History Page: Leaders in MSK Radiology Brian Joseph Cremin (1929-2012).

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of the British radiologist Brian Cremin, one of the pioneers of imaging of skeletal dysplasias.

Kazimierz S. Kozlowski, 1928.

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of the Polish radiologist Kazimierz Kozlowski, whose name is associated with the Kozlowski type of spondylometaphyseal dysplasia.

John P. Caffey, 1895-1978.

This history page in the series "Leaders in MSK Radiology" is dedicated to the achievements of Dr. John Caffey, whose name is associated with infantile cortical hyperostosis, also known as Caffey's disease.

Jacques Calvé, 1875-1954.

This history page in the series "Leaders in MSK Radiology" is dedicated to the memory and achievements of the French physician Jacques Calvé, whose name is partially associated with the medical eponym Legg-Calvé-Perthes disease.

Taurodontism in dental genetics.

Taurodontism is a dental anomaly defined by enlargement of the pulp chamber of multirooted teeth with apical displacement of the pulp floor and bifurcation of the roots. Taurodontism can be an isolated trait or part of a syndrome. A study was conducted to document the dental and craniofacial aspects of genetic thin bone disorders in South Africa. Sixty-four individuals with Osteogenesis imperfecta (OI), one individual with Pyle disease and one with Torg-Winchester syndrome respectively, were assessed clinically, radiographically and at a molecular level. Ten patients with OI XI and those with Pyle disease and Torg-Winchester syndrome had taurodontism. Taurodontism has been identified in several genetic disorders necessitating cognizance of the possible existence and implications of this characteristic when managing patients in the dental environment. Further studies should be directed toward identifying the incidence, etiology, and molecular pathways leading to taurodontism and its relationship to genetic syndromes.

The evolution of the nosology of osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a relatively common genetic skeletal disorder with an estimated frequency of 1 in 20 000 worldwide. The manifestations are diverse and although individually rare, the several different forms contribute to the production of a significant number of affected individuals with considerable morbidity and mortality. During the last decade, there have been extensive molecular investigations into the etiology of OI and these advances have direct relevance to the medical management of the disorder, and the purpose of this review is to document the history and evolution of the nosology of OI. The current nosology, based on molecular concepts, which are crucial in the identification of genotype-phenotype correlations in persons with OI, is also outlined. The successive revisions of the nosology and classification of OI have highlighted the importance of the nomenclature of the condition in order for it to be recognized by clinicians, scientists and patient advocacy groups. In this way, improved counseling of patients and individualized, tailored therapeutic approaches based on the underlying pathophysiology of the individual's type of OI have been facilitated.

Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype.

Detecting genetic modifiers of spondyloepimetaphyseal dysplasia with joint laxity in the Caucasian Afrikaner community.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL) is an autosomal-recessive skeletal dysplasia. A relatively large number of patients with SEMDJL have been identified in the Caucasian Afrikaans-speaking community in South Africa. We used a combination of Genome-Wide Human Single Nucleotide Polymorphism (SNP) Array 6.0 data and whole exomic data to potentially dissect genetic modifiers associated with SEMDJL in Caucasian Afrikaans-speaking patients. Leveraging the family-based association signal in prioritizing candidate mutations, we identified two potential modifier genes, COL1A2 and MATN1, and replicating previously identified mutation in KIF22. Importantly, our findings of genetic modifier genes and previously identified mutations are layered on the same sub-network implicated in syndromes characterized by skeletal abnormalities and intellectual disability, bone and connective tissue fragility. This study has potentially provided crucial insights in identifying the indirect modifying mutation(s) linked to the true causal mutation associated with SEMDJL. It is a critical lesson that one may use constructively especially when the pace of exomic sequencing of rare disorders continues apace.

SMD Kozlowski type caused by p.Arg594His substitution in TRPV4 reveals abnormal ossification and notochordal remnants in discs and vertebrae.

Spondylometaphyseal dysplasia Kozlowski type (SMDK) is a monogenic disorder within the TRPV4 dysplasia spectrum and has characteristic spinal and metaphyseal changes. We report skeletal MR imaging in a two-year-old patient who manifested typical clinical and radiographic features of SMDK. The diagnosis was confirmed by molecular analysis which revealed a mutation NM_021625.4:c.1781G > A - p.(Arg594His) in exon 11 of the TRPV4 gene. We have documented abnormalities in endochondral formation of the long and short tubular bones as well as round bones of the wrists and feet. The vertebral bodies had increased thickness of hyaline cartilage which enveloped ossification centers. The vertebrae and discs also had abnormalities in size, shape and structure. These anomalies were most likely the consequence of notochordal remnants presence within the intervertebral discs and in the vertebral bodies. The advantages of MR imaging in bone dysplasias caused by TRPV4 mutations are emphasized in this article.

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.

Craniofacial manifestations in osteogenesis imperfecta type III in South Africa.

OBJECTIVES: Osteogenesis imperfecta type III (OMIM 259420) is a severe autosomal recessive disorder. Affected individuals have multiple fractures, develop limb deformities with spinal malalignment and stunted stature. MATERIALS AND METHODS: The frequency of Osteogenesis imperfecta type III (OI III) is relatively high in the indigenous Black African population of South Africa. A review of the literature revealed a paucity of information regarding the craniofacial manifestations of the disorder in this ethnic group. The findings in 64 affected persons are documented. RESULTS: These abnormalities are related to the abnormal bone matrix which results in a deformed skull and dental malocclusion. The physiological process of swallowing may be an aetiological factor in the progressive development of a flattened palate. Mild changes in the shape of the head of the mandibular condyle and a lack of cortical bone on the joint surfaces were observed on cone beam computed tomography (CBCT) images. Affected persons had marked variations in the paranasal sinuses, including sinus hypoplasia and partial opacification. Cranial base anomalies were diagnosed from cephalometric radiographs and lateral skull radiographs. Platybasia and a 'J' shaped sella turcica were observed. CONCLUSION: The craniofacial abnormalities emphasize the importance of a raised level of awareness in terms of dental management and the challenges.

Digitotalar dysmorphism: Molecular elucidation.

Dominantly inherited digitotalar dysmorphism (DTD), which is characterised by flexion contractures of digits and 'rocker-bottom' feet due to a vertical talus, was first described in a South African family of European stock in 1972. We review the clinical manifestations and document the molecular basis for DTD in this prototype family. This family was restudied in 1995 and 2006 and biological specimens were obtained for molecular studies. Since the distal arthrogryposes (DAs) are genetically heterogeneous, an unbiased approach to mutation identification was undertaken through whole-exome next-generation sequencing of DNA from a single DTD-affected female. Venous blood specimens were obtained for DNA banking and subsequent molecular studies. Analysis of the nine genes that had previously been shown to cause DAs revealed a pathogenic mutation in exon nine of TNNT3. The presence of the p.(Arg63His) missense mutation at position 63 of TNNT3 was confirmed through direct cycle sequencing of genomic DNA in six affected family members for whom DNA had been archived.

A clinical and molecular investigation of two South African families with Simpson-Golabi-Behmel syndrome.

BACKGROUND: Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked recessive overgrowth syndrome manifesting primarily in boys and characterised by macrosomia, distinctive facial features and multiple congenital abnormalities. Although this rare condition is thought to be underdiagnosed, making a diagnosis is important as affected boys have a 7.5% risk of developing visceral tumours and surveillance is warranted. Mutations in GPC3 are found in up to 70% of boys affected with SGBS. OBJECTIVES: A clinical and molecular investigation of two boys with SGBS, probands B and S, and their mothers. Documentation of the clinical phenotype could assist with diagnosis in affected boys and will lead to early initiation of tumour surveillance. METHODS: Hospital folders were reviewed and clinical consultations arranged for both probands and their mothers. Molecular investigations initially searched for whole-exon deletions in GPC3 followed by gene sequencing. RESULTS: The clinical phenotype of both probands was consistent with that previously reported in the literature. The main features pointing towards the diagnosis were macrosomia, coarse facial features and macroglossia with a midline groove in the tongue. Proband B developed a Wilms tumour. He was found to have a novel mutation causing a premature stop codon. CONCLUSIONS: This research represents the first published report of SGBS in South Africa. Early recognition and confirmation of this condition is important in order to institute tumour surveillance and assist families with accurate recurrence risks.

Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia.

BACKGROUND: Beukes hip dysplasia (BHD) is an autosomal dominant disorder of variable penetrance that was originally identified in a large South African family of European origin. BHD is characterised by bilateral dysmorphism of the proximal femur, which results in severe degenerative osteoarthropathy. Previous studies mapped the disorder to a 3.34 Mb region on chromosome 4q35. OBJECTIVE: To fine-map the BHD locus and identify the disease-causing mutation by direct sequencing. RESULTS: The linked BHD allele was refined to 1.33 Mb, reducing the number of candidate genes from 25 to 16. Analysis of protein coding and invariant splice-site sequences in three distantly related individuals identified a single-candidate disease-causing variant c.868T>C within exon 8 of the ubiquitin-fold modifier 1 (Ufm1)-specific peptidase 2 gene, UFSP2. The presence of this unique mutation was confirmed in all 17 affected members of the BHD family who were genotyped. The mutation segregated with the BHD phenotype in the extended family with a two-point (single marker) LOD score of 10.4 (θ=0.0 and 80% penetrance). The mutation predicts the substitution of a highly conserved amino acid, p.Tyr290His, in the encoded protein. In vitro functional assays performed using purified recombinant wild-type and mutant UFSP2 protein demonstrated that the BHD mutation abolishes UFSP2-mediated C-terminal cleavage of its substrate, Ufm1. CONCLUSION: We report a unique UFSP2 mutation that segregates with the BHD phenotype. The predicted amino acid substitution inactivates UFSP2 proteolytic function, thus implicating the ubiquitin-fold modifier 1 cascade in this form of severe hip osteoarthropathy. The facile polymerase chain reaction-based assay we describe could be used to confirm the diagnosis of BHD, or for presymptomatic testing of members of the extended BHD family.

Novel mutation in the BMPR1B gene (R486L) in a Polish family and further delineation of the phenotypic features of BMPR1B-related brachydactyly.

BACKGROUND: Lehmann et al., [2003, 2006] have documented two different substitutions at position 486 of the BMPR1B gene which resulted in a phenotype of brachydactyly A2 [MIM 112600] or brachydactyly C with symphalangism [MIM 113100]. METHODS: In this article we report a family of Polish extraction with a novel mutation: c.1457G>T (R486L) which segregated with a complex brachydactyly. Clinical and radiological data are presented and details of previously reported patients with a pathogenic change of an amino acid at position 486 of the BMPR1B gene are summarized. CONCLUSION: Our data extends the previously known mutational and radiological spectrum associated with mutations in the BMPR1B gene and confirms the existence of a universal hotspot in the BMPR1B gene in this distinctive autosomal dominant brachydactyly disorder. It is of interest that an affected female in the Polish family had a severe congenital malformation of the venous system in addition to her digital anomalies. This observation raises the possibility of disturbance of embryonic angiogenesis by specific mutations in BMPR1B.

Autopsy observations in lethal short-rib polydactyly syndromes.

The short rib-polydactyly syndromes are a heterogeneous group of lethal autosomal recessive disorders (SRP I-IV), which result from cellular ciliary dysfunction during embryogenesis. Diagnosis is conventionally based on radiographic imaging. Since 1976, postmortem investigations of 5 affected fetuses or stillbirths have been undertaken and the visceral abnormalities have been documented. These anomalies are discussed in the context of prenatal differential diagnosis and prognostication following imaging in pregnancy and at autopsy following miscarriage or stillbirth.

Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience.

Cleidocranial dysplasia (CCD) is an uncommon but well-known genetic skeletal condition. Several hundred affected persons are members of a large extended family in the Cape Town Mixed Ancestry community of South Africa. The clinical manifestations are often innocuous, but hyperdontia and other developmental abnormalities of the teeth are a major feature and may require special dental management. Over the past 40 years, the authors have encountered more than 100 affected persons in Cape Town. Emphasis has been on dental management, but medical, genetic, and social problems have also been addressed. In this article, we have reviewed the manifestations of the disorder in the light of our own experience, and performed a literature search with emphasis on the various approaches to dental management and treatment options in CCD. Advances in the understanding of the biomolecular pathogenesis of CCD are outlined and the international and local history of the disorder is documented.

Confirmation of the recurrent ACVR1 617G>A mutation in South Africans with fibrodysplasia ossificans progressiva.

OBJECTIVE: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic condition in which progressive ossification of fibrous tissue, tendons and ligaments leads to severe physical handicap. Most affected individuals who have been studied have a recurrent 617G>A mutation in the ACVR1/ALK2 gene that codes for activin A type 1 receptor/activin-like kinase 2. The majority of publications on the genetics of FOP have concerned whites or Asians, and no genetic information is available concerning sub-Saharan blacks. The aim of the project was to determine whether or not this mutation is present in affected persons in South Africa. METHOD: Molecular mutational analysis was undertaken on genomic DNA from peripheral blood leukocytes from 6 affected South African of different population groups (4 Xhosa, 1 coloured, 1 white). RESULTS: The 6 persons with FOP were all heterozygous for the ACVR1/ALK2 617G>A mutation. This mutation was absent in 6 controls. CONCLUSION: Confirmation of the presence of this recurrent mutation facilitates diagnostic accuracy in affected persons in South Africa, and allows researchers to narrow the search for molecular targets for rational intervention to the ACVR1/ALK2 domain.

UCT's contribution to medical genetics in Africa - from the past into the future.

The Division of Human Genetics (DHG), Faculty of Health Sciences, University of Cape Town (UCT) - established in 1972 - recently celebrated its 40th anniversary. We review its history, current status and future objectives. Dr Stuart Saunders, former Professor of Medicine and Vice-Chancellor of UCT, played a pivotal role in initiating the DHG. Dr Peter Beighton served as Professor of Human Genetics from 1972 to 1999. In this period, the initial focus was on medical genetics and the development of cytogenetic, biochemical and molecular laboratories, with the help of Prof Jacquie Greenberg. Fourteen clinical and scientific DHG members obtained doctorates; of these, 8 achieved full professorial status. Current Head of the Department, Prof Raj Ramesar, succeeded to the Chair in 1999. Expansion of the molecular laboratories followed. The DHG now has comprehensive programmes for postgraduate scientific training, research and service. Publications during the lifetime of the DHG include more than 540 articles in peer-reviewed medical, genetic and scientific journals, 20 books and contributions to over 40 chapters/editorials in scientific and medical genetic books.