Variable Expression of Campomelic Dysplasia in a Father and his 46, XY Daughter

Campomelic dysplasia (CD, MIM 114290) is characterised by widespread osseous abnormalities including bowing of the long bones, dysplasia of the cartilage of the tracheobronchial tree, and neurological abnormalities leading to high perinatal lethality. A majority of karyotypic males present as phenotypic females. The disorder has only recently been categorised as a dominantly transmitted entity after demonstration of heterozygous mutations in the SOX9 gene on chromosome 17q24.3 or translocations associated with breakpoints upstream of this gene. Despite this mode of transmission, only two well-documented instances of parent-child transmission of the disorder have been described. We report a man of normal intelligence with mild phenotypic and radiological appearances of CD. His first-born child, a phenotypic female with a 46,XY karyotype, presented with significantly more severe skeletal and neurological involvement. Parents of individuals with CD should be examined for minimal manifestations of the disorder, which may represent phenotypic variability in the syndrome or somatic mosaicism.     

The genetic etiology of inhibitory control and behavior problems at 24 months of age

Background: To investigate links between inhibitory control (IC) and behavior problems in early childhood, as well as genetic and environmental covariances between these two constructs. Methods: Parent and laboratory ratings of IC and parent ratings of externalizing and attention deficit hyperactivity disorder behaviors were administered at 24 months of age on a sample of 291 same‐sex twin pairs (131 monozygotic, 160 dizygotic). Results: There were significant phenotypic associations between both IC assessments and the two areas of behavioral maladjustment (correlations ranged from ?.13 to ?.57). Multivariate analyses revealed that phenotypic covariance between IC and behavior problems could be substantially explained by common genetic influences (genetic correlations ranged from ?.30 to ?.74). Parent ratings of IC showed higher phenotypic and genetic correlations with behavior problems than lab ratings of IC. Conclusions: This study is the first to examine the etiology of the covariance between IC and related behavioral difficulties in toddlerhood. Findings suggest that low levels of IC can be considered a genetic risk factor for the development of early emerging behavior problems.     

Branchio-oculo-facial syndrome

Branchio-oculo-facial syndrome (BOFS) is a very rare autosomal dominant disorder with incomplete penetrance and variable expression; with phenotypic variation ranging from mild to severe forms, involving eye, ear, oral and craniofacial structure. We report three members of one family, showing great variability in its phenotypic expression and review the recent literature.     

“Marden-Walker Syndrome”: Neuropathologic Findings in Two Siblings

Neuropathologic examination of two siblings with phenotypic features consistent with Marden-Walker syndrome revealed central nervous system abnormalities which include reduction in the number of spinal anterior horn cells. The occurrence of these changes in a sibling pair provides strong evidence for a genetic etiology. The relationship between the neuropathologic changes and other phenotypic manifestations in this syndrome and in the closely related syndrome of Pena-Shokeir are discussed.     

"Marden-Walker syndrome": neuropathologic findings in two siblings

Neuropathologic examination of two siblings with phenotypic features consistent with Marden-Walker syndrome revealed central nervous system abnormalities which include reduction in the number of spinal anterior horn cells. The occurrence of these changes in a sibling pair provides strong evidence for a genetic etiology. The relationship between the neuropathologic changes and other phenotypic manifestations in this syndrome and in the closely related syndrome of Pena-Shokeir are discussed.     

A twin study of anxiety-related behaviours in pre-school children

BACKGROUND: From middle childhood onwards, substantial evidence points to phenotypic differentiation between anxiety diagnostic categories such as generalised anxiety, separation anxiety, specific phobia, and obsessive-compulsive disorders. However, little is known about the genetics of these categories and especially about the phenotypic and genetic structure of related behaviours in pre-school children. METHODS: We examined the phenotypic differentiation and genetics of mother-reported anxiety-related behaviours in 4,564 four-year-old twin pairs, from a population-based sample. RESULTS: Confirmatory factor analyses provided support for five correlated factors: General Distress, Separation Anxiety, Fears, Obsessive-Compulsive Behaviours, and Shyness/Inhibition. Genetic influences were found on all five factors, but the pattern of influences differed considerably across them, with particularly high heritability estimates for Obsessive-Compulsive Behaviours and Shyness/Inhibition, and substantial shared environmental influence on Separation Anxiety. Multivariate genetic analyses revealed moderate genetic correlations between the five factors. Genetic overlap was particularly pronounced between General Distress and the other anxiety-related behaviours, accounting for about half of their covariance. Genetic variance on Obsessive-Compulsive Behaviours was the least correlated with the other scales. The shared environmental influences correlated highly across the factors, accounting for the greatest proportion of covariation between Separation Anxiety, Fears and Obsessive-Compulsive Behaviours. The non-shared environment influences were largely variable specific. CONCLUSIONS: These data provide evidence for phenotypic and genetic overlap as well as differentiation between aspects of anxiety-related behaviours in young children. We conclude that research with young children will benefit from more specific assessments of anxiety-related behaviours in addition to less differentiated assessments of 'internalising' symptoms.     

45,X/46,XY mosaicism

The clinical findings in ten patients with 45,X/46,XY mosaicism are described. Three girls presented with short stature, delayed sexual development or Turner-like stigmata without signs of virilization. Bilaterally gonadoblastomas were found in two girls, and the gonads in one of these girls also contained mucinous cystadenomas. The remaining seven patients were raised as boys. Three had scrotal hypospadias and mixed gonadal dysgenesis. Three presented as male pseudohermaphrodites with scrotal or penoscrotal hypospadias and bilateral testes. One male was diagnosed in adulthood because of gynecomastia, but had normal male external genitals. The clinical findings illustrate the wide spectrum of phenotypic manifestations of 45,X/46,XY mosaicism, ranging from females with Turner-like phenotypes, phenotypic males and females with mixed gonadal dysgenesis, male pseudohermaphroditism to almost phenotypic normal males.     

Some effect of metformin on insulin resistance in an infant with leprechaunism

Leprechaunism was first recognized in 1954 and is characterized by severe intrauterine and postnatal growth retardation, failure to thrive, lipoatrophy, dysmorphic features (globular eyes, large ears, and micrognathia), hirsutism and acanthosis nigricans. The presented infant, a 30 day-old boy, had multiple phenotypic anomalies, including low-set ears, prominent eyes, decreased subcutaneous fat, hirsutism, breast hyperplasia, and penile enlargement. We found persistent hyperglycemia with remarkably high immunoreactive insulin levels. His phenotypic and laboratory features were consistent with a diagnosis of leprechaunism. We observed some effect of treatment with metformin but not with insulin glargine.     

A child with isolated nephrotic syndrome and WT1 mutation presenting as a 46, XY phenotypic male

Mutations in the WT1 gene can lead to Denys-Drash syndrome or Frasier syndrome and can also cause isolated nephrotic syndrome (NS). Most patients with isolated NS caused by WT1 mutations present as 46, XX phenotypic females. There have been two cases with an onset age younger than 3 years with isolated NS caused by WT1 mutations presenting as 46, XY phenotypic males. We present a 46, XY phenotypic male patient with isolated NS and end-stage renal disease (ESRD) at the age of 6.3 years. He had normal male external genitalia with normal penis length and soft and normal volume of both testes. A mutation, 1051A>G (K351E), in exon 8 of WT1 was identified in the patient. After starting hemodialysis, manifestations of hypertension and renal failure improved, but he died at 6.8 years of age as a result of respiratory failure and heart failure. Our study supports the necessity of searching for mutations in WT1 in 46, XY phenotypic male patients with isolated NS and ESRD.     

Risk factors for early death in transient myeloproliferative disorder without phenotypic features of Down syndrome: a case report and literature review

Not only in newborns with Down syndrome, but newborns without phenotypic features of Down syndrome also develop transient myeloproliferative disorder (TMD). In these cases, trisomy 21 and related chromosomal abnormalities are either constitutionally mosaic or limited to blood cells. Risk factors for early death of these patients are unknown so far. We here report a fatal case of TMD without phenotypic features of Down syndrome and review literature to identify risk factors associated with early death. Not only are gestational age and white blood cell count risk factors for early death in TMD with Down syndrome, but they also appear to be risk factors in TMD without Down syndrome.     

Molecular aspects of Down syndrome

Molecular aspects of Down syndrome (DS), a major genetic cause for mental retardation, commonly associated with trisomy 21 are discussed. Two different hypotheses have been speculated to better understand the disease. One believes that increased gene dosage contributes to the phenotypic abnormalities; the other correlates genetic imbalance with DS pathogenesis. To sustain these hypotheses, different murine models have been developed. Experimental models as well as sequencing of human chromosome 21 helped in speculating a few possible candidate genes for DS. However, the phenotypic changes involved with this neurological disorder vis-a-vis the enhanced number of genes, still remain unexplained. Improvement in screening pattern, model system, as well as better understanding of the disease etiology may help in developing efficacious therapeutic regimes for DS.     

Extra G-positive band at chromosome 9q13 as a recurrent heteromorphism in a Korean population

The extra G-positive, C-negative band within 9q13 has been repeatedly found during chromosomal analyses of amniocenteses with a frequency of 2.4 in 1000 (28 cases in 11,890 chromosomal analyses) in the Korean population. All of the carrier parents with this variant did not have any phenotypic abnormalities and 10 cases that were followed after birth showed that all, except 1 patient with duodenal atresia, had no apparent phenotypic abnormalities. The results of Agilent 244 K oligonucleotide array CGH showed no changes of genomic dosages. We can be sure that the extra bands present are heterochromatic materials of no clinical significance.     

The Genetics of Children's Oral Reading Performance

Measures of reading achievement and verbal ability have been shown to be heritable. Additionally, recent evidence has been suggestive of a major gene effect on reading disability and for problem reading in a sample of normal readers. We report on the etiology of individual differences in oral reading performance, the Slosson Oral Reading Test (SORT), for which biometrical analyses have not been reported in the literature previously. Oral reading performance was measured in a large population-based sample of twins of the Virginia Twin Study of Adolescent Behavioral Development. Biometrical analyses of the SORT suggested that, in both mates and females. 69% of the phenotypic variation was due to heritable influences and 13"v of the variation dm- to shared environmental effects. While the relative importance of genetic and environmental influences is equivalent for males and females, males showed greater phenotypic variability than females.     

Tricho-hepato-enteric syndrome presenting with mild colitis

Introduction  A four and half-year-old girl was admitted to our clinic with the complaints of diarrhea since birth and failure to thrive. Discussion  The characteristic findings in physical examination were facial dysmorphism, hepatomegaly, and wooly hair. Trichorrhexis nodosa was established in microscopic hair examination. Colonoscopy and histopathologic examination of colonic mucosa revealed mild colitis. In the light of previously published cases, this patient was accepted as a mild variant of syndromic (phenotypic) diarrhea or tricho-hepato-enteric syndrome. We conclude that a mild phenotypic variant of this disease exists that may present with colitis.     

XY sex-reversed campomelia

A phenotypic female with campomelic syndrome and XY gonadal dysgenesis is described. A minor structural chromosome abnormality was detected in the mother.     

Generalist genes and learning disabilities: a multivariate genetic analysis of low performance in reading, mathematics, language and general cognitive ability in a sample of 8000 12-year-old twins

Background:  Our previous investigation found that the same genes influence poor reading and mathematics performance in 10-year-olds. Here we assess whether this finding extends to language and general cognitive disabilities, as well as replicating the earlier finding for reading and mathematics in an older and larger sample.
Methods:  Using a representative sample of 4000 pairs of 12-year-old twins from the UK Twins Early Development Study, we investigated the genetic and environmental overlap between internet-based batteries of language and general cognitive ability tests in addition to tests of reading and mathematics for the bottom 15% of the distribution using DeFries–Fulker extremes analysis. We compared these results to those for the entire distribution.
Results:  All four traits were highly correlated at the low extreme (average group phenotypic correlation = .58). and in the entire distribution (average phenotypic correlation = .59). Genetic correlations for the low extreme were consistently high (average = .67), and non-shared environmental correlations were modest (average = .23). These results are similar to those seen across the entire distribution (.68 and .23, respectively).
Conclusions:  The 'Generalist Genes Hypothesis' holds for language and general cognitive disabilities, as well as reading and mathematics disabilities. Genetic correlations were high, indicating a strong degree of overlap in genetic influences on these diverse traits. In contrast, non-shared environmental influences were largely specific to each trait, causing phenotypic differentiation of traits.     

Comparison of multiple measures of ADHD symptomatology: a multivariate genetic analysis

The phenotypic and genetic interrelationships underlying ADHD symptomatology assessed by various instruments were examined on a sample of 735 male and 819 female same-sex twin pairs, aged 8 to 16 years, participating in the first phase of the Virginia Twin Study of Adolescent Behavioral Development (VTSABD). Multivariate analyses were applied to parental and teacher ratings from an investigator-based interview, the CAPA, and three questionnaires (the CBCL and the Rutter Parent and Teacher Scales). Results from patterns of intercorrelations and factor analyses of maternal measures suggested that at the phenotypic level, these assessed the same underlying behavioural construct, which differed from other emotional and behavioural constructs. However, genetic analyses showed that in addition to a common factor underlying the expression of ADHD as assessed across the range of measures, additional genetic factors were identified that were method- and rater-specific. The findings suggest that although the investigator-based interview and the behavioural checklists tap similar aspects of ADHD behaviour, there is additional rater-specific variance.     

Candida isolated from vaginal mucosa of mothers and oral mucosa of neonates: occurrence and biotypes concordance

BACKGROUND: The common occurrence of Candida spp. on the vaginal mucosa of pregnant women suggests this as the source of neonatal candidiasis. METHODS: This study investigated the occurrence of yeasts on the vaginal mucosa of 100 mothers at the time of birth, and on the oral mucosa of their respective neonates, all full-term, on the 1st, 3rd, and 9th days after birth by vaginal (72 cases) and cesarean (28 cases) routes. In each case where concordance at the level of species was found between the isolate from the mother and that from the neonate, tests were made to check for concordance between the genotypic and phenotypic profiles (susceptibility to killer toxins, serotyping, proteinase and phospholipase production, and susceptibility to antifungal agents). RESULTS: For the vaginal-route group, yeasts were recovered from the vaginal mucosa of 47.2% of the mothers and from 25% of the neonates. For the cesarean-route group, these rates were 46.4% and 3.6%, respectively. Species found most frequently in the samples from the mothers and the neonates were, respectively C. albicans and C. guilliermondii. For the vaginal-route group, the rate of mother/neonate concordance at the level of species was 23.5% and no cases of concordance for the cesarean births. Of these cases with species concordance, there was concordance between the genotypic and phenotypic profiles in 6% (2 cases). CONCLUSION: The vaginal mucosa was not the main route of transmission of the Candida species to the neonate, because there was concordance between the genotypic and phenotypic profiles in only 6% (2 cases).     

Perinatally lethal short rib-polydactyly syndromes 1. Variability in known syndromes

Thirteen newborns with lethal short ribpolydactyly (SRP) have been reviewed, 11 with SRP type III (Verma-Naumoff) and 2 with SRP type II (Majewski). In the former group there were three sets of siblings. The excess of males with SRP type III (Verma-Naumoff) is confirmed in this present study. A high frequency of phenotypic females including sex-reversed constitutional males with SRP type I (Saldino-Noonan) is in marked contrast to these findings in SRP type III. Possible hypotheses include variable expressivity in non-Majewski short rib-polydactyly syndromes with sex-reversed and constitutional female cases tending to show more severe phenotypic expression both in terms of major anomalies and skeletal dysplastic effects.