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Biomedical subjects

H Hamersma

Publications and source records attributed to H Hamersma.

At least 19 recordsLinked to original sources
PubMed2003

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 < or =20 years of age. It is evident that sclerosteosis is a severe disorder which places a considerable burden upon affected individuals and their families.

Abnormalities, Multiple↗
PubMed2001

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.

Amino Acid Sequence↗
PubMed2001

Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein.

Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth. The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of approximately 2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Here we report two independent mutations in a novel gene, termed "SOST." Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progressive effect on bone formation observed in individuals affected with sclerosteosis, along with the data presented in this study, together suggest that the SOST gene encodes an important new regulator of bone homeostasis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Dental and oral manifestations of sclerosteosis.

AIMS AND OBJECTIVES: Documentation of the oral and dental manifestations of Sclerosteosis. SETTING AND PARTICIPANTS: Sclerosteosis is a member of the family of genetic craniotubular hyperostoses. This severe progressive sclerosing bone dysplasia has important orofacial manifestations and a wide geographical distribution. Comprehensive oral and dental evaluation of eight affected adults in the Afrikaner community of South Africa was undertaken. RESULTS: Gross asymmetrical hypertrophy of the mandible was present in all eight patients, bilateral or unilateral facial paralysis with weakness of facial muscles due to facial nerve entrapment was present in six. Drooling of saliva and difficulties with mastication were frequent problems in these persons. The teeth were structurally and mechanically normal although there was partial anodontia in two patients and delayed eruption in another. Maxillary (palatal) and mandibular tori were present in every affected person. Due to the hyperostosis of the maxilla and mandible, tooth extraction was often a very difficult matter. There were no instances of post-extraction osteomyelitis of the mandible. CONCLUSIONS: Accurate differentiation of sclerosteosis from the other sclerosing bone dysplasias is crucial for effective dental prognostication and management.

Adult↗
PubMed2000

Contraceptive progestins. Various 11-substituents combined with four 17-substituents: 17alpha-ethynyl, five- and six-membered spiromethylene ethers or six-membered spiromethylene lactones.

Norethisterone (NET) is a 19-nortestosterone derivative with progestagenic and some androgenic activity, which was used in the first generation of contraceptives. NET was succeeded by levonorgestrel (LNG) and later on by desogestrel (DSG) and gestodene (GSD). Although these latter two progestins had increased potency, there was still androgenicity with gestodene and to a lesser extent with desogestrel. New progestins were synthesized in order to further enhance progestagenic and to reduce androgenic activity. Four different chemical moieties were introduced in position 17 of 19-nortestosterone, viz. 17alpha-ethynyl, five- and six-membered spiromethylene ethers, and a six-membered-spiromethylene lactone. In combination with these structures seven different substituents were added at position 11, i.e. methylene, methyl, ethyl, ethenyl, ethynyl, 2-propenyl and 1-propynyl. All substituents except for methylene occupied the 11beta-position. All these 32 compounds were synthesized and analysed in vitro and in vivo against etonogestrel (ETG, 3-keto-desogestrel), the biologically active metabolite of desogestrel. Their relative binding potency to progesterone (PR), androgen (AR) and estrogen (ER) receptors were determined in cell lysates of human breast tumor MCF-7 cells and to glucocorticoid (GR) receptors in that of human leukemic IM-9 cells. Moreover, their relative agonistic activities were assessed in Chinese hamster ovary cell-based transactivation assays. All in vivo activities were determined in McPhail (progestagenic), ovulation inhibition (progestagenic and estrogenic), Hershberger (androgenic), hormone screening (glucocorticoid and estrogen) and Allen-Doisy (estrogenic) tests after oral and for the McPhail test also after subcutaneous administration. The progestagenic binding and transactivation potencies of all compounds in the three 17-spiro series were higher than those of the corresponding analogues in the 17alpha-ethynyl series. None of the compounds showed estrogenic or clear androgenic binding and transactivation potential except for a six-membered-spiromethylene lactone with a propynyl group. This compound showed strong androgenic binding. The glucocorticoid binding and transactivation were very low for the compounds with the 17alpha-ethynyl and the five-membered-spiromethylene ether groups, whereas both six-membered-spiro series showed, clearly with methyl and ethynyl substituents, and less pronounced with methylene and ethenyl, higher binding and transactivation values. For the 17alpha-ethynyl series, the McPhail test showed high potencies with methylene, methyl and ethenyl substituents after oral treatment or with propenyl after subcutaneous administration. The introduction of the spiro substituents in position 17 led to high potencies for other 11-substituents as well. Besides methyl, also ethyl, ethynyl and propynyl were potent substituents. With ovulation inhibition tests, the ethyl, ethenyl and ethynyl substituents were the more potent compounds in all four series. However, compounds with methyl or ethynyl additions appeared to be glucocorticoidal in the hormone screening test irrespective of the 17-substituent, while with the three spiro series even methylene and ethenyl groups became active. Androgenicity was only observed at dose levels at or above 5 mg/kg, which is 2.5-fold weaker than ETG. Moreover, estrogenicity appeared negligible with the three spiro series, while with the 17alpha-ethynyl series methyl, ethyl, ethenyl and ethynyl substituents, a very high estrogenic potential was assessed. Based on the high efficacy and low side-effects, the following compounds show a high selectivity: 17alpha-ethynyl with ethyl, ethenyl and 2-propenyl substituents, six-membered spiromethylene ether with ethyl and six-membered-spiromethylene lactone with ethyl, 2-propenyl or 1-propynyl substituents. (ABSTRACT TRUNCATED)

Administration, Oral↗
PubMed1992

Synthetic approaches toward total synthesis of 12 beta-methyl- and 12-methylene-19-norpregnanes.

The effect of a substituent in the 12-position of progestagens was studied. To this end, various approaches toward the preparation of 12 beta-alkyl- and 12-alkylidenenorpregnanes were investigated. Eventually, the desired compounds 17 beta-hydroxy-12 beta-methyl-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn-3-one (37) and 17 beta-hydroxy-12-methylene-18a-homo-19-nor-17 alpha-pregn-4-en-20-yn- 3-one (38) were obtained in racemic form by total synthesis; they were shown to lack progestagenic activity.

Desogestrel↗
PubMed1985

Ophthalmological complications in the sclerosing bone dysplasias.

The sclerosing bone dysplasias are a group of rare genetic disorders in which overgrowth of the cranio-facial skeleton causes a variety of ophthalmological complications. During the past decade more than 100 South Africans with conditions in this category have been investigated and their ocular manifestations have been appraised. Sclerosteosis was diagnosed in 45 persons. In 70% of the affected adults progressive thickening of the skull led to elevation of intracranial pressure and papilloedema. Proptosis and divergent strabismus was present in 25%, while excessive lacrimation due to bone obstruction of the tear ducts was seen in 28%. Evidence of compression of cranial nerves was present in the majority of patients, but visual loss due to involvement of the second cranial nerve did not occur. Three related patients with the severe autosomal recessive form of oculodento-osseous dysplasia had visual impairment with microphthalmia, microcornea and cataracts, which had been present since birth. The severe autosomal recessive form of osteopetrosis was encountered in two infants, both of whom developed optic atrophy and became blind. The benign autosomal dominant form of osteopetrosis was diagnosed in ten persons; none had ocular involvement. Other sclerosing bone dysplasia patients with ocular involvement included two males with frontometaphyseal dysplasia and gross supra-orbital enlargement and five children with pycnodysostosis and scleral blueing.

Adult↗
PubMed1984

The syndromic status of sclerosteosis and van Buchem disease.

We have examined 50 persons with sclerosteosis in the Afrikaner community of South Africa and 15 individuals with van Buchem disease in Holland. The clinical and radiographic manifestations of these conditions are very similar, the only notable differences being greater severity and syndactyly in the majority of the patients with sclerosteosis. The Afrikaners have Dutch antecedants and it seems likely that these autosomal recessive disorders result from homozygosity of the same faulty genes. The phenotypic variation may be due to the epistatic effect of modifying genes in the Afrikaner population.

Adult↗
PubMed1981

Intracranial calcification in oculodento-osseous dysplasia.

Oculodento-osseous dysplasia (ODOD) is a rare genetic disorder characterized by microphthalmia, hypoplasia of the dental enamel, dysplastic and sclerotic changes in the skeleton and various digital malformations. The occurrence of basal ganglion calcification in this condition is of considerable interest, particularly as it has some biochemical features in common with hypoparathyroidism and pseudohypoparathyroidism. The 2 patients presented in this article did not show any features of an extrapyramidal disorder, but both experienced progressive spasticity in the limbs. The neurological disturbance was not due to compression of the neuraxis by bony overgrowth, but to an associated neurological lesion of undetermined nature. The biochemical abnormalities are discussed but as yet no explanation for the association between intracranial calcification and ODOD can be offered.

Abnormalities, Multiple↗
PubMed1980

The orthopaedic implications of the sclerosing bone dysplasias.

Sclerosing bone dysplasias are a group of unusual disorders with important and frequently lethal complications. During the past 8 years more than 80 patients with disorders of this type have been investigated in the Department of Human Genetics, University of Cape Town. It has emerged that a condition in this category 'sclerosteosis', has a high prevalence in individuals of Afrikaner stock and more than 40 affected patients have been studied. Other conditions which have been investigated during this survey include various types of osteopetrosis, pycnodysostosis and craniometaphyseal dysplasia. In each, specific radiographic features facilitate the diagnostic precision which is crucial for effective prognostication and management. Orthopaedic complications are an important aspect of these disorders.

Bone Diseases, Developmental↗
PubMed1980

Sclerosteosis in old age.

Sclerosteosis is a rare, progressive disorder in which bone overgrowth causes facial distortion and cranial nerve dysfunction. The intracranial pressure usually becomes elevated and sudden death often occurs in adulthood. Servival into old age is unusual, but we have recently had the opportunity to investigate 2 elderly patients. Their clinical and radiographic features suggest that the rate of progression diminishes in later life, and that in exceptional circumstances survival into old age is possible.

Aged↗
PubMed1980

Frontometaphyseal dysplasia: autosomal dominant or X-linked?

The clinical and radiographic manifestations in a 45-year-old male with frontometaphyseal dysplasia (FMD) are documented and depicted. Deafness and degenerative osteoarthropathy in weight-bearing joints were the main clinical problems. Widespread patchy cranial sclerosis was reminiscent of Paget's disease, while digital deformity resembled rheumatoid arthritis. On the basis of a review and tabulation of published reports, evidence emerges to support the concept of X-linked inheritance. The relationship between FMD and osteodysplasty remains a matter for speculation.

Bone Diseases, Developmental↗
PubMed1979

Endocrine function in sclerosteosis.

Sclerosteosis is a rare autosomal recessive condition which is characterized by excessive skeletal overgrowth, distortion of the facies, cranial nerve abnormalities and raised intracranial pressure. Syndactyly and digital malformation are associated features. Radiological examination reveals thickened sclerotic bone maximally involving the skull, including the pituitary fossa. Sclerosis and hyperostosis are present throughout the skeleton. Biochemical and endocrine tests were carred out on 3 patients with sclerosteosis in an attempt to detect any dysfunction of calcium regulation of the pituitary. Results revealed no abnormality of basal parathyroid or calcitonin secretion. Histological examination revealed quantitatively increased bone resorption in comparison with normal subjects, although the pattern resembled osteosclerosis. Regulation of growth hormone, adrenocorticotrophin, gonadotrophin and thyrotrophin function were intact. We conclude that pituitary function and calcium 'homeostasis' are normal in this disorder.

Adult↗
PubMed1979

Sclerosteosis in South Africa.

Sclerosteosis is a potentially lethal inherited disorder of skeletal overgrowth which has a minimum prevalence of 1 in 60,000 in the Afrikaner community of South Africa. Early presenting features are syndactyly and facial palsy, and the diagnosis should be considered in any infant of Afrikaner stock with these abnormalities. No medical treatment is available, but cosmetic surgery, cranial nerve decompression and prophylactic craniectomy be be of value.

Adolescent↗
PubMed1979

Osteopetrosis in South Africa. The benign, lethal and intermediate forms.

Osteopetrosis is an unusual bone disorder in which the skeleton is radiographically dense. The condition is conventionally subclassified into a benign autosomal dominant adult form and a malignant autosomal recessive variety. Among 14 affected individuals whom we have studied, 4 adults had an intermediate type of osteopetrosis in which serious complications included osteomyelitis, pathological fractures and dyshaemopoiesis. The fundamental biochemical relationship of this disorder with the classic forms of osteopetrosis is uncertain. The osteopetroses must be distinguished from other sclerosing bone conditions which have a different course and prognosis. Sclerosteosis and craniometaphyseal dysplasia, both of which occur in South Africa, are of practical importance in this context.

Adolescent↗
PubMed1979

Craniometaphyseal dysplasia--variability of expression within a large family.

Fifteen individuals in five generations of a kindred with branches in South Africa and England had the autosomal dominant form of craniometaphyseal dysplasia. The majority of affected adults had mild to moderate mandibular distortion, while paranasal bossing was a transient manifestation in childhood. Facial palsy with onset in childhood was present either unilaterally or bilaterally in about 30% of the patients, while 50% had auditory dysfunction which varied from mild impairment of hearing to total deafness. Stature and intellect were normal, and bone fragility, osteomyelitis and dyshaemopoesis were not features of the condition. Five other potentially affected family members had deafness or facial palsy of uncertain aetiology in the absence of other stigmata of CMD. It is uncertain whether these complications represent minor degrees of phenotypic expression of the abnormal gene.

Adolescent↗
PubMed1979

Oculodento-osseous dysplasia: heterogeneity or variable expression?

Oculodento-osseous dysplasia (ODOD) has been recognised in three South African patients from two kindreds of Dutch descent. Their ocular, nasal, dental and digital stigmata resembled those of previously reported cases, but their cranial hyperostosis and mandibular overgrowth were of much greater degree. In addition, the two survivors had serious neurological complications consequent upon spinal cord compression at the base of the skull and calcification of the basal ganglia. Two of the patients were the product of marriages between a pair of brothers and a pair of sisters, who were themselves clinically normal. This situation is best explained by autosomal recessive inheritance. As ODOD is usually transmitted as an autosomal dominant, and in view of the unusual severity of the manifestations in our patients, it is possible that the condition is heterogeneous and that they had a distinct autosomal recessive form of the disorder. The presence of minimal stigmata in the mother and two prior generations of our third patient could be equally well interpreted as representing great variation in phenotypic expression of a single dominant gene or manifestation in a heterozygote for a recessive gene.

Abnormalities, Multiple↗