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Rare Diseases Associated with Short Stature: Genetics, Pathogenesis and Therapy
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Rare Diseases Associated with Short Stature: Genetics, Pathogenesis and Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 31 October 2025 | Viewed by 3646

Special Issue Editor

Dr. Michal Ordak

E-Mail Website
Guest Editor
Department of Pharmacotherapy and Pharmaceutical Care, Medical University of Warsaw, St. Banacha 1, 02-097 Warsaw, Poland
Interests: skeletal dysplasias; dwarfism; biomarkers; mutations
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the genetic categorization of skeletal disorders, over 400 unique disease entities have been identified, with many presenting as short stature. The majority of these diseases are rare, with limited knowledge available and the literature often restricted to individual case reports. The insufficient understanding of these rare diseases associated with short stature, along with the limited accessibility of genetic testing, can lead to challenges for physicians when ordering appropriate tests and making accurate diagnoses in infants. Despite short stature being one of the most frequent reasons for consultations with growth specialists, only a small proportion of affected children receive a molecular diagnosis. In the literature, articles on this topic are continually being published, including case reports in which authors describe new genetic mutations and the biomarkers of rare disease entities associated with short stature. The aim of this Special Issue is to provide this group of patients with a comprehensive review so that they are informed of the current state of scientific knowledge.

Dr. Michal Ordak
Guest Editor

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Keywords

  • skeletal disorders
  • dwarfism
  • skeletal dysplasias
  • short stature
  • biomarkers
  • mutations
  • rare disease

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Published Papers (3 papers)

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Research

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16 pages, 961 KiB  
Article
Genetic and Clinical Features of Schimke Immuno-Osseous Dysplasia: Single-Centre Retrospective Study of 21 Unrelated Paediatric Patients over a Period of 20 Years
by Anastasiia Milovanova, Petr Ananin, Tatiana Vashurina, Olga Zrobok, Svetlana Dmitrienko, Alla Ryaposova, Elena Tsygina, Alexander Pushkov, Ilya Zhanin, Daria Chudakova, Aliy Asanov, Olga Shchagina, Aleksander Polyakov, Andrey Fisenko, Kirill Savostyanov and Alexey Tsygin
Int. J. Mol. Sci. 2025, 26(4), 1744; https://doi.org/10.3390/ijms26041744 - 18 Feb 2025
Viewed by 590
Abstract
Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence [...] Read more.
Schimke immuno-osseous dysplasia (SIOD) is a hereditary autosomal-recessive multi-system disorder with early mortality. It has variable clinical presentations, mainly characterised by disproportional short stature, steroid-resistant nephrotic syndrome, spondyloepiphyseal dysplasia, and T-cell immunodeficiency. In the majority of cases, SIOD is caused by pathogenic sequence variants (PSVs) in the SMARCAL1 gene that encodes protein involved in chromatin remodelling. SIOD is an ultra-rare condition, with an incidence of ~1 per 1–3 million live births; data on its genetic and clinical features are scarce. We conducted a retrospective study of 21 paediatric patients with SIOD diagnosed in our centre during the years 2003–2023. The most common extra-renal clinical features were short stature, osseous dysplasia, multiple stigmas, and leukopenia. Proteinuria of varying severity was observed in 16 cases. The five-year overall survival rate (OS) was 89% (95% CI 77–100%), and the ten-year OS was 10%. Next-generation sequencing (NGS) revealed the following PSVs in SMARCAL1 in 19 patients: c.355_500del, c.2542G>T, c.2290C>T, c.2562del, c.2533_2534del, c.1582A>C, c.1933C>T, c.1010T>C, c.1736C>T, c.2070dup, c.2551A>T, c.2149_2150dup, c.939delC, and c.1451T>A; the most common was c.2542G>T, resulting in premature translation termination (p.E848*), and it was found in 14 patients either in a homozygous (four patients) or compound-heterozygous (10 patients) state. According to microsatellite analysis, it is a “founder mutation” in Russia. Full article
(This article belongs to the Special Issue Rare Diseases Associated with Short Stature: Genetics, Pathogenesis and Therapy)
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17 pages, 3404 KiB  
Article
Unraveling the Role of RSPRY1 in TGF-β Pathway Dysregulation: Insights into the Pathogenesis of Spondyloepimetaphyseal Dysplasia
by Gozde Imren, Beren Karaosmanoglu, Bihter Muratoglu, Cansu Ozdemir, Gulen Eda Utine, Pelin Ozlem Simsek-Kiper and Ekim Z. Taskiran
Int. J. Mol. Sci. 2025, 26(3), 1134; https://doi.org/10.3390/ijms26031134 - 28 Jan 2025
Viewed by 939
Abstract
Skeletal dysplasias, characterized by bone, cartilage, and connective tissue abnormalities, often arise due to disruptions in extracellular matrix (ECM) dynamics and growth factor-dependent signaling pathways. RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in bone development, yet its exact [...] Read more.
Skeletal dysplasias, characterized by bone, cartilage, and connective tissue abnormalities, often arise due to disruptions in extracellular matrix (ECM) dynamics and growth factor-dependent signaling pathways. RSPRY1, a secreted protein with RING and SPRY domains, has been implicated in bone development, yet its exact role remains to be determined. RSPRY1 gene mutations are associated with spondyloepimetaphyseal dysplasia (SEMD), a rare skeletal disorder characterized by severe epiphyseal and metaphyseal deformities. This study aimed to determine the molecular and cellular mechanisms by which RSPRY1 deficiency affects skeletal homeostasis. Transcriptome analysis of fibroblasts from patients with homozygous RSPRY1 mutations showed there was significant enrichment of transforming growth factor beta (TGF-β) signaling and ECM-related pathways. Functional wound healing assays showed that RSPRY1 knockout fibroblasts exhibited enhanced motility, a phenotype that was abrogated in RSPRY1 + SMAD3 double knockout fibroblasts, highlighting the SMAD3-dependence of RSPRY1′s effects. The observed limited response to exogenous TGF-β in RSPRY1-deficient cells indicated that there was constitutive pathway activation. These findings show that RSPRY1 is a critical regulator of TGF-β signaling in ECM dynamics and cell motility, contributing to the pathophysiology of SEMD. An improvement in our understanding of the molecular roles of RSPRY1 might yield novel therapeutic strategies that target TGF-β signaling in patients with SEMD and other skeletal dysplasias. Full article
(This article belongs to the Special Issue Rare Diseases Associated with Short Stature: Genetics, Pathogenesis and Therapy)
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Review

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16 pages, 251 KiB  
Review
Clinical and Genetic Insights into Desbuquois Dysplasia: Review of 111 Case Reports
by Hubert Piwar, Michal Ordak and Magdalena Bujalska-Zadrozny
Int. J. Mol. Sci. 2024, 25(17), 9700; https://doi.org/10.3390/ijms25179700 - 7 Sep 2024
Cited by 1 | Viewed by 1491
Abstract
Skeletal disorders encompass a wide array of conditions, many of which are associated with short stature. Among these, Desbuquois dysplasia is a rare but severe condition characterized by profound dwarfism, distinct facial features, joint hypermobility with multiple dislocations, and unique vertebral and metaphyseal [...] Read more.
Skeletal disorders encompass a wide array of conditions, many of which are associated with short stature. Among these, Desbuquois dysplasia is a rare but severe condition characterized by profound dwarfism, distinct facial features, joint hypermobility with multiple dislocations, and unique vertebral and metaphyseal anomalies. Desbuquois dysplasia is inherited in an autosomal recessive manner, with both the DBQD1 (MIM 251450) and DBQD2 (MIM 615777) forms resulting from biallelic mutations. Specifically, DBQD1 is associated with homozygous or compound heterozygous mutations in the CANT1 gene, while DBQD2 can result from mutations in either the CANT1 or XYLT1 genes. This review synthesizes the findings of 111 published case reports, including 54 cases of DBQD1, 39 cases of DBQD2, and 14 cases of the Kim variant (DDKV). Patients in this cohort had a median birth weight of 2505 g, a median length of 40 cm, and a median occipitofrontal circumference of 33 cm. The review highlights the phenotypic variations across Desbuquois dysplasia subtypes, particularly in facial characteristics, joint dislocations, and bone deformities. Genetic analyses revealed a considerable diversity in mutations, with over 35% of cases involving missense mutations, primarily affecting the CANT1 gene. Additionally, approximately 60% of patients had a history of parental consanguinity, indicating a potential genetic predisposition in certain populations. The identified mutations included deletions, insertions, and nucleotide substitutions, many of which resulted in premature stop codons and the production of truncated, likely nonfunctional proteins. These findings underscore the genetic and clinical complexity of Desbuquois dysplasia, highlighting the importance of early diagnosis and the potential for personalized therapeutic approaches. Continued research is essential to uncover the underlying mechanisms of this disorder and improve outcomes for affected individuals through targeted treatments. Full article
(This article belongs to the Special Issue Rare Diseases Associated with Short Stature: Genetics, Pathogenesis and Therapy)
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