Case report: a giant cell-rich gnathic bone lesion in a child with pycnodysostosis.

Pycnodysostosis is a skeletal dysplasia characterized by short stature, generalized osteosclerosis, acro-osteolysis, and recognizable facial features. Oral manifestations are commonly described and include a high-arched palate with dental crowding and malocclusion, hypoplastic enamel, and retained deciduous teeth with impacted permanent teeth, and there is an increased risk of developing osteomyelitis of the jaw. We report here the history of a 9-year-old male with the typical facial and skeletal phenotype of pycnodysostosis but novel oral features. He presented with bilateral progressive facial swelling, which caused functional impairment with chewing and contributed to his severe obstructive sleep apnea (OSA). The severity of his OSA required surgical intervention, and the lesions were resected. Extensive bone remodeling and replacement by fibrous tissue were noted on submucosal dissection, and bilateral subtotal maxillectomies were required. The histopathology of the biopsied lesion was consistent with a giant cell-rich lesion. Genetic testing identified a pathogenic homozygous variant in the CTSK gene, c.953G > A, p. (Cys318Tyr). The proband had a good postsurgical response with sustained improvement in his sleep OSA. We present here the history and clinical characteristics of a patient with typical features of pycnodysostosis and an unusual presentation and histopathology of gnathic bone lesions. This report adds to the body of literature on this rare condition and also highlights the finding of giant cell-rich lesions of the gnathic bones. Giant cell-rich lesions in pycnodysostosis have previously been reported in two cases in the literature. While there is not enough evidence to support a certain association with pycnodysostosis, it is prudent to consider regular oral dental reviews in affected individuals to identify pathology early and avoid such life-threatening complications.

Medicine and the Law.

Congenital high airway obstruction syndrome (CHAOS) is a rare condition that can be diagnosed antenatally by ultrasound. It is usually lethal without immediate intervention at delivery. A 24-year-old woman was diagnosed with fetal CHAOS at 27 weeks' gestation. The couple declined termination of pregnancy. A multidisciplinary team including obstetricians, geneticists, paediatric surgeons, neonatologists and anaesthetists was constituted to plan an ex utero intrapartum treatment (EXIT) procedure. After several simulations, a caesarean section was performed at 38 weeks' gestation under deep inhalational anaesthesia. The fetus was fully delivered with placenta remaining in utero to maintain perfusion. A surgical airway was established via tracheostomy in approximately 5 minutes. The operation was then completed with no maternal complications. The child remains well at 3 years of age. To our knowledge, this is the first EXIT procedure performed for CHAOS in the public sector. This procedure can be lifesaving and is possible with proper planning.

The mechanics of setting up a COVID-19 response: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa.

The SARS-CoV-2 pandemic has challenged the provision of healthcare in ways that are unprecedented in our lifetime. Planning for the sheer numbers expected during the surge has required public hospitals to de-escalate all non-essential clinical services to focus on COVID-19. Western Cape Province was the initial epicentre of the COVID-19 epidemic in South Africa (SA), and the Cape Town metro was its hardest-hit geographical region. We describe how we constructed our COVID-19 hospital-wide clinical service at Groote Schuur Hospital, the University of Cape Town's tertiary-level teaching hospital. By describing the barriers and enablers, we hope to provide guidance rather than a blueprint for hospitals elsewhere in SA and in low-resource countries that face similar challenges now or during subsequent waves.

The mechanics of setting up a COVID-19 response: Experiences of the COVID-19 epidemic from Groote Schuur Hospital, Cape Town, South Africa

The COVID-19 pandemic has challenged the provision of healthcare in ways that are unprecedented in our lifetime. Planning for the sheer numbers expected during the surge has required public hospitals to de-escalate all non-essential clinical services to focus on COVID-19. Western Cape Province was the initial epicentre of the COVID-19 epidemic in South Africa (SA), and the Cape Town metro was its hardest-hit geographical region. We describe how we constructed our COVID-19 hospital-wide clinical service at Groote Schuur Hospital, the University of Cape Town's tertiary-level teaching hospital. By describing the barriers and enablers, we hope to provide guidance rather than a blueprint for hospitals elsewhere in SA and in low-resource countries that face similar challenges now or during subsequent waves

Identification of a single MPV17 nonsense-associated altered splice variant in 24 South African infants with mitochondrial neurohepatopathy.

MPV17-related mitochondrial neurohepatopathy is a rare genetic disorder worldwide. We report on a novel pathogenic variant in the MPV17 gene in 24 unrelated neurohepatopathic infants of non-consanguineous Black South African heritage. Exome sequencing identified homozygosity for a c.106C>T nonsense variant in exon 3 of the human MPV17 gene in 2 unrelated index patients. mRNA analysis revealed transcripts both with and without exon 3, indicating both reduced splice efficiency and premature termination as mechanisms for disease. Carrier frequency in this population was found to be 1 in 68 (95% CI; 1/122-1/38) with an estimated newborn incidence of 1 in 18 496 (95% CI; 1/59 536-1/5776). Affected infants all presented with infantile onset neurohepatopathy with none surviving beyond infancy. This description of a relatively common pathogenic variant underlying a previously uncharacterized severe neurohepatopathy in South Africa will engender increased awareness, earlier diagnosis and possibly improve outcome if preventative or specific therapeutic options can be found.

Bardet Biedl syndrome in South Africa: A single founder mutation.

BACKGROUND: Bardet Biedl syndrome (BBS) is a multisystem disorder characterised by obesity, polydactyly, intellectual disability and loss of vision due to a progressive retinopathy. Although typically a highly heterogeneous autosomal recessive disease, homozygosity for single mutation in BBS 10 has been identified in a significant number of affected individuals tested in South Africa (SA). Objectives. To delineate the ethnic distribution and clinical phenotype in a cohort of SA BBS patients with the K243IfsX15 mutation in BBS 10 and discuss the implications for genetic testing of and counselling for this disorder in SA. METHOD: This was a descriptive cross-sectional study collating clinical and laboratory data retrospectively in a genetically homogenous subgroup of BBS patients from SA. RESULTS: A total of 76 patients from 74 families were tested. Homozygosity for the K243IfsX15 BBS 10 mutation was found in 50 families (67%) and heterozygosity for the same mutation in an additional two affected individuals. With the exception of one patient of mixed ancestry, all were black South Africans from different language groups. This is in keeping with the observation that BBS is more common in this ethnic group compared with white and coloured patients in SA, first made by Prof. Beighton nearly 3 decades ago. A subset of 15 patients available for detailed phenotyping confirmed consistency with well-described features of the disorder, with some overlap with other ciliopathies. The onset of visual impairment was early in our cohort, before the age of 8 years, cognitive impairment was significant, and renal and cardiac abnormalities were infrequently encountered. Conclusion. The high frequency of homozygosity for a single mutation in an ethnic subset of the SA population is strongly suggestive of a founder effect. This has allowed establishment of a diagnostic test with a high yield in our local population. Better understanding of the phenotype will improve earlier recognition of the disorder to allow for appropriate intervention. Testing can confirm but not negate a clinical diagnosis, and can permit carrier and prenatal testing in informative families.

Dental needs of intellectualy disabled children attending six special educational facilities in Cape Town.

OBJECTIVE: To assess the dental needs of a group of children with intellectual disability (ID) attending six special educational facilities in Cape Town, South Africa. Methods. This was a cross-sectional study based on a convenience sampling method. One hundred and fifty-seven children with ID attending six special educational facilities in Cape Town were included in the survey. Five schools were exclusively funded by the State and one school received additional private financial support. The oral examinations complied with guidelines drafted by Special Olympics Special Smiles programme and the Centers for Disease Control, USA. RESULTS: The most common dental disorders requiring management were gingival disease (69%) and untreated dental caries (68%). Almost 50% of the children had missing teeth. Twenty-nine percent needed orthodontic correction of malocclusion and 7% had structural abnormalities of their teeth that required either aesthetic or functional intervention. Fillings were evident in only 8% of the children. Females required more dental treatment than males. The dental needs of children with ID increased with age. There were no significant differences in the dental needs of children attending State-funded schools and those attending the single school that received additional financial assistance. CONCLUSION: The frequency of unmet dental needs of children with ID attending special educational facilities in Cape Town was high and the dental care available to them was minimal. The study highlights the need for improved dental services to ensure that optimal oral health is accessible to children with ID attending special educational facilities in Cape Town.

The tricho-rhino-phalangeal syndrome: oral manifestations and management.

Tricho-rhino-phalangeal Syndrome (TRPS) is a rare inherited dysplasia affecting hair, nasal structure and fingers. A literature review indicated that since first described, three types of manifestations have been identified. A Table summarising the oral manifestations demonstrates the variety of presentations. A South African male child presented with the syndrome and was found to show premature eruption of permanent teeth, a finding that has not been previously reported. His oro-facial manifestations also included malaligned and unerupted crowded teeth, bulbosity of the nasal tip and an elongated philtrum and evidence of mild intellectual impairment. A protocol has been developed to guide the future management of these cases.

Spina bifida: a multidisciplinary perspective on a many-faceted condition.

Open spina bifida or myelomeningocele (SBM) is the most common birth defect involving the central nervous system, second only in incidence to congenital cardiac disease. Outcomes in this disorder were poor until the mid-20th century, when modern neurosurgical techniques (closing the lesion and treating hydrocephalus) and treatment for the neuropathic bladder addressed the major causes of mortality, although SBM may still be poorly treated in the developing world. Initial management - or mismanagement - has a profound impact on survival and long-term quality of life.

Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome.

Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).

Wolf-Hirschhorn syndrome; oro-dental manifestations and management.

The major manifestations of the Wolf-Hirschhorn syndrome are developmental delay, short stature, mental impairment and epilepsy. Clefts of the lip and palate are sometimes present. Dental problems which are overshadowed by the major syndromic manifestations warrant appropriate management. We have documented an affected South African boy, discussed his dental management and reviewed the oro-dental implications of the disorder.

Freeman-Sheldon syndrome: dental and orthodontic implications.

The manifestations of the Freeman-Sheldon syndrome (FSS) in four members of a South African family of Xhosa stock have been documented. Orofacial manifestations are a major syndromic component and warrant early, specialized orthodontic intervention. Our protocol for dental management is outlined and suggestions for holistic oro-dental care are provided.