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Background. Niemann–Pick disease type C is a multisystem orphan disease caused by mutations in the NPC1 and NPC2 genes and characterized by clinical polymorphism. The difficulties of managing such patients lie in the diagnosis and differential diagnostic search with other conditions with cholestasis, as well as the initiation of substrate-reducing therapy in young children. Case report. Previously, a case report of Niemann–Pick disease type C, with the manifestation of the disease in infancy and the appointment of off-label pathogenetic therapy was described. The article presents the results of dynamic monitoring of the child on this therapy, its effectiveness and safety. The leading syndromes in the clinical presentation of the disease were cholestasis, cytolysis, hepatosplenomegaly, as well as psychomotor retardation. An extensive differential diagnostic search was conducted with the exception of diseases such as toxic, viral hepatitis, alpha-1-antitrypsin deficiency, autoimmune liver diseases, aminoacidopathy, Alagille syndrome. Genetic testing on the “Cholestasis” panel revealed a mutation in the NPC1 gene. Biochemical diagnostics showed an increase in the concentration of lysosphingomyelin-509 and increased activity of chitotriosidase in dry blood spots. When sequencing the NPC1 gene by Sanger, the nucleotide substitution chr18:21131617G> A in the homozygous state was detected in the child. At 9 months, by the decision of the medical board, the child was prescribed pathogenetic therapy, the effectiveness of which was confirmed by clinical and laboratory relief of cholestasis, positive dynamics of neurological manifestations, in addition, the drug is satisfactorily tolerated by the patient, despite the preservation of an isolated increase in the level of aspartate aminotransferase. Conclusion. The presented case report confirms the need for a thorough differential diagnostic search with the inclusion of a wide range of diseases with the leading cholestasis for the timely detection of infants with Niemann- Pick disease type C, as well as the importance and effectiveness of early administration of pathogenetic therapy.

Hypophosphatasia (HPP) is a rare disease caused by mutations in the ALPL gene encoding tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa enzyme replacement treatment (ERT) mineralizes the skeleton and improves respiratory function and survival in severe forms of HPP. Our patient was a newborn infant evaluated for respiratory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high concentrations of substrates of the TNSALP and radiologic findings. On day 21 after birth, ERT using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. We were able to discharge the patient when he was seven months old. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction (qPCR). As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with ERT is life-saving in the severe form of HPP. qPCR can detect duplications if a mutation cannot be detected by sequence analysis in these patients.

Hypophosphatasia (HPP) is a rare disease caused by mutations in the ALPL gene encoding tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Duplications of the ALPL gene account for fewer than 1% of the mutations causing HPP. It has been shown that asfotase alfa enzyme replacement treatment (ERT) mineralizes the skeleton and improves respiratory function and survival in severe forms of HPP. Our patient was a newborn infant evaluated for respiratory failure and generalized hypotonia after birth. Diagnosis of HPP was based on low-serum ALP activity, high concentrations of substrates of the TNSALP and radiologic findings. On day 21 after birth, ERT using asfotase alfa (2 mg/kg three times per week, subcutaneous injection) was started. His respiratory support was gradually reduced and skeletal mineralization improved during treatment. We were able to discharge the patient when he was seven months old. No mutation was detected in the ALPL gene by all exon sequencing, and additional analysis was done by quantitative polymerase chain reaction (qPCR). As a result, a novel homozygote duplication encompassing exons 2 to 6 was detected. Early diagnosis and rapid intervention with ERT is life-saving in the severe form of HPP. qPCR can detect duplications if a mutation cannot be detected by sequence analysis in these patients. [ABSTRACT FROM AUTHOR]

Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis. Less common signs of the disease are hepatosplenomegaly, ichthyosis and arthrogryposis. We report a case of Gaucher's disease (type 2) diagnosed in a newborn who presented with Hydrops Fetalis.

Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis. Less common signs of the disease are hepatosplenomegaly, ichthyosis and arthrogryposis. We report a case of Gaucher's disease (type 2) diagnosed in a newborn who presented with Hydrops Fetalis. [ABSTRACT FROM AUTHOR]

Osteogenesis imperfecta is a rare connective tissue disorder characterized by bone fragility and low bone density. Most cases are caused by an autosomal dominant mutation in either COL1A1 or COL1A2 gene encoding type I collagen. However, autosomal recessive forms have been identified. We present a patient with severe respiratory distress due to osteogenesis imperfecta simulating type II, born to a non-consanguineous couple with mixed African-American and African-Hispanic ethnicity. Cultured skin fibroblasts demonstrated compound heterozygosity for mutations in the LEPRE1 gene encoding prolyl 3-hydroxylase 1 confirming the diagnosis of autosomal recessive osteogenesis imperfecta type VIII, perinatal lethal type. [ABSTRACT FROM AUTHOR]

The prognosis of extrahepatic biliary atresia (EHBA) and multiple apparently not linked anomalies has never been disclosed. We reported a rare case affected by biliary, anorectal and esophageal atresia, and collected the uncommon associations of EHBA with multiple unrelated congenital defects to make known the prognosis. An elevated rate of hepatic failure despite surgery and an early poor outcome were found in the above-mentioned associations. A liver transplantation at the first months of life could be considered to improve outcome. [ABSTRACT FROM AUTHOR]

Abstract: Gaucher disease, the most common lysosomal storage disorder, encompasses a wide spectrum of clinical symptoms. The perinatal lethal form is very rare and is considered a distinct form of classic type 2 Gaucher disease. Prominent features of the severe perinatal form are hepatosplenomegaly variable, associated with hydrops fetalis and ichthyosis. Here, we describe a child who presented generalized ichthyosis and died at 25 days of age. Genotype analysis revealed compound heterozygosity for the complex allele [L444P;E326K] and mutation P182L, described for the first time in this patient. Mutations E326K and L444P were on the same chromosome. Expression studies of mutant glucocerebrosidases showed that the double mutant allele had lower activity, 8.5% of wild type, in contrast to the activity of individual E326K and L444P mutant enzymes, 42.7% and 14.1%, respectively. The P182L mutant enzyme showed no glucocerebrosidase activity. A revision of the genotypes identified in a series of Spanish patients with type 2 Gaucher disease showed that the complex allele [L444P;E326K] accounted for 19.2% of patient alleles and that homozygosity for this allele or its heterozygosity with mutation L444P, or another severe mutation such as P182L, was associated with the perinatal lethal presentation of the disease. In contrast, the [L444P;E326K] allele was not detected in patients with classic type 2 diagnosed when several months old. The high frequency of the E326K substitution observed in patients with type 2 as compared to the general population (0.5%) suggests that this change may have a modulating negative effect on the clinical condition of these Gaucher disease patients when present in combination with mutation L444P. The relatively high prevalence of the double mutant allele in Spanish patients prompted us to perform a haplotype analysis, using four polymorphic markers, which suggest a common origin for this allele. During the mutational analysis of the series of type 2 patients, a novel mutation, I260T (c.896T > C), was identified. [Copyright &y& Elsevier]

The paper describes a case of a perinatal lethal Gaucher disease in a 29-week-old fetus with non-immune hydrops, facial dysmorphia, hepatosplenomegaly, and hypoplasia of cerebellum and pons. Gaucher cells were found in the lymph nodes, spleen, lungs, thymus, cerebellum, and bone marrow. No storage cells have been detected in the placenta. There was a significant placental weight increase due to swelling. The diagnosis of Gaucher disease was confirmed by biochemical analysis (deficiency of glucocerebrosidase activity and sharply increased hexanoylsphingosine concentration) and molecular genetic techniques (the presence of two mutations of the GBA gene). Our observation shows that characteristic histologic signs of disease can be detected at early stages of development.