Rare Connective Tissue Disorder Research Articles

Diagnosis and treatment of the Ehlers-Danlos syndromes in China: synopsis of the first guidelines

BackgroundThe Ehlers-Danlos syndromes (EDS) are a group of rare hereditary connective tissue disorders. EDS is clinically and genetically heterogeneous and usually involves multiple systems. There are 14 subtypes of EDS with hallmark features including joint hypermobility, skin hyperextensibility, and tissue fragility. The clinical manifestations and their severity differ among the subtypes, encompassing recurrent joint dislocations, scoliosis, arterial aneurysm and dissection, and organ rupture. Challenges in diagnosis and management arise from the complexity of the disease, which is further complicated by its rarity. The development of clinical guidelines and implementation of coordinated multi-disciplinary team (MDT) approaches have emerged as global priorities.Main bodyChinese Multi-Disciplinary Working Group on the Ehlers-Danlos Syndromes was therefore established. Healthcare professionals were recruited from 25 top hospitals across China. The experts are specialized in 24 fields, including genetics, vascular surgery, dermatology, and orthopedics, as well as nursing care, rehabilitation, psychology, and nutrition. Based on GRADE methodology, the Guidelines were written by the Group supervised by methodologists, following a systemic review of all 4453 articles in PubMed published before August 9, 2023, using the search term “Ehlers Danlos”. A coordinated MDT approach for the diagnosis and management of EDS is highly recommended by the Group, along with 29 specific recommendations addressing key clinical questions. In addition to the treatment plan, the Guidelines also emphasize integrating support from nursing care, rehabilitation, psychology, and nutrition. This integration not only facilitates recovery in hospital settings, but most importantly, the transition from an illness-defined life to a more “normalized” life.ConclusionThe first guidelines on EDS will shorten the diagnostic odyssey and solve the unmet medical needs of the patients. This article is a synopsis of the full guidelines.

Immunogenetics of Systemic Sclerosis

Immunogenetics of Systemic Sclerosis

Journey into the Esophageal Complications: Decoding Systemic Sclerosis with Cutting-Edge Endoscopy, Manometry, and Ambulatory pH-Study.

Systemic Sclerosis (SSc) is a rare connective tissue disorder characterized by autoimmunity, fibrosis, and vasculopathy that affects the skin and internal organs, including the gastrointestinal tract, particularly the esophagus. This article highlights the characteristics and clinical symptoms of esophageal involvement in patients with SSc. This study was conducted between November 2022 to August 2023, including 26 already diagnosed cases of SSc in the Department of Rheumatology and Rehabilitation and Kurdistan Center for Gastroenterology and Hepatology-Sulaymaniyah, Iraq. Esophageal involvement was investigated using esophageal manometry, esophagogastroduodenoscopy (EGD), and 24-hour impedance-pH monitoring. Females were significantly predominant (P = 0.019) regarding the symptoms; 76.9% of the patients had heart burn, 76.9% dysphagia, 73.1% water brush, and 69.2% regurgitation. In total, 69.2% of the patients showed erosive gastrointestinal reflux disease (GERD) on EGD, 76.9% had decreased lower esophageal sphincter pressure (DLESP) and decreased distal esophageal peristaltic contractions (DDEPC) on esophageal manometry, and 84.6% had reflux on pH monitoring. Raynaud's phenomenon is the most common and typically the earliest clinical manifestation of SSc. The presence of erosive GERD was found to significantly increase the risk of developing dysphagia (B = 4.725, P = 0.014, OR = 3.482) and regurgitation (B = 3.521, P = 0.006, OR = 4.030). It is crucial to take gender-specific considerations into account when diagnosing and managing esophageal complications in patients with systemic sclerosis (SSc). Additionally, employing various diagnostic assessments to detect esophageal involvement during SSc is essential. Erosive GERD has been identified as a risk factor that contributes to the development of dysphagia and regurgitation in individuals with SSc.

OA19 Self-reported prevalence and impact of clinical signs, symptoms and events in adults with osteogenesis imperfecta

OA19 Self-reported prevalence and impact of clinical signs, symptoms and events in adults with osteogenesis imperfecta

Extra-Skeletal Manifestations in Osteogenesis Imperfecta Mouse Models.

Osteogenesis imperfecta (OI) is a rare heritable connective tissue disorder of skeletal fragility with an incidence of roughly 1:15,000. Approximately 85% of the pathogenic variants responsible for OI are in the type I collagen genes, COL1A1 and COL1A2, with the remaining pathogenic OI variants spanning at least 20 additional genetic loci that often involve type I collagen post-translational modification, folding, and intracellular transport as well as matrix incorporation and mineralization. In addition to being the most abundant collagen in the body, type I collagen is an important structural and extracellular matrix signaling molecule in multiple organ systems and tissues. Thus, OI disease-causing variants result not only in skeletal fragility, decreased bone mineral density (BMD), kyphoscoliosis, and short stature, but can also result in hearing loss, dentinogenesis imperfecta, blue gray sclera, cardiopulmonary abnormalities, and muscle weakness. The extensive genetic and clinical heterogeneity in OI has necessitated the generation of multiple mouse models, the growing awareness of non-skeletal organ and tissue involvement, and OI being more broadly recognized as a type I collagenopathy.This has driven the investigation of mutation-specific skeletal and extra-skeletal manifestations and broadened the search of potential mechanistic therapeutic strategies. The purpose of this review is to outline several of the extra-skeletal manifestations that have recently been characterized through the use of genetically and phenotypically heterogeneous mouse models of osteogenesis imperfecta, demonstrating the significant potential impact of OI disease-causing variants as a collagenopathy (affecting multiple organ systems and tissues), and its implications to overall health.

Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients.

Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and/or early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Giant aortic aneurysm repair in a child due to arterial tortuosity syndrome.

Arterial tortuosity syndrome is an extremely rare hereditary connective tissue disorder. We present a case of an incidentally diagnosed aneurysm of the aortic root and the ascending aorta caused by arterial tortuosity syndrome, which was confirmed genetically. The aneurysm was repaired surgically. One year after the procedure, there was no further dilation of the aorta or formation of new aneurysms.

Generation of the human induced pluripotent stem cell line (IBKMOLi003-A) from PBMCs of a vascular Ehlers-Danlos syndrome (vEDS) patient carrying the heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene

Ehlers-Danlos syndrome (EDS) belongs to a spectrum of rare heritable connective tissue disorders and is characterised by hyperextensibility, joint hypermobility and tissue fragility. Peripheral blood mononuclear cells (PBMCs) from a vascular EDS (vEDS) patient, known as the rarest EDS subtype, carrying a heterozygous nonsense mutation c.430C > T (p.Q105*) in the COL3A1 gene, which is essential for type III collagen synthesis, were reprogrammed into induced pluripotent stem cells (iPSCs). The generated iPSCs exhibit high expression of pluripotency-associated markers, possess trilineage differentiation capacity and reveal a normal karyotype. This novel patient-specific cell line enables in-depth pathophysiological studies of vEDS.

In silico analysis of mutation spectrum of Ehlers–Danlos, osteogenesis imperfecta, and cutis laxa overlapping phenotypes in Iranian population

BackgroundEhlers–Danlos syndrome (EDS), osteogenesis imperfecta (OI), and cutis laxa (CL) are three rare and heterogeneous connective tissue disorders. Patients with these syndromes have similar manifestations and unpredictable prognosis, making a misdiagnosis highly probable. Some of their subtypes are inherited in autosomal recessive patterns, so they are expected to be prevalent in populations like Iran, where consanguineous marriages are common. In the current work, a cohort of Iranian patients with overlapping phenotypes of the EDS/OI/CL and their mutation spectrum was defined. Based on this, in silico analysis was conducted to anticipate further probable genetic variations. Pathogenicity of EDS, OI, and CL variants in Iranian patients was evaluated using Web servers. A protein interaction network was created by String database and visualized using a Python-based library. The Iranome database was used to predict other genetic mutations in all reported genes of EDS, OI, and CL syndromes.ResultsIn the EDS/OI/CL overlap phenotype, 32 variants in 18 genes have been involved. At least 59% of patients were from families with consanguineous marriages. Interaction analysis showed that COL1A1, COL1A2, CRTAP, LEPRE1, PLOD1, and ADAMTS2 have the most significant impact within the protein network of EDS/OI/CL overlap phenotype. Analyzing the Iranome database revealed 46 variants of EDS, OI, and CL genes potentially disease causing.ConclusionThe overlapping phenotype of EDS, OI, and CL syndromes requires genetic testing (e.g., whole-exome sequencing) to reveal respective variants, which helps to diagnose more accurately and manage the disease more effectively. Particularly in populations with high rates of consanguineous marriages, such as Iran, genetic screening plays a crucial role in premarital and prenatal counseling to prevent the transmission of these rare connective tissue disorders.

Juvenile Systemic Sclerosis Complicated by Interstitial Lung Disease and Myositis: A Case Report

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by fibrosis, vascular alterations, and organ dysfunction. Juvenile systemic sclerosis (jSSc), an infrequent form of the disease, primarily affects children, with an incidence of 0.27 to 1 per million. This report details the case of a 10-year-old male patient diagnosed with jSSc complicated by interstitial lung disease (ILD) and myositis. The patient initially presented with characteristic signs of skin thickening and Raynaud's phenomenon, which later advanced to the emergence of ILD and myositis. The case emphasizes the importance of vigilant screening for ILD in jSSc patients, given the severity and associated increased mortality of the complication, and improves our understanding of the underlying clinical features of this disease. It also calls attention to the challenges of managing the disease effectively and necessitates further research to improve treatment outcomes for such patients.

A Novel Splice Site Mutation in the FBN2 Gene in a Chinese Family with Congenital Contractural Arachnodactyly

AbstractCongenital contractural arachnodactyly (CCA) is a rare connective tissue disorder characterized by arachnodactyly, multiple joint contractures, progressive kyphoscoliosis, pectus deformity and abnormal crumpled ears. FBN2 is the only gene currently known to be associated with CCA. In this study, we report on a prenatal case presented with skeletal, cardiac and spinal malformations. And his father had elongated limbs, contractures of the proximal interphalangeal joints, high myopia and scoliosis. We conducted whole exome sequencing (WES) on the fetus-parental trio and a heterozygous variant (hg19 chr5:127,673,685, c.3598 + 4A &gt; G, NM_001999.4) in intron 27 of the FBN2 gene was successfully identified, inherited from the father. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to evaluate the potential splicing effect of this variant, which confirmed that the variant caused a deletion of exon 27 (126 bp) by disrupting the splice-donor site and destroyed the 17th calcium-binding epidermal growth factor-like (cbEGF) domain. Our research not only finds the etiology of the disease in affected individuals and expands the mutation spectrum of FBN2 gene, but also provides genetic counseling and fertility guidance for this family.

Abstract 13325: Novel Heterozygous EFEMP2 Variant Detected in a Patient With Bilateral Internal Carotid Artery Dissection and Oligodontia

Cutis laxa is a rare connective tissue disorder characterized by sagging or inelastic skin. This phenotype is caused by multiple genotype variants. Biallelic variants in the EFEMP2 gene cause cutis laxa subtype IB characterized by aortic aneurysm, arterial tortuosity, arterial stenosis, joint laxity, arachnodactyly, emphysema, and retrognathia. EFEMP2 encodes fibulin-4, an extracellular matrix protein involved in elastogenesis and modulation of TGF-beta signaling. To date, monoallelic variants in EFEMP2 have not been described as pathogenic. Furthermore, oligodontia has not been associated previously with variants in EFEMP2 . We describe a 67-year-old male with a past medical history of left distal internal carotid artery (ICA) pseudoaneurysm and dissection, right distal ICA dissection, arterial tortuosity, and oligodontia who was found to have a heterozygous variant of uncertain significance in EFEMP2: c.1279_1289del11, p.Arg427CysfsX27. The variant has not been observed previously in large population cohorts and causes a shift in reading frame that substitutes the carboxyl terminal 17 amino acids with 26 alternative amino acids. This carboxyl terminal variant of EFEMP2 has been predicted to interact with PITX2 in yeast two-hybrid analyses. Furthermore, variants in PITX2 have been associated with dental agenesis, including oligodontia. We hypothesize that heterozygous variants in EFEMP2 represent a new syndrome characterized by arteriopathy and dental agenesis.

P22 Will the real scleroderma please stand up?: a case of a rare scleroderma mimic in ED

P22 Will the real scleroderma please stand up?: a case of a rare scleroderma mimic in ED

Surgical Treatment of Cervical Kyphosis and Atlantoaxial Dislocation in a Child With Loeys-Dietz Syndrome: A Case Report and Literature Review.

We report the case of a 3-year-old child with Loeys-Dietz syndrome, a rare genetic connective tissue disorder. The young girl had concurrent cervical kyphosis, atlantoaxial dislocation (AAD), and spinal cord compression. Posterior occipitocervical fusion was performed. Postoperative examination and clinical manifestations confirmed that all pedicle screws were satisfactorily placed, cervical kyphosis and AAD were corrected, and spinal cord compression was relieved. At the 1-year postoperative follow-up, the patient had recovered well, indicating that our operation was successful. To the best of our knowledge, this is the first reported surgical case of cervical kyphosis and AAD caused by Loeys-Dietz syndrome.

Oral Focal Mucinosis of the Tongue: A Rare Localization for a Rare Entity.

Oral focal mucinosis (OFM) is a rare connective tissue disorder that is characterized by the excessive production of hyaluronic acid due to myxoid degeneration of submucosal connective tissue. The disorder typically presents as an asymptomatic nodule or mass in the gingiva or hard palate, and OFM of the tongue is even more unusual. In this report, we present a case of OFM on the tongue in a 72-year-old female patient who presented with a symptomatic lump that had been growing for 6 months on the dorsum of her tongue. The patient reported discomfort and pain while speaking and swallowing, and the lump was visually apparent on examination. OFM is a benign condition that does not have any specific clinical or radiographical features that distinguish it from other more common oral lesions, such as lipoma or fibroma. Therefore, histopathological examination is essential for a definitive diagnosis. The management of OFM typically involves surgical excision of the lesion. In this case, complete surgical removal of the lesion under general anesthesia was performed, and the patient was followed up for 10 months postoperatively. During the follow-up period, there was no evidence of recurrence, and the patient reported significant improvement in her symptoms. In conclusion, OFM is a rare connective tissue disorder that can occur in the oral cavity. Although OFM of the tongue is even rarer, it should be considered in the differential diagnosis of oral lesions. Histopathological examination is essential for definitive diagnosis, and surgical excision is typically the preferred treatment modality.

Health-related quality of life and psychosocial effects of the diagnosis of aortovascular manifestations in Marfan syndrome patients: a qualitative study

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Barts Charity Background Marfan Syndrome (MFS) is a rare autosomal-dominant connective tissue disorder with serious and life-threatening cardiovascular manifestations. Despite the severity of this life-long condition, there is very little evidence on the health-related quality of life (HRQoL) and psychosocial effects of living with MFS and no available evidence on the effect of the aortovascular manifestations. Purpose This study is part of a programme of work aiming to identify the HRQoL and the psychosocial factors affecting MFS patients following the diagnosis of an aortovascular manifestation. Methods This single site qualitative exploratory study was designed to identify quality of life issues affected by the aortovascular diagnosis in MFS from patients’ lived experience. Convenience sampling was employed for this study, with an expected sample size of 20 adult participants who had validated diagnosis of MFS using the revised Ghent criteria[1] and diagnosed with aortovascular manifestations. Interviews, lasting up to 1 hour, were conducted using a semi-structured interview schedule. Each interview was audio-taped and transcribed verbatim. Data saturation assessment was done using the Guest et al.[2] method. Data analysis was undertaken using the Framework method[3], which follows a seven-stage process Results Twenty interviews were undertaken, transcribed and analysed. Participants ranged from 24 to 71 years old (M = 39.6); were 55% male, were primarily Caucasian (n=17, 85%), and 80% completed secondary and post-secondary education. Majority were employed (n=12, 70%) and 40% had greater than average household income. The results identified that patient reported HRQoL and psychosocial factors affecting MFS patients following aortovascular diagnosis include: social and self-stigma, depression, social and health anxiety, loss of personal efficacy, financial burden, loss of self-esteem, worry in building a relationship or family and vital exhaustion. However, patients also expressed that the diagnosis led to disease acceptance, constructive engagement in coping with the condition and self-acceptance. Conclusion These results assist in better understanding the HRQoL and psychosocial factors that affect patients with MFS. This information can support the development of a patient care pathway that includes HRQoL and psychosocial aspects of care to provide a holistic and comprehensive service for this patient group.

Placing joint hypermobility in context: traits, disorders and syndromes.

Joint hypermobility (JHM) is a common physical trait. It may occur alone or in combination with musculoskeletal (MSK) pain, outside or within more complex phenotypes. Hypermobility spectrum disorders (HSD) are diagnosed in individuals with JHM and related MSK pain, when an alternative diagnosis cannot be identified. Conversely, the Ehlers-Danlos syndrome (EDS) encompasses a group of rare hereditary connective tissue disorders featuring JHM along with other pleiotropic manifestations. The 2017 EDS Classification identifies 13 different subtypes. Hypermobile EDS (HEDS) is the only EDS variant still lacking a confirmatory test. Literature was reviewed searching for the most relevant papers related to key arguments. Particular attention was focused on papers published after the 2017 Classification. Definition, epidemiology, assessment tools and patterns of JHM are presented. The morbid nature of the 2017 EDS Classification and of the 'spectrum' is also illustrated. We discuss current limitations and disagreements concerning the 'spectrum', HSD and HEDS. In the clinical context, elucidation of the pathophysiology of pain related to JHM should develop in parallel with the analysis of pleiotropic manifestations of syndromes with JHM. Future challenges concerning classification, nosology, diagnosis and management of JHM, EDS and related disorders are discussed.

ORAL AND DENTAL FINDINGS OF A CHILD WITH WEILL-MARCHESANI SYNDROME TYPE II: A CASE REPORT WITH 3-YEAR FOLLOW-UP

Weill-Marchesani syndrome (WMS, OMIM# 227600) is a genetically determined, rare systemic connective tissue disorder. The syndrome is divided into four types according to mutations in related genes. Given the limited number of individuals with WMS in the literature, no genotype-phenotype correlations for ADAMTS10, ADAMTS17, FBN1, or LTBP2 have been identified. In the accessible literature, none of the limited studies were focused on the oral and dental anomalies of WMS. The present case report describes oral and dental findings of a 63 months old female patients with WMS2.

ORAL CARCINOMA IN A PATIENT WITH SYSTEMIC SCLEROSIS

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by fibrosis, vasculopathy, and inflammation. SSc's disease-related characteristics include skin tightness, puffy fingers, open ulcers, and multi-organ involvement. Studies have also identified a higher risk for the development of malignancy in SSc patients. A 56-year-old woman with SSc presented an asymptomatic white plaque of 20 × 25 mm in the right lower lip. Medical history revealed a previous diagnosis of breast cancer and current diagnosis of colorectal cancer. An incisional biopsy was performed, and histological examination showed architectural and cytological atypia of the full epithelial thickness, consistent with those of a severe, in situ dysplasia/carcinoma. The patient was referred to oncology services. Early localized stage diagnosis of in situ carcinoma of the oral cavity brings more favorable prognosis with better overall management, especially in individuals with SSc who presented systemic overlapping complications. Funding: CAPES. Systemic sclerosis (SSc) is a rare autoimmune connective tissue disorder characterized by fibrosis, vasculopathy, and inflammation. SSc's disease-related characteristics include skin tightness, puffy fingers, open ulcers, and multi-organ involvement. Studies have also identified a higher risk for the development of malignancy in SSc patients. A 56-year-old woman with SSc presented an asymptomatic white plaque of 20 × 25 mm in the right lower lip. Medical history revealed a previous diagnosis of breast cancer and current diagnosis of colorectal cancer. An incisional biopsy was performed, and histological examination showed architectural and cytological atypia of the full epithelial thickness, consistent with those of a severe, in situ dysplasia/carcinoma. The patient was referred to oncology services. Early localized stage diagnosis of in situ carcinoma of the oral cavity brings more favorable prognosis with better overall management, especially in individuals with SSc who presented systemic overlapping complications. Funding: CAPES.

#4852 LATE REFERRAL OF PATIENTS WITH AN UNKNOWN CAUSE OF CHRONIC KIDNEY DISEASE AND MALIGNANT HYPERTENSION

Abstract Introduction Systemic sclerosis (SS) is a rare connective tissue disorder characterized by widespread vascular dysfunction and progressive skin and internal organ fibrosis. Scleroderma renal crisis (SRC) is a life-threatening complication of SS. The estimated incidence of SSc is approximately 20 cases per million per year, and SRC affects about 5-15% of those patients. Case Description A 32-year-old female was admitted to the hospital with dyspnea, edema, HTN, COPD. 4 months before the hospitalization, she had an abrupt onset of HTN (230/120 mm/Hg) and seizures (no abnormal waveforms on EEG). Vital signs: HR 90’, RR 22’, BP 197/121 mmHg, SpO2 90% on room air. PEx: severe jugular venous dilation, crackles in both lungs, 3+ pitting edema bilaterally. The skin appeared abnormal with a modified Rodnan score “9” out of “51” with puffy hands, sclerodactyly, telangiectasia, and Raynaud's phenomena. Lab: creatinine 406 mcmol/L, urea 20.8 mmol/L, T.Ca 2.04 mmol/L, P 1.71 mmol/L, PTH 255.5 pg./mL, Alb 33 g/L, LDH 596 U/L. Urinalysis: UPCR of 4.169 mg/mg creat. microhematuria ANA were positive for centromere pattern with a titer of &amp;gt;400 AU/mL (N &amp;lt;40), CENP-B +++, negative for anti-Scl70, anti-dsDNA, ANCA, Anti-GBM, anti-CCP, RF, anti-Jo1 and anti-Smith antibodies. A kidney biopsy showed acute tubular injury in the early stage, and later stages of interstitial fibrosis and tubular atrophy; chronic active thrombotic microangiopathy (TMA), vascular abnormalities including intimal accumulation of myxoid material, thrombosis, fibrinoid necrosis consistent with Scleroderma Renal Crisis (Fig.3; 4; 5; 6; 7) The patient started treatment with losartan 100mg. 3 months later she started hemodialysis due to diuretic refractory overhydration with severe pulmonary edema resulting in multiple hospital readmissions. Discussion SRC is a dreaded complication of systemic sclerosis that is characterized by new-onset malignant hypertension and progressive acute renal failure, often with associated microangiopathic hemolytic anemia and thrombocytopenia, occurring in ≈ 5–15% of cases, of which 2% occur with the Limited cutaneous systemic sclerosis (lcSS) and 12% in the Diffuse cutaneous systemic sclerosis (dcSS). Histopathologically SRC can be divided into narrowly defined nd-SRC and SSc-associated TMA: nd-SRC is a typical type of SRC, which shows acute renal failure and abrupt onset of moderate-to-significant hypertension. The pathology of nd-SRC shows injured endothelial cells and subsequent intimal thickening in the arcuate and interlobular arteries. The pathology of SSc-TMA shows abnormalities in the capillary wall which eventually leads to microvascular thrombosis. Our case demonstrates severe damage to the kidney, presenting with combined nd-SRC and SSc-TMA, inevitabley leading to irreversible changes resulting in CKD. Notably, until the kidney histopathology workup, neither clinical presentation nor lab tests revealed typical TMA. SRC was at one time almost uniformly fatal, with death often occurring within a few weeks. With the development of ACE-I, survival has improved dramatically, but death rates remain unacceptably high. Unfortunately, some will require chronic dialysis. However, when timely and appropriately managed, renal function can improve considerably, although it may take several months to years, allowing for discontinuation of dialysis. Conclusion SSc should be considered in any patient presenting with malignant hypertension and AKI. SRC can occur in patients without evidence of skin thickening or other manifestations of SSc. Early diagnosis improves outcome. Kidney biopsy should be gold standard in all patients with ``unknown'' causes of the CKD. ACEi remains the cornerstone of the treatment. Renal Transplantation: to discuss after two years after start of dialysis.