'Crommelin-type' symmetrical tetramelic reduction deformity: a new case and breakpoint mapping of a reported case with de-novo t(2;12)(p25.1;q23.3).

We report a male fetus with symmetrical peromelic reduction of the upper limbs (missing distal, mesial and proximal elements) and symmetrical phocomelic reduction of the lower limbs (missing proximal and mesial elements) without other major malformations. We identified 11 previously reported cases with very similar features and have named this entity 'Crommelin-type' symmetrical tetramelic reduction deformity. Interphase fluorescence in-situ hybridization on isolated nuclei from paraffin-embedded tissue was used to map the breakpoints in a previously reported case with a de-novo t(2;12)(p25.1;q23.3). The 2p25.1 breakpoint disrupted ROCK2, encoding Rho-associated, coiled-coil-containing protein kinase. The 12q23.3 breakpoint maps 0-25 kb 5 of CMKLR1, encoding chemokine-like receptor 1. Homozygous loss-of-function of either gene causes no major limb effect in mouse embryos. However, Cmklr1 shows both site-specific and stage-specific expression in mouse limb buds, but no mutations were identified in CMKLR1 or a nearby putative cis-regulatory region in the new case. We cannot assign a specific genetic mechanism in the translocation case but developmental disregulation of gene expression at one, or both, breakpoints may provide an explanation for the phenotype.

Apolipoprotein E e4 and its prevalence in early childhood death due to sudden infant death syndrome or to recognised causes.

BACKGROUND: Specific genetic polymorphisms have been shown to be more common in unexplained infant death. The APOE genotype exhibits opposite effects at the extremes of age with protective effects of e4 on perinatal mortality but detrimental effects as age progresses. OBJECTIVE: To determine whether the APOE e4 allele is associated with early childhood (1 week-2 years) unexplained death ('sudden infant death syndrome', SIDS) or with recognised causes (non-SIDS) and to compare these cohorts with published perinatal and adult data. METHODS: DNA was extracted from spleen tissue of children dying in South East Scotland between 1990 and 2002. APOE alleles (e2, e3, e4) were determined using PCR. Comparisons of allele frequencies between groups were made. RESULTS: There were 167 SIDS cases and 117 non-SIDS cases. Allele distributions of SIDS cases were similar to healthy newborns. Allele distributions of non-SIDS cases were more similar to adults than to healthy newborns. The percentage of children with at least one e4 allele was significantly lower in non-SIDS compared to SIDS (p = 0.016). Non-SIDS cases had a higher frequency of e3 compared to SIDS cases (p = 0.01) and to healthy newborns (0.005). CONCLUSIONS: Children dying from identified causes have different APOE allele distributions from SIDS cases, but are similar to adults. Children dying from SIDS have an allele distribution comparable to healthy newborns. The prevalence of e4 in SIDS is not of an order to contribute significantly to the age-related decline in e4.

Subclassification of anencephalic human fetuses according to morphology of the posterior cranial fossa.

Anencephaly is a designation for congenital absence of the cranial vault with cerebral hemispheres completely missing or decreased to small masses attached to the base of the skull. The etiology is unknown. Whether the bony tissue or soft brain tissue is a primary factor is also unknown. The present study has focused on the posterior cranial fossa in anencephaly. The goal is to determine whether differences in the posterior cranial fossa could provide a basis for subclassification of anencephalic fetal skeletons. Twenty-three human anencephalic fetuses, at gestational ages 13 to 22 weeks, were studied. Radiologic and cephalometric analyses, including measurements of bone sizes and different angles, were performed. Permission for autopsy of the central nervous system was not available. For comparison of anencephalic findings with normal conditions, standards from a recent publication were used. Foot length served as a parameter for age comparison. The study showed 2 morphologic types of the posterior cranial fossa. One type had a fossa cranial morphology close to normal morphology, whereas the other had a malformed and much smaller posterior cranial fossa. The latter condition was presumed to be due to a primary error in chondral and cranial development. The current skeletal subgrouping might be essential for clinicians' or pathologists' future assessment of the autopsy results. The skeletal subgrouping should, if possible, be associated with karyotyping and analysis of the central nervous system. The goal is to distinguish between congenital conditions resulting in anencephaly and acquired conditions resulting in anencephaly.

Sirenomelia sequence according to the distance between the first sacral vertebra and the ilia.

The development of the iliac bones and lower limbs are parallel processes depending on the normal ontogeny of the caudal blastema [O'Rahilly and Müller, 1989; Opitz, 1993; Opitz et al., 2000]. We hypothesized that the pathogenetic mechanisms leading to fused lower limbs would in parallel displace the ilia caudally and medially and that the degree of this displacement might correlate with the severity of the iliac and lower limb defects. Thus the purpose of the study was to test this hypothesis in a sample of 12 sirenomelic fetuses. The fetuses GA 16-39 weeks, spontaneously or therapeutically aborted, were radiographed in the frontal projection as part of a requested autopsy. From each radiograph, a line was drawn connecting the most cranial part or the two ilia. After that the distance was measured vertically between this line and the most cranial part of the first sacral vertebral body (iliac-sacral distance (ISD)). A second distance was measured horizontally between the most lateral part of the two iliae (bi-iliac distance (BD)). As a result, ISD correlates with the iliac/femur phenotype. Separate ilia and femora occur only in cases with normal ISD. Fused ilia or femora or both are seen only in fetuses with mildly increased ISD, whereas a single iliac bone and femur occur only in cases with greatly increased ISD. The increase of the ISD does not correlate with the severity of more distal limb involvement. There was a correlation between the ISD and the BD values; the higher the ISD, the shorter the BD. Based on these findings, we propose an extended classification of Sirenomelia to be tested by other researchers.

Histological examinations of bone and cartilage in the axial skeleton of human triploidy fetuses.

The aim of this study was to examine histologically bone and cartilage in vertebral corpora of axial skeletons of eight human triploid fetuses, gestational ages 14-25 weeks, CRL 100-200 mm. The results were compared to earlier studies on vertebral development in trisomies 21, 18, 13, and to normal corpora development. After radiography in frontal and lateral projections, the vertebral column was sectioned into cervical, thoracic and lumbar segments, decalcified, dehydrated, and embedded in paraffin. The blocks were serially sectioned in the vertical plane and stained with Toluidine blue and Alcian blue/van Gieson. The radiographic characteristics of the vertebral corpora observed in frontal and lateral projection varied from small cleft vertebral corpora to fusions between the individual corpora. Histological examination of the vertebral corpora confirmed the abnormal pattern of ossification seen radiographically. As a new finding abnormal metachromasia of the ground substance was observed in the cartilage. Marked borderlines were registered in the cartilage between regions with differences in metachromasia. These borderlines were similar but more extensive than borderlines observed previously in trisomies 21, 18 and 13.

Midline skeletodental morphology in holoprosencephaly.

OBJECTIVE: The purpose of the present study was to analyze histologically the midline structures in a human fetus with holoprosencephaly and a single median maxillary central incisor. METHODS: A human male fetus, CRL 137 mm, postconceptional age 18 weeks, with a diagnosis of holoprosencephaly, the cebocephalic type (one nostril), and alobar brain development, was investigated. After radiography, the cranial midline structures were examined histologically. RESULTS: The histological examination revealed partial absence of the intermaxillary suture (in the region anterior to the central incisor), absence of the internasal suture, and partial absence of the metopic suture (caudal part). A single midline nasal bone was observed instead of two bilateral nasal bones, and a midline maxillary central incisor was found instead of two bilateral incisors. A short nasal septum, absence of crista galli, and partial absence of cartilaginous tissue anterior to the sella turcica in the region of the presphenoid bone were recorded. CONCLUSIONS: The study shows that in the affected fetus, there were malformations of midline structures anterior to the sella turcica comprising suture development and cartilage development.

Short bi-iliac distance in prenatal Ullrich-Turner syndrome.

The purpose of the present study is to evaluate the bi-iliac distance and the caudo-cranial position of the iliac bones in Ullrich-Turner syndrome (UTS) fetuses compared to recently published standards for normal fetuses. Whole-body radiographs in antero-posterior projections of 24 UTS fetuses (crown-rump lengths, 106-220 mm) were included in the study. From each radiograph, two horizontal (outer and inner bi-iliac distances) and two vertical (caudo-cranial) positions compared to the vertebral column were measured to estimate the position of the iliac bones. The present investigation revealed that both the outer and inner bi-iliac distances were significantly shorter in UTS fetuses than in normal fetuses. We also found that for the inner bi-iliac distance, the growth rate in UTS fetuses was significantly lower than in normal fetuses. This finding suggests not only a lesser growth but also a different growth pattern compared to normal fetuses. Regarding the caudo-cranial position of the iliac bones compared to the lower vertebral column, there was no significant difference for the lower caudo-cranial position, but the upper caudo-cranial position was significantly lower in UTS fetuses than in normal fetuses. The bi-iliac distance and the iliac bone position have not previously been described in Ullrich-Turner syndrome fetuses.

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.

The epidemiology of perinatal death in Jamaica

Information from the Jamaican Perinatal Mortality Survey was used to identify features of mothers and their pregnancies that were independently associated with perinatal death. social, biological, environmental, life style and medical aspects of mothers and their pregnancies were collected on two inter-locking subsamples: (1) all births on the island of Jamaica in the 2 months of September and October 1986, the 'cohort months', and (2) all fetal deaths of weight 500g or more, together with all neonatal deaths, in the 12-month period from 1 September 1986 to 31 August 1987. Singleton survivors from the cohort months were compared with all perinatal deaths in the 12-month period using logistic regression. The first model omitted items concerning past obstetric history, but these were included in the second model. In total, 21 variables entered the first model and 24 the second. The only item that became non-significant when past obstetric history was included was maternal age. The final model compared 1017 perinatal deaths with 7672 survivors. It consisted of the following: union (marital) status (married being at lower risk, P<0.01), maternal employment status (housewives at lowest risk, P<0.001), number of adults in household (the more the higher the risk, P<0.05), the number of children aged <11 (the more the lower the risk, P<0.0001), use of toilet facilities (shared with other households increased risk, P<0.001), maternal height (tall women at reduced risk, P<0.001), mother's report that she was trying to get pregnant (P<0.001), maternal alcohol consumption (drinkers had lower risk, P<0.05), maternal syphilis (higher risk, P<0.0001), bleeding before 28 weeks or more (higher risk, P<0.0001), first diastolic blood pressure (80mm + at higher risk, P<0.0001), highest diastolic blood pressure (100mm + at increased risk, P<0.0001), highest proteinuria (++ or more at increased risk, P<0.0001, vaginal discharge/infection (untreated at increased risk, P<0.001), pre-eclampsia diagnosed in antenatal period (increased risk, P<0.01), maternal diabetes (increased risk, P<0.05), start of antenatal care (first trimester at reduced risk, P<0.01), iron taken (reduced risk, P<0.0001), type of perinatal care available in parish of residence (reduced risk if consultant obstetricians and paediatricians available at all times, P<0.0001), number of miscarriages and terminations (the more the higher the risk, P<0.0001), previous stillbirth (higher risk, P<0.0001), previous early neonatal death (higher risk, P<0.001), previous Caesarean section (higher risk, P<0.01). The implications for reduction in perinatal mortality rates are discussed (Summary)

Deaths associated with intrapartum asphyxia in Jamaica

The Jamaican Perinatal Mortality Survey compared all 2069 perinatal deaths occurring during the 12 months between 1 September 1986 and 31 August 1987 with 10086 survivors born in the 2 months of September and October 1986. The Wigglesworth classification identified 44 percent of the deaths as attributable to intrapartum asphyxia (IPA), and this grouping was largely confirmed by post-mortem examination where it had been carried out. About half of these babies weighed 2500g+ and death should have been largely preventable. Comparison of the 813 IPA singleton deaths with 9919 singleton survivors using logistic regression showed independent associations with maternal employment status, the number of children in the household, maternal height, whether or not the mother was trying to get pregnant, or had ever used an intrauterine contraceptive device. Medical conditions such as syphilis, untreated vaginal infection, bleeding < 28 weeks, bleeding 28+ weeks, highest diastolic and first blood pressures and eclamptic fits antenatally were all strongly associated. Mothers who commenced antenatal care in the first trimester were at reduced risk as were those who took iron during pregnancy. There were at substantial reductions in mortality in areas where better medical facilities were available. To this model, features of previous obstetric history were offered, but the only variables which entered were those relating to prior perinatal deaths and immediately preceding miscarriage and termination. Examination of specific features in the management of labour and delivery is a logical basis for the introduction of changes in practice. Caesarean section is unlikely to be apropriate but it is suggested that more active interventions in terms of use of forceps and/or vacuum extraction may be useful (Summary)

The epidemiology of antepartum fetal death in Jamaica

All perinatal deaths occurring over a 12-month period on the island of Jamaica were classified using the Wigglesworth schema. In all, there were 584 antepartum fetal deaths (incidence 10.7 per 1000 total births). Comparison of the 558 singleton deaths with 9919 singleton survivors revealed, using logistic regression, strong associations with union (marital) status, maternal employment status, the composition of the household, the sole use of a toilet by the household, the parish of residence, whether the mother was trying to get pregnant and the mother's age (the older the mother the higher the risk). Independent of these factors were strong statistically significant relationship with syphilis, diabetes, maternal anaemia, third-trimester bleeding, highest diastolic blood pressure of 90mm or more and highest proteinuria of ++ or more. Mothers who had taken prophylactic iron were at substantially lower risk compared with those who had not. We conclude that appropriated identification and treatment of syphilis, diabetes, anaemia and hypertension give the best chance of reduction of the high antepartum fetal death rate on the island (Summary)

Perinatal mortality survey in Jamaica: aims and methodology

The Jamaican Perinatal Mortality survey was designed to identify the true perinatal mortality rate, and assess the factors which could contribute towards a reduction in perinatal mortality on the island. All births in a 2-month period (n=10527) were compared with all perinatal deaths occurring over a 12-month period (n=2069). Over half the deaths (n=1058) received a detailed post-mortem examination. Use of the Wigglesworth classification identifies the major component of perinatal death in this country to be associated with intrapartum asphyxia (44 percent of deaths). Deaths due to congenital malformations and miscellaneous causes contribute relatively little (<10 percent) to the overall mortality rate. Over a quarter of deaths apparently occur before the onset of labour, a a fifth are prematurely liveborn but die of causes related to immaturity (Summary)

Perinatal mortality in Jamaica 1986-1987

A large population-based study of all stillbirths and neonatal deaths occurring on the island of Jamaica during a 12 month period is described. During this time, 2069 perinatal deaths were identified in an estimated total of 54,400 infants born giving a perinatal death rate of 38.0 per 1000 births. The death rate was 5 times higher among twins than singletons. An attempt was made to obtain detailed postmortem examination of as many cases as possible. In the event, 51 percent of the infants who died perinatally had such postmortem examination. Postmortem rate was affected by sex, multiplicity of the infant, time of death, month of death and area of delivery. Deaths were classified using the Wigglesworth scheme. The distribution of categories was similar in the months when the postmortem rate was 70 percent to the rest of the time period when the post-mortem rate was only 40 percent. The Wigglesworth classification of deaths identified those associated with intrapartum asphyxia as the most important group, accounting for over 40 percent of deaths overall and 59 percent of deaths of infants of more than 2500 g birthweight. Antepartum fetal deaths were the second largest group, comprising 20 percent of deaths. Sixty percent of the infants in this group weighted less than 2500 g at birth. Major malformations were responsible for few perinatal deaths in Jamaica. This simple classification is important as it focuses attention on details of labour and delivery that may require change and is useful in planning future delivery of obstetric and neonatal care. (AU)

Fatal malformations in Jamaica

Babies with major malformations were identified during the Jamaica Perinatal Morbidity and Mortality Survey. They were found in 96 (8.6 percent) of 1112 perinatal and neonatal deaths coming to necropsy and in 28 (2.6 percent) of 1085 not so examined. The central nervous system was most commonly affected, followed by the renal, gastrointestinal, and cardiovascular systems in decreasing order of frequency. Many infants had abnormalities in more than one system and 10 malformations syndromes/sequences were identified. Although at the present time, major malformations make only a small contribution to perinatal and neonatal mortality in Jamaica, their importance will increase when deaths from other causes, such as birth asphyxia, decline. The type of malformation currently fatal in a particular population is relevant when planning diagnostic and surgical services for neonates and infants. It is also important to any discussions about provision of prenatal diagnostic services. (AU)

Maternal mortality in Jamaica: socioeconomic factors

Socioeconomic factors relating to all maternal deaths identified during the 12 months of the Jamaican Perinatal Morbidity and Mortality Survey were compared with a control population of over 10,000 women. The maternal mortality rate was 11.5 per 10,000 livebirths. Initial analyses showed (a) a negative trend in risk of maternal death with increasing maternal education level, (b) that mothers who lived in households with direct pumped water and/or flush toilets enjoyed a reduced risk, (c) mothers who were themselves the major wage earner and (d) those living in households where the major wage earner was a farmer were at increased risk of maternal death. A previous analysis showed that the mothers age, her parity and variables indicating access to medical care were important. Logistic regression showed that only maternal age and toilet facilities were independently associated with maternal mortality (AU)

Maternal mortality in Jamaica: health care provision and causes of death

During the Jamaican Perinatal Mortality and Morbidity Survey, details of 62 maternal deaths occurring in the 12 month period September 1987 to August 1988 were compared with a control population of 95 percent of all births on the island in September and October 1987. The incidence (11.5 per 10,000 livebirths) had not fallen since a study 5 years previously. The mothers who died showed the expected trends with advanced maternal age and high parity. The major cause of maternal mortality was hypertension, (3.5 per 10,000 livebirths) followed by haemorrhage and infection. There was little evidence that these mothers had delayed their first attendance for antenatal care but they were more likely to have reduced access to basic facilities such as health centres and public transport. The risk of maternal death varied with grade of hospital facilities available, particularly for hypertension-related deaths, being lowest in areas with access to a specialist hospital and highest in areas where there were no obstetricians available (AU)

Area variation in perinatal mortality in Jamaica: association with type of hospital services available

Information on the area of maternal residence of 1856 singleton perinatal deaths occurring during a 12 month period (September 1986 - August 1987) were compared with those of 9933 singleton births born during a two month period (September-October 1986) and surviving the first week of life (The Jamaican Perinatal Morbidity and Mortality Survey). The overall mortality ratio of deaths to estimated survivors was 35.7 per 1000. When the area of residence was categorised according to the type of facilities available, there was a clear trend - births to mothers resident in areas with specialist hospital facilities available, had a mortality ratio of 32.0 per 1000, substantially less than those areas with some obstetric and paediatric facilities (rate 39.2 per 1000) or those with only a cottage hospital and no obstetricians (35.8 per 1000). Categorisation of the deaths using the Wigglesworth classification showed significant variation with intrapartum anoxia. This could not be explained by differences in birthweight, or demographic features of the population. It is concluded that access to a specialist hospital results in a significant reduction in mortality associated with intrapartum asphyxia, but not with other types of perinatal death (AU)

Fatal malformations in Jamaica

Babies with major malformations were identified during the Jamaica Perinatal Morbidity and Mortality Survey. They were in 96 (8.6 percent) of 1112 perinatal and neonatal deaths coming to necropsy and in 25 (2.35 percent) of 1085 other deaths. The central nervous system was not most commonly affected, followed by the renal, gastro-intestinal and cardiovascular system in decreasing order of frequency. Many infants had abnormalities in more than one system and 10 malfomation syndromes/sequences were identified. Although at the present time, major malformations make only a small contribution to perinatal and neonatal mortality in Jamaica, its importance will increase as there is a fall in deaths related to perinatal asphyxia, currently the major cause of perinatal mortality in Jamaica. Although many malformations are currently untreatable, it is important to take account of gastro-intestinal defects when planning surgical services for the newborn, since these are the most easily remediable (AU)