Engela Honey

Ultrastructural Investigation of Zimmermann-Laband Syndrome

Zimmermann-Laband syndrome (ZLS) is a very rare autosomal dominant inherited condition characterized by 3 major clinical findings of which gingival hyperplasia are always present. The great heterogenicity of the syndrome is illustrated by the numerous variable clinical findings described in the literature. The purpose of the study was to examine a patient diagnosed with ZLS and to describe possible new characteristics of this rare syndrome, including the ultrastructural morphology using a transmission electron microscope (TEM) of the gingival and dermal fibroblasts. The ultrastrucutral morphology as has not previously been described in the literature. Tissue was collected from the alveolar ridge and skin of the forearm for TEM. TEM studies indicated the presence of prominent fibroblasts situated among numerous regular dense connective tissue bundles. Genetic analysis showed a new chromosomal insertion, ins(12;8)(p11.2;q11.2q24.3), suggesting that the gene responsible for the syndrome lies on chromosome 8.

Noonan syndrome in diverse populations

Noonan syndrome (NS) is a common genetic syndrome associated with gain of function variants in genes in the Ras/MAPK pathway. The phenotype of NS has been well characterized in populations of European descent with less attention given to other groups. In this study, individuals from diverse populations with NS were evaluated clinically and by facial analysis technology. Clinical data and images from 125 individuals with NS were obtained from 20 countries with an average age of 8 years and female composition of 46%. Individuals were grouped into categories of African descent (African), Asian, Latin American, and additional/other. Across these different population groups, NS was phenotypically similar with only 2 of 21 clinical elements showing a statistically significant difference. The most common clinical characteristics found in all population groups included widely spaced eyes and low‐set ears in 80% or greater of participants, short stature in more than 70%, and pulmonary stenosis in roughly half of study individuals. Using facial analysis technology, we compared 161 Caucasian, African, Asian, and Latin American individuals with NS with 161 gender and age matched controls and found that sensitivity was equal to or greater than 94% for all groups, and specificity was equal to or greater than 90%. In summary, we present consistent clinical findings from global populations with NS and additionally demonstrate how facial analysis technology can support clinicians in making accurate NS diagnoses. This work will assist in earlier detection and in increasing recognition of NS throughout the world.

Pregnancy outcomes and birth defects from an antiretroviral drug safety study of women in South Africa and Zambia.

Objective:To evaluate the safety of combination antiretroviral therapy (ART) in conception and pregnancy in different health systems. Design:A pilot ART registry to measure the prevalence of birth defects and adverse pregnancy outcomes in South Africa and Zambia. Methods:HIV-infected pregnant women on ART prior to conception were enrolled until delivery, and their infants were followed until 1 year old. Results:Between October 2010 and April 2011, 600 women were enrolled. The median CD4+ cell count at study enrollment was lower in South Africa than Zambia (320 vs. 430 cells/&mgr;l; P < 0.01). The most common antiretroviral drugs at the time of conception included stavudine, lamivudine, and nevirapine. There were 16 abortions (2.7%), one ectopic pregnancy (0.2%), 12 (2.0%) stillbirths, and 571 (95.2%) live infants. Deliveries were more often preterm (29.7 vs. 18.4%; P = 0.01) and the infants had lower birth weights (2900 vs. 2995 g; P = 0.11) in Zambia compared to South Africa. Thirty-six infants had birth defects: 13 major and 23 minor. There were more major anomalies detected in South Africa and more minor ones in Zambia. No neonatal deaths were attributed to congenital birth defects. Conclusions:An Africa-specific, multi-site antiretroviral drug safety registry for pregnant women is feasible. Different prevalence for preterm delivery, delivery mode, and birth defect types between women on preconception ART in South Africa and Zambia highlight the potential impact of health systems on pregnancy outcomes. As countries establish ART drug safety registries, documenting health facility limitations may be as essential as the specific ART details.

ALG6–CDG in South Africa: Genotype-Phenotype description of five novel patients

ALG6-CDG (formerly named CDG-Ic) (phenotype OMIM 603147, genotype OMIM 604566), is caused by defective endoplasmic reticulum α-1,3-glucosyltransferase (E.C 2.4.1.267) in the N-glycan assembly pathway (Grünewald et al. 2000). It is the second most frequent N-glycosylation disorder after PMM2-CDG; some 37 patients have been reported with 21 different ALG6 gene mutations (Haeuptle & Hennet 2009; Al-Owain 2010). We report on the clinical and biochemical findings of five novel Caucasian South African patients. The first patient had a severe neuro-gastrointestinal presentation. He was compound heterozygous for the known c.998C>T (p.A333V) mutation and the novel c.1338dupA (p.V447SfsX44) mutation. Four more patients, presenting with classical neurological involvement were identified and were compound heterozygous for the known c.257 + 5G>A splice mutation and the c.680G>A (p.G227E) missense mutation. The patients belong to a semi-isolated Caucasian community that may have originated from European pioneers who colonized South Africa in the seventeenth/eighteenth centuries.

Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type): A unique South African disorder

Spondyloepimetaphyseal dysplasia with joint laxity (SEMD-JL) is an autosomal recessive skeletal dysplasia in which stunted stature, articular hypermobility and spinal malalignment are the major manifestations. Structural cardiac abnormalities are sometimes present. Approximately 30 affected children have been recognised previously in the Afrikaans-speaking community in South Africa, and in several, mutations in the B3GALT6 gene have been incriminated. In this article, case details of three additional affected children in two families are documented, and four additional families are mentioned. The Pierre-Robin sequence and unilateral renal agenesis are previously unreported concomitants. The mutational status where known is recorded.

A novel nonsense mutation in the EYA1 gene associated with branchio‐oto‐renal/branchiootic syndrome in an Afrikaner kindred

Branchio‐oto‐renal (BOR) syndrome is an autosomal dominant disorder characterized by the associations of hearing loss, branchial arch defects and renal anomalies. Branchiootic (BO) syndrome is a related disorder that presents without the highly variable characteristic renal anomalies of BOR syndrome. Dominant mutations in the human homologue of the Drosophila eyes absent gene (EYA1) are frequently the cause of both BOR and BO syndromes. We report a South African family of Afrikaner descent with affected individuals presenting with pre‐auricular abnormalities and either hearing loss or bilateral absence of the kidneys. Genetic analysis of the pedigree detected a novel EYA1 heterozygous nonsense mutation in affected family members but not in unaffected family members or a random DNA panel. Through mutational analysis, we conclude that this particular mutation is the cause of BOR/BO syndrome in this family as a result of a truncation of the EYA1 protein that ablates the critical EYA homologous region. To the best of our knowledge, this is the first case of BOR/BO syndrome reported in Africa or in those of the Afrikaner descent.

A novel mutation in ETFDH manifesting as severe neonatal-onset multiple acyl-CoA dehydrogenase deficiency

Neonatal-onset multiple acyl-CoA dehydrogenase deficiency (MADD type I) is an autosomal recessive disorder of the electron transfer flavoprotein function characterized by a severe clinical and biochemical phenotype, including congenital abnormalities with unresponsiveness to riboflavin treatment as distinguishing features. From a retrospective study, relying mainly on metabolic data, we have identified a novel mutation, c.1067G>A (p.Gly356Glu) in exon 8 of ETFDH, in three South African Caucasian MADD patients with the index patient presenting the hallmark features of type I MADD and two patients with compound heterozygous (c.1067G>A+c.1448C>T) mutations presenting with MADD type III. SDS-PAGE western blot confirmed the significant effect of this mutation on ETFDH structural instability. The identification of this novel mutation in three families originating from the South African Afrikaner population is significant to direct screening and strategies for this disease, which amongst the organic acidemias routinely screened for, is relatively frequently observed in this population group.

Williams–Beuren syndrome in diverse populations

Williams–Beuren syndrome (WBS) is a common microdeletion syndrome characterized by a 1.5Mb deletion in 7q11.23. The phenotype of WBS has been well described in populations of European descent with not as much attention given to other ethnicities. In this study, individuals with WBS from diverse populations were assessed clinically and by facial analysis technology. Clinical data and images from 137 individuals with WBS were found in 19 countries with an average age of 11 years and female gender of 45%. The most common clinical phenotype elements were periorbital fullness and intellectual disability which were present in greater than 90% of our cohort. Additionally, 75% or greater of all individuals with WBS had malar flattening, long philtrum, wide mouth, and small jaw. Using facial analysis technology, we compared 286 Asian, African, Caucasian, and Latin American individuals with WBS with 286 gender and age matched controls and found that the accuracy to discriminate between WBS and controls was 0.90 when the entire cohort was evaluated concurrently. The test accuracy of the facial recognition technology increased significantly when the cohort was analyzed by specific ethnic population (P‐value < 0.001 for all comparisons), with accuracies for Caucasian, African, Asian, and Latin American groups of 0.92, 0.96, 0.92, and 0.93, respectively. In summary, we present consistent clinical findings from global populations with WBS and demonstrate how facial analysis technology can support clinicians in making accurate WBS diagnoses.

Osteogenesis imperfecta type 3 in South Africa: Causative mutations in FKBP10

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.

Biallelic BRCA2 mutations in two black South African children with Fanconi anaemia

Fanconi anaemia (FA) is a genotypically and phenotypically heterogeneous genetic condition, characterized cytogenetically by chromosomal instability and breakage secondary to impaired DNA repair mechanisms. Affected individuals typically manifest growth restriction and congenital physical abnormalities and most progress to hematological disease including bone marrow aplasia. A rare genetic subtype of FA (FA-D1) is caused by biallelic mutations in the BRCA2 gene. Affected individuals manifest severe congenital anomalies and significant pigmentary changes and are additionally at risk for early onset leukemia and certain solid organ malignancies, including Wilms tumors and brain tumors. Parents of affected individuals are obligate carriers for heterozygous BRCA2 mutations and are thus potentially at risk for adult onset cancers which fall within the hereditary breast and ovarian cancer spectrum. We present two cases of black South African patients with FA diagnosed with biallelic BRCA2 mutations and discuss the phenotypic consequences and implications for them and their families. Recognition of this severe end of the phenotypic spectrum of FA is critical in allowing for confirmation of the diagnosis as well as cascade screening and appropriate care of family members.