Severe combined immunodeficiency in a child with a healthy adenosine deaminase deficient mother

We investigated adenosine deaminase (ADA) deficient severe-combined immunodeficiency (SCID) in an 8-month-old child with ADA deficient mother. The ADA deficiency in the child was unusual in that the thymic histology was normal. In addition, the thymocytes formed E-rosettes with sheep erythrocytes and were stimulated by T-cell mitogens. ADA activity could not be detected in the child's thymocytes. Studies on the family indicated that the father had about one-half of the normal erythrocyte ADA activity. All the family members with detectable ADA activity appeared to have, according to starch gel electrophoresis of erythrocyte lysates, the common ADA-1 phenotype; however, rigorous identification of phenotype was not possible in this study. The mother had less than 1% of normal ADA activity in both erythrocyte and lymphocyte extracts, but her whole peripheral blood lymphocytes demonstrated about 6% of normal activity. Normal concentrations of ATP and small amounts of dATP were found in the mother's erythrocytes. Deoxyadenosine excretion in her urine was elevated and approximately 5-10% of that excreted by individuals with ADA deficient SCID. These studies suggest that low amounts of ADA activity in erythrocytes and blood lymphocytes of certain individuals may be compatible with good immune function and longevity.     

Insulin-dependent diabetes mellitus and severe atopic dermatitis in a child with adenosine deaminase deficiency

We report a 2.3-year-old girl with complete lack of adenosine deaminase (ADA) activity who presented with severe atopic dermatitis and insulin-dependent diabetes mellitus but only mild recurrent infections. Abnormalities of immune function included profound depletion of CD8+ lymphocytes, hyperimmunoglobulinaemia E, and very low in vitro proliferative response to mitogens. Treatment with polyethylene glycol-conjugated ADA was followed by rapid amelioration of clinical and immunological conditions. The immunological and clinical features of this child suggest that the clinical spectrum of ADA deficiency may be broader than originally supposed.     

Treatment of adenosine deaminase deficiency with adenosine deaminase combined with polyethylene glycol]

Adenosine deaminase (ADA) deficiency is one the causes of severe combined immunodeficiency syndrome. Treatment was, until now, based on bone marrow transplantation. HLA identical bone marrow transplantation yields excellent results while those of HLA haploidentical bone marrow transplantation are not so good. A new therapeutic approach was developed recently, consisting of the intramuscular infusion of ADA enzyme covalently linked to polyethylene glycol (PEG-ADA). We report the results of this treatment in a 14 month-old child presenting with a partial form of ADA deficiency revealed by an opportunistic infection. This treatment corrected the immunodeficiency and the biochemical abnormalities as well. PEG-ADA infusions were well tolerated. The onset of an immunization against the ADA enzyme led to a drop in immunologic functions, which could be partially overcome by more frequent (biweekly) administration of the product. After a 18 month-follow-up the child is doing well, living normally at home. PEG-ADA represents a possible alternative for children presenting with ADA deficiency without any available HLA identical donor.     

Early vasculopathy following radiation in a child with medulloblastoma

A child with severe radiation vasculopathy 15 months following radiation therapy for medulloblastoma is reported. The patient underwent surgical resection of a posterior fossa medulloblastoma, followed by chemotherapy and radiation therapy. He was treated with 55 Gy to the craniospinal axis. Fifteen months later, the patient presented with a subacute neurologic deterioration from multiple ischemic events that resulted from severe radiation vascular injury. We compare and contrast this case to similar case reports in the literature.     

Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase

We describe a patient with severe combined immunodeficiency because of aberrations in adenosine deaminase (ADA) who despite adequate replacement with polyethylene glycol-linked ADA (PEG-ADA) for 13 years developed Burkitt's lymphoma. Although treatment corrected the metabolic abnormalities caused by ADA deficiency, it failed to fully restore cellular immunity.     

Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID)

Adenosin deaminase (ADA) deficiency is the cause for Severe Combined Immunodeficiency (SCID) in about 15% of patients with SCID, often presenting as T (-)B (-)NK (-)SCID. Treatment options for ADA-SCID are enzyme replacement, bone marrow transplantation or gene therapy. We here describe the first patient with ADA-SCID and fatal hepatic failure despite bone marrow transplantation from a 10/10 HLA identical related donor. As patients with ADA-SCID may be at yet underestimated increased risk for rapid hepatic failure we speculate whether hepatitis in ADA-SCID should lead to the immediate treatment with enzyme replacement by pegylated ADA.     

Renal cell carcinoma harboring somatic TSC2 mutations in a child with methylmalonic acidemia

Pediatric renal cell carcinoma (RCC) is a rare cancer that can be associated with inherited diseases including tuberous sclerosis complex (TSC) caused by germline mutations in TSC1 or TSC2. Somatic mutations in TSC1 and TSC2 have also been reported in adult RCC, which predict response to mTOR inhibitors. Here, we present the first case of RCC in a child with methylmalonic acidemia (MMA). Clinical whole exome sequencing of blood and tumor samples confirmed the diagnosis of MMA and revealed two somatic inactivating mutations in TSC2, suggesting the potential consideration of an mTOR inhibitor in the event of tumor recurrence.     

Comparison of red cell transfusion and polyethylene glycol-modified adenosine deaminase therapy in an adenosine deaminase-deficient child: measurement of erythrocyte deoxyadenosine triphosphate as a useful tool

The effect of red cell transfusion and polyethylene glycol-modified adenosine deaminase therapy on biochemical abnormalities, clinical status, and immunologic function in an adenosine deaminase-deficient child was investigated. After red cell transfusions, erythrocyte deoxyadenosine triphosphate (dATP) concentrations decreased about 95% and were closely related to adenosine deaminase activities; deoxyadenosine diphosphate concentrations decreased only approximately 30%. The evolution of dATP levels was also closely related to the improvement in clinical status of the patient. However, immune function was not restored. After polyethylene glycol-modified adenosine deaminase therapy, the concentration of erythrocyte dATP decreased to undetectable levels correlated with an increase of T lymphocyte counts and an increase of lymphocyte responses to mitogens. Immune functions were restored only when dATP levels were below 15 mumols/L. It appears that red cell transfusion therapy is not sufficiently effective to reduce and maintain erythrocyte dATP levels at values compatible with normal immune function. On the contrary, polyethylene glycol-modified adenosine deaminase therapy is a suitable treatment to reduce dATP levels to near undetectable values, allowing the immune function to be restored, dATP measurement is a very useful tool for monitoring and evaluating the degree of efficiency of therapy in adenosine deaminase deficiency.     

Purine dysfunction in cells from patients with adenosine deaminase deficiency.

Conversion of adenosine to inosine is decreased in adenosine deaminase (ADA)-deficient fibroblasts at all concentrations of adenosine tested. Adenosine is not differentially toxic to ADA-deficient fibroblasts except at very high (5 X 10(-4) -1 X 10(-3) M) adenosine levels. Conversion of [14C] adenosine to GTP is not decreased in ADA-deficient cells compared with control cell strains. Adenosine conversion to ATP is the same as that in mutant cells except at high nonphysiologic concentrations, at which it is slightly decreased in ADA-deficient fibroblasts. This effect is probably not related to the biochemical pathology of ADA-deficient lymphocytes in vivo. Uridine, a pyrimidine compound, "rescues" control cells from the effects of adenosine toxicity, as previously reported, but it has no protective effect on ADA-deficient fibroblasts. This suggests that uridine will have no therapeutic role in the treatment of the ADA-deficient form of severe combined immunodeficiency (SCID) disease.     

Cerebral lymphoma in an adenosine deaminase-deficient patient with severe combined immunodeficiency receiving polyethylene glycol-conjugated adenosine deaminase

Polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) provides an alternate therapy to mismatched stem cell transplantation for patients with ADA-deficient severe combined immunodeficiency. Although replacement therapy with PEG-ADA is effective in preventing infections, immune function does not return to normal, and most patients remain lymphopenic. Information is limited regarding the prognosis of patients on long-term ADA-replacement therapy. Here we present a case of a 10-year-old child who was diagnosed with ADA-severe combined immunodeficiency at 4 weeks of age after contracting pneumonia. Treatment with PEG-ADA was begun, the biochemical markers of ADA deficiency normalized, and his clinical progress was very good without significant infections. At 10 years of age, after presenting with headaches and cranial nerve deficits, he was diagnosed with Epstein-Barr virus-positive malignant brain lymphoma. It did not respond to various regimens of aggressive chemotherapy, and the patient expired 5 months later. We speculate that in this patient the immunologic surveillance by T cells may have been defective with respect to elimination of Epstein-Barr virus-infected cells, hence the formation of neoplasm. The possible mechanisms underlying such pathology are reviewed.     

Multiple hornet (Vespa orientalis) stings with fatal outcome in a child

A case of multiple hornet stings is described with a rapidly fatal course due to the combination of massive haemolysis, coagulopathy, rhabdomyolysis, hyperkalaemia, acute renal failure, encephalopathy, hepatotoxicity and hyperglycaemia. These features of systemic envenomation can all be attributed to the toxic properties of Oriental hornet venom described in in vitro and in vivo experimental studies. Greater awareness of these features, aggressive treatment of hyperkalaemia and early institution of treatments such as peritoneal dialysis and plasma exchange may prevent fatalities in such cases.     

A fatal case of Q fever hepatitis in a child

A two-year-old boy of Arabic extraction presented with progressive jaundice and prolonged pyrexia. Both IgM and IgG immunofluorescent antibody titers for Q fever were 1:1280. Two goats and one cow of the domestic animals owned by the family also had positive antibody titers against Q fever. In spite of antibiotic treatment with tetracyclines and chloramphenicol, the hepatic involvement progressed gradually. On the twentieth day of admission the child succumbed from hepatic failure. This child presents a rare case of fatal hepatic failure due to Q fever.     

原发性肾病综合征患儿腺苷酸脱氧酶检测的临床意义

目的 检测原发性肾病综合征(PNS)患儿血清腺苷酸脱氧酶(S-ADA)活性的变化,以评估其细胞免疫状态,并探讨其临床意义.方法 选取初发的PNS患儿30例,应用免疫学技术测定不同病程阶段患儿的S-ADA活性,分析其变化.结果 激素治疗前,激素敏感组(SS)、激素依赖组(SD)和激素抵抗组(SR)患儿S-ADA活性差异无统计学意义(P＞0.05),经激素足量治疗8周后,SS组、SD组S-ADA活性下降,SS组下降最明显(P＜0.01),而SR组变化无统计学意义(P＞0.05);短期缓解期组S-ADA活性下降,但仍明显高于对照组(P＜0.05);长期缓解期组S-ADA活性与对照组相比,差异无统计学意义(P＞0.05).结论 PNS患儿存在细胞免疫功能紊乱,检测S-ADA活性可作为判断临床疗效的指标之一.