Novel finding of lissencephaly and severe osteopenia in a Chinese patient with SATB2-associated syndrome and a brief review of literature.

SATB2-associated syndrome (SAS) is a rare disorder characterized by developmental delay, behavioral problems, and craniofacial anomalies in particular dental and palatal abnormalities. We describe the clinical course, genetic and autopsy findings in a Chinese boy with global developmental delay, hypotonia, epilepsy, recurrent fractures and osteopenia. Brain magnetic resonance imaging showed pachygyria, white matter hypoplasia and hypogenesis of the corpus callosum. Whole-exome sequencing identified a novel heterozygous missense variant c.1555G>A p.(Glu519Lys) in the SATB2 gene. Unfortunately, he died at 26 months of bronchiolitis and pneumonia. Autopsy revealed pachygyria which was more severe anteriorly, dilated lateral and third ventricles and partial agenesis of the corpus callosum. Histology showed features compatible with two-layered lissencephaly. The bone showed disordered lamination and bone matrix. Although SATB2 has been shown to be involved in the regulation of neuronal migration in the developing brain, lissencephaly has not been reported so far. This could represent a more severe phenotype of SAS.

Centrosome-associated CDC25B is a novel disease-causing gene for a syndrome with cataracts, dilated cardiomyopathy, and multiple endocrinopathies.

We describe a unique Chinese girl who presented with intrauterine growth retardation, delayed development, bilateral cataracts, hypothyroidism, growth hormone deficiency, and juvenile dilated cardiomyopathy. She was born to consanguineous parents with a history of one fetal and one infantile death in the family. She died from cardiac failure at the age of 12. In the pursuit of a diagnosis, the family was referred to the Clinics for Rare Diseases Referral and the University of Hong Kong Undiagnosed Disease Program. Whole-exome sequencing analysis revealed a homozygous non-sense variant, NM_021873:c.313G > T (p.Glu105*), in the CDC25B gene, a key regulator of the cell cycle. This variant was located in a region of homozygosity of 25 Mb on chromosome 20. Her parents and two asymptomatic sisters were confirmed to be carriers and one brother did not carry the variant. This is the first report of a natural human knockout of the CDC25B gene. Multiple endocrinopathies and fatal juvenile dilated cardiomyopathy suggests the potential for unfavorable complications in oncology patients receiving CDC25B inhibitors as an emerging targeted therapy.

Left ventricular stiffness in paediatric patients with end-stage kidney disease.

BACKGROUND: We tested the hypothesis that myocardial stiffness is altered in paediatric patients with end-stage kidney disease (ESKD) and explored its association with clinical parameters of chronic kidney disease (CKD). METHODS: Thirty-five patients with ESKD (16 males) aged 17.5 ± 3 years old, 18/35 of whom were receiving dialysis and 17 post kidney transplant, were studied. Left ventricular (LV) myocardial stiffness was determined by measurement of diastolic wall strain (DWS) and stiffness index (SI), while LV diastolic function was interrogated by pulsed-wave and tissue Doppler echocardiography. RESULTS: Compared with available literature data, both dialysis and transplanted patients had significantly lower DWS and greater SI, reduced transmitral early (E) to late diastolic velocity ratio and septal and lateral mitral annular early (e') diastolic velocities, and greater septal and lateral E/e' ratios (all p < 0.05). Multivariate analysis revealed that z score of diastolic blood pressure (ß = 0.43, p = 0.004) and the duration of renal replacement therapy (ß = 0.55, p < 0.001) were significant determinants of LV SI. Subgroup analysis in post-transplant patients showed z score of diastolic blood pressure (ß = 0.54, p = 0.025) remained as a significant determinant of LV SI. CONCLUSION: Increased LV myocardial stiffness is evident in paediatric dialysis and transplanted patients with ESKD, and is associated with blood pressure and duration of renal replacement therapy.

Clinical whole-exome sequencing reveals a common pathogenic variant in patients with CoQ10 deficiency: An underdiagnosed cause of mitochondriopathy.

BACKGROUND: Primary CoQ deficiency occurs because of the defective biosynthesis of coenzyme Q, one of the key components of the mitochondrial electron transport chain. Patients with this disease present with a myriad of non-specific symptoms and signs, posing a diagnostic challenge. Whole-exome sequencing is vital in the diagnosis of these cases. CASE: Three unrelated cases presenting as either encephalopathy or cardiomyopathy have been diagnosed to harbor a common pathogenic variant c.370G > A in COQ4. COQ4 encodes a key structural component for stabilizing the multienzymatic CoQ biosynthesis complex. This variant is detected only among East and South Asian populations. CONCLUSIONS: Based on the population data and our case series, COQ4-related mitochondriopathy is likely an underrecognized condition. We recommend including the COQ4 c.370G > A variant as a part of the screening process for mitochondriopathy in Chinese populations.

Diagnostic yield of array CGH in patients with autism spectrum disorder in Hong Kong.

BACKGROUND: Chromosomal microarray offers superior sensitivity for identification of submicroscopic copy number variants (CNV) and it is advocated to be the first tier genetic testing for patients with autism spectrum disorder (ASD). In this regard, diagnostic yield of array comparative genomic hybridization (CGH) for ASD patients is determined in a cohort of Chinese patients in Hong Kong. METHODS: A combined adult and paediatric cohort of 68 Chinese ASD patients (41 patients in adult group and 27 patients in paediatric group). The genomic DNA extracted from blood samples were analysed by array CGH using NimbleGen CGX-135K oligonucleotide array. RESULTS: We identified 15 CNV and eight of them were clinically significant. The overall diagnostic yield was 11.8 %. Five clinically significant CNV were detected in the adult group and three were in the paediatric group, providing diagnostic yields of 12.2 and 11.1 % respectively. The most frequently detected CNV was 16p13.11 duplications which were present in 4 patients (5.9 % of the cohort). CONCLUSIONS: In this study, a satisfactory diagnostic yield of array CGH was demonstrated in a Chinese ASD patient cohort which supported the clinical usefulness of array CGH as the first line testing of ASD in Hong Kong.

Clinical whole-exome sequencing reveals a novel missense pathogenic variant of GNAO1 in a patient with infantile-onset epilepsy.

BACKGROUND: The cause of infantile-onset epilepsy is complex and is not easily recognized clinically, particularly in paediatric patients who present with non-specific neurological signs, no radiological abnormalities and no metabolic changes. CASE: We report a case of infantile-onset epilepsy in a 10-month-old Chinese girl who presented with non-specific neurological signs, no radiological abnormalities and no biochemical disturbances. She first presented at birth with twitching movements and convulsions of an unknown aetiology. Ambulatory EEG showed epileptic rhythmic activities, the presence of asynchrony and runs of sharp waves over the right parietal and central areas. Given the non-specific neurological features and negative structural and biochemical findings, we applied clinical whole-exome sequencing (WES) to determine the underlying aetiology. WES revealed a novel heterozygous missense pathogenic variant, GNAO1:NM_020988.2:c.118G>A; NP_066268.1:p.Gly40Arg. A genetic analysis of the family confirmed the variant identified is a de novo mutation. CONCLUSIONS: Clinical WES can streamline genetic analysis and sort out pathogenic genes in an unbiased approach. GNAO1 is a disease-causing gene for the autosomal dominant form of early infantile epileptic encephalopathy. The novel pathogenic variant identified in this case should contribute to our understanding of the expanding spectrum of infantile-onset epilepsy.

Oscillometric 24-h ambulatory blood pressure reference values in Hong Kong Chinese children and adolescents.

OBJECTIVES: We aimed to establish community-based normal reference values of 24-h ambulatory blood pressure monitoring (ABPM) for Chinese children and adolescents. Furthermore, we investigated how excluding overweight children affects BP percentiles and compared them with German references. METHODS: In this territory-wide cross-sectional prospective cohort study, 1445 Hong Kong Chinese children and adolescents aged 8-17 years with body height between 119 and 185 cm were recruited. Their ABPM assessment was performed using validated arm oscillometric recorders (A&D TM-2430) and complied with American Heart Association's recommendations. The reference tables were constructed using the LMS method to normalize skewed distribution of ABP data to sex and age or height. RESULTS: The ambulatory BP was higher among boys and the difference between boys and girls progressively widened with age. An increasing trend in daytime and night-time SBP and DBP with age and height was observed in both sexes. The age-specific and sex-specific 95th percentiles from nonoverweight children (n=1147; 79%) were lower than the whole cohort by up to 2.5 and 1 mmHg for SBP and DBP, respectively. In comparison, our overall and nonoverweight reference standards were generally higher than corresponding German references. CONCLUSION: The study provides ambulatory BP standards for Chinese children, with sex-related age-specific and height-specific percentiles. Further longitudinal studies are required for investigating its clinical utility in Chinese.

Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants.

Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT-II variants that underlain the persistent high fever-triggered viral infection-associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection-associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L-carnitine administration in avoiding the high mortality and morbidity of IAE.

Severe acute respiratory syndrome among children.

OBJECTIVE: To study the epidemiologic, clinical, laboratory, and radiologic features, prognostic indicators, and short-term to medium-term outcomes for children with severe acute respiratory syndrome (SARS) and to validate the performance characteristics of a clinical case definition, calculated with respect to SARS-associated coronavirus (SARS-CoV) seroconversion. METHODS: Children <18 years of age, from a single-site outbreak, who satisfied a clinical case definition for SARS, with subsequent serologic confirmation, were treated according to a standard protocol and prospectively monitored. RESULTS: Forty-four children were included. The median age was 12 years. Forty-two children (95.5%) demonstrated an epidemiologic link. Fever, cough, malaise, coryza, sputum production, headache, myalgia, lymphopenia, and elevated lactate dehydrogenase levels were common presenting features. Radiographic findings were nonspecific, but high-resolution computed tomography of the thorax was an early diagnostic aid. A specific reverse transcription-polymerase chain reaction assay for SARS-CoV yielded positive results for <50% of children. Of 9 children who developed hypoxemia, 8 were treated with methylprednisolone. Of 5 children who received intensive care, 3 required assisted ventilation. All children recovered, and serious adverse events in response to treatment were not observed. The outcomes at 3 to 6 months after disease onset, including exercise tolerance, pulmonary functions, and psychologic status, were favorable. An age of >12 years was associated with methylprednisolone therapy for severe illness. After exclusion of the only infant, an age of >12 years was associated with oxygen requirements. Sore throat, high neutrophil count at presentation, and peak neutrophilia were independent factors predicting severe illness. The clinical case definition demonstrated good sensitivity, specificity, and positive and negative predictive values (97.8%, 92.7%, 88%, and 98.7%, respectively) for diagnostic accuracy. CONCLUSIONS: Children are susceptible to SARS-CoV infection. Teenagers resemble adults with respect to disease progression and may develop severe illness. The short-term to medium-term outcomes are good. Sore throat and initial and peak neutrophilia seem to be predictors of severe illness. Our clinical case definition performed well in the epidemic.