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Genetics and Genomics of Skeletal Disorders
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Genetics and Genomics of Skeletal Disorders

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 August 2022) | Viewed by 36833

Special Issue Editors

Dr. Luca Sangiorgi

E-Mail Website
Guest Editor
Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
Interests: skeletal disorders; rare diseases; NGS; biobanks; disease registry; clinical trials
Dr. Evelise Brizola

E-Mail Website
Guest Editor
Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
Interests: rare diseases; skeletal disorders; genetics; pediatrics; neonatology; disease registry; clinical research
Dr. Elena Pedrini

E-Mail Website
Guest Editor
Department of Rare Skeletal Disorders, IRCCS Istituto Ortopedico Rizzoli, 40136 Bologna, Italy
Interests: rare diseases; skeletal disorders; genetics; NGS; biomarkers; disease registry; biobanking

Special Issue Information

Dear Colleagues,

We would like to invite you to participate in this Special Issue, “Genetics and Genomics of Skeletal Disorders”.

The identification of the mechanisms underlying the pathophysiology and therapies of skeletal disorders continues to be an area of significant research. More than 460 different disorders are included under the definition of skeletal disorders, divided in 42 distinct groups according to their phenotype and genotype. Furthermore, these entities present a high level of clinical and genetic heterogeneity; in many cases, mutations in a single gene may lead to a broad variability in clinical expression intra- and extra-familiarly. Over the past two decades, advances in genetic and genomic technologies have strengthened the field of skeletal disorders, increasing the molecular knowledge and discovering the genetic defects underlying many of these diseases. There are still many challenges regarding disease etiologies, pathways, natural history and possible new targets for future therapies; thus, research is highly needed. We welcome original research articles, case reports, reviews and mini-review articles addressing the following aims in skeletal disorders. We also welcome papers from ERN-BOND focusing on rare skeletal diseases.

Dr. Luca Sangiorgi
Dr. Evelise Brizola
Dr. Elena Pedrini
Guest Editors

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Keywords

  • gene discovery
  • mechanisms of the diseases
  • genetic studies of skeletal development
  • natural history
  • next-generation sequencing
  • development of new treatments or repurposing of drugs
  • rare skeletal disease

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Published Papers (12 papers)

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Research

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14 pages, 785 KiB  
Article
Clinical and Genetic Analysis of Multiple Osteochondromas in a Cohort of Argentine Patients
by Silvia Caino, Marisa Angelica Cubilla, Romina Alba, María Gabriela Obregón, Virginia Fano, Abel Gómez, Lorena Zecchini, Pablo Lapunzina, Miriam Aza-Carmona, Karen E. Heath and Carla Gabriela Asteggiano
Genes 2022, 13(11), 2063; https://doi.org/10.3390/genes13112063 - 7 Nov 2022
Cited by 4 | Viewed by 1815
Abstract
Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, EXT1 and EXT2. In this work, [...] Read more.
Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, EXT1 and EXT2. In this work, we report a cross-sectional study including 35 index patients and 20 affected family members. Clinical phenotyping of all 55 affected cases was obtained, but genetic studies were performed only in 35 indexes. Of these, a total of 40% (n = 14) had a family history of MO. Clinical severity scores were class I in 34% (n:18), class II in 24.5% (n:13) and class III in 41.5% (n:22). Pathogenic variants were identified in 83% (29/35) probands. We detected 18 (62%) in EXT1 and 11 (38%) in EXT2. Patients with EXT1 variants showed a height z-score of 1.03 SD lower than those with EXT2 variants and greater clinical severity (II–III vs. I). Interestingly, three patients showed intellectual impairment, two patients showed a dual diagnosis, one Turner Syndrome and one hypochondroplasia. This study improves knowledge of MO, reporting new pathogenic variants and forwarding the worldwide collaboration necessary to promote the inclusion of patients into future biologically based therapeutics. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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8 pages, 246 KiB  
Article
What Is the Exact Contribution of PITX1 and TBX4 Genes in Clubfoot Development? An Italian Study
by Anna Monica Bianco, Giulia Ragusa, Valentina Di Carlo, Flavio Faletra, Mariateresa Di Stazio, Costantina Racano, Giovanni Trisolino, Stefania Cappellani, Maurizio De Pellegrin, Ignazio d’Addetta, Giuseppe Carluccio, Sergio Monforte, Antonio Andreacchio, Daniela Dibello and Adamo P. d’Adamo
Genes 2022, 13(11), 1958; https://doi.org/10.3390/genes13111958 - 27 Oct 2022
Cited by 2 | Viewed by 2178
Abstract
Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are PTIX1 [...] Read more.
Congenital clubfoot is a common pediatric malformation that affects approximately 0.1% of all births. 80% of the cases appear isolated, while 20% can be secondary or associated with complex syndromes. To date, two genes that appear to play an important role are PTIX1 and TBX4, but their actual impact is still unclear. Our study aimed to evaluate the prevalence of pathogenic variants in PITX1 and TBX4 in Italian patients with idiopathic clubfoot. PITX1 and TBX4 genes were analyzed by sequence and SNP array in 162 patients. We detected only four nucleotide variants in TBX4, predicted to be benign or likely benign. CNV analysis did not reveal duplications or deletions involving both genes and intragenic structural variants. Our data proved that the idiopathic form of congenital clubfoot was rarely associated with mutations and CNVs on PITX1 and TBX4. Although in some patients, the disease was caused by mutations in both genes; they were responsible for only a tiny minority of cases, at least in the Italian population. It was not excluded that other genes belonging to the same TBX4-PITX1 axis were involved, even if genetic complexity at the origin of clubfoot required the involvement of other factors. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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18 pages, 2652 KiB  
Article
Combining Gene Mutation with Expression of Candidate Genes to Improve Diagnosis of Escobar Syndrome
by Dorra Najjar, Asma Chikhaoui, Sinda Zarrouk, Saifeddine Azouz, Wafa Kamoun, Nabil Nassib, Sami Bouchoucha and Houda Yacoub-Youssef
Genes 2022, 13(10), 1748; https://doi.org/10.3390/genes13101748 - 27 Sep 2022
Cited by 2 | Viewed by 2028
Abstract
Escobar syndrome is a rare, autosomal recessive disorder that affects the musculoskeletal system and the skin. Mutations in the CHRNG and TPM2 genes are associated with this pathology. In this study, we conducted a clinical and genetic investigation of five patients and also [...] Read more.
Escobar syndrome is a rare, autosomal recessive disorder that affects the musculoskeletal system and the skin. Mutations in the CHRNG and TPM2 genes are associated with this pathology. In this study, we conducted a clinical and genetic investigation of five patients and also explored via in silico and gene expression analysis their phenotypic variability. In detail, we identified a patient with a novel composite heterozygous variant of the CHRNG gene and two recurrent mutations in both CHRNG and TPM2 in the rest of the patients. As for the clinical particularities, we reported a list of modifier genes in a patient suffering from myopathy. Moreover, we identified decreased expression of IGF-1, which could be related to the short stature of Escobar patients, and increased expression of POLG1 specific to patients with TPM2 mutation. Through this study, we identified the genetic spectrum of Escobar syndrome in the Tunisian population, which will allow setting up genetic counseling and prenatal diagnosis for families at risk. In addition, we highlighted relevant biomarkers that could differentiate between patients with different genetic defects. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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10 pages, 476 KiB  
Article
Prenatal Diagnosis and Outcomes in Fetuses with Hemivertebra
by Hang Zhou, You Wang, Ruibin Huang, Fang Fu, Ru Li, Ken Cheng, Dan Wang, Qiuxia Yu, Yongling Zhang, Xiangyi Jing, Tingying Lei, Jin Han, Xin Yang, Dongzhi Li and Can Liao
Genes 2022, 13(9), 1623; https://doi.org/10.3390/genes13091623 - 9 Sep 2022
Cited by 1 | Viewed by 2463
Abstract
Background: There are few studies on the burden of chromosomal abnormalities and single gene disorders in fetal hemivertebra (HV). We aim to investigate the cytogenetic and monogenic risk and evaluate prenatal outcomes of fetal HV. Method: This study included fetuses diagnosed with HV [...] Read more.
Background: There are few studies on the burden of chromosomal abnormalities and single gene disorders in fetal hemivertebra (HV). We aim to investigate the cytogenetic and monogenic risk and evaluate prenatal outcomes of fetal HV. Method: This study included fetuses diagnosed with HV divided into two groups: isolated HV and non-isolated HV. Data on other sonographic structural anomalies, chromosomal and sub-chromosomal abnormalities, monogenic variations detected by WES, and prenatal outcomes are recorded and reviewed. Results: Among 109 fetal HV cases, forty-seven (43.1%) non-isolated HV cases were associated with structural anomalies. Chromosomal test results were available in 58 cases, identifying six (10.3%) chromosomal aberrations involved in four isolated and two non-isolated HV. WES identified four (likely) pathogenic variants in three cases among 16 fetuses with HV, involving three novel variants, 1250G > T and c.1277G> inherited from parents, respectively, in DLL3 and c.7213C > A ** in the FLNB. The live birth rate (LB) was higher in the isolated fetal HV group than in the non-isolated group (67.7% (42/62) vs. 12.5% (12/47), p < 0.001). Conclusion: This study emphasizes the risk of cytogenetic abnormalities in isolated HV. WES yields a diagnostic rate of 18.3% in HV with normal CMA, probably aiding the prenatal counseling and management of fetal HV. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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9 pages, 864 KiB  
Article
Prenatal Diagnosis of Talipes Equinovarus by Ultrasound and Chromosomal Microarray Analysis: A Chinese Single-Center Retrospective Study
by Ruibin Huang, Xin Yang, Hang Zhou, Fang Fu, Ken Cheng, You Wang, Chunling Ma, Ru Li, Xiangyi Jing, Jin Han, Li Zhen, Min Pan, Dongzhi Li and Can Liao
Genes 2022, 13(9), 1573; https://doi.org/10.3390/genes13091573 - 1 Sep 2022
Cited by 4 | Viewed by 1966
Abstract
Background: There are few studies on the detection rate by chromosomal microarray analysis (CMA) of the prenatal diagnosis of talipes equinovarus (TE) compared to conventional karyotyping. We aimed to explore the molecular etiology of fetal TE and examine the detection rate by CMA, [...] Read more.
Background: There are few studies on the detection rate by chromosomal microarray analysis (CMA) of the prenatal diagnosis of talipes equinovarus (TE) compared to conventional karyotyping. We aimed to explore the molecular etiology of fetal TE and examine the detection rate by CMA, which provides more information for the clinical screening and genetic counseling of TE. Methods: In this retrospective study, pregnancies diagnosed with fetal TE were enrolled and clinical data for all cases were retrieved from our medical record database, including demographic data for pregnancies, ultrasound findings, karyotype/CMA results, and pregnant and perinatal outcomes. Results: Among the 164 patients, 17 (10.4%) clinically significant variants were detected by CMA. In 148 singleton pregnancies, the diagnostic rate of clinically significant variants was significantly higher in the non-isolated TE group than in the isolated TE group (10/37, 27.0% vs. 6/111, 5.4%, P < 0.001). In twin pregnancies, 1 (6.3%) pathogenic copy number variant was present in the other 16 twin pregnancies. Conclusions: This study demonstrates that CMA is useful for the prenatal genetic diagnosis of fetal TE. Fetal TE with the associated structural malformation correlates with a higher probability of clinically significant variants. This data may aid prenatal diagnosis and genetic counseling for fetal TE. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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13 pages, 5433 KiB  
Article
Clinical and Genetic Characteristics of Multiple Epiphyseal Dysplasia Type 4
by Tatiana Markova, Vladimir Kenis, Evgenii Melchenko, Aynur Alieva, Tatiana Nagornova, Anna Orlova, Natalya Ogorodova, Olga Shchagina, Alexander Polyakov, Elena Dadali and Sergey Kutsev
Genes 2022, 13(9), 1512; https://doi.org/10.3390/genes13091512 - 24 Aug 2022
Cited by 4 | Viewed by 5051
Abstract
Multiple epiphyseal dysplasias (MED) are a clinically and genetically heterogeneous group of skeletal dysplasias with a predominant lesion in the epiphyses of tubular bones. Variants in the SLC26A2 gene cause their autosomal recessive form (rMED or MED type 4). The accumulation of data [...] Read more.
Multiple epiphyseal dysplasias (MED) are a clinically and genetically heterogeneous group of skeletal dysplasias with a predominant lesion in the epiphyses of tubular bones. Variants in the SLC26A2 gene cause their autosomal recessive form (rMED or MED type 4). The accumulation of data regarding the genotype–phenotype correlation can help in the diagnosis and proper management of these patients. The aim of this study was to survey the clinical and genetic characteristics of 55 patients with MED type 4 caused by variants in the SLC26A2 gene. Diagnosis confirmation was carried out by radiography and custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. This was followed by the validation of the identified variants using automated Sanger sequencing (for six patients) and the direct automatic Sanger sequencing of the coding sequence and the adjacent intron regions of the SLC26A2 gene for 49 patients. Based on the clinical and genetic analysis of our sample of patients, two main MED type 4 phenotypes with early and late clinical manifestations were identified. An early and more severe form of the disease was observed in patients with the c.835C > T variant (p.Arg279Trp), and the late and milder form of the disease was observed in patients with the c.1957T > A variant (p.Cys653Ser) in the homozygous or compound heterozygous state with c.26 + 2T > C. It was also shown that only three pathogenic variants were found in 95.3% of the alleles of Russian patients with MED type 4: c.1957T > A (p.Cys653Ser), c.835C > T (p.Arg279Trp), and c.26 + 2T > C; thus, it can be assumed that the primary analysis of these variants will contribute to the optimal molecular genetic diagnostics of MED type 4. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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11 pages, 16725 KiB  
Article
Prenatal Detection of Novel Compound Heterozygous Splice Site Variants of the KIAA0825 Gene in a Fetus with Postaxial Polydactyly Type A
by Yanyi Yao, Shan Deng and Feng Zhu
Genes 2022, 13(7), 1230; https://doi.org/10.3390/genes13071230 - 11 Jul 2022
Cited by 3 | Viewed by 2452
Abstract
Postaxial polydactyly (PAP) is a common abnormality characterized by extra digits on hands and/or feet. To date, sequence variants in seven genes have been identified in non-syndromic PAP. In the present study, a fetus manifesting non-syndromic postaxial polydactyly type A (PAPA) was found [...] Read more.
Postaxial polydactyly (PAP) is a common abnormality characterized by extra digits on hands and/or feet. To date, sequence variants in seven genes have been identified in non-syndromic PAP. In the present study, a fetus manifesting non-syndromic postaxial polydactyly type A (PAPA) was found by fetal ultrasonography. To better evaluate fetal prognosis, SNP array analysis and trio whole-exome sequencing (trio-WES) were performed to identify the underlying etiology. Although SNP array analysis revealed no abnormality, trio-WES identified compound heterozygous splice site variants in KIAA0825, c.-1-2A>T and c.2247-2A>G in intron 2 and intron 12, respectively. These two splice site variants were absent in control databases and were predicted to influence splicing by in silico analysis. To confirm the potential pathogenicity of the variants, in vitro splicing assays using minigene and RNA from peripheral leukocytes of the heterozygous parents were conducted. Minigene and RT-PCR assays demonstrated that the c.-1-2A>T variant led to the loss of the initiation codon, and the c.2247-2A>G variant mainly resulted in exon 13 skipping. Prenatal WES and subsequent functional studies are important approaches for defining the genetic etiology of fetuses with PAPA and are also essential for accurate genetic counseling and decision making. Taken together, this study expands the spectrum of KIAA0825 variations in PAPA patients and increases the knowledge of the molecular consequences of KIAA0825 splice site variants. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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10 pages, 564 KiB  
Article
Serum Periostin Level and Genetic Polymorphisms Are Associated with Vertebral Fracture in Chinese Postmenopausal Women
by Yi-Ming Guo, Jian-Hao Cheng, Hao Zhang, Jin-Wei He, Hua Yue, Wei-Wei Hu, Jie-Mei Gu, Yun-Qiu Hu, Wen-Zhen Fu, Chun Wang and Zhen-Lin Zhang
Genes 2022, 13(3), 439; https://doi.org/10.3390/genes13030439 - 27 Feb 2022
Cited by 5 | Viewed by 2373
Abstract
Purposes: In order to investigate the association between serum periostin levels and the variation of its encoding gene POSTN and the prevalence of vertebral fractures and bone mineral density (BMD) in Chinese postmenopausal women, an association study was performed. Materials and Methods: 385 [...] Read more.
Purposes: In order to investigate the association between serum periostin levels and the variation of its encoding gene POSTN and the prevalence of vertebral fractures and bone mineral density (BMD) in Chinese postmenopausal women, an association study was performed. Materials and Methods: 385 postmenopausal women were recruited. For participants without a history of vertebral fracture, lateral X-rays of the spine covering the fourth thoracic spine to the fifth lumbar spine were performed to detect any asymptomatic vertebral fractures. Ten tag-single nucleotide polymorphisms (SNP) of POSTN were genotyped. Serum periostin levels, biochemical parameters, and BMD were measured individually. Results: rs9603226 was significantly associated with vertebral fractures. Compared to allele G, the minor allele A carriers of rs9603226 had a 1.722-fold higher prevalence of vertebral fracture (p = 0.037). rs3923854 was significantly associated with the serum periostin level. G/G genotype of rs3923854 had a higher serum periostin level than C/C and C/G (67.26 ± 19.90 ng/mL vs. 54.57 ± 21.44 ng/mL and 54.34 ± 18.23 ng/mL). Furthermore, there was a negative correlation between the serum level of periostin and BMD at trochanter and total hip. Conclusion: Our study suggested that genetic variation of POSTN could be a predicting factor for the risk of vertebral fractures. The serum level of periostin could be a potential biochemical parameter for osteoporosis in Chinese postmenopausal women. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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13 pages, 2043 KiB  
Article
Phenotypic Variation in Vietnamese Osteogenesis Imperfecta Patients Sharing a Recessive P3H1 Pathogenic Variant
by Lidiia Zhytnik, Binh Ho Duy, Marelise Eekhoff, Lisanne Wisse, Gerard Pals, Ene Reimann, Sulev Kõks, Aare Märtson, Alessandra Maugeri, Katre Maasalu and Dimitra Micha
Genes 2022, 13(3), 407; https://doi.org/10.3390/genes13030407 - 24 Feb 2022
Cited by 2 | Viewed by 3321
Abstract
Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic [...] Read more.
Osteogenesis imperfecta (OI) is a syndromic disorder of bone fragility with high variation in its clinical presentation. Equally variable is molecular aetiology; recessive forms are caused by approximately 20 different genes, many of which are directly implicated in collagen type I biosynthesis. Biallelic variants in prolyl 3-hydroxylase 1 (P3H1) are known to cause severe OI by affecting the competence of the prolyl 3-hydroxylation—cartilage associated protein—peptidyl-prolyl cis-trans isomerase B (P3H1-CRTAP-CyPB) complex, which acts on the Pro986 residue of collagen type I α 1 (COL1A1) and Pro707 collagen type I α 2 (COL1A2) chains. The investigation of an OI cohort of 146 patients in Vietnam identified 14 families with P3H1 variants. The c.1170+5G>C variant was found to be very prevalent (12/14) and accounted for 10.3% of the Vietnamese OI cohort. New P3H1 variants were also identified in this population. Interestingly, the c.1170+5G>C variants were found in families with the severe clinical Sillence types 2 and 3 but also the milder types 1 and 4. This is the first time that OI type 1 is reported in patients with P3H1 variants expanding the clinical spectrum. Patients with a homozygous c.1170+5G>C variant shared severe progressively deforming OI type 3: bowed long bones, deformities of ribcage, long phalanges and hands, bluish sclera, brachycephaly, and early intrauterine fractures. Although it remains unclear if the c.1170+5G>C variant constitutes a founder mutation in the Vietnamese population, its prevalence makes it valuable for the molecular diagnosis of OI in patients of the Kinh ethnicity. Our study provides insight into the clinical and genetic variation of P3H1-related OI in the Vietnamese population. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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Review

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11 pages, 917 KiB  
Review
Impact of X-Linked Hypophosphatemia on Muscle Symptoms
by Cecilia Romagnoli, Teresa Iantomasi and Maria Luisa Brandi
Genes 2022, 13(12), 2415; https://doi.org/10.3390/genes13122415 - 19 Dec 2022
Cited by 6 | Viewed by 4609
Abstract
X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. [...] Read more.
X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets and deficiency of renal tubular phosphate transport in humans. XLH is caused by the inactivation of mutations within the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene and follows an X-dominant transmission. It has an estimated frequency of 1 case per 20,000, and over 300 distinct pathogenic variations have been reported that result in an excess of fibroblast growth factor 23 (FGF23) in the serum. Increased levels of FGF23 lead to renal phosphate loss, decreased serum 1,25-dihydroxyvitamin D, and increased metabolism of 1,25-dihydoxyvitamin D, resulting in hypophosphatemia. Major clinical manifestations include rickets, bone deformities, and growth retardation that develop during childhood, and osteomalacia-related fractures or pseudo-fractures, degenerative osteoarthritis, enthesopathy, dental anomalies, and hearing loss during adulthood, which can affect quality of life. In addition, fatigue is also a common symptom in patients with XLH, who experience decreased motion, muscle weakness, and pain, contributing to altered quality of life. The clinical and biomedical characteristics of XLH are extensively defined in bone tissue since skeletal deformations and mineralization defects are the most evident effects of high FGF23 and low serum phosphate levels. However, despite the muscular symptoms that XLH causes, very few reports are available on the effects of FGF23 and phosphate in muscle tissue. Given the close relationship between bones and skeletal muscles, studying the effects of FGF23 and phosphate on muscle could provide additional opportunities to understand the interactions between these two important compartments of the body. By describing the current literature on XLH and skeletal muscle dysfunctions, the purpose of this review is to highlight future areas of research that could contribute to a better understanding of XLH muscular disability and its management. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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15 pages, 14738 KiB  
Review
Spectrum of Skeletal Imaging Features in Osteopetrosis: Inheritance Pattern and Radiological Associations
by Paolo Spinnato, Elena Pedrini, Miriana Rosaria Petrera, Paola Zarantonello, Giovanni Trisolino, Luca Sangiorgi, Maria Carpenzano, Amandine Crombé and Cecilia Tetta
Genes 2022, 13(11), 1965; https://doi.org/10.3390/genes13111965 - 28 Oct 2022
Cited by 6 | Viewed by 5261
Abstract
Osteopetrosis (from the Greek “osteo”: bone; “petrosis”: stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these [...] Read more.
Osteopetrosis (from the Greek “osteo”: bone; “petrosis”: stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these diseases, and the reason for the common term used: “Marble bone disease”. Interestingly, a radiologist, Dr. Albers-Schonberg, described this disease for the first time in Germany in 1904. Indeed, radiology has a key role in the clinical diagnosis of osteopetrosis and is fundamental in assessing the disease severity and complications, as well as in follow-up controls and the evaluation of the response to treatment. Osteopetrosis includes a broad spectrum of genetic mutations with very different clinical symptoms, age onset, and prognosis (from mild to severe). This diversity translates into different imaging patterns related to specific mutations, and different disease severity. The main recognized types of osteopetrosis are the infantile malignant forms with autosomal recessive transmission (ARO—including the rarer X-linked recessive form); the intermediate autosomal recessive form (IAO); and the autosomal dominant ones ADO, type I, and type II, the latter being called ‘Albers-Schonberg’ disease. Imaging features may change among those distinct types with different patterns, severities, skeletal segment involvement, and speeds of progression. There are several classical and well-recognized radiological features related to osteopetrosis: increased bone density (all types with different degrees of severity assuming a ‘Marble Bone Appearance’ especially in the ARO type), different metaphyseal alterations/enlargement including the so-called ‘Erlenmeyer flask deformity’ (particularly of femoral bones, more frequent in ADO type 2, and less frequent in ARO and IAO), ‘bone in bone’ appearance (more frequent in ADO type 2, less frequent in ARO and IAO), and ‘rugger-jersey spine’ appearance (typical of ADO type 2). After conducting an overview of the epidemiological and clinical characteristic of the disease, this review article aims at summarizing the main radiological features found in different forms of osteopetrosis together with their inheritance pattern. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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Other

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7 pages, 238 KiB  
Case Report
Let Time Teach You: A Case Report of a Double Diagnosis of 17P Duplication and Ehlers-Danlos Syndrome
by Paola Castronovo, Sebastiano Aleo, Agostino Seresini, Federico Grilli, Emilio Brunati, Paola Marchisio, Sophie Guez and Donatella Milani
Genes 2022, 13(12), 2197; https://doi.org/10.3390/genes13122197 - 23 Nov 2022
Viewed by 1620
Abstract
Kyphoscoliotic Ehlers–Danlos syndrome and 17p13.3 microduplication share multiple clinical features such as muscle hypotonia, cleft palate, and growth impairment. This paper describes a patient who was first diagnosed with the duplication and a decade later also with FKBP14-kEDS. The latter was initially [...] Read more.
Kyphoscoliotic Ehlers–Danlos syndrome and 17p13.3 microduplication share multiple clinical features such as muscle hypotonia, cleft palate, and growth impairment. This paper describes a patient who was first diagnosed with the duplication and a decade later also with FKBP14-kEDS. The latter was initially overlooked due to the pathogenic significance attributed to the duplication and to the fact that, at the time of the first diagnosis, this specific form of kEDS had yet to be discovered. The patient’s progressive kyphoscoliosis and severe joint laxity were the clinical features that prompted the patient’s physiatrist to reassess the genetic work-up. This extreme latency caused inaccurate management in the patient’s follow-up program, which ultimately may have resulted in preventable clinical complications. This report underlines the importance of remaining up-to-date with patient status, reviewing old cases, and relying on specialist advice to reach a correct diagnosis. Full article
(This article belongs to the Special Issue Genetics and Genomics of Skeletal Disorders)
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