ADAMTSL2 mutations determine the phenotypic severity in geleophysic dysplasia.

Geleophysic dysplasia-1 (GD1) is an autosomal recessive disorder caused by ADAMTS-like 2 (ADAMTSL2) variants. It is characterized by distinctive facial features, limited joint mobility, short stature, brachydactyly, and life-threatening cardiorespiratory complications. The clinical spectrum spans from perinatal lethality to milder adult phenotypes. We developed and characterized cellular and mouse models, to replicate the genetic profile of a patient who is compound heterozygous for 2 ADAMTSL2 variants, namely p.R61H and p.A165T. The impairment of ADAMTSL2 secretion was observed in both variants, but p.A165T exhibited a more severe impact. Mice carrying different allelic combinations revealed a spectrum of phenotypic severity, from lethality in knockout homozygotes to mild growth impairment observed in adult p.R61H homozygotes. Homozygous and hemizygous p.A165T mice survived but displayed severe respiratory and cardiac dysfunction. The respiratory dysfunction mainly affected the expiration phase, and some of these animals had microscopic post-obstructive pneumonia. Echocardiograms and MRI studies revealed a significant systolic dysfunction, accompanied by a reduction of the aortic root size. Histology verified the presence of hypertrophic cardiomyopathy with myocyte hypertrophy, chondroid metaplasia, and mild interstitial fibrosis. This study revealed a substantial correlation between the degree of impaired ADAMTSL2 secretion and the severity of the observed phenotype in GD1.

Risk of Preterm Delivery in Very Advanced Maternal Age Parturients Utilizing In Vitro Fertilization.

OBJECTIVE: Among patients ≥45 years, the birth rate in the United States continues to increase. As fertility declines with age, this cohort often utilizes assisted reproductive technology, specifically in vitro fertilization (IVF). While both advancing maternal age and IVF are independently associated with adverse maternal outcomes, data regarding their additive effect are scant. This article aims to determine if patients who conceive via IVF are at increased risk for preterm birth (PTB) compared to patients with non-IVF pregnancies in a very advanced maternal age (vAMA) cohort (≥45 years). STUDY DESIGN: Retrospective cohort study of all pregnant patients ≥45 years old who delivered at a single institution (2014-2021). Those with incomplete delivery/neonatal records or multiples beyond twins were excluded. We compared individuals who conceived via IVF to those who conceived without IVF. The primary outcome was preterm delivery <37 weeks gestation. Secondary outcomes included other adverse perinatal outcomes. Using multivariable logistic regression, we adjusted for multiple gestation as well as confounders found to be significantly different in the univariable analysis and other known risk factors for PTB. RESULTS: In our study cohort of 420 vAMA patients, individuals who underwent IVF were more likely to be older, privately insured, nulliparous, and with a twin gestation. The PTB rate in vAMA patients who underwent IVF was 24.4 compared to 8.4% in patients who did not use IVF (p < 0.001). After adjusting for confounders, IVF was an independent risk factor for PTB <37 weeks in vAMA patients (adjusted odds ratio {aOR] = 4.3, 95% confidence interval [CI]: 1.7-10.4, p = 0.001). In vitro fertilization was also associated with a composite of adverse maternal outcomes (hypertensive disorder of pregnancy, postpartum hemorrhage, blood transfusion, and unplanned hysterectomy) (aOR 1.7, 95% CI [1.1-2.9], p = 0.03). CONCLUSION: In the vAMA population, conception via IVF is associated with an increased risk of PTB <37 weeks. KEY POINTS: · This study examines IVF as an independent risk factor for PTB in patients ≥45 years at delivery, which has not been specifically addressed in prior studies.. · In vAMA patients, use of IVF is associated with an increased risk of PTB <37 weeks. These patients also have higher rates of cesarean delivery. Neonates from IVF pregnancies are more likely to be very low birth weight or low birth weight.. · Bodies of research exist for both advanced maternal age and assisted reproductive technology, there is a paucity of data specifically in parturients of vAMA who conceive via IVF..

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

Scope of professional roles for genetic counsellors and clinical geneticists in the United Kingdom : Position on behalf of the Association of Genetic Nurses and Counsellors and the Clinical Genetics Society.

This document is written on behalf of the two professional bodies in the United Kingdom that represent genetic counsellors (the Association of Genetic Nurses and Counsellors) and clinical geneticists (the Clinical Genetics Society) and aims to support multidisciplinary working of these professional groups highlighting within a quick-reference format, areas of shared practice and the distinctions between role profiles for a Consultant Clinical Geneticist, Principal/Consultant Genetic Counsellor and the new support role that we have termed 'Genomic Associate', see AGNC career structure [1]. This builds on published documents that articulate the scope of practice of the clinical genetics workforce [2] and specifically the genetic counsellor [3] and clinical geneticist [4] roles.

Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1.

Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13 In the third family, long suspected to have Marfan syndrome, a 2.0 Mb inversion disrupting FBN1 was identified. These findings resolved lengthy diagnostic odysseys of 9-20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.

Teaching social determinants through geographic information system mapping.

BACKGROUND: Many institutions in undergraduate medical education have developed unique curricula to teach social determinants of health (SDOH). Geographic information system (GIS) mapping is one tool that learners could use to understand our built environment and its correlation with health outcomes through data analysis, visualization and active learning. APPROACH: At the University of North Carolina School of Medicine, medical students participate in a 4-year longitudinal curriculum on social and health systems science with the final year dedicated to self-directed learning. This final year course incorporates a GIS-based online module to help students apply their understanding of the health impacts of SDOH. Students create online maps with simulated patient data and identify 'hotspots' with map overlays using ArcGIS software. Students write reflections on their maps based on the implications of SDOH. Thematic analysis of these reflections identified patterns within the narrative data. EVALUATION: From March 2020 to February 2021, 148 fourth-year medical students participated in the GIS learning module. Five major themes were identified: Explored Social Determinant Topics, Inclusion of Geo-mapping in Curriculum, Utility of Geo-mapping in Healthcare, Future Application of ArcGIS for Personal Use, Impressions of ArcGIS Software. Students showed engagement and interest in the exercise, and responses were overall positive. Responses showed understanding of the application of ArcGIS and demonstrated knowledge of social determinants of health. IMPLICATIONS: A self-directed, active learning online module using GIS mapping offers a generally popular, eye-opening and unique method for teaching SDOH in undergraduate medical education.

A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.

BACKGROUND: Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. METHODS: Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon-intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon-intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. RESULTS: We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. CONCLUSIONS: Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases.

Complement blockade with eculizumab for treatment of severe Coronavirus Disease 2019 in pregnancy: A case series.

PROBLEM: We evaluated eculizumab, a complement protein C5 inhibitor, for treatment of severe COVID-19 in pregnant and postpartum individuals. METHOD OF STUDY: Protocol ECU-COV-401 (clinicaltrials.gov NCT04355494) is an open label, multicenter, Expanded Access Program (EAP), evaluating eculizumab for treatment of severe COVID-19. Participants enrolled at our center from August 2020 to February 2021. Hospitalized patients were eligible if they had severe COVID-19 with bilateral pulmonary infiltrates and oxygen requirement. Eculizumab was administered on day 1 (1200 mg IV) with additional doses if still hospitalized (1200 mg IV on Days 4 and 8; 900 mg IV on Days 15 and 22; optional doses on Days 12 and 18). The primary outcome was survival at Day 15. Secondary outcomes included survival at Day 29, need for mechanical ventilation, and duration of hospital stay. We evaluated pharmacokinetic and pharmacodynamic data, safety, and adverse outcomes. RESULTS: Eight participants were enrolled at the Cedars-Sinai Medical Center, six during pregnancy (mean 30 ± 4.0 weeks) and two in the postpartum period. Baseline oxygen requirement ranged from 2 L/min nasal cannula to 12 L/min by non-rebreather mask. The median number of doses of eculizumab was 2 (range 1-3); the median time to hospital discharge was 5.5 days (range 3-12). All participants met the primary outcome of survival at Day 15, and all were alive and free of mechanical ventilation at Day 29. In three participants we demonstrated that free C5 and soluble C5b-9 levels decreased following treatment. There were no serious adverse maternal or neonatal events attributed to eculizumab at 3 months. CONCLUSION: We describe use of eculizumab to treat severe COVID-19 in a small series of pregnant and postpartum adults. A larger, controlled study in pregnancy is indicated.

Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome.

Chromatin is essentially an array of nucleosomes, each of which consists of the DNA double-stranded fiber wrapped around a histone octamer. This organization supports cellular processes such as DNA replication, DNA transcription, and DNA repair in all eukaryotes. Human histone H4 is encoded by fourteen canonical histone H4 genes, all differing at the nucleotide level but encoding an invariant protein. Here, we present a cohort of 29 subjects with de novo missense variants in six H4 genes (H4C3, H4C4, H4C5, H4C6, H4C9, and H4C11) identified by whole-exome sequencing and matchmaking. All individuals present with neurodevelopmental features of intellectual disability and motor and/or gross developmental delay, while non-neurological features are more variable. Ten amino acids are affected, six recurrently, and are all located within the H4 core or C-terminal tail. These variants cluster to specific regions of the core H4 globular domain, where protein-protein interactions occur with either other histone subunits or histone chaperones. Functional consequences of the identified variants were evaluated in zebrafish embryos, which displayed abnormal general development, defective head organs, and reduced body axis length, providing compelling evidence for the causality of the reported disorder(s). While multiple developmental syndromes have been linked to chromatin-associated factors, missense-bearing histone variants (e.g., H3 oncohistones) are only recently emerging as a major cause of pathogenicity. Our findings establish a broader involvement of H4 variants in developmental syndromes.

Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study.

BACKGROUND/OBJECTIVES: In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country. METHODS: Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. RESULTS: One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). CONCLUSION: Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.

Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly.

BACKGROUND: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. METHODS: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. RESULTS: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. CONCLUSION: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.

Pregnancy outcomes in very advanced maternal age women.

BACKGROUND: Advanced maternal age is associated with adverse pregnancy and delivery outcomes. Few studies have directly compared outcomes between women of advanced maternal age (35-44 years old) and women of very advanced maternal age (≥45 years old). OBJECTIVE: We aimed to determine the differences in outcomes between women of advanced maternal age and women of very advanced maternal age. STUDY DESIGN: This was a retrospective cohort study conducted at a large urban US medical center. Demographic and obstetrical data were collected in all patients who delivered within the study window (2012-2018). Characteristics and outcomes were compared between women of advanced maternal age and women of very advanced maternal age. Chi-square analyses were used to compare categorical variables. The Student t test or Wilcoxon tests were used, depending on the distribution, to compare continuous variables. RESULTS: A total of 45,435 women had delivery data for analysis. Of these women, 26,700 (59%) were not of advanced maternal age, 18,286 (40%) were of advanced maternal age, and 449 (1%) were of very advanced maternal age. Race and ethnicity varied significantly by age group. Nulliparity and postpartum hemorrhage were statistically higher in the very advanced maternal age group. Of note, cesarean delivery rates were 69.5% in the very advanced maternal age group and 39.5% in the advanced maternal age group (P<.001). Chronic hypertension, gestational hypertension, preeclampsia with and without severe features, superimposed preeclampsia, and eclampsia were all statistically significantly higher (at least 2-fold) in the very advanced maternal age group than the advanced maternal age group (P<.001). There was no significant difference in the rates of hemolysis, elevated liver enzymes, and low platelet count between the 2 groups. Rates of neonatal intensive care unit admission, Apgar score of <7 at 5 minutes, and neonatal length of stay of >5 days after cesarean delivery were higher in neonates from mothers of very advanced maternal age. Birthweights of neonates were significantly lower in mothers of very advanced maternal age. CONCLUSION: There were several important significant differences in the outcomes between women of very advanced maternal age women and women of advanced maternal age, especially concerning hypertensive disorders and cesarean delivery rates. These findings may influence patient counseling and strategies for antepartum surveillance.

Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study.

OBJECTIVE: To determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease. DESIGN: Cohort study. SETTING: National Health Service, England, including secondary and tertiary care. PARTICIPANTS: 345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018. INTERVENTION: Short read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants. MAIN OUTCOME MEASURE: Definite or probable genetic diagnosis. RESULTS: A definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis. CONCLUSION: Whole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.

Can learning from workplace feedback be enhanced by reflective writing? A realist evaluation in UK undergraduate medical education.

Introduction: Doctors and medical students in the UK are currently required to provide evidence of learning by reflective writing on (among other things) feedback from colleagues. Although the theoretical value of reflecting-on-action is clear, research is still needed to know how to realise the potential of written reflection in medical education. This study arose out of efforts to improve medical student engagement with a reflective writing exercise. We used realist methodology to explain the disinclination of the majority to do written reflection on workplace feedback, and the benefits to the minority.Method: Realist evaluation is a suitable approach to researching complex interventions which have worked for some and not for others. Focus groups were held over a three-year period with year 3 and 4 students. Focus group transcripts were coded for context-mechanism-outcome configurations (the realist approach to analysing data) explaining students' choice not to write a reflection, to write a 'tick-box' reflection or to write for learning. A sub-set of eight students' reflections were also analysed to ascertain evidence of learning through reflection.Results and discussion: 27 students participated in 4 focus groups. Three summary theories emerged showing the importance of context. Firstly, written reflection is effortful and benefits those who invest in it for intrinsic reasons in situations when they need to think more deeply about a learning event. Secondly, following a reflective feedback discussion writing a reflection may add little because the learning has already taken place. Thirdly, external motivation tends to result in writing a 'tick-box' reflection.

Medical Student Leadership Development through a Business School Partnership Model: A Case Study and Implementation Strategy.

BACKGROUND: There is an ongoing call for leadership development in academic health care and medical students desire more training in this area. Although many schools offer combined MD/MBA programs or leadership training in targeted areas, these programs do not often align with medical school leadership competencies and are limited in reaching a large number of students. METHODS: The Leadership Initiative (LI) was a program created by a partnership between a School of Medicine (SOM) and Business School with a learning model that emphasized the progression from principles to practice, and the competencies of self-awareness, communication, and collaboration/teamwork. Through offerings across a medical school curriculum, the LI introduced leadership principles and provided an opportunity to apply them in an interactive activity or simulation. We utilized the existing SOM evaluation platform to collect data on program outcomes that included satisfaction, fidelity to the learning model, and impact. RESULTS: From 2017 to 2020, over 70% of first-year medical students participated in LI course offerings while a smaller percentage of fourth-year students engaged in the curriculum. Most students had no prior awareness of LI course material and were equivocal about their ability to apply lessons learned to their medical school experience. Students reported that the LI offerings provided opportunities to practice the skills and competencies of self-awareness, communication, and collaboration/teamwork. DISCUSSION: Adding new activities to an already crowded medical curriculum was the greatest logistical challenge. The LI was successful in introducing leadership principles but faced obstacles in having participants apply and practice these principles. Most students reported that the LI offerings were aligned with the foundational competencies.

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K+ channelopathies.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K+ channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K+ conductance, referred to as syndromic neurodevelopmental K+ channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.

AIFM1-associated X-linked spondylometaphyseal dysplasia with cerebral hypomyelination.

Spondylometaphyseal dysplasia with cerebral hypomyelination (SMD-H) is a very rare but distinctive phenotype, unusually combining spondylometaphyseal dysplasia with hypomyelinating leukodystrophy. Recently, SMD-H has been associated with variants confined to a specific intra-genic locus involving Exon 7, suggesting that AIFM1 plays an important role in bone development and metabolism as well as cerebral myelination. Here we describe two further affected boys, one with a novel intronic variant associated with skipping of Exon 7 of AIFM1 and the other a synonymous variant within Exon 7 of AIFM1. We describe their clinical course and radiological and genetic findings, providing further insight into the natural history of this condition.

Risk factors for re-presentation for postpartum hypertension in patients without a history of hypertension or preeclampsia.

BACKGROUND: Re-presentation for evaluation of hypertension following discharge after delivery is common. However, a subset of patients who re-present for evaluation of postpartum hypertension do not have a history of hypertension. Identification of those at risk may help guide postpartum management and prevent re-presentations to the hospital. OBJECTIVE: This study aimed to establish risk factors for re-presentation for hypertension within 30 days of discharge after delivery in patients without a history of hypertension compared with women who did not re-present and to distinguish from risk factors for re-presentation for another reason. STUDY DESIGN: Subjects were identified through data extraction from a single institution between January 2012 and December 2018. We included subjects without an International Classification of Diseases, Ninth Revision or International Classification of Diseases, Tenth Revision code for (1) chronic hypertension or (2) a hypertensive disorder of pregnancy during their delivery encounter who re-presented to the hospital within 30 days. Thus, the re-presentation group was divided into the following 2 groups: those who re-presented for hypertension and those who re-presented for any other reason. Each re-presentation group was compared with the cohort of patients who delivered within the study window and did not re-present using the Student t test or Wilcoxon tests for continuous variables and chi-square or Fisher's exact tests for categorical variables. Multivariable regression was also performed on all potentially important risk factors. RESULTS: Factors that emerged as uniquely significant in the re-presentation group for hypertension were maternal age of ≥40 years and antenatal prescription of low-dose aspirin. Black race and body mass index of ≥30 kg/m2, although significant in both re-presentation groups, were more strongly predictive of re-presentation for hypertension. These factors remained independently significant when compared with each other in a multivariable analysis. CONCLUSION: There are identifiable risk factors for postpartum re-presentation for hypertension in patients without a history of hypertension. Upon discharge, providers may consider close blood pressure monitoring and follow-up in patients who have any of the following risk factors: age of ≥40 years, black race, body mass index of ≥30 kg/m2, or those who were prescribed low-dose aspirin in pregnancy.

The third case of TNFRSF11A-associated dysosteosclerosis with a mutation producing elongating proteins.

Dysosteosclerosis (DOS) is a distinct form of sclerosing bone disease characterized by platyspondyly and progressive osteosclerosis. DOS is genetically heterogeneous. Three causal genes, SLC29A3, CSF1R, and TNFRSF11A are reported. TNFRSF11A-associated DOS has been identified in two patients; however, TNFRSF11A is also a causal gene for osteopetrosis, autosomal recessive 7 (OP-AR7). Whole-exome sequencing in a patient with sclerosing bone disease identified novel compound heterozygous variants (c.414_427 + 7del, c.1664del) in TNFRSF11A. We examined the impact of the two variants on five splicing isoforms of TNFRSF11A by RT-PCR. We found that c.1664del resulted in elongated proteins (p.S555Cfs*121, etc.), while c.414_427 + 7del generated two aberrant splicing products (p.A139Wfs*19 and p.E132Dfs*19) that lead to nonsense mediated mRNA decay (NMD). In the previous two cases of TNFRSF11A-associated DOS, their mutations produced truncated TNFRSF11A protein isoforms. The mutations in all three cases thus contrast with TNFRSF11A mutations reported in OP-AR7, which does not generated truncated or elongated TNFRSF11A proteins. Thus, we identified the third case of TNFRSF11A-associated DOS and reinforced the genotype-phenotype correlation that aberrant protein-producing TNFRSF11A mutations cause DOS.

Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis.

Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes. CASE: This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation. MANAGEMENT: She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures. CONCLUSION: This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.