Biomedical subjects
N J Sebire
Publications and source records attributed to N J Sebire.
Analysis of the chromosomal region 19q13.4 in two Chinese families with recurrent hydatidiform mole.
BACKGROUND: Familial recurrent hydatidiform mole is an extremely rare autosomal recessive condition in which affected individuals have a predisposition to molar pregnancies that are diploid but biparental, rather than androgenetic, in origin. A gene for this condition has been previously mapped to a 1.1 Mb region of chromosome 19q13.4. However, investigation of further families is needed to refine the location of the specific gene(s) involved. METHODS: We have recently identified two novel Chinese families in which four affected women had recurrent pregnancy loss including 14 complete hydatidiform moles (CHM). Fluorescent microsatellite genotyping was used to determine the origin of CHM in both families. Using a panel of polymorphic microsatellite markers, genotyping and haplotype analysis of the 19q13.4 chromosomal region was performed in both families. RESULTS: Genotyping of CHM from affected individuals confirmed their biparental origin and diagnosis of familial recurrent hydatidiform mole in both families. However, no significant homozygosity for the 19q13.4 candidate region was found in affected members of either family. CONCLUSION: Genotyping and haplotype analysis has shown that a mutation in 19q13.4 is unlikely to be responsible for recurrent CHM in the two Chinese families investigated and provides further evidence to support the hypothesis that, although extremely rare, this condition shows genetic heterogeneity.
Histomorphometric characterisation of shared and non-shared cotyledonary villus territories of monochorionic placentae in relation to pregnancy complications.
OBJECTIVE: Theoretical estimates and physiological inferences suggest that the structure of a shared cotyledon differs from a non-shared cotyledon. The aim of this study was to characterise the histomorphometry of terminal villi in shared and non-shared cotyledons in monochorionic placentae, both from uncomplicated twins and from those with twin-twin transfusion syndrome (TTTS) or discordant growth restriction (DeltaIUGR). METHODS: Forty-one monochorionic placentae from Caucasian non-smokers were obtained at caesarean section. Their vascular anatomy and placental territories were ascertained by dye injection. After fixation, full thickness histological blocks were obtained by systematic random sampling from each twin's territory and the shared cotyledons. Fifty randomly selected terminal villi were assessed for: (i) median villus diameter (ii) median villus capillary diameter (iii) median fetomaternal diffusion distance (iv) median no. of capillaries/villus (v) degree of vascularization (median percentage cross-sectional area of terminal villi occupied by capillaries) using a stage micrometer and image analysis programme. The histomorphometric findings were then correlated with birthweight discordance, placental territory discordance and DeltaAVAs (no. of AVAs from smaller twin (donor) to larger twin (recipient) minus no. of AVAs from larger to smaller twin). RESULTS: Histomorphometric variables were similar in shared and non-shared cotyledons of uncomplicated MCDA twins. However, the median diameter of terminal villi in shared cotyledons in DeltaIUGR and TTTS placentae was significantly smaller [51.2 microm (48.2-58.3), p<0.001 and 52.6 microm (53.1-50.4), p<0.001], and had a similar number of smaller capillaries, larger fetomaternal diffusion distance and reduced vascularization compared to non-shared IUGR and TTTS placentae. However, Deltadiameter (defined as the difference between median diameters of terminal villi in large minus small twins' territories) rose with increasing birthweight discordance (Pearson correlation coefficient=0.82, p<0.001). Multiple linear regression analysis revealed that Deltadiameter was influenced by placental territory discordance (p<0.001) and birthweight discordance (p<0.01): log10 Deltadiameter=1.38+(0.01 x birthweight discordance)+(0.56 x log10 placental territory discordance) (R2=0.82, p<0.001), but there was no significant relationship with DeltaAVA and AAA. In the TTTS group, Deltadiameter correlated significantly with DeltaAVA only: log10Deltadiameter=1.44+(0.02 x DeltaAVA) (R2=0.3, p<0.001). CONCLUSIONS: This is the first study to characterise the histomorphometry of shared and non-shared cotyledons in MC twins. The findings suggest that abnormal placentation, rather than placental vascular anatomy may be responsible for DeltaIUGR in MC twins, whereas TTTS arises from imbalance in interfetal transfusion with resultant differing terminal villus histomorphometric features in donor, recipient and shared cotyledons.
Epstein-Barr virus-associated lymphoproliferative disorder presenting as apparently isolated gastrointestinal lesions in childhood.
We present an unusual case of post-transplant lymphoproliferative disorder (PTLD) presenting as apparently isolated gastrointestinal lesions in a pediatric renal transplant recipient. The multiple bowel lesions were related to Epstein-Barr virus and demonstrated the appearance of a monomorphic PTLD that was morphologically indistinguishable from diffuse large B-cell lymphoma. The patient responded to therapy with targeted anti-CD20 immunotherapy. PTLD may manifest as apparently isolated gastrointestinal tract lesions in childhood.
Increased first-trimester fetal nuchal translucency thickness in association with chondroectodermal dysplasia (Ellis-Van Creveld syndrome).
Increased nuchal translucency thickness (NT) is an established sonographic marker of fetal chromosomal abnormality. Several structural fetal defects and genetic syndromes including a range of skeletal dysplasias have been reported in association with increased NT. We report the first case of fetal Ellis-Van Creveld syndrome presenting as raised fetal NT at 13 weeks' gestation. Ultrasonography at 18 weeks' gestation demonstrated a narrow thorax, marked shortening of the long bones with bowed femora and hexadactyly of hands and feet. Pregnancy was terminated at 23 weeks' gestation. The postmortem radiological examination revealed short and bowed long bones with rounded metaphyses, postaxial polydactyly of hands and feet, short ribs and narrow thorax. The acetabular roofs were horizontal with medial and lateral spurs. This case adds a further type of severe skeletal dysplasia to the list of genetic syndromes which may present as increased fetal NT in the late first trimester.
The diagnosis of gestational trophoblastic disease in early pregnancy: implications for screening, counseling and management.
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Persistent gestational trophoblastic disease is rarely, if ever, derived from non-molar first-trimester miscarriage.
Traditional epidemiologic data suggest that persistent gestational trophoblastic disease (pGTD), may follow, and be derived from, either molar pregnancy, non-molar term pregnancy or first-trimester non-molar miscarriage. We examined a database of cases of possible or probable hydatidiform moles and proven pGTD derived from the Regional Trophoblastic Disease Unit, Charing Cross Hospital, London. There were 424 cases (6%), in whom the initial registered diagnosis was that of PHM or CHM but central histopathological review diagnosed a definite non-molar hydropic abortion (HA). In eight of the 424 (2%), although the histology of the most recent index pregnancy was that of non-molar miscarriage, there was a previous history of pregnancy affected by hydatidiform mole; two of these developed subsequent pGTD. Of a further 86 cases referred for a histopathological opinion prior to registration which demonstrated definite non-molar HA, none developed pGTD (zero of 510 (0%, 95% CI 0-0.7%)). During the same period there were 352 cases with pGTD requiring chemotherapy. In 31 cases, the only known pregnancy was the preceding apparent non-molar HA. However, of these, there were only three cases in whom the preceding histological products of conception had been centrally reviewed and were suggestive of non-molar pregnancy. However, in all three of these cases, the specimens were inadequate for definite exclusion of molar pregnancy. In one case in whom no material was available for review, molecular genetic analysis using restriction fragment length polymorphisms was carried out, and the choriocarcinoma was genetically derived from a previous molar pregnancy rather than the preceding HA. There were therefore no cases identified on the database of the trophoblastic disease unit of pGTD requiring treatment in whom the trophoblastic tumour could be genetically proven to have arisen from the preceding first trimester non-molar HA. We suggest that the risk of pGTD developing from a histologically confirmed non-molar HA is less than 1 in 50,000 and that the majority of pGTD cases previously reported to have been caused by a non-molar miscarriage probably represent disease due to an unrecognised early molar pregnancy.
Term preeclampsia is associated with minimal histopathological placental features regardless of clinical severity.
Preeclampsia (PET) is a serious complication of pregnancy, which is associated with uteroplacental disease and reduced uteroplacental perfusion. One of the histological features in placentas from pregnancies complicated by PET is infarction, representing focal severe uteroplacental ischaemia. This study examines the relationship between gestation at induced delivery and the prevalence of placental infarction using a placental pathology database to identify induced or operative deliveries on the basis of severe PET. The clinical and pathological findings were reviewed. Thirty-seven cases were identified, (4.9% of all placentas submitted). In 16 (43%), non-peripheral significant infarcts were identified histologically, including 13/20 (65%) requiring delivery before 34 weeks' compared to 3/17 (17%) requiring delivery > or = 34 weeks (z=2.9, P<0.01). Histological infarction is common in placentas from pregnancies complicated by severe PET but the prevalence is significantly greater in cases requiring delivery at earlier gestations, even when similar clinical indications for delivery are applied.
Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies.
Partial or complete hydatidiform mole (HM) affects approximately 1 in 500 to 1,000 pregnancies. Previous small series suggest that histopathologic diagnosis of HM may be difficult in tubal ectopic pregnancies. The histopathology database of a regional Trophoblastic Disease Unit was searched to identify cases with a referral diagnosis of tubal HM, and the histopathologic findings were reviewed. During the study period (1986-2004 inclusive), there were 132 cases. After central review by specialist histopathologists, the final diagnosis was ectopic partial mole in two, ectopic complete mole in five, and ectopic hydatidiform mole (not otherwise specified) in one. The final diagnosis of definite hydatidiform mole was made in eight (6%) cases, significantly less than in referred uterine curettage specimens, in which approximately 90% have a confirmatory diagnosis of HM (Z = 12.9; p < 0.0001). No cases in this series developed persistent gestational trophoblastic disease, the human chorionic gonadotropin concentration spontaneously returning to normal. Ectopic pregnancies, where managed surgically, should be submitted for histopathologic examination; however, the pathologist should be aware that the degree of extravillus trophoblastic proliferation may appear more florid compared with evacuated uterine products of conception. Molar pregnancy should only be diagnosed when strict criteria regarding morphologic abnormalities previously described in uterine evacuation material are applied.
Histopathological features of chronic granulomatous disease (CGD) in childhood.
AIMS: To describe the spectrum of histopathological features encountered in children with chronic granulomatous disease (CGD) at a specialist centre. METHODS AND RESULTS: The histopathological findings of 88 surgical pathology requests from a range of organ systems including upper and lower gastrointestinal tract biopsy series, liver, bladder, bone, lung, skin, soft tissue, bone marrow and lymph node biopsy specimens, in 32 patients aged 4 months to 18 years (median 7 years) with CGD were reviewed. In most tissues the features were those of active chronic inflammation, with or without abscess or granuloma formation, often associated with fungal infection. In some tissues, more characteristic findings were identified, including the presence of pigmented macrophages, especially in hepatic sinusoids and colonic mucosa, where active chronic eosinophil predominant colitis was also observed. CONCLUSIONS: Chronic granulomatous disease may present to histopathologists in a wide range of tissue specimens most often demonstrating features of active chronic inflammation with or without granuloma formation. The presence of numerous pigmented macrophages in association with such inflammation should raise suspicion of the diagnosis. In addition, diffuse granulomatous inflammation of the lung and hepatic abscess formation should be regarded as suggestive of the diagnosis.
Blood film examination for vacuolated lymphocytes in the diagnosis of metabolic disorders; retrospective experience of more than 2,500 cases from a single centre.
BACKGROUND: A range of metabolic diseases can result in abnormal accumulation of metabolic byproducts, resulting in abnormal lymphocyte cytoplasmic vacuolation, identifiable on routine blood film examination. AIMS: This study retrospectively examines the usefulness of blood film examination for vacuolated lymphocytes in a specialist paediatric pathology department in relation to patient's age and presentation. It also describes specific diagnostic features in relation to specific classes of metabolic disease. METHODS: Retrospective review of a histopathology database to identify all blood films examined for the detection of vacuolated lymphocytes during a 15 year period (1989-2004). RESULTS: In total, 2,550 blood films were investigated. The median age at submission was 2 years (range, birth to 88), and>90% of samples were from children<18 years. The most common indications were developmental delay/regression, ataxia, seizures, and cardiomyopathy. Vacuolated lymphocytes were identified in 156 films (6.1%). The frequency of vacuolated lymphocytes varied with clinical presentation, with ophthalmic indications having the highest positive rate (40%). In cases with vacuolated lymphocytes, a wide range of underlying metabolic diagnoses was apparent, the most common being juvenile neuronal ceroid lipofuscinosis and acid maltase deficiency, which accounted for more than half of the diagnoses. CONCLUSIONS: The examination of blood films for lymphocyte vacuolation is clinically useful in patients with a history suggestive of metabolic disease. The test is cheap, rapid, minimally invasive, and provides first line screening, with some findings indicating clues to a specific underlying diagnosis.
Light microscopic examination of scalp hair samples as an aid in the diagnosis of paediatric disorders: retrospective review of more than 300 cases from a single centre.
BACKGROUND: Microscopic examination of scalp hair can provide important diagnostic information in a range of paediatric conditions. It is a non-invasive and cost effective investigation, which is not widely performed. AIMS: To examine retrospectively the value of hair examination by light microscopy, including polarising microscopy, in a specialist paediatric pathology department during a 15 year period (1989-2004) and to describe the morphological abnormalities indicative of specific paediatric conditions. METHODS: Three hundred and twenty two hair samples were submitted. Microscopic changes were analysed in the light of clinical information categorised as: (1) erythroderma, (2) neurological impairment, (3) immunological/haematological defect, (4) ectodermal dysplasia, (5) abnormal hair only, and (6) non-specific/absent clinical details. RESULTS: Abnormalities were evident in 49% of the samples. In 25%, the changes were compatible with specific diagnoses including Menkes disease, Netherton's syndrome, trichothiodystrophy, Griscelli and Chediak-Higashi syndromes, monilethrix, uncombable hair, and loose anagen syndromes. In respect of the clinical presentation groups noted above, diagnostic changes were seen in 41%, 32%, 33%, 0%, 29%, and 0%, respectively. CONCLUSIONS: Morphological light microscopic examination of scalp hair is an inexpensive, rapid, and non-invasive investigation, which can provide valuable diagnostic information in a range of paediatric conditions.
Histopathological features of open lung biopsies in children treated with extracorporeal membrane oxygenation (ECMO).
BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become an established treatment for severe respiratory distress in a range of pediatric conditions. This study describes the histopathological features in a series of 22 children receiving ECMO therapy in whom open lung biopsy was carried out. AIMS: To describe the histopathological features of open lung biopsies in children receiving ECMO therapy. STUDY DESIGN: Retrospective review of clinical material. SUBJECTS: Children receiving ECMO therapy in whom open lung biopsy was carried out. RESULTS: In those investigated in infancy, open lung biopsy allowed a definite diagnosis to be made of the underlying condition in more than 90% of cases. In older children, the histopathological changes were more non-specific and, although providing useful clinical information, a definitive diagnosis could often not be made. In about a quarter of cases, there are additional pathological features, which may be related to ECMO treatment, such as significant intra-alveolar haemorrhage, but ECMO does not in itself impair the diagnostic usefulness of open lung biopsy in these selected patients. CONCLUSION: Open lung biopsy provides clinically useful information in infants receiving ECMO therapy. The histopathological changes may be complex and represent both the effects of ECMO and progression of the underlying disease.
Triploid/diploid mosaicism (69XXY/46XX) presenting as severe early onset preeclampsia with a live birth: placental and cytogenetic features.
Triploid/diploid mosaicism was diagnosed following karyotyping of an infant with musculo-skeletal abnormalities delivered because of severe preeclampsia. An area of the placenta appeared unusual with histology suggestive of trophoblastic abnormality. The importance of detailed histopathological examination and ploidy and flow cytometry studies where diagnostic uncertainty exists are highlighted.
Peripartum cardiomyopathy and diandric triploidy.
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Acardiac twin: too many invasive treatment options--the problem and not the solution.
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Fetal lung lesions: a new classification of fetal lung dysplasia.
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The dynamic placenta: II. Hypothetical model of a fetus driven transplacental water balance mechanism producing low apparent permeability in a highly permeable placenta.
In vitro and isotopic studies in vivo have reported the paradox that the human placenta is highly permeable, water exchanging at 3.6 litres per hour at 35 weeks of gestation, but clinical measurements in vivo show net transfer is minimal, around 2 ml/day. Current theories are based on osmotic pressure balances, but changes in maternofetal hydrostatic pressure change much faster than osmotic factors could respond. An alternative explanation might be that net transfer is not in fact the result of passive mechanisms, but is actively controlled by the fetus itself. The fetus is well equipped to monitor changes in blood volume, such as via sensors in venous and atrial stretch receptors to control ANF and hence urine production. Transplacental water regulation requires modification of transvillus pressures. Placental sub-chorial arteries and veins (of extra-embryonic origin) have different sensitivities from fetal body tissues to some vasoactive substances, and stem villous veins have unusually well developed vascular smooth muscle. It is thus theoretically possible for the fetus to modify subchorial venous resistances, and hence villous capillary pressure with a suitable circulating placental venous constrictive agent. A computer modelling study was undertaken using a fictitious placental venous constricting agent "fictensin", considered to be released by the fetus in proportion to disturbance of vascular volume. The effective placental permeability fell in proportion to the tightness of this fetal control mechanism, suggesting that the apparent placental permeability measured in vivo is a measure of fetal control, not true permeability. However, the range of compensatory pressures that the fetus can produce by this means is limited and failure of such a mechanism could allow flooding or dehydration of the feto-placental unit. This may shed new light on disorders such as polyhydramnios and fetal hydrops.