Pena–Shokeir syndrome : current management strategies and palliative care

Pena–Shokeir syndrome (PSS) type 1, also known as fetal akinesia deformation sequence, is a rare genetic syndrome that almost always results in intrauterine or early neonatal death. It is characterized by markedly decreased fetal movements, intrauterine growth restriction, joint contractures, short umbilical cord, and features of pulmonary hypoplasia. Antenatal diagnosis can be difficult. Ultrasound features are varied and may overlap with those of Trisomy 18. The poor prognosis of PSS is due to pulmonary hypoplasia, which is an important feature that distinguishes PSS from arthrogryposis multiplex congenital without pulmonary hypoplasia, which has a better prognosis. If diagnosed in the antenatal period, a late termination of pregnancy can be considered following ethical discussion (if the law allows). In most cases, a diagnosis is only made in the neonatal period. Parents of a baby affected with PSS require detailed counseling that includes information on the imprecise recurrence risks and a plan for subsequent pregnancies.https://www.dovepress.com/the-application-of-clinical-genetics-journalBiochemistryGeneticsMicrobiology and Plant PathologyObstetrics and GynaecologyPaediatrics and Child Healt

The prevalence and spectrum of thyroid dysfunction among children with Down syndrome attending the paediatric services at two tertiary hospitals in Pretoria, South Africa

This article is submitted in partial fulfilment of the degree of Master of Medicine in the field of Paediatrics at the University of Pretoria by SFM.BACKGROUND : Down syndrome (DS) is the most common chromosomal abnormality in the paediatric setting, and thyroid dysfunction is more commonly encountered in this population than among the general population. The literature shows that the most common type of thyroid dysfunction seen in these children is subclinical hypothyroidism. OBJECTIVE : The purpose of this study was to establish the prevalence and spectrum of thyroid disease in this population with the aim of establishing easy-to-follow protocols. METHOD : A retrospective study was conducted in children with DS who were seen at the paediatric genetic clinic at two academic hospitals. Data were collected from the hospital files and the results were extracted from the National Health Laboratory Service database system. RESULTS : A total of 158 children were recruited; 25 children were excluded as they had had no thyroid function tests done. From the total of 133 included children, 70 (52.6%) were male. Babies born in one of the two hospitals numbered 60 (45.1%), whereas 54.9% were born in the other hospital. A total of 77 (57.9%) were found to have thyroid dysfunction; 55.8% of these patients were male. The most common thyroid abnormality was subclinical hypothyroidism in n=66/133 (49.6%), accounting for 85.7% of the causes of the thyroid dysfunction. Most children (n=45/133 (33.8%)) had their first thyroid function test done before the age of 2 months, followed by the age group of 1 - 5 years (n=34/133 (25.56%)). The total number of children started on treatment for their thyroid dysfunction was n=5/77 (6.49%). CONCLUSION : Thyroid dysfunction is seen more commonly in children with DS compared with the general population, which was very evident in the present study. A standardised protocol will have a significant impact on the early management of these children, to prevent further cognitive impairment, especially in developing countries and at any level of healthcare. The recommendations for thyroid dysfunction screening by the American Academy of Pediatrics can be adjusted and tailored for the South African population. Early diagnosis and referral of children with DS to a secondary- or tertiary-level facility is of utmost benefit for these children for screening and treatment of comorbidities and complications.http://www.sajch.org.za/index.php/SAJCHhj2024BiochemistryGeneticsMicrobiology and Plant PathologyPaediatrics and Child HealthSDG-03:Good heatlh and well-bein

Case report of sudden death in a child with Williams syndrome following administration of anaesthesia

Williams syndrome is a neurodevelopmental disorder characterized by distinctive personality traits, facial features (so called “elfin face”) and cardiac abnormalities, of which supravalvular aortic stenosis is the most common lesion found. The cause is a deletion of a group of genes on chromosome 7q11.23. Administration of anaesthesia to these patients carries a higher risk for sudden death due to the cardiac defects. The purpose of this case study is to demonstrate the entity in the South African population, to review the literature, to put emphasis on the multi-disciplinary approach in the pre-operative management, and to review the medico-legal investigation of intra-operative deaths. Furthermore, administration of anaesthesia in the remote location and to syndromic children will also be discussed.http://www.tandfonline.com/loi/ojaa20hb2016Forensic MedicineGeneticsMaxillo-Facial and Oral Surger

Three new families with recurrent male miscarriages and hypercoiled umbilical cord

No abstract available.http://journals.lww.com/clindysmorphol/pages/default.aspx2016-07-31hb201

Associated syndromes and other genetic variations at a South African cleft lip and palate clinic

A retrospective study was done of data on all patients registered at one of the largest cleft lip and palate clinics in South Africa (n = 3174). The associated syndromes and other genetic variations [(abbreviation:) ASGV] found in the population of persons suffering from facial cleft deformities (FCD) were analysed. 832 (26.2%) cleft lip and/ or palate patients presented with ASGV. Fifty-seven different types of syndromes were recorded of which the Fairbaim-Robin appearance (FRA) (or Pierre Robin sequence) 169 (5.3%), the Demarque-van der Woude syndrome 40 (1.3%), and the holoprosencephaly sequence cases 32 (1.0%) were the three most common ones. The three most common genetic variations found in the non-syndromic patients, were heart involvement 53(1.7%), club foot 42 (1.3%) and various eye problems 39 (1.2%). The main facial cleft deformity, namely the cleft lip, alveolus and palate (CLAP), was found in 26.2% o f the ASGV-group. This particular cleft deformity was recorded at 39.7% in the FCD clinic. On the other hand, the hard and soft palate cleft (hPsP) group was found in 32.9% of patients who also had ASGV; in the total group o f patients registered at the clinic, it accounted for only 16.6%. This means that ASGV occur less commonly in the CLAP group of patients, than in the hPsP group of patients.http://www.curationis.org.zaam2013ay201

A South African family with oculopharyngeal muscular dystrophy : clinical and molecular genetic characteristics

Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD. The proband, a 64-year-old woman, presented to the neurology outpatient department at Steve Biko Academic Hospital, Pretoria. A sibship of 18 individuals was identified, of whom eight had OPMD. Four patients were interviewed and examined clinically, and electromyographic studies were performed. Molecular analysis of the PABPN1 gene was performed by polymerase chain reaction amplification and direct sequencing of exon 1 in three of the patients. Patients presented with ptosis, external ophthalmoplegia, dysphagia, dysarthria and mild proximal weakness. High foot arches and absent ankle reflexes raised the possibility of peripheral neuropathy, but electromyography showed only mildly low sensory amplitudes, and myopathic units in two patients.http://www.samj.org.zaam201

Mutation profiling in South African patients with Cornelia de Lange syndrome phenotype

DATA AVAILABILITY STATEMENT : The variants described here were submitted to ClinVar and can be viewed under Organization ID 508172 or the ClinVar IDs recorded in Table 1. Data available on reasonable request from the corresponding author.BACKGROUND : Cornelia de Lange Syndrome (CdLS) presents with a variable multi-systemic phenotype and pathogenic variants have been identified in five main genes. This condition has been understudied in African populations with little phenotypic and molecular information available. METHODS AND RESULTS : We present a cohort of 14 patients with clinical features suggestive of CdLS. Clinical phenotyping was carried out and cases were classified according to the international consensus criteria. According to this criteria, nine patients had classical CdLS, one had non-classical CdLS and four presented with a phenotype that suggested molecular testing for CdLS. Each patient underwent mutation profiling using a targeted next generation sequencing panel of 18 genes comprising known and suspected CdLS causal genes. Of the 14 patients tested, pathogenic and likely pathogenic variants were identified in nine: eight variants in the NIPBL gene and one in the STAG1 gene. CONCLUSIONS : We present the first molecular data for a cohort of South African patients with CdLS. Eight of the nine variants identified were in the NIPBL gene, the most commonly involved gene in cases of CdLS. This is also the first report of a patient of African ancestry presenting with STAG1-related CdLS.The National Research Foundation and the South African Medical Research Council.http://www.wileyonlinelibrary.com/journal/mgg3hj2024BiochemistryGeneticsMicrobiology and Plant PathologySDG-03:Good heatlh and well-bein

A feasible molecular diagnostic strategy for rare genetic disorders within resource-constrained environments

DATA AVAILABILITY : The datasets used or analyzed during the current study are available on reasonable request. Variant information was submitted to ClinVar and can be viewed under Organization ID 508172.Timely and accurate diagnosis of rare genetic disorders is critical, as it enables improved patient management and prognosis. In a resource-constrained environment such as the South African State healthcare system, the challenge is to design appropriate and cost-effective assays that will enable accurate genetic diagnostic services in patients of African ancestry across a broad disease spectrum. Next-generation sequencing (NGS) has transformed testing approaches for many Mendelian disorders, but this technology is still relatively new in our setting and requires cost-effective ways to implement. As a proof of concept, we describe a feasible diagnostic strategy for genetic disorders frequently seen in our genetics clinics (RASopathies, Cornelia de Lange syndrome, Treacher Collins syndrome, and CHARGE syndrome). The custom-designed targeted NGS gene panel enabled concurrent variant screening for these disorders. Samples were batched during sequencing and analyzed selectively based on the clinical phenotype. The strategy employed in the current study was cost-effective, with sequencing and analysis done at USD849.68 per sample and achieving an overall detection rate of 54.5%. The strategy employed is cost-effective as it allows batching of samples from patients with different diseases in a single run, an approach that can be utilized with rare and less frequently ordered molecular diagnostic tests. The subsequent selective analysis pipeline allowed for timeous reporting back of patients results. This is feasible with a reasonable yield and can be employed for the molecular diagnosis of a wide range of rare monogenic disorders in a resource-constrained environment.In part by the National Research Foundation (NRF) of South Africa, the University of the Witwatersrand FRC individual grant, the National Health Laboratory Service Research Trust and South African Medical Research Council (SAMRC) with funds received from the Self-Initiated Research Grant (SIR). Open access funding provided by University of the Witwatersrand.http://link.springer.com/journal/12687hj2024BiochemistryGeneticsMicrobiology and Plant PathologyNon

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.The South African Medical Research Council and the National Research Foundation.http://www.samj.org.zaam2017Genetic

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 CD4þ cell count at study enrollment was lower in South Africa than Zambia (320 vs. 430 cells/ml; P<0.01). The most common antiretroviral drugs at the time of conception included stavudine, lamivudine, and nevirapine. There were 16 abortions (2.7%), 1 ectopic pregnancy (0.2%), 12 (2.0%) stillbirths, and 571 (95.2%) live infants. Deliveries were more often preterm (29.7 vs. 18.4%; P¼0.01) and the infants had lower birth weights (2900 vs. 2995 g; P¼0.11) 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.President’s Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of Cooperative Agreements U62/CCU123541, 3U2GGH000175–01W1, and 3U2GPS001421.http://www.lww.com/product/?0269-9370hb201