Diastrophic dysplasia (DTD) is caused by biallelic pathogenic variants in the SLC26A2 gene. We report the case of a 49-year-old female with DTD and esophageal stenosis. This broadens the phenotypic spectrum in adult patients with DTD and raises awareness of extra-skeletal manifestations that could develop in later stages of life.

Diastrophic dysplasia (DTD) is a recessive chondrodysplasia caused by pathogenic variants in the SLC26A2 gene encoding for a cell membrane sulfate/chloride antiporter crucial for sulfate uptake and glycosaminoglycan (GAG) sulfation. Research on a DTD animal model has suggested possible pharmacological treatment approaches. In view of future clinical trials, the identification of non-invasive biomarkers is crucial to assess the efficacy of treatments. Urinary GAG composition has been analyzed in several metabolic disorders including mucopolysaccharidoses. Moreover, the N-terminal fragment of collagen X, known as collagen X marker (CXM), is considered a real-time marker of endochondral ossification and growth velocity and was studied in individuals with achondroplasia and osteogenesis imperfecta. In this work, urinary GAG sulfation and blood CXM levels were investigated as potential biomarkers for individuals affected by DTD. Chondroitin sulfate disaccharide analysis was performed on GAGs isolated from urine by HPLC after GAG digestion with chondroitinase ABC and ACII, while CXM was assessed in dried blood spots. Results from DTD patients were compared with an age-matched control population. Undersulfation of urinary GAGs was observed in DTD patients with some relationship to the clinical severity and underlying SLC26A2 variants. Lower than normal CXM levels were observed in most patients, even if the marker did not show a clear pattern in our small patient cohort because CXM values are highly dependent on age, gender and growth velocity. In summary, both non-invasive biomarkers are promising assays targeting various aspects of the disorder including overall metabolism of sulfated GAGs and endochondral ossification.

Diastrophic dysplasia (DTD) is an uncommon pathology which falls under the group of skeletal dysplasias with its first symptoms observed from birth. The pathology is often featured by short stature and abnormally short extremities (also known as short-limbed dwarfism); the osseous structures of the body (bones and joints) are characterized through defective development in many body regions. More than 300 genes were reported to be involved in DTD etiology with autosomal recessive, autosomal dominant and X-linked manner. We describe clinical case of a 42-year-old woman from the west of Ukraine with diastrophic dysplasia and two pathogenic variants c.1020_1022del (p.Val341del) and c.1957T>A (p.Cys653Ser) identified in SLC26A2 gene. SLC26A2-related diastrophic dysplasia was confirmed based on the presence of pathogenic variants in SLC26A2, which is associated with autosomal recessive forms of skeletal dysplasia, combined with phenotypic symptoms and radiographic findings.

UNASSIGNED: Pathogenic variants in the SLC26A2/DTDST gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of SLC26A2/DTDST-related disorders.
UNASSIGNED: The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS). We reviewed data from the literature regarding phenotype, zygosity, and genotype in parallel.
UNASSIGNED: The local cohort enrolled 12 patients, including one with a Desbuquois-like phenotype. All but one showed biallelic mutations, however, only one allele mutated in a fetus presenting ACG1B was identified. The literature review identified 42 articles and the analyses of genotype and zygosity included the 12 local patients.
UNASSIGNED: The R279W variant was the most prevalent among the local patients. It was in homozygosity (hmz) in 2 patients with rMED and in compound heterozygosity (chtz) in 9 patients. The genotype and zygosity review of all patients led to the following conclusions: DTD is the most common phenotype in Finland due to a Finnish mutation (c.727-1G>C). Outside of Finland, rMED is the most prevalent phenotype, usually associated with R279W in hmz. In contrast, DTD\'s genotype is usually in chtz. Despite a large number of variants (38), just 8 are recurrent (R279W, C653S, c.-26+2T>C, R178*, K575Sfs*10, V340del, G663R, T512K). The last 3 in hmz lead to lethal phenotypes. The Finnish mutation is found only in chtz outside of Finland, being associated with all 4 classical phenotypes. The p.R178* and p.K575Sfs*10 variants should be viewed as lethal mutations since both were mainly described with lethal phenotypes and were never reported in hmz. The existence of 9 patients with only one mutated allele suggests that other mutations in the other allele of these patients still need to be unveiled.

UNASSIGNED: Diastrophic dysplasia (DTD) results from SCN26A2 gene mutation, with autosomal recessive inheritance and widely variable phenotype. The gene has been mapped to chromosome 5q32-q33.1.
UNASSIGNED: We present a case of a 4-year-old female with short stature, bilateral feet and knee deformity, and dysplastic facies. SCN26A2 mutations were seen in patient as well as parents. She underwent multiple orthopedic procedures involving metatarsals, gastrosoleus, and distal femur. Based on typical clinical features, DTD was suspected. Genetic studies of patient and parents provided the exact diagnosis in this case.
UNASSIGNED: Genetic diagnosis and family counseling are important caveat of management. Key features like ear abnormalities help to suspect diagnosis which requires a high index of suspicion. Associated bony and soft-tissue abnormalities of lower limb may require surgical intervention for improvement of gait, functions, and cosmesis.

Diastrophic dysplasia (DTD) is a rare osteochondrodysplasia characterized by short-limbed short stature and joint dysplasia. DTD is caused by mutations in SLC26A2 and is particularly common in the Finnish population. However, the disease incidence in Finland and clinical features in affected individuals have not been recently explored. This registry-based study aimed to investigate the current incidence of DTD in Finland, characterize the national cohort of pediatric subjects with DTD and review the disease-related literature. Subjects with SLC26A2-related skeletal dysplasia, born between 2000 and 2020, were identified from the Skeletal dysplasia registry and from hospital patient registry and their clinical and molecular data were reviewed. Fourteen subjects were identified. Twelve of them were phenotypically classified as DTD and two, as recessive multiple epiphyseal dysplasia (rMED). From the subjects with available genetic data, 75% (9/12) were homozygous for the Finnish founder mutation c.-26+2T>C. Two subjects with rMED phenotype were compound heterozygous for p.Arg279Trp and p.Thr512Lys variants. The variable phenotypes in our cohort highlight the wide spectrum of clinical features, ranging from a very severe form of DTD to milder forms of DTD and rMED. The incidence of DTD in Finland has significantly decreased over the past decades, most likely due to increased prenatal diagnostics.

Cervical kyphosis in diastrophic dysplasia (DTD) is a very dangerous deformity which may lead to compression of neural structures resulting in tetraplegia or even. Treatment of this deformity is usually surgical, but no long-term follow-up studies are presented in the literature. Authors present a case of two children with DTD who underwent anterior corpectomy due to severe cervical kyphosis. The kyphotic deformity was corrected and the normal spinal canal width was restored. The effects of the correction remained stable for respectively 6 and 10 years of the follow-up period. The unique follow-up confirms that this type of intervention leads to an effective and long lasting results. Significant cervical kyphosis in patients suffering from DTD may be treated surgically using anterior approach even in young children with a favorable and lasting results.

OBJECTIVE: Accurate understanding of the cause of the underlying pathology in children with diastrophic dysplasia would help in designing targeted management of their locomotion.
METHODS: Diastrophic dysplasia was diagnosed in twelve patients (nine girls and three boys; age range 1-14 years), all of whom presented with small stature and apparent short extremities. Club foot (mostly talipes equinovarus) was the most frequent and consistent abnormality. Concomitant abnormalities such as hip flexion contracture, flexion contractures of the knees with excessive valgus deformity and lateral patellar subluxation, were also encountered. Muscle ultrasound and muscle magnetic resonance imaging imaging showed no myopathic changes and muscle biopsies and the respiratory chain were normal. Serum choline kinase and plasma lactate concentrations were normal.
RESULTS: Surgical correction of the foot and ankle in patients with diastrophic dysplasia is extremely difficult because of the markedly distorted anatomy. In all of these children, plantigrade foot was achieved along with the improved function of the locomotor system. Mutations of the diastrophic dysplasia sulfate transporter (also known as solute carrier family 26 member 2) were encountered.
CONCLUSIONS: Arthrogryposis multiplex is the usual terminology used to describe the abnormality in infants with multiple contractures. Diligent orthopaedic care should be provided based on an accurate understanding of the associated syndromes in such children.

Diastrophic dysplasia (DTD) is an autosomal recessive skeletal dysplasia caused by SLC26A2 mutations. Clinical features include short stature, joint contractures, spinal deformities, and cleft palate. SLC26A2 mutations also result in other skeletal dysplasias, including the milder recessive multiple epiphyseal dysplasia (rMED). DTD is overrepresented in Finland and we speculated that this may have influenced the prevalence and spectrum of SLC26A2-related skeletal conditions also in Sweden. We reviewed the patient registry at Department of Clinical Genetics, Karolinska University Hospital, Stockholm to identify subjects with SLC26A2 mutations. Seven patients from six families were identified; clinical data were available for six patients. All but one patient had one or two copies of the Finnish SLC26A2 founder mutation IVS1+2T>C. Arg279Trp mutation was present in compound heterozygous form in five patients with phenotypes consistent with rMED. Their heights ranged from -2.6 to -1.4 standard deviation units below normal mean and radiographic features included generalised epiphyseal dysplasia and double-layered patellae. Two rMED patients had hypoplastic C2 and cervical kyphosis, a severe manifestation previously described only in DTD. Our study confirms a high prevalence of rMED in Sweden and expands the phenotypic manifestations of rMED.

Mutations in solute carrier family 26 (sulfate transporter), member 2 (SLC26A2) gene result in a spectrum of autosomal recessive chondrodysplasias that range from the mildest recessive form of multiple epiphysial dysplasia (rMED) through the most common diastrophic dysplasia (DTD) to lethal atelosteogenesis type II and achondrogenesis IB. The clinical variability has been ascribed to quantitative effect of mutations of the sulfate transporter activity. Here we describe two Brazilian sisters, born to healthy and non consanguineous parents, with Robin sequence, mild shortening of upper and lower limbs, brachymetacarpalia/tarsalia, additional and accelerated carpal ossification, marked genu valgum, and multiple epiphysial dysplasia. This phenotype was intermediate between DTD and rMED, and both girls have a compound heterozygous mutations for the SLC26A2, a Finnish founder mutation (c.-26 + 2T>C), and R279W. This combination of mutations has been observed in individuals with different phenotypes, including DTD, DTD variant, and rMED. The distinct phenotype of our cases reinforces the hypothesis that other factors may be influencing the phenotype as previously suggested.