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7 September 2024

Clinical and Genetic Insights into Desbuquois Dysplasia: Review of 111 Case Reports

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Department of Pharmacotherapy and Pharmaceutical Care, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1 Str., 02-097 Warsaw, Poland
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Int. J. Mol. Sci.2024, 25(17), 9700;https://doi.org/10.3390/ijms25179700
This article belongs to the Special Issue Rare Diseases Associated with Short Stature: Genetics, Pathogenesis and Therapy
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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 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.

1. Introduction

In the field of the genetic classification of skeletal disorders, over 700 distinct disease entities have been identified, many of which are characterized by short stature. The majority of these disorders are rare, with limited knowledge available, and publications often describe only individual cases. The restricted understanding of these rare conditions that are associated with short stature, coupled with the limited availability of genetic testing, can lead to challenges in ordering appropriate investigations and making accurate diagnoses in infants by physicians. Although short stature is one of the most common reasons for referral to growth specialists, only a small percentage of children with this condition receive a molecular diagnosis [1,2]. One of the rare disorders of this type is Desbuquois syndrome (DBQD). This condition belongs to the group of osteochondrodysplasias and is characterized by severe dwarfism with micromelia, facial dysmorphism, joint hypermobility with multiple dislocations, vertebral and metaphyseal anomalies, and accelerated ossification of the carpal and tarsal bones. Two types of this disorder are distinguished based on the presence (type 1, MIM 251450) or absence (type 2, MIM 615777) of characteristic hand deformities. There is also a variant of DBQD, known as the Kim variant (DDKV), which is characterized by short stature, mild joint anomalies, minor facial deformities, and distinct hand abnormalities. According to the International Nosology of Genetic Skeletal Disorders, DBQD is classified as one of the disorders associated with multiple dislocations. Desbuquois dysplasia type 1 (DBQD1) results from homozygous or compound heterozygous mutations in the calcium-activated nucleotidase 1 (CANT1) gene. CANT1 is an extracellular protein that functions as a tri- and diphosphate nucleotide hydrolase, with the primary role of hydrolyzing uridine diphosphate (UDP), guanosine diphosphate (GDP), uridine triphosphate (UTP), and adenosine diphosphate (ADP). Type 2 results from mutations in the XYLT1 gene on chromosome 16p12. Type 2 can also result from mutations in the CANT1 gene, meaning that the presence or absence of hand anomalies does not definitively determine the molecular cause of the disease. XYLT1 is responsible for the initial step in glycosaminoglycan (GAG) biosynthesis by transferring a xylose residue from UDP-xylose to the serine residues on the core proteins of proteoglycans (PGs), essentially initiating the formation of GAG chains. CANT1, on the other hand, plays a crucial role in maintaining the nucleotide balance necessary for glycosylation processes by hydrolyzing UDP, a byproduct of glycosyltransferase reactions, within the endoplasmic reticulum (ER) and Golgi apparatus. This hydrolysis prevents the accumulation of UDP, which could inhibit glycosyltransferase activity, thereby ensuring the smooth continuation of GAG chain elongation. The dysfunction of CANT1 due to mutations can lead to an impaired ability to remove UDP, which in turn may disrupt the glycosylation process, including GAG elongation and PG maturation. Given that XYLT1 initiates GAG synthesis and CANT1 ensures the continuation of this process by managing nucleotide levels, these two proteins may indeed be functionally linked within the same biosynthetic pathway. Their roles in GAG biosynthesis and PG metabolism suggest that mutations in either gene could lead to similar disruptions in the ECM integrity, particularly in cartilage, which is heavily reliant on GAGs and PGs for its structure and function [3,4]. Since 1966, numerous case reports of patients with DBQD have been published in the literature, but a comprehensive review in this area is lacking. Therefore, the aim of this article is to analyze the published case reports of patients with DBQD, focusing on the clinical symptoms and genetic mutations in this patient group. This review also aims to provide recommendations for future research in this field. International databases, such as Thomson (Web of Knowledge), PubMed/Medline, ScienceDirect, Scopus, and Google Scholar, were searched to find published case reports using the terms “Desbuquois dysplasia,” “DBQD,” or “Desbuquois osteochondrodysplasia” up to the year 2023. The analyzed data included the year of publication, gender, age, height, genetic mutations, radiological parameters, and clinical symptoms. All the symptoms reported by the authors in the published case descriptions were documented.

2. Case Reports

This manuscript reviews 111 published case reports, with the majority (n = 54) in patients diagnosed with DBQD1, followed by DBQD2 (n = 39), and DDKV (n = 14), according to the available data. Based on the available data, the median birth weight was 2505 g, the median birth length was 40 cm, and the median birth OFC (occipitofrontal circumference) was 33 cm (Table 1). Developmental delay or intellectual disability were reported in 20 patients, while motor delay was noted in 15 patients. Among the 81 patients for whom gender was specified, 49 were male and 32 were female.
Table 1. Gender distribution, birth weight, birth length, and birth OFC (cm) in the case reports of patients with Desbuquois syndrome.

3. Clinical Characteristics in Desbuquois Dysplasia

The table below (Table 2) presents a summary of the symptom occurrence by dysplasia type, as well as across all the case reports included in the analysis. In DBQD1, the most frequently observed symptoms include a round/flat face (HP:0000311/HP:0012368), midface retrusion (HP:0011800), proptosis (HP:0000520), a depressed nasal bridge (HP:0005280), micrognathia (HP:0000347), a short neck (HP:0000470), a narrow chest (HP: 0000774), talipes equinovarus (HP:0001762), a broad thumb (HP:0011304), hypotonia (HP:0001252), and clinodactyly (HP:0030084). In DBQD2, compared with DBQD1, a higher percentage of patients exhibit a flat face (HP:0012368), proptosis (HP:0000520), and a cleft palate (HP:0000175). Among patients with DDKV dysplasia, a significantly greater proportion, compared with DBQD1 and DBQD2, present with a round face (HP:0000311), proptosis (HP:0000520), and a depressed nasal bridge (HP:0005280). What distinguishes DDKV dysplasia is the high percentage of patients with hypertelorism (HP:0000316), elongated fingers (HP:0100807), genu varum (HP:0002970), pes planus (HP:0001763), a short hallux (HP:0010109), and a wide sandal gap (HP:0001852).
Table 2. Summary of symptom occurrence by dysplasia type and across all the case reports included in the analysis.
Regarding joint dislocation, a higher percentage of patients with the different types of dysplasia exhibited joint laxity/dislocation (HP:0001382/HP:0001373). Notably, in patients with DDKV dysplasia, there was a higher percentage of dislocations of the knee (HP:0004976) and phalangeal dislocations (HP:0006243). The data presented in the table below also indicate that osteoporosis/osteopenia was observed in a greater percentage of patients with DBQD1 and DBQD2 dysplasia types compared with DDKV. This suggests that the observed osteoporosis in patients with DBQD1 and DBQD2 may have significant clinical implications, as it is well known that this condition can lead to low-trauma fractures. Additionally, nearly all patients were found to have the characteristic prominent lesser trochanter (HP:6000816, often called ‘Swedish key’ or described as a ‘monkey wrench’ appearance). A higher percentage of patients with DDKV dysplasia exhibited an elevated greater trochanter, while this feature was observed in only three patients with DBQD1 dysplasia. A short femoral neck (HP:0100864) was primarily characteristic of patients with DBQD2 dysplasia. Among all the analyzed case reports, nearly 80% showed advanced carpal bone age (HP:0004233). Particularly noteworthy is the accessory ossification of the proximal phalanx, which is typical only in DBQD1 dysplasia. The same applies to the bifid distal phalanx of the thumb (HP:0009611) and triangular epiphysis of the phalanx of the hand (HP:0010238, often called delta phalanx). Over 60% of patients with DDKV dysplasia had phalangeal dislocations, while for the other dysplasia types, these were only sporadically reported. Concerning long bones, a lower percentage of patients with DBQD1 dysplasia exhibited metaphyseal widening (HP:0003016), whereas this feature was more common in the other dysplasia types. The shortening of tubular bones was a typical feature of DBQD2 dysplasia, while premature degenerative spondylosis was characteristic of DDKV dysplasia.

4. Molecular Genetics

Genetic mutation data in the group of patients with Desbuquois dysplasia began to be published in 2009 (Table 3). Among the genetic mutation data available for 65 case reports, over 35% were missense mutations. Nearly 70% of these mutations involved the CANT1 gene. According to the available publication data, parental consanguinity was present in about 60% of patients. Mutations associated with Desbuquois dysplasia exhibit significant diversity, including deletions, insertions, and nucleotide substitutions. These mutations occur in various regions of the genes, including exons (Ex1-Ex10) and introns (In1-In7). Many of these mutations result in the creation of premature stop codons, leading to truncated and likely nonfunctional proteins, such as p.Trp125Ter, p.Tyr178LeufsTer4, and p.Arg598AlafsTer7. Although the identified premature termination codons in Desbuquois dysplasia are likely to lead to nonsense-mediated mRNA decay (NMD), resulting in the absence of truncated protein products, there is currently no direct evidence in the literature that is specific to this disease, confirming whether NMD is the predominant outcome or if any truncated proteins are indeed produced. Frameshift mutations, which drastically alter the protein’s structure and function, are also common. Additionally, substitutions that change single amino acids, such as p.Arg300Cys, p.Arg300His, and p.Val226Met, have been identified, potentially affecting protein conformation and activity. These mutations highlight significant disruptions in the genes that are critical for proper bone development, which is characteristic of Desbuquois dysplasia.
Table 3. Genetic mutation data in patients with Desbuquois dysplasia.

5. Discussion

To the best of our knowledge, this is the first comprehensive review summarizing published case reports of patients with Desbuquois dysplasia. A total of 111 case reports on this condition were included in this review. The analysis of genetic mutations in patients with Desbuquois dysplasia reveals significant variability in both the types of mutations and their locations within the genes. Among the available case reports, missense mutations account for over 35% of all mutations, highlighting their importance in the pathogenesis of this dysplasia. Such mutations, involving the substitution of a single amino acid, can have diverse effects at the protein level, ranging from subtle conformational changes to significant disruptions in protein function. In the context of Desbuquois dysplasia, where proper protein function is crucial for bone development, even minor structural changes can lead to serious clinical consequences.
Mutations in the CANT1 gene play a pivotal role in the pathogenesis of Desbuquois dysplasia, which is also reflected in their significance in various types of cancers, such as lung and kidney cancer. The high frequency of missense mutations in CANT1 in patients with Desbuquois dysplasia suggests that disruptions in this gene’s function may lead to significant alterations in bone development, similar to how they influence cancer progression through signaling pathways, such as NF-κB. Understanding the role of CANT1 in cancers may provide valuable insights for further research into its role in Desbuquois dysplasia, particularly in the context of the tissue microenvironment and cellular response. Although the mechanisms in Desbuquois dysplasia differ from those observed in oncology, the potential of CANT1 as a biomarker suggests that it may also be significant in the diagnosis or prognosis of this condition. Further research is needed to more precisely determine how mutations in CANT1 affect bone tissue development and function in Desbuquois dysplasia. Thus, experience from studies on CANT1 in cancer may serve as a valuable reference point in the context of genetic disorders such as Desbuquois dysplasia [49,50].
A review of the available data from 111 published case reports of patients with Desbuquois dysplasia indicates a predominance of DBQD1 cases, which may suggest a higher prevalence of this form of the disease in the population or a greater ease in diagnosing it compared with DBQD2 and DDKV. The observed developmental delays, including motor and intellectual delays, affecting a significant number of patients, underscore the need for further research on the pathogenesis of these disorders in the context of Desbuquois dysplasia, as well as the necessity for early therapeutic intervention. The analysis of clinical symptoms across different types of Desbuquois dysplasia (DBQD1, DBQD2, DDKV) reveals significant phenotypic differences that have both diagnostic and prognostic implications. These variants differ in the frequency of certain features, suggesting that they may arise from distinct genetic mechanisms or developmental processes. Particularly noteworthy is the variability in bone deformities and joint characteristics, which may impact disease progression and necessitate a more individualized therapeutic approach. In studies on achondroplasia, such as CLARITY, specific risk factors—such as the presence of hydrocephalus requiring shunt placement or the need for cervicomedullary decompression—were found to significantly increase the likelihood of surgical intervention. These findings underscore the importance of identifying individual risk factors when tailoring personalized therapeutic strategies, ensuring that treatment is optimized for each patient’s specific clinical profile [51]. A similar approach can be applied in the treatment of patients with Desbuquois dysplasia, where phenotypic differences, such as the presence of joint dislocations or specific bone deformities, may require adjustments in therapeutic strategies. Current clinical therapies for patients with skeletal dysplasias, including achondroplasia, are predominantly palliative, although enzyme replacement therapies have been introduced for certain conditions in recent years. The success of these therapies is based on an accurate molecular diagnosis and a thorough understanding of the pathogenic pathways that affect bone growth and development. In achondroplasia, a personalized therapeutic approach, grounded in the precise identification of mutations and their associated pathogenic mechanisms, is becoming increasingly feasible due to the advancements in molecular technology [52]. In the case of Desbuquois dysplasia, a similar approach could yield significant benefits. Although targeted therapies for Desbuquois dysplasia are currently lacking, future research should focus on identifying specific biomarkers and understanding the pathogenic pathways involved. Such knowledge could enable the development of personalized treatment methods that are more effective and tailored to the individual needs of patients. Advances in molecular diagnostics and genetic technology offer the potential for an earlier and more accurate diagnosis of Desbuquois dysplasia, which in the future could pave the way for the introduction of gene therapies or other causative treatments. Therefore, in the coming years, it is crucial to conduct research on Desbuquois dysplasia that may contribute to the personalization of medical care and improve treatment outcomes in these patients. The management of patients with Desbuquois dysplasia requires a multidisciplinary approach tailored to the specific clinical manifestations and the severity of the condition. A regular physical therapy program is recommended to address joint laxity and to prevent or delay the onset of early-onset osteoarthritis, which is a common complication. Surgical interventions may be necessary for severe joint dislocations, spinal deformities, or other significant skeletal abnormalities [45,53]. Additionally, careful airway management is crucial, particularly in cases where craniofacial abnormalities complicate tracheal intubation. The use of supraglottic devices, like the CobraPLA, may provide a viable alternative for maintaining a secure airway. However, the success of such devices may vary, and backup plans, including the use of advanced intubation techniques, should be prepared [54].
This review highlights the significant variability in genetic mutations associated with Desbuquois dysplasia and their impact on clinical phenotypes. The predominance of DBQD1 cases in the literature suggests that further studies should investigate whether this reflects a true higher prevalence or whether it is a consequence of diagnostic biases. Additionally, the observation of developmental delays in a significant proportion of patients underscores the importance of early diagnosis and intervention. Future research should focus on several key areas: firstly, further studies are needed to deepen our understanding of the correlation between specific mutations and the clinical manifestations of Desbuquois dysplasia, which could help to refine the diagnostic criteria and improve prognostic predictions. Secondly, investigating the pathogenic pathways involving CANT1 and other relevant genes in Desbuquois dysplasia, particularly in comparison with their roles in other conditions, such as cancers, could uncover new insights into the disease’s underlying mechanisms and identify potential biomarkers for earlier diagnosis or predicting disease progression. Thirdly, given the phenotypic variability observed among patients, there is a need for personalized therapeutic strategies that are tailored to individual clinical profiles. Future research should explore the potential for developing targeted therapies, such as enzyme replacement or gene therapies, based on the molecular and genetic characteristics of each patient. Moreover, conducting longitudinal studies in patients with Desbuquois dysplasia would provide valuable data on disease progression, response to treatment, and long-term outcomes, helping to identify critical periods for intervention that might improve patient outcomes. Finally, the development and implementation of advanced molecular diagnostic techniques could facilitate an earlier and more accurate diagnosis of Desbuquois dysplasia, allowing for early intervention and potentially improving the quality of life and prognosis in affected individuals. While significant progress has been made in understanding Desbuquois dysplasia, ongoing research is essential to translate these findings into improved clinical care. The integration of molecular genetics into clinical practice holds the promise of more effective and individualized treatments for patients with this rare and challenging condition.

Author Contributions

Conceptualization: H.P. and M.O.; Methodology: H.P. and M.O.; Formal Analysis: H.P. and M.O.; Writing—Original Draft Preparation: H.P. and M.O.; Review and Final Approval: H.P., M.O. and M.B.-Z. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were generated.

Conflicts of Interest

The authors declare no conflict of interest.

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