Sean Sellars

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.

Childhood deafness in southern Africa: An aetiological survey of 3,064 deaf children

We have completed a survey of the causes of deafness in 3,064 children with defective hearing who attend special schools in Southern Africa. Specific genetic or multifactorial syndromes were diagnosed in 7 per cent, familial undifferentiated deafness was recognized in 11 per cent, while in 25 per cent the deafness was acquired.

Hearing Impairment and Pigmentary Disturbancea

Hearing impairment is a variable manifestation of several heritable conditions in which pigmentation of the skin or eyes is abnormal. Some of these disorders are well recognized although uncommon, while others are virtually private syndromes. Practical issues concerning the major conditions of this type are reviewed in this article on a basis of a survey of 4452 profoundly deaf children attending special schools in Southern Africa, together with investigations in affected families. The Waardenburg syndrome (WS), which is the most common deafness-depigmentation disorder, was present in 121 (2.7%) of the 4452 deaf scholars. Further studies in 7 multigeneration affected families confirmed phenotypic variability and indicated a need for internationally agreed diagnostic criteria. In 4 Cape Town families of mixed ancestry the WS-I gene was linked to the 2q37 locus, but in another large kindred no linkage could be demonstrated. Nonallelic heterogeneity is possible. There is uncertainty concerning possible interrelationship between WS and piebaldism. The phenotypic consistency of a South African family in which 7 persons in 3 generations had gross piebaldism in the absence of disturbance of hearing or involvement of the eyes and periorbital structures is suggestive that this disorder and WS are separate entities. Molecular investigations indicate that the gene for piebaldism in this kindred is not situated at the WS-I locus 2q37. Deafness and hyperpigmentation are present in neurofibromatosis type II (acoustic neuromata) and the multiple lentigines syndrome, while retinal pigmentation is a feature of the Usher syndrome. This latter entity is apparently much less common in Southern Africa than in other parts of the world.

Familial aggregation of streptomycin ototoxicity: autosomal dominant inheritance?

Eight members of a large kindred of mixed ancestry from a remote rural area of South Africa were investigated for deafness. In each, severe permanent perceptive hearing loss had developed during antituberculous therapy with streptomycin sulphate in conventional doses. Although unproven by the data available in this study, the familial aggregation and pattern of distribution of sensitivity to streptomycin suggested autosomal dominant inheritance.

Autosomal recessive inheritance of Charcot-Marie-Tooth disease associated with sensorineural deafness

Three siblings with a combination of sensorineural deafness and the Charcot‐Marie‐Tooth syndrome have been investigated in a consanguineous Indian kindred. This syndrome, which to the best of our knowledge has not previously been reported, is probably inherited as an autosomal recessive trait.

Chemical burns of the oesophagus

Chemical burns of the oesophagus caused by ingestion of corrosives present a difficult and potentially dangerous problem of management. Initial failure to recognize the seriousness of the injury and inexperience in the handling of the severer burn may result in consequences which are both life-threatening and life-long. Analysis of 95 patients who had ingested caustic substances is presented. Ninty-one sustained burns of the mouth, 39 of the hypopharynx or oesophagus, and 31 had laryngeal burns. Sixty-three were children of 15 years and under. Caustic soda, especially in children, was the most common substance ingested. Severe oesophageal strictures developed early in 17 patients and in a further 21 oesophageal stricturing occurred late. A protocol for the management of these patients is discussed.

The sphenoid sinus mucocoele

Mucocoeles, mucopyocoeles and empyemas of the sphenoid sinus are rare, but potentially dangerous. Their occurrence is accompanied by a multitude of clinical symptoms and signs, which confuse the diagnosis and may lead to its mismanagement. The treatment of this condition is surgical and in its early states essentially simple. At Groote Schuur Hospital over a 6-year period (1972-1977) 6 patients with mucocoeles, mucopyocoeles or abscesses of the sphenoid sinuses have been seen. Their clinical presentation, radiological findings and surgical treatment are described and discussed. Correctly managed this condition should completely resolve; however, there is a mortality associated with delay or misdiagnosis.

Bilateral facial nerve palsies ; Groote Schuur Hospital experience

Bilateral facial nerve palsies are rare. This article details the Cape Town experience of 24 patients with this condition seen over the past 20 years and highlights the three main groups in which these bilateral facial nerve palsies occurred. These are Bells palsy, fracture of the temporal bones and sclerosteosis. A variety of other rare causes was also found. Bells palsy remains a diagnosis of exclusion though there has been some evidence to suggest implication of the Herpes simplex virus. The mechanism whereby temporal bone fractures cause bilateral facial nerve palsies is discussed. The clinical presentation and management of sclerosteosis is also discussed.

An evaluation of the Shandon Papspin liquid-based oral test using a novel cytologic scoring system.

OBJECTIVES The aim of this study was to evaluate a cost-effective oral liquid-based cytology screening test, Shandon Papspin (PS). STUDY DESIGN We compared the diagnostic accuracy of PS with surgical biopsy in 69 patients. Transepithelial cytology specimens were obtained with the use of cervical cytobrushes. Cytology specimens were graded and scored by using a novel oral cytologic grading and scoring system. RESULTS Histologic diagnosis of dysplasia or malignancy was made in 51/69 cases, and cytology identified 49/51 cases, with a sensitivity of 96% and specificity of 100%. The best cutoff value for distinguishing reactive/mildly dysplastic lesions from high grade/invasive squamous cell carcinoma was determined to be a cytologic score of 3, representing a sensitivity of 95% and specificity of 96%. CONCLUSIONS PS appears to be an accurate and economical test for detection of high-risk dysplasias and cancers, but the real significance of this method will be its diagnostic accuracy in studies focusing strictly on lesions with a low level of clinical concern.

Angiocentric T-cell lymphoma: an extensive lesion involving the posterior tongue, hypopharynx and supraglottis.

Angiocentric T-cell lymphoma, which in the past has been grouped with a variety of granulomatous diseases, occur uncommonly as a destructive condition of the posterior nasal space and midface. We report on a patient with a chronic granular ulcerative lesion involving the posterior tongue, hypopharynx and supraglottis.