Mortality rates in subjects with fetal alcohol spectrum disorders and their siblings

BACKGROUND: Our objective was to estimate the mortality rate in subjects with fetal alcohol spectrum disorders (FASD) and their siblings whose FASD status was unknown. METHODS: We used the state FASD Registry to link subjects with FASD to a North Dakota birth certificate. We were able to link 304 of 486 cases (63%). We used the birth certificates to identify the mother and children born to the mother (siblings). We then searched for death certificates for both the FASD cases and their siblings. We then calculated the annual and age‐adjusted mortality rates for the siblings of the Registry cases and compared them with mortality rates from North Dakota. RESULTS: The FASD case mortality rate was 2.4%, with a 4.5% mortality rate for their sibings, accounting for 14% of all deaths when compared to the North Dakota residents matched by age and year of death. The sibling deaths accounted for 21.5% of all cause mortality matched by age and year of death. The age‐standardized mortality ratios were 4.9 for the FASD cases and 2.6 for their siblings whose FASD status was unknown. CONCLUSIONS: Mortality rates for FASD cases and their siblings were increased and represent a substantial proportion of all cause mortality in North Dakota. Prevention of FASD may be a useful strategy to decrease mortality. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Epstein-Barr virus infection in the neonatal period and in childhood

In an attempt to detect and characterize congenital, neonatal and early childhood EBV infections, a prospective sero-epidemiological study was undertaken in 112 newborn infants and their mothers, 25 additional newborns undergoing exchange transfusion, 114 randomly selected hospitalized infants aged 0 to 3 years, and 109 siblings and parents of these infants. Leukocyte culture was attempted in all the newborns and in 25 pre- and post-transfusion.The findings of EBV seroconversion in six patients without clearly apparent illness, infectious mononucleosis in only one case with significant EBV antibody rise, seroreversion in three cases in early childhood, higher newborn than maternal EBV antibody titres in three cases and the establishment of two permanent lymphoblastoid cell lines from newborns following exchange transfusion raise the possibility of abortive primary EBV infection in early life. Congenital or neonatal infections following exchange transfusions, however, could not be substantiated with certainty since the EBV antibodies did not persist at follow-up except possibly in two cases. Parenteral transmission of the EB virus by exchange transfusion at birth is probably prevented by the presence of EBV antibodies in either donor or recipient.     

Chromosomal radiosensitivity of Down syndrome lymphocytes at different stages of the cell cycle

Summary Data on 151 non-mosaic 47,XXY males from Sardinia, previously reported by Filippi (1986), were analysed for associations with parental ages at birth, sib order and sex ratio among siblings. The results confirm those of earlier Scottishbased studies in that: (1) there was a significant increase in risk of 47,XXY livebirths at advanced parental ages; (2) maternal age, and maternal age alone, was sufficient to explain the effect; (3) there were no independent effects of paternal age or sib order once maternal age had been taken into account; (4) there was no evidence of any distortion of the sex ratio among siblings. Estimates of relative risk at different maternal ages were compatible with those from the Scottish studies, and pooled estimates are therefore derived. They suggest, for example, that the risk at maternal age 40 years is 2–3 times that at age 30 years. In 33 cases, the parental origin of the supernumerary X chromosome was determined by analysing the segregation of genetic markers. The mean parental ages of 19 maternal cases were significantly raised above those of controls, whereas those of 14 paternal cases were slightly, and marginally significantly, reduced. The conclusions were essentially unaffected by whether the Sardinian population, the siblings of cases or a group of 94 unrelated Sardinian males were used as controls.     

Clinical, genetic, and epidemiological factors in neural tube defects.

We examined clinical, genetic, and epidemiologic factors among 512 probands with nonsyndromal neural tube defects (NTDs). Data were analyzed after grouping the probands in four different ways with respect to pathological features and putative pathogenic mechanisms. Apparently unrelated congenital anomalies occurred more frequently among probands with craniorachischisis (62%), encephalocele (30%), or multiple NTDs (25%) than among probands with anencephaly (14.7%) or spina bifida (10.1%) (P much less than .0001). Unrelated congenital anomalies occurred less often among probands with low spina bifida (6.7%) than among probands with high spina bifida (19.5%). NTDs were seen in 7.8% of the siblings of probands with high spina bifida but in only 0.7% of the siblings of probands with low spina bifida, in 2.2% of the siblings of anencephalic probands, and in none of the siblings of probands with craniorachischisis, encephalocele, or multiple NTDS (P less than .001). In all 16 families in which two siblings had NTDs, both had either defects of the type associated with abnormal primary neurulation or defects of the type associated with abnormal canalization. High spina bifida and multiple NTDs were found more frequently than expected among the Sikh probands (P less than .02). The frequency of non-NTD congenital anomalies was higher among siblings of Sikh probands (8.8%) than among siblings of other probands (2.4%) (P less than .05). This excess was due to the occurrence of hydrocephalus without spina bifida in four of 68 siblings of Sikh probands.     

Is there a familial link between Down's syndrome and neural tube defects? Population and familial survey

Objective To verify whether Down''s syndrome and neural tube defects arise more often in the same family than expected by chance.Design Population and familial survey.Setting Network of maternity hospitals in the Latin American collaborative study of congenital malformations (ECLAMC) in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay, and Venezuela between 1982 and 2000.Probands 2421 cases of neural tube defects, 952 of hydrocephalus, and 3095 of Down''s syndrome registered from a total of 1 583 838 live births and stillbirths.Main outcome measures Observed number of cases of Down''s syndrome among siblings of probands with a neural tube defect or hydrocephalus and number expected on the basis of maternal age; observed number of cases of neural tube defects or hydrocephalus among siblings of probands with Down''s syndrome and number expected according to the prevalence in the same population.Results Five cases of Down''s syndrome occurred among 5404 pregnancies previous to a case of neural tube defect or hydrocephalus, compared with 5.13 expected after adjustment by maternal age. Twelve cases of neural tube defect or hydrocephalus occurred among 8066 pregnancies previous to a case of Down''s syndrome, compared with 17.18 expected on the basis of the birth prevalence for neural tube defects plus hydrocephalus in the same population.Conclusion No association occurred between families at risk of neural tube defects and those at risk of Down''s syndrome.     

Congenital dyserythropoietic anemia type I: report of a pair of siblings in Japan.

This is the first case of two siblings with congenital dyserythrobpoietic anemia (CDA) type I to be reported from a Japanese family. Both of these cases showed characteristic morphological aberration of erythroid precursors, ineffective erythropoiesis, and negative acidified serum test. The ultrastructural study of erythroblasts also revealed characteristics quite compatible with CDA type I.     

Mortality and survival for Down syndrome in Japan.

Mortality and survival data for 1,052 Japanese patients with Down syndrome who were born between 1966 and 1975 were analyzed. The survival rate at age 10 was estimated to be about 86%. Mortality in each age group for Down syndrome was elevated over that of the general population. In the survival rate at age 10, there was no significant difference between males and females, but the difference between cases with and without congenital heart disease was highly significant. Using data from this study-for mortality up to age 10-and from the study of institutionalized cases for mortality over age 10, a hypothetical life table was constructed; it shows that the life expectancy at birth for cases with Down syndrome is nearly 50 years.     

Zur Funktion von Warnfarben: Die Reaktion junger Stare auf wespenähnlich schwarz-gelbe Attrappen

Social regulation of developmental rate of the African cichlid fish, Haplochromis bur-toni, was studied experimentally. Broods were raised under three different social conditions: total isolation, with no visual, physical or chemical contact with siblings; physical isolation, with no physical or chemical contact with siblings; and in social groups. Development of behavior and color patterns were observed in fish from 2 to 14 weeks of age. Males were sacrificed at 4-week intervals to measure growth and maturation state. Results showed that developmental rate is influenced by the social environment. Males with no territories (raised in groups) grew and matured more slowly than those in all other conditions. These males were not prevented from maturing but both the rate and phenotypic expression of maturation were inhibited.     

Familial Fibrocystic Pulmonary Dysplasia: A Detailed Family Study

Six cases of familial fibrocystic pulmonary dysplasia are described involving five siblings and their father. The clinical findings and radiological features were similar in all six patients although there was some variation in the period of survival following the onset of the disease. In three the diagnosis was confirmed pathologically; the two brothers, who did not have lung biopsies, had disturbances in respiratory function which are considered typical of the impaired diffusion produced by interstitial fibrosis. One hundred and five members of the family were surveyed for evidence of this disease, but no further cases were discovered. Four of the patients had some elevation of their gamma globulin. Immunoelectrophoretic analysis, which was performed on three of the patients, the two healthy siblings, and 16 of their offspring, showed elevated immunoglobulin patterns. This evidence suggests the possibility of an inherited aberration in the immune response in this family.     

46XY siblings with inadequate virilization and CNS deficiency

Familial expression of inadequate virilization of 46XY siblings is often reported as an isolated anomaly. We recently evaluated two families with 2 siblings who had a 46XY karyotype, ambiguous genitalia or micropenis, facial anomalies and mental retardation. There is no evidence of gonadotropin deficiency, defects of steroidogenesis, or androgen insensitivity. While there was a testosterone response to human chorionic gonadotropin stimulation in all 3 tested, gonadotropin levels were elevated in 2 of the infants suggestive of faulty seminiferous tubules, 1 of whom later had elevated luteinizing hormone levels. These kindreds may represent a new syndrome with either an X-linked recessive or sex-limited autosomal dominant form of inheritance, with partial testicular failure, multiple congenital anomalies, and mental retardation.     

Smoking during pregnancy and congenital limb deficiency.

OBJECTIVE--To examine genetic and environmental factors in the origin of isolated congenital limb deficiencies. DESIGN--Case-control study with questionnaire at a family interview of cases of isolated congenital limb deficiencies (six types), negative controls (matched for age, sex, and place of residence), and positive controls (cases of sentinel anomalies). SETTING--The database of the Hungarian Congenital Abnormality Registry, 1975-84, complemented by three other sources of ascertainment (1,575,904 births). SUBJECTS--537 case-control pairs; 392 positive controls. MAIN OUTCOME MEASURES--Smoking during pregnancy, congenital limb deficiencies. RESULTS--The adjusted rate of smoking during pregnancy was significantly higher in the mothers of cases of terminal transverse defect (relative odds 1.48; 95% confidence interval 0.98 to 2.23; P = 0.017). This finding supports the hypothesis of vascular disruption as a cause of congenital limb deficiency. CONCLUSIONS--Maternal smoking during pregnancy raises the relative odds for terminal transverse limb deficiencies.     

The Effects of Birth Order and Birth Interval on the Phenotypic Expression of Autism Spectrum Disorder

A rise in the prevalence of diagnosed cases of autism spectrum disorder (ASD) has been reported in several studies in recent years. While this rise in ASD prevalence is at least partially related to increased awareness and broadened diagnostic criteria, the role of environmental factors cannot be ruled out, especially considering that the cause of most cases of ASD remains unknown. The study of families with multiple affected children can provide clues about ASD etiology. While the majority of research on ASD multiplex families has focused on identifying genetic anomalies that may underlie the disorder, the study of symptom severity across ASD birth order may provide evidence for environmental factors in ASD. We compared social and cognitive measures of behavior between over 300 first and second affected siblings within multiplex autism families obtained from the Autism Genetic Resource Exchange dataset. Measures included nonverbal IQ assessed with the Ravens Colored Progressive Matrices, verbal IQ assessed with the Peabody Picture Vocabulary Test, and autism severity assessed with the Social Responsiveness Scale (SRS), an instrument established as a quantitative measure of autism. The results indicated that females were more severely impacted by ASD than males, especially first affected siblings. When first and second affected siblings were compared, significant declines in nonverbal and verbal IQ scores were observed. In addition, SRS results demonstrated a significant increase in autism severity between first and second affected siblings consistent with an overall decline in function as indicated by the IQ data. These results remained significant after controlling for the age and sex of the siblings. Surprisingly, the SRS scores were found to only be significant when the age difference between siblings was less than 2 years. These results suggest that some cases of ASD are influenced by a dosage effect involving unknown epigenetic, environmental, and/or immunological factors.     

A Novel Familial Mutation in the PCSK1 Gene That Alters the Oxyanion Hole Residue of Proprotein Convertase 1/3 and Impairs Its Enzymatic Activity

Four siblings presented with congenital diarrhea and various endocrinopathies. Exome sequencing and homozygosity mapping identified five regions, comprising 337 protein-coding genes that were shared by three affected siblings. Exome sequencing identified a novel homozygous N309K mutation in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene, encoding the neuroendocrine convertase 1 precursor (PC1/3) which was recently reported as a cause of Congenital Diarrhea Disorder (CDD). The PCSK1 mutation affected the oxyanion hole transition state-stabilizing amino acid within the active site, which is critical for appropriate proprotein maturation and enzyme activity. Unexpectedly, the N309K mutant protein exhibited normal, though slowed, prodomain removal and was secreted from both HEK293 and Neuro2A cells. However, the secreted enzyme showed no catalytic activity, and was not processed into the 66 kDa form. We conclude that the N309K enzyme is able to cleave its own propeptide but is catalytically inert against in trans substrates, and that this variant accounts for the enteric and systemic endocrinopathies seen in this large consanguineous kindred.     

Evidence implicating heterozygous deletion of chromosome 7 in the pathogenesis of familial leukemia associated with monosomy 7.

Complete or partial monosomy 7 is a recurring cytogenetic abnormality in acute myelogenous leukemia (AML) and myeloproliferative syndromes (MPS) and is particularly common in patients with Fanconi's anemia and in secondary AML. A familial form of monosomy 7 has been recognized in which two or more siblings develop MPS or AML before age 20. We tested the hypothesis that a recessive cancer susceptibility locus on chromosome 7 was important in the pathogenesis of leukemia in familial monosomy 7 by determining the parental origins of the chromosome 7 retained in the bone marrows of three pairs of affected siblings. We found no overlapping region where all three pairs retained DNA derived from the same paternal or maternal chromosome. These data suggest that inactivation of a single allele of a putative tumor-suppressor gene may be sufficient to contribute to leukemic transformation in familial monosomy 7.     

Molecular genetic evidence of clinical heterogeneity in Fukuyama-type congenital muscular dystrophy

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive severe muscular dystrophy associated with brain malformation. The gene responsible for FCMD was mapped to chromosome 9q31, a region in which convincing evidence of strong linkage disequilibrium between FCMD and mfd220 (D9S306) was recently found. FCMD is also characterized clinically by a peak motor function which, at best, allows patients to sit unassisted or slide on the buttocks. However, a small fraction of patients acquire the capacity to walk unassisted. Whether such ambulant cases belong to the FCMD spectrum or to a different disease entity has been a topic of considerable debate. We performed linkage analysis for ten families with ambulant cases using DNA markers flanking the FCMD locus. The mfd220 locus yielded a significant lod score of 3.09 for ambulant FCMD. We also found evidence for linkage disequilibrium between ambulant FCMD and mfd220. We further conducted haplotype analysis in FCMD siblings with different phenotypes, one of whom was ambulant while the other was not. The results indicate that the FCMD siblings share exactly the same haplotype at nine marker loci spanning 23.3 cM surrounding the FCMD locus. On the basis of these results, we conclude that, genetically, ambulant cases are, in fact, part of the FCMD spectrum. Received: 28 June 1996     

Studies on familial hypotransferrinemia: unique clinical course and molecular pathology.

Some unsolved problems--late onset of anemia and growth retardation (at age 7 years), healthy siblings showing very low transferrin (TF) level, and unexplained mode of inheritance--were found in family members of a congenital atransferrinemia already reported in 1972. The long-term clinical, laboratory, and developmental observations revealed that after 5 years of apo-TF supplementary therapy the patient's anemia gradually disappeared, and he started to grow again without further therapy. Immunoelectrophoretic study disclosed a severe deficiency of both TF and haptoglobin in the patient. The recovery from his anemia and the resumption of his physical development were dependent only on his TF level: that is, from a negligible level it increased to 10-20 mg/dl (normal, 205-370 mg/dl), a level similar to that of his TF-deficient siblings, who had been in good health since birth. The TF analysis of the patient and his family suggests that the minimum TF requisite in this family may be close to 10-20 mg/dl; subjects with more than 20 mg/dl are apparently healthy; with less than 10 mg/dl they may develop severe growth retardation and anemia, and extreme deficiency may be lethal. Also, coexisting haptoglobin deficiency might alleviate hemosiderosis. Further, the isoelectric focusing study disclosed that there was only a small amount of TF variant in these siblings including the patient. The study of the family confirmed that this variant was produced by an allelic gene derived from their father. So, the original diagnosis of congenital atransferrinemia should be revised as familial hypotransferrinemia transmitted with autosomal recessive mode, and the subjects with a recessive character may be compound heterozygotes of the "variant" allele and the "null" allele.     

Thyroglobulin and microsomal antibodies in patients with insulin dependent diabetes mellitus and their relatives.

The sera for 88 parents and 9 siblings of 73 patients with insulin dependent diabetes mellitus in childhood and 437 controls matched in age and sex, were tested by the thyroglobulin and microsome-coated tanned red cell hemagglutination test (Fuji-Zoki Co. Tokyo). None of 73 children with diabetes mellitus had antithyroglobulin antibodies, whereas twelve (16.4%) had antimicrosomal antibodies compared with the incidence of 0.4% and 1.1%, respectively, in 437 controls. In the parents and siblings of these probands, thyroid antibodies were also found in increased incidence. The incidence of antimicrosomal antibodies in the 68 mothers was significantly higher than in controls matched for age and sex, but the incidence of the positive thyroid antibodies in the 20 fathers and 9 siblings was not significantly different from that in control populations. The incidence of thyroid antibodies tended to be higher, though not significant, in parents and siblings of diabetic children with positive thyroid antibodies than in those of diabetics with negative ones. These findings suggest that immunogenetic factors may be responsible for the pathogenesis of some cases of diabetes mellitus in childhood.     

Nestmate Recognition in Leptothoracine Ants: Testing Fielde's Progressive Odor Hypothesis

Fielde's progressive odor hypothesis postulates that certain hereditary nestmate recognition odors in adult ants change progressively with age such that workers will often not accept older siblings that differ from them in age by as little as 40–60 days unless they eclosed among siblings of that age class and learned their recognition cues. Fielde's hypothesis was based on extensive but unsystematic experimental studies which fail to provide unequivocal evidence for this phenomenon. The present study tested this hypothesis for three closely-related ant species, Leptothorax ambiguus, L. curvispinosus, and L. longispinosus, by introducing workers between groups with known age structures and a minimum age difference of eight months. The results invalidate Fielde's hypothesis for these ants. However, progressive odors may yet be found in other species and may be associated with age polyethism.     

Geographic and social factors that affect the age of puberty

1866 girls aged 11-15 1/2 years in Northwest Slovakia were interviewed at their schools concerning the age at menarche, number of siblings, and altitude of their residence. 518 of the girls had undergone menarche. An angular transformation of the data was carried out, and an analysis of the variance of percentages of young girls who had attained puberty was performed. An increase in the number of girls attaining puberty with age was observed as expected, but decreases in the proportion attaining puberty at a given age corresponding with an increase in the number of siblings or of altitude were also observed. The age f pubety for those with 0-1 siblings was 14.32 years; for each additional 2 siblings, it increased by about .105 years, or about 5 weeks. The average age of puberty for girls whose homes were located at 450 m above sea level or less was 14.19 years, with each additional 100 meters of altitude adding about .253 years, or 3 months, to the age at menarche. The effects of both altitude and number of siblings were statistically significant.