Functional biology of the Steel syndrome founder allele and evidence for clan genomics derivation of COL27A1 pathogenic alleles worldwide.

Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.

SPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl-/- murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl-/- zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.

Pulmonary Tuberculosis: Role of Radiology in Diagnosis and Management.

Tuberculosis is a public health problem worldwide, including in the United States-particularly among immunocompromised patients and other high-risk groups. Tuberculosis manifests in active and latent forms. Active disease can occur as primary tuberculosis, developing shortly after infection, or postprimary tuberculosis, developing after a long period of latent infection. Primary tuberculosis occurs most commonly in children and immunocompromised patients, who present with lymphadenopathy, pulmonary consolidation, and pleural effusion. Postprimary tuberculosis may manifest with cavities, consolidations, and centrilobular nodules. Miliary tuberculosis refers to hematogenously disseminated disease that is more commonly seen in immunocompromised patients, who present with miliary lung nodules and multiorgan involvement. The principal means of testing for active tuberculosis is sputum analysis, including smear, culture, and nucleic acid amplification testing. Imaging findings, particularly the presence of cavitation, can affect treatment decisions, such as the duration of therapy. Latent tuberculosis is an asymptomatic infection that can lead to postprimary tuberculosis in the future. Patients who are suspected of having latent tuberculosis may undergo targeted testing with a tuberculin skin test or interferon-γ release assay. Chest radiographs are used to stratify for risk and to assess for asymptomatic active disease. Sequelae of previous tuberculosis that is now inactive manifest characteristically as fibronodular opacities in the apical and upper lung zones. Stability of radiographic findings for 6 months distinguishes inactive from active disease. Nontuberculous mycobacterial disease can sometimes mimic the findings of active tuberculosis, and laboratory confirmation is required to make the distinction. Familiarity with the imaging, clinical, and laboratory features of tuberculosis is important for diagnosis and management. ©RSNA, 2017.

Novel EED mutation in patient with Weaver syndrome.

Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features. Pathogenic variants in EZH2, a histone methyltransferase, have previously been identified as a cause of Weaver syndrome. However, the underlying molecular cause in many patients remains unknown. We report a patient with a clinical diagnosis of Weaver syndrome whose exome was initially non-diagnostic. Reports in the medical literature of EED associated overgrowth prompted re-analysis of the patient's original exome data. The patient was found to have a likely pathogenic variant in EED. These findings support that Weaver syndrome is a disorder with locus heterogeneity and can be due to pathogenic variants in either EZH2 or EED. This case highlights the utility of exome sequencing as a clinical diagnostic tool for novel gene discovery as well as the importance of re-examination of exome data as new information about gene-disease associations becomes available. © 2016 Wiley Periodicals, Inc.

Adult presentation of X-linked Conradi-Hünermann-Happle syndrome.

Conradi-Hünermann-Happle syndrome, or X-linked dominant chondrodysplasia punctata type 2 (CDPX2), is a genodermatosis caused by mutations in EBP. While typically lethal in males, females with CDPX2 generally manifest by infancy or childhood with variable features including congenital ichthyosiform erythroderma, chondrodysplasia punctata, asymmetric shortening of the long bones, and cataracts. We present a 36-year-old female with short stature, rhizomelic and asymmetric limb shortening, severe scoliosis, a sectorial cataract, and no family history of CDPX2. Whole exome sequencing (WES) revealed a p.Arg63del mutation in EBP, and biochemical studies confirmed a diagnosis of CDPX2. Short stature in combination with ichthyosis or alopecia, cataracts, and limb shortening in an adult should prompt consideration of a diagnosis of CDPX2. As in many genetic syndromes, the hallmark features of CDPX2 in pediatric patients are not readily identifiable in adults. This demonstrates the utility of WES as a diagnostic tool in the evaluation of adults with genetic disorders.

Lysinuric Protein Intolerance Presenting with Multiple Fractures.

Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism caused by mutations in SLC7A7, which encodes a component of the dibasic amino acid transporter found in intestinal and renal tubular cells. Patients typically present with vomiting, diarrhea, irritability, failure to thrive, and symptomatic hyperammonemia after protein-rich meals. Long-term complications may include pulmonary alveolar proteinosis, renal disease, and osteoporosis. We present a 5-year-old male who was followed in our skeletal dysplasia clinic for 3 years for multiple fractures, idiopathic osteoporosis, and short stature in the absence of typical features of LPI. Whole exome sequencing performed to determine the etiology of the osteoporosis and speech delay identified a nonsense mutation in SLC7A7. Chromosome microarray analysis identified a deletion involving the second allele of the same gene, and biochemical analysis supported the diagnosis of LPI. Our patient's atypical presentation underscores the importance of maintaining a high index of suspicion for LPI in patients with unexplained fractures and idiopathic osteoporosis, even in the absence of clinical symptoms of hyperammonemia after protein rich meals or other systemic features of classical LPI. This case further demonstrates the utility of whole exome sequencing in diagnosis of unusual presentations of rare disorders for which early intervention may modify the clinical course.

Osteogenesis imperfecta without features of type V caused by a mutation in the IFITM5 gene.

Osteogenesis imperfecta (OI) is typically caused by mutations in type 1 collagen genes, but in recent years new recessive and dominant forms caused by mutations in a plethora of different genes have been characterized. OI type V is a dominant form caused by the recurrent (c.-14C > T) mutation in the 5'UTR of the IFITM5 gene. The mutation adds five residues to the N-terminus of the IFITM5, but the pathophysiology of the disease remains to be elucidated. Typical clinical features present in the majority of OI type V patients include interosseous membrane calcification between the radius and ulna and between the tibia and fibula, radial head dislocation, and significant hyperplastic callus formation at the site of fractures. We report a 5-year-old child with clinical features of OI type III or severe OI type IV (characteristic facies, gray sclerae, typical fractures) and absence of classical features of OI type V with a de novo recurrent IFITM5 mutation (c.-14C > T), now typical of OI type V. This highlights the variability of OI caused by IFITM5 mutations and suggests screening for mutations in this gene in most cases of OI where type 1 collagen mutations are absent.

Imaging features of intravesical urachal cysts in children.

BACKGROUND: Urachal cysts, part of the spectrum of congenital urachal anomalies, are typically extrinsic to the urinary bladder. OBJECTIVE: The purpose of this study is to present the salient imaging features of a pediatric series of unusual intravesical urachal cysts that protrude into the bladder lumen. MATERIALS AND METHODS: Five children with intravesical urachal cysts depicted on imaging studies were retrospectively identified during a 6-year period at a children's hospital. The clinical charts and findings on ultrasound (US) and voiding cystourethrogram (VCUG) were reviewed. RESULTS: In all five children, US revealed a thin-walled ovoid cystic structure containing anechoic fluid or echogenic debris and residing along the midline of the anterosuperior aspect of the urinary bladder protruding into the bladder lumen. Histological examination of the partial cystectomy specimen from one child revealed a cystic urachal remnant with intestinal mucosal lining and reactive lymphoid hyperplasia. The cysts in the four other children were managed conservatively without operative intervention. CONCLUSION: The purpose of this report is to expand the spectrum of urachal remnant anomalies to include these newly recognized intravesical urachal cysts, which are characterized on US by the presence of a thin-walled cyst along the midline anterosuperior aspect of the urinary bladder.

Recurrent tracheoesophageal fistula after thoracoscopic repair: vanishing clips as a potential sign.

We present a case of a neonate who underwent surgery for esophageal atresia (EA) with tracheoesophageal fistula (TEF) with an unusual finding on postoperative chest radiographs. In retrospect, this was a clue to a recurrent TEF: disappearance of the surgical clips from the site of surgical repair. Knowledge of this radiographic finding could aid in the diagnosis of a recurrent fistula in patients with previous repair of EA.

Sagittal orientation of ingested coins in the esophagus in children.

OBJECTIVE: The classic teaching has been that coins in the esophagus are oriented in the coronal plane projecting en face on frontal radiographs and tangentially on lateral views, whereas coins in the trachea are oriented sagittally and appear tangential on frontal radiographs and en face on lateral radiographs. We evaluated the clinical presentation and radiographic appearance in eight cases of esophageal coins in children with an atypical sagittal orientation on chest radiographs. MATERIALS AND METHODS: The clinical records and chest radiographs of eight children with sagittally oriented esophageal coins were retrospectively reviewed. Patient age, sex, type of coin, location of the coin within the esophagus, method of coin removal, presence of underlying esophageal anomalies, treatment, and complications related to the coin ingestion or removal were recorded. RESULTS: The age of the eight children ranged from 3.8 to 17.7 years (mean, 7.8 years). The coins were lodged at the level of the aortic arch in seven of the eight patients and at the level of the distal third of the esophagus in one patient. In one of the eight cases, the coin was originally in the sagittal plane but spontaneously reoriented into the coronal plane. CONCLUSION: Our case series reveals that the classic teaching that coins with a sagittal orientation on chest radiographs are in the trachea is usually not correct. A coin seen with a sagittal orientation on a chest radiograph will likely be within the esophagus.

Radiographic abnormalities in Rothmund-Thomson syndrome and genotype-phenotype correlation with RECQL4 mutation status.

OBJECTIVE: The purpose of this study was to summarize the radiographic skeletal findings in patients with Rothmund-Thomson syndrome (RTS) and to determine whether there is an association between the presence of skeletal abnormalities and the mutational status of the RECQL4 gene. SUBJECTS AND METHODS: Twenty-eight subjects with RTS underwent skeletal surveys and RECQL4 DNA mutation testing. Radiographs were reviewed by two radiologists. RECQL4 mutation testing by DNA sequencing of the gene was performed by a diagnostic laboratory. Genotype-phenotype analysis by Fisher's exact test was performed to investigate whether there was a correlation between mutation status and skeletal abnormalities. RESULTS: Twenty-one (75%) of the subjects had at least one significant skeletal abnormality, the more common being abnormal metaphyseal trabeculation, brachymesophalangy, thumb aplasia or hypoplasia, osteopenia, dislocation of the radial head, radial aplasia or hypoplasia, and patellar ossification defects. Three subjects had a history of destructive bone lesion (osteosarcoma). Genotype-phenotype analysis showed a significant correlation between RECQL4 mutational status and the presence of skeletal abnormalities (p < 0.0001). CONCLUSION: Skeletal abnormalities are frequent in persons with RTS. Many of these abnormalities are not clinically apparent but are detectable on radiographs. The presence of skeletal abnormalities correlates with RECQL4 mutation status, which has been found to correlate with risk of osteosarcoma. Skeletal surveys aid in both diagnosis and management of RTS.

Incomplete double aortic arch with atresia of the distal left arch: distinctive imaging appearance.

OBJECTIVE: We present 10 patients with double aortic arch with atresia of the distal left arch segment, a form of incomplete double aortic arch, and describe the distinct MRI and CT findings for this potentially symptomatic vascular ring. CONCLUSION: Knowledge of the distinctive imaging appearance of this congenital arch anomaly can direct the radiologist to the correct preoperative diagnosis.

A dominantly inherited spondylometaphyseal dysplasia with "corner fractures" and congenital scoliosis.

Spondylometaphyseal dysplasia (SMD) is a term applied to a varied group of skeletal dysplasias that principally involve the spine and the metaphyses of long bones. SMD Sutcliffe or "Corner Fracture" type is characterized by short stature, developmental coxa vara, fragmented appearance of the metaphyses ("corner fractures"), abnormally shaped vertebrae, odontoid hypoplasia, and dominant inheritance. We report a family with a dominantly inherited SMD with "corner fractures" and severe, congenital scoliosis but neither coxa vara nor odontoid abnormalities. This could either represent phenotypic variability in SMD-"Corner Fracture" type, or be a new, dominantly inherited SMD. The presence of severe, congenital scoliosis and short stature is present in all members of this family, and not typically seen in SMD-"Corner Fracture" type, supporting our hypothesis that this might represent a new, dominantly inherited SMD.

The hand in Smith-Magenis syndrome (deletion 17p11.2): evaluation by metacarpophalangeal pattern profile analysis.

BACKGROUND: Brachydactyly has been described on physical examination in patients with Smith-Magenis syndrome (SMS). Metacarpophalangeal pattern profile analysis (MCPPPA), a method of graphic depiction of the relative size of the bones of the hand, has been used to objectively evaluate radiographs of the hand in patients with SMS in two small series: a single case and a study of four patients. This technique has confirmed brachydactyly and has suggested conflicting MCPPPA results. OBJECTIVE: The purpose of our study was to evaluate the hand by MCPPPA in a large series of patients with SMS. PATIENTS AND METHODS: We measured the bones of the hand and performed MCPPPA in 29 confirmed cases of SMS. RESULTS: Our results in 29 patients demonstrated a different MCPPPA in patients with SMS than previously reported. The analysis confirmed brachydactyly and the previously described trend of more pronounced shortening of the distal bones relative to the more proximal bones, but also demonstrated a previously undescribed pattern: relative enlargement of the proximal phalanx of the thumb and middle phalanx of the fifth finger. However, statistical analysis suggested that the pattern was not highly characteristic. CONCLUSION: MCPPPA of 29 patients with SMS demonstrates a pattern different than previously reported, but not highly characteristic.