RASopathies for Radiologists.

RASopathies are a heterogeneous group of genetic syndromes caused by germline mutations in a group of genes that encode components or regulators of the Ras/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include neurofibromatosis type 1, Legius syndrome, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome, central conducting lymphatic anomaly, and capillary malformation-arteriovenous malformation syndrome. These disorders are grouped together as RASopathies based on our current understanding of the Ras/MAPK pathway. Abnormal activation of the Ras/MAPK pathway plays a major role in development of RASopathies. The individual disorders of RASopathies are rare, but collectively they are the most common genetic condition (one in 1000 newborns). Activation or dysregulation of the common Ras/MAPK pathway gives rise to overlapping clinical features of RASopathies, involving the cardiovascular, lymphatic, musculoskeletal, cutaneous, and central nervous systems. At the same time, there is much phenotypic variability in this group of disorders. Benign and malignant tumors are associated with certain disorders. Recently, many institutions have established multidisciplinary RASopathy clinics to address unique therapeutic challenges for patients with RASopathies. Medications developed for Ras/MAPK pathway-related cancer treatment may also control the clinical symptoms due to an abnormal Ras/MAPK pathway in RASopathies. Therefore, radiologists need to be aware of the concept of RASopathies to participate in multidisciplinary care. As with the clinical manifestations, imaging features of RASopathies are overlapping and at the same time diverse. As an introduction to the concept of RASopathies, the authors present major representative RASopathies, with emphasis on their imaging similarities and differences. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.

Pediatric Ribs at Chest Radiography: Normal Variants and Abnormalities.

Normal variants and abnormalities of the ribs are frequently encountered on chest radiographs. Accurate identification of normal variants is crucial to avoid unnecessary investigations. A meticulous evaluation of rib abnormalities can provide valuable insights into the patient's symptoms, and even when no osseous condition is suspected, rib abnormalities may offer critical clues to underlying conditions. Rib abnormalities are associated with various conditions, including benign tumors, malignant tumors, infectious and inflammatory conditions, vascular abnormalities, metabolic disorders, nonaccidental injuries, malformation syndromes, and bone dysplasias. Abnormalities of the ribs are classified into three groups based on their radiographic patterns: focal, multifocal, and diffuse changes. Focal lesions are further subdivided into nonaggressive lesions, aggressive lesions, and infectious and inflammatory disorders. Radiologists should be aware of individual disorders of the pediatric ribs, including their imaging findings, relevant clinical information, and underlying pathogenesis. Differential diagnoses are addressed as appropriate. Since chest radiographs can suffice for diagnosis in certain cases, the authors emphasize a pattern recognition approach to radiographic interpretation. However, additional cross-sectional imaging may be necessary for focal lesions such as tumors or inflammatory conditions. Awareness of disease-specific imaging findings helps ascertain the nature of the lesion and directs appropriate management. ©RSNA, 2023 Quiz questions for this article are available in the supplemental material.

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.

Peritumoral Hyperintensity at Hepatobiliary Phase Gadoxetic Acid-enhanced MRI in Hepatic Neuroendocrine Tumors.

BACKGROUND/AIM: To identify the imaging and clinical features of hepatic neuroendocrine tumors (NETs) associated with peritumoral hyperintensity in the hepatobiliary phase of gadoxetic acid-enhanced magnetic resonance (MR) imaging. PATIENTS AND METHODS: Fifty-seven patients with hepatic NETs were enrolled. Based on the degree of peritumoral hyperintensity, patients were divided into three groups: group 0 (no peritumoral hyperintensity), group 1 (lower peritumoral hyperintensity), and group 2 (higher peritumoral hyperintensity). The imaging and clinical findings were compared among the three groups. RESULTS: Apparent diffusion coefficient (ADC) values of group 2 were significantly lower than those of group 0 and group 1. Atypical (cholangiocarcinoma-like) enhancement pattern in the arterial phase was significantly more frequently observed in group 2 as compared to that in group 0 and group 1. Group 2 patients showed significantly poorer progression-free survival than group 0 patients. CONCLUSION: Hepatic NETs with greater peritumoral hyperintensity exhibit greater malignant potential.

A primer on skeletal dysplasias.

Skeletal dysplasia encompasses a heterogeneous group of over 400 genetic disorders. They are individually rare, but collectively rather common with an approximate incidence of 1/5000. Thus, radiologists occasionally encounter skeletal dysplasias in their daily practices, and the topic is commonly brought up in radiology board examinations across the world. However, many radiologists and trainees struggle with this issue because of the lack of proper resources. The radiological diagnosis of skeletal dysplasias primarily rests on pattern recognition-a method that is often called the "Aunt Minnie" approach. Most skeletal dysplasias have an identifiable pattern of skeletal changes composed of unique findings and even pathognomonic findings. Thus, skeletal dysplasias are the best example to which the Aunt Minnie approach is readily applicable.

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

Radiologic Features of Type II and Type XI Collagenopathies.

Type II collagen is a major component of the cartilage matrix. Pathogenic variants (ie, disease-causing aberrations) in the type II collagen gene (COL2A1) lead to an abnormal structure of type II collagen, causing a large group of skeletal dysplasias termed type II collagenopathies. Because type II collagen is also located in the vitreous body of the eyes and inner ears, type II collagenopathies are commonly associated with vitreoretinal degeneration and hearing impairment. Type II collagenopathies can be radiologically divided into two major groups: the spondyloepiphyseal dysplasia congenita (SEDC) group and the Kniest-Stickler group. The SEDC group is characterized by delayed ossification of the juxtatruncal bones, including pear-shaped vertebrae. These collagenopathies comprise achondrogenesis type 2, hypochondrogenesis, SEDC, and other uncommon subtypes. The Kniest-Stickler group is characterized by disordered tubular bone growth that leads to "dumbbell" deformities. It comprises Kniest dysplasia and Stickler dysplasia type 1, whose radiographic manifestations overlap with those of type XI collagenopathies (a group of disorders due to abnormal type XI collagen) such as Stickler dysplasia types 2 and 3. This phenotypic overlap is caused by type II and type XI collagen molecules sharing part of the same connective tissues. The authors describe the diagnostic pathways to type II and type XI collagenopathies and the associated differential diagnoses. In addition, they review the clinical features and genetic bases of these conditions, which radiologists should know to participate in multidisciplinary care and translational research. Online supplemental material is available for this article. ©RSNA, 2020.

Trends in hospitalization and readmission for pediatric epilepsy and underutilization of epilepsy surgery in the United States.

BACKGROUND: Previous studies have shown the healthcare utilization for medically refractory epilepsy and epilepsy surgery until 2012 with disparities according to race/ethnicity and socioeconomic status. To extend these data and add other utilization information, we retrospectively investigated the nationwide trends in hospitalization and readmission during 2010-2015. METHOD: We extracted data on inpatients who were diagnosed with epilepsy and those who received epilepsy surgery using the national inpatient sample and nationwide readmission database during 2010-2015. We estimated healthcare utilization related to pediatric epilepsy, the number of epilepsy surgeries, hospitalization rates and 30-day readmission rates. RESULTS: 100,000-120,000 children were hospitalized due to epilepsy each year. Hospitalization rates and 30-day readmission rates were 214.6-262.3 per 1000 patient-years and 72.4-78.0 per 1000 discharges, respectively. 1400-2000 children with epilepsy received epilepsy surgery, but the proportions of medically refractory epilepsy were estimated as 0.8 %-1.2 %. Disparities in patients receiving epilepsy surgery by race/ethnicity were observed during 2010-2012, but they were not after 2013. Children with higher household income levels had consistently higher proportions of receiving epilepsy surgery than those with lower levels. The hospitalization costs for epilepsy surgery were constant at $55,780-$60,813 after adjusting for healthcare cost inflation, whereas the cost for epilepsy were slightly elevated from $15,984 to $17,426. CONCLUSIONS: We provide novel insights into the current healthcare utilization for epilepsy and epilepsy surgery. Although the disparity of epilepsy surgery seemed to be mitigated, surgery in children with medically refractory epilepsy was still underutilized.

Skeletal ciliopathies: a pattern recognition approach.

Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal ciliopathy forms a subset of ciliopathies characterized by distinctive skeletal changes. Common skeletal ciliopathies include Jeune asphyxiating thoracic dysplasia, Ellis-van Creveld syndrome, Sensenbrenner syndrome, and short-rib polydactyly syndromes. These disorders share common clinical and radiological features. The clinical hallmarks comprise thoracic hypoplasia with respiratory failure, body disproportion with a normal trunk length and short limbs, and severely short digits occasionally accompanied by polydactyly. Reflecting the clinical features, the radiological hallmarks consist of a narrow thorax caused by extremely short ribs, normal or only mildly affected spine, shortening of the tubular bones, and severe brachydactyly with or without polydactyly. Other radiological clues include trident ilia/pelvis and cone-shaped epiphysis. Skeletal ciliopathies are commonly associated with extraskeletal anomalies, such as progressive renal degeneration, liver disease, retinopathy, cardiac anomalies, and cerebellar abnormalities. In this article, we discuss the radiological pattern recognition approach to skeletal ciliopathies. We also describe the clinical and genetic features of skeletal ciliopathies that the radiologists should know for them to play an appropriate role in multidisciplinary care and scientific advancement of these complicated disorders.

Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Pediatric oncologic emergencies: Clinical and imaging review for pediatricians.

Children with cancer are at increased risk of life-threatening emergencies, either from the cancer itself or related to the cancer treatment. These conditions need to be assessed and treated as early as possible to minimize morbidity and mortality. Cardiothoracic emergencies encompass a variety of pathologies, including pericardial effusion and cardiac tamponade, massive hemoptysis, superior vena cava syndrome, pulmonary embolism, and pneumonia. Abdominal emergencies include bowel obstruction, intussusception, perforation, tumor rupture, intestinal graft-versus-host disease, acute pancreatitis, neutropenic colitis, and obstructive uropathy. Radiology plays a vital role in the diagnosis of these emergencies. We here review the clinical features and imaging in pediatric patients with oncologic emergencies, including a review of recently published studies. Key radiological images are presented to highlight the radiological approach to diagnosis. Pediatricians, pediatric surgeons, and pediatric radiologists need to work together to arrive at the correct diagnosis and to ensure prompt and appropriate treatment strategies.

MR imaging findings in some rare neurological complications of paediatric cancer.

Neurological complications of paediatric cancers are a substantial problem. Complications can be primary from central nervous system (CNS) spread or secondary from indirect or remote effects of cancer, as well as cancer treatments such as chemotherapy and radiation therapy. In this review, we present the clinical and imaging findings of rare but important neurological complications in paediatric patients with cancer. Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. Paraneoplastic neurological syndromes, hyperviscosity syndrome, haemophagocytic lymphohistiocytosis and infection are found in the pre-treatment phase, while Trousseau's syndrome, posterior reversible encephalopathy syndrome and methotrexate neurotoxicity are found in the treatment phase; though some complications overlap between the pre-treatment and treatment phases. Hippocampal sclerosis, radiation induced tumour, radiation induced focal haemosiderin deposition and radiation-induced white matter injury are found in the post-remission phase. With increasingly long survival after treatment, CNS complications have become more common. It is critical for radiologists to recognise neurological complications related to paediatric cancer or treatment. Magnetic resonance imaging (MRI) plays a significant role in the recognition and proper management of the neurological complications of paediatric cancer. TEACHING POINTS: • Neurological complications of paediatric cancer include various entities. • Neurological complications are classified into three phases: pre-treatment, treatment and post-remission. • Radiologists should be familiar with clinical and imaging findings of neurological complications. • MRI features may be characteristic and lead to early diagnosis and proper treatments.

Nationwide Trend Analysis of Pediatric Inpatients With Immune Thrombocytopenia in the United States.

BACKGROUND: Several studies have reported the epidemiology of immune thrombocytopenia (ITP) among children in the United States and other countries. However, recent trends in ITP among hospitalized children and hospital course remain unknown at a national level in the United States. METHOD: Hospital discharge records of patients with ITP aged 19 years and younger were obtained for the years 2003, 2006, 2009, and 2012 using the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates in the United States with trend analyses. Multivariable regression models were used to ascertain trends of health care utilizations, hospitalization costs, and length of stay. RESULTS: Total annual hospitalization rates due to ITP ranged from 6.13 per 100,000 children in 2003 to 6.22 per 100,000 children in 2012 (Ptrend=0.86). The lowest proportions of hospitalizations were observed in August. The proportions of inpatients treated with intravenous immunoglobulin increased from 18.5% in 2003 to 39.9% (Ptrend< 0.001), while those examined with bone marrow aspiration decreased from 7.8% in 2003 to 6.5% in 2012 (Ptrend=0.01). Total hospitalization costs and length of stay changed from $6147 and 3.78 days in 2003 to $9328 and 2.55 days in 2012. CONCLUSIONS: We provided insights of epidemiology of ITP and health care utilizations in the United States. Further studies, including cost-effective analyses, will be required to justify the increasing trends in health care costs and intravenous immunoglobulin.

Acute chest syndrome among children hospitalized with vaso-occlusive crisis: A nationwide study in the United States.

PURPOSE: Acute chest syndrome (ACS) is a common complication among pediatric inpatients with sickle cell disease and vaso-occlusive crisis (VOC). However, little is known about the factors associated with ACS complication. The present study assessed the epidemiological features of children hospitalized with VOC and ascertained factors associated with ACS complication. METHODS: Hospital discharge records of patients with VOC aged <20 years were obtained for the years 2003, 2006, 2009, and 2012 from the Kids' Inpatient Database. Data were weighted to estimate the annual hospitalization rates with respect to gender and race/ethnicity in the United States. Multivariable logistic regression was conducted to ascertain factors associated with ACS complication after adjusting for patient and hospital characteristics. RESULTS: The total annual hospitalizations for VOC increased from 22,511 in 2003 to 24,292 in 2012. Multivariable logistic regression analysis showed that children aged 5-9 years had 2.59 times higher odds of ACS than children aged 15-19 years (95% confidence interval [CI], 2.32-2.88). Comorbidity of asthma (odds ratio [OR], 1.42; 95% CI, 1.31-1.54) and obstructive sleep apnea (OR, 1.70; 95% CI, 1.31-2.20) were associated with ACS development. ACS was also associated with male gender and the summer and fall seasons. CONCLUSION: We reported nationwide estimates of the annual hospitalization rate for childhood VOC in the United States and demonstrated the major risk factors associated with ACS complication. Vigilance is needed for ACS complications in high-risk VOC admissions.

Imaging Findings of Metabolic Bone Disease.

Metabolic bone diseases are a diverse group of diseases that result in abnormalities of (a) bone mass, (b) structure mineral homeostasis, (c) bone turnover, or (d) growth. Osteoporosis, the most common metabolic bone disease, results in generalized loss of bone mass and deterioration in the bone microarchitecture. Impaired chondrocyte development and failure to mineralize growth plate cartilage in rickets lead to widened growth plates and frayed metaphyses at sites of greatest growth. Osteomalacia is the result of impaired mineralization of newly formed osteoid, which leads to characteristic Looser zones. Hypophosphatasia is a congenital condition of impaired bone mineralization with wide phenotypic variability. Findings of hyperparathyroidism are the result of bone resorption, most often manifesting as subperiosteal resorption in the hand. Renal osteodystrophy is the collection of skeletal findings observed in patients with chronic renal failure and associated secondary hyperparathyroidism and can include osteopenia, osteosclerosis, and "rugger jersey spine." Hypoparathyroidism is most commonly due to iatrogenic injury, and radiographic findings of hypoparathyroidism reflect an overall increase in bone mass. Thyroid hormone regulates endochondral bone formation; and congenital hypothyroidism, when untreated, leads to delayed bone age and absent, irregular, or fragmented distal femoral and proximal tibial epiphyses. Soft-tissue proliferation of thyroid acropachy is most often observed in the hands and feet. The findings of acromegaly are due to excess growth hormone secretion and therefore proliferation of the bones and soft tissues. Vitamin C deficiency, or scurvy, impairs posttranslational collagen modification, leading to subperiosteal hemorrhage and fractures. ©RSNA, 2016.

Autosomal recessive brachyolmia: early radiological findings.

Brachyolmia (BO) is a heterogeneous group of skeletal dysplasias with skeletal changes limited to the spine or with minimal extraspinal features. BO is currently classified into types 1, 2, 3, and 4. BO types 1 and 4 are autosomal recessive conditions caused by PAPSS2 mutations, which may be merged together as an autosomal recessive BO (AR-BO). The clinical and radiological signs of AR-BO in late childhood have already been reported; however, the early manifestations and their age-dependent evolution have not been well documented. We report an affected boy with AR-BO, whose skeletal abnormalities were detected in utero and who was followed until 10 years of age. Prenatal ultrasound showed bowing of the legs. In infancy, radiographs showed moderate platyspondyly and dumbbell deformity of the tubular bones. Gradually, the platyspondyly became more pronounced, while the bowing of the legs and dumbbell deformities of the tubular bones diminished with age. In late childhood, the overall findings were consistent with known features of AR-BO. Genetic testing confirmed the diagnosis. Being aware of the initial skeletal changes may facilitate early diagnosis of PAPSS2-related skeletal dysplasias.

Radiological findings of perivascular epithelioid cell tumour (PEComa) of the falciform ligament.

Perivascular epithelioid cell tumour (PEComa) encompasses a group of mesenchymal tumours composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. A subset of PEComa that typically arises from the falciform ligament and/or ligamentum teres is termed clear cell myomelanocytic tumour of the falciform ligament/ligamentum teres. To date, its imaging findings have not been described. Here, we report the first radiological description of a pathologically confirmed tumour. The patient was a 5-year-old girl with a palpable abdominal mass. US, CT, MR and FDG-PET revealed a midline, well-defined, solid anterior abdominal wall tumour below the rectus abdominis and contiguous with the umbilicus that was hypervascular and FDG avid. Awareness of these imaging findings facilitates the diagnosis of this distinctive tumour.

Bent bone dysplasia (BBD)-FGFR2 type: the radiologic manifestations in early gestation.

Bent bone dysplasia-fibroblast growth factor receptor 2 type (BBD-FGFR2) is a recently identified skeletal dysplasia caused by specific FGFR2 mutations, characterized by craniosynostosis and prenatal bowing of the long bones. Only a few cases have been published. We report an affected fetus terminated at 21 weeks of gestation. The clinical and radiologic manifestations mostly recapitulate previous descriptions; however we suggest additional hallmarks of this disorder in early gestation. These hallmarks include distinctive short, thick clavicles and wavy ribs, as well as vertebral bodies that showed striking anteroposterior shortening. Femoral fractures were also present in our case. Although craniosynostosis is a hallmark of the disease, clinicians should be aware that craniosynostosis might not be readily apparent on plain films early in gestation.