Autosomal dominant stapes ankylosis with broad thumbs and toes,hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG,the gene encoding noggin

Although fixation of the stapes is usually progressive and secondary to otosclerosis, it may present congenitally, with other skeletal manifestations, as an autosomal dominant syndrome-such as proximal symphalangism (SYM1) or multiple-synostoses syndrome (SYNS1), both of which are caused by mutations in NOG, the gene encoding noggin. We describe a family that was ascertained to have nonsyndromic otosclerosis but was subsequently found to have a congenital stapes ankylosis syndrome that included hyperopia, a hemicylindrical nose, broad thumbs and great toes, and other minor skeletal anomalies but lacked symphalangism. A heterozygous nonsense NOG mutation-c.328C-->T (Q110X), predicted to truncate the latter half of the protein-was identified, and a heterozygous insertion in NOG-c.252-253insC, in which the frameshift is predicted to result in 96 novel amino acids before premature truncation-was identified in a previously described second family with a similar phenotype. In contrast to most NOG mutations that have been reported in kindreds with SYM1 and SYNS1, the mutations observed in these families with stapes ankylosis without symphalangism are predicted to disrupt the cysteine-rich C-terminal domain. These clinical and molecular findings suggest that (1) a broader range of conductive hearing-loss phenotypes are associated with NOG mutations than had previously been recognized, (2) patients with sporadic or familial nonsyndromic otosclerosis should be evaluated for mild features of this syndrome, and (3) NOG alterations should be considered in conductive hearing loss with subtle clinical and skeletal features, even in the absence of symphalangism.     

Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22.

Multiple synostoses syndrome is an autosomal dominant disorder characterized by premature onset of joint fusions, which initially affect the interphalangeal joints, by characteristic facies, and by deafness. We performed linkage analysis on a large Hawaiian family with multiple synostoses syndrome. Because another autosomal dominant disorder, proximal symphalangism, shares some clinical symptoms with multiple synostoses syndrome and has been linked to markers at loci at chromosome 17q21-22, we tested the hypothesis that multiple synostoses syndrome is linked to the same chromosomal region. Using polymorphic markers from the proximal symphalangism interval, we conducted linkage analysis and showed that the multiple synostoses-syndrome phenotype is linked to the same chromosomal region. A maximum LOD score of 3.98 at recombination fraction of .00 was achieved for the marker at locus D17S787. Further genetic analysis identified individuals with recombinant genotypes, allowing localization of the disease gene within the interval D17S931-D17S792, a 16-cM region. These data provide evidence that multiple synostoses syndrome and proximal symphalangism may be allelic disorders.     

Pedal symphalangism in modern American and Japanese skeletons

Pedal symphalangism is a surprisingly common heritable trait of the human foot. In individuals exhibiting the trait, the joint between the intermediate and distal phalanges of one or more lateral toes never develops, resulting in toes with two phalanges rather than three. This study was undertaken to explore variation in the frequency of pedal symphalangism among groups with widely different geographic ancestry, and to consider the applicability of this trait to skeletal biological distance studies. A total of 460 Euro-American, 191 African-American and 99 Japanese skeletons were examined for presence of pedal symphalangism. The American individuals date to the first half of the 20th c, while the Japanese individuals date to the late 19th and early 20th c. Although the country of ancestry is unknown for most of the American individuals, the Euro-Americans appear to be largely northern European, with roots in Germany, Ireland and Scandinavia, while the African-Americans are primarily descendants of slaves with roots in west African countries such as Nigeria, Benin, Togo, Ghana and Sierra Leone. Frequencies of fifth toe pedal symphalangism were calculated and compared among all three samples and found to be significantly higher in modern Japanese (83.7%) than in either Euro-Americans (46.4%) or African-Americans (44.0%). The Euro- and African-American frequencies were statistically indistinguishable for symphalangism of the fifth toe. In the fourth toe, however, the opposite result was found. The African-American frequency (7.9%) was significantly higher than the Euro-American frequency (2.6%), while no difference was found between the African-Americans and Japanese (11.7%). Since fourth toe pedal symphalangism has never been observed in the absence of fifth toe involvement, some of the same genes are clearly involved in producing the trait in both toes. However, differences in the pattern of fourth and fifth toe expression among the three groups identified in this study suggest that additional genetic or developmental factors may play a role in expression of pedal symphalangism in each of the toes.     

A 1.6-Mb Microdeletion in Chromosome 17q22 Leads to NOG-Related Symphalangism Spectrum Disorder without Intellectual Disability

Microdeletions in chromosome 17q22, where the NOG gene resides, have been reported leading to the NOG-related symphalangism spectrum disorder (NOG-SSD), intellectual disability and other developmental abnormalities. In this study we reported a dominant Chinese Han family segregating with typical NOG-SSD symptoms including proximal symphalangism, conductive hearing loss, amblyopia and strabismus, but not intellectual disability. Sanger sequencing identified no pathogenic mutation in the coding regions of candidate genes NOG, GDF5 and FGF9. SNP genotyping in the genomic region surrounding NOG identified loss of heterozygosity in the affected family members. By array comparative genomic hybridization and quantitative real-time polymerase chain reaction, we identified and mapped the breakpoints of a novel 1.6-Mb microdeletion in chromosome 17q22 that included NOG and twelve other genes. It is the first microdeletion reported in chromosome 17q22 that is associated with NOG-SSD only but not with intellectual disability. Our results may help identifying the dosage sensitive genes for intellectual disability and other developmental abnormalities in chromosome 17q22. Our study also suggested that genomic deletions in chromosome 17q22 should be screened in the NOG-SSD patients in which no pathogenic mutation is identified by conventional sequencing methods.     

Symphalangismus,Strabismus und Mittelohrmißbildung

Zusammenfassung Es wird über die Kombination von Symphalangismus und Mittelohrmißbildung innerhalb einer Familie berichtet. Für die Skeletfehlentwicklung und für die Mittelohrmißbildung wird der gleiche Gendefekt verantwortlich gemacht. Der kongenitale Strabismus bei den Geschwistern kann nicht sicher zu den anderen beiden Mißbildungen in Beziehung gebracht werden. Der genetische Zusammenhang einer erstmals bei Symphalangismus beschriebenen Spina bifida mit den Finger- und Zehenmißbildungen wird abgelehnt.

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Symphalangism, strabism, and anomaly of the middle ear

Summary This report describes a combination of symphalangism and anomaly of the middle ear in a family. The same genetic defect is thought to be responsible for both the deformation of the skeleton and the anomaly of the middle ear. The authors are not sure whether there is any connection between the congenital strabismus and the two other anomalies of brother and sister. The assumption of a genetic connection between spina bifida, which was described for the first time with symphalangism, and the anomalies of the fingers and toes is rejected.

     

Distal symphalangism: a report of two families

This study describes distal symphalangism in 36 individuals in two families, one of which is the largest pedigree of this rare defect yet documented. Distal symphalangism is ankylosis or rigidity of the distal interphalangeal joints of the hands and/or feet. The findings of this report substantiate the mutation as an autosomal dominant phenotype. Several manifestations of distal symphalangism were observed, including the lack of cutaneous creases over affected joints, brachydactyly, fourth-finger hypophalangism, absent nails, and rudimentary nails. Variability ranged from just toes affected, to a single finger affected, to all fingers and all lesser toes affected. The most common expression of the mutant gene was rigid index fingers. Craniosynostosis, premature closure of the sutures of the skull, was encountered twice in the larger of the two families. It is a possible pleiotropic effect of distal symphalangism.     

The embryology of angiosperms: Its broad application to the systematic and evolutionary study

Embryology allows one to work with a wide array of characters (more than 50 in general) for each taxon of angiosperms. This paper, while providing a brief review of recent studies on Myrtales and associated families by me and my co-workers, discusses evidence for the general utility of embryological characters for the study of plant systematics. In particular, evidence is given that characters of seed coat anatomy may be best applied to the study of specific and sectional (and even familial) relationships, those of seed appendages as well as of integumentary morphology and histogenesis to the study of generic relationships, and other major characters to the study of familial relationships. Embryology thus provides many features that are complex and, when properly applied along with evidence from other sources, offers good indications of relationships at various taxonomic level, from the ordinal to the specific level. Despite its evident systematic value and increasing need, however, information on embryological characters is still lacking for a majority of genera, and even at the family level, data is lacking or insufficiently available for more than 30% of families. Recipient of the Botanical Society Award for Young Scientists, 1987.     

Waardenburg syndrome: A rare genetic disorder, a report of two cases

Waardenburg syndrome (WS) is a rare genetic disorder. Patients have heterochromia or eyes with iris of different color, increased inter-canthal distance, distopia canthorum, pigmentation anomalies, and varying degree of deafness. It usually follows autosomal dominant pattern. In this report, two cases have been discussed but no familial history of WS has been found. Counseling of the patient is necessary and cases of irreversible deafness have been treated.     

GDF5 is a second locus for multiple-synostosis syndrome

Multiple-synostosis syndrome is an autosomal dominant disorder characterized by progressive symphalangism, carpal/tarsal fusions, deafness, and mild facial dysmorphism. Heterozygosity for functional null mutations in the NOGGIN gene has been shown to be responsible for the disorder. However, in a cohort of six probands with multiple-synostosis syndrome, only one was found to be heterozygous for a NOGGIN mutation (W205X). Linkage studies involving the four-generation family of one of the mutation-negative patients excluded the NOGGIN locus, providing genetic evidence of locus heterogeneity. In this family, polymorphic markers flanking the GDF5 locus were found to cosegregate with the disease, and sequence analysis demonstrated that affected individuals in the family were heterozygous for a novel missense mutation that predicts an R438L substitution in the GDF5 protein. Unlike mutations that lead to haploinsufficiency for GDF5 and produce brachydactyly C, the protein encoded by the multiple-synostosis-syndrome allele was secreted as a mature GDF5 dimer. These data establish locus heterogeneity in multiple-synostosis syndrome and demonstrate that the disorder can result from mutations in either the NOGGIN or the GDF5 gene.     

Hereditary geniospasm: linkage to chromosome 9q13-q21 and evidence for genetic heterogeneity.

Hereditary geniospasm is an unusual movement disorder causing episodes of involuntary tremor of the chin and the lower lip. Episodes typically start in early childhood and may be precipitated by stress, concentration, and emotion. Hereditary geniospasm is inherited as an autosomal dominant trait, and its cause is not known. We report the results of a genomewide genetic linkage study in a four-generation British family with hereditary geniospasm. Positive two-point LOD scores were obtained for 15 microsatellite markers on the peri-centromeric region of chromosome 9. A maximum two-point LOD score of 5.24 at theta = .00 was obtained for the marker D9S1837. Construction of haplotypes defined an interval of 2.1 cM between the flanking markers D9S1806 and D9S175, thus assigning one locus for hereditary geniospasm to the proximal long arm of chromosome 9q13-q21. Hereditary geniospasm in a second British family is not linked to this region, indicating genetic heterogeneity. These findings may have implications for other inherited focal movement disorders that as yet remain unmapped.     

Testing for familial correlation in age-at-onset

The analysis of family-study data sometimes focuses on whether a dichotomous trait tends to cluster in families. For traits with variable age-at-onset, it may be of interest to investigate whether age-at-onset itself also exhibits familial clustering. A complication in such investigations is that censoring by age-at-ascertainment can induce artifactual familial correlation in the age-at-onset of affected members. A further complication can be that sample inclusion criteria involve the affection status of family members. The purpose here is to present an approach to testing for correlation that is not confounded by censoring by age-at-ascertainment and may be applied with a broad range of inclusion criteria. The approach involves regression statistics in which subjects's covariate terms are chosen to reflect age-at-onset information from the subjects's affected family members. The results of analyses of data from a family-study of panic disorder illustrate the approach.     

An analysis of seven infants with Brachmann-de Lange syndrome, of whom two identical twin sisters

An analysis of seven infants with Brachmann-de Lange syndrome, of whom two identical twin sisters: Brachmann-de Lange syndrome (BDLS) is characterized by typical facial features, intrauterine growth retardation, short stature, microbrachycephaly, hirsutism and limb anomalies. Here, we reviewed the findings of seven infants with BDLS, of whom two were identical twin sisters of normal parents. All of the infants' parents were normal, and no consanguinity between the parents was noted although the ratio of consanguineous marriages is very high (21.1%) in Turkey. It is well known that most cases of BDLS are sporadic, some cases of this disorder are inherited in an autosomal dominant trait. Our findings suggested that familial cases of BDLS were infrequent, and vast majority of cases appeared to be sporadic and the occurrence of the syndrome in the identical twin sisters of normal parents was also thought a heterogeneity in this condition, overlapping with other conditions and syndromes as mentioned by Fryns et al.     

Sex-linked inheritance of cleft palate

Summary A family pedigree is reported in which males in four generations are affected with midline isolated cleft palate. This is the second report of cleft palate inherited as a sex-linked recessive trait, and it emphasizes the importance of careful pedigree construction when counseling families of children afflicted with this disorder.     

Thrombophilia gene mutations in oculoauriculovertebral spectrum

Oculoauriculovertebral spectrum or Goldenhar syndrome is a phenotypically and probably genetically heterogeneous disorder characterized by hemifacial microsomia (unilateral ear abnormalities and ipsilateral mandibular hypoplasia) as well as vertebral anomalies and epibulbar dermoid/lipodermoids. Although most cases of the Goldenhar syndrome are sporadic, both autosomal recessive and dominant inheritance have been reported so far. In this report, we describe the clinical aspects of two familial cases with evidence of autosomal dominant inheritance and a non-familial case, and compare them with the reports in the literature. One of our familial cases was a ten day old female infant of a mother with left hemifacial microsomia. She had multiple bilateral preauricular tags and a "fleshy masse" on her right cheek. The other familial case was a two months old male infant whose father had hemifacial asymmetry. He had unilateral microtia, and abnormal antihelix, a skin tag in the contralateral ear associated with bilateral sensorineural hearing loss. The third case was a sporadic case who was 2 years old boy with preauricular skin tag, right hemifacial microsomia and limbal dermoid at the temporal limbus of the right eye. As there were no other associated defects, the cases we presented here were thought to be mild variations of the Goldenhar spectrum. The most commonly encountered mutations of thrombophilia genes were studied. We believe that the interfamilial and intrafamilial clinical variabilities observed in these cases reinforce the necessity of a careful examination for the whole family with regards to the stigmata of Goldenhar syndrome.     

A recurrent mutation in type II collagen gene causes Legg-Calvé-Perthes disease in a Japanese family

Legg-Calvé-Perthes disease (LCPD) is a common childhood hip disorder characterized by sequential stages of involvement of the capital femoral epiphyses, including subchondral fracture, fragmentation, re-ossification and healing with residual deformity. Most cases are sporadic, but familial cases have been described, with some families having multiple affected members. Genetic factors have been implicated in the etiology of LCPD, but the causal gene has not been identified. We have located a missense mutation (p.G1170S) in the type II collagen gene (COL2A1) in a Japanese family with an autosomal dominant hip disorder manifesting as LCPD and showing considerable intra-familial phenotypic variation. This is the first report of a mutation in hereditary LCPD. COL2A1 mutations may be more common in LCPD patients than currently thought, particularly in familial and/or bilateral cases.     

Brachydactylia with symphalangism,probably autosomal recessive

Summary Association, in one patient, of the following malformations: brachydactylia of all segments but terminal phalanges; proximal symphalangism of many fingers and toes; abnormalities of carpal and tarsal bones; partial duplication of both big toes; mild hypertelorism. Genetic transmission seems to be recessive autosomal.     

Familial interstitial deletion of chromosome 4 (p15.2p16.1)

Interstitial deletion of the proximal short arm of chromosome 4, extending from p14 to p16.1 region, results in a distinct clinical syndrome. This proximal 4p deletion syndrome is characterized by variable degrees of mental retardation, unusual facies and minor dysmorphic features. Majority of the patients also show a tall, ectomorphic habitus and normal to excessive linear growth with age. While there have been several cases of such interstitial del(4p) cases reported, familial transmission of this condition has not been documented in the literature. This is the first report of a familial transmission of proximal del(4p) from a mother to her daughter, with both patients showing similar features. This report of the familial transmission of del(4p) has wider implications in genetic counseling.     

Familial benign hypercalcemia--from clinical description to molecular genetics.

Familial benign hypercalcemia (or familial hypocalciuric hypercalcemia), a syndrome of lifelong hypercalcemia inherited as an autosomal dominant trait, is distinct from the multiple endocrine neoplasia syndromes and other forms of inherited parathyroid disease. Familial benign hypercalcemia results from the inappropriate secretion of parathyroid hormone despite hypercalcemia, enhanced renal tubular reabsorption of calcium (independent of parathyroid hormone), and apparent tissue resistance to adverse effects of hypercalcemia. Heterozygosity for the familial hypercalcemia trait is benign, although homozygosity for the trait may lead to severe neonatal primary hyperparathyroidism. Genetic linkage studies show that most persons affected with familial hypercalcemia have a mutation on the long arm of chromosome 3 (3cen-q21), although one phenotypically indistinguishable family appears to have a mutation on the short arm of chromosome 19 (19p), and another family has neither 3q nor 19p mutations. One group has recently shown mutations in a putative parathyroid cell-surface calcium receptor that are plausible causes for the chromosome 3q variant of the familial hypercalcemia syndrome. Perhaps the other genes for this syndrome encode proteins representing hitherto-unknown regulators of systemic calcium metabolism independent of parathyroid cell calcium sensing or proteins involved in signal transduction from the calcium receptor.