Neonatal hypotonia: don't forget the Prader-Willi syndrome

During the neonatal period the diagnosis of the Prader-Willi syndrome (PWS) is difficult because the syndrome is expressed mainly by severe hypotonia at this age and the typical clinical features of later life are not yet present. AIM: To identify all the PWS clinical markers in severe hypotonic newborns, which could facilitate an early diagnosis of the syndrome. METHODS: Twenty-one PWS newborns (14 males and 7 females) with severe hypotonia at birth were evaluated. Paediatricians skilled in syndromology carried out a careful clinical examination. Fluorescent in situ hybridization (FISH) analysis and/or a methylation test was used to confirm the PWS clinical diagnosis. RESULTS: The clinical diagnosis of PWS was reached at a mean age of 7.4 mo with genetic confirmation at 11 mo of life. In 12 newborns at least 3 craniofacial features were present (57%), suggesting the diagnosis of PWS. Two craniofacial dysmorphic characteristics were described in 6 newborns and only 1 in 3 cases. Cryptorchidism was monolateral in 6 and bilateral in 7 patients; in one newborn both testes were in scrotum. A micropenis was described in one patient and hypoplasia of the labia minora was reported in two females. CONCLUSIONS: Diagnosis by means of dysmorphologic evaluation is difficult in the neonatal period. The presence of severe hypotonia should always induce neonatologists to perform specific genetic tests in order to obtain an early diagnosis of PWS.     

儿童慢性咳嗽的程序式诊断方法探讨

目的 分析儿童慢性咳嗽的病因分布,并对儿童慢性咳嗽的程序式诊断方法进行探讨。方法 参考Morice的慢性咳嗽诊断程序,对81例慢性咳嗽儿童进行逐步评估。最后的诊断结果分为明确诊断、疑似诊断和病因未明。结果 明确诊断65例（80．3％）,疑似诊断15例（18．5％）,病因未明1例。81例慢性咳嗽中前几位病因依次为气管、支气管异物（16．9％）,咳嗽变异型哮喘／哮喘（15．7％）,肺部感染（后）（14．5％）,鼻后滴注综合征（8．4％）,先天气管、支气管狭窄或其他发育异常（7．2％）。不同的年龄阶段病因分布有一定特征性。结论 儿童慢性咳嗽的病因复杂,应用程序式诊断方法可明确大部分病因,其病因分布具有年龄特点;病史、体检、影像学检查及肺功能测定在儿童慢性咳嗽的病因诊断中发挥重要作用;诊断过程应予动态评价,及时随访。最后对Morice诊断程序作出补充。     

Diagnosis of perinatal stroke II: mechanisms and clinical phenotypes

Introduction:  Here (and in an accompanying article dealing with definitions, differential diagnosis and registration), a structured sequential diagnostic flow is proposed to discern clinical phenotypes for perinatal stroke, including arterial ischaemic stroke (AIS), cerebral sinovenous thrombosis (CSVT) and haemorrhagic stroke.
Material and results:  For neonatal AIS, the diagnostic sequence is infection, trauma, embolism, arteriopathy, other, primary thrombosis and unclassifiable; for neonatal CSVT, the sequence is infection, trauma, venopathy, other, primary thrombosis and unclassifiable. The proposed hierarchical diagnostic flows are an initial step towards a standard for registration of the causes of neonatal stroke. Such standardization should guide attempts at prevention and intervention. An extensive literature search and study of a retrospective cohort of 134 newborn infants with stroke suggest that embolism is the most common identifiable cause for stroke in general (25%), preceding trauma (10%) and infection (8%). Other causes, such as asphyxia, acute blood loss, extracorporeal membrane oxygenation, genetic disorders or prothrombotic conditions, are seen in <5% of cases. For neonatal AIS, the presence of an embolic phenotype is 33% in this cohort. The designation unclassifiable scored 34% for the entire stroke group and 25% for neonatal AIS. Complex arterial stroke with multiple arteries involved is often seen when the underlying cause is infection, cranial trauma or embolism. One important conclusion is that a means of prevention is avoidance of embolism from thrombosis outside the brain.
Conclusion:  To prevent the occurrence and recurrence of neonatal ischaemic stroke, clinicians must develop a standardized diagnostic approach that results in characterization of the clinical phenotype.     

Der hypotone Säugling

The floppy infant represents a challenge with respect to the clinical competence of the treating physician and requires a close cooperation between pediatricians, neuropediatricians and neonatologists. A precise clinical differentiation of additional signs and symptoms is essential in order to create an efficient hypothesis-based diagnostic approach. Muscle hypotonia as an isolated neurological symptom is unspecific. Only the broader context of additional signs and symptoms enables the physician to postulate assumed differential diagnoses, which subsequently have to be tested using the correct diagnostic tool. Over the last few years advances in neuroimaging, neurometabolics, molecular and genetic testing have considerably broadened this spectrum of diagnostic tools. The following article focuses on the differential diagnosis of disorders which are associated with neonatal and infantile hypotonia referred to by the term floppy infant.     

Genetic evaluation of the floppy infant

Hypotonia in infants in the first year of life is a common diagnostic and management challenge for pediatricians and neonatologists. Several published clinical studies have shown that a substantial proportion of cases are accounted for by genetic disorders. Rapid advances in biotechnology, bioinformatics, and molecular genetic testing have made it possible to offer specific genetic diagnoses in a timely manner. The value of clinical examination in the localization of hypotonia within the nervous system as the first step towards a diagnosis cannot be overemphasized. Due importance should be given to specific features on examination and in the selection of appropriate laboratory tests to minimize laboratory costs. Inborn errors of metabolism, although infrequently encountered, are of importance. Based on clinical evidence from published studies, an algorithm is suggested that would incorporate the clinical features and testing modalities in providing a high diagnostic yield for the clinician.     

Perinatal dyskinesia as a presenting feature in Prader Willi Syndrome

Prader Willi Syndrome (PWS) is a complex genetic disorder. Infants present with hypotonia and feeding difficulties, usually without respiratory symptoms, but with distinctive facial features. Early neonatal diagnosis can however be difficult in children with only subtle distinctive appearances or with atypical clinical signs, leading to a significant delay in the diagnosis. To highlight the diagnostic difficulties we reviewed our experience of infants with PWS referred to our tertiary centre. We describe 14 patients, 10 of whom presented in the neonatal period. All had axial hypotonia, and poor feeding. Twelve had a paucity of movement, 11 had distinctive features and 10 had a reduced level of alertness in the neonatal period. In addition to these typical features, four patients had prominent limb dyskinesia, which has only been reported once before in infants with PWS. We draw attention to this relatively common but poorly acknowledged sign that can be seen at presentation of PWS.     

Identification of a novel compound heterozygote SCO2 mutation in cytochrome c oxidase deficient fatal infantile cardioencephalomyopathy

Fatal infantile cardioencephalomyopathy (OMIM No. 604377) is a disorder of the mitochondrial respiratory chain and is characterised by neonatal progressive muscular hypotonia and cardiomyopathy because of severe Cytochrome c oxidase deficiency. Here we report a novel mutation in the Cytochrome c oxidase assembly gene SCO2 in an infant with fatal infantile cardioencephalomyopathy despite normal initial metabolic screening. CONCLUSION: In newborns with unexplained muscular hypotonia and cardiomyopathy genetic testing of mitochondrial respiratory chain disorders might be helpful to establish a final diagnosis and guide treatment decisions.     

Recent developments in diagnostics and treatment of neonatal cholestasis

Neonatal cholestasis is characterized by conjugated hyperbilirubinemia in the newborn and young infant and is a sign common to over 100 hepatobiliary and/or metabolic disorders. A timely evaluation for its etiology is critical in order to quickly identify treatable causes such as biliary atresia, many of which benefit from early therapy. An expanding group of molecularly defined disorders involving bile formation, canalicular transporters, tight junction proteins and inborn errors of metabolism are being continuously discovered because of advances in genetic testing and bioinformatics. The advent of next generation sequencing has transformed our ability to test for multiple genes and whole exome or whole genome sequencing within days to weeks, enabling rapid and affordable molecular diagnosis for disorders that cannot be directly diagnosed from standard blood tests or liver biopsy. Thus, our diagnostic algorithms for neonatal cholestasis are undergoing transformation, moving genetic sequencing to earlier in the evaluation pathway once biliary atresia, “red flag” disorders and treatable disorders are excluded. Current therapies focus on promoting bile flow, reducing pruritus, ensuring optimal nutrition, and monitoring for complications, without addressing the underlying cause of cholestasis in most instances. Our improved understanding of bile formation and the enterohepatic circulation of bile acids has led to emerging therapies for cholestasis which require appropriate pediatric clinical trials. Despite these advances, the cause and optimal therapy for biliary atresia remain elusive. The goals of this review are to outline the etiologies, diagnostic pathways and current and emerging management strategies for neonatal cholestasis.     

Can clinical signs identify newborns with neuromuscular disorders?

OBJECTIVE: To evaluate retrospectively the prevalence of neuromuscular disorders in 83 newborns referred to a tertiary care center because of hypotonia and weakness and/or contractures, with a possible diagnosis of neuromuscular disorder. We also aimed to establish whether clinical signs could help to identify infants with neuromuscular disorders. STUDY DESIGN: Sixty-six of the 83 infants who fulfilled the inclusion criteria (79.5%) had an identifiable disorder, which was a neuromuscular disorder in 39 (46.9%). RESULTS: Absent or extremely reduced antigravity movements were mainly found in infants with neuromuscular disorders (sensitivity and specificity 97.4% and 75%), whereas partial range antigravity movements were more frequent in infants with other diagnosis. Contractures were mainly found in infants with peripheral nerve or muscle involvement but also were relatively frequent in infants with genetic or metabolic syndromes (sensitivity 69.2%, specificity 61.3%). Reduced fetal movements and abnormal liquor were frequent but not present consistently in infants with neuromuscular disorders (sensitivity 46.1% and 38.4%) and were found rarely in infants with other disorders (specificity 88.6% and 75.0%). CONCLUSIONS: Severe muscle weakness and contractures are the most reliable indicators of a neuromuscular disorder and should be carefully assessed in an infant with neonatal hypotonia.     

Pregnancy loss, stillbirth, and neonatal death. A guide for the pediatrician.

The complete clinical evaluation of pregnancy loss, stillborn infants, and neonatal deaths can result in the anticipation of an accurate diagnosis in a high percentage of cases. Appropriate focused fetal studies may include a clinical examination, fetal karyotype, photographs, skeletal radiographs, fetal autopsy, examination of the placenta and cord, and occasionally cultures or DNA studies. Knowledge of specific causes of fetal death and their clinical presentation can greatly assist the pediatrician in choosing the most appropriate studies. Many of the disorders leading to fetal death carry significant genetic recurrence risks, making an accurate diagnosis even more crucial. As our understanding of the causes of pregnancy loss improves, so does our ability to provide families with accurate counseling regarding their reproductive options.     

Fever of unknown origin in 185 paediatric patients: a single-centre experience

Aim: We conducted a prospective study to evaluate the causes and outcome in children with fever of unknown origin (FUO). Methods: From 1990 to 1999, 185 children with FUO were evaluated. Initial evaluation included routine haematological analysis, Epstein-Barr virus (EBV) serology, urine, stool or blood cultures, chest X-ray and tuberculin probe. Results: In 131 (70%) patients diagnosis was established, and 70 (37.8%) had infectious disease. EBV infection was the most common infection followed by visceral leishmaniasis (VL), urinary tract infection (UTI) and tuberculosis. Autoimmune disorders were diagnosed in 24 (12.9%), Kawasaki disease in 12 (6.4%), malignant diseases in 12 (6.4%) and miscellaneous conditions in 15 (8.1%) patients. In the remaining 54 (30%) patients, diagnosis was not established and most of them had self-limited disease. During the investigation, 26 (14%) patients developed serious organ dysfunction and five patients (two with virus-associated haemophagocytic syndrome, one with VL and two unknown) died.

Conclusion: The most important infectious causes of FUO in our study were EBV infection and VL. Kawasaki disease represented a significant cause of FUO at the beginning of our study because it was not recognized by primary-care physicians. We report myelodysplastic syndrome as another emerging cause of paediatric FUO. Repeated clinical examination and careful use of specific laboratory examinations, invasive diagnostic procedures or imaging are crucial in approaching paediatric FUO.     

Neonatal myasthenia gravis]

BACKGROUND: Myasthenia gravis, an autoimmune disease of young women, is due to the dysfunction of neuromuscular transmission. The newborn of a myasthenic mother inconstantly presents a transitory neonatal myasthenic syndrome. Maternal aggravation, or even myasthenic crisis with respiratory failure, can occur in the first three months post-partum. CASE REPORT: Mrs. S., para two without appreciable medical history, delivered normally a boy weighing 4 kg with an Apgar score of 10/10. At 3 h of life the newborn was admitted to the neonatal care unit for grunting and axial hypotonia. Diagnoses of maternal-fetal infection and fetal distress were excluded. The dissociated pattern of neurological disorders (refusal to drink, axial hypotonia, hypomimia, but good contact and normal alertness) led to search for neuromuscular causes or poison. Myasthenia gravis was then considered and confirmed by maternal electromyography, allowing the diagnosis of transient neonatal myasthenia gravis and early diagnosis and treatment of the maternal myasthenic crisis in a specialized care unit. The outcome of both mother and child was favorable under treatment. CONCLUSION: Lack of maternal myasthenia gravis history should not result in excluding the diagnosis of transitory neonatal myasthenia gravis when evocative neonatal neurological signs are present. The symptomatology in the newborn may indeed reveal maternal myasthenia gravis, allowing an early diagnosis in both the mother and the newborn.     

Ehlers-Danlos Syndrome Type VI in a 17-Year-Old Iranian Boy with Severe Muscular Weakness – A Diagnostic Challenge?

Background

The Ehlers-Danlos syndrome type VI (EDSVI) is an autosomal recessive connective tissue disease which is characterized by severe hypotonia at birth, progressive kyphoscoliosis, skin hyperelasticity and fragility, joint hypermobility and (sub-)luxations, microcornea, rupture of arteries and the eye globe, and osteopenia. The enzyme collagen lysyl hydroxylase (LH1) is deficient in these patients due to mutations in the PLOD1 gene.

Case Presentation

We report a 17-year-old boy, born to related parents, with severe kyphoscoliosis, scar formation, joint hypermobility and multiple dislocations, muscular weakness, rupture of an ocular globe, and a history of severe infantile hypotonia. EDS VI was suspected clinically and confirmed by an elevated ratio of urinary total lysyl pyridinoline to hydroxylysyl pyridinoline, abnormal electrophoretic mobility of the α-collagen chains, and mutation analysis.

Conclusion

Because of the high rate of consanguineous marriages in Iran and, as a consequence thereof, an increased rate of autosomal recessive disorders, we urge physicians to consider EDS VI in the differential diagnosis of severe infantile hypotonia and muscular weakness, a disorder which can easily be confirmed by the analysis of urinary pyridinolines that is highly specific, sensitive, robust, fast, non-invasive, and inexpensive.     

When do we need to perform a diagnostic lumbar puncture for neurometabolic diseases? Positive yield and retrospective analysis from a tertiary center

Neurometabolic diseases diagnosed by cerebrospinal fluid (CSF) examination are GLUT1 deficiency, serine-deficiency syndromes, glycine encephalopathy, cerebral folate deficiency, neonatal vitamin-responsive epileptic encephalopathies, disorders of monoamine metabolism, and y-amino butyric acid (GABA) metabolism. We retrospectively analyzed and compared the demographic, clinical, laboratory, and neuroimaging features of 62 patients in whom CSF examination was performed. Of the 62 patients, 16 (25.8%) had a final diagnosis, including succinic semialdehyde dehydrogenase (SSADH) deficiency (n=4), aromatic amino acid decarboxylase (AADC) deficiency (n=4), L-dopa-responsive dystonia (n=3), glycine encephalopathy (n=2), pyridoxal-phosphate-dependent seizures (n=l), cerebral folate deficiency (n=1), and serine biosynthesi defect (n=1). Parental consanguinity was present in all patients except one Positive yield of a diagnostic lumbar puncture (LP) for the diagnosis of inherited neurotransmitter metabolism disorder was 25.8% overall. Oculogyric crisis (50%), diurnal variation (81.8%) and consanguinity (93.8%) were the only statistically significant variables between patients with and without a specific diagnosis. It is challenging to diagnose neurotransmitter defects, since there is no ideal set of clinical symptoms. In our cohort, consanguinity, diurnal variation and abnormal ocular movements were the most significant findings associated with a diagnosis of a specific neurometabolic disorder based on CSF examination. Early diagnosis is of great importance not only for specific treatment, but also for genetic counseling and prenatal diagnosis.     

Main causes of aplastic anemia misdiagnosed as immune thrombocytopenia in children北大核心CSCD

目的归纳曾被误诊为免疫性血小板减少症(ITP)的50例儿童再生障碍性贫血(再障)的主要原因和鉴别诊断经验,以供临床参考。方法参照儿童再障和ITP诊断标准,回顾性分析2007年1月至2020年12月上海市同济医院儿科收治的外院误诊病例的病初资料和本院复诊检测结果,归纳误诊原因和鉴别诊断要点。结果在同期收治的165例儿童再障中,共有50例(30.3%)曾被误诊为ITP。分析归纳主要误诊原因为:1.临床表现不符合"典型ITP",未按照国际指南标准行必要的骨髓检查以明确诊断,共22/50例。2.骨髓检测结果解读有误。在28例初诊行骨髓涂片检查者中,6例(21%)骨髓显示典型再障骨髓象,但仍被诊断为ITP。3.骨髓涂片结果不典型者,未行骨髓活检以助诊断(15/28例,54%)。4.初诊时符合ITP诊断标准,但经糖皮质激素等治疗无效后,未行必要复查以核实诊断(7/28例,25%)。结论临床应严格参照执行相关疾病诊断标准,以避免经验性错误。诊断ITP需要慎重,尤其是临床表现不典型,或一线药物无效者,必须进行骨髓检查(必要时行骨髓活检),并按诊断标准正确解读检测结果,以避免临床误诊或漏诊。     

The diagnostic protocol in children and adolescents with syncope: a multi-centre prospective study

Aim: The appropriate diagnostic protocol for children with syncope has not been well established. A diagnostic protocol was developed and prospectively implemented to improve the diagnostic performance of paediatricians.
Methods: The study population included 474 consecutive patients (range 6–17 years) presenting with a syncopal spell in one of the five participating hospitals of China. In step 1, all patients underwent initial evaluation for history, physical examination, standing test and standard electrocardiography (ECG). In step 2, priority was given to cardiographic tests for possibly cardiogenic syncope, or electroencephalographic examination and brain imaging for suspected neurological syncope, or psychiatric tests for suspected psychiatric syncope. Patients with unexplained syncope underwent head-up tilt testing (HUT).
Results: The initial evaluation gave a definite diagnosis in 59 (12.4%) and possible diagnosis in 54 of the 474 patients. Further testing gave a definite diagnosis for 326 patients (69.7%). After the entire diagnostic protocol, definite diagnosis was established in 385 patients (81.1%). Autonomic-mediated reflex syncope (AMS) accounted for 73.0% of cases. The average cost of diagnostic results per patient was RMB 1030.24 ± 150.09 ($118.42 ± 17.25).
Conclusion: The use of a simplified diagnostic protocol for children and adolescents with syncope improves diagnostic yield.     

28例儿童肺部弥漫性疾病的病因和诊断分析

目的 探讨儿童肺部弥漫性疾病的病因和诊断思路。方法 回顾性分析28例肺部弥漫性疾病患儿的诊断以及确诊过程。结果 确定病因25例,包括支原体肺炎1例、沙眼衣原体肺炎2例、巨细胞病毒肺炎2例、EB病毒肺炎1例、血型播散性肺结核3例、金黄色葡萄球菌败血症性肺炎1例、肺隐球菌病1例、侵袭性肺曲霉菌病2例、广泛支气管扩张合并肺部感染2例、特发性肺含铁血黄素沉着症1例、特发性肺纤维化1例、HIV合并淋巴细胞间质性肺炎1例、鸽粪引起的外源性变应性肺泡炎1例、韦格内肉芽肿1例、郎格罕细胞组织细胞增生症2例、恶性淋巴瘤3例。疑似诊断3例,包括奴卡菌感染1例、少年类风湿性关节炎合并肺纤维化1例、HIV合并卡氏肺囊虫1例。18患儿经X线检查、病史和体格检查以及其他非创伤性检查诊断,8例经皮肤活检或肺活检诊断,2例由尸解确诊。结论 儿童肺部弥漫性疾病的病因包括肺部感染性疾病、特发性疾病和全身疾病的肺部表现。影像学表现、病史和体格检查以及其他非创伤性检查能确定多数患儿的病因,少数病例需经创伤性检查诊断。     

Clinical characteristics of hypotonia: a survey of pediatric physical and occupational therapists.

PURPOSE: This study extended previous work on defining characteristics of children with hypotonia. METHODS: A survey regarding previously identified characteristics of hypotonia, examination tools, interventions, and prognosis was sent to a random sample of 500 physical therapists and 500 occupational therapists. RESULTS: A total of 268 surveys were returned, for a response rate of 26.8%. Characteristics most frequently observed in children with hypotonia included decreased strength, hypermobile joints, and increased flexibility. Observation was the most commonly cited assessment tool and 85% of those surveyed believe that characteristics of hypotonia improve with therapy. CONCLUSIONS: Despite agreement among physical and occupational therapists on characteristics of hypotonia and potential for improvement, clear clinical guidelines for the diagnosis and quantification of hypotonia have yet to be determined. Research is needed to develop an operational definition of hypotonia, develop valid tests and assess effectiveness of intervention.     

Diagnostic approach to primary ciliary dyskinesia: a review

Primary ciliary dyskinesia (PCD) is a heterogeneous disease with impaired mucociliary transport leading to respiratory disorders, hearing impairment and male infertility. PCD can be diagnosed by clinical features together with functional and structural analysis of the cilia. To prevent bronchiectasis with a marked reduction in quality of life, early diagnosis is essential. The rarity of PCD and the costs of ultrastructural analysis of cilia require a rational diagnostic concept. We therefore reviewed the literature and compared clinical manifestations as well as functional and structural analyses of the cilia in 28 patients (23 children, 5 adults) investigated between 1990 and 1998. All were thoroughly examined for other possible diseases before biopsy, and ten patients (35.7%; eight children, two adults) were diagnosed as having PCD. From the literature review and our findings we conclude that ciliary investigation is indicated (a) in patients who remain suspected of having PCD despite thorough clinical examination and exclusion of other disorders such as cystic fibrosis, allergy, immunologic disorders and α₁-antitrypsin deficiency; (b) in patients with situs inversus suffering from chronic and/or recurrent airway infections; and (c) in patients with neonatal respiratory distress syndrome of “unknown” cause (i.e. after exclusion of hyaline membrane disease, aspiration syndromes, neonatal pneumonia, and pneumothorax as well as cardiovascular and metabolic diseases). Conclusion The combination of extensive clinical examination with functional and ultrastructural analysis of the cilia results in a high degree of accuracy in diagnosing PCD. Received: 30 November 1998 / Accepted: 20 July 1999     

儿童间质性肺疾病的分类和诊断程序

儿童间质性肺疾病是一组庞大而异质性的肺疾病,以弥漫性渗出和气体交换障碍为特征.儿童间质性肺疾病的分类主要为:婴儿特有的间质性肺疾病;原发于肺部的间质性肺疾病,包括特发性间质性肺炎;伴肺部浸润的系统性疾病;已知原因的疾病.儿童间质性肺疾病诊断应先根据病史、临床表现以及影像学检查,确定是否为间质性肺疾病;进一步通过病原学、血清学检查等寻找病因,如病因仍不明确则需通过侵袭性检查获得诊断和病理分型.