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

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

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

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

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

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

To evaluate the safety of combination antiretroviral therapy (ART) in conception and pregnancy in different health systems

The phenotype of floating-harbor syndrome:clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Background\ud Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome.\ud \ud Methods and results\ud Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations.\ud \ud Conclusions\ud This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.The authors would like to thank the families for their cooperation and permission to publish these findings. SdM would like to thank Barto Otten. Funding was provided by the Government of Canada through Genome Canada, the Canadian Institutes of Health Research (CIHR) and the Ontario Genomics Institute (OGI-049), by Genome Québec and Genome British Columbia, and the Manton Center for Orphan Disease Research at Children’s Hospital Boston. KMB is supported by a Clinical Investigatorship Award from the CIHR Institute of Genetics. AD is supported by NIH grant K23HD073351. BBAdV and HGB were financially supported by the AnEUploidy project (LSHG-CT-2006-37627). This work was selected for study by the FORGE Canada Steering Committee, which consists of K. Boycott (University of Ottawa), J. Friedman (University of British Columbia), J. Michaud (University of Montreal), F. Bernier (University of Calgary), M. Brudno (University of Toronto), B. Fernandez (Memorial University), B. Knoppers (McGill University), M. Samuels (Université de Montréal), and S. Scherer (University of Toronto). We thank the Galliera Genetic Bank - “Telethon Genetic Biobank Network” supported by Italian Telethon grants (project no. GTB07001) for providing us with specimens

The phenotype of Floating-Harbor syndrome: Clinical characterization of 52 individuals with mutations in exon 34 of SRCAP

Background: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease-causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome. Methods and results. Clinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from

Inspiratory muscle training in severe spinal muscular atrophy : a case report

BACKGROUND/AIMS : Inspiratory muscle training aims to preserve or improve respiratory muscle strength in children with neuromuscular diseases in order to prevent or minimise pulmonary morbidity. The aim of this study was to determine the effect of inspiratory muscle training on clinical outcomes and health-related quality of life in a child with advanced neuromuscular disease and severe pulmonary restriction. METHODS : A one patient pre-test post-test study design was implemented. General function, spirometry, peak expiratory cough flow and health-related quality of life were measured at baseline and after a 6-week inspiratory muscle training programme. Inspiratory muscle strength (maximal inspiratory mouth pressure and sniff nasal inspiratory pressure) was measured every 2 weeks. The patient used a tapered flow threshold inspiratory training device (POWERbreathe K3) at an intensity of ± 30% of maximal inspiratory mouth pressure twice a day, 5 days per week. FINDINGS : The non-ambulatory 10-year-old girl with type 2 spinal muscular atrophy initially had a forced vital capacity of 18% predicted and peak expiratory cough flow of 60 litres/minute. A substantial improvement was seen in inspiratory muscle strength between baseline and 4 weeks. Patient health-related quality of life improved and patient satisfaction was high, with a score of 9/10. The patient developed a lower respiratory tract infection towards the end of the inspiratory muscle training period. No other adverse events occurred. CONCLUSIONS : Improved inspiratory muscle strength and health-related quality of life was associated with inspiratory muscle training in a child with advanced spinal muscular atrophy. Controlled clinical trials are recommended to determine the safety and efficacy of inspiratory muscle training in children with advanced spinal muscular atrophy and severe respiratory muscle weakness to inform clinical practice.The URC Equipment Grant (Western Cape); Sefako Makgatho Health Sciences University Research Development grant and the South African Society of Physiotherapy (PhD grant).https://www-magonlinelibrary-com.uplib.idm.oclc.org/journal/ijtrhj2020BiochemistryGeneticsMicrobiology and Plant Patholog

Holoprosencephaly with clefts : data of 85 patients, treatment and outcome : Part 1 : History, subdivisions, and data on 85 holoprosencephalic cleft patients

Cleft patients with Holoprosencephaly (HPE) constitute a controversy due to a variable facial appearance. HPE appearance varies from only a columella to a prolabium‑premaxilla complex agenesis up to a common unilateral or bilateral cleft lip and palate with a single central incisor, various brain deformities, and/or even normal brain development. It is challenging to designate such various appearances, to understand their etiopathogenesis, and to choose the most appropriate management. Literature was reviewed for diagnostic criteria, pregnancy history, clinical findings, brain development, survival rate, initial perioperative management, and postsurgical midfacial growth in cleft patients with HPE. The findings were compared with a clinical database of 85 cleft patients with HPE at the Department of Maxillofacial and Oral Surgery, University of Pretoria. AIMS OF PART 1: The aim of the study is to overcome disparities widely existing among clinicians regarding definitive diagnostic criteria, especially in cases with a common appearance of a uni‑ or bilateral cleft lip alveolus or cleft lip, alveolus and palate deformity, and cases presenting facial structural agenesis. MATERIALS AND METHOD : A literature search related to diagnostic criteria was compared to results of a cleft HPE database from a single tertiary institution. RESULTS : HPE cleft cases can be allocated to one of the following subdivisions: (1) columella complex agenesis (Ag‑Colum), (2) prolabium‑premaxilla‑columella complex agenesis in cleft lip‑alveolus deformities (Ag‑CLA), (3) prolabium‑premaxilla‑columella agenesis in cases with complete cleft lip alveolus palate (Ag‑CLAP), and (4) standard type (holoprosencephaly in patients with a standard cleft) with uni‑ or bilateral CLA or CLAP, hard and soft palate cleft (hPsP), and atrophic premaxillae, with or without single central incisor. Further, incidence, variation in brain development, and appearances in HPE cleft patients of different races and gender, epilepsy, and early death are discussed. CONCLUSION : This paper adds new data and facts to the existing literature related to cleft lip and palate patients suffering from HPE.Dr. EM Honey is supported by the South African Medical Research Council under a Self‑Initiated Research Grant.The South African Medical Research Councilhttp://www.amsjournal.comam2020BiochemistryGeneticsMaxillo-Facial and Oral SurgeryMicrobiology and Plant Patholog