Mental retardation, acromegalic face, and megalotestes in two half-brothers: a specific form of X-linked mental retardation without fra(X) (q)?

We describe a family with two half-brothers affected with severe mental retardation. The phenotype in the affected individuals is characterized by apparent acromegaly, profound mental retardation, and hyperactivity. The mother has analogous but less severe facial anomalies and mild mental impairment. Screening for fra(X) (q) was negative in peripheral lymphocytes using methotrexate for fra(X) enhancement. The clinical findings in our patients are similar to those described by Fryns et al. [1986] in two patients with acquired lesions of the central nervous system. CT investigations in one of our patients showed areas of hyperdensity in the pontine region and a small subarachnoid cyst. The pedigree suggests X-linked inheritance. The association of apparent acromegaly, CNS anomalies, megalotestes, and mental retardation in this family supports the hypothesis that a distinct syndrome may exist with phenotype anomalies more severe than those characteristic for the Martin-Bell syndrome but without fragile X.

Fra(X) frequency on the active X-chromosome and phenotype in heterozygous carriers of the fra(X) form of mental retardation.

Female heterozygotes of the fra(X) form of mental retardation show variable degrees of mental impairment and phenotype expression of the disorder. This might be an effect of inactivation of the X-chromosome which carries the fra(X)(q). Prior replication studies in heterozygous carriers gave contradictory results with respect to possible genotype-phenotype correlation. In the interpretation of these studies it is important to understand the effect of BrdU on the fra(X)(q) expression. In a group of 13 hemizygous patients with fra(X)(q) and 7 heterozygous carriers we studied the effect of BrdU on fra(X) expression. In the heterozygous carriers the use of BrdU resulted in a significant suppression of the fra(X)(q), while in hemizygous patients no difference in fra(X)(q) frequency with or without BrdU could be observed. It can be concluded that BrdU suppresses the fra(X)(q) preferentially on the inactive X-chromosome. Thus the fra(X)(q) frequency on the active X-chromosome is of primary importance in phenotype correlation studies among heterozygous carriers. In our group of heterozygous carriers we observed a negative correlation between (IQ) phenotype and fra(X)(q) expression on the active X-chromosome. This suggests that the gene for the fra(X)(q) form of mental retardation is on the X-chromosome and undergoes inactivation.

Brief clinical report: an unusual bandlike web in an infant with lethal multiple pterygium syndrome.

We report on a patient with a lethal multiple pterygium syndrome who also had an unusual, bandlike web across one axilla and partial intestinal atresia. Umbilical cord wrapping with subsequent vascular compromise appears to be the most likely pathogenetic mechanism for the additional anomalies.

Folic acid treatment in males and females with fragile-(X)-syndrome.

Ten males with the fragile X (fra(X] syndrome were treated with folic acid (10 mg/day) for 4 months in a double-blind design study. To eight heterozygotes with mental impairment and fra(X), folic acid was given for 4 months (10 mg/day) in an effort to study possible beneficial effects of folic acid. Psychological and cytogenetic testing were carried out during the trial. There was no improvement in concentration, fine motor co-ordination, or comprehension in the adult male and female patients of the study. One patient showed improvement under a control medications. In the females, improvement was seen only in the youngest patient, a 5-year-old girl. Folate treatment does not seem to be effective in fra(X) adults, but may have some effect in children of both sexes with the disorder. Cytogenetic studies using peripheral lymphocytes showed that the fra(X) frequency decreased significantly (t = 0.00856; 1% level) only in cells cultured in a folic acid-free medium but not in cells cultured in a medium with added antifolate (methotrexate). This shows a "contamination effect" of folate-free culture medium after oral folic acid treatment of these patients. The decrease of fra(X) involves primarily the early-replicating X when culturing with folic acid-free medium. A synergistic suppression effect of "external folate" and BrdU is the most likely explanation of this phenomenon.

Normal male carriers in the fra(X) form of X-linked mental retardation (Martin-Bell syndrome).

Evidence for the transmission of X-linked mental retardation through normal male carriers is reviewed in 6 kindreds. In these pedigrees we identified 15 unaffected males who likely had passed the gene on through their daughters. Fifty-one mentally retarded grandsons or great grandsons descended from these male carriers. In total, these males had 50 daughters with only 2 of them being of low intelligence. Two of the male carriers were recently identified through fra(X)- positive results in their mentally normal daughters. Among the sibs of these males, mentally retarded brothers were found in 3 families. This was unexpected since earlier observations suggested that the risk for mental retardation among sibs of nonmanifesting carriers is exceedingly low.

Guidelines for the preparation and analysis of the fragile X chromosome in lymphocytes.

The following guidelines were adopted by an Ad Hoc Committee convened at the Fourth International Workshop on the Fragile X Syndrome and X-Linked Mental Retardation to establish minimum cytogenetic standards for the preparation and analysis of the fragile X chromosome. The intention of the committee was to develop and provide practical standards for the routine cytogenetic detection of the fragile X. The guidelines describe reasonable criteria for effective tissue culture methods for eliciting the Xq27.3 fragile site in vitro and for the analysis of such chromosome preparations.

Relationship between age and IQ among fragile X males: a multicenter study.

Longitudinal decline in IQ among fragile X males was reported recently. However, there are problems in retesting IQ that may affect scores. Two such factors are intertest time interval and score obtained on the first test. To determine the generality of IQ score changes, we examined 101 fragile X males from 6 centers. To ensure high test-retest reliability, only results from Stanford-Binet and Wechsler tests were used. Thus there were retest scores from 60 subjects. Test-retest reliability between first and last scores was very good (r = 0.85) and comparable to those seen in nonfragile X mentally retarded individuals. Also computed were z-scores of differences in IQ scores. The z-score differences were distributed about a mean at 1 SD below the expected zero value. Eighteen subjects showed statistically significant decreases in IQ, 6 showed statistically significant increases, while 5 showed the same scores. Z-score differences were not correlated with type of residence or elapsed intertest interval, but were negatively correlated with first score obtained, indicating a regression-to-the-mean effect. Using a multiple regression analysis, we found first score obtained, age tested, and age retested significant predictors of score differences, accounting for 19% of the total variance. These results suggest that factors previously identified as affecting retest scores have a smaller effect than originally thought. It is suspected that decline in IQ is associated with dynamic neurological processes and needs to be investigated further.

Clinico-neurological investigations in the fra(X) form of mental retardation.

A clinical, neurological and electroencephalographic investigation was undertaken in 29 previously cytogenetically verified hemizygous males with the fra(X) form of mental retardation (age range 3.5 to 59 years); in addition, 6 heterozygous females were examined. All male patients displayed the known physical aspects of this syndrome together with associated abnormalities of the palate, skeleton, connective tissue and endocrine system. The most prominent neurological features were different forms of oculomotor disturbances, minor motor and pyramidal signs, incoordination, muscle hypotonia, gait and speech abnormalities. There was no increased frequency either in seizures or in epileptic EEG discharges. Some patients had a slowing of background activity in EEG. About 50% of all patients displayed autistic-like behaviour, short attention span and/or hyperactivity. In accordance with the literature, the findings indicate that there are no neurological, electroencephalographic or neuroradiological features which occur specifically in this syndrome. The need to differentiate the findings from those resulting from encephalopathic mechanisms during the gestational and perinatal period is stressed. A distinct typing of seizures and EEG changes is needed in each patient, before definite conclusions about an association of seizures and fra(X) syndrome are drawn. In view of the lack of correlation between IQ and the clinical-neurological measures, a more practical approach to quantifying the mental impairment is proposed.

Encephalocele, radial defects, cardiac, gastrointestinal, anal, and renal anomalies: a new multiple congenital anomaly (MCA) syndrome?

We present two unrelated female patients with a complex pattern of congenital malformations including encephalocele, oesophageal atresia, abnormal lung lobation, congenital heart defects, anal anomalies, liver, spleen and radial defects. Clinical variability between the two cases can be seen as a result of variable expression. The pattern of anomalies in these two unrelated patients suggest that they may represent the same, as yet unknown, syndrome.

Caudal dysplasia and femoral hypoplasia-unusual facies syndrome: different manifestations of the same disorder?

The Caudal Dysplasia syndrome and the Femoral Hypoplasia-Unusual Facies syndrome have been reported to be more frequent among infants of diabetic mothers. We report a newborn girl who presented with features compatible with both syndromes. The possibility that both conditions represent different manifestations of the same disorder is discussed.

Screening for fra(X)(q) in a population of mentally retarded males.

Among 242 institutionalized mentally retarded males in Northern Germany screened for fra(X)(q), 15 (6.2%) with severe mental retardation expressing fra(X)(q) were detected. One patient displayed Klinefelter's syndrome in addition. All fra(X)(q) males showed the typical facial signs, but three of the adults did not express macroorchidism. A preliminary estimation of an overall frequency of 1:2000 males for the fra(X)(q) condition is suggested.

Hemifacial deficiency induced by a shift in dominance of the mouse mutation far: a possible genetic model for hemifacial microsomia.

Hemifacial deficiency appeared in 10% of juvenile mice when BALB/cGaBc mice carrying the recessive lethal mutation far were crossed with ICR/Bc. The hemifacial deficiency increased to 15-20% after one backcross to ICR/Bc and then remained at that level for 11 additional generations of backcrossing of far into ICR/Bc. Neither the ICR/Bc strain nor BALB/cGaBc (+/far) produces hemifacial deficiency. Genetic and anatomical studies of adults and fetuses showed that the hemifacial deficiency was due to +/far in the ICR/Bc strain genome; that is, far becomes an incomplete dominant in the ICR/Bc strain background. The hemifacial deficiency (38% of +/far) is probably caused by premature synostosis of the maxilla and premaxilla, observable on day 16 of gestation. An additional 20% of +/far in ICR/Bc have cleft palate and die at birth. Most +/far in both strains have a hidden anomaly, bilateral splitting of the maxillary branch of the trigeminal nerve. far/far homozygotes of both strain backgrounds have a syndrome of severe bilateral deficiency of the derivatives of the maxillary prominence. In human pedigrees, where the equivalents of the dominance modifiers in BALB/cGaBc and ICR/Bc would segregate within families, it would be difficult to recognize that sporadic hemifacial deficiency and severe bilateral maxillary deficiency were due to the same gene. We suggest that human bilateral and unilateral abnormalities of tissue derived from the first branchial arch should be analyzed with the awareness that, in mice, at least, the two kinds of syndrome are due to the same mutant gene.

Heterozygous female carriers of the marker-X-chromosome: IQ estimation and replication status of fra(X)(q).

The IQ levels of 18 female carriers with the marker X chromosome were evaluated, and cytogenetic studies after BrdU incorporation were performed. A highly significant correlation between mental capacity and replication pattern of the X chromosomes could be demonstrated. Heterozygous females with normal intelligence showed a clear tendency to carry the fragile site at the late replicating X chromosome, while other female carriers with lower intelligence or mental impairment expressed their fragile site mainly with the early replicating X chromosome. This observation could be interpreted as an expression of Lyonisation .

Transmission of the marker X syndrome trait by unaffected males: conclusions from studies of large families.

It is well established that apparently unaffected males can be transmitters of the marker X syndrome trait. Cytogenetic and clinical investigations of these male transmitters are only rarely reported for most of these male transmitters are dead by the time the syndrome is diagnosed in their families. We report on cytogenetic and clinical investigations of two unaffected male carriers of the disorder from two large families. Pedigree analysis of these families revealed six other cases of possible male transmission of the marker X syndrome trait. Mental impairment was not reported from the siblings of these unaffected male carriers and could not be observed in their daughters. The mode of transmission of the disorder cannot be fully explained by X-linked inheritance. The phenomenon of unaffected males transmitting the disorder could be due to an autosomal suppressor systeme. Our findings indicate that male transmission may be important for the frequency of the disorder.

Isochromosome 18q with karyotype 46,XX,i(18q). Cytogenetics and pathology.

Cytogenetic and morphological findings of a 20-gestational-week-old female fetus with karyotype 46,XX,i(18q) are reported. The fetus displayed clinical features resembling Edward's syndrome. No characteristic symptoms of monosomy 18p could be observed.

Amelia: incidence and associated defects in a large population.

Amelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 was studied using the records of a population-based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.

[Neurofibromatosis--new clinical and molecular genetic aspects]. / Neurofibromatose--neue klinische und molekulargenetische Aspekte.

Neurofibromatosis is not a single entity. Seven types of the disorder are now known, which can be differentiated by clinical and genetic features. The wide variety of clinical manifestations makes close interdisciplinary cooperation necessary, in which the dermatologist frequently has a key role. The most frequent forms are peripheral neurofibromatosis (NF1) and central neurofibromatosis (NF2), for which separate gene localizations have been found on chromosomes 17 and 22, respectively, by molecular genetics techniques. The meanwhile possible prenatal diagnosis raises ethical questions.

Limb reduction defects in over one million consecutive livebirths.

Limb reduction defects occurring among 1,213,913 consecutive livebirths in British Columbia during the period 1952-1984 inclusive were reviewed. A total of 659 cases of limb reduction defects were identified, 393 of them involving the long bones and 190 of them more than one limb. The time period 1966-1984, during which ascertainment was consistent, was evaluated, and an incidence of 5.97 per 10,000 livebirths (1 in 1,692 live births) was found. The data were evaluated for trends over time, sex ratio, and regional and ethnic distribution. Associated anomalies of other organ systems in these cases were analyzed, and overall about one-half of the cases have additional defects. The majority of these additional defects affect the musculoskeletal system and include such entities as clubfoot, hip dislocation, and congenital contractures. Defects are also frequent in other organ systems, such as the cardiovascular, gastrointestinal, and genitourinary systems. By far the most common limb defects are terminal longitudinal defects then terminal transverse defects. Of all cases of limb defects, 75% are upper limb and 25% lower limb. We found no evidence that one side is affected more frequently. About 6.5% of cases had another family member registered with a skeletal defect; 12.9% of cases died within the first year of life, the majority (85%) of those dying having additional defects. Etiological considerations are discussed for some subgroups.(ABSTRACT TRUNCATED AT 250 WORDS)

[Knee pterygium syndrome in a newborn infant]. / Kniepterygium-Syndrom bei einem Neugeborenen.

We report on a newborn boy with popliteal pterygium syndrome. Congenital anomalies included popliteal pterygia, symblepharon, cleft lip and palate with syngnathia, severe hypoplasia of both thumbs, a characteristic nail anomaly of both first toes, multiple syndactylies, and a hypoplastic scrotum with cryptorchidism. Mental development can be expected to be normal. Overall prognosis of the disorder after detailed operative correction is apparently favorable. Differential diagnosis is discussed in detail. The syndrome is autosomal dominantly inherited, our patient represents an isolated case.