POLSKI
Introduction
ARCS1 syndrome, also called arthrogryposis, is a rare, multisystem congenital disorder that is inherited in an autosomal recessive manner. This disease is characterized by severe defects in multiple organs, including the liver, kidneys, skin, central nervous system, and musculoskeletal system. It is caused by mutations in the genes VPS33B (Vacuolar protein sorting 33 homolog B) on chromosome 15q26.1 (responsible for 75% of cases) and VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator - 25% of cases) [1-5].
About 100 cases of this disease have been described until today. Patients have a significantly shortened life expectancy, often dying before the age of 7 months due to multiple organ complications. Currently, there is no effective therapeutic therapy for this syndrome, which causes a poor prognosis for patients [6-12].
In this article, we present a case report of a family in which children with a congenital defect associated with autosomal recessive inheritance of the VPS33B gene were born in a subsequent twin pregnancy.
Aim
The aim of the work describing the ARCS1 syndrome - arthrogryposis was to understand this rare autosomal recessive multisystem disease, which is characterized by a variety of symptoms and complications affecting the liver, kidneys, skin, central nervous system and musculoskeletal system. This syndrome is caused by mutations in the VPS33B (Vacuolar protein sorting 33 homolog B) genes on chromosome 15q26.1, which account for about 75% of cases of the disease, and the VIPAR (VPS33B interacting protein, apical-basolateral polarity regulator) genes, which are responsible for the remaining 25% of cases. Mutations in these genes lead to disorders in the functioning of cells and organs, which causes characteristic symptoms in patients [1-4,6,8,10,12].
The prevalence of ARCS1 is not exactly known, but about 100 cases have been described so far. Due to the rarity of the disease, its diagnosis may be difficult and requires specialized genetic testing [10].
The first reported case in this family concerned the first child born from the first pregnancy of a 26-year-old healthy woman. A male newborn born at 36 hbd by spontaneous delivery. Birth weight was 2620 g, body length 48 cm, the clinical condition of the newborn infant according to the Apgar scale was 8/8/9 points. At the end of the second week of life, the first symptoms of ARCS1 syndrome began to appear. In the following months, the patient was hospitalized many times due to recurrent urinary and respiratory tract infections, severe dehydration and metabolic acidosis. In addition, increases in blood bilirubin (up to 6.62 mg/dl) and serum bile acids (up to 75.7 µmol/l), elevated alkaline phosphatase (470-818 U/l) and hypothyroidism were observed, as suggested by a high thyroid stimulating hormone (TSH) level of 16.71 uU/mL. NMR imaging showed hypoplasia of the corpus callosum, which is a typical finding of ARCS1. Despite intensive medical care and multiple hospitalizations, the patient died at 13 months of age due to complications associated with progressive multiple organ failure.
In order to confirm the diagnosis and identify the cause of the disease, molecular studies were performed in which 17 exons of the VPS33B gene were sequenced using the Sanger DNA sequencing method. Sequence analysis showed the presence of the homozygous mutation c.1235_1236delinsG (p.Pro412ArgfsTer7) in the VPS33B gene. This was the first report in the scientific literature to describe this particular mutation as the cause of ARCS1 syndrome.
This case was an important scientific report because for the first time the homozygous mutation c.1235_1236delinsG (p.Pro 412ArgfsTer7) in the VPS33B gene was described as the cause of ARCS1 syndrome. The prognosis for patients with this disease is unfavorable, and recurrent infections and other complications lead to death at an early age.
Two years later, this patient, previously diagnosed with the homozygous c.1235_1236delinsG (p.Pro412ArgfsTer7) mutation in the VPS33B gene, was pregnant again. It was a twin pregnancy, developing normally, which ended in premature delivery at 32/33 hbd by caesarean section. Due to the presence of ARCS1 in the mother, there was a high risk of inheriting the disease. In order to improve fetal lung maturity and minimize the risk of immature lungs, the patient received a full course of steroid therapy. Due to the onset of labor between 32/33 weeks of gestation, two fetuses were delivered by caesarean section.
The results of genetic tests in twins showed that 1 twin daughter is healthy. He is a carrier of the VPS 33B mutation. The examined lesion c.1235-1236delinsG is in one VPS33B allele/heterozygous/fetus 1 healthy VP gene carrier/. The second twin - a daughter was born with a genetic defect -I fused ARC type 1 change (c.1235-1236 dellins G); (1235-1236 delinsG) exon 17 variant; (in both alleles of the VPSB33 gene (in a homozygous system) protein system p.(Pro412Argfs7). The genetic result allowed the diagnosis of the lethal ARCS33B syndrome - as in the first child of this couple born two years earlier. The first child born in good general condition, birth weight 1680 g, with transient respiratory disorders, no abnormalities in physical and laboratory examination, second child born in average general condition with Apgar 6/6/7/7, birth weight 1470g, reduced muscle tone, peripheral cyanosis, respiratory disorders, with a picture of respiratory failure. The physical examination showed muscle atrophy in the thighs, limited abduction in the hip joints, the right foot was raised, and excoriations on the back. In laboratory tests, elevated bilirubin levels associated with yellowing of the integuments with olive skin color with increasing symptoms of cholestasis. Negative infection parameters. In the ultrasound image of the abdominal cavity, the kidneys were free of stasis and deposits, with a doubled pelvicalyceal system. Other abdominal organs without pathological changes. The ultrasound image of the CNS showed a clearer lumen of the more widely spaced frontal horns of the more left lateral ventricles, with increased echogenicity of the periventricular brain, suspicion of partial agenesis of the corpus callosum. The chest and abdominal X-rays showed asymmetry of the aeration of the lung fields, the left one was properly aerated, the right one was of reduced transparency with homogenous patchy densities of the first degree. Despite intensive medical care and multiple hospitalizations, the patient died at the age of 6 months due to complications associated with progressive multiple organ failure.
Discussion
ARCS1 syndrome is a rare autosomal recessive inherited disorder that causes multiple organ dysfunction. It was first described in 1973 [1,2]. Patients with ARCS1 have a poor prognosis and are at risk of serious life-threatening conditions such as dehydration, recurrent infections, metabolic acidosis, and internal bleeding. This disease is manifested by three main features - arthrogryposis, renal dysfunction and cholestasis, and many other systemic symptoms, such as recurrent febrile illnesses, ichthyosis, bleeding tendency, deafness, mental retardation and central nervous system abnormalities [1-3,13]. Most patients with ARCS1 die before the first year of life due to recurrent infections and bleeding. This disease is sometimes difficult to distinguish from certain types of cholestasis and disorders of bile acid synthesis, such as PFIC1, because they have similar clinical manifestations. ARCS1 and ARCS2 syndromes are caused by mutations in the VPS33B and VIPAS39 genes, which encode the VPS33B and VIPAR proteins, respectively. These proteins form a complex that interacts with the RAB11A protein. VPS33B and VIPAR are expressed in many organs such as kidney, liver, heart, lung, brain, skin and skeletal muscle. This explains the multiple organ symptoms seen in both ARCS1 and ARCS2 [14,15].
ARCS1 is associated with an unknown prevalence. So far, about 100 cases have been identified in which kidney damage caused by abnormal polarization of the epithelial tubules has been observed. This polarity defect leads to disturbances in the endocytosis process. Clinically, this is manifested by the presence of glucose in the urine (glycosuria), excessive excretion of phosphate (hyperphosphaturia), the presence of protein in the urine (proteinuria), and the development of full-blown Fanconi disease. Incorrect polarization of hepatocyte membranes, resulting from their damage, is the basis of jaundice, associated with elevated transaminase values and the occurrence of cholestasis [1,3,4,7,8]. Histopathology is not specific in case of this disease. In ARCS1 syndrome, the characteristic symptom of dysmorphism is arthrogryposis, which is the most distinct and recognizable feature of this condition [1,3,7,11].
For many years, molecular testing of the ARCS1 team was based on the PCR method, focusing mainly on known point mutations. However, this strategy could lead to false-negative results [1]. In our cases, a new, previously unreported mutation was observed in two children from two separate pregnancies. Both children manifested typical clinical symptoms of ARCS1 syndrome. Despite some progress in treating symptoms, the prognosis of ARCS1 remains unfavorable. Patients typically die in early infancy, and the causes of death are often recurrent infections, dehydration, metabolic acidosis, or internal bleeding.
In the study case, the homozygous mutation c.1235_1236delinsG (p.Pro412ArgfsTer7) in the VPS33B gene was identified. Genetic tests confirmed the heterozygous carrier of this mutation in one allele in the parents of the examined children. The parents did not show any clinical symptoms of the disease. This new, pathogenic genetic sequence change has not previously been reported in databases such as dbSNP, gnomAD, HGMD and ClinVar. This mutation leads to premature termination of protein translation, suggesting its pathological significance. The risk of passing this mutation to offspring is 25% and remains constant for future pregnancies of this couple.
Most reported cases of ARCS are characterized by severe disease and early mortality. In a study by Gissen et al [16] 62 patients with ARCS from 35 families were described, none of whom were older than 20 months at the time of publication. However, reports indicate that affected individuals who have the VPS33B c.1225 + 5G-C mutation may present a slightly milder phenotype [17].
Patients with ARCS show a variety of skin and musculoskeletal changes suggesting a common phenotype. The VPS33B gene plays a role in the maturation of collagen, which is an essential component of the basement membrane and a key factor in the development of cell polarity. In addition, hepatocyte polarity abnormalities and elevated bile acid levels have been implicated in the development of skin lesions and pruritus in patients with ARCS [18,19].
In the physical examination of our patient, muscle atrophy in the thighs was noteworthy, he was hypotonic, had contractures of the limbs, the clubfoot was raised upwards, limited abduction in the hip joints, excoriations on the back. The patient had cholestatic jaundice, hepatomegaly with elevated levels of bilirubin, AST, ALT and GGTP without observed biliary obstruction, with yellowing of the integuments and olive skin color, with increasing symptoms of cholestasis. Negative infection parameters. The patient had prolonged clotting times. Renal tubular dysfunction was characterized by phosphaturia, generalized aminoaciduria, and renal tubular acidosis. The ultrasound image showed kidneys without stagnation and deposits, with doubled pelvicalyceal system. Other abdominal organs without pathological changes. The ultrasound image of the CNS showed a clearer lumen of the more widely spaced frontal horns of the more left lateral ventricles, with increased echogenicity of the periventricular brain, suspicion of partial agenesis of the corpus callosum. The chest X-ray showed asymmetry of the aeration of the lung fields. Despite intensive medical care and multiple hospitalizations, the patient died at the age of 6 months due to complications associated with progressive multiple organ failure.
Unfortunately, the ARC team currently has no treatment options for a cure, and mortality is imminent. Patients with this condition die within days or months from complications such as sepsis, severe dehydration, and acidosis. In this situation, the only available approach is supportive care, which includes intensive hydration and the provision of high-calorie parenteral nutrition or preparations rich in medium-chain triglycerides. In addition, patients may receive regular supplementation of ADEK vitamins and ursodeoxycholic acid. Unfortunately, in the described case, our patient died before the age of 6 months due to sepsis. In order to make a diagnosis and start treatment at an early stage, an in-depth analysis of the family history is recommended, identification of characteristic clinical symptoms and analysis of genetic mutations. The family should also receive support in the form of genetic counselling.
