The risk of having a second retarded child

We have studied segregation ratios in 282 Israeli families with normal, nonconsanguineous parents and retarded offspring without specific etiologic diagnosis. Severity of retardation and nature of medical history significantly affected recurrence risk, while sex of propositus and sibs and presence or absence of epilepsy, cerebral palsy, microcephaly, and short stature did not. Segregation rations were 0.095 in cases of severe retardation with normal medical history, 0.216 for mild retardation with normal medical history, 0.230 in cases of all retardation with maternal reproductive inefficiency, and 0.110 for all retardation with other reported prenatal, perinatal, or infantile complications. Estimated recurrence risks in most simplex families dropped sharply with each additional normal child. The recurrence risks are higher than some previously published estimates. Different ascertainment criteria may be responsible for this variation. The criteria used here were compatible with a 3.2% population prevalence of mental retardation with a 0.223 segregation ratio in multiplex sibships. It is recommended that future studies of recurrence risks include similar data permitting evaluation of sensitivity of ascertainment criteria.     

Liver histology in the arthrogryposis multiplex congenita, renal dysfunction, and cholestasis (ARC) syndrome: report of three new cases and review.

We report three cases from two unrelated families of infants with arthrogryposis multiplex congenita, cholestatic jaundice, and renal Fanconi's syndrome. In both families the parents were consanguineous. All three children died by 7 months of age. This association was first reported in 1973 by Lutz-Richner and Landolt and again in another family by Nezelof et al in 1979. However, because of differing liver histology the two sibships were considered to have two separate conditions. Based on the histological findings in one of our cases we propose that all cases described so far represent variation within a single syndrome.     

328例非特异性精神发育迟滞的隐性基因分析

采用分离分析和血缘分析方法，对山东省遗传病调查中发现的３２８个父母双方均正常的中、重度非特异性精神发育迟滞（ＮＳＭＲ）家系进行了分析。结果表明，多发家庭先证者的平均近婚系数显著高于一般群体，分离比接近０．２５。提示隐性基因在中、重度ＮＳＭＲ发生中起一定作用。在重度ＮＳＭＲ，散发病例占４０．７％，Ｘ连锁隐性遗传占９．１２％，常染色体隐性遗传占５０．１８％。常染色体隐性基因位点数的最小估计值为２４，各位点的平均基因频率为０．００３５，携带者总频率为１７．５４％；在中度ＮＳＭＲ，散发病例占６１．５％，Ｘ连锁隐性遗传占１１．５３％，常染色体隐性遗传占２６．９７％，常染色体隐性基因位点数的最小估计值为１３２，各位点的平均基因频率为０．００２１，携带者总额率为５４．９５％。     

Level of functioning of siblings and parents of probands of varying degrees of retardation

A further analysis of already published data supports the position that retardates of low ability level less frequently have retarded siblings, retarded parents, and parents low in occupational level than do retardates higher in ability level. The analysis supports the position that there are two types of retarded individuals, persons retarded as a result of gene or chromosomal anomalies, brain injury, etc., who more frequently occur in the lower-level retardate group, and persons whose retardation represents polygenic segregation, who more frequently occur in the higher-level group.     

Recurrence risks and prognosis in severe sporadic osteogenesis imperfecta.

A study was carried out in the United Kingdom of patients with severe osteogenesis imperfecta (OI), born with fractures to normal parents, in order to determine recurrence risks. A total of 105 cases from 98 families survived the perinatal period and 60 cases from 57 families were stillborn or died during the first week of life. The majority of the perinatal survivors correspond to the overlapping group of Sillence type III and sporadic type IV OI. In 40 of these, the radiograph at birth was available and in 37 it showed a characteristic appearance similar to that described previously for type III OI. The other three cases had radiological type IIB OI at birth and died before 26 months of age. The patients with perinatally lethal OI were subdivided on radiological appearance into Sillence type IIA (30 cases, described in the previous paper), type IIB (12 cases from 11 families), and type IIC (three cases from three families), and in five cases from three families the radiological appearance was the same as that of the 37 perinatal survivors described above. Ten cases from 10 families were not classified because their radiographs were unavailable. To analyse the empirical recurrence risks, patients were grouped according to radiological appearance at birth. Those with a type III-like pattern numbered 42 cases and they were grouped with the other cases of severe deforming OI who survived the perinatal period, for whom no x ray at birth was available, making a total of 107 cases. Taking one affected child per family as the proband, there were 98 probands. They had 146 sibs, of whom 10 were affected, giving an empirical recurrence risk of 6.9%. This is consistent with the disease arising as a new dominant mutation in about three quarters of families and as a recessive in about one quarter in this heterogeneous group. It is reasonable to give a recurrence risk of up to 25% in cases with parental consanguinity and a risk of 4.4% in cases with unrelated parents. Fifteen patients (14 probands) with Sillence type IIB OI had 13 sibs, one affected, giving an empirical recurrence risk of 7.7%. The parents were consanguineous in three families and the evidence for autosomal recessive inheritance for the majority in this group is probably stronger. The three patients with type IIC OI had three healthy sibs and the 10 unclassifiable perinatally lethal cases had 22 sibs, all normal. The radiological appearance at birth predicts prognosis to some extent; essentially, the better the bone morphology and mineralisation the longer the survival.     

Fragile X syndrome screening of families with consanguineous and non-consanguineous parents in the Iranian population

Fragile X syndrome is the most common form of inherited mental retardation (MR). It is caused by the expansion of CGG triplet repeats in the fragile X mental retardation 1 (FMR1) gene. In mentally retarded males, the frequency of fragile X syndrome is approximately 2–3 percent, but little is known about its proportion in mentally retarded patients from countries where parental consanguinity is common.The objective of this study was to estimate the frequency of fragile X syndrome (FXS) in mentally retarded patients from Iran. We examined a total of 508 families with MR that had been referred to the Genetics Research Center (GRC) in Tehran of which 467 families had at least two mentally retarded children. In 384 families, the parents were related and in 124 they were not related of which most of them had putative or established X-linked inheritance pattern. Full FMR1 mutations were found in 32 of the 508 families studied (6.3%), in 19 out of 124 families with apparently unrelated parents (15.3%), and in 13 of the 384 consanguineous families (3.4%). Thus, in Iran, the relative frequency of FXS seems to be high, and in patients with unrelated parents is much higher. We also show that even in families with consanguineous parents, FXS has to be ruled out before assuming that familial MR is due to autosomal recessive gene defects. Molecular studies are in progress to explain the high proportion of FMR1 mutations in mentally retarded offspring of unrelated Iranian parents.     

小学儿童父母体罚的基本特点

目的:考察我国小学儿童遭受父母体罚的基本特点。方法:采用Straus编制的亲子冲突解决策略量表测查938名小学儿童的父母。结果:63.2%的小学儿童父母在近半年内对孩子实施过体罚,实施体罚的平均次数约为8次;我国父母使用最普遍的体罚方式依次是用手打孩子的屁股,打孩子的手、胳膊或腿,打孩子的脸、头或揪孩子的耳朵,体罚孩子最多的身体部位依次为屁股,手和胳膊;父母对男孩实施轻度体罚和严厉体罚的普遍性及实施严厉体罚的频繁性均显著均高于女孩;父母对一、二、三年级儿童实施轻度体罚和严厉体罚的普遍性显著高于对四、五、六年级儿童的体罚;低中社经地位家庭中的父母对儿童实施轻度体罚和严厉体罚的普遍性及实施严厉体罚的频繁性均显著高于高社经地位家庭的父母。结论:在我国,父母体罚的普遍性和频繁性均较高,且其发生情况与儿童的性别,年龄和家庭的社经地位有关。     

Overgrowth and trisomy 15q26.1-qter including the IGF1 receptor gene: report of two families and review of the literature

Overgrowth is rarely associated with chromosomal imbalances. Here we report on four children from two unrelated families presenting with overgrowth and a terminal duplication of the long arm of chromosome 15 diagnosed using cytogenetic and FISH studies. In both cases, chromosome analysis of the parents showed a balanced translocation involving 15q26.1-qter. Molecular and cytogenetic studies showed three copies of the insulin-like growth factor 1 receptor (IGF1R) gene. This finding suggests that overgrowth observed in our patients might be causally related to a dosage effect of the IGF1R gene, in contrast to severe growth retardation observed in patients with terminal deletion of 15q. The present observation emphasises the importance of chromosome analysis in patients with overgrowth and mental retardation. Moreover, it further delineates a specific phenotype related to trisomy 15q26.1-qter with macrosomia at birth, overgrowth, macrocephaly and mild developmental delay being the major clinical features.     

An immunodeficiency disease with RAG mutations and granulomas

We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein-Barr virus (EBV). Other findings were hypogammaglobulinemia, a diminished number of T and B cells, and sparse thymic tissue on ultrasonography. Molecular analysis revealed that the patients were compound heterozygotes for mutations in recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygous carriers of a RAG mutation. The mutations were associated with reduced function of RAG in vitro (3 to 30% of normal activity). The parents and one sibling in the three families were healthy.     

Prenatal diagnosis of Fukuyama-type congenital muscular dystrophy by microsatellite analysis

We applied microsatellite analysis to prenatal diagnosis of Fukuyama- type congenital muscular dystrophy (FCMD), an autosomal recessive severe muscular dystrophy associated with brain malformations. Recent identification of the FCMD gene locus at 9q31-q33 provided the basis for prenatal diagnosis and carrier detection. We recently developed new microsatellite markers which are closer to the FCMD gene and improved the phenotype probability. Nine fetuses in eight unrelated FCMD families, including a twin pregnancy, were analysed using the newly developed markers. Four fetuses showed over 99% probability of being healthy either as normal homozygote (n = 1) or heterozygote carrier (n = 3) and were born without signs of FCMD. The other five fetuses were diagnosed with a probability of FCMD of 99% or greater; all of the latter parents decided to terminate the pregnancies. Brain malformations characteristic of FCMD in one of the aborted fetuses confirmed the diagnosis of FCMD at 19 weeks of gestation.      

Hunter disease (mucopolysaccharidosis type II) in a karyotypically normal girl

A female child of healthy, unrelated parents presented at 12 months of age with a history of moderately severe developmental delay, macrocephaly, dysmorphic facies, hypotonia, hepato-splenomegaly, mild generalized dysostosis multiplex, mucopolysacchariduria (dermatan and heparan sulfates), and Alder-Reilly bodies in peripheral blood leukocytes. Iduronate sulfatase activity in plasma was markedly depressed: 0.11 units/ml/h (normal, 1.75 ±0.56, N = 6). Analyses of arylsulfatases A, B, and C, heparan N-sulfatase, α-mannosidase, β-mannosidase, β-glucuronidase, β-hexosaminidase, β-galactosidase, and α-fucosidase activities in plasma, leukocytes, and/or cultured skin fibroblasts were all normal. Urinary sulfatide excretion was also within normal limits. Karyotypes of peripheral blood leukocytes and cultured skin fibroblasts were normal. Serum iduronate sulfatase activities in the parents were in the normal range (father, 1.63 units/ml/h; mother, 1.25 units/ml/h). The results of analyses of restriction fragment length polymorphisms (RFLP) of DNA from cultured skin fibroblasts with the use of probes for loci extending from Xpter to Xq28 showed X chromosome heterozygosity and confirmed the paternal origin of one of the X chromosomes. Studies on sulfur-35 uptake in mixed fibroblast cultures showed cross-correction of [³⁵S]-glycosaminoglycan accumulation between cells from the patient and normal cells or cells from a patient with Hurler disease; however, there was no cross-correction between cells from the patient and those from boys affected with classical Hunter disease. This represents only the second confirmed case of Hunter disease reported in a karyotypically normal girl.     

Urofacial (ochoa) syndrome

Between 1965 and 1986 we saw 36 children with enuresis and urinary tract infection in association with "inversion" of facial expression when laughing. Urologic work-up of these patients disclosed characteristic findings of mild neuropathic bladder in all cases, with severe urinary tract damage in most of them. The clear association of distortion in facial expression and neuropathic bladder with resultant damage to the genitourinary tract should prompt urological evaluation of individuals with "inversion" of facial expression. About two thirds of the patients also had moderate to severe constipation. We suggest the term urofacial syndrome for this disorder. The occurrence of the disorder in multiple sibs, normal parents, increased parental consanguinity, and equal sex ratio indicate autosomal recessive inheritance.     

A national survey about parent awareness of the risk of severe brain injury from playing football

A survey was conducted to determine the level of awareness among parents of high school football players about the risk of severe brain injury. A national sample of 1007 randomly selected households was interviewed by telephone during February, 1992. All interviewees were parents of high school football players who either were currently playing football or had played within the previous 5 years. Survey questions measured the extent to which parents were aware both of the risks associated with playing high school football and the existing helmet warnings about those risks. Overall, the survey results demonstrated that parents of high school football players were uninformed about both the risk of severe brain injury from playing high school football and the football helmet warnings about that risk. Specifically, unprompted, most parents mentioned broken bones, knee injuries, sprains, or shoulder injuries as hazards associated with playing football. Few parents mentioned severe brain damage, even when prompted. Further, the overwhelming majority of parents incorrectly believed that wearing a football helmet generally eliminated the risk of severe brain injury. Very few parents had received information from any source about the risks of head injury or had heard that no football helmet can provide complete protection against this hazard. Few parents were aware of the warning label on the helmet or knew what the label said, even when prompted. In short, parents were unaware of the risk of severe brain damage, misinformed about a football helmet's ability to protect against this risk, and uninformed about the football helmet warning label about this risk.     

Estimated Frequency of Genetic and Nongenetic Causes of Congenital Idiopathic Cerebral Palsy in West Sweden

Mathematical analysis of prenatal and perinatal risk factors was performed on the first 681 published cases of idiopathic congenital cerebral palsy (born 1959–1970) in the west Swedish population‐based cerebral palsy (CP) study. Analysis indicates that an estimated 40% of etiologically undiagnosed cases of CP in the community (48% of those born at term and 24% of those born prematurely) are genetically caused. These proportions of genetic causation are no less in CP than in idiopathic mental retardation. Genetic causes account for 60% of maturely born hemiplegics, 45% of maturely born spastic diplegics, 32% of premature spastic diplegics and virtually all cases of pure ataxia. About 23% of CP cases in the community have suffered nongenetic brain damage in accordance with the two‐stage model. The residue of 37% is characterized by a single risk factor, usually perinatal.     

The c.3040C > T mutation in <Emphasis Type="Italic">COL1A1</Emphasis> is recurrent in Korean patients with infantile cortical hyperostosis (Caffey disease)

Infantile cortical hyperostosis (ICH) is characterized by spontaneous episodes of subperiosteal new bone formation in the long bones, mandible, and clavicle during infancy. A heterozygous missense mutation, c.3040C > T (p.R1014C), in the type I collagen α1 chain gene (COL1A1) was reported in families with the autosomal dominant form of ICH. We examined six consecutive cases of ICH from five unrelated families and their parents. The mutation was identified in all patients and two parents tested. Our result supported that ICH is caused by the single mutation in COL1A1 with incomplete penetrance.     

Elevated Epstein-Barr virus seroreactivity among unaffected members of families with nasopharyngeal carcinoma

Serum antibodies to Epstein–Barr virus (EBV) antigens can be used to predict the risk of nasopharyngeal carcinoma (NPC). To investigate whether EBV seropositivity rates were higher among healthy family members from multiplex and sporadic families with NPC (i.e., families with multiple or single cases) compared to the general population, a study was conducted on 2,665 unaffected individuals from 140 multiplex and 413 sporadic families. The titers of the IgA antibody to the EBV capsid antigen (VCA‐IgA) were compared to those of 904 controls from the general population. The VCA‐IgA titer was correlated among sibling pairs to a high significance in both family types (P < 0.0001 and P = 0.0005 for the multiplex and the sporadic families, respectively); parent–offspring pairs also showed significant correlation (P < 0.0001 and P = 0.0002, respectively); and spouse pairs were correlated, but at lower significance levels (P = 0.0790 and P = 0.0040, respectively). When compared to the controls, among first‐degree relatives in the multiplex families, the age‐ and gender‐adjusted odds ratio (OR) was 2.06 (95% confidence interval 1.56–2.71), 3.55 (2.24–5.64), and 2.25 (1.57–3.23) for siblings, parents, and children, respectively. In the sporadic families, the adjusted OR was 1.55 (1.21–2.00) and 2.08 (1.51–2.86) for siblings and parents, respectively. The adjusted P‐value of spouses lost significance in the multiplex families, but remained significant in the sporadic families (P = 0.0146). In conclusion, EBV seropositivity rates were elevated among unaffected family members in both multiplex and sporadic families with NPC. J. Med. Virol. 83:1792–1798, 2011. © 2011 Wiley‐Liss, Inc.     

急性毒鼠强中毒的脑电图分析

目的:探讨急性毒鼠强中毒时脑电图的变化及与临床的关系。方法:对13例急性毒鼠强中毒的脑电图进行回顾性分析及随访。结果:13例患者中正常范围内脑电图1例,轻度异常脑电图2例,均为轻度中毒患者。这2例患者的脑电图在一周后复查时恢复正常范围。5例中度异常脑电图均为中度中毒患者,在一周后复查时4例脑波恢复α波,但仍有较多量的θ波,复型慢波及阵发性尖波消失。另1例为6-7Hz的θ波,并仍有少量的复型慢波及阵发性尖波。5例重度异常脑电图其中4例为重度中毒患者,1例为中度中毒患者。第一次复查时脑波虽有改善但仍可见复型慢波及阵发性高幅尖波。这10例中一重度异常脑电图的患者在3月后第二次复查时,其中8例脑电图恢复正常范围,另2例脑波虽恢复到8-9Hz的α波,但仍有较多量的θ波及少量的复型慢波,阵发性尖波消失。结论:毒鼠强中毒患者脑电图的异常程度与中毒程度及临床症状相一致。其动态变化可反映病情的转归。提示脑电图检查可反映脑损害的程度,可为临床诊断,预后,评估提供依据。     

Recurrent deletions and reciprocal duplications of 10q11.21q11.23 including CHAT and SLC18A3 are likely mediated by complex low-copy repeats

We report 24 unrelated individuals with deletions and 17 additional cases with duplications at 10q11.21q21.1 identified by chromosomal microarray analysis. The rearrangements range in size from 0.3 to 12 Mb. Nineteen of the deletions and eight duplications are flanked by large, directly oriented segmental duplications of >98% sequence identity, suggesting that nonallelic homologous recombination (NAHR) caused these genomic rearrangements. Nine individuals with deletions and five with duplications have additional copy number changes. Detailed clinical evaluation of 20 patients with deletions revealed variable clinical features, with developmental delay (DD) and/or intellectual disability (ID) as the only features common to a majority of individuals. We suggest that some of the other features present in more than one patient with deletion, including hypotonia, sleep apnea, chronic constipation, gastroesophageal and vesicoureteral refluxes, epilepsy, ataxia, dysphagia, nystagmus, and ptosis may result from deletion of the CHAT gene, encoding choline acetyltransferase, and the SLC18A3 gene, mapping in the first intron of CHAT and encoding vesicular acetylcholine transporter. The phenotypic diversity and presence of the deletion in apparently normal carrier parents suggest that subjects carrying 10q11.21q11.23 deletions may exhibit variable phenotypic expressivity and incomplete penetrance influenced by additional genetic and nongenetic modifiers.