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Aim This study examined the effects of prenatal alcohol exposure on childhood development trajectories in a rural South African community between 2003 and 2008. Methods We assessed 121 children at 7-12 months (year one) and 5-6 years (year five) using the Griffiths Mental Developmental Scales – Extended Revised, which measures sensorimotor, cognitive and social development, with lower scores indicating developmental delay. We also interviewed their mothers or caregivers. Three groups were identified: 29 with fetal alcohol syndrome (FAS) or partial FAS (pFAS), 57 more who had been exposed to alcohol and 35 controls who had not. Results The scale's total score was higher in the controls than in the FAS/pFAS group at years one and year five and in the alcohol exposed group at year five. Many groups’ trajectories declined when compared with global norms, but the trajectories in the FAS/pFAS and the alcohol exposed groups declined more than the controls for eye-hand and performance and total score. Earlier pregnancy recognition in the FAS/pFAS group correlated strongly (r= -0.77) with higher GQ in year five. Conclusion FAS/pFAS and prenatal alcohol exposure affected the Griffiths scores more than the control group. Efforts are needed to detect pregnancy early and reduce alcohol exposure. This article is protected by copyright. All rights reserved.

Background: Fetal alcohol spectrum disorder (FASD) and fetal alcohol syndrome (FAS) are common in some South African populations, notably those of mixed ancestry descent in rural areas and small towns. Little is known about FAS/FASD prevalence in the majority of South Africans: city dwellers of Black African ethnicity. This study describes the prevalence of FAS in a South African city, comparing 2 suburbs with predominantly mixed ancestry (Roodepan) and Black African (Galeshewe) populations that house over 60% of the city population. Methods: We conducted a tiered, active case ascertainment study for the prevalence of FAS and also detected some less clinically specific FASD cases. All first-grade learners in the 2 suburbs were eligible for anthropometric screening, and screen-positive learners were assessed for dysmorphic features of FAS. Those with suggestive clinical features received neurocognitive assessment, and maternal or collateral interview. Final diagnosis was made following a case conference. Results: Complete ascertainment of FAS status was made in 1,503 (94.7%) of 1,587 eligible learners (435 in Roodepan and 1,152 in Galeshewe). Overall, FAS was diagnosed in 83 (5.5%, 95% confidence interval [CI]=4.4 to 6.8) learners and FASD in 96 (6.4%, 95% CI=5.2 to 7.7). Levels of FAS were high in both areas: 26 (6.3%, 95% CI=4.2 to 9.2) learners from Roodepan, compared to 57 (5.2%, 95% CI=4.0 to 6.7) from Galeshewe (p=0.39). No cases were previously diagnosed. The mortality rate for mothers of FASD children from Galeshewe was 19 of 65 (29%), compared to 3 of 31 (9.7%; p=0.03) for Roodepan. Interviewed mothers in Galeshewe were older and had higher body mass index. Conclusions: Prevalence of FAS is high in both Galeshewe and Roodepan, and the lack of prior diagnoses indicates that awareness remains low. The maternal mortality rate was especially high in Galeshewe. The unexpectedly high burden of FAS in an urban area with predominantly Black African population mandates extension of surveillance and intervention measures in southern Africa.

Introduction During fetal alcohol spectrum disorder (FASD) prevalence studies in South Africa, cases of fetal alcohol syndrome (FAS) were identified that presented differently from the 2016 Hoyme et al. modified Institute of Medicine (IOM) criteria. We compared diagnostic outcomes of children diagnosed with FAS using a combination of the 2005 Hoyme et al. criteria and the "gestalt method" in South Africa to the diagnosis they would have received using the latest Hoyme et al. criteria. The frequency with which dysmorphic features presented was compared to the frequency with which they were reported in the revised criteria which drew on a larger sample. Methods Data were gathered from four South African FASD prevalence studies. Dysmorphology data, anthropometric data, and final diagnosis for participants (N = 917) were extracted. Results Of the 390 participants with diagnoses of "full FAS," 175 would not have received a "full FAS" diagnosis using the 2016 criteria. Of these, 21 would have received a pFAS diagnosis, and 154 would have received a diagnosis of ARND or a "no-FASD" diagnosis. The frequency of all but five dysmorphic features differ significantly between this sample and the sample examined for the 2016 criteria. There is more variability in the features present in the current sample. Discussion Differences regarding diagnostic outcomes and prevalence of dysmorphic features suggest that strict application of the diagnostic criteria may miss children who present with FAS. We recommend including gestalt-based screening in a research setting where the clinical experience is available to inform future guidelines.

Background. A relatively high frequency of autosomal recessively inherited osteogenesis imperfecta (OI) type 3 (OI-3) is present in the indigenous black southern African population. Affected persons may be severely handicapped as a result of frequent fractures, progressive deformity of the tubular bones and spinal malalignment. Objective. To delineate the molecular basis for the condition. Methods. Molecular investigations were performed on 91 affected persons from seven diverse ethnolinguistic groups in this population. Results. Following polymerase chain reaction amplification and direct cycle sequencing, FKBP10 mutations were identified in 45.1% (41/91) OI-3-affected persons. The homozygous FKBP10 c.831dupC frameshift mutation was confirmed in 35 affected individuals in the study cohort. Haplotype analysis suggests that this mutation is identical among these OI-3-affected persons by descent, thereby confirming that they had a common ancestor. Compound heterozygosity of this founder mutation was observed, in combination with three different deleterious FKBP10 mutations, in six additional persons in the cohort. Four of these individuals had the c.831delC mutation. Conclusion. The burden of the disorder, both in frequency and severity, warrants the establishment of a dedicated service for molecular diagnostic confirmation and genetic management of persons and families with OI in southern Africa.

IntroductionFetal alcohol spectrum disorders (FASD) are one of the leading preventable causes of intellectual disabilities (ID). Not much is known about the topic of pediatric incontinence related to FASD, for example nocturnal enuresis (NE), daytime urinary incontinence (DUI), and fecal incontinence (FI). So far, incontinence problems have been examined among children with other specific syndromes.ObjectiveThe aim of the present study is to investigate the possible presence of incontinence among children with FASD in a South African cohort.Study designThe South African version of the combined questionnaire including the "Parental Questionnaire: Enuresis/Urinary Incontinence" and "Encopresis Questionnaire - Screening Version"; and lower urinary tract symptoms (LUTS) were assessed by the "International-Consultation-on-Incontinence-Questionnaire - Pediatric Lower Urinary Tract Symptom" (ICIQ-CLUTS) among 99 interviewees (e.g. mothers, grandparents) of children with FASD. Moreover, scores on the "Griffiths Mental Development Scales - Extended Revised" (GMDS-ER) were obtained of all included children for further statistical analysis.ResultsThe overall incontinence rate was 20% (n = 20), in children diagnosed within the FASD spectrum (fetal alcohol syndrome or FAS n = 17, partial fetal alcohol syndrome or pFAS, n = 1, alcohol related neuro-developmental disorder or ARND n = 2). NE affected 16% (n = 16) of children with a FASD (FAS n = 13, pFAS n = 1, and ARND n = 2). DUI was reported in one child (FAS), and FI in 4% (n = 4) of children (again, only FAS). No indication of lower urinary tract symptoms (LUTS) in the clinical range was reported (sample mean score = 5.17). Based on the GMDS-ER, 88% of the children scored lower than 10th percentile.DiscussionThis is a first study to examine the problems of incontinence among children diagnosed within the spectrum of FASD. The rates for children with a FASD are lower than the rates for many children with special needs, but much higher than for typically developing children. Children with a FASD are mainly affected by NE.ConclusionThe problem of incontinence among children with a FASD in South Africa needs to be assessed and considered for clinical management. Future research is necessary to examine problems of incontinence in relation to cognitive and behavioral functioning among children with a FASD, as well as identifying possible causes.

Background. Fetal alcohol spectrum disorder (FASD) is an under-diagnosed condition in South Africa (SA). Fetal alcohol syndrome and FASD community prevalence studies were undertaken in 17 towns in three of the nine provinces in SA. Objective. The objective for all the studies was to determine the FASD prevalence rates by assessing the grade 1 learners in all the studies, using international FASD diagnostic criteria. Methods. The same methodology was used for all the studies in Gauteng, Western and Northern Cape provinces. Consenting grade 1 learners received anthropometric screening, clinical examinations and neurodevelopmental assessments. Structured interviews were used to assess maternal alcohol consumption during pregnancy. Results. Reported prevalence rates ranged from 29 to 290 per 1 000 live births. Conclusion. FASD rates from studies conducted in SA are among the highest worldwide. FASD affects all communities in SA and is therefore a major public health concern in SA. Multidisciplinary and intersectoral interventions are urgently required to raise awareness about the dangers of prenatal alcohol exposure and the devastating effect of FASD on the lives of children, families and communities.

Mixed ancestry populations in South Africa have amongst the highest rates of fetal alcohol syndrome (FAS) worldwide. Defining the drinking patterns of women with a FAS child guides FAS preventive interventions.Data were drawn from FAS prevalence surveys conducted in three districts: Witzenberg (Cape Winelands), Frances Baard (inland mining town) and Saldanha Bay (coastal towns). 156 mothers and 50 proxy informants of school-entry children diagnosed with FAS and partial-FAS were interviewed, and compared with 55 controls recruited in Saldanha Bay.Study participants were of low socio-economic status (SES), and a majority of children were either in foster care (12%) or had been cared for by relatives for long periods (44%). Of cases, 123/160 (77%) reported current drinking, similar between sites. During pregnancy, only 35% (49/139) of cases had stopped drinking, varying between sites (from 21% to 54% in chronological order of surveys; p0.001), while 6% (7/109) increased drinking. Though many women who stopped in pregnancy resumed postpartum, cessation in pregnancy was strongly associated with discontinuation in the long run (OR=3.3; 95%CI=1.2-8.9; p=0.005). At interview, 36% of cases (54/151) and 18% of controls (9/51) were at risk of an alcohol-exposed pregnancy (p=0.02). Median maternal mass of cases was 22kg lower than controls, with 20% being underweight and 14% microcephalic.Increasing rates of drinking cessation during pregnancy over time suggest rising awareness of FAS. Cessation is associated with recidivism after pregnancy but also with reduced long-term drinking. Interventions should target alcohol abstinence in pregnancy, but extend into the puerperium.

Aims: Prevalence of fetal alcohol spectrum disorders (FASDs) is remarkably high in several provinces of South Africa; yet population-level knowledge of the harms of maternal drinking remains low. In two heavily affected areas, we assessed effective- ness of interventions to heighten awareness of these harms and to alter social norms about drinking in pregnancy. Methods: FASD prevalence, maternal knowledge and drinking behaviours were investigated in two Northern Cape Province towns, before and after interventions which included highlighting FASD using local media and health promotion talks at health facilities. Independently, two dysmorphologists and a neuropsychometrist examined children at 9 and 18 months. Results: Pre-intervention maternal knowl- edge of alcohol harms was low and FASD prevalence 8.9% (72/809). Interventions reached high coverage and knowledge levels increased substantially. FASD prevalence was 5.7% post-intervention (43/751; P= 0.02); 0.73 lower odds, controlling for maternal age and ethnicity (95% confidence interval= 0.58-0.90). No change was detected in more severe FASD forms, but in the whole population, median dysmorphology scores reduced from 4 (inter-quartile range (IQR) = 2-7) to 3 (IQR = 1-6; P=0.002). Conclusion: This, the first prevention study using FASD outcomes, suggests that universal prevention might reduce FASD by ~30% and have population-level effects. This supports intensifying universal interventions where knowledge of harms of maternal drinking is low. These efforts need to be accompanied by alcohol-dependence treatment to lower more severe FASD forms.

Complete monosomy 21 is claimed to be a rare chromosomal disorder in which the cytogenetic investigation is bedevilled by technical difficulties. We describe the disparate clinical features in two patients in whom an initial diagnosis of monosomy 21 was made by routine karyotyping. Fluorescence in situ hybridisation (FISH) confirmed a translocation of chromosome 21 material to the short arm of chromosome 5 and to the X chromosome, respectively. The usefulness of FISH in the investigation of subtle chromosomal rearrangements is hereby demonstrated. These findings also cast doubt on the existence of "pure" monosomy 21 as an entity, and suggest that partial monosomy 21 is a more likely occurrence.

Sixty-four patients with pseudoxanthoma elasticum (PXE) were investigated in a nationwide study within South Africa and Zimbabwe. Thirty-nine individuals formed a distinct clinical subgroup. These persons were found exclusively among people of Afrikaner descent, whose origins are mainly derived from Dutch and French-Huguenot stock. This disorder was inherited as an autosomal recessive trait and presented mild to moderate cutaneous and cardiovascular manifestations. However, after the third decade of life severe visual impairment developed and culminated in blindness in 8 people by the age of 50. The cause of the visual defect was progressive extension of angioid streaks into the macula with neovascularization and haemorrhage. Laser therapy may have prevented further bleeding in 4 instances. The severity of ocular involvement contrasted with the mildness of the skin changes, and in this respect the condition seems to differ from previously delineated autosomal recessive forms of PXE.

The mesomelic dysplasias are a heterogeneous group of genetic disorders with predominant skeletal manifestations in the forearms and shanks. We have documented, over a thirteen-year period, the clinical and radiographic course of the condition in a boy with the Langer type of mesomelic dysplasia. It has been suggested that dyschondrosteosis or the Madelung deformity are the phenotypic manifestations of the gene which causes Langer mesomelic dysplasia in the homozygote. Several relatives on both sides of the family which we studied had malformations of their forearms, in keeping with this concept. However, these anomalies differed from those of dyschondrosteosis and the classical Madelung deformity; the exact syndromic status of the heterozygous phenotype remains unsettled.

Eight members of a 3-generation kindred of Indian descent with congenital contractural arachnodactyly (Beals syndrome) have been appraised. Considerable variation was noted in the clinical features of affected persons, and the previously unreported associated finding of clubbing of the fingers and toes was evident in two individuals. The family was investigated using conventional serum and protein markers, and RFLP probes for type I and II collagen. No linkage in affected members could be demonstrated with type I collagen probes.

Thirty-one sets of conjoined twins were born in Southern Africa during the period February 1974 to May 1982 with a striking increase in incidence in 1974 and 1975. There was no ethnic or social predilection, but clustering of cases occurred in a remote area of Zimbabwe. No aetiological agent was discovered, and there was no seasonal variation in the time of conception. Female conjoined twins accounted for 62% of cases, and twenty sets were of the thoracopagus type. Four pairs were separated, three of which were of the xiphopagus subtype and have survived.

Idiopathic hemihypertrophy is a specific entity which is distinct from the numerous other causes of limb overgrowth. In our investigation of eleven new cases in South Africa and Australia, no genetic or other aetiological factors could be recognised. There were no differences in bone age between the normal and hypertrophied limbs and the pattern of growth through life showed that relative body proportions remained the same. Idiopathic hemihypertrophy is associated with mild mental retardation, genito-urinary anomalies and an oncogenic potential. Regular clinical surveillance for abdominal tumours is recommended.

Objectives The prevalence and characteristics of fetal alcohol syndrome (FAS) and partial fetal alcohol syndrome (PFAS) were determined in a third primary school cohort in a community in South Africa (SA). Methods An active case ascertainment, two-tier screening methodology, and the revised Institute of Medicine diagnostic criteria were employed among 818 first grade pupils. Characteristics of children with FAS and PFAS are contrasted with a randomly selected control group. Data were collected and analyzed for children in the study regarding: (1) physical growth and development, including dysmorphology, (2) intelligence and behavioral characteristics, and (3) their mother's social, behavioral, and physical characteristics. Results The rate of FAS and PFAS in this area continues as the highest reported in any overall community and is much higher than rates elsewhere. In this cohort it is 68.0–89.2 per 1000. Severe episodic drinking on weekends among mothers of children with FAS and PFAS accounts for 96% of all alcohol consumed. Various measures of maternal drinking are significantly correlated with negative outcomes of children in the areas of non-verbal intelligence (−0.26), verbal intelligence (−0.28), problem behavior (0.31), and overall dysmorphology score (0.59). Significantly more FAS and PFAS exists among children of rural residents (OR = 3.79). Conclusions A high rate of FAS and PFAS was again documented in this community, and it has increased. Given population similarities, we suspect that other communities in the Western Cape Province of South Africa also have high rates. Programs for prevention are needed.

Fetal alcohol syndrome (FAS) is a devastating developmental disorder resulting from alcohol exposure during fetal development. It is a considerable public health problem worldwide and is characterized by central nervous system abnormalities, dysmorphic facial features, and growth retardation. Imprinted genes are known to play an important role in growth and development and therefore four imprinting control regions (ICRs), H19 ICR, IG-DMR, KvDMR1 and PEG3 DMR were examined. It is proposed that DNA methylation changes may contribute to developmental abnormalities seen in FAS and which persist into adulthood. The participants included FAS children and controls from the Western and Northern Cape Provinces. DNA samples extracted from blood and buccal cells were bisulfite modified, the ICRs were amplified by PCR and pyrosequencing was used to derive a quantitative estimate of methylation at selected CpG dinucleotides: H19 ICR (six CpG sites; 50 controls and 73 cases); KvDMR1 (7, 55, and 86); IG-DMR (10, 56, and 84); and PEG3 DMR (7, 50, and 79). The most profound effects of alcohol exposure are on neuronal development. In this study we report on epigenetic effects observed in blood which may not directly reflect tissue-specific alterations in the developing brain. After adjusting for age and sex (known confounders for DNA methylation), there was a significant difference at KvDMR1 and PEG3 DMR, but not the H19 ICR, with only a small effect (0.84% lower in cases; p = 0.035) at IG-DMR. The two maternally imprinted loci, KvDMR1 and PEG3 DMR, showed lower average locus-wide methylation in the FAS cases (1.49%; p < 0.001 and 7.09%; p < 0.001, respectively). The largest effect was at the PEG3 DMR though the functional impact is uncertain. This study supports the role of epigenetic modulation as a mechanism for the teratogenic effects of alcohol by altering the methylation profiles of imprinted loci in a locus-specific manner.

Objective To examine the effects of prenatal alcohol exposure ascertained prospectively on infant visual acuity across a range of exposures and factors that mediate or moderate these effects. Study design Infant visual acuity was examined in 131 Cape Coloured (mixed ancestry) maternal-infant pairs in Cape Town, South Africa. Drinking patterns were documented by maternal reporting during pregnancy. Grating acuity was assessed with Teller Acuity Cards (TAC) at 6.5 months after term. Data were analyzed by correlation, multiple regression, and analysis of variance. Results Greater average daily prenatal alcohol exposure was related to poorer acuity, as indicated by lower TAC scores. The effect of alcohol on acuity was significant primarily for infants born to mothers ≥30 years of age at delivery, in comparison to infants born to younger mothers. This effect was not mediated by gestational age or birth size or attributable to alcohol-related neurocognitive deficits. Conclusions This study linked prenatal alcohol exposure ascertained prospectively to poorer visual acuity in infancy. The results are consistent with clinical and animal evidence of alcohol-related disruption of the visual system.

Objectives. We defined risk factors for fetal alcohol syndrome (FAS) in a region with the highest documented prevalence of FAS in the world. Methods. We compared mothers of 53 first-grade students with FAS (cases) with 116 randomly selected mothers of first-grade students without FAS (controls). Results. Differences between case and control mothers in our study population existed regarding socioeconomic status, religiosity, education, gravidity, parity, and marital status. Mothers of children with FAS came from alcohol-abusing families in which heavy drinking was almost universal; control mothers drank little to no alcohol. Current and past alcohol use by case mothers was characterized by heavy binge drinking on weekends, with no reduction of use during pregnancy in 87% of the mothers. Twenty percent of control mothers drank during pregnancy, a rate that declined to 12.7% by the third trimester. The percentage who smoked during pregnancy was higher for case mothers than for control mothers (75.5% vs 30.3%), but the number of cigarettes smoked was low among case mothers. The incidence of FAS in offspring of relatively young women (28 years) was not explained by early drinking onset or years of drinking (mean, 7.6 years among case mothers). In addition to traditional FAS risk factors, case mothers were smaller in height, weight, head circumference, and body mass index, all anthropomorphic measures that indicate poor nutrition and second-generation fetal alcohol exposure. Conclusions. Preventive interventions are needed to address maternal risk factors for FAS.

Aims: To determine the alcohol exposure and pharmacokinetics of alcohol in a group of women who had given birth to children with FAS, compared with women who had not given birth to FAS children. Methods: 10 women who had given birth to FAS children (FAS mothers) and 20 Controls were studied to determine how they metabolize alcohol in a single limited-access quasi-experimental session of voluntary consumption of alcohol. They had free choice in the consumption of any amount of their favourite beverage for ∼2.5 h, but their drinking was terminated if the breath alcohol concentrations (BrAC) exceeded 150 mg%. BrACs was measured during ethanol consumption and for several hours after, for estimation of alcohol exposure and pharmacokinetics. Results: FAS mothers consumed significantly larger amounts of alcohol, and achieved significantly higher peak BrAC levels than Controls. The rate of decline of alcohol from the circulation (β-60) showed a 2-fold variation across subjects but there was no significant difference between the two groups. Conclusions: This study did not show any difference in alcohol pharmacokinetics in free-choice drinking by non-pregnant women, who either have given or have never given birth to FAS children. However, mothers of FAS children tend to consume more alcohol per session. Future studies in larger samples will be needed to confirm these findings and to examine drinking patterns and other factors that may increase the risk of FAS in children of women who drink alcohol during pregnancy. ( Received 18 March 2004; first review notified 4 May 2004; in revised form 12 July 2004; accepted 17 July 2004 )

We describe an 18-month-old boy with Costello syndrome (CS) with proven partial growth hormone (GH) deficiency and hypoglycemic episodes. The hypoglycemia is deemed to be due to cortisol deficiency. This report represents the second published case of cortisol deficiency in the CS. A brief review of the endocrine disturbances in the syndrome is provided. We highlight the need for careful endocrinological evaluation of individuals with CS.

Data were obtained from three samples of women of childbearing age. One sample of women is from prenatal clinics serving Plains Indian women. The second sample is of women from the Plains whose children were referred to special diagnostic developmental clinics, as their children were believed to have developmental issues consistent with prenatal alcohol consumption. The third sample is of women from South Africa, each of whom has given birth to a child diagnosed with full fetal alcohol syndrome (FAS). Data across samples conform to expected trends on many variables. For example, the maternal age at time of pregnancy, a major risk factor for FAS, ranged from a mean of 23.5 years for the prenatal clinic sample, to 23.8 years for the developmental clinic sample, to 27.6 for the sample of women who have delivered children with FAS. Other variables of maternal risk for FAS expected from the extant literature, such as high gravidity and parity, binge drinking, heavy intergenerational drinking in the mother's extended family and immediate social network, and length of drinking career, were compared across the three samples with variable results. However, normative measures of drinking problems are unreliable when reported across cultures. An unexpected finding from this three-sample comparison was the differential risk found when comparing U.S. women to South African women. Women in the U.S. Plains Indian samples report a high consumption of alcohol in a binge pattern of drinking, yet there is less detectable damage to the fetus than among the South African women. Body mass index (BMI) and lifelong and current nutrition may have a substantial impact, along with the above factors, in relative risk for an FAS birth. The level of risk for producing a child with FAS is influenced by environmental and behavioral conditions that vary between populations and among individual women. Also, because many syndromes are genetically based, there is a need for full behavioral and genetic histories of the mother, family, and child being studied. Collecting extensive behavioral information as well as genetic histories will provide the requisite information for making an accurate diagnosis of FAS.

Pseudoxanthoma elasticum (PXE) is a heritable elastic tissue disorder recently shown to be attributable to mutations in the ABCC6 ( MRP6) gene. Whereas PXE has been identified in all ethnic groups studied to date, the prevalence of this disease in various populations is uncertain, although often assumed to be similar. A notable exception however is the prevalence of PXE among South African Afrikaners. A previous report has suggested that a founder effect may explain the higher prevalence of PXE in Afrikaners, a European-derived population that first settled in South Africa in the 17th century. To investigate this hypothesis, we performed haplotype and mutational analysis of DNA from 24 South African families of Afrikaner, British and Indian descent. Among the 17 Afrikaner families studied, three common haplotypes and six different disease-causing variants were identified. Three of these mutant alleles were missense variants, two were nonsense mutations and one was a single base-pair insertion. The most common variant accounted for 53% of the PXE alleles, whereas other mutant alleles appeared at lower frequencies ranging from 3% to 12%. Haplotype analysis of the Afrikaner families showed that the three most frequent mutations were identical-by-descent, indicating a founder origin of PXE in this population.

Background: Even though fetal alcohol syndrome (FAS) has been reported in nonwestern nations, there is a paucity of information on neurodevelopment in the affected children from those nations. This article reports on a study of cognitive-motor development in a group of children with FAS from a community in the Western Cape Province in South Africa. Methods: Thirty-four children with FAS and 34 controls from grade 1 (school entry level) classes participated. The two groups comprised Afrikaans-speaking children of mixed ancestry (South African Colored) and were matched for age, sex, and family income. The Griffiths Mental Development Scales were used to assess cognitive motor development of the participants. Results: A multivariate analysis of covariance was performed to test the group effect on the combined Griffiths subscales adjusting for maternal education. The results showed a significant group effect. Follow-up analyses revealed that a combination of four subscales (Speech and Hearing, Performance, Practical Reasoning, and Eye and Hand Coordination) primarily contributed to the overall effect. Although there was a marginal effect on the Personal-Social subscale, no significant effect on the Locomotor (gross motor) subscale was found. Conclusions: The results showed that the FAS group was markedly deficient only in higher-order cognitive-motor competencies.

We have recently mapped the genetic defect underlying pseudoxanthoma elasticum (PXE), an inherited disorder characterized by progressive calcification of elastic fibers in skin, eye, and cardiovascular system, to chromosome 16p13.1. Here we report further data on the fine-mapping and genomic structure of this locus. Haplotype analysis of informative PXE families narrowed the locus to an interval of less than 500 kb located between markers D16B9621 and D16S764. Three overlapping YAC clones were found to cover this region through YAC-STS content mapping. An overlapping BAC contig was then constructed to cover this interval and the surrounding region. About 80% of this chromosomal region has been fully sequenced using the BAC shotgun technique. Gene content and sequence analysis predicted four genes (MRP1, MRP6, PM5, and a novel transcript) and two pseudogenes (ARA and PKD1) within this interval. By screening a somatic cell hybrid panel we were able to precision-map the breakpoint of Cy185 and the starting point of a chromosomal duplication within 20 kb of BAC A962B4. The present data further refine the localization of PXE, provide additional physical cloning resources, and will aid in the eventual identification of the genetic defect causing PXE.

Proteus syndrome is a complex disorder comprising malformations and overgrowth of multiple tissues. The disorder is highly variable and appears to affect patients in a mosaic manner. This intrinsic variability has led to diagnostic confusion associated with a dearth of longitudinal data on the natural history of Proteus syndrome. To clarify some of these issues, a workshop on Proteus syndrome was held in March 1998 at the National Institutes of Health, and participants developed recommendations for diagnostic criteria, differential diagnosis, and guidelines for the evaluation of patients. This is a review of those recommendations.

Mseleni joint disease (MJD) and Handigodu joint disease (HJD) are familial skeletal disorders that affect several hundred persons in northern Zululand, South Africa and in the Shimoga district of southern India, respectively. Severe precocious, progressive degenerative osteoarthropathy, which occurs in both conditions, causes marked physical handicap by adulthood. The clinical and radiological manifestations of MJD and HJD are very similar and it is possible that they represent the same entity. HJD appears to be inherited as an autosomal dominant trait, while MJD clusters in families without a definite Mendelian pattern. It is possible that an environmental factor is active in the pathogenesis of both disorders and comparative investigations would be fruitful. The predominance of severe degenerative osteoarthropathy in both disorders may have important implications for the elucidation of the pathogenesis of the common conventional forms of osteoarthropathy.

Background. Fetal alcohol syndrome (FAS) is common in parts of South Africa; rural residence is a frequently cited risk factor. We conducted a FAS school prevalence survey of an isolated rural community in a West Coast village of Western Cape Province, so obtaining the first directly measured rate, focusing specifically on a South African rural area, of FAS and partial FAS (PFAS). Methods. The study area (Aurora village), a community of about 2 500 people in a grain-producing region, has one primary school. All learners were eligible for study inclusion. Initial anthropometry screening was followed by a diagnostic stage entailing examination by a dysmorphologist for features of FAS, neurodevelopmental assessment, and an interview assessing maternal alcohol consumption. Results. Of 160 learners screened, 78 (49%) were screen-positive, of whom 63 (81%) were clinically assessed for FAS. The overall FAS/PFAS rate among the screened learners was 17.5% (95% confidence interval 12.0 - 24.2%), with 16 (10.0%) children having FAS and 12 (7.5%) PFAS. High rates of stunting, underweight and microcephaly were noted in all learners, especially those with FAS or PFAS. Five (18%) mothers of affected children were deceased by the time of assessment. Conclusion. We describe very high rates of FAS/PFAS in an isolated rural part of the Western Cape that is not located in a viticultural region. Our study suggests that the prevalence of FAS may be very high in isolated communities, or in particular hot-spots. It adds to the growing evidence that FAS/PFAS is a significant, and underestimated, health problem in South Africa. Expanded screening and surveillance programmes, and preventive interventions, are urgently needed.

Schwartz-Jampel syndrome (SJS, MIM 255800), also known as chondrodystrophic myotonia, is a rare autosomal recessive disorder characterized by generalized myotonia, skeletal abnormalities and facial dysmorphism. Using homozygosity mapping, we localized the SJS locus to chromosome 1p34-p36.1 in a 8 cM interval flanked by markers D1S199 and D1S234. Families of different ethnic backgrounds (Tunisia and South Africa) showed genetic linkage to the same locus. Moreover, one Algerian family also demonstrated evidence of genetic linkage to 1p34-p36.1. Taken altogether, our results suggest genetic homogeneity, at least in the group of families analyzed.

The aim of the study was to document the frequency of neural tube defects (NTD) over a 20-year period in Cape Town and to determine the effects of race, gender, maternal age, parity, and season of conception on the prevalence. Multiple sources of ascertainment were used, including all maternity hospital records, neurosurgical and spinal defects clinic data, as well as those from the Human Genetics Department and Fetal Abnormality Group. The prevalence rates for NTD fluctuated between 1.74 and 0.63 per 1,000 births, but showed no significant trends over the 20-year period. Prevalence rates were highest for the white population group at 2.56 per 1,000 births compared to 0.95 per 1,000 for blacks and 1.05 per 1,000 for those of mixed ancestry. The higher rates in the whites, who are of British and European extraction and belong to the more affluent section of the community, would suggest that the possible effects of nutrition and infection are overshadowed by genetic factors. There was a female preponderance for both spina bifida (M: F ratio 0. 89) and anencephaly (M: F ratio 0. 67). The highest NTD rates were found at both ends of the maternal age range ( 35 years of age). The prevalence was highest at the extremes of birth order (1.65 and 1.58 for birth order 1and > 7, respectively, and 0.56 and 0.45 for birth order 5 and 6, respectively). A seasonal variation occurred which differed from that reported for the Northern Hemisphere and may reflect local climatic conditions. © 1994 Wiley-Liss, Inc.

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder akin to, but usually less severe than, Marfan syndrome. The clinical features are marfanoid habitus, arachnodactyly, crumpled ears, camptodactyly of the fingers and adducted thumbs, mild contractures of the elbows, knees, and hips, and mild muscle hypoplasia especially of the calf muscles. Many patients have kyphoscoliosis and mitral valve prolapse and, very occasionally, aortic root dilatation and ectopia lentis have been described. Linkage to a gene coding for fibrillin on chromosome 5q23-31 has been shown in several kindreds. The prognosis for a normal lifespan is good and improvement in joint contractures is usual.

Objective: To describe the extent and nature of developmental delay at different stages in childhood in a community in South Africa, with a known high rate of Fetal Alcohol Spectrum Disorder (FASD). Method: A cohort of infants, clinically examined for FASD at two time periods, 7-12 months (N= 392; 45 FASD) and 17-21 months of age (N= 83, 35 FASD) were assessed using the Griffiths Mental Developmental Scales (GMDS). Results: Infants and children with FASD perform worse than their Non-FASD counterparts over all scales and total developmental quotients. Mean quotients for both groups decline between assessments across subscales with a particularly marked decline in the hearing and language scale at Time 2 (scores dropping from 110.6 to 83.1 in the Non-FASD group and 106.3 to 72.7 in the FASD group; P=0.004). By early childhood the developmental gap between the groups widens with low maternal education, maternal depression, high parity and previous loss of sibling/s influencing development during early childhood. Conclusion: The FASD group show more evidence of developmental delay over both time points compared to their Non-FASD counterparts. Demographic and socio-economic factors further impact early childhood. These findings are important in setting up primary level psycho-educational and national prevention programmes especially in periurban communities with a focus on early childhood development and FASD. Keywords: Developmental Delay; Fetal Alcohol Syndrome (FAS); Griffiths Mental Developmental Scales (GMDS)

Most forms of osteogenesis imperfecta are caused by dominant mutations in either of the two genes, COL1A1 and COL1A2, that encode the pro alpha 1(I) and pro alpha 2(I) chains of type I collagen, respectively. However, a severe, autosomal recessive form of OI type III with a comparatively high frequency has been recognised in the black populations of southern Africa. We preformed linkage analyses in eight OI type III families using RFLPs associated with the COL1A1 and COL1A2 loci to determine whether mutations in the genes for type I collagen were responsible for this form of OI. Recombination between the OI phenotype and polymorphic markers at both loci was shown in three of the eight families investigated. The combined lod scores for the eight families were -10.6 for COL1A1 and -11.2 for COL1A2. Further, we examined the type I procollagen produced by skin fibroblast cultures derived from 15 affected and 12 unaffected subjects from the above eight families plus one further family. We found no evidence for defects in the synthesis, structure, secretion, or post-translational modification of the chains of type I procollagen produced by any of the family members. These results suggest that mutations within or near the type I collagen structural genes are not responsible for this form of OI.

Background. The large glycoprotein fibrillin is a structural component of elastin-containing microfibrils found in many tissues. The Marfan syndrome has been linked to the fibrillin gene on chromosome 15, but congenital contractural arachnodactyly, which shares some of the physical features of the syndrome, has been linked to the fibrillin gene on chromosome 5. Methods. Using specific markers for the fibrillin genes, we performed genetic linkage analysis in 28 families with the Marfan syndrome and 8 families with four phenotypically related disorders — congenital contractural arachnodactyly (3 families), ectopia lentis (2), mitral-valve prolapse syndrome (2), and annuloaortic ectasia (1). Results. Genetic linkage was established between the Marfan syndrome and only the fibrillin gene on chromosome 15, with a maximum lod score of 25.6 (odds for linkage, 1025.6:1). Ectopia lentis was also linked to the fibrillin gene on chromosome 15, whereas congenital contractural arachnodactyly was linked to the...

Schwartz-Jampel syndrome is a rare autosomal recessive disorder. Joint contractures, generalised myotonia, skeletal anomalies, and facial dysmorphism are common features; malignant hyperthermia is a potentially lethal complication during anaesthesia.

To describe the prevalence, characteristics and risk factors for fetal alcohol syndrome (FAS) and partial FAS among schoolgoing children in Grade 1 in Northern Cape Province, South Africa.A cross-sectional study using a two-tiered method for ascertainment of FAS/partial FAS cases, comprising: screening of growth parameters, diagnostic assessment for screen-positive children using clinical and neurocognitive assessments, and maternal history of drinking during pregnancy. Mothers or caregivers of FAS children and matched controls were interviewed.Primary schools in De Aar (8) and Upington (15). Subjects. Grade 1 pupils in 2001 (De Aar, N=536) and 2002 (Upington, N=1299).FAS or partial FAS.The prevalence of FAS/partial FAS was high: 64/536 (119.4/1000, 95% CI 93.2-149.9) in De Aar, and 97/1299 (74.7/1 000, 95% CI 61.0-90.3) in Upington. Overall, 67.2 per 1000 children (95% CI 56.2-79.7) had full FAS features. Growth retardation was also common in this population: 66.6% (1181/1774) were underweight, 48.3% (858/1776) stunted, and 15.1% had a head circumference2 SD for age. Mothers of children with FAS were less likely to have full-time employment or have attended secondary school and had lower body mass index, and about 80% currently smoked. Over two-thirds of all pregnancies had been unplanned.A very high proportion of pupils (nearly 1 in 10) had FAS/partial FAS, the rate in De Aar being the highest yet described in South Africa. FAS/partial FAS may contribute to the extremely high rate of growth retardation in South Africa as a whole and is a major cause of learning disability. These epidemiological features are important in designing preventive interventions.

Objectives: This is a third exploration of risk factors for the two most severe forms of fetal alcohol spectrum disorders (FASD), fetal alcohol syndrome (FAS) and Partial FAS (PFAS), in a South African community with the highest reported prevalence of FAS in the world. Methods: In a case control design, interview and collateral data concerning mothers of 72 first grade children with FAS or PFAS are compared with 134 randomly selected maternal controls of children from the same schools. Results: Significant differences were found between the mothers of FASD children and controls in socio-economic status, educational attainment, and a higher prevalence of FASD among rural residents. The birth order of the index children, gravidity, and still birth were significantly higher among mothers of FASD children. Mothers of children with a FASD are less likely to be married and more likely to have a male partner who drank during the index pregnancy. Current and gestational alcohol use by mothers of FASD children is bingeing on weekends, with no reduction in drinking reported in any trimester in 75 to 90% of the pregnancies that resulted in an FAS child or during 50 to 87% of PFAS-producing pregnancies. There was significantly less drinking among the controls in the second and third trimesters (11 to 14%). Estimated peak blood alcohol concentrations (BAC)s of the mothers of PFAS children range from 0.155 in the first trimester to 0.102 in the third, and for mothers of FAS children the range is from 0.197 to 0.200 to 0.191 in the first, second, and third. Smoking percentage during pregnancy was significantly higher for mothers of FASD children (82 to 84%) than controls (35%); but average quantity smoked is low in the 3 groups at 30 to 41 cigarettes per week. A relatively young average age of the mother at the time of FAS and PFAS births (28.8 and 24.8 years respectively) is not explained by early onset of regular drinking (mean = 20.3 to 20.5 years of age). But the mean years of alcohol consumption is different between groups, 16.3, 10.7, and 12.1 years respectively for mothers of FAS, FASD, and drinking controls. Mothers of FAS and PFAS children were significantly smaller in height and weight than controls at time of interview. The child’s total dysmorphology score correlates significantly with mother’s weight (−0.46) and BMI (−0.39). Bivariate correlations are significant between the child’s dysmorphology and known independent demographic and behavioral maternal risk factors for FASD: higher gravidity and parity; lower education and income; rural residence; drinks consumed daily, weekly, and bingeing during pregnancy; drinking in all trimesters; partner's alcohol consumption during pregnancy; and use of tobacco during pregnancy. Similar significant correlations were also found for most of the above independent maternal risk variables and the child’s verbal IQ, non-verbal IQ and behavioral problems. Conclusions: Maternal data in this population are generally consistent with a spectrum of effects exhibited in the children. Variation within the spectrum links greater alcohol doses with a greater severity of effects among children of older and smaller mothers of lower socio economic status in their later pregnancies. Prevention is needed to address known maternal risk factors for FASD in this population.

We report on an infant with 7 toes of the left foot in a mirror configuration in association with ipsilateral duplication of the calcaneus and fibula, tibial aplasia, femoral hypoplasia, and a teratomatous sacrococcygeal tumour. The possible pathogenetic mechanisms leading to this limb abnormality are discussed with special emphasis on a field morphogen gradient hypothesis.

Nine women between the ages of 22 and 56 years underwent cosmetic surgery for correction of the severe cutaneous stigmata of pseudoxanthoma elasticum (PXE). The outcome was generally favorable, and follow-up for up to 15 years showed only moderate regression of the skin manifestations. No serious intraoperative or postoperative complications occurred, although tissue friability, poor wound healing, and keloid formation were noted in a minority of persons. An unexpected problem of extrusion of calcium particles through the surgical wound occurred in two individuals. This resulted in delayed healing and unsightly scars.

Aims: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterized by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 gene (ATP binding cassette family C member 6) which encodes MRP6 (multidrug resistance-associated protein 6). This study aimed to investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations. Patients and methods: Mutation data were collected on an international case series of 270 PXE patients (239 probands; 31 affected family members). A dHPLC-based assay was developed to screen for mutations in all 31 exons eliminating pseudogene co-amplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. Results: Overall 316 mutant alleles in ABCC6 were identified in 239 probands, including 39 novel mutations. Mutations were found to cluster in exons 24 and 28 corresponding to the second nucleotide binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. Conclusions: This study emphasizes the principal role of ABCC6 mutations in the pathogenesis of PXE, while the reasons for phenotypic variability remain to be explored.

This study investigated whether there were differential effects of substantial prenatal alcohol exposure on letter and category fluency in children. Given that children with prenatal alcohol exposure are often impaired in executive functioning and that letter fluency taxes executive processes more than category fluency, it was expected that children with fetal alcohol syndrome (FAS) would be more impaired in letter than in category fluency. A second objective of the study was to examine the developmental trends in the two types of fluency in children with prenatal alcohol exposure. It was hypothesized that between the ages of 6 and 9 years, these FAS children would show age-related changes in category fluency but not in letter fluency.As part of a neuropsychological test battery designed for an international collaborative study of FAS in South Africa, tests of letter and category fluency were administered in Afrikaans. The participants were 62 children with FAS and 61 controls matched with respect to age, gender (58 boys and 65 girls), ethnicity, and socioeconomic status.Results showed that the FAS group had relatively greater difficulty with letter fluency than with category fluency and that the FAS group generated fewer words in both fluency conditions. Contrary to the expectation, however, alcohol-affected children demonstrated age-related linear trends in both letter and category fluency.This is the first study of verbal fluency involving a large sample of well-diagnosed children with FAS conducted in a nonwestern environment. The results are nonetheless consistent with those obtained in western countries in studies of children with various levels of prenatal alcohol exposure and various levels of fetal alcohol spectrum disorder. This study suggests that at least some aspects of the cognitive profile associated with prenatal alcohol exposure may be generalizable across cultural and ethnic boundaries.

Message in a bottle: the making of fetal alcohol syndrome, by Janet Golden, is the most comprehensive and easily read text on the history, politics, public health debate, legislation, psychosocial and family dynamics, and media discussion concerning fetal alcohol syndrome (FAS). This is a must-read for any professional involved in the study of alcohol abuse and neurodevelopmental outcomes of children, fetal medicine, pediatrics, social work, psychiatry, and other areas of mental health. The book chronologically delves into the controversial medical debates that have raged for more than 30 years regarding FAS. Golden discusses evidence that the characteristics of FAS were known long before its modern description in the Lancet in 1973 by Jones and Smith (1) based on their observations of mental deficiencies and physical abnormalities in children born to alcoholic mothers in Seattle. This contention is supported by sporadic physician accounts of epilepsy and mental retardation in children prenatally exposed to alcohol during the “gin epidemic” in 18th-century London and the brilliant observations of British physician William Sullivan in 1899, who performed the first scientific study of children of alcoholic mothers, which revealed the teratogenicity of alcohol. The formation in 1970 of a new NIH Center, the National Institute on Alcohol Abuse and Alcoholism (NIAAA), is well chronicled. Interestingly, the NIAAA did not recognize FAS as a public health hazard in its initial reports. Subsequent to the paper by Jones and Smith (1), frequent sensationalized reports in the news media discussed “alcoholic babies” (2), issues surrounding abortion in alcohol-abusive women (3), and “martinis and motherhood” (4). In addition, almost 2,000 articles on FAS appeared in professional journals between 1973 and 1985. The cost of alcohol abuse was addressed in reports to Congress, and FAS-related national mortality losses were estimated at $24 billion, while productivity losses amounted to an additional $27 billion. Mounting evidence, increased public awareness about alcohol and other drug use during pregnancy, and heated social debate likely contributed to the US surgeon general’s warning in 1988 advising pregnant women “not to drink alcoholic beverages.” Many local initiatives and state programs devoted to adult education about FAS resulted from continued research, and the Alcohol Beverage Labeling Act came into being in 1989. A link between alcohol abuse and other illicit drug use was also clearly demonstrated. Risk factors for FAS such as very poor socioeconomic circumstances, advanced maternal age, genetic predispositions, and many others have since been described. The weight of evidence and public health messages have gradually held sway, and there is now considerable attention, funding, and research dedicated to the subject. However, it is interesting that, to this day, many clinicians remain skeptical of the teratogenic effects of alcohol. Perhaps the most compelling aspect of Message in a bottle is Golden’s discussions of the litigation against mothers who abuse alcohol (and other drugs) during pregnancy and other legal and moral issues. Rehabilitation, incarceration, and feminist and civil rights activities have often been the subject of public forums and reports in diverse media. Other issues concerning the culpability of FAS-affected persons in serious crimes such as murder, arson, and rape are also addressed. Golden recounts the tortuous story of Robert Alton Harris, a convicted double murderer whose failed attempts to have his death sentence overturned, based in part on the fact that he suffered from FAS, galvanized public opinion. Golden appropriately ends with the following statement: “At the heart of these paradoxes lies our profound cultural ambivalence about women’s obligations as mothers, about the status of the fetus, about personal responsibility, and about alcoholism.” Nevertheless, equipoise among the societal, biological, and ethical considerations relating to FAS has now been largely achieved and is well described in this book.

Objective To test the sensitivity and specificity of fatty acid ethyl esters (FAEEs) extracted from meconium to identify alcohol-using pregnant women with a sensitive and specific methodology, gas chromatography-tandem mass spectroscopy (GC/MS/MS). Study design Twenty-seven samples of meconium were obtained from infants from the mixed race community in Cape Town, South Africa, who were enrolled in a longitudinal neurobehavioral study. Maternal alcohol use was reported prospectively during pregnancy. FAEEs were isolated from meconium and quantitated by GC/MS/MS. Results Ethyl oleate was the FAEE that correlated most strongly with maternal self-reported drinking, especially with the average ounces of absolute alcohol ingested per drinking day. Ethyl oleate was most strongly related to drinking in the second and third trimesters (Pearson r = .55 and .40, respectively). At a threshold of 1.5 average ounces of absolute alcohol ingested per drinking day, the area under the receiving operator characteristic curve was .92 (95% confidence interval, 0.74–0.97). Using a cut-off value of 32 ng/g, sensitivity was 84.2% and specificity was 83.3%. Conclusions Ethyl oleate concentration in meconium assayed by GC/MS/MS provides a highly sensitive and specific indicator of maternal alcohol use during pregnancy.

Factors associated with alcohol consumption during pregnancy and with fetal alcohol syndrome (FAS) births were examined as part of a larger epidemiologic study of FAS in a community in the Western Cape Province of South Africa.Using retrospective case-control methodology, 31 mothers who had given birth to FAS children 6 to 9 years previously were compared with 31 matched controls on a variety of demographic, socioeconomic, drinking, family and maternity variables. Descriptive analyses were utilized to determine major differential characteristics between the two groups.In this community with a very high rate of FAS and rather uniform low socioeconomic status, the two groups were found to be comparable with respect to age, annual income, ethnic background, age of initiation of regular drinking, age at birth of the index child, gravidity and parity. However, mothers of FAS children reported initiating drinking at an earlier age, as well as reporting higher rates of heavy alcohol consumption in their extended family, current use of alcohol, drinking before and during pregnancy, and smoking of tobacco (percentage who smoke) during each trimester of the pregnancy. Mothers of FAS children had lower educational attainment and reported lower religiosity than control mothers.This study in South Africa draws upon the experience of mothers of 31 children with FAS to confirm many of the same high-risk variables identified in maternal risk studies in the United States and Europe. Some factors associated with less maternal alcohol abuse in this high-risk population were also identified, which may be helpful for implementing prevention in this region as well as in other developing countries.

A distinctive phenotype of severe microcephaly and self-limiting dilated cardiomyopathy has been observed in two sibs suggesting autosomal recessive inheritance. Mental retardation, delayed developmental milestones, and minor dysmorphism were additional features.

Widespread epiphyseal stippling was demonstrated radiologically during the early months of life in 7 children with acrodysostosis. This finding, which does not seem to have been previously documented in this disorder, is important in the differential diagnosis.

The vestibular and ototoxic effects of the aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known; streptomycin, in particular, has been found to cause irreversible, profound, high frequency sensorineural deafness in hypersensitive persons. Aminoglycoside ototoxicity occurs both sporadically and within families and has been associated with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal RNA gene. We report on the molecular analysis of a South African family with streptomycin induced sensorineural deafness in which we have found transmission of this same predisposing mutation. It is now possible to identify people who are at risk of hearing loss if treated with aminoglycosides in the future and to counsel them accordingly. In view of the fact that aminoglycoside antibiotics remain in widespread use for the treatment of infections, in particular for tuberculosis, which is currently of epidemic proportions in South Africa, this finding has important implications for the family concerned. In addition, other South African families may potentially be at risk if they carry the same mutation.

The 20-year birth prevalence of Down syndrome in Cape Town, South Africa, was determined. All cases delivered to mothers in Cape Town, plus terminations following prenatal diagnosis, between 1 January 1974 and 31 December 1993 were ascertained. There were 784 Down syndrome pregnancies, of which 95% were trisomies. The 32 terminations comprised 18.3% of the white, 5.8% of the coloured (mixed race) and 1.4% of the black cases. The overall prevalence rate was 1.49 per 1000 (white 1.88, coloured 1.54 and black 1.29 per 1000). Analysis for linear trends showed a significant decline in rates for the total population and for whites, a downward trend for coloureds, but no decline for blacks. Over the last 5-year period the prevalence rates in all three population groups were 1.3 per 1000. An increasing risk with advancing maternal age was confirmed, but no maternal age-specific differences in rates by race were demonstrated.

We have investigated 2 young South African girls with aplasia cutis congenita, epibulbar dermoids, and strabismus. This unique association of anomalies was first documented in two unrelated boys by Toriello et al. [1993: Am. J. Med. Genet. 45:764-766]. Our clinical and histological findings are markedly similar, and we think this to be the second report of individuals with this rare syndrome.