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.     

Hipofosfatasia: manifestaciones clínicas,recomendaciones diagnósticas y opciones terapéuticas

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations.Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia.On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options.     

新生儿X-连锁慢性肉芽肿病4例分析暨文献复习

目的了解X-连锁慢性肉芽肿病（X-CGD）患儿的临床特点、治疗方法及基因突变类型。方法选择我科2013年4-12月经基因检测明确诊断为X-CGD的病例,总结患儿起病时间、症状、影像学表现、病原学检查、治疗及转归情况,了解基因突变类型。结果研究期间共收治4例X-CGD患儿,均为男婴,起病日龄13~17天,诊断日龄24-34天,1例有家族史。首发症状发热3例,咳嗽1例。肺CT表现为结节、不规则、球形或类圆形高密度灶。痰培养1例为烟曲霉菌和金黄色葡萄球菌,1例为白色念珠菌,2例阴性;血培养均阴性;血清半乳甘露聚糖（GM）试验阳性3例。应用抗细菌联合抗真菌治疗2-3周,4例均好转出院,随访6个月3例未复发,1例出院后未按医嘱服药生后5个月因反复严重感染死亡。CYBB基因突变分析示缺失突变1例,插入突变1例,错义突变2例,患儿母亲均为携带者。结论本病在新生儿期呼吸道症状及体征相对较轻,但影像学显示肺部病变严重,肺CT表现为多发结节或团块影,常规体液和细胞免疫功能正常的新生儿应考虑X-CGD。CYBB基因突变分布广泛,异质性明显,基因突变分析将成为产前诊断的重要工具。     

Scorpion sting in children. A review of 51 cases

Scorpion sting in children is a hazardous and potentially lethal condition. Fifty-one infants and children were admitted to the Pediatric Departments at the Hadassah-Hebrew University Hospitals in Jerusalem, during a 5-year period, following scorpion sting. Fifteen (29.4%) had severe systemic signs of envenomation and two (3.9%) died. Analysis of our data showed that patients with severe toxicity were brought to the hospital after a significantly longer time lapse than were the patients with mild-to-moderate symptoms. The current management of children with scorpion envenomation consists of administration of specific antivenom and close surveillance in an intensive care unit, where vital signs and continuous cardiac monitoring enable early initiation of therapy for life-threatening complications, such as cardiac and respiratory failure, convulsions, or hypertension.     

A Case of Vitamin D Deficiency without Elevation of Serum Alkaline Phosphatase in a Carrier of Hypophosphatasia

Elevated serum alkaline phosphatase (ALP) is a screening marker for the diagnosis of vitamin D deficiency, which may fail to be diagnosed if serum ALP is not elevated. Here, we describe a case of vitamin D deficiency without elevation of serum ALP. A 1-year-old Japanese girl was referred to our hospital for the evaluation of genu varum. Her serum intact PTH level was elevated, while her serum ALP level was normal. Furthermore, her serum 25-hydroxyvitamin D level was reduced, and her urine phosphoethanolamine (PEA) level was mildly elevated. ALPL gene analysis revealed she was a heterozygous carrier of hypophosphatasia (c.1559delT). Serum intact PTH and urine PEA evaluations were helpful for diagnosing vitamin D deficiency and hypophosphatasia carrier status, respectively. Therefore, the possibility of vitamin D deficiency without elevation of serum ALP should be considered.     

新生儿磷酸酶过少症

低磷酸酯酶症是一种少见的先天性代谢疾病。该文对其发病机制、分型及临床表现、鉴别诊断、治疗和预后进行了综述,并介绍了在该院诊断明确的1例新生儿型的罕见病例,患儿为出生30 min女婴,产前B超提示胎儿双顶径与四肢长骨不成比例,生后即有明显的颅骨软化、呼吸困难和紫绀等表现,血碱性磷酸酶（ALP）显著低下,X线表现及尸检结果均提示骨骼矿化极度低下,4 d后因呼吸衰竭死亡。     

新生儿重症监护室内假丝酵母菌败血症感染九例分析

目的分析新生儿重症监护室内假丝酵母菌败血症的临床特点。方法总结9例确诊病例的临床特征,进行易感因素分析。结果9例均为早产儿,极低出生体重儿6例。9例真菌感染前全部接受广谱抗生素治疗及静脉营养,8例留置中心静脉导管（ PICC, percutaneous inserted central catheter）,3例曾机械通气。生后8～22d出现呼吸暂停、灌注差、反应差等症状,7例血小板减少,7例C反应蛋白升高。血培养白色假丝酵母菌1例,近平滑假丝酵母菌2例,季也蒙假丝酵母菌6例,5例PICC导管尖端培养和血培养同时阳性,且为同一菌株。9例均接受抗真菌及对症支持治疗,6例治愈,1例放弃治疗自动出院,2例死亡。结论新生儿假丝酵母菌败血症的高危因素包括早产、留置PICC、长期应用广谱抗生素、机械通气等,症状常不典型,可伴有血小板减少,C反应蛋白轻中度升高等,早期积极治疗预后较好。     

4月龄以内起病的炎症性肠病7例临床特点及基因诊断病例系列报告

目的 总结4月龄内起病的炎症性肠病（IBD）的临床特点和基因诊断,引起临床医师对以不明原因腹泻起病的小婴儿IBD的重视。方法 收集北京大学第一医院儿科2007至2015年收治的7例4月龄以内起病的IBD临床资料和其中5例行相关基因（IL10RA、IL10RB、IL6、NOD2、IRGM、ABCB1、ATG16L1、IL23R和IRF5）突变的检测资料。结果 7例患儿起病时间生后4 d至4月龄,均以腹泻、血便或便潜血阳性为首发症状,伴体重增长不良,肠外症状主要表现为发热、口腔溃疡和肛周病变。5例有阳性家族史。辅助检查多表现为血WBC、PLT、CRP、ESR升高,5例自身抗体阳性。肠镜特点为结肠广泛多发溃疡,病理多表现为非特异性的肠道炎症,可有隐窝炎及脓肿。5例行基因检测均发现IL10RA突变。患儿均予抗感染、更换为氨基酸配方奶或免乳糖奶喂养,加用美沙拉秦口服,部分患儿应用激素、免疫抑制剂及沙利度胺。2例死亡,5例好转。结论 对以不明原因的腹泻、血便起病的小婴儿要注意IBD的可能,早期诊治,改善预后。小婴儿IBD可能存在IL10RA基因突变。     

精氨酸血症致急性肝功能衰竭6例研究

目的 分析急性肝功能衰竭在精氨酸血症患者中的发病情况.方法 回顾性分析2018年1月至12月首都医科大学附属北京友谊医院肝脏移植中心确诊的6例精氨酸血症患儿,收集其相关医疗数据,并对已留存患儿的血液进行检测,对ARG1基因突变进行分析.结果 6例患儿均有凝血功能异常,3例(50％)符合急性肝功能衰竭诊断,国际标准化比值...     

INVESTIGATION OF 89 CHILDREN BORN BY DRUG-DEPENDENT MOTHERS I

ABSTRACT. Among 89 infants born by opiate- and methadone-addicted mothers 20% were preterm and 31% were light for gestational age. Mean gestational age. Mean gestational age and birth weight were lower in infants of mothers who had taken mainly opiates compared with infants of mothers who had taken mainly methadone. Preterm labor was more frequent among women who had been acutely withdrawn on methadone within the last month before birth than among women who were maintained on methadone at birth. 85% of the newborns had withdrawal symptoms and 12% had convulsions the severity of which was not correlated with the type of drug abuse. The duration of withdrawal, however, correlated with the amount of methadone taken by the mother at birth. 20% had signs of perinatal asphyxia and had an increased frequency of neonatal convulsions. These babies represent a special high-risk group of newborns. Prevention, therapy and care demand extraordinary combined efforts by politicians, social welfare personnel, midwives, doctors and nurses.     

Nitric oxide in the treatment of neonatal pulmonary hypertension

This study describes the effects of nitric oxide in newborns with persistent pulmonary hypertension. We studied 9 infants with severe respiratory failure characterized by hypoxemia and pulmonary hypertension. All infants met ECMO criteria and the oxygenation index (OI) was greater than 25. Mean birth weight was 2698 -/+ 661 g and gestational age was 36.4 -/+ 2.6 weeks. Nitric oxide was administered in a Y circuit in the inspiratory line of the mechanical ventilator. Nitric oxide and NO2 concentrations were monitored with electrochemical analyzers (PACI and PACII-Draeger). Pulmonary hypertension was diagnosed with clinical and echocardiografic criteria, with detection of right to left shunt with color doppler. All patients showed a dramatic improvement in oxigenation after nitric oxide administration. The drug reduced the mean OI, which was 48.5 before its administration, to 17.7 after 30', 14.1 after 6 hours, and 10.5 after 12 hours. We observed in all patients a reduction in pulmonary vascular resistance, reversal of the right to left shunt without any effects on systemic arterial pressure. Metahemoglobin levels did not reach 1.5% in any patient. Only one out of the 9 patients died, after reversal of the pulmonary hypertension, from other complications of perinatal asphyxia. Our data show that nitric oxide is a promising drug in the treatment of neonatal pulmonary hypertension and that it may reduce the need of ECMO in severe respiratory failure.     

Neurodevelopmental outcome of infants with birth asphyxia treated with magnesium sulfate

BACKGROUND: A neuroprotective effect of MgSO(4) has been shown in some animal models of perinatal hypoxic-ischemic brain damage. The aim of the present paper was to determine whether postnatal MgSO(4) infusion (250 mg/kg per day i.v. for 3 days, in combination with dopamine) is safe in infants with severe birth asphyxia, and also observe effects on neurodevelopmental outcome at 18 months. METHODS: Inclusion criteria were clinical history consistent with perinatal asphyxia; gestational age at least 37 weeks; 5 min Apgar score < or =6; failure to initiate spontaneous respiration within 10 min after birth; and symptoms of encephalopathy. On each day MgSO(4) was infused over 1 h in combination with dopamine (5 microg/kg per min). Changes in vital signs, clinical course of encephalopathy, laboratory variables, and adverse events were monitored. Infants were followed for 18 months. RESULTS: Thirty infants were studied. Mean birthweight was 2878 g; mean gestational age, 39.6 weeks, and median 5 min Apgar score, 3. All required endotracheal intubation for resuscitation. Median age at MgSO(4) initiation was 5 h. All infants had moderate or severe hypoxic-ischemic encephalopathy. Mean serum Mg(2+) concentration remained at least 1.3 mmol/L. MgSO(4) caused no change in physiological variables including mean arterial pressure. Two infants died as neonates, while six of 28 survivors had severe neurodevelopmental disability at 18 months; the remaining 22 had no neurodevelopmental disability. CONCLUSION: Postnatal infusion of MgSO(4) with dopamine caused no change in physiological variables. Deaths and severe sequelae were less frequent than in reported cases with the same grade of hypoxic-ischemic encephalopathy severity, and this treatment may improve neurodevelopmental outcome in infants with severe birth asphyxia.     

Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation

Mutations of the perforin gene (PRF1) are present in a proportion of patients with hemophagocytic lymphohistiocytosis (HLH). We found that all identified infants with HLH of African descent (17 from USA, 4 from Europe) have 50delT-PRF1 (16 homozygotes, 5 compound heterozygotes), accounting for the most frequently observed PRF1 mutation. Two additional patients with HLH, self-reporting as Hispanic, carried 50delT, but no Caucasians were identified with 50delT. To test the hypothesis that this mutation represents a single haplotype, DNA from 23 patients with HLH and 30 African-American control subjects was sequenced for the PRF1 gene, including portions of the intron containing known single nucleotide polymorphisms (SNPs). The same groups were genotyped at 3 microsatellites proximal to PRF1. The SNP profiles of patients with 50delT-PRF1 were identical, and 5 novel SNPs were identified among African-American control subjects. Patients with 50delT-PRF1 were also found to have had an earlier age of disease onset than patients with other PRF1 mutations. Extent of haplotype sharing and variability of microsatellite alleles in 50delT-PRF1 chromosomes suggest that this mutation arose approximately 1000 to 4000 years ago and is restricted to patients of African descent.     

Severe phenotypes of SMARD1 associated with novel mutations of the IGHMBP2 gene and nuclear degeneration of muscle and Schwann cells

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a very rare autosomal recessive form of spinal muscular atrophy manifested in low birth weight, diaphragmatic palsy and distal muscular atrophy. Caused by a mutation in the IGHMBP2 gene, the disease is addressed here by reference to five Polish patients in which SMARD1 has been confirmed genetically. All presented a severe form of the disease and had evident symptoms during the second month of life; with four displaying weak cries, feeding difficulties and hypotonia from birth. Two were afflicted by severe dysfunction of the autonomic nervous system. Ultrastructural analysis of a muscle biopsy revealed progressive degeneration within the nuclei of the muscle cells and Schwann cells. Neuromuscular junctions were also defective. It proved possible to identify in our patients 6 novel IGHMBP2 mutations: three missense (c.595G>C, c.1682T>C and c.1794C>A), two nonsense (c.94C>T and c.1336C>T) and one in-frame deletion (c.1615_1623del). One nonsense mutation (c.429C>T) that had been described previously was also identified. Observation of our patients makes it clear that clinical picture is still the most important factor suggesting diagnosis of SMARD1, though further investigations concerning some of the symptoms are required. As the IGHMBP2 gene is characterized by significant heterogeneity, genetic counseling of affected families is rendered more complex. IGHMBP2 protein deficiency can lead to the degeneration of nuclei, in both muscle and Schwann cells.     

新生儿李斯特菌败血症临床诊治分析

目的 探讨新生儿李斯特菌败血症的临床特点及诊治.方法 回顾性分析2008年1月至2013年6月于我院新生儿重症监护病房收治、血培养阳性的产单核细胞增生性李斯特菌败血症新生儿,记录母亲孕产史,患儿围产期情况、临床表现、实验室检查、治疗经过及预后等,结合相关文献对新生儿产单核细胞增生性李斯特菌败血症临床特点进行探讨.结果 共收治10例新生儿李斯特菌败血症患儿,男8例,女2例;早产儿3例;48h内发病8例,＞7天发病2例;母亲围产期发热6例;羊水异常10例.临床表现：10例均反应差,呼吸异常7例,发热5例,惊厥2例,休克1例.实验室检查：血WBC升高（＞19.5＆#215;109/L）6例,降低2例（＜5＆#215;109/L）,正常2例.白细胞分类单核细胞百分比升高10例;CPR升高10例.血培养产单核细胞增生性李斯特菌10例,合并化脓性脑膜炎3例.治疗：美罗培南8例,青霉素加头孢类抗生素2例;转归：治愈7例,好转1例,自动出院后死亡2例.结论 新生儿李斯特菌败血症病情凶险,病死率高,对于有高危因素的新生儿应作为重点监护对象,血常规中白细胞分类单核细胞百分比＞8％、脑脊液常规白细胞以单核细胞为主者,应高度怀疑单核细胞增生性李斯特菌败血症,做到早发现、早治疗.     

The phenotype and long-term follow-up in 11 patients with juvenile selenoprotein N1-related myopathy.

The selenoprotein N1-related myopathies comprise rigid spine muscular dystrophy, the "classical" form of multiminicore disease, a desmin-related myopathy with Mallory body like inclusions and a form of congenital fiber-type disproportion. To define the phenotype and long-term clinical course in juvenile Selenoprotein N1-related myopathies 11 juvenile patients from eight families with SEPN1 mutations were assessed over a mean period of 7.2 years. Clinical findings, histomorphological studies, respiratory investigations and genetic data were analyzed: age of manifestation varied within the first 2 years of life with muscle hypotonia, lag of head control and delayed motor development. Further gross motor development was normal in 9/11 patients. All patients were ambulant for at least 1000 m at a mean age of 13.7 years. Eight patients exhibited a rigid spine diagnosed at a mean age of 10 years. All patients had respiratory impairment with a vital capacity ranging from 18% to 65%. Four patients were intermittently nocturnally ventilated at a mean age of 11 years. Body mass index was below 20 (kgm(-2)) in all patients. Muscle biopsies of eight individuals revealed multiminicores (n=2), congenital fiber-type disproportion (n=1), myopathic changes with single cores (n=2) and unspecific myopathic features (n=3). Mutations were distributed throughout the entire SEPN1 gene. Although the phenotype of juvenile selenoprotein N1-related myopathies is homogenous regarding the main symptoms we describe a variable degree of clinical severity. Major complications were early respiratory failure, impaired increase in weight and orthopedic problems. There seems to be no correlation between skeletal muscle weakness and respiratory failure.     

Severe neonatal centronuclear (myotubular) myopathy: an X-linked recessive disorder

Prenatal onset and rapidly fatal course of centronuclear myopathy are described in four male newborns including two brothers. Diagnosis was established by muscle biopsy within the first week of life in two and at autopsy in the two other patients: Central nuclei, central aggregation of oxydative enzyme activity in the majority of muscle fibers and type 1 fibre hypotrophy were demonstrated. Prenatal manifestation included polyhydramnios, reduced fetal movements and breech presentation. All four newborns developed respiratory insufficiency requiring artificial ventilation immediately after birth. Severe muscular weakness and hypotonia as well as hardly elicitable grasping, deep tendon reflexes and Moro response were noticed. Additional findings included high arched palate, joint contractures, thin ribs, lung hypoplasia, abundant skin and cryptorchidism. In two families, the pedigree contains other affected males, suggesting X-linked inheritance. Seven female carriers were clinically healthy and one of them showed normal muscle histology. Fourteen previously published neonatal cases of centronuclear myopathy are reviewed and compared with our findings. This severe perinatal form of centronuclear myopathy has to be considered in male fetuses and newborns with polyhydramnios and respiratory failure due to muscular weakness or in infants who died of unexplained postnatal asphyxia. Diagnosis should be established by muscle biopsy.     

Perinatal lethal hypophosphatasia; Clinical,radiologic and morphologic findings

Clinical, radiographic and morphologic analysis of nineteen cases of perinatal (lethal) hypophosphatasia was performed. Three families each had two affected offspring. All of the patients had lethal short limb dwarfism with very soft calvaria. Other clinical findings included polyhydramnios, blue sclerae and spurs in the mid-portion of the forearms and lower legs. Considerable variability was found in the skeletal radiographs. In addition to the well known radiographic features such as generalized decrease in the size of ossified bones with some bones not ossified at all, other changes observed included: 1) marked variability in the amount of bone ossification; 2) variability between patients as to which bones were most severely affected; 3) unusually dense, round, flattened, butterfly shaped; and saggitally clefted vertebral bodies; 4) variability in femoral shape including chromosome like, campomelic like, and shortening with or without metaphyseal cupping or irregularities; 5) osteochondral projections (Bowdler spurs) of the midshaft of the fibula and ulna. Recognition of the marked clinical and radiographic variability in this autosomal recessive lethal skeletal dysplasia is important for accurate genetic counseling and prenatal diagnosis.     

过度惊吓反应症临床及遗传学特征（附６例报告）

目的　分析6例过度惊吓反应症患儿的临床及遗传学特征。 方法　对2011年6月至2018年5月于北京大学第一医院诊断的6例过度惊吓反应症患儿的临床表现、诊治过程、脑电图（EEG）及神经影像学、遗传学结果等进行分析。 结果　6例中男5例、女1例。6例均为新生儿早期起病,均可因不经意的听觉或触觉刺激诱发过度惊跳反应和全身僵硬症状,3例曾出现短暂窒息发作,1例曾惊吓后摔倒致外伤。6例点鼻反射均阳性,4例合并疝。EEG示1例正常,5例为不典型放电或一过性异常。4例曾行头颅磁共振检查未见明显异常。经遗传学分析,6例中3例携带GLRA1基因杂合突变,2例携带GLRB基因复合杂合突变,1例经全外显子测序未发现基因突变。6例给予氯硝西泮治疗, 1例全身僵硬及过度惊吓反应均基本消失, 5例全身僵硬症状消失、偶有惊跳反应。6例智力发育均正常,2例存在宽基底步态状行走姿势。1例有相同症状而窒息死亡的明确家族史。 结论　过度惊吓反应症具有典型临床表现,点鼻反射阳性,可行基因诊断确诊。该病对氯硝西泮有良好的治疗反应。早期经临床诊断及基因确诊,及时、恰当治疗,对于改善预后至关重要。     

Scorpion sting in children in the Jerusalem area: a review of 54 cases.

Fifty-four children from the Jerusalem area were studied prospectively following scorpion envenoming. Their ages ranged from 11 months to 10 years. Severe symptoms (convulsions, brain oedema, shock, respiratory distress and myocarditis) were encountered in 19. Respiratory distress was the main feature in 17 of the children, in two cases owing to pulmonary oedema and in a third because of adult respiratory distress syndrome and myocarditis; mechanical ventilation was required in three cases. The severity of the symptoms and signs was not related to sex, age, weight, interval between scorpion sting and admission or to the type of offending scorpion; it was most likely dependent upon the susceptibility of the individual and/or the dose of venom injected by the scorpion. Intravenous antivenom quickly reversed the symptoms, and no side-effects were seen in the patients studied. The two patients who died had not received the antivenom intravenously. We recommend that specific antivenom should be given intravenously in all children who show significant symptoms. Furthermore, a longer period of observation is necessary following scorpion sting in this age group.