Spondyloepiphyseal Dysplasia Research Articles

A case of spondyloepiphyseal dysplasia tarda caused by a novel intragenic deletion of TRAPPC2.

Spondyloepiphyseal dysplasia tarda (SEDT; MIM # 313400) is a rare X-linked recessive skeletal disease characterized by disproportionate short stature with vertebral malformation and degenerative changes involving the spine and major joints (1). During infancy and early childhood, affected males show normal development and unremarkable findings on radiographs (1). Clinical expression of SEDT begins with a flattening of the growth curve before puberty. At this time, radiographs show characteristic deformities of the vertebrae, including platyspondyly with a posterior hump. Degenerative joint disease is a common problem in male patients making hip joint replacement often necessary in the fourth or fifth decade of life (2). The causative gene of SEDT is TRAPPC2, which encodes trafficking protein particle complex subunit 2, a 140 amino acid protein, also known as Sedlin. TRAPPC2 may play a role in vesicular transport from the endoplasmic reticulum to the Golgi (3, 4). To date, 50 TRAPPC2 mutations have been reported in families with SEDT of different ethnic origin (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/ac). The underlying mutations are spread over the entire coding region of the TRAPPC2 gene comprising exons 3-6, without clear genotype-phenotype correlation. Here, we report a Japanese SEDT patient with a novel intragenic deletion mutation in TRAPPC2.

Novel WISP3 mutations causing spondyloepiphyseal dysplasia tarda with progressive arthropathy in two unrelated Chinese families

Spondyloepiphyseal dysplasia tarda with progressive arthropathy (SEDT-PA) is an autosomal recessive skeletal disorder resulting from pathogenic mutations in the Wnt1-inducible signaling pathway protein 3 (WISP3) gene. This disorder predominantly involves the skeletal system, with the leading features of platyspondyly, metaphyseal dysplasia of limbs and extremities, and progressive degeneration of joints. To date, 53 distinct forms of WISP3 mutations have been detected globally, eleven of which originated from Chinese patients. In the current study, we reported the clinical manifestations and radiographic features of two unrelated Chinese SEDT-PA patients. Through genetic analysis, two novel mutations (c.624delA, c.105dupT) as well as one recurrent mutation (c.342T>G) were identified in the WISP3 gene. Our study contributed to the further expansion of the WISP3 mutation spectrum, and demonstrated the genotype-phenotype relationship between mutations in the WISP3 gene and clinical findings of SEDT-PA.

Mechanisms of Aberrant Organization of Growth Plates in Conditional Transgenic Mouse Model of Spondyloepiphyseal Dysplasia Associated with the R992C Substitution in Collagen II

Mutations in collagen II, a main structural protein of cartilage, are associated with various forms of spondyloepiphyseal dysplasia (SED), whose main features include aberrations of linear growth. Here, we analyzed the pathomechanisms responsible for growth alterations in transgenic mice with conditional expression of the R992C collagen II mutation. Specifically, we studied the alterations of the growth plates of mutant mice in which chondrocytes lacked their typical columnar arrangement. Our studies demonstrated that chondrocytes expressing the thermolabile R992C mutant collagen II molecules endured endoplasmic reticulum stress, had atypical polarization, and had reduced proliferation. Moreover, we demonstrated aberrant organization and morphology of primary cilia. Analyses of the extracellular collagenous deposits in mice expressing the R992C mutant collagen II molecules indicated their poor formation and distribution. By contrast, transgenic mice expressing wild-type collagen II and mice in which the expression of the transgene encoding the R992C collagen II was switched off were characterized by normal growth, and the morphology of their growth plates was correct. Our study with the use of a conditional mouse SED model not only indicates a direct relation between the observed aberration of skeletal tissues and the presence of mutant collagen II, but also identifies cellular and matrix elements of the pathomechanism of SED.

Clinical and radiological presentation of a child with progressive pseudorheumatoid dysplasia

The role of WNT pathway in bone formation and maintenance has been extensively studied since the identification of mutations in key signalling WNT mediators in diseases with high or low bone-mass phenotypes. In humans, loss-of-function mutations in WISP3, encoding Wnt1-inducible signaling protein 3, cause progressive pseudorheumatoid dysplasia (PPD), an autosomal recessive form of spondyloepiphyseal dysplasia tarda. Individuals with PPD appear normal at birth, have subtle clinical symptoms by 3 years of age and develop later a severe degenerative joint disease with multiple contractures and reduction in joint mobility. Radiologically patients with PPD have multiple sites of epiphyseal enlargement in addition to platyspondyly.

English

BACKGROUND: Spondyloepiphyseal dysplasia as a sign of untreated congenital hypothyroidism is rare nowadays due to implementation of neonatal screening and increased awareness of pediatricians to detect hypothyroidism earlier. But neonatal screening is not routinely done in the developing countries. Congenital hypothyroidism is still unrecognized in some parts of developing world. OBJECTIVE: To describe the clinical, radiographic features and to stress the importance of screening of hypothyroidism during infancy and childhood and its current management. METHODS: Detailed history, physical examination and investigations. CONCLUSION: This report underscores the importance of detailed family history and physical examination in the diagnosis of spondyloepiphyseal dysplasia due to untreated congenital hypothyroidism, which was not screened for hypothyroidism during neonatal life. Being a treatable cause, hypothyroidism should always be considered as differential diagnosis of spondyloepiphyseal dysplasia, especially if the patient belongs to the developing world.

Occipitocervical Fusion in Skeletal Dysplasia

Retrospective cohort study. This study describes clinical and radiological results of a new cable technique for occipitocervical fusion (OCF) in children with skeletal dysplasia (SD). Anatomical variability and poor bone quality make upper cervical surgery technically challenging in patients with SD. We present a new cable technique for OCF in children with SD when the posterior elements are not of a size or quality for other types of instrumentation. Retrospective review of 24 patients with SD (8 boys, 16 girls) who underwent OCF between 2001 and 2011. In this technique, cables provide compression across a bone graft that is prevented from entering the canal and the graft resists excessive lordosis. Demographic and radiographical data are presented. All patients were followed for initial outcomes of surgery, and 20 patients (83%) were followed for 2 years or more for mid- and long-term outcomes. Mean age at surgery was 6.5 years and mean follow-up was 4.1 ± 2.4 years. This technique was used as a primary procedure in 20 and a revision procedure in 4 patients. Diagnoses included Morquio syndrome (6), spondyloepiphyseal dysplasia (9), spondyloepimetaphyseal dysplasia (5), metatropic dysplasia (3), and Kniest syndrome (1). Ten patients had upper cervical instability and features of cervical myelopathy, and the remaining 14 patients had instability and signal changes on magnetic resonance image. Fusion extended from occiput to C2 in 71% patients, and upper cervical decompression was needed in 92% patients. Postoperatively, all patients were immobilized in a halo vest for mean duration of 12 weeks. Fusion was achieved in all patients. Complications included halo pin-tract infections (7), junctional instability (2), and extension of fusion (4). This new cable technique is a good alternative for OCF in patients with SD who have altered anatomy at the craniocervical junction not amenable to rigid internal fixation. 4.

Complex orthopaedic management of patients with skeletal dysplasias

Skeletal dysplasias are challenging for diagnostics and treatment. We present a series of fifteen patients with different forms of skeletal dysplasias with age ranged from 6 to 17 years with variable clinical presentations managed as a part of the project of scientific cooperation between Turner Paediatric Orthopaedic Institute and Orthopaedic Hospital Vienna-Speising. The spectrum of diagnoses included multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia congenita, diastrophic dysplasia, metaphyseal dysplasia, spondylometaphyseal dysplasia, Stickler syndrome, Kniest dysplasia, and anauxetic dysplasia. Complex treatment, which included axial correction and juxta-articular realignment, was performed as a single-stage, or consecutive surgery. Surgical techniques included corrective osteotomies with internal fixation, guided growth technique and external fixation devices. Best results (full axial correction, normal alignment of the joint) were achieved in 8 patients, including 2 patients with metaphyseal dysplasia, 2 patients with multiple epyphyseal dysplasia, 2 patients with spondyloepyphyseal dysplasia, patient with Stickler syndrome and patient with spondylometaphyseal dysplasia. Good results (partial correction at the present time) were seen in 4 patients (2 patients with Kniest dysplasia, 1 - with multiple epyphyseal dysplasia and 1 - with anauxetic dysplasia). Satisfactory results (non-progressive condition in previous progression) were obtained in 2 patients with diastrophic dysplasia, and poor results (progression of the deformity) - in 1 patient with diastrophic dysplasia. Positive results in most of the cases of our series make promising future for usage of complex approach for orthopedic management of children with skeletal dysplasias; advanced international cooperation is productive and helpful for diagnostics and management of rare diseases.

Advances in bone dysplasias

The prevalence of bone dysplasias is estimated to be one case per 1000 inhabitants, which suggests that, at some point in the career of an orthopedic surgeon, he will face with one of these patients. The aim of this paper is to review the general aspects of bone dysplasias and focus on those, which due to their frequency and importance, we consider most relevant (achondroplasia, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, osteogenesis imperfecta), reviewing their fundamental features and the latest therapeutic advances. There is no cure for these diseases, so early diagnosis and appropriate therapeutic management become the key to improving quality of life of these patients.

Expanding the clinical spectrum of B4GALT7 deficiency: homozygous p.R270C mutation with founder effect causes Larsen of Reunion Island syndrome.

First described as a variant of Larsen syndrome in Reunion Island (LRS) in the southern Indian Ocean, 'Larsen of Reunion Island syndrome' is characterized by dwarfism, hyperlaxity, multiple dislocations and distinctive facial features. It overlaps with Desbuquois dysplasia, Larsen syndrome and spondyloepiphyseal dysplasia with dislocations ascribed to CANT1, FLNB and CHST3 mutations, respectively. We collected the samples of 22 LRS cases. After exclusion of CANT1, FLNB and CHST3 genes, an exome sequencing was performed in two affected second cousins and one unaffected sister. We identified a homozygous missense mutation in B4GALT7, NM_007255.2: c.808C>T p.(Arg270Cys) named p.R270C, in the two affected cases, not present in the unaffected sister. The same homozygous mutation was subsequently identified in the remaining 20 LRS cases. Our findings demonstrate that B4GALT7 is the causative gene for LRS. The identification of a unique homozygous mutation argues in favor of a founder effect. B4GALT7 encodes a galactosyltransferase, required for the initiation of glycoaminoglycan side chain synthesis of proteoglycans. This study expands the phenotypic spectrum of B4GALT7 mutations, initially described as responsible for the progeroid variant of Ehlers-Danlos syndrome. It further supports a common physiopathological basis involving proteoglycan synthesis in skeletal disorders with dislocations.

Novedades en displasias óseas

The prevalence of bone dysplasias is estimated to be one case per 1,000 inhabitants, which suggests that, at some point in the career of an orthopaedic surgeon, he will face with one of these patients. The aim of this paper is to review the general aspects of bone dysplasias and focus on those, which due to their frequency and importance, we consider most relevant (achondroplasia, multiple epiphyseal dysplasia, spondyloepiphyseal dysplasia, osteogenesis imperfecta), reviewing their fundamental features and the latest therapeutic advances. There is no cure for these diseases, so early diagnosis and appropriate therapeutic management, becomes the key to improving quality of life of these patients.

Early prenatal diagnosis for a family affected with X-linked spondyloepiphyseal dysplasia tarda family

X-linked spondyloepiphyseal dysplasia tarda (SEDL) is a rare osteochondrodysplasia caused by mutations of SEDL gene, which usually onset in late childhood without systemic complications. In this study, we have provided prenatal diagnosis for an affected family with a combined strategy including direct sequencing, fetal-sex identification and microsatellite linkage analysis. Two amniotic fluid samples from carrier gravida and 7 blood samples from individuals in this SEDL pedigree were obtained. Genomic DNA was extracted from the samples using standard phenol-chloroform method. SRY and AMEL genes were employed to assess fetal sex. Microsatellite DXS16 was genotyped for linkage analysis. A pathogenic mutation of the SEDL gene was identified by bi-directionally direct sequencing of the third exon as well as its exon/intron boundaries. Two male fetuses were confirmed by fetal-sex assessment. The mutation of the SEDL gene was identified as a nucleotide substitution of the splice acceptor site in intron 2, IVS2-2A>C. DNA sequencing indicated that one fetus is hemizygote carrying the mutation, whilst another is not a carrier. Linkage analysis was identical with the sequencing results. Follow-up also confirmed the result of prenatal diagnosis. Fetal-sex assessment combined with microsatellite linkage analysis and bi-directionally direct sequencing is a more accurate and ready strategy for prenatal diagnosis of families affected with SEDL.

Mutation in the type II collagen gene (COL2AI) as a cause of primary osteoarthritis associated with mild spondyloepiphyseal involvement

ObjectiveTo define the clinical, radiologic and molecular characteristics of a patient with early progressive osteoarthritis and mild spondyloepiphyseal dysplasia. MethodsWe describe an 18-year-old girl with early progressive osteoarthritis and mild spondyloepiphyseal dysplasia. The index case underwent a physical examination, anthropometric measurements and radiologic and laboratory studies. DNA of the patient and her only living parent (mother) was sequenced for the type II collagen gene (COL2A1). ResultsMild scoliosis was noticed in the proband at the age of 13 years. At the same age, she began to have arthralgia in almost all the joints and osteoarthritis progressed fast, necessitating a hip, knee and ankle prosthesis at the age of 18 years. She was eumorphic with no ocular or hearing abnormalities. Molecular testing of the COL2A1 gene revealed a p.Gly204Val mutation. The mutation was absent in the healthy mother. ConclusionThis patient provides further proof that an early osteoarthritic phenotype can be caused by a mutation in the COL2A1 gene.

A novel SMARCAL1 mutation associated with a mild phenotype of Schimke immuno-osseous dysplasia (SIOD)

BackgroundSchimke immuno-osseous dysplasia (SIOD, OMIM #242900) is an autosomal-recessive pleiotropic disorder characterized by spondyloepiphyseal dysplasia, renal dysfunction and T-cell immunodeficiency. SIOD is caused by mutations in the gene SMARCAL1.Case presentationWe report the clinical and genetic diagnosis of a 5-years old girl with SIOD, referred to our Center because of nephrotic-range proteinuria occasionally detected during the follow-up for congenital hypothyroidism. Mutational analysis of SMARCAL1 gene was performed by polymerase chain reaction (PCR) and bidirectional sequencing. Sequence analysis revealed that patient was compound heterozygous for two SMARCAL1 mutations: a novel missense change (p.Arg247Pro) and a well-known nonsense mutation (p.Glu848*).ConclusionThis report provided the clinical and genetic description of a mild phenotype of Schimke immuno-osseous dysplasia associated with nephrotic proteinuria, decreasing after combined therapy with ACE inhibitors and sartans. Our experience highlighted the importance of detailed clinical evaluation, appropriate genetic counseling and molecular testing, to provide timely treatment and more accurate prognosis.

Anesthetic management of Schimke syndrome

To the Editor: Schimke syndrome is a rare autosomal recessive inherited disorder that is characterized by disproportionately short stature, spondyloepiphyseal dysplasia, hyperlordosis, facial dimorphism resembling mucopolysacchariduria, progressive nephropathy, and defective cellular immunity [1, 2]. We report the anesthetic management of a 10-yearold girl with Schimke syndrome undergoing renal transplantation. It is important to perform a detailed preoperative evaluation in patients with Schimke syndrome. Special attention should be given to airway assessment because of syndrome characteristics such as short neck, microcephaly, lordosis, and facial appearance (ESM Fig. 1). As the patient had a short neck, large tongue, and dimorphic face, we prepared all equipment (different-sized laryngeal mask airways, different-sized laryngoscopes and tracheostomy sets) to be available for the management of a difficult pediatric airway. Although we inserted an appropriate oropharyngeal airway, mask ventilation of the patient was difficult even with two hands, probably because of her large tongue and short neck. After injection of a muscle relaxant, we could perform mask ventilation and tracheal intubation. We believe that we were able to use the muscle relaxant safely because we had sugammadex for rescue events. Neurological symptoms in patients with Schimke dysplasia have been described previously as transient ischemic attacks, probably related to vascular stenosis, and ulceration resulting from atherosclerosis and thrombus formation: such stroke episodes can lead to death [3]. Extra care was taken to maintain stable blood pressure during surgery. In conclusion, difficult airway management and special attention to thrombotic events and epileptic seizures are the important issues involved in anesthetic management of this syndrome.

Trs20 is Required for TRAPP III Complex Assembly at the PAS and its Function in Autophagy

The modular TRAPP complex acts as a guanine-nucleotide exchange factor (GEF) for Ypt/Rab GTPases. Whereas TRAPP I and TRAPP II regulate the exocytic pathway, TRAPP III functions in autophagy. The TRAPP subunit Trs20 is not required for assembly of core TRAPP or its Ypt1 GEF activity. Interestingly, mutations in the human functional ortholog of Trs20, Sedlin, cause spondyloepiphyseal dysplasia tarda (SEDT), a cartilage-specific disorder. We have shown that Trs20 is required for TRAPP II assembly and identified a SEDT-linked mutation, Trs20-D46Y, which causes a defect in this process. Here we show that Trs20 is also required for assembly of TRAPP III at the pre-autophagosomal structure (PAS). First, recombinant Trs85, a TRAPP III-specific subunit, associates with TRAPP only in the presence of Trs20, but not Trs20-D46Y mutant protein. Second, a TRAPP complex with Ypt1 GEF activity co-precipitates with Trs85 from wild type, but not trs20ts mutant, cell lysates. Third, live-cell colocalization analysis indicates that Trs85 recruits core TRAPP to the PAS via the linker protein Trs20. Finally, trs20ts mutant cells are defective in selective and non-selective autophagy. Together, our results show that Trs20 plays a role as an adaptor in the assembly of TRAPP II and TRAPP III complexes, and the SEDT-linked mutation causes a defect in both processes.

Mucopolysaccharidosis IVA (Morquio A syndrome) and VI (Maroteaux–Lamy syndrome): under-recognized and challenging to diagnose

ObjectiveMucopolysaccharidosis IVA (MPS IVA, or Morquio A syndrome) and VI (MPS VI, or Maroteaux–Lamy syndrome) are autosomal recessive lysosomal storage disorders. Skeletal abnormalities are common initial presenting symptoms and, when recognized early, may facilitate timely diagnosis and intervention, leading to improved patient outcomes. Patients with slowly progressing disease and nonclassic phenotypes can be particularly challenging to diagnose. The objective was to describe the radiographic features of patients with a delayed diagnosis of MPS IVA or VI.Materials and MethodsThis was a retrospective study. The records of 5 MPS IVA and 3 MPS VI patients with delayed diagnosis were reviewed. Radiographs were evaluated by a radiologist with special expertise in skeletal dysplasias.ResultsAn important common theme in these cases was the appearance of multiple epiphyseal dysplasia (MED) with epiphyseal changes seemingly confined to the capital (proximal) femoral epiphyses. Very few patients had the skeletal features of classical dysostosis multiplex.ConclusionsRadiologists should appreciate the wide phenotypic variability of MPS IVA and VI. The cases presented here illustrate the importance of considering MPS in the differential diagnosis of certain skeletal dysplasias/disorders, including MED, some forms of spondylo-epiphyseal dysplasia (SED), and bilateral Perthes-like disease. It is important to combine radiographic findings with clinical information to facilitate early testing and accurate diagnosis.

Human genetic disorders and knockout mice deficient in glycosaminoglycan.

Glycosaminoglycans (GAGs) are constructed through the stepwise addition of respective monosaccharides by various glycosyltransferases and maturated by epimerases and sulfotransferases. The structural diversity of GAG polysaccharides, including their sulfation patterns and sequential arrangements, is essential for a wide range of biological activities such as cell signaling, cell proliferation, tissue morphogenesis, and interactions with various growth factors. Studies using knockout mice of enzymes responsible for the biosynthesis of the GAG side chains of proteoglycans have revealed their physiological functions. Furthermore, mutations in the human genes encoding glycosyltransferases, sulfotransferases, and related enzymes responsible for the biosynthesis of GAGs cause a number of genetic disorders including chondrodysplasia, spondyloepiphyseal dysplasia, and Ehlers-Danlos syndromes. This review focused on the increasing number of glycobiological studies on knockout mice and genetic diseases caused by disturbances in the biosynthetic enzymes for GAGs.

A novel nonsense mutation in the sedlin gene (SEDL) causes severe spondyloepiphyseal dysplasia tarda in a five-generation Chinese pedigree

Spondyloepiphyseal dysplasia tarda (SEDT) is an X-linked recessive osteochondrodysplasia characterized by disproportionately short stature and degenerative joint disease. The objective of this study was to describe a novel nonsense mutation in the sedlin gene (SEDL) causing severe SEDT in a large Chinese pedigree. The clinical features of all affected individuals and female carriers were presented. Four affected males of the family were diagnosed with SEDT according to their clinical and radiological features. Direct DNA sequencing of SEDL was performed. Reverse-transcription polymerase chain reaction (RT-PCR) experiments of total RNA from blood lymphocytes were performed to confirm the defect in SEDL. DNA sequencing revealed that all of the affected males carried a nonsense mutation (c.61G>T) in SEDL that has not been previously reported. The c.61G>T mutation resulted in a premature translation termination codon (GAG>TAG) at amino acid position 21 (p.E21*), and was predicted to initiate the degradation of mutant transcripts through the nonsense-mediated mRNA decay pathway. Two female carriers showed typical sequencing chromatograms of a heterozygote. Following genetic counseling, individual IV7 gave birth to a healthy baby. Therefore, identification of the novel nonsense mutation (c.61G>T) in the SEDT family enables carrier detection, genetic counseling, and prenatal diagnosis. The detailed genotype/phenotype descriptions contribute to the SEDL mutation spectrum. The continued identification of mutations in SEDT patients will greatly aid further elucidation of the role of the sedlin protein in normal bone growth.

Dental abnormalities and preventive oral care in Schimke immuno-osseous dysplasia

Schimke immuno-osseous dysplasia (SIOD) is a rare, severe, autosomal recessive disorder that results in spondyloepiphyseal dysplasia, renal dysfunction, immunodeficiency, facial dysmorphism and growth failure. Little is known about oral features associated with SIOD. Some of the dental anomalies encountered are specific to SIOD and have only been reported in individuals with SIOD. This paper describes the clinical and radiographic dental manifestations of SIOD in two Caucasian brothers. Both lived to be about 10 years old. After a variety of symptoms were reported, a diagnosis of SIOD was finally made when the brothers were, respectively, 5 and 8 years old. At that time, dental anomalies, such as dyschromia, bulbous crowns, short and thin roots, had not been taken into account to establish the diagnosis. However, knowledge of the dental features characteristic of this disease could have helped make the diagnosis. Although both were caries- and periodontal disease-free, special attention was focused on prevention, including dietary counselling, plaque control, oral hygiene instructions and the use of fluoridated toothpaste. The two patients were followed every 6 months, for over 2 years (until their death), by both a private dentist and a university hospital dentist, which helped them maintain good oral health. Oral hygiene was assessed at each appointment and fissure sealants were placed by the private practitioner on their first permanent molars. This report describes dental anomalies specific to SIOD that could facilitate diagnosis. Clinicians and dentists should work in collaboration to diagnose and treat children with SIOD. These patients require regular and specific dental management because of their fragile health and their characteristic dental anomalies. Ideally, preventive visits should be scheduled every 6 months in addition to curative visits as needed.

Novel SMARCAL1 Bi-allelic Mutations Associated with a Chromosomal Breakage Phenotype in a Severe SIOD Patient

Chromosomal instability syndromes include a group of rare diseases characterized by defective DNA-damage-response and increased risk of chromosomal breakage. Patients display defects in the recognition and/or repair of DNA damage, with a subsequent high rate of malignancies and abnormal gene rearrangements. Other clinical manifestations, such as immunodeficiency, neurodevelopmental delay and skeletal abnormalities, are present in some of these syndromes. We studied a patient with profound T-lymphocyte defect, neurodevelopmental delay, facial dysmorphism, nephrotic syndrome and spondyloepiphyseal bone dysplasia typical of SIOD. Karyotype and chromosome fragility assays on patients' peripheral blood mononuclear cells showed an abnormal rate of spontaneous breaks. Cell cycle analysis of patient's fibroblasts following replication stress induced by hydroxyhurea revealed a delay in their release from S-phase to G2. When using higher concentrations of hydroxyhurea no patient fibroblast colonies could survive, compared with control fibroblasts. Whole-exome sequencing revealed novel compound heterozygote mutations in SMARCAL1 gene, resulting in putative frame shifts of encoded SMARCAL1 from each allele and no detected protein in patient's cells. The patient's youngest brother was found to have similar manifestations of SIOD but of less severity, including short stature, facial dysmorphism and typical osseous dysplasia, but no clinical findings suggestive of immunodeficiency and no chromosomal fragility. Similar to his sister, the brother carries both bi-allelic mutations in SMARCAL1 gene. We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. Our results are consistent with the recently outlined role of SMARCAL1 protein in DNA damage response.