ABSTRACT
BACKGROUND: Lethal fetal akinesia deformation sequence (FADS) describes a clinically and genetically heterogeneous phenotype that includes fetal akinesia, intrauterine growth retardation, arthrogryposis and developmental anomalies. Affected babies die as a result of pulmonary hypoplasia. We aimed to identify the underlying genetic cause of this disorder in a family in which there were three affected individuals from two sibships. METHODS: Autosomal-recessive inheritance was suggested by a family history of consanguinity and by recurrence of the phenotype between the two sibships. We performed exome sequencing of the affected individuals and their unaffected mother, followed by autozygosity mapping and variant filtering to identify the causative gene. RESULTS: Five autozygous regions were identified, spanning 31.7 Mb of genomic sequence and including 211 genes. Using standard variant filtering criteria, we excluded all variants as being the likely pathogenic cause, apart from a single novel nonsense mutation, c.188C>A p.(Ser63*) (NM_002478.4), in MYOD1. This gene encodes an extensively studied transcription factor involved in muscle development, which has nonetheless not hitherto been associated with a hereditary human disease phenotype. CONCLUSIONS: We provide the first description of a human phenotype that appears to result from MYOD1 mutation. The presentation with FADS is consistent with a large body of data demonstrating that in the mouse, MyoD is a major controller of precursor cell commitment to the myogenic differentiation programme.
Subject(s)
Arthrogryposis/genetics , Fetal Growth Retardation/genetics , High-Throughput Nucleotide Sequencing , MyoD Protein/genetics , Aborted Fetus , Animals , Arthrogryposis/pathology , Exome/genetics , Female , Fetal Growth Retardation/pathology , Humans , Lung/pathology , Mice , Mutation , Pedigree , Phenotype , PregnancyABSTRACT
Neuroinvasive astrovirus (VA1-HMO-C) is an emerging life-threatening infection in immunocompromised hosts. We describe an 8-month-old child who died of VA1/HMO-C encephalitis following bone marrow transplantation. The diagnosis was only made post-mortem using RNA deep sequencing of the brain. Repeat analysis of the post-mortem brain tissue using polymerase chain reaction specific primers for VA1/HMO-C was positive. Astrovirus VA1/HMO-C should be included in the evaluation of patients with similar encephalitis.
Subject(s)
Astroviridae Infections/virology , Bone Marrow Transplantation/adverse effects , Encephalitis, Viral/virology , Hematopoietic Stem Cell Transplantation/adverse effects , Immunosuppressive Agents/adverse effects , Leukemia, Myeloid, Acute/surgery , Mamastrovirus/isolation & purification , Opportunistic Infections/virology , Transplantation Conditioning/adverse effects , Biopsy , Brain/diagnostic imaging , Brain/pathology , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 11/genetics , Diarrhea/etiology , Encephalitis, Viral/cerebrospinal fluid , Encephalitis, Viral/diagnostic imaging , Encephalitis, Viral/pathology , Enteritis/complications , Enteritis/virology , Fatal Outcome , Feces/virology , Female , Graft vs Host Disease/drug therapy , Humans , Immunocompromised Host , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/therapeutic use , Infant , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Magnetic Resonance Imaging , RNA, Viral/isolation & purification , Sequence Analysis, RNA , Translocation, GeneticABSTRACT
Elite sport and the measures imposed to prevent 'men' from 'cheating' by posing as women in women's events cast interesting light on notions of sex and gender. Some women have testes, organs that produce testosterone, because they are trans women or they have an intersex state. Testosterone is recognised as a performance-enhancing substance in at least some circumstances, and therefore, women with testes may possess an advantage when competing in some sport against women without testes, though this has never been subjected to rigorous scientific testing. The International Olympic Committee and the International Association of Athletics Federation have decreed that such individuals can compete only if they undergo medical and surgical treatment, which is likely to mean gonadectomy. This might be considered to impose an unethical demand on the individual concerned and constitute an infringement of bodily autonomy for that individual. It also suggests a binary view of sex/gender that is simplistic and not scientifically accurate. I discuss this approach and consider alternative methods of approaching the problem of women with testes in athletics.
Subject(s)
Athletes , Body Constitution , Disorders of Sex Development , Gender Identity , Gonads/surgery , Sports/ethics , Testis , Testosterone/blood , Disorders of Sex Development/diagnosis , Disorders of Sex Development/metabolism , Female , Humans , Male , Sex Determination Analysis , Testosterone/biosynthesisABSTRACT
In England and Wales, it is usually lawful for those with parental responsibility to consent to treatment on children who have not acquired legal capacity, providing that they are acting in the child's best interests. Whilst in most instances this process is unproblematic and the decisions made are non-controversial, there are troubling examples where this is more problematic. The difficulties for a family with a child who has an intersex condition will be considered to illustrate that there may be cases of medical and surgical treatment where even though both parents and doctors agree on a course of action in good faith, the treatment administered may not necessarily be in the best interests of the child. Sometimes, procedures carried out on an infant apparently in their best interests may later be a cause of regret to the child as an adult. The law in England and Wales will be examined to investigate other examples of controversial treatments of young children involving legal interventions to consider whether there are any parallels and what the implications of these might be to the intersex child. A model suggested by a Columbian legal case from 1995 is discussed. The courts ruled that infantile sex assignment surgery is lawful only following very stringent consent procedures. The possibility is considered that guidelines defining the consent procedure may afford some protection for the intersex child.
ABSTRACT
Congenital hyperinsulinism causes profound hypoglycemia, which may persist or resolve spontaneously. Among 13 children with congenital hyperinsulinism, elevated incretin hormone concentrations were detected in 2 with atypical, persistent disease. We suggest that incretin biomarkers may identify these patients, and that elevated hormone levels may contribute to their pathophysiology.
Subject(s)
Biomarkers/blood , Congenital Hyperinsulinism/blood , Incretins/blood , KATP Channels/genetics , Child, Preschool , Congenital Hyperinsulinism/genetics , Humans , Infant , Infant, Newborn , Mutation , United KingdomABSTRACT
Enterocolitis is common after cord blood transplantation (CBT) and a specific, non-graft-versus-host disease (GVHD) entity with specific histopathologic features ("cord colitis") has been described in some cases in selected series. Immune suppression is not without risk, and we have used it only when biopsy features are consistent with classical GVHD. In the absence of biopsy features of classical GVHD, our management of intestinal failure has been supportive, and we have withdrawn immune suppression to allow immune reconstitution and better prevent relapse of malignant disease and reduce infectious complications. We evaluated our approach over an 11-year period in a retrospective study of all patients at our large pediatric CBT center who experienced intestinal failure necessitating endoscopy and biopsy in the post-CBT period. We conducted a blinded histopathologic review of gastrointestinal (GI) biopsy specimens from all patients who had undergone GI endoscopy for intestinal failure in the post-CBT period. Patient records were evaluated to determine clinical HSCT course and outcome data, including mortality, relapse, and infection, as well as the duration of immune suppression and parenteral nutrition. Out of 144 patients who underwent CBT during the study period, 25 (17%) experienced intestinal failure requiring endoscopy. Thirteen patients were diagnosed with acute GVHD after blinded review of biopsy specimens, and 12 patients had non-GVHD enterocolitis. Management in the absence of GVHD on GI biopsy is supportive, with withdrawal of immune suppression in patients with malignant disease and continuing in accordance with institutional practice in those with nonmalignant disease. Compared with the GVHD cohort, the non-GVHD enterocolitis cohort had superior overall survival (91% versus 41%; P = .04) and a shorter duration of immune suppression (mean, 112 days versus 180 days; P = .049), reflecting these different management approaches. These results demonstrate that different histopathologic findings in those with intestinal failure after CBT likely indicates a different etiology from GVHD and mandates a different clinical management strategy to achieve optimal clinical outcomes.
Subject(s)
Cord Blood Stem Cell Transplantation , Enterocolitis , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Intestinal Failure , Child , Humans , Cord Blood Stem Cell Transplantation/adverse effects , Retrospective Studies , Neoplasm Recurrence, Local/complications , Hematopoietic Stem Cell Transplantation/adverse effects , Graft vs Host Disease/etiology , Endoscopy, Gastrointestinal/adverse effects , Endoscopy, Gastrointestinal/methods , Enterocolitis/etiology , Enterocolitis/complications , Chronic Disease , RecurrenceABSTRACT
Congenital hyperinsulinism (CHI) is characterised by inappropriate insulin secretion causing profound hypoglycaemia and brain damage if inadequately controlled. Pancreatic tissue isolated from patients with diffuse CHI shows abnormal proliferation rates, the mechanisms of which are not fully resolved. Understanding cell proliferation in CHI may lead to new therapeutic options, alongside opportunities to manipulate ß-cell mass in patients with diabetes. We aimed to generate cell-lines from CHI pancreatic tissue to provide in vitro model systems for research. Three pancreatic mesenchymal stem cell-lines (CHIpMSC1-3) were derived from patients with CHI disease variants: focal, atypical and diffuse. All CHIpMSC lines demonstrated increased proliferation compared with control adult-derived pMSCs. Cell cycle alterations including increased CDK1 levels and decreased p27Kip1 nuclear localisation were observed in CHIpMSCs when compared to control pMSCs. In conclusion, CHIpMSCs are a useful in vitro model to further understand the cell cycle alterations leading to increased islet cell proliferation in CHI.
ABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0222350.].
ABSTRACT
Background: Congenital Hyperinsulinism (CHI) is an important cause of severe and persistent hypoglycaemia in infancy and childhood. The focal form (CHI-F) of CHI can be potentially cured by pancreatic lesionectomy. While diagnostic characteristics of CHI-F pancreatic histopathology are well-recognized, correlation with clinical phenotype has not been established. Aims: We aimed to correlate the diversity in clinical profiles of patients with islet cell organization in CHI-F pancreatic tissue. Methods: Clinical datasets were obtained from 25 patients with CHI-F due to ABCC8/KCNJ11 mutations. 18F-DOPA PET-CT was used to localize focal lesions prior to surgery. Immunohistochemistry was used to support protein expression studies. Results: In 28% (n = 7) of patient tissues focal lesions were amorphous and projected into adjoining normal pancreatic tissue without clear delineation from normal tissue. In these cases, severe hypoglycaemia was detected within, on average, 2.8 ± 0.8 (range 1-7) days following birth. By contrast, in 72% (n = 18) of tissues focal lesions were encapsulated within a defined matrix capsule. In this group, the onset of severe hypoglycaemia was generally delayed; on average 46.6 ± 14.3 (range 1-180) days following birth. For patients with encapsulated lesions and later-onset hypoglycaemia, we found that surgical procedures were curative and less complex. Conclusion: CHI-F is associated with heterogeneity in the organization of focal lesions, which correlates well with clinical presentation and surgical outcomes.
ABSTRACT
Objectives: We aimed to characterize mosaic populations of pancreatic islet cells from patients with atypical congenital hyperinsulinism in infancy (CHI-A) and the expression profile of NKX2.2, a key transcription factor expressed in ß-cells but suppressed in δ-cells in the mature pancreas. Patients/Methods: Tissue was isolated from three patients with CHI-A following subtotal pancreatectomy. CHI-A was diagnosed on the basis of islet mosaicism and the absence of histopathological hallmarks of focal and diffuse CHI (CHI-D). Immunohistochemistry was used to identify and quantify the proportions of insulin-secreting ß-cells and somatostatin-secreting δ-cells in atypical islets, and results were compared with CHI-D (n = 3) and age-matched control tissues (n = 3). Results: In CHI-A tissue, islets had a heterogeneous profile. In resting/quiescent islets, identified by a condensed cytoplasm and nuclear crowding, ß-cells were reduced to <50% of the total cell numbers in n = 65/70 islets, whereas δ-cell numbers were increased with 85% of islets (n = 49/57) containing >20% δ-cells. In comparison, all islets in control tissue (n = 72) and 99% of CHI-D islets (n = 72) were composed of >50% ß-cells, and >20% δ-cells were found only in 12% of CHI-D (n = 8/66) and 5% of control islets (n = 3/60). Active islets in CHI-A tissue contained proportions of ß-cells and δ-cells similar to those of control and CHI-D islets. Finally, when compared with active islets, quiescent islets had a twofold higher prevalence of somatostatin/NKX2.2+ coexpressed cells. Conclusions: Marked increases in NKX2.2 expression combined with increased numbers of δ-cells strongly imply that an immature δ-cell profile contributed to the pathobiology of CHI-A.
Subject(s)
Congenital Hyperinsulinism/genetics , Congenital Hyperinsulinism/pathology , Genetic Predisposition to Disease , Islets of Langerhans/pathology , Nuclear Proteins/genetics , Transcription Factors/genetics , Biopsy, Needle , Child, Preschool , Cohort Studies , Congenital Hyperinsulinism/surgery , Female , Homeobox Protein Nkx-2.2 , Homeodomain Proteins , Humans , Immunohistochemistry , Infant , Islets of Langerhans/metabolism , Male , Mosaicism , Pancreatectomy/methods , Prognosis , Reference Values , Severity of Illness Index , Thyroid Nuclear Factor 1ABSTRACT
OBJECTIVES: To quantify islet cell nucleomegaly in controls and tissues obtained from patients with congenital hyperinsulinism in infancy (CHI) and to examine the association of nucleomegaly with proliferation. METHODS: High-content analysis of histologic sections and serial block-face scanning electron microscopy were used to quantify nucleomegaly. RESULTS: Enlarged islet cell nuclear areas were 4.3-fold larger than unaffected nuclei, and the mean nuclear volume increased to approximately threefold. Nucleomegaly was a normal feature of pediatric islets and detected in the normal regions of the pancreas from patients with focal CHI. The incidence of nucleomegaly was highest in diffuse CHI (CHI-D), with more than 45% of islets containing two or more affected cells. While in CHI-D nucleomegaly was negatively correlated with cell proliferation, in all other cases, there was a positive correlation. CONCLUSIONS: Increased incidence of nucleomegaly is pathognomonic for CHI-D, but these cells are nonproliferative, suggesting a novel role in the pathobiology of this condition.
Subject(s)
Cell Nucleus/pathology , Congenital Hyperinsulinism/pathology , Islets of Langerhans/pathology , Cell Nucleus/ultrastructure , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Islets of Langerhans/ultrastructure , Male , Microscopy, ElectronABSTRACT
Diffuse congenital hyperinsulinism in infancy (CHI-D) arises from mutations inactivating the KATP channel; however, the phenotype is difficult to explain from electrophysiology alone. Here we studied wider abnormalities in the ß-cell and other pancreatic lineages. Islets were disorganized in CHI-D compared with controls. PAX4 and ARX expression was decreased. A tendency toward increased NKX2.2 expression was consistent with its detection in two-thirds of CHI-D δ-cell nuclei, similar to the fetal pancreas, and implied immature δ-cell function. CHI-D δ-cells also comprised 10% of cells displaying nucleomegaly. In CHI-D, increased proliferation was most elevated in duct (5- to 11-fold) and acinar (7- to 47-fold) lineages. Increased ß-cell proliferation observed in some cases was offset by an increase in apoptosis; this is in keeping with no difference in INSULIN expression or surface area stained for insulin between CHI-D and control pancreas. However, nuclear localization of CDK6 and P27 was markedly enhanced in CHI-D ß-cells compared with cytoplasmic localization in control cells. These combined data support normal ß-cell mass in CHI-D, but with G1/S molecules positioned in favor of cell cycle progression. New molecular abnormalities in δ-cells and marked proliferative increases in other pancreatic lineages indicate CHI-D is not solely a ß-cell disorder.
Subject(s)
Congenital Hyperinsulinism/genetics , Glucagon-Secreting Cells/metabolism , Insulin-Secreting Cells/metabolism , Somatostatin-Secreting Cells/metabolism , Case-Control Studies , Cell Lineage , Cell Proliferation , Child , Child, Preschool , Congenital Hyperinsulinism/metabolism , Cyclin-Dependent Kinase 6/metabolism , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Fetus/cytology , Glucagon-Secreting Cells/cytology , Homeobox Protein Nkx-2.2 , Homeodomain Proteins/metabolism , Humans , Infant , Infant, Newborn , Insulin/metabolism , Insulin-Secreting Cells/cytology , Mutation , Nuclear Proteins , Paired Box Transcription Factors/metabolism , Potassium Channels, Inwardly Rectifying/genetics , Somatostatin-Secreting Cells/cytology , Sulfonylurea Receptors/genetics , Transcription Factors/metabolism , Zebrafish ProteinsABSTRACT
BACKGROUND: Insulinomas are a rare cause of hyperinsulinaemic hypoglycaemia (HH) in children. The clinical features, investigations, management and histology of these rare pancreatic tumours in children have not been described in a large cohort of patients. METHODS: We conducted a retrospective review of cases diagnosed between 2000 and 2012, presenting to two referral centres in the United Kingdom. Clinical, biochemical, imaging (magnetic resonance imaging (MRI) and 6-L-¹8F-fluorodihydroxyphenylalanine (¹8F-DOPA) PET/CT scanning) and histological data were collected. RESULTS: Nine children (age range 2-14.5 years) were diagnosed during the study period at Great Ormond Street Hospital (n=5) and Royal Manchester Children's Hospital (n=4). The combination of abdominal MRI scan (7/8) and ¹8F-DOPA PET/CT scan (2/4) correctly localised the anatomical location of all insulinomas. Before surgery, diazoxide therapy was used to treat hypoglycaemia, but only four patients responded. After surgical resection of the insulinoma, hypoglycaemia resolved in all patients. The anatomical localisation of the insulinoma in each patient was head (n=4), uncinate process (n=4) and tail (n=2, one second lesion) of the pancreas. Histology confirmed the diagnosis of insulinoma with the presence of sheets and trabeculae of epithelioid and spindle cells staining strongly for insulin and proinsulin, but not for glucagon or somatostatin. Two children were positive for MEN1, one of whom had two separate insulinoma lesions within the pancreas. CONCLUSIONS: We describe a cohort of paediatric insulinoma patients. Although rare, insulinomas should be included in the differential diagnosis of HH, even in very young children. In the absence of a single imaging modality in the preoperative period, localisation of the tumour is achieved by combining imaging techniques, both conventional and functional.