Hospital admissions and surgical treatment of children with lower-limb deficiency in Finland.

BACKGROUND AND AIMS: There are no population-based studies about hospital admissions and need for surgical treatment of congenital lower-limb deficiencies. The aim is to assess the impact children with lower-limb deficiencies pose to national hospital level health-care system. MATERIALS AND METHODS: A population-based study was conducted using the national Register of Congenital Malformations and Care Register for Health Care. All 185 live births with lower-limb deficiency (1993-2008) were included. Data on hospital care were collected until 31 December 2009 and compared to data on the whole pediatric population (0.9 million) live born in 1993-2008. RESULTS: The whole pediatric population had annually on average 0.10 hospital admissions and the mean length of in-patient care of 0.3 days per child. The respective figures were 1.5 and 5.6 in terminal lower-limb amputations (n = 7), 1.1 and 3.9 in long-bone deficiencies (n = 53), 0.6 and 1.9 in foot deficiencies (n = 26) and 0.4 and 2.6 in toe deficiencies (n = 101). Orthopedic surgery was performed in 72% (5/7) of patients with terminal amputations, in 62% (33/53) of patients with long bone, in 58% (14/24) of patients with foot and in 25% (25/101) of patients in toe deficiencies. Half (54%) of all procedures were orthopedic operations. CONCLUSION: In congenital lower-limb deficiencies the need of hospital care and the number of orthopedic procedures is multiple-fold compared to whole pediatric population. The burden to the patient and to the families is markedly increased, especially in children with terminal amputations and long-bone deficiencies of lower limbs.

The implementation of a nationwide anomaly screening programme improves prenatal detection of major cardiac defects: an 11-year national population-based cohort study.

OBJECTIVE: To evaluate whether a nationwide prenatal anomaly screening programme improves detection rates of univentricular heart (UVH) and transposition of great arteries (TGA), and whether maternal risk factors for severe fetal heart disease affect prenatal detection. DESIGN: Population-based cohort study. SETTING: Nationwide data from Finnish registries 2004-14. POPULATION: A total of 642 456 parturients and 3449 terminated pregnancies due to severe fetal anomaly. METHODS: Prenatal detection rates were calculated in three time periods (prescreening, transition and screening phase). The effect of maternal risk factors (obesity, in vitro fertilisation, pregestational diabetes and smoking) was evaluated. MAIN OUTCOME MEASURES: Change in detection rates and impact of maternal risk factors on screening programme efficacy. RESULTS: In total, 483 cases of UVH and 184 of TGA were detected. The prenatal detection rate of UVH increased from 50.4% to 82.8% and of TGA from 12.3% to 41.0% (P < 0.0001). Maternal risk factors did not affect prenatal detection rate, but detection rate differed substantially by region. CONCLUSIONS: A nationwide screening programme improved overall UVH and TGA detection rates, but regional differences were observed. Obesity or other maternal risk factors did not affect the screening programme efficacy. The establishment of structured guidelines and recommendations is essential when implementing the screening programme. In addition, a prospective screening register is highly recommended to ensure high quality of screening. TWEETABLE ABSTRACT: Implementation of a nationwide prenatal anomaly screening improved detection rates of UVH and TGA.

Mechanical analysis of cranial distractor attachment with three different resorbable fixation systems.

Distraction osteogenesis (DO) has become increasingly popular to correct craniosynostosis. Disadvantages of DO include the secondary operation needed for device removal and titanium screw related dura injury. To reduce invasiveness of the secondary device removal operation and to overcome titanium-related problems, fixation of the cranial distractor with resorbable materials is a potential alternative. New resorbable fixation methods, such as ultrasound-activated pins (UAPs) or heat-activated pins (HAPs), allow faster attachment on thinner bone than conventional resorbable screws (CRSs) since tapping is not required. However, resorbable materials are designed to be attached with a resorbable plate, not with a titanium distractor. We evaluated the suitability of CRSs, HAPs and UAPs for the cranial distractor fixation in a laboratory setting with a mechanical testing machine. Fracture tests were conducted in two directions with respect to the longitudinal axis; vertical i.e. axial pull-out strength, and horizontal i.e. shear strength. Mean maximum pull-out strength for CRS, HAP and UAP was 48.9 N, 32.5 N and 14.7 N, respectively. Mean maximum shear strength for CRS, HAP and UAP was 40.8 N, 77.9 N and 38.9 N, respectively. According to our in vitro tests, the cranial distractor attachment with four CRSs or six HAPs per footplate would provide sufficient fixation stability.

Force measurements during posterior calvarial vault osteodistraction: A novel measurement method.

Posterior calvarial vault osteodistraction (PCVO) has become increasingly popular in the correction of craniosynostosis. When compared to cranioplasty, PCVO offers a shorter, less invasive operation, greater intracranial volume advancement and a lower rate of relapse. In general, distraction protocols are based primarily on clinical observations rather than systematic research. Faster distraction protocols may reduce complications. However, distraction protocols producing higher forces can increase complications. Thus, we need to understand these forces in order to improve distraction protocols and devices. We developed a force measurement method that can be used on PCVO devices. Here, we present preliminary data about the forces developed during PCVO. We measured the forces in four bicoronal craniosynostosis patients during PCVO. We observed a linear-like trend between the force increase and the distraction distance within distraction sessions. We also observed a step-wise force increase between distraction sessions and found that the distraction force relaxed rapidly shortly after the distraction session. The mean maximum pre-distraction force for one distracter was 20.4 N, while the mean maximum end-distraction force for one distracter was 57.6 N. Our data suggests that current treatment protocols might be re-evaluated favouring shorter distraction distances and more frequent distraction sessions.

Promoting ossification of calvarial defects in craniosynostosis surgery by demineralized bone plate and bone dust in different age groups.

Correction of calvarial defects after calvarial vault reconstruction (CVR) is challenging in craniosynostosis patients of advanced age and typically employs autologous bone. Demineralized bone matrix (DBM) is a potential alternative material for autologous bone, but its use has not been extended to correct calvarial defects. CVR patients operated at the Department of Plastic Surgery, Helsinki University Hospital, during 2008-2010 were retrospectively reviewed. Inclusion criteria of the study were CVR patients who received DBM plate, with or without bone dust, on calvarial defects and who had suitable uncovered defect on the contralateral side as control. This study included 17 craniosynostosis and one positional plagiocephaly patient, whose mean age was 6.9 years (range 0.9-19 years). The mean follow-up time was 5.6 years. The fusion degree of all defects was measured from 1 week to 1 year postoperatively using three-dimensional computed tomography (3D CT) images by the OsiriX© method. Medical records were reviewed for DBM-related complications. A total of 26 defects were covered with a DBM plate (mean area 11.1 cm2) and 26 control defects were identified (mean area 7.8 cm2). The mean fusion degree of the DBM defects was 74% and 54% for the controls (p < 0.001). The mean fusion degree of nine DBM defects that lacked bone dust deposition was 66% and 55% for the nine controls (p < 0.059). The difference between the DBM and control defects was statistically significant for patients older than 30 months (p < 0.03). No DBM-related complication was observed. DBM plate is a safe and useful material to promote ossification in calvarial defects in CVR. Furthermore, DBM appears to be more effective in older patients (>30 months) than in younger patients or when used with bone dust.

Major congenital anomalies in children born after frozen embryo transfer: a cohort study 1995-2006.

STUDY QUESTION: Is there a different risk for major congenital anomalies (CAs) in children born after frozen-thawed embryo transfer (FET) compared with children born after fresh embryo transfer (ET)? SUMMARY ANSWER: Children born after FET have a similar risk of developing major CAs as children born after fresh ET. WHAT IS KNOWN ALREADY: The perinatal outcome in children born after FET is as good as that after fresh ET. Children born as a result of assisted reproductive technology (ART) have an increased risk for CAs when compared with spontaneously conceived children, but the knowledge on the risk for CAs in specific organ systems of children born after FET is limited. STUDY DESIGN, SIZE, DURATION: This register-based cohort study includes women who have undergone ART treatments with ET leading to singleton births (n = 4772) between the years 1995 and 2006. The women were identified from the registers of the infertility clinics, and the corresponding births were matched with data from the Finnish Medical Birth Register (FMBR). The 10% random sample of women with spontaneous pregnancies from the FMBR served as the reference group (n = 31,243). The study data were linked with the Register of Congenital Malformations using the mothers' and children's personal identification numbers to get information on CAs. Furthermore, the personal identification numbers of the ART women were linked with the Register of Induced Abortions to find their selective terminations of pregnancy for severe foetal anomalies. PARTICIPANTS, SETTING, METHODS: The study was focused on singleton births and included 1830 children born after FET, 2942 children born after fresh ET and 31 243 children born after spontaneous pregnancies. Only major CAs were analysed in keeping with European Concerted Action on Congenital Anomalies and Twins. The risk estimates for CAs were adjusted for the children's year of birth and maternal age, parity and socioeconomic status. The total prevalence of major CAs was counted, including both births and selective terminations of pregnancy for major fetal anomalies (n = 33). MAIN RESULTS AND THE ROLE OF CHANCE: Among singletons at least one major CA was reported in 77 cases (4.2%) in the FET group, 132 cases (4.5%) in the fresh ET group and 994 cases (3.2%) in the reference group. The risk for at least one major CA of the children born after FET was not increased compared with the children born after fresh ET [adjusted odd ratio (aOR) 0.95; 0.71-1.27]. Furthermore, no increased risks according to the organ system affected were found between these two ART groups. When comparing the children born after ART (FET and fresh ET) with the reference group children, the risk of having at least one major CA was moderately increased in the ART group (aOR 1.24; 1.05-1.47). LIMITATIONS, REASONS FOR CAUTION: Because of the study design we were neither able to examine the aetiology of infertility nor could we compare the data with a group of subfertile women to account for the effect of infertility per se on CAs. WIDER IMPLICATIONS OF THE FINDINGS: Perinatal outcomes of FET children, including the risks for CAs, are good and comparable with outcomes of other ART children indicating that slow freezing is a safe method to use during ART treatments. STUDY FUNDING/COMPETING INTEREST(S): University Hospital of Oulu and Helsinki, Finland. THL covered the data linkages and the work of Annukka Ritvanen and Mika Gissler. There are no competing interests to be reported.

Congenital anomalies and first life year surveillance in Type 1 diabetic births.

AIMS: To evaluate the rate of congenital anomalies (CA) and the reasons for mortality from 22 weeks of gestation until 1 year of age in births by Type 1 diabetic mothers. METHODS: Population-based cohort study using combined data from four national health registers in Finland during 1991-1995, including 954 singleton pregnancies complicated by Type 1 diabetes. RESULTS: Sixty births (629/10 000) involved registered major CA, of which 68% (n = 41) were isolated and 22% (n = 13) multiple anomalies, and in six cases, a syndrome was diagnosed (10%). After the exclusion of syndromes, the total number of anomalies was 73. Of the malformed infants, 63% were boys. The total rate of deaths among births until 1 year of age was higher in diabetic than in non-diabetic mothers (19.9/1000 vs. 8.1/1000): especially the rates of stillborns (odds ratio 2.4; 95% confidence interval 1.2-4.7) and post-neonatal deaths (3.8; 1.6-9.2) were higher. Of perinatal mortality (PNM) from the 22nd gestational week to the age of 7 days (13.6/1000), 23% were due to CA, 23% to prematurity, and the rest were intrauterine, mostly unexplained, deaths. Respiratory distress syndrome was the main cause of death among infants. CONCLUSIONS: The rate of CAs in Type 1 diabetic pregnancies is still high, but their proportion as a cause of PNM has decreased. Though PNM rate was low, post-neonatal mortality was significantly increased, reflecting the shift of deaths from the perinatal period to a later age.

Cancer in siblings of children with cancer in the Nordic countries: a population-based cohort study.

BACKGROUND: In some rare inherited disorders such as Li-Fraumeni syndrome, relatives of children with cancer are at increased risk of cancer. We aimed to assess relations between childhood cancer and sibling risk, and evaluate the influence of recessive conditions in cancer causation. METHODS: We did a population-based cohort study in the Nordic countries of 42277 siblings of 25605 children with cancer. Children with cancer were identified from records in the five Nordic cancer registries, and their siblings from nationwide population registries. Cancers in siblings were documented through record linkage with cancer registries and compared with national incidence rates. We also assessed cancer incidence in parents to identify familial cancer syndromes. FINDINGS: 284.2 cancers were expected in siblings, whereas 353 were diagnosed (standardised incidence ratio 1.24 95% CI 1.12-1.38). Risk ratios for siblings were highest in the first decade of life (2.59, 1.89-3.46). We excluded 56 families with genetic syndromes linked to cancer, which reduced this ratio from 1.7 to 1.0 (0.7-1.3) for siblings younger than 20 years, and from 1.3 to 1.0 (0.8-1.3) for those aged 20-29 years. We found no new patterns of familial cancer that indicated inherited susceptibility, or evidence that recessive conditions might contribute to cancers not explained by syndromes. 40% of cancers in siblings that occurred before age 20 years could be attributed to known genetic factors, whereas 60% remained unexplained. INTERPRETATION: Apart from rare cancer syndromes, paediatric cancer is not an indicator of increased cancer risk in siblings.

Decreasing late mortality among five-year survivors of cancer in childhood and adolescence: a population-based study in the Nordic countries.

PURPOSE: To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases. PATIENTS AND METHODS: This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk. RESULTS: The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment. CONCLUSION: Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.

On the symmetry of limb deficiencies among children with multiple congenital anomalies.

In humans, unpaired organs are placed in a highly ordered pattern along the left-right axis. As indicated by animal studies, a cascade of signaling molecules establish left-right asymmetry in the developing embryo. Some of the same genes are involved also in limb patterning. To provide a better insight into the connection between these processes in humans, we analysed the symmetry of limb deficiencies among infants with multiple congenital anomalies. The study was based on data collected by the International Clearinghouse for Birth Defects Monitoring Systems (ICBDMS). Registries of the ICBDMS provided information on infants who, in addition to a limb deficiency, also had at least one major congenital anomaly in other organ systems. We reviewed 815 such cases of which 149 cases (18.3 %) were syndromic and 666 (81.7 %) were nonsyndromic. The comparisons were made within the associated limb deficiencies, considering the information on symmetry, using a comparison group with malformations associated not involved in the index association. Among the non-syndromic cases, the left-right distribution of limb deficiencies did not differ appreciably between limb deficiency subtypes (e.g., preaxial, transverse, longitudinal). The left-right distribution of limb anomalies did not differ among most types of non-limb anomalies, though a predominance of left-sided limb deficiencies was observed in the presence of severe genital defects - odds ratio [OR], 2.6; 95 % CI, 1.1-6.4). Limb deficiencies (LDs) were more often unilateral than bilateral when accompanied by gastroschisis (OR, 0.1) or axial skeletal defects (OR, 0.5). On the contrary, LDs were more often bilateral than unilateral when associated with cleft lip with or without cleft palate (OR, 3.9) or micrognathia (OR, 2.6). Specifically, we found an association between bilateral preaxial deficiencies and cleft lip, bilateral amelia with gastroschisis and urinary tract anomalies, and bilateral transverse deficiencies and gastroschisis and axial skeleton defects. Of 149 syndromic cases, 62 (41.6 %) were diagnosed as trisomy 18. Out of the 30 cases of trisomy 18 with known laterality, 20 cases were bilateral. In the remainder the right and left sides were equally affected. Also, in most cases (74.4 %) only the upper limbs were involved. In conclusion the left-right distribution of limb deficiencies among some non-limb anomalies may suggest a relationship between the development of the limb and the left-right axis of the embryo.

Limb defects associated with major congenital anomalies: clinical and epidemiological study from the International Clearinghouse for Birth Defects Monitoring Systems.

Although limb defects associated with other congenital anomalies are rarely studied, they may provide insights into limb development that may be useful for etiologic studies and public health monitoring. We pooled data from 11 birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring Systems. We identified 666 infants, born from 1983 through 1993, who had a non-syndromal limb defect plus at least one other major malformation (rate 12.9/100,000 population). We used observed/expected ratios and log-linear models to detect association patterns. We found that specific limb defects occurred with relatively distinct sets of malformations. Preaxial limb defects occurred more frequently with microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeleton defects; postaxial defects with hypospadias; transverse defects with craniofacial defects, micrognathia, ring constrictions, and muscular defects; intercalary defects with omphalocele; split hand/foot with encephalocele; and amelia with anorectal atresia, omphalocele, severe genitalia defects, unilateral kidney dysgenesis, gastroschisis, and ring constriction. Log-linear modeling identified higher order associations among some of these same malformations.

Congenital malformations in twins: an international study.

Data provided by nine registries based in European and Latin America countries were analyzed to assess whether there is an excess of malformations in twins compared to singletons. Specific congenital malformations were coded according to the ninth revision of the International Classification of Diseases (ICD). Malformation rates and rate ratios (RR) for twins compared to singletons were calculated for each registry, and the homogeneity of the RRs was tested using the test of Breslow and Day. If departure from homogeneity in the different registries was not significant, registry-adjusted RRs with 95% confidence intervals were calculated. Overall, among 260,865 twins, 5,572 malformations were reported. A total of 101 different types of malformations or groups of defects was identified, and a homogeneous estimate of the RRs among registries was found for 91.1% of the malformations. Thirty-nine of the 92 malformations with homogeneous estimates of RRs were more common in twins than in singletons. For the remaining nine malformations, heterogeneous estimates of RRs were obtained. This study confirms the majority of already known associations and further identifies previously unreported malformations associated with twins. In conclusion, there is an excess of malformations in twins compared with singletons, and all anatomical sites are involved. The number of specific malformations associated with twins is higher than that previously reported in smaller studies.

Molecular cytogenetic study of patients with Pallister-Killian syndrome.

The Pallister-Killian syndrome (PKS) is characterized by tissue limited chromosomal mosaicism, i.e. the presence of a supernumerary metacentric chromosome [i(12p)] often confined to skin fibroblasts while the karyotype of cultured lymphocytes is normal. In the present study, chromosome painting by chromosomal in situ suppression (CISS) hybridization and interphase cytogenetic procedures employing biotinylated or digoxigenin labelled probes was carried out. These probes comprised a chromosome 12 specific library (LA 12NS01) and chromosome 12 centromere specific alpha-satellite (pSP12-1). They were used to analyse and quantify the presence of i(12p) in lymphocytes, granulocytes/monocytes, skin fibroblasts and buccal mucosal cells from five patients and one aborted fetus with PKS, and ten normal donors. CISS hybridization on mitotic skin fibroblasts reliably indicated the presence of i(12p) cells, even when metaphases of poor quality were included in the analysis. Two of the five patients showed i(12p) in a small proportion (< or = 0.5%) of the cultured lymphocytes too. The interphase cytogenetics procedure did not reveal the isochromosome in lymphocytes or granulocytes/monocytes in any of the patients. Two of the six patients had a twofold increase in the number of buccal mucosal cells with three hybridization signals over control values. However, for mucosal cells, methodological improvements are required. For cytogenetic diagnosis of PKS, cultured fibroblasts subjected to chromosome painting by CISS hybridization with a chromosome 12 specific library probe are recommended.

Cardio-facio-cutaneous syndrome: three additional cases and review of the literature.

We report on 3 patients with the cardio-facio-cutaneous (CFC) syndrome. Each of them was a sporadic case in the family. The severity of the psychomotor retardation varied from mild to severe. Skin manifestations were often minimal, but each patient had abnormally curly and brittle hair. A skin biopsy from one of the patients showed vellus hair cysts filled with keratin, and the hair follicles were surrounded by unusually thick fibrotic sheaths.

Craniofrontonasal dysostosis: variable expression in a three-generation family.

A family with craniofrontonasal dysostosis (craniofrontonasal dysplasia) is described. There were three severely affected females, two of them daughters of apparently healthy parents. Examination of the male relatives revealed orbital hypertelorism and other minor anomalies in two of them, including the father of the two affected daughters. This family emphasizes the wide variation in the phenotype of craniofrontonasal dysostosis and suggests that male relatives with minor manifestations of the syndrome may be at high risk of having severely affected daughters. The expression of the gene may be modified by the sex.

Trisomy 12 mosaicism in amniocytes and dysmorphic child despite normal chromosomes in fetal blood sample.

Trisomy 12 mosaicism (44 per cent) was detected prenatally in cultured amniocytes. A cordocentesis was performed to confirm the result. Only normal cells were found in the fetal blood sample. The fetus was estimated to be at a low risk of having a chromosomal abnormality and the pregnancy continued. Eight days after birth, a congenital heart defect was detected in the child. Several dysmorphic features were also evident. Further karyotyping of different tissues revealed normal blood and urinary cells but trisomic cells in the placenta (100 per cent) and in skin fibroblasts (25 per cent). The child died at 5 weeks of age. In this case, the fetal blood sample failed to reveal the real chromosome constitution of the fetus.

Pallister-Killian syndrome: cytogenetic and molecular studies.

Pallister-Killian syndrome is a dysmorphic syndrome characterized by a tissue-limited mosaicism: a majority of fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. In this study, the interpretation of the extra chromosome as composed of two short arms of chromosome 12 is confirmed, using molecular methods. Furthermore, restriction fragment length polymorphisms indicate that the two arms are identical, which is compatible with the hypothesis of an isochromosome 12p. A new feature which may be important in understanding the mechanism of origin of the abnormality is described: the proportion of abnormal mitoses falls dramatically during long-term culture of fibroblasts.