Jessica Gardner

The natural history of sclerosteosis

Sclerosteosis (SCL) is a severe, progressive, autosomal‐recessive craniotubular hyperostosis (MIM 269500). The determinant gene (SOST) has been isolated, and genotype–phenotype correlations, as well as the elucidation of pathogenetic mechanisms, are dependent upon the documentation of the natural history of the condition. For this reason, the course and complications in 63 affected individuals in South Africa, seen over a 38‐year period, have been analyzed. Thirty‐four of these persons died during the course of the survey, 24 from complications related to elevation of intracranial pressure as a result of calvarial overgrowth. The mean age of death in this group of individuals was 33 years, with an even gender distribution. Facial palsy and deafness, as a result of cranial nerve entrapment, developed in childhood in 52 (82%) affected persons. Mandibular overgrowth was present in 46 (73%) adults and syndactyly in 48 (76%). In South Africa in 2002, 29 affected persons were alive, 10 being ≤20 years of age. It is evident that sclerosteosis is a severe disorder which places a considerable burden upon affected individuals and their families.

Autosomal Dominant Craniometaphyseal Dysplasia Is Caused by Mutations in the Transmembrane Protein ANK

Craniometaphyseal dysplasia (CMD) is a rare skeletal disorder characterized by progressive thickening and increased mineral density of craniofacial bones and abnormally developed metaphyses in long bones. Linkage studies mapped the locus for the autosomal dominant form of CMD to an approximately 5-cM interval on chromosome 5p, which is defined by recombinations between loci D5S810 and D5S1954. Mutational analysis of positional candidate genes was performed, and we describe herein three different mutations, in five different families and in isolated cases, in ANK, a multipass transmembrane protein involved in the transport of intracellular pyrophosphate into extracellular matrix. The mutations are two in-frame deletions and one in-frame insertion caused by a splicing defect. All mutations cluster within seven amino acids in one of the six possible cytosolic domains of ANK. These results suggest that the mutated protein has a dominant negative effect on the function of ANK, since reduced levels of pyrophosphate in bone matrix are known to increase mineralization.

Familial streptomycin ototoxicity in a South African family: a mitochondrial disorder.

The vestibular and ototoxic effects of the aminoglycoside antibiotics (streptomycin, gentamycin, kanamycin, tobramycin, neomycin) are well known; streptomycin, in particular, has been found to cause irreversible, profound, high frequency sensorineural deafness in hypersensitive persons. Aminoglycoside ototoxicity occurs both sporadically and within families and has been associated with a mitochondrial DNA (mtDNA) 1555A to G point mutation in the 12S ribosomal RNA gene. We report on the molecular analysis of a South African family with streptomycin induced sensorineural deafness in which we have found transmission of this same predisposing mutation. It is now possible to identify people who are at risk of hearing loss if treated with aminoglycosides in the future and to counsel them accordingly. In view of the fact that aminoglycoside antibiotics remain in widespread use for the treatment of infections, in particular for tuberculosis, which is currently of epidemic proportions in South Africa, this finding has important implications for the family concerned. In addition, other South African families may potentially be at risk if they carry the same mutation.

Broad clavicles in trisomy 8 mosaicism: a new sign.

Abstract Symmetrical clavicular widening was observed in a boy with mosaic trisomy for chromosome 8. This sign may be considered in conjunction with other clinical and radiographic features as an indication for chromosomal studies.

Lethal non-rhizomelic dysplasia epiphysealis punctata.

We describe two new cases of a rare form of lethal chondrodysplasia punctata (so-called X-linked dominant, non-rhizomelic form), a condition characterized by widespread multicentric stippled calcifications of the cartilaginous parts of the long bones, spine, ribs and flat bones. The mother of one of the patients had bone dysplasia consistent with the X-linked dominant form of chondrodysplasia punctata. We suggest that a skeletal survey, including lateral view of the spine, together with biochemical studies of peroxisomal status are indicated in all newborns with severe, unusual forms of chondrodysplasia punctata. In this way, accurate categorization of the lethal, non-rhizomelic types of this condition will be facilitated.

Osteochondrodystrophies with marked platyspondyly and distinctive peripheral anomalies

Abstract Two patients with a unique generalised bone dysplasia demonstrating severe distinctive platyspondyly are reported. This group of crippling disorders defies metabolic and histological classification. The radiographic examination is, at present, the only practical method of documentation of these rare disorders.