Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS.

BACKGROUND: Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management. METHODS: We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed. RESULTS: Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell. CONCLUSIONS: We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis.

BCGitis in a patient with transient hypogammaglobulinemia of infancy.

Reactions to the Bacille Calmette-Guerin (BCG) vaccine are not uncommon and have been reported in association with immunodeficiency syndromes. We report a case of an infant developing a localized BCG reaction, confirmed histologically, associated with transient hypogammaglobulinemia of infancy. Conservative management of localized BCG reactions is appropriate in most cases.

Ichthyosis prematurity syndrome: a case report and review of known mutations.

Ichthyosis prematurity syndrome (IPS; Mendelian Inheritance in Man 608649) is classified as a syndromic autosomal recessive ichthyosis. Here we describe two siblings with IPS and report a recurrent homozygous mutation (c.1430T>A) that is predicted to lead to a p.Val477Asp substitution in fatty acid transport protein 4. This mutation has arisen for the second time in an entirely distinct population from the Scandinavian population where it was first described.

First report of sudden death due to myocarditis caused by adenovirus serotype 3.

Myocarditis is a rare cause of sudden death in childhood. We describe the sudden death of a child from viral myocarditis, which we demonstrate was likely caused by an uncontrolled inflammatory response to a disseminated adenovirus serotype 3 infection originating in the tonsil.

Can a more detailed evaluation of excision margins refine cytologic follow-up of women post-LLETZ for high-grade dysplasia?

The relationship between dysplastic changes in the cervical epithelium and progression to in situ carcinoma and invasive carcinoma has been extensively studied. The removal of dysplastic epithelium through the long loop excision of the transformation zone (LLETZ) in 95% of the cases is curative. About 18% to 37% of LLETZ specimens with dysplasia at the margins have recurrent/residual disease. Earlier small studies suggest that the degree of dysplasia at the margins could predict for recurrence and allow a risk-based stratification of follow-up. We tested this hypothesis in a large group of women post-LLETZ for high-grade dysplasia with follow-up histology and cytology over a 12-year period. The cases were divided according to the excision margin status for dysplasia and if positive, low-grade or high-grade dysplasia. The groups were compared to assess whether the LLETZ specimens' margin status had an impact on the subsequent cytology or histology results. Positive follow-up results were defined as any grade of dysplasia in cytology or histology. Two thousand three hundred twenty-one women had LLETZs containing high-grade dysplasia over the 12-year period. One thousand five hundred thirty-four (66.1%) women had full histology and cytology follow-up available. Eight hundred twenty (53.4%) LLETZ specimens had positive margins and 714 (46.6%) had negative margins. The grade of dysplasia at the margins was available in 796 cases (97%) with 115 (15%) showing low-grade dysplasia and 680 (85%) high-grade dysplasia. One hundred seventy (20.7%) of the specimens with positive margins had positive follow-up results compared with 105 (14.7%) of the specimens with negative margins. The presence of dysplasia at an LLETZ margin is associated with dysplasia on follow-up cytology and histology (P=0.0021); however, the grade of dysplasia at the excision margin is not predictive of recurrent/residual dysplasia.

A novel association of gastric ischaemia and aortic coarctation.

We report a newborn who presented with acute abdominal distension secondary to gastric ischaemia with an associated undiagnosed coarctation of the descending aorta. This is the first description of such a previously unrecognised association, which is discussed further with reference to the current literature.

Coeliac screening in a high-risk population: paediatric type 1 diabetes-a review of current guidelines and practice.

BACKGROUND AND AIMS: Coeliac disease (CD) is more common in those with type 1 diabetes mellitus (T1DM) and may be asymptomatic despite the presence of intestinal histological changes. Optimal screening practice guidelines differ internationally. We undertook a retrospective audit to determine the efficacy of current screening practice for CD in T1DM in our centre. METHODS: All children and adolescents < 16 years, diagnosed with T1DM in our service and continuing to attend the service in January 2017 were included. Data on CD screening was collected and compared to current NICE, NASPGHAN and ESPGHAN guidelines. RESULTS: Of the 355 patients attending our service, 253 attended from T1DM diagnosis and all had CD screening performed in our centre. In 37 of 253 patients, IgA-TTG was positive, providing a cumulative prevalence of 14.6%. Of these, 31(83.78%) with an elevated TTG on screening had no recorded gastrointestinal symptoms or CD-related clinical signs. Of the 35 TTG plus EMA-positive patients, 22/35 (59.46%) had diagnostic endoscopic biopsy. Nineteen (83.4%) had CD confirmed, 1 (4.54%) had negative biopsy and 2 (9%) had equivocal, non-diagnostic changes. CONCLUSIONS: Timely diagnosis of CD can prevent chronic ill health in affected individuals, and in patients with T1DM, CD is an independent risk factor for increased morbidity and mortality. Given the high prevalence of atypical symptoms and silent CD in those with T1DM, in this and other studies, and the benefits of detection and treatment of CD, screening is essential. Large-scale data collection allowing for the development of evidence-based guidelines is required.

Infantile pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is rare in infants. There have been 12 cases of PG in infants (<12 months old) reported in the past 25 years, to our knowledge. Six of these cases have been successfully controlled with systemic steroids, and one case with topical steroids alone. We report a case of an 8-month-old infant whose PG was aggressive and unresponsive to systemic steroids. Adjuvant treatment with cyclosporine was required to achieve healing. We review the previous cases of infantile PG and the therapeutic options in this age group.

A Case of Juvenile Onset Neuronal Intranuclear Inclusion Disease With a Negative Antemortem Skin Biopsy.

Neuronal intranuclear (hyaline) inclusion disease (NIID) is a rare neurodegenerative disorder with a variable clinical presentation and multiple subtypes. We present the clinicopathologic details of a patient with juvenile-onset NIID and discuss the pathogenesis. We also discuss the utility of antemortem skin biopsy which was negative in our case.

Incidence of Low-Grade Testicular Injury in Orchidectomy Specimens Post-testicular Torsion.

INTRODUCTION: Following detorsion and orchidopexy for testicular torsion, predominantly animal studies have reported a risk of autoimmune and reperfusion injury to the contralateral testis. As a result, when testicular viability is compromised, orchidectomy is readily performed. This practice increases the likelihood of testes with potentially reversible injury being excised. We aim to determine the incidence of such occurrences and review the available evidence for and against early orchidectomy when testicular viability is doubtful. MATERIALS AND METHODS: Data for a 15-year period from two pediatric institutions on testicular torsion in children younger than 16 years were reviewed. Using a previously published grading system, the orchidectomy specimens in this cohort with early low-grade injury were analyzed. Low-grade injury suggests the possibility of restitutio ad integrum implying restoration of exocrine and endocrine function of the affected testes. RESULTS: Between both institutions, 222 scrotal explorations were performed for testicular torsion; 20 neonatal and 202 outside the neonatal period (age range [median]: 1-28 days [3 days] and 3 months-16 years [13 years], respectively). Of these scrotal explorations, 17 neonatal and 66 nonneonatal orchidectomies were required (85 vs. 33%, respectively; p < 0.0001). From these orchidectomy specimens, 5 (6%) were found to have low-grade injury. The ages of these five children ranged from 9 to 16 years (median 15, mean 13.6 years). Their symptom duration ranged from 8 to 37 hours (median 14, mean 18 hours) and two of these children had a preoperative ultrasound documenting no flow to the testis. CONCLUSION: The finding of histopathological features that may represent salvageability of a torted testis occurs relatively rarely. Because of this possibility, appropriate intraoperative steps to check for reperfusion must be undertaken prior to orchidectomy. More evidence for the use of antioxidants and tunica albuginea decompression to improve testes salvage rates is required. The potential for exocrine and endocrine function if partial testicular atrophy occurs and the evidence for contralateral autoimmune testicular damage in pre- and postpubertal males require further investigation.

Symmetrical thalamic calcification: A trio whole exome sequencing negative series.

Symmetrical thalamic calcification or bilateral symmetrical thalamic gliosis presents at delivery with hypertonia, fixed flexion contractures and prominent bulbar signs, without preceding perinatal asphyxia. At post-mortem, there is evidence of bilateral symmetrical selective thalamic neuronal encrustation and gliosis. To date, 27 cases are published with no underlying diagnosis identified. Two affected children from singleton pregnancies were reported and therefore, a genetic cause proposed. No previous reports have performed genetic testing to confirm or reject this hypothesis. We report three additional cases of this rare condition, expanding the clinical and pathological phenotype. We performed trio whole exome sequencing, the first in this cohort of patients, and did not identify a pathogenic variant. As postulated in the original report, the likely underlying mechanism is antenatal hypoxia in the third trimester.

The value of neonatal autopsy.

BACKGROUND AND OBJECTIVE: Neonatal autopsy rates were in decline internationally at the end of the last century. Our objective was to assess the current value of neonatal autopsy in providing additional information to families and healthcare professionals. METHODS: We conducted a review of neonatal autopsies performed in a tertiary perinatal centre over an 11-year period. Primary outcomes measured were the annual neonatal autopsy rates and concordance rates between clinical and autopsy diagnoses of the primary cause of death. Secondary outcomes were the clinical, genetic and audit value of the examinations. Findings were used to inform the consent process, and the effect this had on institutional post-mortem rates was assessed over the subsequent 5-year period. RESULTS: There was a marked decline in the annual neonatal autopsy rate from 73% in 1994 to 48% in 2004. 164 cases met the inclusion criteria for review. Complete concordance for cause of death was reached in 91% of cases. Previously unsuspected or unconfirmed clinical conditions, other than the primary cause of death, were uncovered at autopsy in 85 cases. Detailed information on inheritable conditions was obtained in 45 cases. Findings with perceived 'audit value' for clinical practice were identified in 29 cases. The dissemination of this information to staff and families contributed to the stabilisation of the consent rate in the following 5-year period. CONCLUSION: Neonatal autopsy remains a valuable diagnostic tool as it provides critical clinical and audit information for healthcare professionals and families.

Sudden unexplained death in childhood (1-4 years) in Ireland: an epidemiological profile and comparison with SIDS.

OBJECTIVE: To examine the incidence of sudden unexplained death in children 1-4 years old (SUDC) in Ireland and to compare the epidemiological profile of SUDC with that of SIDS. DESIGN: All cases of sudden unexplained death in children <5 years in Ireland between 1994 and 2008 were reviewed. Epidemiological information obtained from parental questionnaires and post-mortem reports was examined, and data on cases ≥52 weeks compared with cases <52 weeks. RESULTS: SUDC accounted for 5% (n=44) of deaths in children aged 1-4 years during 1994-2008. During this period, the SIDS rate dropped from 0.71 to 0.34 per 1000 live births, while the SUDC rate increased from 0.08 to 0.18 deaths per 10 000 population aged 1-4 years. The median age of SUDC cases was 71.5 weeks, and the male/female ratio was 1.3:1. All died during a sleep period, 71% between 10pm and 8am, and more than two-thirds were found prone. Fewest cases occurred during July-September (11%), and a greater proportion occurred at weekends (55%). 52% (17/33) had symptoms (any) in the 48 h before death, and 35% (11/31) visited their general practitioner because of illness in the week preceding death. SUDC differed from SIDS in prevalence of maternal smoking (38% vs 72%, p<0.001), bed-sharing (17% vs 49%, p<0.001), and whether found prone (72% vs 23%, p<0.001). CONCLUSION: While SUDC shares some characteristics with SIDS, there are also some important differences. Further data collection will help determine whether SIDS and SUDC represent the same pathophysiological entity. Standardisation of protocols for investigating sudden deaths is urgently required for accurate diagnosis of cases.

Parvovirus infects cardiac myocytes in hydrops fetalis.

Parvovirus infection during pregnancy is an important cause of hydrops fetalis. It is attributed to anemia caused by viral-induced destruction of red blood cells. Infection of other organs has been reported including the heart, liver, and lungs. Few of these reports, however, convincingly demonstrate virions within the functional parenchyma of the tissue. This is of particular concern regarding myocardium in the context of hydrops fetalis which is, in part, due to cardiac failure. The problem in routine pathology practice is that most fetuses with the infection are macerated. This, in part, probably explains the paucity of published information on cardiac involvement. This study examined five cases of fatal hydrops fetalis with variable maceration with serologically proven parvovirus B19 infection. Transmission electron microscopy of cardiac tissue demonstrated intranuclear virions in both erythroid precursor cells and in cardiac myocytes in three of these cases. In each of these, immuno-gold electron microscopy provided confirmatory evidence of parvovirus infection. Virions were not identifiable where maceration had caused disintegration of nuclei in the myocytes. In addition, virions were absent in the three negative control cases where retroplacental hemorrhage was confirmed as the cause of death. This study suggests that parvovirus infection of cardiac myocytes may play a more important role in causing hydrops fetalis than previously realized. It also demonstrates that maceration should not discourage the use of electron microscopy.