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Biomedical subjects

H G Brunner

Publications and source records attributed to H G Brunner.

At least 91 records · Page 5Linked to original sources
PubMed1999

Radial defects and testicular dysfunction: a new syndrome?

We describe two unrelated male patients with radial ray defects and increased serum concentrations of follicle stimulating hormone due to testicular dysfunction. This combination of features has not previously been described. Several mouse genes are known to be involved in preaxial limb development and male fertility, suggesting that the combination of radial ray defects and testicular dysfunction may represent a new syndrome in humans. Abnormalities of spermatogenesis or sperm function may constitute an under-recognized feature of human multiple congenital malformation syndromes.

Adult↗
PubMed1998

Activating and inactivating mutations in LH receptors.

The glycoprotein hormones luteinizing hormone (LH) and human chorionic gonadotropin (hCG), both of which act through the LH receptor, play an important role in the regulation of both male and female gonadal function. Testicular androgen production by the Leydig cells is almost entirely dependent on LH/hCG action, while in the ovary LH triggers both oestrogen and progestin secretion and ovulation of the Graaffian follicles. In this review we discuss the various mutations that have been found in the LH receptor gene in the human and the lessons that can be learned from the phenotypes of the carriers of these mutations.

Female↗
PubMed1998

Monoamine oxidase A deficiency: biogenic amine metabolites in random urine samples.

We have recently described an association between abnormal behaviour and monoamine oxidase A (MAO-A) deficiency in several males from a single large Dutch kindred. A characteristically abnormal excretion pattern of biogenic amine metabolites was present in 24-hour urine of affected males. Because of this strikingly abnormal metabolite pattern observed in 24 hour urine samples of MAO-A deficient males we hypothesized that it should be possible to diagnose this condition by examining random urine samples. We therefore studied multiple urine samples obtained over a two-week study period from two males with selective MAO-A deficiency. The results demonstrate that the characteristic abnormalities in the excretion of biogenic amines and their metabolites were faithfully present in every one of 12 independent samples obtained from the MAO-A deficient males over the two-week study period. We conclude that MAO-A deficiency can be reliably diagnosed by measuring the ratio of normetanephrine (NMN) to VMA (or that of NMN to MHPG) in random urine samples.

Biogenic Amines↗
PubMed1998

Congenital corneal anesthesia in children with the VACTERL association.

PURPOSE: To describe ocular manifestations in patients with the VACTERL (vertebral, anal, cardiovascular, tracheoesophageal, renal, and limb defects) association. METHOD: We reviewed the medical records of patients with the VACTERL association who had undergone treatment for amblyopia at the orthoptic department. RESULTS: A striking similarity was found in three unrelated children, who, in addition to clinical manifestations of VACTERL association, showed total corneal anesthesia of one or both eyes that had resulted in recurrent corneal erosions, keratitis, and permanent corneal opacities. Other ocular manifestations included nonparalytic strabismus, anisometropia, and amblyopia. CONCLUSION: Congenital corneal anesthesia may be part of the VACTERL association.

Abnormalities, Multiple↗
PubMed1998

Does intracytoplasmic sperm injection lead to a rise in the frequency of microdeletions in the AZFc region of the Y chromosome in future generations?

Microdeletions in the AZFc region of the Y chromosome are found in oligo- and azoospermic men. These mutations were genetically lethal before the intracytoplasmic sperm injection (ICSI) era but they can nowadays be transmitted to next generations via ICSI. We have tried to answer the question, 'Does ICSI lead to a significant rise in the frequency of these microdeletions in future generations?', by developing a mathematical model for Y-linked mutations with two variables (fitness and mutation frequency). To illustrate this model we have made estimates according to three imaginary scenarios. Using the assumptions described, the model predicted that the frequency of microdeletions in the AZFc region would increase in each generation until a plateau was reached. The higher the fitness, the higher the plateau and the later the plateau would be reached. Taking realistic estimates for fitness (0.5) and spontaneous mutation frequency (0.0001), the maximum increase in men with microdeletions would be twofold. This maximum would be already reached after five generations. However, if the fitness of these men were improved and approached 1.0, the mechanism of selection would disappear and finally all men would have the deletion in the AZFc region. Because of the assumptions in these scenarios, these estimates have limitations. The model presented shows that the rise in the frequency of men with microdeletions in the AZFc region in future generations would be limited as long as the fitness of these men remained limited.

Chromosome Deletion↗
PubMed1998

Screening male intracytoplasmic sperm injection candidates for mutations of the follicle stimulating hormone receptor gene.

Follicle stimulating hormone (FSH) is considered to be essential for spermatogenesis. Therefore, genetic abnormalities of FSH signalling on testicular Sertoli cells would be expected to affect sperm production negatively in males. Inactivating FSH receptor mutations have been reported earlier in both males and females. All affected males had elevated FSH serum concentrations and abnormal sperm parameters. We postulated that inactivating FSH receptor mutations might be a cause of oligozoospermia or azoospermia and reviewed the clinical data of 151 male intracytoplasmic sperm injection (ICSI) candidates with special attention to FSH serum concentrations. The exclusion criteria for mutation screening of the FSH receptor gene were: a history of operative sterilization or testicular malignancy, congenital abnormality other than cryptorchidism, and a chromosomal aberration or a Y-chromosome microdeletion. The inclusion criteria were: male (ICSI candidate) with azoospermia or oligoasthenoteratozoospermia (OAT) and elevated FSH serum concentrations. In total, 23 males with OAT and five males with azoospermia were tested for mutations of the coding sequences and the intron-exon boundaries of the FSH receptor gene by polymerase chain reaction (PCR) followed by single strand conformation polymorphism analysis (SSCP). Neutral polymorphisms were readily detected using this technique in both probands and controls. None of the 28 selected patients showed a pathogenic FSH receptor mutation. Mutations in the FSH receptor gene are not a common cause of infertility in ICSI candidates.

Cytoplasm↗
PubMed1998

The prevalence of PAX2 mutations in patients with isolated colobomas or colobomas associated with urogenital anomalies.

The PAX2 gene is mutated in patients with ocular colobomas, vesicoureteral reflux (VUR), and kidney anomalies (renal-coloboma syndrome, OMIM 120330). The three abnormalities which make up this syndrome also occur in isolation, but the causal genes are not known. PAX2 encodes a transcription factor of the paired box class of DNA binding proteins, important for the development of the urogenital tract, optic nerve and adjacent retina, inner ear, and CNS. In this paper we have investigated the prevalence of PAX2 mutations in patients with ocular colobomas, microphthalmos, or retinal anomalies, either in isolation or with associated urogenital anomalies. Using PCR-SSCP, most or all exons of PAX2 were examined in blood DNA from 99 patients who have either ocular anomalies alone or a combination of ocular and urogenital conditions. PAX2 mutations were not detected in patients with ocular colobomas, either in isolation or with associated abnormalities, except in one patient with typical renal-coloboma syndrome. We conclude that PAX2 mutations are unlikely to be common in patients with ocular colobomas in isolation or in patients with ocular colobomas and associated anomalies, except for patients with typical renal-coloboma syndrome where PAX2 is known to be the aetiological cause.

Abnormalities, Multiple↗
PubMed1998

A homozygous mutation in the luteinizing hormone receptor causes partial Leydig cell hypoplasia: correlation between receptor activity and phenotype.

Leydig cell hypoplasia (LCH) is characterized by a decreased response of the Leydig cells to LH. As a result, patients with this syndrome display aberrant male development ranging from complete pseudohermaphroditism to males with micropenis but with otherwise normal sex characteristics. We have evaluated three brothers with a mild form of LCH. Analysis of their LH receptor (LHR) gene revealed a homozygous missense mutation resulting in a substitution of a lysine residue for a isoleucine residue at position 625 of the receptor. In vitro analysis of this mutant LHR, LHR(I625K), in HEK293 cells indicated that the signaling efficiency was significantly impaired, which explains the partial phenotype. We have compared this mutant LHR to two other mutant LHRs, LHR(A593P) and LHR(S616Y), identified in a complete and partial LCH patient, respectively. Although the ligand-binding affinity for all three mutant receptors was normal, the hormonal response of LHR(A593P) was completely absent and that of LHR(S616Y) and LHR(I625K) was severely impaired. Low cell surface expression explained the reduced response of LHR(S616Y), while for LHR(I625K) this diminished response was due to a combination of low cell surface expression and decreased coupling efficiency. For LHR(A593P), the absence of a reduced response resulted from both poor cell surface expression and a complete deficiency in coupling. Our experiments further show a clear correlation between the severity of the clinical phenotype of patients and overall receptor signal capacity, which is a combination of cell surface expression and coupling efficiency.

Adult↗
PubMed1997

Oto- spondylo-megaepiphyseal dysplasia (OSMED): clinical description of three patients homozygous for a missense mutation in the COL11A2 gene.

We describe a syndrome of midface hypoplasia, non-progressive sensorineural deafness and epiphyseal dysplasia in 3 sibs born to consanguineous parents. Clinical and roentgenographic findings are compatible with a diagnosis of oto-spondylo-megaepiphyseal dysplasia (OSMED). Histologic study of cartilage shows severe osteoarthritis, which may necessitate joint replacements in early adulthood. Ultrastructurally, collagen fibrils are increased in diameter and show aggregation. These findings have not been reported previously and may be diagnostic of OSMED. The affected sibs are homozygous for a COL11A2 missense mutation. We compare the clinical findings in our patients with a group of patients who have a dominantly inherited, non-ocular form of Stickler syndrome due to a COL11A2 splice-site mutation. Both syndromes include midface hypoplasia, epiphyseal dysplasia, and deafness, more pronounced in OSMED. Since mutations affecting the collagen XI genes can obviously result in a spectrum of phenotypes, we performed a literature-search using POSSUM, OSSUM, and the LDDB to identify conditions that might also be caused by mutations in one of the collagen XI genes. A number of conditions matched the search terms in all databases. Of these, Marshall syndrome is very similar to OSMED. Considering these phenotypic similarities and the close association between the COL11A1 and COL11A2 gene products, we propose that Marshall syndrome may be caused by a mutation in COL11A1. We also identify a number of other conditions that could be caused by mutations in one of the collagen XI genes.

Abnormalities, Multiple↗
PubMed1997

Ectodermal dysplasia, cleft lip/palate, and severe cutaneous and osseous syndactyly in a mentally retarded girl: a new multiple malformation syndrome.

A 13-year-old mentally retarded girl with severe cutaneous and osseous syndactyly of the hands and feet, cleft lip/palate, and ectodermal dysplasia is presented. We conclude that the pattern of malformations described represents a new multiple malformation syndrome. A comparison with Zlotogora-Ogür syndrome is presented.

Abnormalities, Multiple↗
PubMed1997

Congenital conductive hearing loss in the lacrimoauriculodentodigital syndrome.

An inherited middle ear anomaly that was causing hearing impairment in a 12-year-old girl was treated successfully by a stapedotomy combined with a malleovestibulopexy. Cup-shaped ears, abnormal or absent thumbs, and skeletal deformities of the forearms were present in several members of 3 generations of a family. An autosomal dominant pattern of inheritance was recognized. These features are present in a number of previously described syndromes, but they correspond best with the lacrimoauriculodentodigital syndrome.

Abnormalities, Multiple↗
PubMed1997

A new type of maxillofacial dysostosis, inherited as an X-linked or autosomal recessive trait.

Two brothers with congenital conductive hearing loss and phenotypic characteristics of maxillofacial dysostosis are described. In the oldest boy a malformed ossicular chain was present and the conductive hearing loss was improved by a malleo-vestibulo-pexy, with post-operative hearing gain of approximately 30 dB. Although superficially similar to Treacher Collins syndrome, the facial characteristics are more typical of maxillofacial than of mandibulofacial dysostosis. These cases most likely represent a new type of maxillofacial dysostosis inherited as an X-linked or autosomal recessive trait.

Abnormalities, Multiple↗
PubMed1996

Cytogenetic abnormalities in two new patients with Pitt-Rogers-Danks phenotype.

We describe 2 patients with a combination of findings strikingly similar to those described by Pitt et al. [1984], consisting of severe mental retardation, pre- and postnatal growth retardation, history of seizures, microcephaly, ocular proptosis, mid-face hypoplasia, short and flat philtrum, and wide mouth. Our cases included, a total of only 9 patients has been described. One of our patients was treated with growth hormone and responded with a marked increase in growth velocity and skeletal maturation. Chromosome analysis was performed; both patients have a deletion of 4p as is found in Wolf-Hirschhorn syndrome. A comparison is made between our patients and patients with the Wolf-Hirschhorn syndrome (4p-). We conclude that the Pitt-Rogers-Danks phenotype is associated with 4p- in our two patients and that the syndromic status of the Pitt-Rogers-Danks status should be reassessed.

Abnormalities, Multiple↗
PubMed1996

Benign familial hematuria due to mutation of the type IV collagen alpha4 gene.

Benign familial hematuria (BFH) is characterized by autosomal dominant inheritance, thinning of the glomerular basement membrane (GBM) and normal renal function. It is frequent in patients with persistent microscopic hematuria, but cannot be clinically differentiated from the initial stages of Alport syndrome, a severe GBM disorder which progresses to renal failure. We present here linkage of benign familial hematuria with the COL4A3 and COL4A4 genes at 2q35-37 (Zmax = 3.58 at theta = 0.0). Subsequently, a glycine to glutamic acid substitution was identified in the collagenous region of the COL4A4 gene. We conclude that type IV collagen defects cause both benign hematuria and Alport syndrome. Furthermore, our data suggest that BFH patients can be carriers of autosomal recessive Alport syndrome.

Basement Membrane↗