Browsing by Author "Smit, Liani"

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    Charge syndrome : genetic aspects and dental challenges, a review and case presentation
    (BMC (part of Springer Nature), 2020-05-08) Chetty, Manogari; Roberts, Tina Sharon; Elmubarak, Mona; Bezuidenhout, Heidre; Smit, Liani; Urban, Mike
    Background: CHARGE syndrome (CS) is a rare genetic condition (OMIM #214800). The condition has a variable phenotypic expression. Historically, the diagnosis of CHARGE syndrome was based on the presence of specific clinical criteria. The genetic aetiology of CS has since been elucidated and attributed to pathogenic variation in the CHD7 gene (OMIM 608892) at chromosome locus 8q12. Case presentation: A South African female of mixed ancestry heritage, aged 4 years, was referred for dental assessment to the Faculty of Dentistry, University of the Western Cape, in 2018. She had a diagnosis of CHARGE syndrome confirmed by a Medical Geneticist from the Division of Molecular Biology and Human Genetics at the University of Stellenbosch. The patient had a long prior history of health and developmental problems, with the correct diagnosis becoming apparent over time. She presented with many oral and craniofacial features warranting consideration by the dentist including micrognathia, hypoplastic nasal bones, cranial nerve dysfunction, bruxism, craniofacial anomalies and compromised sensory perception. The treatment was mainly preventive and, although she fed through a percutaneous endoscopic gastrostomy tube (PEG), maintenance of her oral hygiene was necessitated. Conclusion: CS is a multisystem condition and the optimal care for an individual is with a specialist multidisciplinary team. The numerous systemic problems affecting these individuals take precedence in their care, and often there is neglect of their dental concerns. Given the abnormalities frequently present in the oral and craniofacial region, the authors recommend that a team of dental and other medical specialists be involved in the management of individuals with CS.
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    CHARGE syndrome : genetic aspects and dental challenges, a review and case presentation
    (BMC, 2020-05) Chetty, Manogari; Roberts, Tina Sharon; Elmubarak, Mona; Bezuidenhout, Heidre; Smit, Liani; Urban, Mike
    Background: CHARGE syndrome (CS) is a rare genetic condition (OMIM #214800). The condition has a variable phenotypic expression. Historically, the diagnosis of CHARGE syndrome was based on the presence of specific clinical criteria. The genetic aetiology of CS has since been elucidated and attributed to pathogenic variation in the CHD7 gene (OMIM 608892) at chromosome locus 8q12. Case presentation: A South African female of mixed ancestry heritage, aged 4 years, was referred for dental assessment to the Faculty of Dentistry, University of the Western Cape, in 2018. She had a diagnosis of CHARGE syndrome confirmed by a Medical Geneticist from the Division of Molecular Biology and Human Genetics at the University of Stellenbosch. The patient had a long prior history of health and developmental problems, with the correct diagnosis becoming apparent over time. She presented with many oral and craniofacial features warranting consideration by the dentist including micrognathia, hypoplastic nasal bones, cranial nerve dysfunction, bruxism, craniofacial anomalies and compromised sensory perception. The treatment was mainly preventive and, although she fed through a percutaneous endoscopic gastrostomy tube (PEG), maintenance of her oral hygiene was necessitated. Conclusion: CS is a multisystem condition and the optimal care for an individual is with a specialist multidisciplinary team. The numerous systemic problems affecting these individuals take precedence in their care, and often there is neglect of their dental concerns. Given the abnormalities frequently present in the oral and craniofacial region, the authors recommend that a team of dental and other medical specialists be involved in the management of individuals with CS.
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    Lethal Multiple Pterygium Syndrome: A South African case series with genomic investigation using whole exome sequencing
    (Stellenbosch : Stellenbosch University, 2020-12) Smit, Liani; Urban, Michael; Uren, Caitlin; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences: Molecular Biology and Human Genetics.
    Introduction:Lethal multiple pterygium syndrome (LMPS) is a rare andlethal neuromuscular disorder of the fetus. Cases are characterised by absent fetal movement (fetal akinesia) causing arthrogryposis with pterygia of major joints and inevitable intrauterine lethality. LMPS is a genetically heterogenous single gene disorder, following either autosomal or X-linked recessive patterns of inheritance. Epidemiologic, phenotypic, and genomic LMPS data have not been established in a South African population. Methods:Cases matching the LMPS definition were ascertained retrospectively (2011-2015) and prospectively (2016-2018) from medical genetic and fetal medicine records at Tygerberg Hospital. Comprehensive phenotyping was performed using prenatal ultrasound, clinical, photographic, radiologic and autopsy sources. Genomic investigationusingwhole exome sequencing (WES), was undertaken in an initial trio (affected fetus and unaffected parents) aimed at detecting disease-causing variants in known or novel genes associated with LMPS. Results:Over an 8-year period, 20 women with25 affected fetuses (11 females, 10 males, 4 unknown sex) were identified of predominantly Black South African ancestry (18/20). 20% of women had knownLMPS recurrence with the same non-consanguineous partner. Our data support an estimated LMPS prevalencerate of 1 in 20,000 inour referral area which manages approximately 50,000 deliveries per year. LMPS or non-AbstractIntroduction:Lethal multiple pterygium syndrome (LMPS) is a rare andlethal neuromuscular disorder of the fetus. Cases are characterised by absent fetal movement (fetal akinesia) causing arthrogryposis with pterygia of major joints and inevitable intrauterine lethality. LMPS is a genetically heterogenous single gene disorder, following either autosomal or X-linked recessive patterns of inheritance. Epidemiologic, phenotypic, and genomic LMPS data have not been established in a South African population. Methods:Cases matching the LMPS definition were ascertained retrospectively (2011-2015) and prospectively (2016-2018) from medical genetic and fetal medicine records at Tygerberg Hospital. Comprehensive phenotyping was performed using prenatal ultrasound, clinical, photographic, radiologic and autopsy sources. Genomic investigationusingwhole exome sequencing (WES), was undertaken in an initial trio (affected fetus and unaffected parents) aimed at detecting disease-causing variants in known or novel genes associated with LMPS. Results:Over an 8-year period, 20 women with25 affected fetuses (11 females, 10 males, 4 unknown sex) were identified of predominantly Black South African ancestry (18/20). 20% of women had knownLMPS recurrence with the same non-consanguineous partner. Our data support an estimated LMPS prevalencerate of 1 in 20,000 inour referral area which manages approximately 50,000 deliveries per year. LMPS or non-viability was antenatally recognized in 72% (18/25), with 78% (14/18) of women opting for termination of pregnancy. Half of women (2/4) who continued,developed complications, i.e. preeclampsia and hydrops fetalis precluding vaginal delivery (1/4) andsevere polyhydramnios with acute severe hypertension (1/4). Antenatal non-recognition of non-viability (7/25) occurred outside the Fetal Medicine unit and often resulted in unnecessary Caesarean section (2/7). First trimester sonographyhad a 100% (3/3) detection rate of severe fetal akinesia, i.e. multiple fixed flexion joint deformities, increased nuchal translucency, generalised oedema and reduced or absent fetal movements, but not pterygia. In addition to these findings, 2ndand 3rdtrimester fetal anatomy sonography in 16 pregnancies detected abnormal positioning of the feet (75%), pulmonary hypoplasia (63%), micrognathia (56%), pterygia (50%) and camptodactyly (50%). Fetal hydrops increased from 66% during the 1sttrimester to 80% after 24 weeks. Dysmorphology assessments (22/25) supplemented by photographic phenotyping (7/25), radiologic (6/25) and autopsy (10/25) examinations supportedantenatal findings. Several patterns emerged, includingsimilar facial dysmorphology (5/7), abnormal curvature of the spine (6/6) and evidence for possible cardiac and smooth muscle involvement, i.e. cardiac hypoplasia (2/10) on autopsy,and genitourinary tract dilatation (5/25) on ultrasound.Muscle histology was non-contributory, though immunohistochemistry was unavailable. Initial trio WES did not detect disease-causing variants in known LMPS or fetal akinesia genes but identified ASCC3is a possible gene of interest in LMPS. Conclusion:Our data suggest a 50-fold increased incidence of LMPS in our population compared to previous international estimates and appears more commonamong Black South Africans. Dysmorphic, X-ray and autopsy findings are similar to previous case reports, withadditionalfindings suggesting possible cardiac and smooth muscle involvement in addition to skeletal muscle. The genetic basis of LMPS in our population remains uncertain as no causative mutations were detected on a single trio subjected to WES. While geneticheterogeneity is possible, our case series supports an autosomal recessive pattern of inheritance, with recurrence risk implicationsfor couples. Severe fetal akinesia is detectable from 1sttrimester ultrasound and the presence of hydrops fetalis should prompt review for evidence of fetal akinesia. Early recognition of LMPS and non-viability allows for improved pregnancy management. In ongoing pregnancies there is a need for awareness of increased risk of pregnancy complications and attention to appropriate delivery management. Further genomic investigations may clarify the genetic contribution of LMPS in our population, which could be unique.