Miller (Genee-Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH.

Biallelic mutations in the gene encoding DHOdehase [dihydroorotate dehydrogenase (DHODH)], an enzyme required for de novo pyrimidine biosynthesis, have been identified as the cause of Miller (Genée-Weidemann or postaxial acrofacial dysostosis) syndrome (MIM 263750). We report compound heterozygous DHODH mutations in four additional families with typical Miller syndrome. Complementation in auxotrophic yeast demonstrated reduced pyrimidine synthesis and in vitro enzymatic analysis confirmed reduced DHOdehase activity in 11 disease-associated missense mutations, with 7 alleles showing discrepant activity between the assays. These discrepancies are partly explained by the domain structure of DHODH and suggest both assays are useful for interpretation of individual alleles. However, in all affected individuals, the genotype predicts that there should be significant residual DHOdehase activity. Urine samples obtained from two mutation-positive cases showed elevated levels of orotic acid (OA) but not dihydroorotate (DHO), an unexpected finding since these represent the product and the substrate of DHODH enzymatic activity, respectively. Screening of four unrelated cases with overlapping but atypical clinical features showed no mutations in either DHODH or the other de novo pyrimidine biosynthesis genes (CAD, UMPS), with these cases also showing normal levels of urinary OA and DHO. In situ analysis of mouse embryos showed Dhodh, Cad and Umps to be strongly expressed in the pharyngeal arch and limb bud, supporting a site- and stage-specific requirement for de novo pyrimidine synthesis. The developmental sensitivity to reduced pyrimidine synthesis capacity may reflect the requirement for an exceptional mitogenic response to growth factor signalling in the affected tissues.

Malignant rhabdoid tumor of the orbit in an infant.

We present the case of an infant with rapidly progressing orbital tumor that had initial radiological and clinical features of both rhabdomyosarcoma and capillary hemangioma. The patient was eventually diagnosed with malignant rhabdoid tumor of the orbit. We discuss the salient histological and radiological features of our case and review the literature on orbital malignant rhabdoid tumors.

Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling.

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.

Health and wellbeing of people with intellectual disability in New South Wales, Australia: a data linkage cohort.

PURPOSE: People with intellectual disability (ID) experience high rates of physical and mental health problems, while access to appropriate healthcare is often poor. This cohort was established to develop an epidemiological profile related to the health, health service use, disability services, mortality and corrective services records of people with ID. PARTICIPANTS: The cohort contains 92 542 people with ID (40% females) with a median age of 23 years (IQR: 12-43 years) and 2 004 475 people with a neuropsychiatric or developmental disorder diagnosis (50% females) with a median age of 51 years (IQR: 29-73 years) from New South Wales, Australia. The whole sample contains records for 2 097 017 individuals with most data sets spanning financial years 1 July 2001 to 30 June 2016. A wide range of data from linked population data sets are included in the areas of disability, health, corrective services and targeted specialist support services in public schools, Public Guardian and Ombudsman services. FINDINGS TO DATE: This study includes one of the largest cohorts of people with ID internationally. Our data have shown that the presence of ID is significantly associated with emergency department presentations and psychiatric readmissions after the first psychiatric admission based on a subcohort of people with a psychiatric admission. Adults with ID experience premature mortality and over-representation of potentially avoidable deaths compared with the general population. FUTURE PLANS: Within the health service system, we will examine different components, that is, inpatient, emergency adult services, children and younger people services and costs associated with healthcare as well as mortality, cause and predictors of death. The neuropsychiatric and developmental disorders comparison cohort allows comparisons of the physical health, mental health and service use profiles of people with ID and those with other neuropsychiatric disorders.

In a Genomic Era, Placental Pathology Still Holds the Key in the Nondysmorphic Stillbirth.

Objective To explore the relative utility of genetic testing in contrast to placental pathology in explaining causation of death in the structurally normal stillborn population. Methods A retrospective review of a structurally normal stillborn infant cohort in South East Scotland between 2011 and 2015, defined by death at or after 24 weeks of gestation. We reviewed pathology reports and collected demographic data on cases. This information was collated with genetic test results (quantitative fluorescent polymerase chain reaction and microarray analysis) and placental pathology to create a database for analysis. Primary Results Within the structurally normal population (n = 131), there were 125 genetic tests performed and 11 abnormal results. Sixty-six microarray analyses were performed, and 2 (3%) of the results were thought likely to reflect cause of stillbirth (1 case of incomplete trisomy 4 and 1 case of deletion of chromosome Xp in a female). Analysis was significantly limited in 2 cases as parental samples were not available. The placental pathology was available in a total of 129 cases; significant findings were identified in 100 cases; 79 (61%) showed changes that were considered to have caused death (including cord "accidents"), and a further 21 (16%) showed findings likely to influence the management of subsequent pregnancies. Conclusions We reaffirm the utility of placental examination in the investigation of stillbirth. In cases of nondysmorphic stillbirth where placental pathology does not explain the cause of stillbirth, microarray analysis of fetal DNA can add further diagnostic information in 3% of cases but can add further diagnostic confusion, and it is important that parental bloods are taken to minimize this risk.

Effectiveness of a multidisciplinary chronic pain program for treatment of refractory patients with complicated chronic pain syndromes.

BACKGROUND: Interventional pain physicians commonly encounter patients with a treatment refractory "chronic pain syndrome". Such patients have a chronically painful medical disorder that is complicated by a number of psychosocial factors, including psychiatric and substance use disorders, physical deconditioning, dependency upon the healthcare system, and perceived impairments that are out of proportion to objective medical findings. OBJECTIVE: The objective of the following study was to determine the effectiveness of a multidisciplinary chronic pain program for adult patients with treatment refractory chronic pain syndromes. METHODS: The following sequential, prospective, observational case series presents treatment outcome data on a 4-week multidisciplinary chronic pain program for adult patients with complex chronic pain syndromes that were refractory to standard pain management. Prior to enrollment in the program, patients had been treated with pain medications, physical therapy, and interventional procedures. Data were collected and analyzed on variables including pain ratings, healthcare utilization, opioid medication use, and perceived physical functioning at program admission and discharge as well as at intervals of 3 months, 6 months and 12 months post-discharge. RESULTS: Analysis of the data reveal statistically significant improvements in the variables of interest across most time parameters. CONCLUSIONS: Results demonstrate that participation in a chronic pain program is an effective intervention for selected patients with refractory pain.

Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.

Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.

Ten years of neonatal autopsies in tertiary referral centre: retrospective study.

OBJECTIVES: To measure the neonatal autopsy rate at a tertiary referral centre and identify trends over the past decade. To identify factors that may influence the likelihood of consent being given for autopsy. To examine any discordance between diagnoses before death and at autopsy. DESIGN: Retrospective review of patients' records. SETTING: Tertiary neonatal referral centre affiliated to university. OUTCOME MEASURES: Sex, gestational age, birth weight, type of delivery, and length of stay in neonatal unit for baby. Maternal age, marital status, history of previous pregnancies, and details of who requested permission for autopsy. Concordance between diagnoses before death and at autopsy. RESULTS: An autopsy was performed in 209/314 (67%) cases. New information was obtained in 50 (26%) autopsies. In six (3%) cases this information was crucial for future counselling. In 145 (74%) there was complete concordance between the clinical cause of death and the findings at autopsy. From 1994 onwards the autopsy rate in the neonatal unit fell. The only significant factor associated with consent for autopsy was increased gestational age. CONCLUSIONS: Important extra information can be gained at neonatal autopsies. This should help parents to make an informed decision when they are asked to give permission for their baby to have an autopsy. These findings are of particular relevance in view of the recent negative publicity surrounding neonatal autopsies and the general decline in the neonatal autopsy rate over the decade studied.