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Objectives The aim of this study is to quantify the mortality rate, direct healthcare costs, and cumulative life costs of pediatric patients with spinal muscular atrophy (SMA) type 1, type 2, and type 3 born in Hong Kong. Methods Data were collected from genetically confirmed SMA patients born in or after 2000 from the Hospital Authority medical database. Patients were followed up from birth until they died, left Hong Kong, reached 18 years, or initiated disease-modifying treatment. Study outcomes included incidence risks of mortality, cumulative direct medical costs—attendances of special outpatient clinics, emergency department, allied health services, and mean length of stay in hospitals over time. Total direct medical costs were calculated as unit costs multiplied by utilization frequencies of corresponding healthcare services at each age. Results Seventy-one patients with SMA were included. Over a median follow-up period of 6 years, the overall incidence rate of death was 5.422/100 person-years (95%CI 3.542–7.945/100 person-years). 67.7% and 11% of deaths occurred in SMA1 and SMA2 groups, respectively. The median age of death was 0.8 years in SMA1 and 10.9 years in SMA2. The mean cumulative direct medical costs in overall SMA, SMA1, SMA2 and SMA3 groups per patient were US$935,570, US$2,393,250, US$413,165, and US$40,735, respectively. Interpretation: Our results confirmed a significantly raised mortality and extremely high healthcare burden for patients with SMA especially SMA type 1 and 2 without disease-modifying treatment. Study evaluating health and economic impact of newborn screening and early treatment is needed.

Hemoglobin (Hb) Hammersmith is a rare form of unstable β-chain hemoglobinopathy causing hemolytic anemia. This rare event led to a more serious transfusion-dependent phenotype in a patient. It was successfully cured by haploidentical hematopoietic stem cell transplantation (HSCT).A 9-year-old mainland Chinese male with a history of neonatal unconjugated hyperbilirubinemia was diagnosed to have hemoglobin (Hb) Hammersmith. He required regular blood transfusion but was unable to be transfused to desired parameters for 8 years prior to transplant due to social and geographical reasons. He subsequently developed marrow hyperplasia and progressive splenomegaly (down to umbilicus level), suggestive of extramedullary hematopoiesis. Eventually, the family came to Hong Kong and complied to a more intensive transfusion regimen and preconditioning chemotherapy 3 months prior to transplant. He underwent haploidentical HSCT using paternal TCRαβ/CD45RA-depleted graft but suffered from graft rejection, despite splenic irradiation for massive splenomegaly. It was successfully salvaged with second HSCT with unmanipulated graft from the same donor with additional serotherapy and donor lymphocyte infusions.Allogenic haploidentical HSCT for hemoglobin Hammersmith is feasible but adequate immunosuppression during conditioning is crucial. Precise adoptive cell therapy can promote durable engraftment.

Much research on children in high-risk environments has focused on the biological consequences of maltreatment, adversity, and trauma. Whether other early-life stress sources such as family financial hardship are implicated in the cellular mechanism of disease development remains unclear. This study investigated the long-term effect of childhood exposure to family financial pressure on telomere length. It involved two waves of data collection occurring when participants reached Grade 3 (W1) and 7 (W2), respectively. In W1, parents reported family demographics and perceived financial stressors and pressure. In W2, participants provided buccal swab samples for measurement of their telomere length. Data from 92 participants (Mage in W2 = 13.2 years; 56.5% male) were analyzed. The main type of stressors reported by parents who perceived high family financial pressure in W1 were child-level stressors including affordability of their medical and educational expenses. Participants exposed to high parent-perceived family financial pressure in W1 had shorter telomeres in W2 when compared to those exposed to low parent-perceived family financial pressure (β = −0.61, p = 0.042). Subgroup analyses revealed stronger associations in girls than boys. These findings reveal an important spillover effect between parental financial perceptions and stress and children’s health at the cellular level.

Here we describe the clinical course and unique molecular findings in a female neonate with infantile hemispheric glioma (IHG). The patient presented at the age of 17 days with macrocephaly and suboptimal weight gain. MRI brain revealed an 8.5cm mass over the right frontal region with significant mass effect and entrapment of ventricles. Urgent ventriculoperitoneal shunt insertion and biopsy of the highly vascular lesion was performed. Pathology was compatible with glioblastoma multiforme. Methylation profiling classified the sample as inflammatory tumor tissue (MNP v11b4), while panel RNA-sequencing revealed a fusion event between HMBOX1 and ALK which has not been described in primary CNS tumors. Long-read sequencing with the Nanopore system further revealed complex genomic rearrangement involving an interposed genomic fragment from a third chromosome with validation by Sanger sequencing. Based on an integrated diagnosis of IHG, the patient went on to receive neoadjuvant chemotherapy per the CNS-14 protocol (cyclophosphamide, carboplatin, etoposide) with significant tumor shrinkage. Near total removal of the lesion was achieved after 4 cycles of chemotherapy and adjuvant treatment with 4 additional cycles was given. The patient tolerated therapy well other than self-limiting transaminitis. At the end of treatment, the patient enjoyed intact neurology and satisfactory developmental progress. Our case report illustrates the value a multi-pronged approach to characterizing rare pediatric CNS tumors. The precise delineation of breakpoints in fusion-driven tumors might be of value in the design of cfDNA-based assays. (APYL and CTLC contributed equally to the submission)

Purpose We aim to determine if the loss of white matter fractional anisotropy (FA), measured by diffusion tensor magnetic resonance imaging (DTI), in post-treatment childhood medulloblastoma (MED) and acute lymphoblastic leukemia (ALL) survivors correlate with intelligence quotient (IQ) scores. Materials and Methods MED and ALL survivors (n = 30; 20 male, 10 female; age range, 6.0 to 22.1 years; mean, 13.1 years) were recruited for DTI and IQ tests. In this cross-sectional study, age-matched normal control (n = 55; 32 male, 23 female; age range, 6.0 to 23 years; mean, 12.1 years) DTI was obtained to compute percentage difference in white matter FA (ΔFA%) for each patient compared with the age-matched control group. Multivariate regression analysis was performed to determine the relationships between ΔFA%, age at treatment, irradiation dose, time interval from treatment, and full-scale IQ (FSIQ), verbal IQ (VIQ), and performance IQ (PIQ). Receiver operating characteristics curves were used to determine the best ΔFA% cutoffs for predicting FSIQ, VIQ, and PIQ of less than 85. Results ΔFA% had a significant effect on FSIQ (adjusted r2 = 0.439; P < .001), VIQ (adjusted r2 = 0.237; P = .028), and PIQ (adjusted r2 = 0.491; P < .001) after adjusting for the effects of age at treatment, irradiation dose, and time interval from treatment. The best ΔFA% value to predict less than 85 scores in FSIQ, VIQ, and PIQ was −3.3% with specificities of 100% and sensitivities ranging from 77.8% to 87.5%. Conclusion Our preliminary findings suggest that white matter FA may be a clinically useful biomarker for the assessment of treatment-related neurotoxicity in post-treatment childhood cancer survivors.

To investigate the pattern of malignancies in Chinese patients with neurofibromatosis type 1.Historical cohort study.Queen Mary Hospital and Duchess of Kent Children's Hospital in Hong Kong.Patients with neurofibromatosis type 1 seen between January 1995 and August 2011.We identified 123 Chinese patients with neurofibromatosis type 1, diagnosed at a median age of 4.9 years (range, 0.1-16.1 years); 75 (61%) were males. They were followed up for a median of 9.7 years (range, 0.2-27.6 years). Most (80%) of the patients participated in our surveillance programme. Twelve patients developed malignancies at the ages of 0.8 to 41.6 years. These malignancies included: peripheral nerve sheath tumours (n=3), juvenile myelomonocytic leukaemia (n=2), optic nerve glioma (n=1), thalamic pilocytic astrocytoma (n=1), rhabdomyosarcoma (n=1), osteosarcoma (n=1), neuroblastoma (n=1), anaplastic large cell lymphoma (n=1), and breast carcinoma and subsequently carcinoma of the ampulla of Vater (n=1). Among them, three had their tumours (optic glioma, thalamic astrocytoma, sacral malignant peripheral nerve sheath tumour) initially detected by surveillance imaging. Four patients survived without disease progression, three are alive with active disease, the remaining five died (when aged 3 to 56 years) with progressive or relapsed malignancies. The latter patients died from a neuroblastoma, a juvenile myelomonocytic leukaemia, a malignant peripheral nerve sheath tumour, a lymphoma, and a second primary tumour (carcinoma of ampulla of Vater, at the age of 56 years). In neurofibromatosis type 1 patients with malignancy, overall 30-year survival was significantly shorter than in those without malignancy (35% vs 93%, P0.001).Chinese patients with neurofibromatosis type 1 are susceptible to different malignancies which contribute to mortality. These findings are similar to reports from overseas. Outcomes were unfavourable, except in patients having low-grade gliomas. Surveillance imaging may help early detection of deep-seated malignancies but the benefits accruing from such monitoring warrants prospective evaluation.

Haemolytic uraemic syndrome is an important cause of acute renal impairment in childhood. We review the incidence, and clinical and laboratory features of haemolytic uraemic syndrome in a Chinese population. Five patients were identified from 2006 to 2008. All patients were young children with associated invasive Streptococcus pneumoniae pulmonary infection. Serotypes 3, 14, and 19A were confirmed in four patients. The classical post-diarrhoeal form associated with Escherichia coli (O157:H7) infection was not seen. One patient died of acute respiratory failure. Streptococcus pneumoniae infection, as an associated condition in haemolytic uraemic syndrome, is important and relatively common in Chinese patients, especially among children. The acute clinical picture is similar to that reported in the western literature, except for an uncommon association with meningitis. The medium-term renal outcome of the Chinese population appears to be more favourable than the Caucasians. Widespread vaccination against Streptococcus pneumoniae may have resulted in changes in bacterial epidemiology and clinicians should be continuously aware of this severe disease. The use of washed blood components for transfusion in the acute stage requires further study.

To provide a synopsis of current haemophilia care in Hong Kong.Retrospective survey.All haematology units of the Hospital Authority in Hong Kong.All patients with haemophilia A and haemophilia B.To date, there were 222 mild-to-severe haemophilia patients (192 type A, 30 type B) under regular public care in Hong Kong (43% were considered severe, 33% moderate, and 24% mild), which gave a crude prevalence of 6.8/100 000 male inhabitants. A total of 12.8 million units of Factor VIII and 3 million units of Factor IX were prescribed annually. This amounts to 1.83 units of FVIII per capita of the population, which is comparable to that of other developed countries. Leading causes of mortality were human immunodeficiency virus-related complications (10 cases) and cerebral bleeding (2 cases). The life expectancy of patients with severe haemophilia in Hong Kong is improving; currently the oldest patient is 60 years old. Such improved survival may be due to enhanced factor availability, prompt treatment of bleeding episodes at home, safer factor products, and better antiviral treatment. Primary prophylaxis is the accepted standard of care for severe and moderate cases, and "Factor First" has become hospital policy. However, 12 patients continue to present treatment challenges, due to the documented presence of factor inhibitors. In all, 28, 100, and 14 cases respectively were positive for human immunodeficiency virus, hepatitis C virus, and hepatitis B virus; the youngest patients with the corresponding infections being 28, 13, and 22 years old. Comprehensive care with dedicated physiotherapy, surgical support, and radionucleotide synovectomy may reduce morbidity further.A multidisciplinary approach can further improve the future care for haemophilia patients in Hong Kong.

Anthracycline has been shown to degrade titin that plays a role in myocardial twisting and untwisting. This study aimed to test the hypothesis that left ventricular (LV) twisting and untwisting motion may be altered in children after anthracycline therapy.Thirty-six childhood leukemia survivors aged 15.6 ± 5.5 years and 20 healthy controls aged 16.8 ± 7.7 years (P = 0.54) were studied. LV twisting and untwisting motion was determined using speckle tracking imaging, whereas LV ejection fraction and systolic and diastolic mitral annular velocities were determined respectively by three-dimensional and tissue-Doppler echocardiography.Compared with controls, patients had significantly lower LV ejection fraction (P = 0.01) but similar systolic and diastolic mitral annular velocities (all P0.05). Their peak LV torsion (P = 0.003), systolic twisting velocity (P0.001), and diastolic untwisting velocity (P = 0.04) were significantly lower than controls, which could be attributable to their reduced apical rotation (P = 0.03) and apical untwisting rate (P = 0.002). For the whole cohort, LV systolic torsion and twisting velocity correlated significantly with apical untwisting rate (P0.001) and LV diastolic untwisting velocity (P0.001). In patients, none of the twisting or untwisting parameters were found to correlate with cumulative anthracycline dose (all P0.05). Twenty-eight (78%) patients had LV ejection fractions ≥50%. Although their systolic and diastolic mitral annular velocities were similar to those of controls, their peak LV torsion (P = 0.005), apical untwisting rate (P = 0.01), and LV systolic twisting velocity (P = 0.001) remained significantly lower.Impairment of LV twisting and untwisting motion is evident in children after anthracycline therapy, even in those with "normal" LV ejection fractions.

Four patients (age 3-11 years at diagnosis) with relapsed acute promyelocytic leukemia (APL), 12-38 months from diagnosis, were treated with oral arsenic trioxide (As(2) O(3) ). One patient was treated with oral As(2) O(3) monotherapy and chemotherapy. Three patients failed initial oral or intravenous As(2) O(3) monotherapy were treated with oral As(2) O(3) plus ATRA followed by long-term oral maintenance (cumulative As(2) O(3) dose 280-2,100 mg). All patients achieved molecular remission, at a median follow up of 122 (10-132) months with no adverse effects. Oral As(2) O(3) , particularly in prolonged maintenance with oral ATRA may obviate the need of stem cell transplantation in relapsed pediatric APL.

To review the treatment outcome of rhabdomyosarcoma in Hong Kong Chinese children.Retrospective review.University teaching hospital, Hong Kong.Consecutive cases of rhabdomyosarcoma diagnosed and treated by the Department of Paediatrics and Adolescent Medicine of Queen Mary Hospital between 1989 and 2005. Each patient was staged and treated according to the Intergroup Rhabdomyosarcoma Study guidelines.Overall and event-free survival rates, and toxicity data.Of 19 patients (8 males and 11 females), 14 (74%) were younger than 10 years old. The median age at diagnosis was 6 (range, 0.5-17) years. Primary sites of rhabdomyosarcoma included: the head and neck (n=8; 6 classified as cranial parameningeal), genitourinary (3), extremity (3), pelvis (3), and trunk (2). Thirteen (68%) had embryonal and six (32%) had alveolar histology. Two, 2, 9, and 6 were classified as belonging to Intergroup Rhabdomyosarcoma Study groups 1, 2, 3, and 4, respectively. Respective 5-year overall and event-free survival rates of the entire cohort were 49% (95% confidence interval, 26-73%) and 32% (10-55%), with a median follow-up of 3.4 (range, 0.2-16.7) years. In non-metastatic cases (Intergroup Rhabdomyosarcoma Study groups 1-3), the 5-year overall survival rate was 66% (95% confidence interval, 39-93%) and in metastatic cases (group 4) it was 17% (0-46%). The 5-year overall survival rate for patients aged less than 10 years was 60% (95% confidence interval, 33-87%) compared to 20% (0-55%) in those aged 10 years and over. Significant treatment-related toxicities including myelosuppression, infections, peripheral neuropathy, and second cancers were encountered.Treatment outcome of rhabdomyosarcoma in this cohort of Chinese children was less favourable than that reported in international studies. Whilst the main reason could have been related to the high proportion of metastatic cases, also non-metastatic cases faired worse. Improved outcomes may be achieved by advances in multidisciplinary (paediatric oncology, pathology, radiotherapy, and surgery) management and supportive care.

Neuroblastoma, a form of neuroblastic tumor, is one of the most common neoplasms seen in early childhood. The diverse clinical behavior of this tumor is most probably explainable by the heterogeneity in the associated genetic changes. We investigated 12 neuroblastoma patients for MYCN amplification and chromosome 2 aneusomy by fluorescence in situ hybridization (FISH) and results were correlated with conventional cytogenetics. Samples from both primary tumor tissue and bone marrow metastasis were available in two cases. The copy number of MYCN oncogene paralleled that of chromosome 2 in 10 cases, whereas two cases (16.7%) showed numerous distinct signals within the nuclei of the tumor cells, consistent with MYCN amplification as double minute (dmin). The morphology of dmin in one case was of an extremely small type and might potentially be missed by conventional chromosome analysis. Discordant cytogenetics and FISH results was observed between primary tumor and metastasis disease in one case, with loss of chromosome 2 tetrasomic and pentasomic cells as well as over-representation of chromosome 2 disomic cells harboring MYCN amplification in bone marrow deposits. Our study reaffirmed the need for MYCN status to be determined in light of chromosome 2 copy number, as recommended by published guidelines. We also showed that genetic heterogeneity might occur between primary tumor and bone marrow metastasis. Finally, atypical dmin morphology when encountered would need confirmation by FISH study.