Imaging approaches for the diagnosis of genetic diseases affecting the female reproductive organs and beyond.

This review aims to provide an overview of neoplastic lesions associated with genetic diseases affecting the female reproductive organs. It seeks to enhance our understanding of the radiological aspects in diagnosing genetic diseases including hereditary breast and ovarian cancer syndromes, Lynch syndrome, Peutz-Jeghers syndrome, nevoid basal cell carcinoma syndrome, and Swyer syndrome, and explores the patterns and mechanisms of inheritance that require elucidation. Additionally, we discuss the imaging characteristics of lesions occurring in other regions due to the same genetic diseases.

Few-Shot Meta-Learning for Recognizing Facial Phenotypes of Genetic Disorders.

Computer vision has useful applications in precision medicine and recognizing facial phenotypes of genetic disorders is one of them. Many genetic disorders are known to affect faces' visual appearance and geometry. Automated classification and similarity retrieval aid physicians in decision-making to diagnose possible genetic conditions as early as possible. Previous work has addressed the problem as a classification problem; however, the sparse label distribution, having few labeled samples, and huge class imbalances across categories make representation learning and generalization harder. In this study, we used a facial recognition model trained on a large corpus of healthy individuals as a pre-task and transferred it to facial phenotype recognition. Furthermore, we created simple baselines of few-shot meta-learning methods to improve our base feature descriptor. Our quantitative results on GestaltMatcher Database (GMDB) show that our CNN baseline surpasses previous works, including GestaltMatcher, and few-shot meta-learning strategies improve retrieval performance in frequent and rare classes.

Prenatal diagnosis of genetic aberrations in fetuses with short femur detected by ultrasound: A prospective cohort study.

OBJECTIVES: To investigate the genetic aberrations in fetuses with short femur and explore the relationships with respect to degree of femoral shortening and the initial diagnostic gestational age GA. METHODS: Singleton pregnancies with fetal short femur who consented to amniocentesis and to single nucleotide polymorphism (SNP) array and Sanger sequencing for G380R mutations in FGFR3 gene were enrolled in this 5-year period prospective study. Clinical follow-up assessments were performed after birth. RESULTS: Of a total of 161 fetuses, the prevalence of genetic aberrations was 16.2% (26/161), comprised of 65.4% (17/26) with chromosomal abnormalities and 34.6% (9/26) with G380R mutations. All fetuses with chromosomal abnormalities had FL 2-4SDs below GA. Fewer chromosomal abnormalities were detected in fetuses with short femurs presenting in the third trimester. Significantly more FGFR3 mutations were detected in fetuses with FL below -4SDs. All fetuses with FL 2-4SDs below GA diagnosed as achondroplasia were between 22 and 24 gestational weeks, and all of those diagnosed in third trimester had FL below -4SDs. CONCLUSION: In this small cohort study, we demonstrated that different degrees of femur shortness may be attributed to different genetic aberrations. SNP array should be regarded as the first-tier test for fetuses with FL 2-4SDs below GA. The prognoses for fetuses with FL 2-4SDs below GA was significantly better than those with FL below 4SDs.

VEXAS syndrome.

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a monogenic disease of adulthood caused by somatic mutations in UBA1 in hematopoietic progenitor cells. Patients develop inflammatory and hematologic symptoms. Myeloid-driven autoinflammation and progressive bone marrow failure lead to substantial morbidity and mortality. Effective medical treatments need to be identified. Reports in the current issue of Blood describe novel UBA1 genetic variants, treatment options, and insight into disease pathophysiology. VEXAS syndrome represents a prototype for a new class of diseases.

Biomarkers for liver disease in urea cycle disorders.

BACKGROUND: Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. As therapies for hyperammonemia associated with urea cycle dysfunction have improved, chronic complications, such as liver disease, have become increasingly apparent in individuals with UCDs. Liver disease in UCDs may be associated with hepatic inflammation, hepatic fibrosis, portal hypertension, liver cancer and even liver failure. However, except for monitoring serum aminotransferases, there are no clear guidelines for screening and/or monitoring individuals with UCDs for liver disease. Thus, we systematically evaluated the potential utility of several non-invasive biomarkers for liver fibrosis in UCDs. METHODS: We evaluated grey-scale ultrasonography, liver stiffness obtained from shear wave elastography (SWE), and various serum biomarkers for hepatic fibrosis and necroinflammation, in a cohort of 28 children and adults with various UCDs. RESULTS: Overall, we demonstrate a high burden of liver disease in our participants with 46% of participants having abnormal grey-scale ultrasound pattern of the liver parenchyma, and 52% of individuals having increased liver stiffness. The analysis of serum biomarkers revealed that 32% of participants had elevated FibroTest™ score, a marker for hepatic fibrosis, and 25% of participants had increased ActiTest™ score, a marker for necroinflammation. Interestingly, liver stiffness did not correlate with ultrasound appearance or FibroTest™. CONCLUSION: Overall, our results demonstrate the high overall burden of liver disease in UCDs and highlights the need for further studies exploring new tools for identifying and monitoring individuals with UCDs who are at risk for this complication. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov (NCT03721367).

Pulmonary Alveolar Microlithiasis.

Online supplemental material is available for this article.

Genetic disorders associated with the RANKL/OPG/RANK pathway.

The RANKL/OPG/RANK signalling pathway is a major regulatory system for osteoclast formation and activity. Mutations in TNFSF11, TNFRSF11B and TNFRSF11A cause defects in bone metabolism and development, thereby leading to skeletal disorders with changes in bone density and/or morphology. To date, nine kinds of monogenic skeletal diseases have been found to be causally associated with TNFSF11, TNFRSF11B and TNFRSF11A mutations. These diseases can be divided into two types according to the mutation effects and the resultant pathogenesis. One is caused by the mutations inducing constitutional RANK activation or OPG deficiency, which increase osteoclastogenesis and accelerate bone turnover, resulting in juvenile Paget's disease 2, Paget disease of bone 2, familial expansile osteolysis, expansile skeletal hyperphosphatasia, panostotic expansile bone disease, and Paget disease of bone 5. The other is caused by the de-activating mutations in TNFRSF11A or TNFSF11, which decrease osteoclastogenesis and elevate bone density, resulting in osteopetrosis, autosomal recessive 2 and 7, and dysosteosclerosis. Here we reviewed the current knowledge about these genetic disorders with paying particular attention to the updating genotype-phenotype association in the TNFRSF11A-caused diseases.

Radiographic characteristics of alveolar microlithiasis and pulmonary ossification following chronic corticosteroid therapy in a dog.

A 10-year-old, neutered female, Australian Shepherd was referred for acute respiratory distress and a history of chronic exogenous steroid administration. On thoracic radiographs, a severe increase in mineral opacity characterized as a generalized unstructured interstitial pulmonary pattern, diffuse calcinosis cutis, and moderate hepatomegaly were noted. Cor pulmonale was identified on echocardiography. The patient developed a pneumothorax following sampling and had a cardiac arrest. Postmortem histopathology of the lungs revealed pulmonary interstitial mineralization and alveolar microlithiasis. This report supports including generalized pulmonary mineralization due to chronic exogenous steroid administration as a differential diagnosis for dogs with these clinical and imaging findings.

Clinicopathological and imaging features of pulmonary alveolar microlithiasis in a dog - a case report.

BACKGROUND: The aetiology of pulmonary alveolar microlithiasis (PAM) in animals is still unknown. In humans, this pulmonary disorder is a rare autosomal recessive disorder triggered by a mutation in the gene SLC34A2, which causes deposition and aggregation of calcium and phosphate in the pulmonary parenchyma with formation of microliths. Although histopathological examination is required for a definite diagnosis, in humans, imaging modalities such as computed tomography can demonstrate typical patterns of the disease. This is the first description of the computed tomographic (CT) features of a histologically confirmed PAM in dogs. CASE PRESENTATION: The following report describes a case of a 7-year-old female Boxer dog evaluated for paroxysmal loss of muscle tone and consciousness with excitement. The main differential diagnoses considered were syncope, seizures, and narcolepsy-cataplexy. The results of the complete blood count, serum biochemistry panel, urinalysis, arterial blood pressure, echocardiography, abdominal ultrasound, Holter monitoring, and ECG were all within normal limits. Additional exams included thoracic radiographs, head and thorax CT, bronchoalveolar lavage (BAL), and CT-guided cytology. Thoracic radiographs revealed micronodular calcifications in the lungs, with sandstorm appearance. Computed tomography of the thorax showed the presence of numerous mineralized high-density agglomerates of multiple sizes throughout the pulmonary parenchyma, a reticular pattern with ground glass opacity and intense mineralized fibrosis of the pleural lining. Head CT was unremarkable. BAL and CT-guided cytology were inconclusive, but imaging features strongly suggest the diagnosis of PAM, which was histologically confirmed after necropsy. CONCLUSIONS: This case report contributes to the clinicopathological and imaging characterization of pulmonary alveolar microlithiasis in dogs. In this species, the diagnosis of PAM should be considered when CT features evidence a reticular pattern with ground glass opacity and the presence of an elevated number and size of calcifications.

Fully Automatic Landmarking of Syndromic 3D Facial Surface Scans Using 2D Images.

3D facial landmarks are known to be diagnostically relevant biometrics for many genetic syndromes. The objective of this study was to extend a state-of-the-art image-based 2D facial landmarking algorithm for the challenging task of 3D landmark identification on subjects with genetic syndromes, who often have moderate to severe facial dysmorphia. The automatic 3D facial landmarking algorithm presented here uses 2D image-based facial detection and landmarking models to identify 12 landmarks on 3D facial surface scans. The landmarking algorithm was evaluated using a test set of 444 facial scans with ground truth landmarks identified by two different human observers. Three hundred and sixty nine of the subjects in the test set had a genetic syndrome that is associated with facial dysmorphology. For comparison purposes, the manual landmarks were also used to initialize a non-linear surface-based registration of a non-syndromic atlas to each subject scan. Compared to the average intra- and inter-observer landmark distances of 1.1 mm and 1.5 mm respectively, the average distance between the manual landmark positions and those produced by the automatic image-based landmarking algorithm was 2.5 mm. The average error of the registration-based approach was 3.1 mm. Comparing the distributions of Procrustes distances from the mean for each landmarking approach showed that the surface registration algorithm produces a systemic bias towards the atlas shape. In summary, the image-based automatic landmarking approach performed well on this challenging test set, outperforming a semi-automatic surface registration approach, and producing landmark errors that are comparable to state-of-the-art 3D geometry-based facial landmarking algorithms evaluated on non-syndromic subjects.

[Selective muscular atrophy in a family with hereditary myopathy with early respiratory failure].

Hereditary myopathy with early respiratory failure (HMERF) with heterozygous mutations in the titin gene (TTN) is characterized by respiratory failure developing from the early phase of limb weakness or gait disturbance. Here, we describe a characteristic distribution of muscle involvement in three members of a HMERF family with a TTN mutation. Despite the differences in severity exhibited among the father, daughter and son, the systemic imaging studies showed a similar pattern among these individuals. The semitendinosus and fibularis longus muscles were selectively affected, as described previously. In addition, we found marked atrophy in the sternocleidomastoid and psoas major muscles, regardless of the disease severity. The atrophy in selective trunk muscles observed in routine CT scans can be useful for the differential diagnosis of hereditary myopathies with heart and respiratory failure.

Cardiovascular Magnetic Resonance Imaging of Inherited Heart Conditions.

Imaging modalities are central to diagnosis and prognostication of confirmed or suspected inherited cardiomyopathies. The availability and use of cardiovascular magnetic resonance imaging (CMR) to supplement traditional modalities has increased substantially and has several advantages over traditional imaging techniques. CMR is unique in its ability to easily acquire images in any plane. Moreover, advances in CMR sequences have begun to enable characterisation of the myocardium without the need for invasive biopsy and has provided a major step forward in the understanding of inherited heart disease pathology and genotype-phenotype interactions. This review summarises the current role of CMR in inherited cardiomyopathies depending on their genotype and phenotype status, using arrhythmogenic right ventricular dysplasia/cardiomyopathy and hypertrophic cardiomyopathy as prototypical examples.

Genetic syndromes associated with isolated fetal growth restriction.

Early onset fetal growth restriction (FGR) may be due to impaired placentation, environmental or toxic exposure, congenital infections or genetic abnormalities. Remarkable research, mainly based on retrospective series, has been published on the diverse genetic causes. Those have become more and more relevant with the improvement in the accuracy of the analysis techniques and the rising of breakthrough genomewide methods such as the whole genome sequencing. However, no publication has presented an integrated view of management of those fetuses with an early and severe affection. In this review, we explored to which extent genetic syndromes can cause FGR fetuses without structural defects. The most common chromosomal abnormalities (Triploidies and Trisomy 18), submicroscopic chromosomal anomalies (22q11.2 microduplication syndrome) and single gene disorders (often associated with mild ultrasound findings) related to early and severe FGR had been analysed. Finally, we addressed the impact of epigenetic marks on fetal growth, a matter of growing importance. At the end of this review, we should be able to provide an adequate counseling to parents in terms of diagnosis, prognosis and management of those pregnancies.

Desquamative interstitial pneumonia in a non-smoker with neurofibromatosis type 1 (Von Recklinghausen syndrome).

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with multiple systemic manifestations. Pulmonary involvement has been reported in the form of interstitial fibrosis, emphysema, pulmonary hypertension and thoracic neoplasm. We report a case of desquamative interstitial pneumonia in a non-smoker with NF1.

Infantile Onset of Spinocerebellar Ataxia Type 5 (SCA-5) in a 6 Month Old with Ataxic Cerebral Palsy.

Spinocerebellar ataxia type 5 (SCA-5) is a predominantly slowly progressive adult onset ataxia. We describe a child with a presentation of ataxic cerebral palsy (CP) and developmental delay at 6 months of age. Genetic testing confirmed a c.812C>T p.(Thr271Ile) mutation within the SPTBN2 gene. Seven previous cases of infantile onset SCA-5 are reported in the literature, four of which had a CP presentation. Early onset of SCA-5 presents with ataxic CP and is a rare cause of cerebral palsy.

Congenital Cystic Lesions of the Bile Ducts: Imaging-Based Diagnosis.

Congenital cystic lesions of the bile ducts represent a spectrum of liver and biliary system lesions, resulting from abnormal embryologic development of the ductal plate. These disorders include Caroli disease, choledochal cysts, autosomal dominant polycystic liver disease, congenital hepatic fibrosis, and biliary hamartomas. Each disorder carries a peculiar clinical presentation, prognosis, and risk of complications. Knowledge of radiological findings of fibropolycystic liver diseases is crucial for their appropriate detection and for differential diagnosis with other similar hepatic cystic lesions, in order to avoid relevant misdiagnosis. The aim of this review is to provide an illustrative summary of the most relevant imaging findings of these conditions as encountered on ultrasound, computed tomography, and magnetic resonance imaging, and provide pearls for imaging-based differential diagnosis.