婴儿型低磷酸酶血症1例报告

<正>低磷酸酶血症(hypophosphatasia,HPP)由Rathbun在1948年首次提出^[1]。它主要是由组织非特异性碱性磷酸酶(tissue non-specific alkaline phosphatase,TNSALP)活性减低引起钙磷代谢异常,从而导致骨骼或牙齿矿化障碍的遗传代谢性疾病,也可出现癫痫、肌无力等症状。TNSALP由ALPL (the liver/bone/kidney alkaline phosphatase gene)基因编码,该基因的致病变异常导致TNSALP活性改变,     

低碱性磷酸酶血症一家系临床与基因分析

目的探讨组织非特异性碱性磷酸酶(TNSALP)基因检测在低碱性磷酸酶血症(HPP)产前诊断中的作用。方法回顾分析1例新生儿HPP患儿的临床资料,以及全外显子组测序检测TNSALP基因结果;采集家系成员外周血,及患儿母亲第2胎孕17周胎儿的羊水细胞,进行候选基因突变的Sanger测序验证。结果患儿,男性、6日龄,主要表现为多发性骨折,肢体缩短弯曲,呼吸困难,生后9天死于呼吸衰竭;血清碱性磷酸酶下降,血钙轻度下降,血磷正常,血清25羟维生素-D和甲状旁腺激素均正常;X线显示全身骨骼严重矿化不良,长骨干骺端增大呈杯口状,多发性骨折;基因测序结果显示患儿TNSALP基因存在一复合杂合性错义突变,分别为位于第6外显子内的杂合性错义突变c.542CT导致第181位氨基酸由丝氨酸突变为亮氨酸(p.S181L),第10外显子内杂合性错义突变c.1016GA导致第339位氨基酸甘氨酸突变为谷氨酸(p.G339E);患儿父母表型均正常,c.542CT突变遗传自父亲,c.1016GA突变遗传自母亲。胎儿未检出这两种突变。结论 TNSALP基因分析可应用于HPP的诊断以及产前诊断。     

低碱性磷酸酶血症六例临床和基因分析

目的:分析低碱性磷酸酶血症(HPP)患儿的临床特点、基因变异类型及随访资料。方法:回顾性总结分析2010年10月至2019年1月北京儿童医院内分泌遗传代谢中心收治的6例HPP患儿的临床资料,并对其中5例患儿及家系进行致病基因测序分析,总结其临床特点和基因变异类型及转归。结果:6例HPP患儿中男5例、女1例,年龄2月龄至6岁4月龄,血碱性磷酸酶均明显降低(2~49 U/L),婴儿型4例、儿童型与牙型各1例。婴儿型患儿均有纳差、体重增长缓慢及高钙血症,儿童型与牙型患儿均有牙齿脱落,儿童型患儿伴有跛行等运动功能改变。5例患儿及其中4个家系发现10个组织非特异性碱性磷酸酶基因变异,7个错义变异,1个插入变异,1个移码变异,1个缺失变异,其中3个为新发变异(p.Y28C、p.268,F>L、p.A176V)。4例婴儿型HPP患儿中3例死亡,1例好转后失访,儿童型和牙型HPP患儿经治疗后好转。结论:HPP各型之间的临床表现变异性大又相互重叠,儿童型及牙型预后较好,婴儿型预后较差,基因检测是明确诊断的主要方法。     

新复合杂合突变致婴儿型低磷酸酯酶症1例及其家系分析

该文对1例婴儿型低磷酸酯酶症(HPP)患儿及其家系进行临床特点分析及碱性磷酸酯酶基因(ALPL)检测。先证者,男,5个月,多发骨骼畸形:胸骨凹陷、双侧桡骨弯曲畸形、双膝外翻畸形,伴喂养困难、体重下降、发育迟滞、反复肺炎并呼衰,血碱性磷酸酶显著降低。患儿父母、姐姐、叔父、姨母(其他家系成员未能配合)中除父母及姨母的碱性磷酸酶略低,姨母可见脊柱侧弯畸形,余均无临床表型及实验室异常。患者ALPL基因检测到来源于母亲的c.228delG突变及来源于父亲的c.407GA复合杂合突变,其姨母携带c.228delG突变。c.407GA突变为已报道的HPP致病突变,c.228delG为新的致病性突变。低磷酸酯酶症是由ALPL基因突变所致,ALPL基因检测是有效的诊断方法。该研究拓展了ALPL基因突变谱,为HPP的基因诊断提供了理论依据。     

5 例低磷酸酯酶症患儿临床及遗传学分析

目的总结低磷酸酯酶症(HPP)的临床及遗传学特点。方法回顾分析5 例HPP患儿的临床资料,以及患儿及其亲属的外周血高通量测序及Sanger验证结果。结果 5例患儿均有骨骼矿化不良以及血清碱性磷酸酶降低,3例伴有惊厥等神经系统症状。5例HPP患儿高通量测序共发现ALPL6个突变位点,c.346GA(p.A116T)、c.1097至c.1099del CCT复合杂合突变(p.T366_S367deli)、c.1014至c.1015ins G(p.H338fs)、c.1446CA(p.482HQ)复合杂合突变、c.920CT(p.P307L)、c.883AG(p.M295V),其中c.1014_c.1015ins G、c.1097_c.1099del CCT、c.1446CA为首次报道,蛋白质结构预测均为可能有害,ACMG评级为可能致病。结论确诊5例HPP患儿,发现 3种新型突变,丰富了人类ALPL基因突变数据库。     

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甲状旁腺功能减低症(HPP)是新生儿和儿童低钙血症的常见病因之一,其发病是由于甲状旁腺素(PTH)分泌减少和(或)功能障碍所导致的一组临床综合征。临床特征主要为低血钙引起的症状,低钙血症及高磷血症。在儿童HPP众多的病因中,以特发性HPP多见,患病率为0·72/10万,假性HPP患病率为0·34/10万[1]。1病因分类在PTH合成、释放及与受体结合发挥生理效应的全过程中,任何环节的障碍均可导致HPP的发生。其病因主要包括PTH的生成减少、分泌抑制以及作用障碍3类[2]。1.1PTH生成减少PTH合成障碍主要有特发性和继发性两类病因,儿童以特发性H…     

婴儿型低磷酸酯酶症1例

低磷酸酯酶症(hypophosphatasia,HOPS)是一种罕见的遗传代谢性疾病,以骨骼、牙齿矿化障碍和组织非特异性ALP(TNSALP)活性低下为特征.其中婴儿型HOPS病情严重,病死率高,常易误诊.现报告1例,以加深对该病的认识.     

表现为类佝偻病的遗传性疾病

总结在发育儿科或儿童保健门诊因腿弯、前囟未闭、头发少等类佝偻病症状就诊的遗传性疾病的临床特点、致病基因及治疗进展,这些遗传性疾病包括低血磷抗维生素D佝偻病、低碱性磷酸酶血症、软骨发育不全、维生素D依赖性佝偻病、致密性骨发育不全和外胚层发育不全。低血磷抗维生素D佝偻病的患儿经常以腿弯、生长迟缓就诊,生化检查血磷明显降低,临床容易诊断。该病治疗与营养性维生素D缺乏性佝偻病不同,需要用1,25羟维生素D3和磷酸盐合剂治疗。低碱性磷酸酶血症特点为碱性磷酸酶明显降低,血钙和磷正常,是由于TNSALP基因突变所致。软骨发育不全患儿除腿弯外,还存在短肢型矮小和特殊面容,血钙、磷和碱性磷酸酶等生化检查均正常,骨骼X线及FGFR3基因检测有助于诊断。维生素D依赖性佝偻病为常染色体隐性遗传,治疗中可选择补充生物活性的维生素D。致密性骨发育不全患儿可因前囟大就诊,此类患儿除了前囟大以外,还伴有下颌角消失、牙齿及指甲发育差等表现,系TSK基因突变所致。外胚层发育不全患儿可因头发少就诊,易误诊为营养性维生素D缺乏性佝偻病,与EDA、EDAR、EDARADD及WNT 10A 4种基因有关。     

MK-801对新生大鼠脑缺氧缺血后Caspase-3激活及其对凋亡的影响

目的：探讨N-甲基-D-天冬氨酸(NMDA)受体拮抗剂MK-801对新生大鼠缺氧缺血(HI)后半胱天冬酶-3(Caspase-3)激活及凋亡的影响。方法：7日龄新生大鼠在HI后即刻给予腹腔注射MK-801 0.5 mg/kg,在HI后24 h取脑制作脑组织连续切片进行微管相关蛋白 2(MAP-2),Caspase-3免疫组化染色及发夹寡核苷酸探针(Hairpin Probe, HPP)原位杂交,计算脑损伤面积及Caspase-3,HPP阳性细胞数。结果：①MK-801干预组脑损伤面积为(23±5)%,较生理盐水对照组(52±12)%明显降低,P<0.01;②MK-801干预组Caspase-3及HPP阳性细胞数(65±8)/高倍视野,(61.6±11.5)/高倍视野,与对照组(40±6.7)/高倍视野,(12.6±5.2)/高倍视野相比均明显减少,其中HPP阳性细胞数减少比Caspase-3阳性细胞数减少更明显。结论：MK-801能明显抑制Caspase-3的激活,减少神经元的凋亡,减轻缺氧缺血性脑损伤(HIBD)的程度。     

妊娠期低水平铅暴露对新生儿血清钙、骨钙素及骨碱性磷酸酶的影响

目的研究妊娠期低水平铅暴露对新生儿血清钙(Ca)、骨钙素(OC)及骨碱性磷酸酶(BALP)的影响。方法于新生儿娩出断脐后采集脐静脉血5 ml分别检测血铅、血清钙、血清骨钙素及骨碱性磷酸酶,将新生儿以血铅值50μg/L、100μg/L为界分为低铅组(<50μg/L)、相对高铅组(50～99μg/L)和高铅组(≥100μg/L),研究脐血铅对新生儿骨代谢相关指标的影响。结果新生儿脐血铅水平与其血清骨钙素、血清钙水平呈负相关,与骨碱性磷酸酶水平呈正相关。高铅组与低铅组比较,血清骨钙素水平、血清钙几何均数水平显著降低;高铅组碱性磷酸酶水平显著高于相对高铅组及低铅组。结论妊娠期低水平铅暴露可能干扰了新生儿骨代谢。     

Homozygosity for TNSALP mutation 1348c>T (Arg433Cys) causes infantile hypophosphatasia manifesting transient disease correction and variably lethal outcome in a kindred of black ancestry

OBJECTIVE: To determine the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP) defect underlying transiently reversible and variably lethal infantile hypophosphatasia (HPP) in a kindred and to characterize HPP prevalence in black people. STUDY DESIGN: In 1986, we reported temporary correction of severe HPP in an American kindred of black ancestry where "infantile" HPP was fatal in 2 of 3 affected individuals representing 2 sibships. This transient improvement in 1 patient followed efforts to increase TNSALP activity endogenously and suggested dysregulation of the gene (TNSALP). Here, we sequenced the coding exons and splice sites of the kindred's TNSALP alleles and reviewed our 30-year experience with HPP to assess its prevalence in black people. RESULTS: Homozygosity for TNSALP missense mutation 1348C>T (Arg433Cys) accounted for this kindred's infantile HPP. The TNSALP promoter sequence was normal. Modeling of TNSALP(433Cys) suggested compromise of the catalytic site. Ethnicity was identified for the 119 families with HPP studied in St. Louis, and race was ascertained for an additional 159 of our 235 consult and HPP families worldwide. In this experience, only this family was of black ancestry. CONCLUSIONS: Infantile HPP from homozygous TNSALP(433Cys) can remit and thus harbor clues regarding the phenotypic variation and perhaps treatment of HPP.     

Enzyme-replacement therapy in perinatal hypophosphatasia: Case report and review of the literature

Hypophosphatasia (HPP) is a rare disease resulting from alterations of the ALPL gene encoding tissue-nonspecific alkaline phosphatase (TNSALP). Perinatal HPP is mainly characterized by bone hypomineralization and severe respiratory insufficiency. We describe a full-term boy diagnosed with perinatal HPP after birth, showing dramatic improvement after treatment with Asfotase Alfa, an enzyme-replacement therapy (ERT) prescribed in HPP cases. He initially presented with respiratory insufficiency due to bone hypomineralization, and severe pulmonary hypoplasia that required tracheostomy and invasive ventilation for 8 months. He was taken off ventilation at 41 weeks of age. He also presented complications including hypercalcemia, craniosynostosis, nephrocalcinosis, hypotonia, and a severe feeding disorder. He is still alive at 30 months of age, and his respiratory status and tonus is steadily improving. This case reflects the progression of HPP patients with specific therapy added to symptomatic management. Some aspects of the disease are now well known, such as nephrocalcinosis and craniosynostosis, related to the natural course of the disease, which persisted despite the ERT. The long-term prognosis and outcome for this newborn child remain unknown.     

Childhood hypophosphatasia: a case report due to a novel mutation]

Hypophosphatasia is characterized by defective bone mineralization associated with impaired activity of the tissue non-specific alkaline phosphatase (TNSALP) due to mutations in the TNSALP gene. We describe a child with a mutation that has not been described up to now. CASE REPORT: A 4-year-old child presented with clinical symptoms of rickets and premature loss of decideous teeth. Reduced serum alkaline phosphatase activity and radiographic features led to the diagnosis of hypophosphatasia, which was confirmed by genetic investigation. The molecular study showed two missense mutations, of which one is a novel mutation. CONCLUSION: Hypophosphatasia is suspected in a child with rickets and premature loss of decideous teeth. Such symptoms should prompt the search of a reduced serum alkaline phosphatase activity. The clinical and molecular diagnosis of the disease is important for the genetic counseling but also for a proper determination of prognosis, as it is related to the type of mutation.     

Chronic multifocal non-bacterial osteomyelitis in hypophosphatasia mimicking malignancy

Background  

Hypophosphatasia (HP) is characterized by a genetic defect in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and predominantly an autosomal recessive trait. HP patients suffer from reduced bone mineralization. Biochemically, elevated concentrations of substrates of TNSALP, including pyridoxal-5'-phosphate and inorganic pyrophosphate occur in serum, tissues and urine. The latter has been associated with chronic inflammation and hyperprostaglandinism.     

Reversible electrophysiological abnormalities in hypokalemic periodic paralysis

Compound muscle action potential (CMAP) amplitude declines during a paralytic attack in patients with hypokalemic periodic paralysis (HPP). However, serial motor nerve conduction studies in HPP have not been commonly reported. We report a 9 year old girl with HPP, who had severely reduced CMAPs in all motor nerves at presentation during the episode of quadriparesis. However, the amplitude of CMAPs increased and reached normal levels as the serum potassium concentration and motor power returned to normal state.     

Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia

A total of 22 Japanese patients with hypophosphatasia were included in a study analysing the relationship between mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene and the severity of the phenotype in Japanese patients with hypophosphatasia. The enzymatic activity of some of the identified mutant TNSALP proteins was also examined using corresponding expression vectors. Eighteen mutations, including 6 novel ones, were identified in the patients. Among them, the common mutations were F310L and T1559del. Of note, five patients with F310L mutation in one of the alleles exhibited a relatively mild phenotype without respiratory complications despite its perinatal onset. In contrast, the T1559del mutation is associated with perinatal lethal and infantile forms when not found in patients with the F310L mutation. The genotype-phenotype relationship was, to some extent, consistent with the enzymatic activity of the mutant ALP proteins; mutations K207E and G409C found in a surviving case of infantile hypophosphatasia, as well as F310L, retained some residual activities, whereas T1559del caused a complete loss of activity. Conclusion:In Japanese patients, the common mutations F310L and T1559del are associated with the relatively mild and lethal forms of hypophosphatasia, respectively. Our results may enhance the importance of genotyping patients with hypophosphatasia to predict their prognosis.     

Health Promotion in a Low-income Primary School: Children with and Without DCD Benefit,but Differently

ABSTRACT

Poor motor performance and reduced physical fitness are characteristic of children with Developmental Coordination Disorder (DCD). These features have also been identified more frequently among children living in low socio-economic circumstances. Aims: To evaluate the outcomes of a nine-week health promotion program (HPP) on the motor performance and fitness levels of children (6–10 years) with and without DCD attending a low-income primary school. Methods: The HPP was designed and implemented by undergraduate physiotherapy students using guidelines from the World Health Organization School Health Initiative and their physiotherapy curriculum. Children with DCD (n = 22) and a control group without DCD (n = 19) participated in the evaluation. Motor skill, functional strength, aerobic capacity, and anaerobic power were measured at baseline and after nine weeks. Results: Both groups of children improved on all measures at the conclusion of the HPP. Children with DCD showed greater improvement than the control group in motor performance and the control group showed greater improvement on one of the anaerobic fitness outcomes. Conclusions: A school-based HPP that focuses on increasing opportunities for physical activity may be effective in improving motor performance in children with DCD and can increase fitness levels in general.     

Wachstumsstillstand als einziges klinisches Zeichen eines erhöhten Hirndrucks bei einer Patientin mit Hypophosphatasie vom infantilen Typ

Background. Hypophosphatasia is a rare inherited disorder characterised by defective bone mineralisation and deficiency of the tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is classified into four subtypes according to the time of its first presentation. The severity of the disease depends on the remaining activity of the liver/bone/kidney alkaline phosphatase which explains the clinical variety of the disease. Case report. We report on a patient suffering from the infantile type of hypophosphatasia. Mutation analysis revealed an already known point mutation for the maternal and a so far not described mutation of the TNSALP gene for the paternal allele. The girl showed a good development during her first two years of life despite the poor prognosis for this condition. A chronically raised intracranial pressure solely lead to a growth stop in her second year of life. In an infant with hypophosphatasia a raised intracranial pressure due to craniosynostosis must be excluded during follow-up examinations on a regular basis despite missing clinical symptoms.