Search

Background: Mobile devices provide new opportunities for the prevention of overweight and obesity in children. We aimed to co-create and test an app that provided comprehensible feedback to parents on their child's growth and delivered a suite of age-specific information about nutrition and activity. Methods: A two-phased approach was used to co-create the digital growth tool - See How They Grow - and test its feasibility. Phase one used focus groups and a national online survey to gather requirements and build the app. Phase two involved testing the app over 12-weeks, with parents or carers of children aged ≤ 2-years. All research activities were undertaken exclusively through the app. Participants were recruited using social media and hard copy materials. Findings: Four focus groups and 101 responses to the national survey informed the features and functions to include in the final app. Two hundred and twenty-five participants downloaded the app, resulting in 208 eligible participants. Non-Māori/Non-Pacific (78%) and Māori (14%) had the highest downloads. Fifty-four per cent of participants were parents of children under 6-months. These participants were more likely to regularly use the app than those with children older than 6-months (64% vs 36%, P =0.011). Over half of the participants entered three measures (n=101, 48%). Of those that completed the follow-up survey (n=101, 48%), 72 reported that the app helped them better understand how to interpret growth charts. Interpretation: With minor modifications, the app could be an effective tool to support parents understanding of growth trajectories and what they mean for their children. A larger trial is needed to evaluate if the app can have a measurable impact on increasing knowledge and behaviour, and therefore on preventing childhood overweight and obesity. Funding Statement: This study was funded through a contestable funding round by Cure Kids, the National Science Challenge: a Better Start and Precision Driven Health. The funders had no influence on the design, implementation, interpretation or reporting of the study findings. Declaration of Interests: None. Ethics Approval Statement: The study has Ethics approval from the NZ Auckland University Human Participants Ethics Committee; Co-creation and Development Study Reference 020166, Feasibility Study Reference 022248. All participants gave consent to participate. The feasibility study was registered on the Australia New Zealand Clinical Trial registration (ACTRN12619000905167).

We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood–brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient’s neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate, and lipoate) replacement therapy.

Early diagnosis of inborn errors of metabolism (IEM)—a large group of congenital disorders—is critical, given that many respond well to targeted therapy. Newborn screening programs successfully capture a proportion of patients enabling early recognition and prompt initiation of therapy. For others, the heterogeneity in clinical presentation often confuses diagnosis with more common conditions. In the absence of family history and following clinical suspicion, the laboratory diagnosis typically begins with broad screening tests to circumscribe specialised metabolite and/or enzyme assays to identify the specific IEM. Confirmation of the biochemical diagnosis is usually achieved by identifying pathogenic genetic variants that will also enable cascade testing for family members. Unsurprisingly, this diagnostic trajectory is too often a protracted and lengthy process resulting in delays in diagnosis and, importantly, therapeutic intervention for these rare conditions is also postponed. Implementation of mass spectrometry technologies coupled with the expanding field of metabolomics is changing the landscape of diagnosing IEM as numerous metabolites, as well as enzymes, can now be measured collectively on a single mass spectrometry-based platform. As the biochemical consequences of impaired metabolism continue to be elucidated, the measurement of secondary metabolites common across groups of IEM will facilitate algorithms to further increase the efficiency of diagnosis.

Purpose: In many children with cancer and characteristics suggestive of a genetic predisposition syndrome, the genetic cause is still unknown. We studied the yield of pathogenic mutations by applying whole-exome sequencing on a selected cohort of children with cancer. Experimental Design: To identify mutations in known and novel cancer-predisposing genes, we performed trio-based whole-exome sequencing on germline DNA of 40 selected children and their parents. These children were diagnosed with cancer and had at least one of the following features: (1) intellectual disability and/or congenital anomalies, (2) multiple malignancies, (3) family history of cancer, or (4) an adult type of cancer. We first analyzed the sequence data for germline mutations in 146 known cancer-predisposing genes. If no causative mutation was found, the analysis was extended to the whole exome. Results: Four patients carried causative mutations in a known cancer-predisposing gene: TP53 and DICER1 (n = 3). In another 4 patients, exome sequencing revealed mutations causing syndromes that might have contributed to the malignancy (EP300-based Rubinstein–Taybi syndrome, ARID1A-based Coffin–Siris syndrome, ACTB-based Baraitser–Winter syndrome, and EZH2-based Weaver syndrome). In addition, we identified two genes, KDM3B and TYK2, which are possibly involved in genetic cancer predisposition. Conclusions: In our selected cohort of patients, pathogenic germline mutations causative or likely causative of the cancer phenotype were found in 8 patients, and two possible novel cancer-predisposing genes were identified. Therewith, our study shows the added value of sequencing beyond a cancer gene panel in selected patients, to recognize childhood cancer predisposition. Clin Cancer Res; 24(7); 1594–603. ©2018 AACR.

Autism is an etiologically heterogeneous developmental disorder for which the range of genetic investigations has expanded considerably over the past decade. Introduction of chromosomal microarray (CMA) to clinical practice has expanded the range of conditions which pediatricians are able to detect. This study reviewed the utilization, yield and cost of genetic investigations in a sample of children with pervasive developmental disorders (PDD) in an Australian metropolitan child development service. Six hundred and ninety eight patients with PDD were identified from the clinic population. One hundred and ten (15.7%) of the clinic population had undergone investigation with chromosomal microarray, 140 (20.0%) with karyotype (KT), and 167 (23.9%) with Fragile X testing (FRGX). Twelve (10.9%) CMA findings were reported, of which seven (6.3%) were felt to be the likely cause of the child’s clinical features. Five (3.5%) KT findings were reported, of which four (2.9%) were felt to be the likely cause of the child’s clinical features. Two patients (1.2%) were identified with Fragile X expansions. One fifth of the clinic’s recent PDD population had undergone testing with CMA. CMA appears to have increased the diagnostic yield of the genetic investigation of autism, in line with internationally reported levels. Number needed to test (NNT) and cost per incremental diagnosis, were also in line with internationally reported levels.

Background Pachyonychia congenita (PC) is a rare inherited disorder of keratinization characterised by hypertrophic nail dystrophy, painful palmoplantar blisters, cysts, follicular hyperkeratosis and oral leukokeratosis. It is associated with mutations in five differentiation-specific keratin genes, KRT6A, KRT6B, KRT6C, KRT16, or KRT17. Objectives Living with Pachyonychia Congenita can be isolating. The aim of this paper is to document a single patient's experience within a national context. Method We report the case of a 2 year old female with an atypical presentation of PC due to a mutation in KRT6A with severely hypertrophic follicular keratoses, skin fragility, relative sparing of nail hypertrophy on one hand and failure to thrive in early infancy. In collaboration with the International Pachyonychia Congenita Research Registry (IPCRR), a database search was performed using Australian residency and KRT6A mutation as inclusion criteria. The IPCRR database was also searched for a matching KRT6A mutation. Six Australian patients were identified in addition to one patient with an identical mutation residing in the United States. The detailed standardized patient questionnaire data was manually collated and analysed. Results Fingernail hypertrophy and oral leukokeratosis were the most common features. There was no recording of asymmetric distribution in any other Australian patient. Trouble nursing as an infant and follicular hyperkeratosis also occurred in the American patient, however they did not have asymmetric distribution and the oral leukokeratosis appeared later in life. Conclusion This case has unique features. Sharing information can assist patients navigating life with this condition.

Isolated mitochondrial respiratory chain complex III deficiency has been described in a heterogeneous group of clinical presentations in children and adults. It has been associated with mutations in MT-CYB, the only mitochondrial DNA encoded subunit, as well as in nine nuclear genes described thus far: BCS1L, TTC19, UQCRB, UQCRQ, UQCRC2, CYC1, UQCC2, LYRM7, and UQCC3. BCS1L, TTC19, UQCC2, LYRM7, and UQCC3 are complex III assembly factors. We report on an 8-year-old girl born to consanguineous Iraqi parents presenting with slowly progressive encephalomyopathy, severe failure to thrive, significant delays in verbal and communicative skills and bilateral retinal cherry red spots on fundoscopy. SNP array identified multiple regions of homozygosity involving 7.5% of the genome. Mutations in the TTC19 gene are known to cause complex III deficiency and TTC19 was located within the regions of homozygosity. Sequencing of TTC19 revealed a homozygous nonsense mutation at exon 6 (c.937C > T; p.Q313X). We reviewed the phenotypes and genotypes of all 11 patients with TTC19 mutations leading to complex III deficiency (including our case). The consistent features noted are progressive neurodegeneration with Leigh-like brain MRI abnormalities. Significant variability was observed however with the age of symptom onset and rate of disease progression. The bilateral retinal cherry red spots and failure to thrive observed in our patient are unique features, which have not been described, in previously reported patients with TTC19 mutations. Interestingly, all reported TTC19 mutations are nonsense mutations. The severity of clinical manifestations however does not specifically correlate with the residual complex III enzyme activities.

The Mitochondrial tRNALeu (MT-TL1) mutation, m.3243A>G constitutes the commonest identified mitochondrial genome mutation. Characteristically, giving rise to MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes), a phenotypic spectrum associated with this genetic variant is now apparent. We report on the first patient with infantile hemiparesis, without comorbid encephalopathy, attributed to this variant. This further expands the recognized disease spectrum and highlights the need to consider mitochondrial genomic mutations in cases of cryptogenic focal neurological deficit in infancy. The potential for genetic disease modifiers is additionally discussed. usc Refereed/Peer-reviewed

Background Cerebellar vermis hypoplasia has been associated with a large number of chromosomal abnormalities and metabolic disorders, with few candidate genes clearly linked to isolated cerebellar vermis hypoplasia. Patient Description We describe on a 12-year-old boy with inferior vermian hypoplasia associated with a novel de novo microdeletion. He presented with intellectual, speech and language impairment, unilateral facial nerve weakness, marked constipation, and bilateral hand and foot anomalies that were not consistent with any previously described syndrome. His hand features were digital reductions similar to those seen in 4q34 deletion syndrome, known as the "tale of the nail" sign. Cranial magnetic resonance imaging demonstrated isolated inferior cerebellar vermis hypoplasia. Results A de novo 1.4 Mb interstitial deletion was identified at 8q13.1-q13.2 on chromosomal microarray. This copy number variant involves 18 human genome reference sequence genes, with 11 Mendelian Inheritance in Man genes. Homozygous mutations in one of these genes (CSPP1) has recently been recently described as causing Joubert syndrome. Conclusion We propose that the constellation of clinical features in this child represents a novel microdeletion syndrome and hypothesize that CSPP1 or other genes within the deleted region contribute to the cerebellar development. usc Refereed/Peer-reviewed

Aim This study aimed to determine the utilisation, yield and cost of screening genetic investigations in a sample of children diagnosed with pervasive developmental disorders (PDD; DSM-IV). The purpose was to inform development of strategies for genetic investigation of children with these disorders. Methods 699 patients with PDD were identified, and genetic investigations evaluated. A sub-group of 219 patients underwent clinical chart audit, and the resulting clinical characteristics evaluated in the context of investigation use and findings. Results 24.8%, 15.9% and 25.1% of the clinic population had undergone investigation with chromosomal microarray (CMA), karyotype (KT) and fragile X testing, respectively. CMA is associated with a cost reduction of $3437 less per diagnosis compared with KT (p = 0.026). Several characteristics were associated with increased odds of a significant CMA finding, most significant of which was comorbid epilepsy (odds ratio 10.4; p Discussion CMA appears to increase the diagnostic yield of screening genetic investigations in PDD. This finding is consistent with what has been seen in other populations internationally. CMA reduces cost per incremental diagnosis with comparison to KT, amongst children with PDD. Epilepsy was found to be a significant predictor of a pathogenic finding on chromosomal microarray.