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Haematological manifestations of arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: A case report
Abstract
Arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC) syndrome is a rare, fatal, multisystem disorder. Bleeding problems, which occur spontaneously and post organ biopsies, have been reported in these patients. We report the case of an infant who had life-threatening spontaneous nasal bleeding. A detailed assessment of her platelet function and morphology is presented.
... It is not known if Arnold Chiari malformation is a component of ARC syndrome or a coincidence because there was no published data to be found in the medical literature. Tendency to spontaneous bleeding is reported in these patients and it is considered that Grey Platelet syndrome and a dysfunction of alpha granules are the causes of these bleeding episodes (4,8). In a case report, spontaneous nasal bleeding could be stopped only by the delivery of a platelet suspension (8). ...
... Tendency to spontaneous bleeding is reported in these patients and it is considered that Grey Platelet syndrome and a dysfunction of alpha granules are the causes of these bleeding episodes (4,8). In a case report, spontaneous nasal bleeding could be stopped only by the delivery of a platelet suspension (8). Our patient had several prolonged oral mucosal bleeding episodes despite normal coagulation tests. ...
... Akbar et al. (9) have shown that the VPS33B gene is involved in phagosome and endosome maturation and is responsible for the recognition of microorganisms. Staphylococcus species, Escherichia coli and Pseudomonas aeruginosa were shown as causative agents (8,9). Episodes of suppurative otitis media caused by Pseudomonas aeruginosa were observed in our patient. ...
Arthrogryposis, renal tubular dysfunction and cholestasis (ARC) syndrome is a rare, autosomal recessive multisystem disorder. Severe growth retardation, ichthyosis, recurrent febrile disease, platelet abnormalities, sensorineural hearing loss, hypotonia and corpus callosum dysgenesis were later included as further features of this syndrome. We present a case of ARC syndrome diagnosed by genetic analysis.
... This mutation has been shown to result in a truncated protein that may maintain some residual wild type function due to the formation of VPS33B-VIPAR complex-containing clusters(3). Table II) (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). There is a wide range of platelet abnormalities in patients with ARC syndrome. ...
... However, 9 out of these 11 patients with severe bleeding had a normal platelet count and morphology (2). Platelet function testing in these patients may be informative as those in whom aggregation or PFA-100 testing was performed had demonstrated abnormal responses (2,9,11,15). Findings on platelet aggregation in these patients has been variable. ...
... Findings on platelet aggregation in these patients has been variable. Our patient demonstrated decreased aggregation to all agonists except ristocetin, while others have found abnormal responses to ADP and collagen (9,15), and decreased aggregation to arachidonic acid, epinephrine and ADP (11). One note of caution is that ARC syndrome diagnoses in some studies were solely by the evaluation of peripheral blood smears. ...
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare disorder associated with platelet abnormalities resembling gray platelet syndrome. Affected patients have normal platelet numbers but abnormal morphology and function. Bleeding symptomatology ranges from postprocedural to spontaneous life-threatening hemorrhage. We report a patient with ARC syndrome and compound heterozygous mutations in VPS33B (vacuolar protein sorting 33B) who presented with significant bleeding requiring numerous admissions and transfusions. She was treated with prophylactic platelet transfusions and ε-aminocaproic acid. This was well-tolerated and significantly decreased transfusion requirements and admissions for bleeding. Our experience provides support for consideration of prophylactic measures in these patients as well as the possibility of using prophylaxis in related disorders.
... 7 Platelet morphology is abnormal in ARC syndrome with large, agranular, and pale-appearing platelets seen in grey platelet syndrome. 8 Our case had large, agranular, pale-appearing platelets on review of peripheral blood smear and had abnormal responses to epinephrine and ADP, but normal responses to collagen and ristocetin in platelet aggregation studies, as Saadah et al. reported. 8 Organ biopsy can be dangerous because of the risk of severe bleeding in an ARC suspected patient. ...
... 8 Our case had large, agranular, pale-appearing platelets on review of peripheral blood smear and had abnormal responses to epinephrine and ADP, but normal responses to collagen and ristocetin in platelet aggregation studies, as Saadah et al. reported. 8 Organ biopsy can be dangerous because of the risk of severe bleeding in an ARC suspected patient. Mutation analysis should be preferred for diagnosis. ...
Mutlu M, Aslan Y, Aktürk-Acar F, Çakır M, Erduran E, Kalyoncu M. ARC syndrome. Turk J Pediatr 2017; 59: 487-490. Arthrogryposis-renal dysfunction-cholestasis (ARC) is an autosomal recessive multisystem disorder characterized by arthrogryposis, renal tubular dysfunction and neonatal cholestasis with low gamma glutamyl transpeptidase activity. Most of the mutations in ARC syndrome are associated with the vacuolar protein sorting 33B (VPS33B) gene on chromosome 15q26.1. Herein, we report a female newborn with ARC syndrome caused by homozygous mutations in VPS33B [IVS1-2A > C (c.97-2A > C)].
... Bleeding problems have also been observed in this syndrome secondary to abnormal platelet's morphology and function. Few reports on ARC syndrome have described abnormal platelets [2,[4][5][6]. We report two new cases of ACR syndrome who presented documented abnormality of platelet's morphology and function. ...
... 1. Most of the reported cases of ACR syndrome in the literature were in Pakistani infants, rarely in Saudi Arabia, Turkey, Oman, North Africa , Italy , Asia and Portugal [5] ; suggesting that the occurrence of this condition is common in communities where the rate of consanguineous marriage is very high. Our patients were born to consanguineous parents and have a charged family's history of similar cases. ...
... Lysosome-associated neurodegeneration is induced by a combination of mechanisms, most importantly, the accumulation of undegraded material (Jiang et al., 2014) and dysregulated signaling (Peng et al., 2012a). These events cause cellular stress and ultimately lead to apoptosis, which is especially damaging in neuronal tissues since these post-mitotic cells have little Arhan et al., 2009;Bull et al., 2006;Cullinane et al., 2009;Cullinane et al., 2010;Elmeery et al., 2013;Giraud et al., 2017;Gissen et al., 2004;Gissen et al., 2006;Hershkovitz et al., 2008;Huang et al., 2017;Ilhan et al., 2016;Jang et al., 2009;Kim et al., 2011;Li et al., 2014;Moon et al., 2017;Saadah et al., 2013;Sanseverino et al., 2006;Seo et al., 2015;Taha et al., 2007;Tornieri et al., 2013;Wang et al., 2014;Weyand et al., 2016;Zhou and Zhang, 2014 regenerative capacity. Mutations in CHEVI or HOPS components commonly cause neurological defects in the C. elegans, D. melanogaster, zebrafish and mice animal models (Fernandes et al., 2014;Harrington et al., 2012;Kim et al., 2004;Peng et al., 2012b;Suzuki et al., 2003;Zhang et al., 2016). ...
Multisubunit tethering complexes (MTCs) are multitasking hubs that form a link between membrane fusion, organelle motility and signaling. CORVET, CHEVI and HOPS are MTCs of the endo-lysosomal system. They regulate the major membrane flows required for endocytosis, lysosome biogenesis, autophagy and phagocytosis. In addition, individual subunits control complex-independent transport of specific cargoes and exert functions beyond tethering, such as attachment to microtubules and SNARE activation. Mutations in CHEVI subunits lead to arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome, while defects in CORVET and, particularly, HOPS are associated with neurodegeneration, pigmentation disorders, liver malfunction and various forms of cancer. Diseases and phenotypes, however, vary per affected subunit and a concise overview of MTC protein function and associated human pathologies is currently lacking. Here, we provide an integrated overview on the cellular functions and pathological defects associated with CORVET, CHEVI or HOPS proteins, both with regard to their complexes and as individual subunits. The combination of these data provides novel insights into how mutations in endo-lysosomal proteins lead to human pathologies.
... 位氨基酸构成，可与 SNAREs 紧密结合，参与囊 泡与细胞器及细胞膜之间的锚定 [10][11]13,[17][18] [10,19] 。而 ARC 综合征患儿， 由于囊泡功能不全，胆汁分泌受阻，低浓度的胆 汁酸盐对 GGT 的洗脱作用微弱，故患儿血浆 GGT 水平可正常 [19][20] 。虽有文献 [5] 报道 ARC 综合征的 患儿可能存在高 GGT 水平，但目前认为，正常水 平 GGT 可作为诊断 ARC 综合征的 4 个临床特点之 一(关节挛缩、肾小管功能不全、胆汁淤积及正 常水平 GGT) [15,21] 。 ARC 综合征作为一种预后不良的常染色体隐 性遗传病，绝大部分患儿因严重营养不良、反复感 染、严重酸中毒、肝衰竭及凝血异常而死亡 [15,[22][23] 。 本文患儿诊治结局不良，符合这一特点。本病内 科治疗效果虽有限，但熊去氧胆酸、还原型谷胱 甘肽及利福平等可能轻微缓解胆汁淤积及瘙痒症 状 [11] 。针对部分患者的关节挛缩、髋关节脱位等 畸形，手术矫正可恢复部分关节功能 [24] ；但由于 ARC 综合征患儿免疫功能差及远期生存率低，除 非严重病理性骨折或感染，不建议积极骨科手术 治疗 [25] 。Dehghani 等 [26] ...
Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is an autosomal recessive disorder caused by mutations in the VPS33B or VIPAS39 gene. The aim of this study was to investigate the clinical features and VPS33B gene mutations of an infant with ARC syndrome. A 47-day-old female infant was referred to the hospital with the complaint of jaundiced skin and sclera for 45 days and abnormal liver function for 39 days. The patient had been managed in different hospitals, but the therapeutic effects were unsatisfactory due to undetermined diagnosis. Physical examination showed jaundice of the skin and sclera. Systemic skin was dry with desquamation in the limbs and trunk. There were no positive signs on cardiopulmonary examination. The liver was palpable 2.0 cm under the right subcostal margin. The hips and knees were flexed, and the extension was limited, with low muscular tone in the four limbs. Biochemical analysis demonstrated raised serum total bile acids, bilirubin (predominantly conjugated bilirubin) and transaminases, but the γ-glutamyl transpeptidase level was normal. Routine urine test revealed increased glucose as well as red and white blood cells. On genetic analysis, the infant was proved to be homologous for a VPS33B mutation c.1594C>T(p.R532X). She was definitely diagnosed to have ARC syndrome. Symptomatic and supportive therapy was given, but no improvement was observed, and the infant finally died at 3 months and 29 days of life.
... La thrombopathie associée est liée à un déficit en contenu des granules alpha plaquettaires qui rend compte de la coloration anormale des plaquettes souvent de grande taille et dépourvues de granulations azurophiles, comme bien illustré dans cette observation. Ce déficit peut être responsable d'accidents hémorragiques sévères révélés au décours d'une biopsie et liés à des troubles de l'agrégation plaquettaire [17]. L'enfant présenté ici ne présentait pas de saignement spontané et les parents ont refusé la réalisation de prélèvements sanguins pour explorer l'hémostase. ...
ARC syndrome (arthrogryposis - renal dysfunction - cholestasis) is a rare lethal multisystemic autosomal recessive disease. A newborn of consanguineous parents of Algerian descent presented cholestatic jaundice, dehydration, and Fanconi syndrome at 10 days of life. The blood smear showed a very characteristic gray appearance of platelets. A homozygous mutation was evidenced in the VPS33B gene. This gene codes for a protein involved in trafficking of intracellular vesicles. The mutation (c.604-2A>G) present in the heterozygous state in the parents affects an invariant base of the splice acceptor site and to our knowledge has not been reported yet. This child died at the age of 3 months. Prenatal diagnosis was offered to the family; another pregnancy was carried to completion and a girl was born without the disease. The combination of cholestasis and proximal tubulopathy should suggest the diagnosis in a newborn with orthopedic problems. A blood smear greatly facilitates diagnosis.
Copyright © 2016 Elsevier Masson SAS. All rights reserved.
... Additional features like ichthyosis in half of patients is faulty differentiation of epidermis because of lack of absorption of free fatty acids [8]. Large, pale and agranular platelets are seen in about a fourth of ARC syndrome patients, can be associated with absent or abnormal alpha granules on electron microscopy [9]. Other features are agenesis of corpus callosum (20%), congenital heart diseases (10%), sensory neural deafness, spontaneous life threatening bleeding and hypothyroidism [2,10]. ...
... Self-limiting intraabdominal hemorrhage often occurs in patients with ARC, in the absence of abnormal platelet morphology; therefore, normal routine platelet analysis cannot assess the risk of bleeding in ARC syndrome [9]. Despite the increased number of β-granules, similar to Grey platelet syndrome, platelets from patients with ARC syndrome develop abnormal biosynthesis and function of α-granules, which are essential for platelet aggregation, thrombogenesis, inflammation, and tumorigenesis [26,27]. Studies have demonstrated that a VPS33B-VPS16B complex participates in α-granule formation, since this complex was tracked with transport vesicles destined toward the development of mature α-granules [28,29]. ...
Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare but fatal autosomal recessive multisystem disorder caused by mutations in the VPS33B or VIPAR gene. The classical presentation of ARC includes congenital joint contractures, renal tubular dysfunction, and cholestasis. Additional features include ichthyosis, central nervous system malformation, platelet anomalies, and severe failure to thrive. Diagnosis of ARC syndrome relies on clinical features, organ biopsy, and mutational analysis. However, no specific treatment currently exists for this syndrome.Conclusion
This is an overview of the latest knowledge regarding the genetic features and clinical manifestations of ARC syndrome. Greater awareness and understanding of this syndrome should allow more timely intervention with potential for improving long-term outcome.
Inherited platelet defects lead to bleeding symptoms of varying severity. Typically, easy bruising, petechiae, epistaxis, and mucocutaneous bleeding are observed in affected patients. The platelet defects are classified into disorders affecting either platelet surface receptors or intracellular organelles of platelets. The latter are represented by platelet storage pool diseases (SPD) which share a defect of platelet granules. Platelet α-granules, δ-granules, or both may be affected resulting in the clinical picture of α-SPD (e.g. Gray platelet syndrome, Quebec platelet disorder, arthrogryposis, renal dysfunction, and cholestasis syndrome), δ-SPD (e.g. Hermansky-Pudlak syndrome, Chediak-Higashi syndrome, Griscelli syndrome), or αδ-SPD (e.g. X-linked thrombocytopenia, Wiskott-Aldrich syndrome). Diagnosis of SPD is very extensive and requires platelet aggregation and flow cytometry analyses with interpretation from a specialist. Many of these disorders share common treatments, however, efficacy can vary between different patients. Therapy regiments with tranexamic acid, DDAVP, activated FVIIa, and platelet transfusions have been published. Stem cell or bone marrow transplantations are preserved for severe defects. Here, we describe the pathophysiology, clinical manifestations, and diagnosis of the major human SPDs.
To describe the clinical phenotype in infants with ARC syndrome, the association of arthrogryposis, renal tubular acidosis, and cholestasis.
The medical records for six patients with ARC syndrome were reviewed, presenting over 10 years to three paediatric referral centres.
All patients had the typical pattern of arthrogryposis. Renal Fanconi syndrome was present in all but one patient, who presented with nephrogenic diabetes insipidus. Although all patients had severe cholestasis, serum gamma glutamyltransferase values were normal. Many of our patients showed dysmorphic features or ichthyosis. All had recurrent febrile illnesses, diarrhoea, and failed to thrive. Blood films revealed abnormally large platelets.
ARC syndrome exhibits notable clinical variability and may not be as rare as previously thought. The association of Fanconi syndrome, ichthyosis, dysmorphism, jaundice, and diarrhoea has previously been reported as a separate syndrome: our observations indicate that it is part of the ARC spectrum.
ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.
Bleeding problems are associated with defects in platelet alpha-granules, yet little is known about how these granules are formed and released. Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome. We have characterized platelets from patients with ARC syndrome and observed reduced aggregation with arachidonate and adenosine diphosphate (ADP). Structural abnormalities seen in ARC platelets included increased platelet size, a pale appearance in blood films, elevated numbers of delta-granules, and completely absent alpha-granules. Soluble and membrane-bound alpha-granule proteins were significantly decreased or undetectable in ARC platelets, suggesting that both the releasable protein pools and membrane components of alpha-granules were absent. The role of VPS33B in platelet granule biogenesis was evaluated by immunofluorescence microscopy in normal human megakaryocytes. VPS33B colocalized appreciably with markers of alpha-granules, moderately with late endosomes/lysosomes, minimally with delta-granules/lysosomes, and not with cis-Golgi complexes. VPS33B protein expression determined by immunoblotting confirmed the presence of VPS33B in control fibroblasts but not in ARC fibroblasts, and in normal megakaryocytes but not in platelets. We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion.
We aimed to describe abnormal platelet morphology and its clinical significance in infants who were diagnosed with arthrogryposis renal dysfunction and cholestasis (ARC) syndrome. We collected all of the cases of ARC syndrome referred to a single pediatric referral center. In all patients, platelet counts and analysis of platelet morphology were performed with peripheral blood smear specimens. Electron microscopy images were obtained to examine the ultrastructure of the platelets. Over the 12-year period, 12 cases of ARC syndrome were identified. The sex ratio (male:female) was 1:1. The median birth weight was 3.15 kg (range, 2.3 to 3.8 kg). Failure to thrive was observed in all the patients. The major cause of death was recurrent febrile illness and pneumonia. The median age at death was 8.9 months (range, 2.6 to 28.8 kg). Their median body weight at death was 3.1 kg (range, 2.6 to 6.0 kg). Close examination of their peripheral blood smear (n=11) specimens showed large, pale, agranular platelets similar to those seen in gray platelet syndrome. Electron microscopic images of the platelets (n=7) revealed a lack of alpha; granules. Agranular platelets are a common finding in ARC syndrome. Agranular platelets should be considered as a cardinal feature of ARC syndrome and can be useful as a noninvasive diagnostic marker for ARC syndrome.
We describe six infants, from consanguineous marriages, with a new syndrome comprising the Fanconi syndrome, ichthyosis, musculoskeletal abnormalities, jaundice and diarrhoea. In addition two of the infants were found to have abnormal platelet morphology--the grey platelet syndrome. No evidence of a recognised metabolic disorder was found in any of the six infants, nor did they appear to be typical of any previously described syndromes. Their progress was poor: they required high fluid and bicarbonate intakes and all died by the age of 6 months of dehydration, acidosis and sepsis.
We report on five patients from three families with neurogenic arthrogryposis, cholestasis and tubular renal dysfunction. Despite a similar clinical picture the liver histology showed a broad pathological spectrum, ranging from pigment storage to parenchymal giant cell transformation and ductopenia. The findings are compared with those of other cases from the literature in search of a correct nosology of the syndrome characterized by arthrogryposis, renal and liver disease.
Conclusion
We propose to consider the picture of arthrogryposis, renal tubular dysfunction and cholestasis as a single syndrome.
We report on 4 children from 2 unrelated families who appear to have the lethal ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) together with the additional findings of nephrogenic diabetes insipidus and cerebral anomalies, including deafness. With increased survival time in our patients, paucity of the intrahepatic bile ductules and cholestasis progressed to cirrhosis, growth was severely impaired, and severe mental retardation became apparent. No evidence was found for peroxisomal, chromosomal, or mitochondrial disorders. We propose to amend the ARC mnemonic to ARCC-NDI (A-Arthrogryposis, R-renal Fanconi, C-cerebral, C-cholestasis, NDI-nephrogenic diabetes insipidus) to name the major manifestations of this syndrome, several of which have not been appreciated.
We report for the first time from the Arabian Gulf area 3 patients with arthrogryposis multiplex congenita, cholestasis and renal tubular dysfunction from a Saudi family with 2 other siblings and 3 cousins who possibly died with a similar clinical picture. We also document for the second time in literature other findings in this syndrome including cerebral abnormalities (hypoplastic corpus callosum), congenital heart disease and nerve deafness. We suggest that some of these cases might benefit from ursodeoxycholic acid therapy. We believe that this autosomal recessive disorder is possibly under-diagnosed in this region with a high consanguineous marriage rate.
ARC syndrome is a rare disorder consisting of arthrogryposis, renal tubular acidosis and cholestatic liver disease. We report the case of a 5-week-old patient who underwent a percutaneous liver biopsy complicated by hemorrhage, and was subsequently diagnosed with ARC syndrome. A review of the literature demonstrates that these patients are at increased risk of bleeding caused by platelet dysfunction. The evaluation and management of unexpected hemorrhage in pediatric patients as a result of undiagnosed congenital bleeding problems is discussed.
ARC syndrome, the association of arthrogryposis, renal tubular dysfunction and cholestasis, is a rare genetic disorder. We report two Saudi infants from two different families with ARC syndrome. Magnetic resonance imaging of the brain of one of the infants showed lissencephaly, a previously unreported finding in this syndrome. We also review 39 ARC cases reported in the literature using the Medline database from January 1966 to September 2004.