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Introduction: Seasonal inactivated influenza vaccine (IIV) is routinely recommended during pregnancy to protect both mothers and infants from complications following influenza infection. While previous studies have evaluated the risk of major structural birth defects in infants associated with prenatal administration of monovalent pandemic IIV, fewer studies have evaluated the risk associated with prenatal seasonal IIV., Methods: We conducted a population-based cohort study of 125,866 singleton births between 2012 and 2016 in Western Australia. Birth registrations were linked to the state's registers for congenital anomalies and a state prenatal vaccination database. We estimated prevalence ratios (PR) of any major structural birth defect and defects by organ system. Vaccinated pregnancies were defined as those with a record of IIV in the first trimester. Inverse probability treatment weighting factored for baseline probability for vaccination. A Bonferroni correction was applied to account for multiple comparisons., Results: About 3.9% of births had a major structural birth defect. Seasonal IIV exposure during the first trimester was not associated with diagnosis of any major structural birth defect diagnosed within 1 month of birth (PR 0.98, 95% CI: 0.77, 1.28) or within 6 years of life (PR 1.02, 95% CI: 0.78, 1.35). We identified no increased risk in specific birth defects associated with seasonal IIV., Conclusion: Based on registry data for up to 6 years of follow-up, results suggest there is no association between maternal influenza vaccination and risk of major structural birth defects. These results support the safety of seasonal IIV administration during pregnancy., (© 2022 The Authors. Birth Defects Research published by Wiley Periodicals LLC.)

Aim: To describe the birth prevalence and characteristics of congenital heart defects in a geographically defined Australian population., Methods: This descriptive, population-based study examined congenital heart defects in live births, stillbirths and pregnancy terminations ascertained by the Western Australian Register of Developmental Anomalies, 1990-2016. Birth prevalence (per 1000 births) was stratified by severity, known cause, maternal and birth characteristics, and primary diagnosis; and prevalence ratios were calculated for Aboriginal versus non-Aboriginal births. Temporal trends in prevalence, diagnosis age and infant mortality were examined., Results: For births 1990-2010 (allowing 6 years for complete case ascertainment by 2016), 6419 cases were identified; prevalence was 11.5 per 1000 births (95% confidence interval (CI), 11.2-11.8). Severe defects were ascertained in 2.5 per 1000 births (95% CI 2.4-2.7). Most cases were liveborn (5842, 91.0%), and 28.9% had other birth defects. Prevalence was slightly higher in Aboriginal births (prevalence ratio 1.1; 95% CI 1.0-1.2); and the infant mortality rate more than doubled (13.4% vs. 5.8%, P < 0.001). Prenatal diagnosis increased over time but, in remote areas, was significantly lower for Aboriginal versus non-Aboriginal cases (3.1% vs. 9.3%; P = 0.008). A cause was identified in 920 cases (14.3%), more often for severe defects (347, 24.4%); 63% of known causes were rare diseases. Congenital heart defects associated with fetal alcohol spectrum disorder were much more common in Aboriginal births (prevalence ratio 82; 95% CI 28-239)., Conclusions: Earlier detection of congenital heart defects and improved survival has occurred over time, although discrepancies between ethnic groups and regions warrant further investigation and strategic action., (© 2021 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Craniofacial dysmorphism is associated with thousands of genetic and environmental disorders. Delineation of salient facial characteristics can guide clinicians towards a correct clinical diagnosis and understanding the pathogenesis of the disorder. Abnormal facial shape might require craniofacial surgical intervention, with the restoration of normal shape an important surgical outcome. Facial anthropometric growth curves or standards of single inter-landmark measurements have traditionally supported assessments of normal and abnormal facial shape, for both clinical and research applications. However, these fail to capture the full complexity of facial shape. With the increasing availability of 3D photographs, methods of assessment that take advantage of the rich information contained in such images are needed. In this article we derive and present open-source three-dimensional (3D) growth curves of the human face. These are sequences of age and sex-specific expected 3D facial shapes and statistical models of the variation around the expected shape, derived from 5443 3D images. We demonstrate the use of these growth curves for assessing patients and show that they identify normal and abnormal facial morphology independent from age-specific facial features. 3D growth curves can facilitate use of state-of-the-art 3D facial shape assessment by the broader clinical and biomedical research community. This advance in phenotype description will support clinical diagnosis and the understanding of disease pathogenesis including genotype-phenotype relations.

Genomic testing for a genetic diagnosis is becoming standard of care for many children, especially those with a syndromal intellectual disability. While previously this type of specialised testing was performed mainly by clinical genetics teams, it is increasingly being 'mainstreamed' into standard paediatric care. With the introduction of a new Medicare rebate for genomic testing in May 2020, this type of testing is now available for paediatricians to order, in consultation with clinical genetics. Children must be aged less than 10 years with facial dysmorphism and multiple congenital abnormalities or have global developmental delay or moderate to severe intellectual disability. This rebate should increase the likelihood of a genetic diagnosis, with accompanying benefits for patient management, reproductive planning and diagnostic certainty. Similar to the introduction of chromosomal microarray into mainstream paediatrics, this genomic testing will increase the number of genetic diagnoses, however, will also yield more variants of uncertain significance, incidental findings, and negative results. This paper aims to guide paediatricians through the process of genomic testing, and represents the combined expertise of educators, clinical geneticists, paediatricians and genomic pathologists around Australia. Its purpose is to help paediatricians navigate choosing the right genomic test, consenting patients and understanding the possible outcomes of testing., (© 2021 The Authors Journal of Paediatrics and Child Health published by John Wiley & Sons Australia, Ltd on behalf of Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Exome sequencing has enabled molecular diagnoses for rare disease patients but often with initial diagnostic rates of ~25-30%. Here we develop a robust computational pipeline to rank variants for reassessment of unsolved rare disease patients. A comprehensive web-based patient report is generated in which all deleterious variants can be filtered by gene, variant characteristics, OMIM disease and Phenolyzer scores, and all are annotated with an ACMG classification and links to ClinVar. The pipeline ranked 21/34 previously diagnosed variants as top, with 26 in total ranked ≤7th, 3 ranked ≥13th; 5 failed the pipeline filters. Pathogenic/likely pathogenic variants by ACMG criteria were identified for 22/145 unsolved cases, and a previously undefined candidate disease variant for 27/145. This open access pipeline supports the partnership between clinical and research laboratories to improve the diagnosis of unsolved exomes. It provides a flexible framework for iterative developments to further improve diagnosis.

Addressing Indigenous rights and interests in genetic resources has become increasingly challenging in an open science environment that promotes unrestricted access to genomic data. Although Indigenous experiences with genetic research have been shaped by a series of negative interactions, there is increasing recognition that equitable benefits can only be realized through greater participation of Indigenous communities. Issues of trust, accountability and equity underpin Indigenous critiques of genetic research and the sharing of genomic data. This Perspectives article highlights identified issues for Indigenous communities around the sharing of genomic data and suggests principles and actions that genomic researchers can adopt to recognize community rights and interests in data.

Objectives: To describe the prevalence and characteristics of microcephaly in a geographically defined Australian population., Design, Setting and Participants: Descriptive epidemiological study of microcephaly cases ascertained by the Western Australian Register of Developmental Anomalies, 1980-2015, defining microcephaly as an occipito-frontal head circumference below the third percentile or more than two standard deviations below the mean sex- and age-appropriate distribution curve., Main Outcome Measures: Microcephaly prevalence (per 10 000 births) was calculated for cases with known and unknown causes, and by demographic characteristics. Temporal trends were analysed, and prevalence ratios (PRs) and 95% CIs calculated for Aboriginal and non-Aboriginal births., Results: For births during 1980-2009 (ie, with at least 6 years' follow-up and therefore complete case ascertainment), 416 cases were identified, a prevalence of 5.5 per 10 000 births (95% CI, 4.95-6.02), or 1 in 1830 births. There was no significant temporal trend in prevalence (P = 0.23). Most cases were in live-born children (389, 93.5%), and other major birth defects were diagnosed in 335 of the affected children (80%). Prevalence was higher in Aboriginal births (PR, 4.5; 95% CI, 3.55-5.73). A cause of microcephaly was identified in 186 cases (45% of cases), and more often for Aboriginal (64 cases, 70%) than non-Aboriginal births (122 cases, 38%). The most frequent known cause of microcephaly in Aboriginal births was fetal alcohol spectrum disorder (FASD; 11 per 10 000 births); monogenic (0.68 per 10 000) and chromosomal conditions (0.59 per 10 000 births) were the most common causes in non-Aboriginal births., Conclusions: These data provide a baseline for prospective surveillance of microcephaly. We identified a high proportion of cases without known cause, highlighting the need for clinicians to carefully investigate all possibilities, including emerging infections. FASD is an important cause of microcephaly in the Aboriginal population.

Purpose: It has been argued that rare diseases should be recognized as a public health priority. However, there is a shortage of epidemiological data describing the true burden of rare diseases. This study investigated hospital service use to provide a better understanding of the collective health and economic impacts of rare diseases., Methods: Novel methodology was developed using a carefully constructed set of diagnostic codes, a selection of rare disease cohorts from hospital administrative data, and advanced data-linkage technologies. Outcomes included health-service use and hospital admission costs., Results: In 2010, cohort members who were alive represented approximately 2.0% of the Western Australian population. The cohort accounted for 4.6% of people discharged from hospital and 9.9% of hospital discharges, and it had a greater average length of stay than the general population. The total cost of hospital discharges for the cohort represented 10.5% of 2010 state inpatient hospital costs., Conclusions: This population-based cohort study provides strong new evidence of a marked disparity between the proportion of the population with rare diseases and their combined health-system costs. The methodology will inform future rare-disease studies, and the evidence will guide government strategies for managing the service needs of people living with rare diseases.Genet Med advance online publication 22 September 2016.

Silver-Russell syndrome (SRS) and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome are described in isolation. However, their co-occurrence has only been rarely reported. Here, we present a case report of an adolescent with SRS who was diagnosed with MRKH during the evaluation of primary amenorrhoea. Multiplex ligation-dependent probe amplification analysis showed a normal methylation pattern and normal dosage at 11p15.5. A PubMed search for all peer-reviewed publications (original articles and reviews) using the key words Silver-Russell syndrome, Mayer-Rokitansky-Küster-Hauser syndrome, genetics, hypomethylation and reproductive anomalies identified three cases of SRS with MRKH, two of which were associated with significant hypomethylation of the H19 imprinting control region of the 11p15.5 locus. This report highlights the association between SRS and MRKH. The absence of hypomethylation and normal dosage at 11p15.5 suggests these two rare entities share alternative aetiopathogenic mechanisms., (© 2014 The Authors. Journal of Paediatrics and Child Health © 2014 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

Context: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant disorder that arises as a consequence of mutations in the STK11 gene that encodes LKB1. PJS males often have estrogen excess manifesting as gynecomastia and advanced bone age. We and others have previously described an increase in testicular aromatase expression in PJS patients. However, the underlying mechanism has not yet been explored., Objective: The aim of this study was to characterize the role of LKB1 in regulating the expression of aromatase in boys with PJS via signaling pathways involving AMP-activated protein kinase (AMPK) and cyclic AMP-responsive element binding protein-regulated transcription coactivators (CRTCs)., Patients: We studied testicular biopsies from two boys with STK11 mutations: a 13-year-old boy and an unrelated 4-year-old boy with prepubertal gynecomastia and advanced bone age, as well as breast tissue from the 13-year-old boy., Results: Loss of heterozygosity of STK11, measured by the absence of LKB1 immunofluorescence, was observed in Sertoli cells of abnormal cords of testis samples from affected individuals. This was associated with loss of p21 expression and decreased phosphorylation of AMPK, known downstream targets of LKB1, as well as the increased expression of aromatase. Similar results of low LKB1 expression in cells expressing aromatase were observed in the mammary epithelium from one of these individuals. Nuclear expression of the CRTC proteins, potent stimulators of aromatase and known to be inhibited by AMPK, was significantly correlated with aromatase., Conclusions: Loss of heterozygosity of the STK11 gene leads to an increase in aromatase expression associated with an increase in CRTC nuclear localization, thereby providing a mechanism whereby PJS results in increased endogenous estrogens in affected males.

With advances in therapeutics for rare, genetic and syndromic diseases, there is an increasing need for objective assessments of phenotypic endpoints. These assessments will preferentially be high precision, non-invasive, non-irradiating, and relatively inexpensive and portable. We report a case of a child with an extensive lymphatic vascular malformation of the head and neck, treated with an mammalian target of Rapamycin (mTOR) inhibitor that was assessed using 3D facial analysis. This case illustrates that this technology is prospectively a cost-effective modality for treatment monitoring, and it supports that it may also be used for novel explorations of disease biology for conditions associated with disturbances in the mTOR, and interrelated, pathways.

We report on a 3-year-old girl, from a 3-generation family with an FGFR3 Pro250Arg mutation, who in addition to craniosynostosis, had a laterality disorder and hepatoblastoma, following a pregnancy complicated by maternal insulin-dependent diabetes. The clinical features possibly result from the combined effects of the maternal diabetes and the familial FGFR3 mutation, thus representing a unique gene-environment interaction that may have implications for the understanding of the phenotypes described in this child.