Fetal Skeletal Dysplasia.

Skeletal dysplasias (SDs) are a diverse group of genetic disorders. Diagnosis can be difficult as many are rare and with varied presentations, but with knowledge of the most common SDs presenting prenatal and with an algorithm that uses both sonographic and MR imaging techniques, directed genetic testing and counseling can be provided for many families.

Truncating variants in PAPSS2 gene: A cause of early prenatal onset brachyolmia?

Brachyolmia is a rare form of skeletal dysplasia characterized by a wide genetic and clinical heterogeneity. This condition is usually diagnosed postnatally, and very few cases of prenatal diagnosis have been described so far. Here, we report a case of a pregnant woman at 20 weeks' gestation referred to our center because of fetal short long bones. On targeted ultrasound, mild bowing of the femurs and fibulae and mild micrognathia were also observed. Exome sequencing analysis showed the presence in compound heterozygosity of two pathogenic variants-both truncating variants-in the 3-prime-phosphoadenosine 5-prime-phosphosulfate synthase 2 (PAPSS2) gene, known to cause brachyolmia type 4 (OMIM #612847). Of note, all of the few cases reported prenatally have indeed truncating variants. Hence, we speculate this kind of variant is likely responsible for a complete loss of function of the protein leading to an earlier and more severe phenotype.

Prenatal ultrasound findings and prenatal diagnosis of fetal skeletal dysplasia.

OBJECTIVE: To analyze the value of prenatal ultrasound and molecular testing in diagnosing fetal skeletal dysplasia (SD). METHODS: Clinical data, prenatal ultrasound data, and molecular results of pregnant women with fetal SD were collected in the ultrasound department of our clinic from May 2019 to December 2021. RESULTS: A total of 40 pregnant women with fetal SD were included, with 82.5% exhibiting short limb deformity, followed by 25.0% with central nervous system malformations, 17.50% with facial malformations, 15% with cardiac malformations, and 12.5% with urinary system malformations. The genetic testing positive rate was 70.0% (28/40), with 92.8% (26/28) being single-gene disorders due to mutations in FGFR3, COL1A1, COL1A2, EVC2, FLNB, LBR, and TRPV4 genes. The most common SD subtypes were osteogenesis imperfecta (OI), thanatophoric dysplasia (TD), and achondroplasia (ACH). The gestational age (GA) at initial diagnosis for TD, OI, and ACH was 16.6, 20.9, and 28.3 weeks, respectively (p < 0.05), with no significant difference in femoral shortening between the three groups (p > 0.05). Of the OI cases, 5 out of 12 had a family history. CONCLUSION: Short limb deformity is the most prevalent phenotype of SD. When fetal SD is suspected, detailed ultrasound screening should be conducted, combined with GA at initial diagnosis, family history, and molecular evidence, to facilitate more accurate diagnosis and enhance prenatal counseling and perinatal management.

Osteofibrous dysplasia: a narrative review.

Osteofibrous dysplasia (OFD) is a rare, benign, self-limited bone disorder with a relatively low incidence, accounting for approximately 0.2% of all primary bone tumors. It was frequently found intra-cortical of the mid-shaft of the tibia. OFD can also occur in other skeletal regions, including the fibula, ulna, radius, femur, humerus, ischium, rib, tarsus, metatarsals, vertebral, and capitate. OFD can present with asymptomatic, mass, pain, swelling, deformity, and even pathological fracture. OFD might be misdiagnosed as adamantinoma (AD) and because they are three subtypes origin from the same family of bone tumors and have similar imaging features. Moreover, pathology could provide evidence for an accurate diagnosis of OFD, but misdiagnosis may occur due to small sampling materials. To date, few studies have comprehensively introduced the epidemiology, clinical manifestations, pathogenesis, radiological features, pathology, and treatment for OFD. We herein discuss clinical signs, diagnosis methods, and treatment options of OFD to improve the understanding of OFD, which is helpful for accurate diagnosis and appropriate treatment.

The transphyseal osteotomy for the slipped proximal tibial epiphysis in tibia vara.

This study aimed to describe a novel transphyseal osteotomy (TPO) for acute deformity correction in children with bilateral tibia vara and the atraumatic 'slipped proximal tibial epiphysis' (SPTE) entity. We described the clinical and radiological findings in five children (10 limbs) with tibia vara that were treated with the TPO. The criteria for the SPTE were met in nine (9/10) cases. The surgical technique and short-term results of the TPO are reported. The median age was 9 years (range, 6-9), with obesity (BMI > 95th centile) present in all children. The medial tibial plateau was not significantly depressed (the median angle of depression of the medial plateau measured 30° (range, 20°-32°). The mean medial proximal tibial angle of 33° (range, 8°-71°) was corrected to 82° (range, 77°-86°), the mean anatomic posterior proximal tibial angle of 48° (range, 32°-70°) was corrected to 72° (range, 61°-86°), and the median internal tibial rotation of 45° (range, 20°-50° internal rotation) was corrected to neutral rotation (range, 10° internal-10° external rotation). There were two complications: one case of recurrent deformity and one case of intra-articular extension of the osteotomy. We describe a novel TPO that aims to simultaneously correct all aspects of the deformity, stabilise the physis, and prevent recurrence through epiphysiodesis. Further research is required to determine its efficacy and safety. The atraumatic SPTE appears to represent a specific morphological presentation in tibia vara. Level of evidence: 4.

The Effect of Guided Growth Surgery on Langenskiold Stage and Mechanical Axis in Early-Onset Blount Disease: A Retrospective Case Series.

INTRODUCTION: Our understanding of the efficacy of guided growth surgery with tension-band plating (TBP) in early-onset Blount disease is evolving. Preliminary work has demonstrated that TBP can normalize the mechanical axis, yet its effect on Langenskiöld stage (LS) has not previously been reported. The primary outcome of this study was improvement in LS after TBP. Secondary outcomes were improvement in LS at most recent follow-up and improvement in mechanical axis deviation (MAD), mechanical medial proximal tibial angle, and mechanical lateral distal femoral angle at treatment completion and most recent follow-up. METHODS: A retrospective review was done of patients with early-onset Blount disease treated with TBP between January 1, 2010, and December 31, 2019, across two institutions. Inclusion criteria were a radiographic diagnosis of early-onset Blount disease (LS changes present), surgery with TBP, and follow-up beyond implant removal. Radiographs before surgery, at removal of hardware (ROH), and at most recent follow-up were evaluated. RESULTS: Twenty-five limbs in 16 children who underwent TBP at a mean age of 5.8 ± 2.3 years were included. Implants were in situ a mean of 1.9 ± 0.7 years. The mean follow-up after ROH was 3.6 ± 1.4 years. LS ranged from 1 to 5 preoperatively with 14 of 25 limbs (56%) staged ≥3. LS improved in 15 of 25 limbs (60%) at ROH and in 21 of 25 limbs (84%) at most recent follow-up. Langenskiöld changes resolved in 7 of 25 limbs (28%) at most recent follow-up. Preoperatively, the MAD was varus in all limbs, but at ROH, the MAD had improved in 22 of 23 limbs with neutral or valgus alignment in 20 of 23 limbs (87%). At most recent follow-up, 16 of 23 limbs (70%) maintained improved alignment. DISCUSSION: There was improvement/resolution of LS and varus deformity in early-onset Blount disease in most patients who underwent TBP. Based on these results, TBP for early-onset Blount disease should be the first-line surgical treatment. LEVEL OF EVIDENCE: IV.

The Effect of Socioeconomic Deprivation on Radiographic Deformities in Children With Blount Disease.

BACKGROUND: Blount disease can occur at any time during the growth process, primarily with a bimodal distribution in children younger than 4 years old and adolescents. The disease process most commonly presents in Black adolescents, with disease severity positively correlated with obesity. Given the known associations among race, obesity, and socioeconomic status, we investigated the relationship between the degree of social deprivation and severity of lower extremity deformities among a community-based cohort with Blount disease. METHODS: A retrospective review of hospital records and radiographs of patients with previously untreated Blount disease was conducted. Patients were classified as having early-onset or late-onset Blount disease based on whether the lower limb deformity was noted before or after the age of 4 years. The area deprivation index (ADI), a nationally validated measure that assesses socioeconomic deprivation by residential neighborhood, was calculated for each patient as a surrogate for socioeconomic status. Higher state (range: 1 to 10) or national (range: 1 to 100) ADI corresponds to increased social deprivation. Full-length standing radiographs from index clinic visits were evaluated by 2 reviewers to measure frontal plane deformity. The association of ADI with various demographic and radiographic parameters was then analyzed. RESULTS: Of the 65 patients with Blount disease, 48 (74%) children were Black and 17 (26%) were non-black children. Nineteen children (32 limbs) had early-onset and 46 children (62 limbs) had late-onset disease. Black patients had significantly higher mean state (7.6 vs. 5.4, P =0.009) and national (55.1 vs. 37.4, P =0.002) ADI values than non-black patients. Patients with severe socioeconomic deprivation had significantly greater mechanical axis deviation (66 mm vs. 51 mm, P =0.008). After controlling demographic and socioeconomic factors, the results of multivariate linear regression showed that only increased body mass index (ß=0.19, 95% CI: 0.12-0.26, P <.001) and state ADI (ß=0.021, 95% CI: 0.01-0.53, P =.043) were independently associated with greater varus deformity. CONCLUSIONS: Socioeconomic deprivation was strongly associated with increased severity of varus deformity in children with late-onset Blount disease. Our analysis suggests that obesity and socioeconomic factors are the most influential with regard to disease progression. LEVEL OF EVIDENCE: Level III.

Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.

Prenatal diagnosis of bone dysplasias.

Bone dysplasias are individually rare but collectively common. The prenatal diagnosis of bone dysplasias, especially perinatally lethal dysplasias, is of major interest to obstetric services. The current nosology of genetic skeletal disorders addresses over 400 disorders. However, in clinical practice, we encounter only a limited number of disorders, such as FGFR3-related dysplasias, osteogenesis imperfecta, and type II collagenopathies. The recent development of non-invasive prenatal genetic testing using cell-free fetal DNA in maternal blood samples has had a major impact on the prenatal diagnosis of genetic diseases. However, imaging examinations remain critical for the final diagnosis of bone dysplasias because molecular testing only shows genetic variants, and not their pathogenicity - most variants are clinically insignificant. Bone dysplasias are typically suspected when limb shortening is identified by screening ultrasound. Further assessment can be followed by more detailed ultrasound, magnetic resonance imaging (MRI), and CT. Based on these data, rational decision-making is feasible, even when the definitive prenatal diagnosis is not feasible. Here, we highlight key images of common bone dysplasias obtained by currently available modalities.

Skeletal Dysplasia Families: A Stepwise Approach to Diagnosis.

Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These disorders are rare individually, but collectively they are common (approximate incidence of one in 5000 births). Radiologists occasionally encounter skeletal dysplasias in daily practice. In the 1980s, Professor Juergen Spranger proposed a concept suitable for the diagnosis of skeletal dysplasias termed bone dysplasia families. He stated that (a) different bone dysplasias that share a similar skeletal pattern can be grouped into a "family," (b) the final diagnosis is feasible through the provisional recognition of a pattern followed by a more careful analysis, and (c) families of bone dysplasias may be the result of similar pathogenetic mechanisms. The prototypes of bone dysplasia families include dysostosis multiplex family, achondroplasia family, spondyloepiphyseal dysplasia congenita family, and Larsen syndrome-otopalatodigital syndrome family. Since Spranger's proposal, the concept of bone dysplasia families, along with advancing genetic techniques, has been validated and further expanded. Today, this molecularly proven concept enables a simple stepwise approach to be applied to the radiologic diagnosis of skeletal dysplasias. The first step is the categorization of a given case into a family based on pattern recognition, and the second step is more meticulous observation, such as identification of different severities of the same pattern or subtle but distinctive findings. Since major skeletal dysplasias are limited in number, radiologists can be familiar with the representative patterns of these disorders. The authors describe a stepwise radiologic approach to diagnosing major skeletal dysplasia families and review the clinical and genetic features of these disorders. Published under a CC BY 4.0 license. Quiz questions for this article are available through the Online Learning Center. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article.

Prenatal Diagnosis of Skeletal Dysplasias: What Can CT Do for You?

Skeletal dysplasias (SDs) are a heterogeneous group of heritable disorders that affect development of bone and cartilage. Because each SD is individually rare and because of the heterogeneity within and among disorders, prenatal diagnosis of a specific SD remains challenging. Molecular genetic diagnosis involves invasive testing, which some patients are not amenable to. Further, genetic analysis is time consuming, and results may not become available in time to make pregnancy management decisions. Low-dose fetal CT can aid in the prenatal evaluation of SDs. The main downside is the low but true risk of fetal radiation exposure. As such, fetal CT should only be performed when there is concern for a severe skeletal dysplasia and the diagnosis is in question after a detailed ultrasound or if molecular genetic testing is unavailable and when prenatal diagnosis may affect management or counseling. Fetal CT should be obtained after consultation with geneticists, maternal-fetal medicine specialists, and fetal radiologists, and sometimes orthopedic surgeons or neonatologists. The purpose of this study was to review the technique of and indications for fetal CT, as well as discuss fetal radiation risk. Illustrative cases will demonstrate when and how CT may be helpful in the diagnosis of SDs.

Dysplasia Epiphysealis Hemimelica in the Lower Extremity.

BACKGROUND: Because of the rarity of dysplasia epiphysealis hemimelica (DEH), little is known about the relationship between disease classification and clinical symptoms or patient outcomes. This studies therefore aims to characterize DEH of the lower extremity and correlate radiographic classification to presenting symptomatology and need for surgical intervention. METHODS: A multi-center, retrospective review of all patients with DEH of the lower extremity over a 47-year period was conducted. Demographic data, presenting complaints, treatments, and symptoms at final follow-up were recorded. Radiographs were reviewed to classify lesions using the Universal Classification System for Osteochondromas (UCSO) and document the presence of solitary or multiple lesions within the involved joint. Correlative statistics were used to determine whether presenting complaints, lesion location or radiographic classification predicted the need for surgery or a pain-free outcome. RESULTS: Twenty-eight patients met inclusion criteria with an average age at presentation of 7.8 years. The ankle was the most commonly affected joint with 20/28 patients (71%) having lesions of the talus, distal tibia, or distal fibula. Patients with chief complaints of pain were more likely to undergo surgery than those with complaints of a mass or deformity ( P =0.03). Ankle lesions were more likely to be managed operatively than those of the hip or knee ( P =0.018) and all 12 patients with talar lesions underwent surgery. Neither the number of lesions nor lesion classification was predictive of surgical intervention or a pain-free outcome after surgery. Patients presenting with pain were more likely to have a pain-free outcome (11/14 patients) after surgery ( P =0.023) whereas all patients presenting with deformity who underwent surgery had pain at final follow-up. CONCLUSIONS: Although no single radiographic characteristic of DEH was predictive of surgical intervention or outcome, painful lesions of the ankle, and lesions of the talus were more likely to be managed operatively. Although surgery does not always result in a pain-free outcome, the operative management of painful lesions was more likely to provide a pain-free outcome than surgery for deformity or a mass.

Treatment of Dysplasia Epiphysealis Hemimelica with Autologous Chondrocyte Implantation: A Case Report.

Case: We present a case of dysplasia epiphysealis hemimelica (DEH) involving the posteromedial distal femur in a 4-year-old girl. The patient underwent lesion resection with internal fixation of the articular cartilage followed by autologous chondrocyte implantation (ACI) to restore the articular surface and epiphysis. At the 7-year follow-up, the patient had no pain or difficulty with participation in sports. Advanced imaging showed a stable articular surface with evidence of durable cartilage integration. Conclusion: DEH is a rare disease often treated by resection. In cases where the articular surface of the knee is involved, we have demonstrated that augmentation with ACI can be an effective treatment option.

An unconventional presentation of Hip Joint Trevor disease with the involvement of the whole capital femoral epiphysis: A case report and literature review.

Dysplasia epiphysealis hemimelica (DEH) or Trevor's disease is a rare, nonhereditary developmental disorder of skeleton affecting epiphysis and short bones of limbs and characterized by a benign overgrowth of the medial half of the epiphysis resembling osteochondroma. We herein report an unconventional presentation of Trevor's disease of the hip with the involvement of the whole epiphysis. Only a few cases of DEH with such unusual features were found in the literature. The aim of this case report is to spread the awareness among the doctors about an unusual case of DEH with the involvement of the whole capital femoral epiphysis which has been neglected for 10 years. We also discuss the natural history of the development of disease, challenges faced during the course of treatment, clinical results, and complications.

Comparative Evaluation of the Radiographic Parameters for Screening Early Blount Disease.

BACKGROUND: Radiographic findings in young children with physiological bowing sometimes difficult to distinguish from early Blount disease. However, early diagnosis of the disease is critical because of the poor treatment outcomes for Blount disease. In this study, we aim to evaluate the accuracy of the metaphyseal-diaphyseal angle (MDA) compared with the medial metaphyseal beak (MMB) angle for differentiating between physiological bowing and early Blount disease and to determine which parameter to adequately screen for the subsequent development of Blount disease. METHODS: A retrospective study was conducted on children aged 1 to 3 years old who were brought to our outpatient clinic with bowed leg between 2000 and 2017. Data on the patients' age, sex, and affected sides were collected. Radiographic measurements of the femorotibial angle (FTA), MDA, and MMB angle were evaluated from the initial radiographs. An observer repeated the measurements on all the radiographs 2 weeks after they were first done. RESULTS: In total, 158 legs were considered from 79 children (48 males/31 females), whose average age was 26.0±6.1 months old. Eighty-seven legs were diagnosed with Blount disease and 71 legs had physiological bowing. Using single cutoff values of 16 degrees for the MDA showed low sensitivity (50.6%), very high specificity (100.0%), and a very high positive predictive value (PPV); while using MMB angle cutoff values ≥122 degrees showed very high sensitivity (92.0%), high specificity (80.3%), and a high PPV. Considering the MDA and MMB angle simultaneously showed very high sensitivity (93.1%), high specificity (80.3%), and a high PPV. The area under the receiver operating characteristic curve of the MDA and MMB showed excellent (0.89) and outstanding (0.93) discriminative ability, respectively. When combining the MDA and MMB angles, it was also considered outstanding performance (area under the receiver operating characteristic curve=0.95). CONCLUSIONS: The MMB angle represents a potential radiographic screening parameter for predicting early Blount disease in children 1 to 3 years old, offering high sensitivity and specificity. The MDA showed excellent specificity as a confirmation parameter for Blount disease patients. Applying both the MDA and MMB angles is another option to increase early recognition and confirm the diagnosis in early Blount disease patients. LEVEL OF EVIDENCE: Level II.

Molecular cytogenetic characterization of 2q deletion and Xq duplication associated with nasal bone dysplasia in prenatal diagnosis: A case report and literature review.

OBJECTIVE: We report a prenatal case of male fetus with a 2q13 deletion and an Xq27.3q28 duplication, presenting nasal bone dysplasia by ultrasound examination. And we compare the similarities of clinical features of cases consisting of similar 2q deletion and Xq duplication. CASE REPORT: A 30-year-old woman was referred for prenatal diagnosis and genetic counseling at 24 weeks of gestation. Prenatal ultrasound showed nasal bone dysplasia of the fetus. Amniocentesis revealed the karyotype of the fetus as 46, XY and the results of chromosomal microarray analysis was arr[GRCh37] 2q13(110467258-111370025)x1, arr[GRCh37]Xq27.3q28(144050780-149748782)x2. The parents both have normal karyotypes. The couple chose to continue the pregnancy and finally delivered a male infant at 39 weeks of gestation. His weight was 2850 g and length was 50 cm. Physical examination of the newborn revealed no apparent anomalies. Until the boy was one year old, there was no abnormalities in his growth and development. The long-term follow-up till adulthood for the healthy infant is necessary. CONCLUSION: The development of CMA plays a critical role in prenatal diagnosis and genetic counseling for unidentified chromosomal anomalies. More clinical information and further studies of patients with these anomalies will identify the pathogenicity of the involving genes and improve the understanding of the phenotype-genotype correlation.