lethality
Overview — One of the most important determinations that needs to be made prenatally is whether the condition is lethal: resulting in intrauterine death or in neonatal death (from respiratory failure caused by pulmonary hypoplasia (image 4)). After a lethal prognosis is established, evaluation of key sonographic features is performed to attempt to determine a specific diagnosis.
Prediction of lethality on prenatal ultrasound has been reported to be highly accurate, ranging from 81 to more than 99 percent [13,14,16,70]. In the largest prospective study using a standardized ultrasound approach to the evaluation of these disorders, lethality was accurately predicted in 96.8 percent of 500 cases in the International Skeletal Dysplasia Registry [13].
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 lethal skeletal dysplasias, including thanatophoric dysplasia, achondrogenesis, and osteogenesis imperfecta type IIA, the survival rate was 50 percent in the neonatal period and 28.9 percent at one year of life [71]. 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. Because of such data, it has been suggested that a diagnosis of lethality should be replaced by the term "lethal or life-limiting" to more fully encompass the potential postnatal clinical course with aggressive medical support [72]. 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 want heroic measures 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 worse the prognosis. The majority of cases identified in the first trimester represent lethal skeletal dysplasias [17]. In the first trimester, the combination of increased nuchal translucency, short femurs, abnormal skull shape, lack of or low degree of mineralization, and small chest is highly predictive of a lethal skeletal dysplasia [17,73]. When increased nuchal translucency is associated with skeletal dysplasia, approximately 85 percent of cases are lethal skeletal dysplasias [17,73].
Second and third trimester prognostic findings — It is important to use multiple sonographic parameters to obtain the most accurate diagnosis of lethality (caused by the pulmonary hypoplasia associated with the small chest circumference) [74]. Findings suggestive of pulmonary hypoplasia include (image 4):
●Thoracic circumference <5th percentile, measured at the level of the four-chamber heart view
●Thoracic to abdominal circumference ratio <0.6 [1,24]
●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 [75]
●Markedly narrowed anteroposterior diameter (sagittal view)
●Concave or bell-shaped contour of the thorax (coronal view)
●Heart to chest circumference ratio >50 percent [24]
●Femur length (FL) to abdominal circumference ratio <0.16; this ratio is even more predictive when associated with polyhydramnios [1,24,37]
A comparative study of eight different methods for the prediction of fetal lung hypoplasia determined that the lung volumes and the thoracic circumference to abdominal circumference ratios performed best [76]; however, the majority of these studies were performed in the congenital diaphragmatic hernia population and may not be generalizable to this population [77,78].
Although several studies have described normal fetal lung volumes, there are limited data on lung volumes measured by ultrasound and magnetic resonance imaging (MRI) in fetuses with musculoskeletal disorders [79]. One study showed the feasibility of three-dimensional ultrasound for measuring lung volumes in fetuses with skeletal dysplasia and found that it could accurately predict lethal pulmonary hypoplasia in these cases [80], but larger studies are needed to confirm these results. It should be noted that measurements after 32 weeks were not performed due to technical limitations.
Another study of a cohort of 23 patients with skeletal dysplasia reported that an observed/expected total fetal lung volume less than 47.9 percent on MRI was a predictor of a lethal skeletal dysplasia [79]. This value is larger than that for lethal 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 [76-78]. Several reviews have demonstrated high variability in lung volume nomograms in different studies due to differing methodologies [81-83]. This suggests MRI could be reserved for borderline cases of pulmonary hypoplasia and difficult diagnostic scenarios.
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 2010 and 2015 Nosology and Classification of Genetic Skeletal Disorders system in up to 99 percent of cases [6,25,66].
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 [84]. For example, if there is an increased risk of recurrence, some parents may choose to have preimplantation genetic testing, egg/sperm or embryo donation, early prenatal diagnosis, or avoid subsequent pregnancy.
It is preferable for the autopsy to be performed by a perinatal pathologist. If the parents decline a full postmortem evaluation, then a minimally invasive evaluation including external evaluation and imaging 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, as well as gene panel and WES/WGS when no specific diagnosis is suspected [85]. If ES 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 'Gene sequencing'.)
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)
OVERVIEW OF THE LETHAL 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 2019 Nosology and Classification of Genetic Skeletal Disorders [25,66].
Lethal skeletal dysplasias are described below. When a lethal 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) [86]. The most important determinant of lethality is the degree of pulmonary hypoplasia.
Thanatophoric dysplasia — Thanatophoric dysplasia (TD) is the most common lethal 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 (TD1) TD is the more common form of TD [50,60,87] 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 [50,60], along with frontal bossing and midface hypoplasia, but no cloverleaf skull deformity.
Type 2 (TD2) TD 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 [68,86] 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 [88].
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 [43,89].
Achondrogenesis — Achondrogenesis is the second most common lethal 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) [26,90-92]:
●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) [93].
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 [88].
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 [94,95]. (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 [96]:
●Severe micromelia, with femur length (FL) more than 3 standard deviations 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 5). Demineralization of the cranium causes it to deform upon gentle pressure with the ultrasound transducer (image 6). 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 [97] 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.
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 [98]. Most cases (77 percent) are lethal 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 [48]. Similar, less severe hypoplasia of the scapulae may be present in Antley-Bixler syndrome (multisynostotic osteodysgenesis).
Ultrasound features may include [99,100]:
●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 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 [101].
Skeletal ciliopathies — Defects in the biosynthesis and/or function of primary cilia cause a spectrum of disorders collectively referred to as ciliopathies [102]. 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 perinatal lethal short-rib polydactyly syndromes (SRPS) and the less severe asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, and cranioectodermal dysplasia phenotypes.
●Short-rib polydactyly syndromes – SRPS are a heterogeneous group of rare and lethal 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) [97,103]. 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 [25]. 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 Jeune asphyxiating thoracic dystrophy have similar features but less severe micromelia and thoracic narrowing than the SRPS and are not 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)'.)
Jeune asphyxiating thoracic dystrophy is genetically heterogeneous autosomal recessive condition and is known to be caused by homozygous or compound heterozygous variants in the DYNC2H1, IFT80, WDR34, TTC21B, WDR19 WD, IFT172, and IFT140 genes. It can be associated with renal cystic disease. Variants in KIAA0753 were found to be associated with SRPS and Joubert syndrome, thus expanding the phenotype of skeletal ciliopathy [104]. (See "Chest wall diseases and restrictive physiology", section on 'Asphyxiating thoracic dystrophy'.)
Fibrochondrogenesis — Fibrochondrogenesis is a rare lethal osteochondrodysplasia with an autosomal recessive inheritance. Ultrasound features include [105,106]:
●Micromelia with metaphyseal flaring (dumbbell shape)
●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 lethal 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 [107]:
●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 variants in the filamin B gene and atelosteogenesis type 2 is autosomal recessive and is caused by homozygous or compound heterozygous 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 [108,109].
The rhizomelic form of CDP appears as severe, symmetrical, predominantly rhizomelic limb shortening [97,110]. 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 lethal 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 [111]. The possibility of maternal autoimmune disease should be considered when the etiology of the CDP cannot be identified [3].
Other lethal skeletal dysplasias — Other lethal skeletal dysplasias include Boomerang dysplasia, de la Chapelle dysplasia, and Schneckenbecken dysplasia. These are rare and difficult to diagnose accurately on prenatal ultrasound.
SUMMARY AND RECOMMENDATIONS
●Background – The lethal fetal skeletal dysplasias comprise a heterogeneous and complex group of conditions that affect bone growth and development. The three most common conditions detected prenatally are thanatophoric dysplasia, osteogenesis imperfecta type 2, and achondrogenesis. (See 'Introduction' above and 'Background' above.)
●Prenatal diagnosis
•Two-dimensional ultrasound is the primary imaging modality used for the initial assessment of a potentially affected fetus. (See 'Initial ultrasound evaluation' above.)
•When fetal skeletal dysplasia is suspected on ultrasound (eg, femur length [FL] below the fifth percentile for gestational age or 2 standard deviations below the mean for gestational age or a qualitative bone abnormality), the mother should be referred promptly to a tertiary center for specialized fetal evaluation (table 1 and table 2). (See 'Evaluation of the fetus with a mildly shortened femur' above and 'Establishing a diagnosis' above.)
●Genetic testing – When both parents are affected with the same or different autosomal dominant skeletal disorders, the fetus is at high risk of lethality 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 prenatal or preimplantation genetic diagnosis. (See 'Role of molecular diagnostic testing' above.)
●Pregnancy management
•Predicting lethality – A primary goal following the diagnosis of fetal skeletal dysplasia is to predict lethality or the life-limiting effect. It is important to use multiple parameters to determine that the fetus has a skeletal dysplasia and to evaluate whether it is lethal/life-limiting. Secondary goals are to determine the diagnosis or to narrow the differential diagnosis. (See 'Predicting lethality' above.)
•Counseling – Once a determination regarding the lethality and possible diagnosis is made, the couple should be counseled and given options by a team which includes perinatal imaging specialists, medical geneticists, maternal-fetal medicine specialists, and neonatologists. If 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.)
●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 microarray and molecular analysis.
Once all of the information is gathered, the parents should be seen again to discuss the results and the implications these may have on their future reproductive plans. (See 'Postnatal/post-termination evaluation' above.)
