Bilateral Femoral Neck Pseudarthrosis in an Adolescent Girl With Congenital Spondyloepiphyseal Dysplasia. The Treatment Journey: A Case Report.

CASE: We describe the surgical management of a girl with dwarfism and congenital spondyloepiphyseal dysplasia, who presented in adolescence with coxa vara and bilateral pseudarthrosis between the femoral neck and the diaphysis, with asymmetric distal migration at both sites and leg length discrepancy. The patient at 16 years underwent valgus osteotomy in situ and femoral neck fixation in the left hip. The right hip was operated 19 months later. CONCLUSION: Hip dysplasia is common in spondyloepiphyseal dysplasia, but a debilitating nontraumatic bilateral pseudarthrosis at the base of the femoral neck has not been previously reported. Valgus corrective osteotomies of the femur in situ led to union and allowed the patient to walk.

Tracheobronchopathia Osteochondroplastica - to Biopsy or not to Biopsy? A Relook at The Rare Disease.

BACKGROUND: Tracheobronchopathia osteochondroplastica (TPO) is a rare idiopathic disease involving the tracheobronchial tree. It is mostly an incidental finding with non-specific clinical manifestations. It has typical bronchoscopic, radiological features and biopsy is usually considered non-essential. The study aimed to determine whether biopsy makes a difference in the management of patients. METHODS: All patients diagnosed with TPO in our institution over 15 years (2005 to 2020) were included in this study. Their medical records, chest computed tomography (CT), and bronchoscopy reports were retrospectively reviewed, and data were analysed. All the CT images were reviewed by a senior chest radiologist. RESULTS: From the 20,000 bronchoscopies and 260,000 CT thorax images obtained, 28 cases were diagnosed as TPO based on either bronchoscopy or radiology or both. Among the 19 cases diagnosed through bronchoscopy, 16 underwent a biopsy. In addition to TPO features, biopsy showed additional diagnoses in 6 cases. In 9 cases, TPO was not initially diagnosed by CT but by bronchoscopy. In 8 patients, TPO was diagnosed incidentally on CT performed for other reasons. On follow-up with the treatment of underlying/co-existing concomitant aetiologies, clinical improvement was noted in all patients. None of them progressed to respiratory failure or airway obstruction until the last follow-up. CONCLUSION: Among patients who underwent bronchoscopic biopsy of TPO lesions, 38% had biopsy results showing an alternative aetiology, which led to changes in the treatment plan for all these patients. Hence, a bronchoscopic biopsy of TPO lesions should be performed to rule out other aetiologies.

RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C-terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders.

Osteochondrodysplasia and the c.1024G>T variant of TRPV4 gene in Scottish Fold cats: genetic and radiographic evaluation.

OBJECTIVES: The objectives of this study were to investigate the c.1024G>T SNP in the TRPV4 gene in Scottish Straight and Fold cats, and to evaluate the pattern of skeletal phenotype and the evolution of radiological signs of Scottish Fold osteochondrodysplasia (SFOCD) over time in heterozygous subjects. METHODS: DNA was obtained from blood samples of 17 cats (Scottish Fold: n = 12; Scottish Straight: n = 5) and subsequently genotyped by sequencing in a 249 bp region of the TRPV4 gene (exon 6), including the known c.1024G>T causative mutation for osteochondrodysplasia. Orthopaedic and radiographic analyses were performed on animals carrying the mutant allele. RESULTS: Genotyping by sequencing confirmed that all and only the Scottish Fold cats carried the mutant allele in a heterozygous asset. Furthermore, two other exon variants, already described in the literature as silent variants, were found in some of the sampled cats. Comparative orthogonal radiographic views of the shoulder, elbow, carpus, hip, stifle and tarsus were obtained. A mediolateral projection of the thoracic and lumbar column was also performed. Three out of four cats were clinically and radiographically examined again 1.5 years later. CONCLUSIONS AND RELEVANCE: Although the presence of the mutant allele in all the tested Scottish Fold cats was confirmed, only 1/12 showed clinical signs of SFOCD. Furthermore, no cats in the 1.5-year follow-up showed skeletal changes. Although significant, the c.1024G>T mutation in the TRPV4 gene, supposedly, is not the only cause or risk of developing SFOCD.

A novel variant in BMPR1B causes acromesomelic dysplasia Grebe type in a consanguineous Moroccan family: Expanding the phenotypic and mutational spectrum of acromesomelic dysplasias.

Acromesomelic dysplasia Grebe type (AMD Grebe type) is an autosomal recessive trait characterized by short stature, shortened limbs and malformations of the hands and feet. It is caused by variants in the growth differentiation factor 5 (GDF5) or, in rare cases, its receptor, the bone morphogenetic protein receptor-1B (BMPR1B). Here, we report a novel homozygous BMPR1B variant causing AMD Grebe type in a consanguineous Moroccan family with two affected sibs from BRO Biobank. Remarkably, the affected individuals showed additional features including bilateral simian creases, lumbar hyperlordosis, as well as lower limb length inequality and dislocated hips in one of them, which were never reported previously for AMD Grebe type patients. The identified novel BMPR1B variant (c.1201C>T, p.R401*) is predicted to result in loss of function of the BMPR1B protein either by nonsense-mediated mRNA decay or production of a truncated BMPR1B protein. Thus, these findings expand the phenotypic and mutational spectrum of AMD, and may improve the diagnosis of AMD and enable appropriate genetic counselling to be offered to patients.

Severe Aortic Root Dilatation in a Patient With Larsen Syndrome.

We present a five-year-old female diagnosed with Larsen syndrome at birth with severe aortic root dilatation, failure to thrive, and developmental delay. This report highlights the specific physical findings, imaging, genetics, and surgical treatment, along with a brief overview of Larsen syndrome.

Five siblings expand the spectrum of GPC6-related skeletal dysplasia.

Skeletal dysplasias broadly include disorders of cartilage or bone. Omodysplasia-1 is a type of skeletal dysplasia caused by biallelic loss of function variants in the GPC6 gene. GPC6 codes for the protein glypican 6 (GPC6) (OMIM *604404), which stimulates bone growth. We report a family in which five out of nine children were presented with a skeletal dysplasia characterized phenotypically by mild short stature and rhizomelia. All affected individuals were found to have homozygous missense variants in GPC6: c.511 C>T (p.Arg171Trp). Radiograph findings included rhizomelic foreshortening of all four extremities, coxa breva, and ulna minus deformity. Using a Hedgehog (Hh) reporter assay, we demonstrate that the variant found in this family results in significantly reduced stimulation of Hh activity when compared to the wild-type GPC6 protein, however protein function is still present. Thus, the milder phenotype seen in the family presented is hypothesized due to decreased GPC6 protein activity versus complete loss of function as seen in omodysplasia-1. Given the unique phenotype and molecular mechanism, we propose that this family's findings widen the phenotypic spectrum of GPC6-related skeletal dysplasias.

CHST3-related skeletal dysplasia in 14 patients: Identification of 8 novel variants and further expansion of the phenotypic spectrum.

Biallelic variants in CHST3 gene result in congenital dislocation of large joints, club feet, short stature, rhizomelia, kypho-scoliosis, platyspondyly, epiphyseal dysplasia, flared metaphysis, in addition to minor cardiac lesions and hearing loss. Herein, we describe 14 new patients from 11 unrelated Egyptian families with CHST3-related skeletal dysplasia. All patients had spondyloepiphyseal changes that were progressive with age in addition to bifid distal ends of humeri which can be considered a diagnostic key in patients with CHST3 variants. They also shared peculiar facies with broad forehead, broad nasal tip, long philtrum and short neck. Rare unusual associated findings included microdontia, teeth spacing, delayed eruption, prominent angulation of the lumbar-sacral junction and atrial septal defect. Mutational analysis revealed 10 different homozygous CHST3 (NM_004273.5) variants including 7 missense, two frameshift and one nonsense variant. Of them, the c.384_391dup (p.Pro131Argfs*88) was recurrent in two families. Eight of these variants were not described before. Our study presents the largest series of patients with CHST3-related skeletal dysplasia from the same ethnic group. Furthermore, it reinforces that lethal cardiac involvement is a critical clinical finding of the disorder. Therefore, we believe that our study expands the phenotypic and mutational spectrum, and also highlights the importance of performing echocardiography in patients harboring CHST3 variants.

Spondyloepimetaphyseal dysplasia with joint laxity type 2: Aggregating the literature and reporting on the life of a 66-year-old man.

Spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (SEMDJL2), is a rare bone dysplasia that results from hotspot (amino acids148/149) mutations in KIF22. Clinically, affected individuals present with generalized joint laxity, limb malalignment, midface hypoplasia, gracile digits, postnatal short stature, and occasionally, tracheolaryngomalacia; additionally, radiological features include severe epi-metaphyseal abnormalities and slender metacarpals. This report evaluates the progression of SEMDJL2 throughout the life of the oldest individual reported in the literature-a 66-year-old man with a pathogenic KIF22 variant (c.443C > T, p.Pro148Leu). The proband developed many of the clinical and radiological alterations consistent with the presentation of other individuals in the literature. Interestingly, throughout his life, joint limitation progressed, beginning with knee and elbow stricture (year 20), and later, limitation of the shoulders, hips, ankles, and wrists (year 40). This differs from previous case reports, where joint limitation is identified in 1-to-2 joints. Cumulatively, the progressive body-wide joint limitation resulted in early retirement (year 45) and difficulty completing daily tasks and managing personal hygiene culminating in the need for assisted living (year 65). In conclusion, we report on the clinical and radiological developments of a 66-year-old man with SEMDJL2, that developed significant joint limitation in adulthood.

Evolution of clinical and radiological presentations of spondyloepimetaphyseal dysplasia, RPL13-related: Description of 11 further cases.

Spondyloepimetaphyseal dysplasia (SEMD), RPL13-related is caused by heterozygous variants in RPL13, which encodes the ribosomal protein eL13, a component of the 60S human ribosomal subunit. Here, we describe the clinical and radiological evolution of 11 individuals, 7 children and 4 adults, from 6 families. Some of the skeletal features improved during the course of this condition, whilst others worsened. We describe for the first time "corner fractures" as a feature of this dysplasia which as with other dysplasias disappear with age. In addition, we review the heights and skeletal anomalies of these reported here and previously in a total of 25 individuals from 15 families. In this study, six different RPL13 variants were identified, five of which were novel. All were located in the apparently hotspot region, located in intron 5 and exon 6. Splicing assays were performed for two of the three previously undescribed splicing variants. Until now, all splice variants have occurred in the intron 5 splice donor site, incorporating an additional 18 amino acids to the mutant protein. Here, we report the first variant in intron 5 splice acceptor site which generates two aberrant transcripts, deleting the first three and four amino acids encoded by exon 6. Thus, this study doubles the number of SEMD-RPL13-related cases and variants reported to date and describes unreported age-related clinical and radiological features.

Kazimierz S. Kozlowski, 1928.

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of the Polish radiologist Kazimierz Kozlowski, whose name is associated with the Kozlowski type of spondylometaphyseal dysplasia.

Early prenatal diagnosis of a recurrent case of short-rib thoracic dysplasia 3 due to compound heterozygosity for variations in the DYNC2H1 gene: an "ultrasound first" approach.

Short-rib thoracic dysplasia 3 with or without polydactyly (OMIM # 613091) represents a clinical spectrum encompassing a heterogeneous group of skeletal dysplasias associated with homozygous or compound heterozygous mutations of DYNC2H1. We describe the case of a couple with two consecutive therapeutic abortions due to a diagnosis of short-rib thoracic dysplasia mutations. In the first pregnancy, the diagnosis has been made at 21 weeks. In the second one, an accurate and early ultrasound examination allowed a diagnosis at 12 weeks. DYNC2H1 mutations were confirmed in both cases. In this report, we underline the importance of an ultrasound evaluation at the end of the first trimester of pregnancy in the detection of early signs of skeletal dysplasias. An early prenatal diagnosis of a short-rib skeletal dysplasia, such as for other severe skeletal dysplasias, is critical to offer a couple the chance of a weighted, informed, and less traumatic decision about the continuation of the pregnancy.

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.

Severe tracheobronchopathia osteochondroplastica in an asymptomatic patient.

Tracheobronchopathia osteochondroplastica (TO) is a rare condition affecting the lumen of the tracheobronchial tree. It is characterised by the presence of multiple osseous and cartilaginous nodules with posterior wall sparing. While it is a benign condition, it can cause narrowing of the tracheal lumen and subglottis to varying degrees. Approximately 400 cases have been reported worldwide, with an incidence of 0.3% in autopsies and between 1 in 125 and 1 in 5000 on bronchoscopy. As most patients are asymptomatic, this may contribute to underdiagnoses and relative low incidence. Severity of the condition is often unrelated to patient symptomatology. We present a patient with one of the most severe cases of TO seen at our institution. Despite being asymptomatic, significant tracheal and bronchial narrowing was found incidentally on laryngobronchoscopy.

A Chinese case of CHST3-related skeletal dysplasia and a systematic review.

PURPOSE: We reported a case with carbohydrate sulfotransferase 3 (CHST3) spondyloepiphyseal dysplasia and made a systematic review of all previously reported cases. METHODS: A 14.8-year-old boy underwent clinical, radiological, and genetic evaluations. The patients and five age-matched healthy boys accepted high-resolution peripheral quantitative computed tomography evaluation. All CHST3-related skeletal dysplasia cases from PubMed and Embase were collected and summarized. The genotype-phenotype correlation was analyzed. RESULTS: The proband complained of aggravated joint pain and had a compression fracture of L2 during his second decade. Physical examination showed a height Z score of -4.94, short limbs, and restricted movement of the elbows and knees. X-rays showed carpal epiphyseal dysplasia, enlargement of elbow and knee joints, and subluxation of the left hip. Echocardiography showed abnormal cardiac valves. Compared with the norm, his total and trabecular volumetric bone mineral density (BMD), and the microarchitecture of the trabecular bone had trends to be worse at the distal radius and tibia. Two novel missense variants of c.1343T>G and c.761C>G in CHST3 were inherited from his father and mother, respectively. In the systematic review, short stature, limited joint extension, joint pain, and joint dislocation were the most common characteristics of this disorder. Height Z score and the proportion of hearing impairment had no significant differences between the missense and nonmissense mutations groups. CONCLUSION: Progressive joint pain and movement restriction are the main characteristics of CHST3-related skeletal dysplasia. BMD and bone microarchitecture of this disorder needs further exploration. There is no apparent genotype-phenotype correlation in this disorder.

An adolescent case of sellar osteochondromyxoma in the setting of spondyloepiphyseal dysplasia.

PURPOSE: Osteochondromyxomas (OMX) are rare congenital bone tumors that have only been described in the context of Carney complex syndrome (CNC). Data on OMX as a separate entity and in association with other disorders remain limited, making both diagnosis and treatment difficult. METHODS: A case report of a 17-year-old female diagnosed with sellar OMX is presented in the setting of spondyloepiphyseal dysplasia (SED). We discuss the radiographic and histopathological interpretations in addition to reviewing the current literature on OMX. RESULTS: A successful gross total resection of the tumor was achieved via an endonasal endoscopic transsphenoidal approach. A diagnosis was established radiographically and pathologically. CONCLUSION: The diagnosis and treatment of OMX are best achieved via tissue biopsy. Following confirmed osteochondromyxoma cases long term for recurrence and outcomes will be essential in understanding its natural tumor history and in establishing standard treatments.

Clinical, radiological and molecular studies in 24 individuals with Dyggve-Melchior-Clausen dysplasia and Smith-McCort dysplasia from India.

BACKGROUND: Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC types 1 and 2) are rare spondyloepimetaphyseal dysplasias with identical radiological findings. The presence of intellectual disability in DMC and normal intellect in SMC differentiates the two. DMC and SMC1 are allelic and caused by homozygous or compound heterozygous variants in DYM. SMC2 is caused by variations in RAB33B. Both DYM and RAB33B are important in intravesicular transport and function in the Golgi apparatus. METHODS: Detailed clinical phenotyping and skeletal radiography followed by molecular testing were performed in all affected individuals. Next-generation sequencing and Sanger sequencing were used to confirm DYM and RAB33B variants. Sanger sequencing of familial variants was done in all parents. RESULTS: 24 affected individuals from seven centres are described. 18 had DMC and 6 had SMC2. Parental consanguinity was present in 15 of 19 (79%). Height <3 SD and gait abnormalities were seen in 20 and 14 individuals, respectively. The characteristic radiological findings of lacy iliac crests and double-humped vertebral bodies were seen in 96% and 88% of the affected. Radiological findings became attenuated with age. 23 individuals harboured biallelic variants in either DYM or RAB33B. Fourteen different variants were identified, out of which 10 were novel. The most frequently occurring variants in this group were c.719 C>A (3), c.1488_1489del (2), c.1484dup (2) and c.1563+2T>C (2) in DYM and c.400C>T (2) and c.186del (2) in RAB33B. The majority of these have not been reported previously. CONCLUSION: This large cohort from India contributes to the increasing knowledge of clinical and molecular findings in these rare 'Golgipathies'.

Spondyloepimetaphyseal dysplasia-Maroteaux type due to dominant TRPV4 mutation: expanding the phenotype with a case report.

INTRODUCTION: Dominant pathogenic mutations in the TRPV4 gene give rise to a wide spectrum of abnormal phenotypes, including bone dysplasia as well as spinal muscular atrophy and hereditary motor and sensory neuropathy. Spondyloepimetaphyseal dysplasias (SEMDs) are autosomal dominant skeletal dysplasias characterized by mild epiphyseal dysplasia, flared metaphyses, prominent joints, spondyler dysplasia, and brachydactyly with various carpal, metacarpal, and finger malformations. CASE PRESENTATION: We present a boy who has the clinical and radiological signs of SEMD-M with a dominant TRPV4 mutation. He also has some striking findings that have not been seen in these patients before, and they may be able to provide assistance to medical professionals in the process of diagnosis.These include a shorter distance between his lumbar vertebrae, congenital contractures, and an arachnoid cyst.

Natural history and genetic spectrum of the Turkish metaphyseal dysplasia cohort, including rare types caused by biallelic COL10A1, COL2A1, and LBR variants.

BACKGROUND: Metaphyseal chondrodysplasias are a heterogeneous group of diseases characterized by short and bowed long bones and metaphyseal abnormality. The aim of this study is to investigate the genetic etiology and prognostic findings in patients with metaphyseal dysplasia. METHODS: Twenty-four Turkish patients were included in this study and 13 of them were followed for 2-21 years. COL10A1, RMRP sequencing and whole exome sequencing were performed. RESULTS: Results: Seven heterozygous pathogenic variants in COL10A1 were detected in 17 patients with Schmid type metaphyseal chondrodysplasia(MCDS). The phenotype was more severe in patients with heterozygous missense variants (one in signal peptide domain at the N-terminus of the protein, the other, class-1 group mutation at NC1 domain) compared to the patients with truncating variants. Short stature and coxa vara deformity appeared after 3 and 5 years of age, respectively, while large femoral head resolved after the age of 13 years in MCDS group. Interestingly, one patient with severe phenotype also had a biallelic missense variant in NC1 domain of COL10A1. Three patients with biallelic mutations in RMRP had prenatal onset short stature with short limb, and typical findings of cartilage hair hypoplasia (CHH). While immunodeficiency or recurrent infections were not observed, resistant congenital anemia was detected in one. Biallelic mutation in LBR was described in a patient with prenatal onset short stature, short and curved limb and metaphyseal abnormalities. Unlike previously reported patients, this patient had ectodermal findings, similar to CHH. A biallelic COL2A1 mutation was also found in the patient with lower limb deformities and metaphyseal involvement without vertebral and epiphyseal changes. CONCLUSION: Long-term clinical characteristics are presented in a metaphyseal dysplasia cohort, including rare types caused by biallelic COL10A1, COL2A1, and LBR variants. We also point out that the domains where mutations on COL10A1 take place are important in the genotype-phenotype relationship.