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

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

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

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

A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension : a case report

BACKGROUND : Application of whole genome sequencing (WGS) enables identification of non-coding variants that play a phenotype-modifying role and are undetectable by exome sequencing. Recently, non-coding regulatory single nucleotide variants (SNVs) have been reported in patients with lethal lung developmental disorders (LLDDs) or congenital scoliosis with recurrent copy-number variant (CNV) deletions at 17q23.1q23.2 or 16p11.2, respectively. CASE PRESENTATION : Here, we report a deceased newborn with pulmonary hypertension and pulmonary interstitial emphysema with features suggestive of pulmonary hypoplasia, resulting in respiratory failure and neonatal death soon after birth. Using the array comparative genomic hybridization and WGS, two heterozygous recurrent CNV deletions: ~ 2.2 Mb on 17q23.1q23.2, involving TBX4, and ~ 600 kb on 16p11.2, involving TBX6, that both arose de novo on maternal chromosomes were identified. In the predicted lung-specific enhancer upstream to TBX4, we have detected seven novel putative regulatory non-coding SNVs that were absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. CONCLUSIONS : Our findings further support a recently reported model of complex compound inheritance of LLDD in which both non-coding and coding heterozygous TBX4 variants contribute to the lung phenotype. In addition, this is the first report of a patient with combined de novo heterozygous recurrent 17q23.1q23.2 and 16p11.2 CNV deletions.Additional file 1. Schematic representation of 16p11.2 copy-number variant (CNV) deletion region. A) The 16p11.2 CNV region (hg19) depicting the identified deletion in the presented patient with pulmonary hypoplasia. The genes mapping within the deletion and complex low-copy repeats flanking the recurrent deletion are shown. B) Alignment tracks showing whole genome sequencing coverage at 16p11.2 CNV region in the father, mother, and child (upper, middle, and bottom track, respectively).Additional file 2. The list of single nucleotide variants used for determination of the parental origin of 16p11.2 and 17q23.2 copynumber variant deletions.Additional file 3. Distribution of the selected SNVs identified by whole genome sequencing in the 17q23.1q23.2 copy-number variant (CNV) deletion region (hg19) showing their enrichment. A) Enrichment of variants with minor allele frequency (MAF) < 10% (GnomAD, r2.0.2) observed in the presented patient (AD094). B) Enrichment of variants with MAF < 10% (GnomAD, r2.0.2) observed in the patient AD094 and previously reported patients with lethal lung developmental disorder and 17q23.1q23.2 CNV deletion.Additional file 4. Non-coding single nucleotide variants in the lungspecific enhancer region, identified in newborns with 17q23.1q23.2 copynumber variant deletion or TBX4 mutation and lethal lung disease and absent in the control individuals with the same deletion but without lung abnormalities.The US National Institutes of Health (NIH), National Heart Lung and Blood Institute (NHLBI).https://bmcmedgenomics.biomedcentral.comam2020Anatomical PathologyBiochemistryGeneticsMicrobiology and Plant Patholog

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.The Medical Research Council of South Africa under project title: Investigating the aetiology of South African pediatric patients diagnosed with mitochondrial disorders.https://www.elsevier.com/locate/jns2019-01-15hj2018GeneticsPaediatrics and Child Healt