Familial lipomyelomeningocele: a further report

Lipomyelomeningocele is a form of spina bifida occulta with a distinct pathogenesis that differentiates it from open neural tube defects. Familial forms are rare and the condition may be polygenic. We report on 2 affected siblings with similar lesions and raise the possibility of an autosomal recessive pattern of inheritance with implications for genetic counselling.     

Spinal dysraphia as an autosomal dominant defect in four families

Four families were selected randomly on the basis of the occurrence of spina bifida cystica and/or spina bifida occulta in one or more family members. Sixty-three relatives were studied clinically and roentgenologically; their roentgenograms were evaluated blindly. Twenty-eight were clinically and roentgenologically normal; 35 were diagnosed as having spina bifida occulta (SBO), spina bifida cystica (SBC), vertebral anomalies, and/or external defects usually interpreted as evidence for SBO. Excluding one proband we found the frequency of SBO to be 19/51 (37%) and the frequency of all types of spinal/vertebral defects (excluding five probands) to be 30/58 (52%). The distribution of these defects in the four families was analyzed using likelihood methods corrected for random ascertainment. The log likelihood values for sporadic, recessive, and dominant models were ?26.69, ?20.95, and ?18.90, respectively, indicating a higher likelihood of autosomal dominant inheritance than sporadic occurrence or recessive inheritance. The penetrance probability in this dominant model, estimated by maximum likelihood, is 0.749 ± 0.100. Further examination of these data suggests that SBO and SBC represent different expressions of the same dominant gene in these kindreds.     

Radiographic method to assess the prevalence of sacral spina bifida occulta

Spina bifida occulta of the sacrum is the most common type of spinal deformity. Many authors have published data on the frequency of spina bifida occulta, with varying results. Some possible reasons for this variability could include the differing methods used to gather data and differing ways of classifying the condition. This study attempts to develop an X-ray method to study sacral spina bifida occulta in a standardized fashion, using an angulated antero-posterior technique. This technique is then used to estimate the frequency of sacral spina bifida occulta in an Australian sample. The sacra of 53 cadavers were X-rayed and the level of closure of the sacral spinal canal recorded. The X-ray technique was validated by open dissection of six of the cadavers studied and was shown to be accurate to half a sacral segment. No sacra with a completely open sacral canal were found, two sacra (4%) were open from S2 down to S5 and ten sacra (19%) were open from S3 down to S5. The most common condition (43%) recorded was where S4 and S5 only were open. Eighteen cadavers (34%) showed only S5 open, and interestingly, no sacra were recorded as having the dorsal sacral arch completely closed. A study of a larger sample will follow using the validated X-ray technique.     

Split-cord malformation in a girl with Angelman syndrome: a mere coincidence?

We present a case of a girl with both Angelman syndrome and split-cord malformation. The child was initially referred at the age of 2.5 years, for developmental delay and a possible diagnosis of spina bifida occulta, based on the presence of a hair tuft located on the midline of the lumbar area. Magnetic resonance imaging of the spine showed split-cord malformation below L1, whereas a cytogenetically detected deletion of chromosome bands 15q11-q13 (SNRPN) confirmed the clinical diagnosis of Angelman syndrome. Split-cord malformation or diastematomyelia is a rare form of spina bifida occulta that occurs sporadically and is not particularly related to specific syndromes. Hair patches or other distinctive cutaneous stigmata such as those seen in the present case have not, to our knowledge, been reported in other patients with Angelman syndrome; therefore, the association of Angelman syndrome and split-cord malformation in this child is probably coincidental. Spinal cord abnormalities have not been consistently reported in patients with Angelman syndrome; only one adult patient with Angelman syndrome and spina bifida occulta has been reported, and this association was probably considered fortuitous. However, some relatively uncommon clinical features such as deterioration of gait, lower limb malformations, and bladder dysfunction, particularly as the patients age, although nonspecific, are reminiscent of such a cause. We therefore urge clinicians to look for cutaneous stigmata along the spine and consider the evaluation of the spinal cord in children with apparent paraparesis, out of proportion to that usually seen in Angelman syndrome, should our case report not just be a coincidental observation.     

Familial occurrence of lumbar spondylolysis and spondylolisthesis

In a Finnish kindred consisting of 192 descendants from two marriages of a male ancestor born in 1868, the lumbar spines of 105 of the 170 living members were X-rayed. Spondylolysis was found in 22 individuals. In addition, six of them had spondylolisthesis, four had spina bifida occulta, and two had a transitional lumbar/sacral vertebra. Seven members of the kindred without spondylolysis had spina bifida occulta and 10 had transitional lumbar vertebrae.
The pedigree is consistent with autosomal dominant inheritance and incomplete (about 75 %) penetrance for spondylolysis. It raises the question of a common aetiology for several congenital disturbances in the formation of lumbar vertebrae and possibly supports the concept of a variable expressivity of a "spondylolysis gene".     

A five-generation family with sacral agenesis and spina bifida: possible similarities with the mouse T-locus

In man, a malformation that recalls some of the defects associated with T/t mutants in the mouse is sacral agenesis. We report on a family with a high incidence of sacral malformation, ranging from a complete absence of the sacrum (SA), with or without spina bifida aperta, to a spina bifida occulta (SBO) that could only be detected by x-ray. The condition appeared in a man with four children who were all affect, and thereafter, to varying degrees, in 17 of his 28 descendants. Segregation analysis has been performed in this family, using the Elston and Stewart transmission probability model [1971]. The two traits (SA and SBO) were first studied separated and then together. A fully penetrant major dominant gene is show to cause SA. When the phenotypes SA and SBO are considered together, Mendelian transmission is rejected. This could be explained genetically by two alternative hypotheses: genetic heterogeneity or a dominant major gene transmitted in excess by heterozygotes (tau Aa A = 0.896), suggesting a segregation distortion property of an allele at a T-like locus.     

Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects

It is now well recognized that periconceptional folic acid or folic acid containing multivitamin supplementation reduces the risk of neural tube defects (NTDs). Recently we were able to show that homozygosity for a thermolabile variant of the enzyme methylenetetrahydrofolate reductase is associated with an increased risk for spina bifida in patients recruited from the Dutch population. However, this genetic risk factor could not account for all folic acid preventable NTDs. In an attempt to identify additional folate related enzymes that contribute to NTD etiology we now studied the methylenetetrahydrofolate dehydrogenase gene on chromosome 14q24 which encodes a single protein with three catalytic properties important in the folate metabolism. The cDNA sequence of 38 familial and 79 sporadic patients was screened for the presence of mutations by single strand conformation polymorphism (SSCP) analysis followed by sequencing. Two amino acid substitutions were identified. The first one (R293H) was detected in a patient with familial spina bifida and not in 300 control individuals. The mutation was inherited from the unaffected maternal grandmother and was also present in two younger brothers of the index patient, one of them displaying spina bifida occulta and the other being unaffected. The second change turned out to be an amino acid polymorphism (R653Q) that was present in both patients and controls with similar frequencies. Our results so far provide no evidence for a major role of the methylenetetrahydrofolate-dehydrogenase (MTHFD) gene in NTD etiology. However, the identification of a mutation in one family suggests that this gene can act as a risk factor for human NTD.     

HLA Gene and Haplotype Frequencies in Spina Bifida. Population and Family Studies

The search for HLA association in spina bifida is particularly interesting since this condition can be associated with the effects of the T locus in mice. Gene and haplotype frequencies in 32 unrelated patients suffering from spina bifida were studied. Gene frequency of HLA—B5 and haplotype frequency of A2, B5 were increased without reaching signification levels. Fourteen families were examined clinically and radiologically. A high frequency of spina bifida occulta and other vertebral abnormalities was found without evidence of linkage with HLA haplotypes.     

Is PATCHED an important candidate gene for neural tube defects? Cranial and thoracic neural tube defects in a family with Gorlin syndrome: a case report

. The relationship of mutations in the patched gene PTCH and nevoid basal cell carcinoma (NBCC) or Gorlin syndrome is well established. Animal studies have implicated the hedgehog-patched signalling pathway in neurulation and neural tube defects (NTDs). Spina bifida occulta and bifid vertebrae are well recognized in NBCCS, but there appears to be only one report of open spina bifida. We report a father and two sons with a truncating PTCH mutation and the major features of NBCCS. One son had open thoracic spina bifida and the other had an occipital meningocoele. We believe this to be the first report of cranial NTD in NBCCS and suggest that consideration be given to including PTCH analysis in genetic association studies in NTDs as the hedgehog pathway is integral to normal human neurulation.     

Morphology of experimental spina bifida in the chick embryo.

Open malformations of the central nervous system may involve the brain or spinal cord, or both. Preliminary experiments in which a window was cut in the shell overlying early chick embryos (with removal of 2 ml of albumen) produced a range of neural and non-neural malformations. Exposure of Stage 5--10 embryos at 26 hours of incubation produced open brain and cord defects. Embryos were recovered at 11--12 days for gross examination. Open cord defects in 12 day experimental embryos could be divided morphologically into 2 types. One group showed an everted symmetrical plaque of neural tissue. In the other group the cord defect was more irregular, partly covered by skin, and often combined with rump and trunk defects. Skeletal staining showed that vertebral lesions increased in severity in a cranio-caudal sequence. Spina bifida occulta was found in the cervical and upper thoracic regions; spina bifida manifesta, associated with open cord defects, occurred from the lower thoracic to the sacral regions; vertebral deletions were almost confined to the caudal region. Spina bifida manifesta at the site of open cord defects also showed 2 distinct patterns. Regular cord defects were associated with regular spinal defects, showing loss of spinous processes, reduction of laminae and eversion of the pedicles. Irregular cord defects were associated with more irregular spinal defects showing vertebral deletions or fusions, rumplessness, and pelvic reduction. Neither group, however, showed local kyphosis or scoliosis. Early neurogenesis in the avian and human embryos is very similar with development of the spinal cord from neural plate and tail bud materials which fuse in an overlap zone. These experimental defects in the chick embryo, separable into regular and irregular types thus provide a useful model for investigation of the embryogenesis of spina bifida.     

OEIS complex--a population study

Using a novel method for the analysis of infants with multiple malformations, we investigated the cluster of associated malformations called the OEIS (omphalocele, bladder exstrophy, imperforate anus, spine defect) complex among 5,260 infants with multiple malformations identified in four large registers of congenital malformations, corresponding to 5.84 million births. The existence of the OEIS complex was clearly demonstrated and malformations entering it could be defined. Other than the four classical malformations, omphalocele, bladder exstrophy, imperforate anus, and spine malformation, a strong association with spina bifida and intersex was stressed. Spine malformations occurred not only in the lumbosacral level but also more cranially, and an association also with upper spina bifida could be demonstrated. No specific association with any other malformation, including cardiac defects, was apparent. The OEIS complex is an unusually clearly defined entity among the various nonrandom associations which have been described.     

OEIS complex — a population study

Using a novel method for the analysis of infants with multiple malformations, we investigated the cluster of associated malformations called the OEIS (omphalocele, bladder exstrophy, imperforate anus, spine defect) complex among 5,260 infants with multiple malformations identified in four large registers of congenital malformations, corresponding to 5.84 million births. The existence of the OEIS complex was clearly demonstrated and malformations entering it could be defined. Other than the four classical malformations, omphalocele, bladder exstrophy, imperforate anus, and spine malformation, a strong association with spina bifida and intersex was stressed. Spine malformations occurred not only in the lumbosacral level but also more cranially, and an association also with upper spina bifida could be demonstrated. No specific association with any other malformation, including cardiac defects, was apparent. The OEIS complex is an unusually clearly defined entity among the various nonrandom associations which have been described. Am. J. Med. Genet. 92:62–68, 2000. © 2000 Wiley‐Liss, Inc.     

Problem in diagnostic radiology

The case of a 58-year-old woman is described. She presented with what initially seemed to be a transient ischaemic attack. Clinical imaging, however,revealed an intracranial lipoma of the cisterna magna associated with a defect of the occipital bone and spina bifida occulta of the atlas.     

Spina bifida: a diagnostic dilemma in paleopathology

This article provides information regarding the etiology, pathogenesis, and skeletal manifestation of spina bifida or spinal dysraphisms. On the basis of a review of the medical literature, it addresses discrepancies in documentation and interpretation of spina bifida in paleopathology. Furthermore, it offers suggestions for use of universal terminology and highlights the difficulties in the specific diagnosis of dysraphisms in skeletal remains. In addition, the necessity of examining the entire skeleton for abnormalities to distinguish simple delay/failure of fusion of the posterior neural arches from other occult spinal dysraphisms is emphasized, as it is the need for stratification of the sample by age and sex when reporting frequencies of sacral spina bifida occulta.     

Sib risk of neural tube defect: is prenatal diagnosis indicated in pregnancies following the birth of a hydrocephalic child?

Recurrence frequencies of central nervous system malformations in sibs of probands with anencephalus or spina bifida range between 1% and 7%. The frequency of hydrocephalus among sibs of such probands is low (0.21%) but, nevertheless, is increased 2 to 5-fold when compared to general population frequencies. Anencephalus and spina bifida cystica were observed in 1.65% of sibs of children with hydrocephalus, a 2- to 8-fold increased over the population frequencies. These data indicate that some aetiological factors may be common to all three malformations. The risk figure of 1.65% for anencephalus and spina bifida in sibs born after the birth of a hydrocephalic proband constitutes sufficient indication for prenatal diagnosis by alphafetoprotein determination of the amniotic fluid.     

Possible causal heterogeneity in spina bifida cystica

A study was performed to determine whether causal heterogeneity can be demonstrated among the nonsyndromal spina bifida cysticas based on the vertebral level of the defect. Two groups were compared, probands with defects at or above T 11, likely representing defects of neuralization, and probands with defects at or below T 12, likely defects of canalization. Differences between the two groups were found with respect to reproductive history and occurrence of other malformations. A high degree of concordance for the type of defect among affected sib pairs was also observed. These findings indicate that there is probably heterogeneity within the spina bifida cysticas based on the level of the defect.     

The Neu-Laxova syndrome

A study was performed to determine whether causal heterogeneity can be demonstrated among the nonsyndromal spina bifida cysticas based on the vertebral level of the defect. Two groups were compared, probands with defects at or above T 11, likely representing defects of neuralization, and probands with defects at or below T 12, likely defects of canalization. Differences between the two groups were found with respect to reproductive history and occurrence of other malformations. A high degree of concordance for the type of defect among affected sib pairs was also observed. These findings indicate that there is probably heterogeneity within the spina bifida cysticas based on the level of the defect.     

Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida

The dihydrofolate reductase (DHFR) enzyme is important for folate availability, folate turnover and DNA synthesis. The 19-bp deletion in intron-1 of DHFR has been associated with the risk of having spina bifida affected offspring, supposedly by changing DHFR gene expression. A 9-bp repeat in exon 1 of the mutS homolog 3 (MSH3) gene was recently demonstrated to be also located in the 5'UTR of DHFR and may possibly affect DHFR gene expression as well. We examined the association between these DHFR variants and spina bifida risk and investigated their effect on DHFR expression. Our study population, consisting of 121 mothers of a spina bifida affected child, 109 spina bifida patients, 292 control women and 234 pediatric controls was screened for the DHFR 19-bp deletion and the DHFR 9-bp repeat. DHFR gene expression was measured in 66 spina bifida patients, using real-time PCR analysis. In this study population, the DHFR 19-bp del/del genotype was not associated with spina bifida risk in mothers and children (OR: 0.8; 95%CI: 0.4-1.5 and OR: 1.2; 95%CI: 0.6-2.2, respectively) and both the WT/del and the del/del genotype did not affect DHFR expression relative to the WT/WT genotype (relative expression=0.89, p=0.46 and relative expression=1.26, p=0.24, respectively). The DHFR 9-bp repeat was not associated with spina bifida risk in mothers and children. DHFR expression of the 6/6 allele was 73% increased compared to the 3/3 allele, although not significantly (relative expression=1.73, p=0.09). We did not find evidence for an effect of the DHFR 19-bp deletion or 9-bp repeat on spina bifida risk in mothers and children. An effect of the 6/6 repeat genotype on DHFR expression cannot be ruled out.     

Congenital malformations associated with anencephaly and iniencephaly.

The necropsy reports of 294 cases of anencephaly and 50 cases of iniencephaly have been examined, and a tubulated list of associated malformations produced. Cases were divided by sex and the presence or absence of spina bifida. Forty-one per cent of the series had other malformations, and other malformations were more common in those cases with spina bifida than in those without. The most frequent single malformations were: hydronephrosis (8%), cleft palate (8%), diaphragmatic hernia (5%), exomphalos (5%), hare lip (4%), and horseshoe kidney (4%). It is suggested that the presence of other malformations in anencephaly or iniencephaly may imply some aetiological heterogeneity.