Nosology of genetic skeletal disorders: 2023 revision

The "Nosology of genetic skeletal disorders" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395

Mental Retardation and Abnormal Skeletal Development (Dyggve-Melchior-Clausen Dysplasia) Due to Mutations in a Novel, Evolutionarily Conserved Gene

Dyggve-Melchior-Clausen dysplasia (DMC) and Smith-McCort dysplasia (SMC) are similar, rare autosomal recessive osteochondrodysplasias. The radiographic features and cartilage histology in DMC and SMC are identical. However, patients with DMC exhibit significant developmental delay and mental retardation, the major features that distinguish the two conditions. Linkage studies localized the SMC and DMC disease genes to chromosome 18q12-21.1, providing evidence suggesting that they are allelic disorders. Sequence analysis of the coding exons of the FLJ90130 gene, a highly evolutionarily conserved gene within the recombination interval defined in the linkage study, identified mutations in SMC and DMC patients. The affected individuals in two consanguinous DMC families were homozygous for a stop codon mutation and a frameshift mutation, respectively, demonstrating that DMC represents the FLJ90130-null phenotype. The data confirm the hypothesis that SMC and DMC are allelic disorders and identify a gene necessary for normal skeletal development and brain function

Predictors of Vape Shops Going out of Business in Southern California.

ObjectivesVape shops have proliferated in the United States (US) in recent years. As of May 2016, the US Food and Drug Administration (FDA) asserted its authority to regulate electronic nicotine delivery systems. It is critical to understand how these polices have affected the vape shop industry, as the rise and fall of vape shop proliferation has the potential for influencing public health.MethodsIn this longitudinal study, we examined factors associated with vape shop (N = 77) closure over a 2-1/2-year period in southern California. We assessed predictors of vape shops going out of business using a multivariate logistic regression model.ResultsAmong 77 vape shops assessed at baseline, 44.2% closed over a 2-1/2-year period. The absence of a "bar type" physical environment (OR = 2.64, 95% CI = 1.12-6.20), poorer shop accessibility (OR = 7.11, 95% CI = 1.17-43.24), fewer reports of qualified personnel (OR = 2.28, 95% CI = 1.12-4.64), less average time spent in shop by customers (OR = 4.8, 95% CI = 1.18-19.60), a narrower e-liquid flavor selection (OR = 6.55, 95% CI = 1.56-27.49), and less vape device diversity (OR = 2.36, 95% C = 1.13-4.91) predicted vape shop closure.ConclusionsThe rise and subsequent decline in vape shops could potentially affect public health. However, there needs to be more research on their association with public health.

Predictors of Vape Shops Going out of Business in Southern California.

ObjectivesVape shops have proliferated in the United States (US) in recent years. As of May 2016, the US Food and Drug Administration (FDA) asserted its authority to regulate electronic nicotine delivery systems. It is critical to understand how these polices have affected the vape shop industry, as the rise and fall of vape shop proliferation has the potential for influencing public health.MethodsIn this longitudinal study, we examined factors associated with vape shop (N = 77) closure over a 2-1/2-year period in southern California. We assessed predictors of vape shops going out of business using a multivariate logistic regression model.ResultsAmong 77 vape shops assessed at baseline, 44.2% closed over a 2-1/2-year period. The absence of a "bar type" physical environment (OR = 2.64, 95% CI = 1.12-6.20), poorer shop accessibility (OR = 7.11, 95% CI = 1.17-43.24), fewer reports of qualified personnel (OR = 2.28, 95% CI = 1.12-4.64), less average time spent in shop by customers (OR = 4.8, 95% CI = 1.18-19.60), a narrower e-liquid flavor selection (OR = 6.55, 95% CI = 1.56-27.49), and less vape device diversity (OR = 2.36, 95% C = 1.13-4.91) predicted vape shop closure.ConclusionsThe rise and subsequent decline in vape shops could potentially affect public health. However, there needs to be more research on their association with public health.

Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1

To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.; Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.; The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.; Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far

Brief Report: Peripheral Osteolysis in Adults Linked to ASAH1 (Acid Ceramidase) Mutations: A New Presentation of Farber's Disease

To establish a diagnosis and provide counseling and treatment for 3 adult patients from one family presenting with peripheral osteolysis.; Following clinical and radiographic assessment, exome sequencing, targeted gene resequencing, and determination of enzyme activity in cultured fibroblasts were performed.; The proband (age 40 years) had a history of episodic fever and pain in childhood that subsided around puberty. He and 2 of his older sisters (ages 58 and 60 years, respectively) showed adult-onset progressive shortening of fingers and toes with redundancy of the overlying skin. Radiographs showed severe osteolysis of the distal radius and ulna, carpal bones, metacarpal bones, and phalanges. Sequencing of the known genes for recessively inherited osteolysis, MMP2 and MMP14, failed to show pathogenic mutations. Exome sequencing revealed compound heterozygosity for mutations c.505T>C (p.Trp169Arg) and c.760A>G (p.Arg254Gly) in ASAH1, the gene coding for acid ceramidase. Sanger sequencing confirmed correct segregation in the family, and enzyme activity in fibroblast cultures from the patients was reduced to ∼8% of that in controls, confirming a diagnosis of Farber's disease.; Our findings indicate that hypomorphic mutations in ASAH1 may result in an osteoarticular phenotype with a juvenile phase resembling rheumatoid arthritis that evolves to osteolysis as the final stage in the absence of neurologic signs. This observation delineates a novel type of recessively inherited peripheral osteolysis and illustrates the long-term skeletal manifestations of acid ceramidase deficiency (Farber's disease) in what appear to be the oldest affected individuals known so far