Constitutional abnormalities of IDH1 combined with secondary mutations predispose a patient with Maffucci syndrome to acute lymphoblastic leukemia

Maffucci syndrome is a nonhereditary disorder caused by somatic mosaic isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations and is characterized by multiple enchondromas along with hemangiomas. Malignant transformation of enchondromas to chondrosarcomas and secondary neoplasms, such as brain tumors or acute myeloid leukemia, are serious complications. A 15‐year‐old female with Maffucci syndrome developed B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). A somatic mutation in IDH1 was detected in hemangioma and leukemic cells. KRAS mutation and deletion of IKZF1 were detected in leukemic cells. Patients with Maffucci syndrome may, therefore, be at risk of BCP‐ALL associated with secondary genetic events that affect lymphocyte differentiation.     

Sudden unexpected death in an infant with L-2-hydroxyglutaric aciduria

Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11 months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older sister with developmental delay, ataxia, and tremor revealed l-2-hydroxyglutaric aciduria and subcortical white matter changes with hyperintensity of the basal ganglia and dentate nuclei at brain magnetic resonance imaging. Both children were homozygous for a splice site mutation in the L2HGDH gene. Sudden death has not been reported in association with l-2-hydroxyglutaric aciduria so far, but since this inborn error of metabolism is potentially treatable, early diagnosis may be important.     

Complete durable response of a pediatric anaplastic oligodendroglioma to temozolomide alone: Case report and review of literature

Anaplastic oligodendroglioma (AO) is rare in children. Treatment typically consists of varying combinations of surgery, chemotherapy, and radiotherapy. We present a pediatric case of frontal lobe AO with periventricular subcallosal extension and local leptomeningeal involvement. The isocitrate dehydrogenase (IDH) wild‐type tumor was MGMT methylated and contained an ATRX mutation, BRAF alteration, and 1p/19q co‐deletion; a combination of alterations mostly encountered in pediatric oligodendrogliomas. The patient underwent a near total resection and had a complete, durable response to temozolomide alone, suggesting that conservative management without radiation may be appropriate in some cases. We review the literature of this uncommon subtype of glioma in children.     

A neonate with a unique non‐Down syndrome transient proliferative megakaryoblastic disease

Transient myeloproliferative disorder (TMD) is a leukemia type that occurs typically in newborns. In Down syndrome, TMD is referred to as transient abnormal myelopoiesis (TAM).³² Recently, transientness has also been reported in acute myeloid leukemia patients with germline trisomy 21 mosaicism, and even in cases with somatic trisomy 21, with or without GATA1 mutations. TMD cases without trisomy 21 are rare, and recurrent genetic aberrations that aid in clinical decision‐making are scarcely described. We describe here a TMD patient without trisomy 21 or GATA1 mutation in whom single‐nucleotide polymorphism analysis of leukemic blasts revealed a novel combined submicroscopic deletion (5q31.1–5q31.3 and 8q23.2q24).     

Permanent neonatal diabetes in siblings with novel C109Y INS mutation transmitted by an unaffected parent with somatic mosaicism

Mutations involving the insulin (INS) gene are a common cause of permanent neonatal diabetes (PND). Although INS mutations typically occur de novo and germline INS mutations transmitted to offspring by unaffected parents has been described, somatic mosaicism in a parent with an INS mutation has not been previously reported. We describe two siblings (one brother and one sister) with PND (26‐ and 19‐yr old diagnosed at 3 and 7 months old, respectively), whose parents were unaffected. We performed genetic analysis of leukocyte DNA for this family. Both patients were found to carry the novel heterozygous c.326G>A substitution in exon 3 of INS, resulting in a p.C109Y change of the insulin protein. Analyses of leukocyte DNA from the parents revealed low level mutation in the sequencing trace of the father, raising the possibility of somatic mosaicism. Real‐time polymerase chain reaction (PCR) analysis showed he had approximately 73% of the mutant allele relative to his affected son. This first report of somatic mosaicism in an unaffected parent with an INS mutation suggests that parental mosaicism may be responsible for the transmission of PND in patients with de novo INS mutations. As such, appropriate counseling for recurrent risks should be considered and we recommend that molecular genetic testing for future siblings at birth should be offered to the parents of children with INS mutation.     

Expression of two functionally different androgen receptors in a patient with androgen insensitivity

Recently, we demonstrated a previously unknown high rate of de novo mutations of the androgen receptor (AR) gene in androgen insensitivity syndrome (AIS) with some resulting in somatic mosaicism of mutant and wild type AR alleles. However, data on the genotype-phenotype relationship in the latter patients are sparse. We present here a 46,XY newborn with ambiguous genitalia carrying a mosaic of an 866 GTG (Val) → ATG (Met) mutation with the wild type AR gene. This mutation has usually been associated with complete AIS. Accordingly, we found markedly impaired transactivation due to the mutant Met⁸⁶⁶ AR. Essential information arose from Scatchard analysis of methyltrienolone binding on cultured genital skin fibroblasts. We demonstrated for the first time the expression of two functionally different ARs (K_d1: 5.58 nM = mutant, K_d2: 0.06 nM = wild type) in one AIS individual. This finding not only represents an important confirmation for the presence of the somatic mosaicism in the patient, it also indicates the most likely molecular mechanism responsible for the unexpectedly strong virilization of the patient: Androgen action through the wild type AR expressed by part of the somatic cells. Conclusions The present case clearly demonstrates the molecular mechanism by which somatic mosaicism of the androgen receptor gene can modulate in vivo androgen action. It underlines the importance of particular notice on somatic mosaicism in all androgen insensitivity syndrome patients carrying de novo mutations of the androgen receptor gene. Received: 24 August 1998 / Accepted in revised form: 5 January 1999     

Single-voxel MR spectroscopy and diffusion-weighted MRI in two patients with <Emphasis Type="SmallCaps">l</Emphasis>-2-hydroxyglutaric aciduria

l-2-Hydroxyglutaric aciduria is a rare inherited, neurometabolic disorder. The underlying metabolic defect and the pathophysiology of l-2-hydroxyglutaric aciduria have not yet been defined. We present MR spectroscopy and cranial MR imaging findings, including diffusion-weighted sequences in two male siblings (aged 10 and 12 years). MR spectroscopy revealed a multiplet at 2.10–2.50 ppm and two broad peaks at 0.9–1.6 ppm. The multiplet at 2.10–2.50 ppm might have been created by elevated glutamate and glutamine or l-2-hydroxyglutaric acid itself, which has a similar chemical structure to glutamate. Diffusion-weighted images demonstrated increased diffusion of water molecules in the white-matter lesions.     

Novel DCX mutation‐caused lissencephaly in a boy and very mild heterotopia in his mother

We describe a novel mutation in DCX in a family in which a proband boy had classical lissencephaly and his mother had extremely mild subcortical band heterotopia. No factors that would make the mother's symptoms milder, such as somatic mosaicism or skewed X chromosome inactivation, were observed. From this family, we conclude that a DCX mutation causes a pleiotropic phenotype in the female even if X chromosome inactivation pattern is not skewed, and the novel missense mutation in DCX produced relatively mild dysfunction of the doublecortin protein.     

广西黑衣壮族高胆红素血症新生儿UGT1A1基因突变分析

目的 探讨广西黑衣壮族高胆红素血症新生儿尿苷二磷酸葡萄糖醛酸转移酶1A1（UGT1A1）基因的突变分布特点及其与高胆红素血症的关系。方法 提取黑衣壮族高胆红素血症新生儿（病例组）及对照组新生儿血液基因组DNA各100例,对UGT1A1 启动子TATA盒及所有外显子进行PCR扩增及直接测序。结果 检测到UGT1A1 启动子TATA盒（TA）7插入突变、第1外显子G71R错义突变及第5外显子中4个SNP位点（rs199539868、rs114982090、rs1042640、rs8330）。病例组的G71R等位基因频率显著高于对照组（PP>0.05）。Logistic回归分析显示UGT1A1 TATA盒、G71R、rs1042640及rs8330对新生儿高胆红素血症发生的OR值（95%CI）分别为0.846（0.440,1629）、3.932（1.745,8.858）、0.899（0.364,2.222）。结论 UGT1A1基因（TA）7插入突变与G71R错义突变是广西黑衣壮族高胆红素血症新生儿的常见突变类型,4个SNP 位点（rs199539868、rs114982090、rs1042640、rs8330）为国内首次报道。UGT1A1 G71R错义突变是广西黑衣壮族新生儿高胆红素血症的危险因素。     

A novel missense mutation in SUCLG1 associated with mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria

Mitochondrial DNA depletion, encephalomyopathic form, with methylmalonic aciduria is associated with mutations in SUCLA2, the gene encoding a β subunit of succinate-CoA ligase, where 17 patients have been reported. Mutations in SUCLG1, encoding the α subunit of the enzyme, have been reported in only one family, where a homozygous 2 bp deletion was associated with fatal infantile lactic acidosis. We here report a patient with a novel homozygous missense mutation in SUCLG1, whose phenotype is similar to that of patients with SUCLA2 mutations.     

Azacitidine and Sorafenib Therapy in a Pediatric Patient With Refractory Acute Myeloid Leukemia With Monosomy 7 and Somatic PTPN11 Mutation

Monosomy 7 is a well‐documented cytogenetic aberration in pediatric acute myeloid leukemia (AML) and may occur in combinations with molecular abnormalities including PTPN11 mutation. PTPN11 mutations contribute to leukemogenesis through upregulation of Ras pathway signaling. We present the case of a 3‐year‐old female with AML with monosomy 7 and somatic PTPN11 mutation who was refractory to conventional AML chemotherapy but responded to a novel regimen of azacitidine and sorafenib followed by stem cell transplantation. Combination therapy with azacitidine and sorafenib may be an effective therapeutic strategy for patients with AML with Ras pathway abnormalities.     

Vitamin D deficiency and its relationship with cardiac iron and function in patients with transfusion-dependent thalassemia at Chiang Mai University Hospital

Background: Vitamin D deficiency is common in patients with thalassemia. Vitamin D deficiency could be related to cardiac dysfunction. Increased parathyroid hormone (PTH) is also known to be associated with heart failure. Objectives: To determine the prevalence of Vitamin D deficiency and to explore the impact of Vitamin D deficiency on cardiac iron and function in patients with transfusion-dependent thalassemia. Method: A cross-sectional study in patients with Transfusion-dependent thalassemia was conducted. Patients with liver disease, renal disease, type 1 diabetes, malabsorption, hypercortisolism, malignancy, and contraindication for MRI were excluded. Calcium, phosphate, PTH, vitamin D-25OH were measured. CardiacT2^* and liver iron concentration (LIC) and left ventricular ejection fraction (LVEF) were determined. Results Sixty-one (33M/28F) patients with Transfusion-dependent thalassemia were enrolled. The prevalence of Vitamin D deficiency was 50.8%. Patients with cardiac siderosis had tendency for lower D-25OH than those without siderosis (15.9 (11.7–20.0) vs. 20.2 (15.85–22.3) ng/mL); p = 0.06). Serum calcium, phosphate, PTH, LIC, cardiac T2^*, and LVEF were not different between the groups with or without Vitamin D deficiency. Patients with Vitamin D deficiency had significantly lower hemoglobin levels compared to those without Vitamin D deficiency (7.5 (6.93–8.33) vs. 8.1 (7.30–8.50) g/dL; p = 0.04). The median hemoglobin in the last 12 months was significantly correlated with D-25OH. Cardiac T2^* had significant correlation with PTH. Conclusion: Vitamin D deficiency is prevalent in patients with Transfusion-dependent thalassemia. Vitamin D level is correlated with hemoglobin level. Vitamin D status should be routinely assessed in these patients. Low PTH is correlated with increased cardiac iron. This study did not demonstrate an association between Vitamin D deficiency and cardiac iron or function in patients with Transfusion-dependent thalassemia.     

Genetics of McCune-Albright syndrome

McCune-Albright syndrome (MAS) is a rare proteiform disease due to postzygotic, somatic mutations at codon R201 of the GNAS1 gene that results in cellular mosaicism. Different methods have been used in the molecular analysis of DNA samples from several tissues of patients with one or more MAS signs, with various mutation detection rates. We review data from the literature to investigate whether patient inclusion criteria for GNAS1 analysis, the molecular methods used to search for R201 mutations, and the type of tissues analysed, can influence the mutation detection rate in MAS. Our study indicates that to overcome the problems related to GNAS1 analysis in MAS, sensitive and specific molecular methods must be used to look for the mutation from all available affected tissues and from easily accessible tissues, and even more so in the presence of atypical and monosymptomatic forms of MAS.     

Exome capture and massively parallel sequencing identifies a novel HPSE2 mutation in a Saudi Arabian child with Ochoa (urofacial) syndrome

We describe a child of Middle Eastern descent by first-cousin coupling with idiopathic neurogenic bladder and high-grade vesicoureteral reflux at 1 year of age, whose characteristic facial grimace led to the diagnosis of Ochoa (urofacial) syndrome at age 5 years. We used homozygosity mapping, exome capture and paired-end sequencing to identify the disease causing mutation in the proband. We reviewed the literature with respect to the urologic manifestations of Ochoa syndrome. A large region of marker homozygosity was observed at 10q24, consistent with known autosomal recessive inheritance, family consanguinity and previous genetic mapping in other families with Ochoa syndrome. A homozygous mutation was identified in the proband in HPSE2: c.1374_1378delTGTGC, a deletion of 5 nucleotides in exon 10 that is predicted to lead to a frameshift followed by replacement of 132 C-terminal amino acids with 153 novel amino acids (p.Ala458Alafsdel132ins153). This mutation is novel relative to very recently published mutations in HPSE2 in other families. Early intervention and recognition of Ochoa syndrome with control of risk factors and close surveillance will decrease complications and renal failure.     

Activity of enzymes involved in energy production in the small intestine during suckling-weaning transition of pigs

The effect of weaning on a potential metabolic capacity of key enzymes involved in the energy production by porcine enterocytes was investigated. The activity of citrate synthase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, glutamate dehydrogenase, alanine aminotransferase and aspartate aminotransferase was determined in the small intestine epithelium of piglets during suckling-weaning transition. Investigations were performed on 5-week-old (suckling), 6-week-old (1st week after weaning) and 7-week-old (2nd week after weaning) piglets. The activity of glutamate dehydrogenase decreased (p < 0.05) during the 1st week after weaning, and remained numerically lower during the 2nd week after weaning than in suckling piglets. The activities of isocitrate dehydrogenase and alanine aminotransferase showed the same pattern as the glutamate dehydrogenase activity and decreased numerically during the 1st and 2nd weeks. The activities of citrate synthase and alpha-ketoglutarate dehydrogenase were numerically lower in post-weaned piglets (1st and 2nd weeks) than in suckling piglets. In contrast, the activity of aspartate aminotransferase was high and remained unchanged from week 5 to the 2nd week post-weaning. The activities of alanine and aspartate aminotransferase were positively correlated in suckling piglets (r = 0.98, p < 0.05) and at the 1st week after weaning (r = 0.99, p < 0.01). Also, both aminotransferases were positively correlated to the activity of alpha-ketoglutarate dehydrogenase in suckling piglets (r = 0.95, p < 0.05 and r = 0.95, p < 0.05) and to the activity of isocitrate dehydrogenase during the 1st week after weaning (r = 0.99, p < 0.001 and r = 0.99, p < 0.01). The results indicate additional capacity of the tricarboxylic acid (TCA) cycle for transformation of alpha-ketoglutarate from other sources than acetyl-CoA such as glutamine, glutamate and other amino acids. Further, the high activity of aspartate aminotransferase also suggests a high capacity of porcine small intestinal epithelium to provide the TCA cycle with oxaloacetate during the suckling-weaning transition.     

Rett综合征的临床特点及MECP2基因突变分析

目的 分析典型的Rett综合征患者的临床特点,并对患儿甲基化CpG结合蛋白-2（MECP2）基因进行突变分析。方法 使用PCR扩增和测序的方法 对近期诊断的9例RETT综合征患儿及其父母MECP2基因的3个外显子进行检测。结果 在9例患儿中发现5例存在MECP2基因的杂合突变,突变率超过50%,其中1例为碱基插入导致的移码突变（c.913insT）;其余4例为点突变,分别为位于外显子3的c.316C>T（R106W）,位于外显子4的c.502C>T（R168X）、c.808C>T（R270X）和c.1126C>T（P376S）,其中c.913insT为首次发现的突变,这些患儿父母均未检测到突变。2例患儿MECP2基因突变位于转录抑制区域,与其他患儿相比,这2个患儿语言功能几乎丧失,且发育明显落后。结论 该研究确诊的5例Rett综合征的患儿存在MECP2基因突变,且多数位于外显子4上;MECP2蛋白转录抑制区域突变可能影响患儿语言功能及发育明显落后。     

SIRT1在急性髓系白血病患儿骨髓活检组织中的表达及临床意义

目的 了解SIRTl 在急性髓系白血病（AML）患儿骨髓活检组织中的表达水平,并分析其与AML 预后的相关性。方法 回顾性分析2009 年7 月至2012 年4 月确诊为AML 并于初诊时行骨髓活检检查的54 例患儿的临床资料。采用免疫组织化学染色方法检测患儿骨髓活检组织中SIRTl 的表达;根据SIRT1 的表达情况将病例分为SIRT1 阴性组（n=10）和SIRT1 阳性组（n=44）,再根据SIRT1 表达的阳性程度进一步将SIRT1 阳性组分为（+）组（n=8）、（2+）组（n=7）和（3+）组（n=29）,比较各组患儿的预后。Cox 多因素回归分析患儿长期生存的危险因素。结果 SIRT1（3+）组病死率明显高于SIRT1 阴性组（PPPP=0.045,危险系数绝对值=2.071,95%CI：1.017~4.219）。结论 部分AML患儿骨髓活检组织存在SIRTl表达增高情况,且SIRTl高表达与不良预后相关。     

Riboflavin treatment in a case with l-2-hydroxyglutaric aciduria

L-2-hydroxyglutaric aciduria (LHGuria) is a rare neurometabolic disorder, which has characteristic clinical and laboratory features. The recent findings imply that LHG dehydrogenase is responsible for the disease and is FAD-dependent. Therefore, it might be expected that riboflavin could enhance any residual activity. We present our observations from nearly 2-year-long riboflavin treatment in a 16-year-old boy with LHGuria. During riboflavin treatment of 100 mg/d, partial improvement in his cognitive and motor performances was observed. Urinary LHG excretion decreased from 5990 mmol/mol creatinine to 1490 mmol/mol creatinine. Moreover, when riboflavin treatment was interrupted, significant disturbances in both symptoms and urinary LHG excretion (6360 mmol/mol creatinine) occurred in the patient. After the resettlement of riboflavine treatment, the patient resumed to his previous clinical status in a week. The improvement went further minimally under the dose of 200 mg/d, but no further improvement happened with 300 mg/d. The present case suggests that riboflavin could be considered as a potential therapeutic approach in LHGuria until the optimal treatment of LHGuria is established.     

Hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia

Two cases of hyperinsulinaemic hypoglycaemia associated with persistent hyperammonaemia in unrelated infants of 7 days and 4 months of age are reported. Blood ammonia levels were 100–300 μmol/l (normal values<40 μmol/l). The hyperammonaemia was asymptomatic and not associated with any of the abnormalities of amino acids or organic acids observed in urea cycle enzyme defects. Orotic aciduria was normal. The hyperammonaemia was not influenced by the levels of blood glucose nor by subtotal pancreatectomy. On admission blood glucose was ca. 1.2 mmol/l (21.6 mg/dl) corresponding to blood insulin levels of 35 and 22 mU/l respectively in both infants. Continuous intravenous glucose perfusion was necessary to prevent hypoglycaemia. Furthermore 2-oxoglutaric acid in urine was increased in the second infant to 3.15 mg/mg creatinine (normal 0.41 +/−0.12). This may point to mutations in the glutamate dehydrogenase gene. Conclusion 2-Oxoglutaric aciduria may be an important clue to the diagnose in this syndrome. Received: 6 January 1998 / Accepted: 25 November 1998