'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.

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.

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.

Perinatal mortality in Jamaica 1986-1987

A large population-based study of all stillbirths and neonatal deaths occuring on the island of Jamaica during a 12 month period is described. During this time, 2069 perinatal deaths were identified from an estimated population of 54,400 total births giving a perinatal death rate of 38.0 per 1000 total births. The death rate was 5 times higher among twins than singletons. An attempt was made to obtain detailed postmortem examination of as many deaths as possible. In the event, 51 por ciento of perinatal deaths received such a postmortem examination, for the most part by 3 specially trained pathologists working in the capital. Postmortem rate was affected by sex, multiplicity of the infant, month of death and area of delivery. Deaths were classified using Wigglesworth scheme. The distribution categories was similar in the months when the postmortem rate was 70 por ciento to the rest of the time period when the post-mortem rate was only 40 por ciento . The Wigglesworth classification of deaths identified those associated with intrapartum asphyxia as the most important group, accounting for over 40 por ciento of deaths. This simple classification is important as it focusses attention on details of labour and delivery that may require change and is useful in planning future delivery of obstetric and neonatal care.

Perinatal mortality in Jamaica: the role of intrapartum asphyxia and birth trauma

Data from the Jamaican Perinatal Morbidity and Mortality Survey, 1986-1987, were analysed in order to examine the frequency of pathological markers of asphyxia and birth trauma amongst fresh stillbirths and neonatal deaths in babies coming to necropsy. A total number of 1112 necropsies were performed. There were 295 normally formed fresh stillbirths and 463 neonatal deaths, 264 of whom died on the last day of life. One hundred and seventy (57.6 por ciento ) fresh stillbirths showed signs of asphyxia and 64 (21.7 por ciento ) had evidence of birth trauma. Signs of asphyxia were common in all the birth weight groups in 1st day neonatal deaths, being least common in the 0-999g group (19.6 por ciento ) and most common in those weighing 2500-3499g (48.7 por ciento ). Birth trauma was most common in infants with birth weights of over 2500g. It is of great concern that a large proportion of mature fresh stillbirths and neonatal deaths in Jamaica show pathological evidence of intrapartum asphyxia or birth trauma at necropsy. The problems underlying these deaths and the methods of preventing them need urgent attention.

Fatal malformations in Jamaica

Babies with major malformations were identified during the Jamaica Perinatal Morbidity and Mortality Survey. They were in 96 (8.6 por ciento ) of 1112 perinatal and neonatal deaths coming to necropsy and in 25 (2.35 por ciento ) 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.

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.

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

During the Jamaian 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 por ciento 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.

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.