bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermal stability and folding of the collagen triple helix and the effects of mutations in osteogenesis imperfecta on the triple helix of type I collagen
Authors: Bächinger Hans Peter , Morris Nicholas P. , Davis Janice M.
Published: June 2005

Osteogenesis imperfecta (OI) is an inherited disease in which 90% of the cases result from mutations in the 2 genes, proα1 and proα2, coding for type I collagen. Type I collagen is a trimeric molecule, (α1)2α2, which is dominated both structurally and functionally by the 300 nm triple‐helical domain. Most OI mutations occur in this domain and almost all point mutations result in the substitution of other amino acids for the obligate glycine which occurs at every third residue. The phenotypic effects of these mutations are frequently attributed in part to alterations in the stability and rate of folding of the triple helix. In order to better understand the relationship between glycine substituions and stability we review current concepts of the forces governing triple helical stability, denaturational and predenaturational unfolding, and the techniques of measuring stability. From observations on the stability of several collagen types as well as synthetic tripeptides, we present a model for stability based on the contribution of individual and neighboring tripeptide units to the local stability. Although in preliminary form, this empirical model can account for the observed shifts in the Tm of many of the point mutations described. The folding of the triple helix is reviewed. The involvement of peptidyl prolyl cis‐trans isomerase in this process in vivo is demonstrated by the inhibition of collagen folding in fibroblasts by cyclosporin A. An hypothesis based on the relationship between the thermal stability at the site of mutation and the propensity for renucleation of folding is proposed.
Formation of mineralized nodules by bone derived cells in vitro: A model of bone formation?
Authors: Beresford Jon N. , Graves Steven E. , Smoothy Caroline A.
Published: June 2005

The identification of the factors which regulate the proliferation and differentiation of cells of the osteoblast lineage remains one of the major challenges in the field of bone cell biology. Although considerable progress has been made in the isolation and culture of cells of the osteoblast lineage from both animal and, more recently, human bone, uncertainties have persisted as to the extent to which these cell populations retain the ability to differentiate into functional osteoblasts in vitro.

The formation in vitro of mineralized nodules that exhibit the morphological, ultrastructural and biochemical characteristics of embryonic/woven bone formed in vivo, represents the first evidence that the differentiation of functional osteoblasts can occur in cultures of isolated animal bone‐derived cell populations. It is clear, however, that the culture conditions employed at present only permit a small number of cells to differentiate to the extent of being capable of organising their extracellular matrix into a structure that resembles that of bone. Moreover, it has generally been found that the reproducible mineralization of this extracellular matrix requires supplementation of the culture medium with mM concentrations of β‐GP, which raises doubts as to the physiological relevance of this process.

The formation of nodules has also been observed in cultures of human bone‐derived cells. As found in cultures of animal bonederived cells, reproducible mineralization of these nodules will occur in the presence of β‐GP. We have shown, however, that in the presence of the long acting ascorbate analogue Asc‐2‐P, the formation and mineralization of nodules can occur in the absence of β‐GP. The nodules formed in human bone‐derived cell cultures have yet to be characterized as rigorously as those formed in cultures of animal bone‐derived cells and thus it remains to be shown that they resemble bone formed in vivo.
Linkage analysis in dominantly inherited osteogenesis imperfecta
Authors: Sykes Bryan
Published: June 2005

The only serious attempts at linkage in osteogenesis imperfecta (OI) have shown that the disease is linked to type 1 collagen genes in all families studied in which it segregrates as a clear mendelian dominant trait. For prenatal diagnosis the probability that a new family is linked can be taken as greater than 0.95 and this figure is augmented as more meioses are studied. Some phenotype correlations, notably between the OI type IV phenotype and linkage to COL1A2 and between presenile hearing loss in OI type I and linkage to COL1A1, can be used to improve risk estimates substantially in families where there are no segregation data to distinguish whether COL1A1 or COL1A2 is the mutant locus.
Molecular heterogeneity in osteogenesis imperfecta type I
Authors: Willing Marcia C. , Pruchno Charles J. , Byers Peter H.
Published: June 2005

Osteogenesis imperfecta (OI) type I is characterized by bone fragility without significant deformity, osteopenia, normal stature, blue sclerae, and autosomal dominant inheritance. Dermal fibroblasts from most affected individuals produce about half the expected amount of type I collagen, suggesting that the OI type I phenotype results from a variety of mutations which alter the apparent expression of either COL1A1 or COL1A2, the genes encoding the chains of type I collagen. Short‐pulse labeling of dermal fibroblasts with [3H]proline from affected individuals in 19 families indicates that most have alterations in the expected 2:1 synthetic ratio of proα1(I): proα2(I), with most having decreased production of proα1(I). Ratios of COL1A1:COL1A2 mRNA from these individuals, using slot‐blot hybridization, indicate that they fall into different groups, but that most have decreased COL1A1 mRNA levels, compared with controls. These data suggest that most of our OI I families have COL1A1 mutations. Copy number and size of the COL1A1 gene by restriction endonuclease analysis of genomic DNA from affected individuals are normal in the families examined. We have identified one 3 generation family in which all affected members have one normal COL1A1 allele and another with a 5 base‐pair deletion near the 3′ end of the gene. The deletion creates a shift in the translational reading‐frame and predicts the synthesis of an elongated proα1(I) chain. In a second family, a father and a son have a single exon deletion that results from a splicing mutation. Chemical cleavage analysis of amplified cDNA from affected individuals in different regions of the COL1A1 gene, including the promoter, suggests that several individuals have point mutations within the coding region of the gene, while one individual may have a small deletion within the α1(I) carboxyl‐terminal propeptide region. Our data provide evidence for significant molecular heterogeneity within the OI type I phenotype and indicate that a variety of mutations can result in decreased synthesis of type I collagen.
Possible role of overglycosylation in the type I collagen triple helical domain in the molecular pathogenesis of osteogenesis imperfecta
Authors: Tenni Ruggero , Valli Maurizia , Rossi Antonio , Cetta Giuseppe
Published: June 2005

The underlying defect in patients affected by a form of osteogenesis imperfecta (OI) clarified at the molecular level regards the amount or the structure of type I collagen synthesized. This leads to a decreased and/or abnormal mineral deposition in bone and affects bone mass and/or strength. Abnormal interactions between collagen molecules in the presence of mutant trimers could give rise to abnormal fibrils, which, in turn, can determine incorrect interactions with noncollagenous matrix macromolecules. The interactious can be disturbed or modulated by an abnormal distribution on the collagen fibril surface of electrically charged or hydrophobic groups, or by an increased presence of sugar moieties linked to hydroxylysyl residues due to chain post‐translational overmodifications (lysyl overhydroxylation and hydroxylysyl over‐glycosylation) of the portion of the triple helical domain of abnormal type I collagen molecules N‐terminal with respect to the defect localization.
Evaluation of growth hormone axis and responsiveness to growth stimulation of short children with osteogenesis imperfecta
Authors: Marini Joan C. , Bordenick Stephanie , Heavner Gale , Rose Susan , Chrousos George P.
Published: June 2005

Growth deficiency is a cardinal manifestation of severe Osteogenesis Imperfecta (OI) and occurs frequently in moderate to mild OI. We have investigated the status of the hormones related to growth in 28 children with OI. Our goals were to determine whether there were any abnormalities of these hormones, whether the abnormalities correlated with types of OI, and whether OI bone could be safely stimulated to grow. The study group included 14 females and 14 males. Using the criteria developed by Sillence et al. [1979], 13 children had OI type III, 12 had OI type IV, and 3 had OI type I. Evaluation included 3 standard hGH provocative tests (AITT, L‐Dopa), GRF stimulation, 24 hr q20 minute sampling of unstimulated growth hormone, and a somatomedin generation test. All patients except one had normal responses to standard provocative stimuli. Responses to GRF fell into 2 groups: one with a mean response similar to that of normal children, and one with a mean response resembling that of GH deficient children. The group with low response to GRF had a significantly lower area under the curve in the 24‐hr test of unstimulated GH than did the normal response group. The OI children as a group showed a blunted IGF‐1 response during the Somatomedin Generation Test, with 18/28 children having less than a two‐fold stimulation. No test results correlated with OI type.

Ten OI children were enrolled in a pilot growth stimulation study. Two children received protropin and 8 received clonidine for at least 6 months. Both children treated with protropin and 4/8 treated with clonidine experienced at least a doubling of their pre‐treatment growth rates. Lack of growth hormone response did not correlate with type of OI or parameters from the hormonal evaluation. We speculate that there is a group of OI children who have a hypoactive growth hormone axis. Some OI bone appears to respond to GH and a treatment trial with protropin is planned for a larger number of children.
Marden‐Walker phenotype: Spectrum of variability in three infants
Authors: Ramer Jeanette C. , Frankel Carl A. , Ladda Roger L.
Published: June 2005

The physical, radiographic, and pathologic findings in 3 new patients with Marden‐Walker syndrome (MWS) are compared with those of previously described children with the syndrome. Over 75% of the children with MWS have blepharophimosis, psychomotor retardation, small mouth, micrognathia, kyphosis/scoliosis, and multiple contractures. Minimal diagnostic criteria have yet to be defined attesting to the broad range of variability and potential genetic heterogeneity in this disorder. © 1993 Wiley‐Liss, Inc.
Phocomelia, oligodactyly, and acrania: The Schinzel‐Phocomelia syndrome
Authors: Chitayat David , Stalker Heater J. , Vekemans Michel , Delneste Danielle , Azouz E. Michel
Published: June 2005

We report on a girl born with phocomelia of both lower limbs, with 3‐toed feet and partial sacral agenesis. She had normal growth of the upper limbs and trunk, and normal intelligence. Ultrasound study performed during the subsequent pregnancy documented a large skull defect with an intact brain. Fetal autopsy following the termination of that pregnancy was not done. We think this is a further report of the phocomelia syndrome with additional anomalies as reported by Schinzel [Hum Genet 84:539–541, 1990]. © 1993 Wiley‐Liss, Inc.
Confirmation that the velo‐cardio‐facial syndrome is associated with haplo‐insufficiency of genes at chromosome 22q11
Authors: Kelly David , Goldberg Rosalie , Wilson David , Lindsay Elizabeth , Carey Alisoun , Goodship Judith , Burn John , Cross Ian , Shprintzen Robert J. , Scambler Peter J.
Published: June 2005

The velo‐carido‐facial syndrome (VCFS) and DiGeorge sequence (DGS) have many similar phenotypic characteristics, suggesting that in some cases they share a common cause. DGS is known to be associated with monosomy for a region of chromosome 22q11, and DNA probes have been shown to detect these deletions even in patients with apparently normal chromosomes. Twelve patients with VCFS were examined and monsomy for a region of 22q11 was found in all patients. The DNA probes used in this study could not distinguish the VCFS locus and the DGS locus, indicating that the genes involved in these haplo‐insufficiencies are closely linked, and may be identical. The phenotypic variation of expression in VCFS and DGS may indicate that patients without the full spectrum of VCFS abnormalities but with some manifestations of the disorder may also have 22q11 deletions. © 1993 Wiley‐Liss, Inc.
Exclusion of type II and type VI procollagen gene mutations in a five‐generation family with multiple epiphyseal dysplasia
Authors: Weaver Eric J. , Summerville Gregg P. , Yeh George , Hervada‐Page Maria , Oehlmann Ralph , Rothman Richard , Jimenez Sergio A. , Knowlton Robert G.
Published: June 2005

We have studied a family with an autosomal dominant form of multiple epiphyseal dysplasia (MED) inherited through at least 5 generations. Bilateral deformity of the hips with subsequent degenerative arthritis was the most common and most severe change observed in the affected relatives. Abnormalities of the knees, ankles, and shoulders were also noted in some affected individuals. Radiological examination showed changes in affected joints consistent with epiphyseal dysplasia. In early stages, the articular surfaces appeared flattened or irregular in shape. In advanced stages, epiphyseal fragmentation, joint surface erosion, and extensive remodeling were observed.

The abnormalities of the epiphyses suggested that the primary defect might be in a structural component of the epiphyseal cartilage matrix. The gene encoding type II collagen (COL2A1) was tested for genetic linkage to MED in this family by restriction fragment length polymorphism (RFLP) analysis. Recombination between COL2A1 and MED was observed, ruling out COL2A1 as the site of the mutation. The genes encoding the 3 chains of type VI collagen were also excluded on the basis of discordant inheritance. The disease in this family is therefore not the result of mutations in the genes encoding type II or type VI collagen. © 1993 Wiley‐Liss, Inc.
Axial mesodermal dysplasia spectrum
Authors: Stewart Fiona J. , Nevin Norman C. , Brown Stephen
Published: June 2005

We report on a 4‐month‐old boy with manifestations of both the oculo‐auriculovertebral spectrum and the caudal regression sequence. He has preauricular appendages, thoracic and lumbar hemivertebrae, anomalies of the ribs, dextrocardia, sacral “dysplasia”, dislocated hips, bilateral talipes equinovarus, imperforate anus, recto‐vesical fistula, malformed scrotum, and undescended testes. As suggested by Russell et al. [1981], who reported a patient with similar anomalies, the spectrum of anomalies probably is due to a generalized alteration in mesodermal cell migration during the primitive streak period. The term “axial mesodermal dysplasia spectrum” best describes the widespread anomalies in the cranial and caudal regions. © 1993 Wiley‐Liss, Inc.
Tricho‐rhino‐phalangeal syndrome type I (TRP I) due to an apparently balanced translocation involving 8q24
Authors: Marchau Fabienne E. , Van Roy Bernadette C. , Parizel Paul M. , Lambert Julien R. , De Canck Ilse , Leroy Jules G. , Gevaert Carine M. , Willems Patrick J. , Dumon Jan E.
Published: June 2005

Tricho‐rhino‐phalangeal (TRP) syndromes type I and II are caused by a defective gene located on chromosome 8q24.1. We report a family with 2 sibs affected with TRP type I in combination with an apparently balanced chromosome (8;18) translocation involving 8q24.11. It is very likely that the 8q24 translocation breakpoint is physically linked to the TRP gene(s), thereby facilitating future efforts to clone the TRP gene(s). © 1993 Wiley‐Liss, Inc.
Protein‐losing gastroenteropathy with facial anomaly and growth retardation: A mild case of Hennekam syndrome
Authors: Yasunaga Michiho , Yamanaka Chutaro , Mayumi Mitsufumi , Momoi Tohru , Mikawa Haruki
Published: June 2005

A 7‐year‐old boy with a peculiar face, protein‐losing gastroenteropathy and growth retardation is reported. Although he has a face similar to those 5 cases reported previously by Hennekam et al. (Am J Med Genet 34:593–600, 1989) and Gabrielli et al. (Am J Med Genet 40:244–247, 1991), he is not mentally retarded nor does he have severe lymphedema. This patient seems to have a mild case of the Hennekam syndrome. © 1993 Wiley‐Liss, Inc.
Kallmann syndrome associated with complex chromosome rearrangement
Authors: Casamassima Anthony C. , Wilmot Patrick L. , Vibert Betsy K. , Shapiro Lawrence R.
Published: June 2005

We report on a male with Kallmann syndrome (KS) and an apparently balanced complex chromosome rearrangement (CCR): 46,XY,t(3;9)(9;12)(q13.2;q21.2p13;q15). This is the first known report of a CCR in the KS and the second reported case of a definitive autosomal chromosome abnormality with KS. Possible relationships between the cytogenetic abnormality and KS are discussed. © 1993 Wiley‐Liss, Inc.
Spastic paraplegia, epilepsy, and mental retardation in several members of a family: A novel genetic disorder
Authors: Gigli G. L. , Diomedi M. , Bernardi G. , Placidi F. , Marciani M. G. , Calia E. , Maschio M. C. E. , Neri G.
Published: June 2005

We report on a family in which an association between spastic paraplegia and epilepsy has been observed.

This disorder is an autosomal dominant trait with incomplete penetrance and variable expressivity. The onset was limited to the first four decades of life; the symptoms were typically those of progressive weakness and spasticity of lower limbs. Epilepsy was present in members of three of the four generations on whom we have information.

The concomitance of spastic paraplegia and epilepsy in several members of the same family is unlikely to be fortuitous and probably represents the pleiotropic effect of a single mutant gene. © 1993 Wiley‐Liss, Inc.
Balanced reciprocal translocation mosaicism associated with an abnormal phenotype
Authors: Aughton David J. , AlSaadi Abdul A. , Canady Alexa I. , Lucas Barbara M.
Published: June 2005

Balanced reciprocal translocation mosaicism is rarely reported in humans. Only two previous cases have been associated with an abnormal phenotype. We report on a third case of apparently balanced reciprocal translocation mosaicism associated with an abnormal phenotype, largely different from those reported previously. Since low levels of mosaicism may not be detected in routine cytogenetic analyses, balanced reciprocal translocation mosaicism may be associated with an abnormal phenotype more often than has been recognized to date. © 1993 Wiley‐Liss, Inc.
Concurrence of supravalvular aortic stenosis and peripheral pulmonary stenosis in three generations of a family: A form of arterial dysplasia
Authors: Kumar Anil , Stalker Heather J. , Williams Charles A.
Published: June 2005

Isolated supravalvular aortic stenosis (SVAS) commonly is an autosomal dominant trait; it may also occur in the Williams syndrome (WS). While peripheral pulmonary stenosis (PPS) can occur in the same individual with familial isolated SVAS, concurrence of these lesions in different relatives of a family is uncommon. We describe five affected individuals in one family; three had isolated SVAS, one had isolated PPS, and one had SVAS and PPS. Based on this family and review of literature, we suggest that SVAS is a form of arterial dysplasia encompassing PPS in its spectrum. It is developmentally distinct from other left heart obstructive lesions that are hypothesized to be related to blood flow abnormalities in the developing embryo. We also conclude that the clinical disorder in this family represents one that is distinct from WS. © 1993 Wiley‐Liss, Inc.
Cranial nerve abnormalities in CHARGE association
Authors: Byerly Kyna A. , Pauli Richard M.
Published: June 2005

Many children with the CHARGE association have facial paralysis and feeding and swallowing difficulties. Indeed, facial paralysis and pharyngeal incoordination may be important diagnostic indicators of CHARGE association [Davenport et al., 1986a; Mitchell et al., 1985]. We describe an individual with dysfunction of multiple cranial nerves (Möbius sequence) and CHARGE association, a previously unrecognized combination. Our review of 150 patients from the literature and 13 patients from this center with CHARGE association documented that dysfunction of cranial nerves is frequent in CHARGE association, and that often cranial nerve abnormalities are multiple. Such multiple cranial nerve abnormalities may be the primary underlying cause for the facial paralysis, feeding difficulties and sensorineural hearing loss seen in many individuals with CHARGE association. © 1993 Wiley‐Liss, Inc.
Visceral anomalies in the Apert syndrome
Authors: Cohen M. Michael , Kreiborg Sven
Published: June 2005

We report on visceral anomalies found in 136 patients with Apert syndrome. Autopsies were only performed on 12 of these cases. Thus, the percentage of anomalies found in our patients should be considered a minimum estimate because of the possibility of clinically silent visceral anomalies, minor internal anomalies, and anatomic variations. Cardiovascular and genitourinary anomalies were found most commonly, occurring in 10% and 9.6%, respectively. As expected, complex and multiple cardiac anomalies were frequently associated with early death. Among genitourinary anomalies, hydronephrosis (3%) and cryptorchidism (4.5%, n =; 66 males) occurred most commonly. In contrast, anomalies of the respiratory system (1.5%) and gastrointestinal anomalies (1.5%) occurred with lower frequency. The finding of a solid cartilaginous trachea is particularly important because no case was diagnosed during life but rather, only at autopsy. Because cardiovascular and genitourinary anomalies occur with significant frequency, they should be considered in the workup of all Apert newborn infants. We also recommend MRI study of the trachea in any infant with signs and symptoms of lower respiratory compromise. © 1993 Wiley‐Liss, Inc.
Exstrophy of the cloaca in a 47,XXX child: Review of genitourinary malformations in triple‐X patients
Authors: Lin Henry J. , Ndiforchu Fombe , Patell Shibani
Published: June 2005

Cloacal exstrophy, unilateral renal agenesis, and Müllerian anomalies occurred in a live‐born infant with a 47,XXX chromosome constitution. The patient extends the range of genitourinary anomalies reported in triple‐X patients. Screening asymptomatic patients for urinary tract abnormalities may be useful in searching for silent malformations potentially associated with this karyotype. © 1993 Wiley‐Liss, Inc.
Holzgreve syndrome: Recurrence in sibs
Authors: Thomas I. T. , Honore G. M. , Jewett T. , Velvis H. , Garber P. , Ruiz C.
Published: June 2005

We report on 2 sibs with cardiac and renal abnormalities. The first had hypoplastic left heart sequence and renal hypoplasia; the second had a complex congenital heart defect, renal agenesis, and cleft lip and palate. We suggest that these cases represent the first familial examples of the Holzgreve syndrome. As such, they demonstrate the phenotypic variability seen in sibs, and may serve to further delineate the syndrome. © 1993 Wiley‐Liss, Inc.
Mosaic 5p tetrasomy
Authors: Stanley Wayne S. , Powell Cynthia M. , Devine Grace C. , Ellingham Tara , Samango‐Sprouse Carole A. , Vaught Donna R. , Murphy Bridget A. , Rosenbaum Kenneth N.
Published: June 2005

We report on a mildly abnormal 5‐year‐old girl with seizures, psychomotor retardation, and areas of hyperpigmentation who had a super‐numerary marker chromosome in fibroblasts which was identified as an i(5p). To our knowledge, this is the first reported case of tetrasomy 5p. She shares in common some, but not all, manifestations of the dup (5p) syndrome. Cytogenetic analysis of relatives showed that the phenotypically apparently normal mother, maternal grandmother, and a brother of the proband also had a marker chromosome in their lymphocytes which was unrelated to the i(5p). © 1993 Wiley‐Liss, Inc.
Atypical clinical presentation of ataxia telangiectasia
Authors: Willems Patrick J. , Van Roy Bernadette C. , Kleijer Wim J. , Van der Kraan Magna , Martin Jean‐Jacques
Published: June 2005

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous tel‐angiectasias, immunodeficiency with recurrent infections, IgA and IgE deficiency, and increased incidence of malignancies. The pathognomonic biological abnormalities consist of spontaneous chromosomal instability resulting in a high in vivo occurrence of cells with translocations, especially involving chromosomes 7 and 14, and a relative insensitivity of DNA replication in vitro to radiation exposure.

We report on a patient with the biological hallmarks of AT but with atypical clinical manifestations. Although progressive cerebellar ataxia was present, the neurological picture was broader than that usually seen in AT and included peripheral polyneuropathy and spinal atrophy. On the other hand, tel‐angiectasias, recurrent infections, malignancies, IgA deficiency, or other immunological abnormalities were not present. This illustrates that the clinical picture of AT is broad and nonspecific, and highlights the diagnostic value of cytogenetic analysis and studies of radioresistance of DNA synthesis. © 1993 Wiley‐Liss, Inc.
Sandrow syndrome of mirror hands and feet and facial abnormalities
Authors: Kogekar Nandini , Teebi Ahmad S. , Vockley Jerry
Published: June 2005

In 1970, Sandrow et al. (J Bone Joint Surg 52‐A:363–370) described a syndrome of ulnar and fibular dimelia with facial abnormalities present in 2 generations in a family. We describe a new patient with similar manifestations, establishing this constellation of anomalies as a distinct syndrome. © 1993 Wiley‐Liss, Inc.
Mirror hands and feet with a distinct nasal defect, an autosomal dominant condition
Authors: Martin Rick A. , Jones Marilyn C. , Jones Kenneth L.
Published: June 2005

We report on a father and daughter with mirror hands and feet and a distinct nasa defect and compare their condition to a similar one reported previously in one other family. © 1993 Wiley‐Liss, Inc.
Heterogeneity versus variability in megalocornea‐mental retardation (MMR) syndromes: Report of new cases and delineation of 4 probable types
Authors: Verloes Alain , Journel Hubert , Elmer Catherine , Misson Jean‐Paul , Le Merrer Martine , Kaplan Josseline , Van Maldergem Lionel , Deconinck H. , Meire Françoise
Published: June 2005

Megalocornea (corneal diameter ≥ 13 mm) is associated with mental and neurological impairment, and minor anomalies in Neuhäuser syndrome (megalocornea‐mental retardation syndrome). Here we report 4 new cases of megalocornea and mental retardation. Those unrelated patients have a consistent pattern of anomalies with possible recessive inheritance which clearly differs from that of the original patients of Neuhäuser et al. [1975]. We discuss the heterogeneity of the syndromes with megalocornea and mental retardation. Based on these caes and on a review of the literature, we suggest a provisional clinically oriented classification in 5 subtypes: (1) a recessive form type Neuhäuser (with iris hypoplasia and minor anomalies), (2) a recessive form type Frank‐Temtamy (with camptodactyly, scoliosis and growth retardation), (3) a recessive type 3 including our 4 personal cases (with normal irides, severe hypotonia, relative or absolute macrocephaly and minor anomalies), (4) a possible Frydman type (with normal irides, megalencephaly and obesity), and (5) provisionally unclassifiable cases. © 1993 Wiley‐Liss, Inc.
Effect of laboratory or clerical error on presymptomatic risk calculations for Huntington disease: A simulation study
Authors: King T. M. , Brandt J. , Meyers D. A.
Published: June 2005

Linked markers are useful in prenatal diagnosis as well as presymptomatic diagnosis in late age‐of‐onset diseases such as Huntington disease (HD). It is widely assumed that most laboratory or clerical errors will be detected because of incompatibility of marker haplotypes within the family. However, errors in marker phenotypes that are compatible but wrong may result in a consultand being given an incorrect risk estimate. We have addressed this issue using simulated marker data in pedigress similar to those seen in our HD testing program. In Family Structure I (an 11‐member, 3‐generation family), a particular family was more likely to be detected as inconsistent than incorrectly assigned. In a small nuclear family (Family Structure IV), Fewer errors would be detected, and more would appear consistent but give incorrect risk estimates (e.g., low risk misclassified as noninformative or high). Given the presence of tight linkage, risk estimates are often calculated based on a small number of relatives. However, these computer simulations demonstrated that increasing the number of relatives types decrease the probability that the family will remain consistent with an error present, and, therefore, decreases the probability of an incorrect assignment of risk. It is important to decrease the level of such errors by duplicated readings of raw marker data and validation of computer input. © 1993 Wiley‐Liss, Inc.
Brachydactyly type A‐4 (Temtamy type) with short stature in a Japanese girl and her mother
Authors: Ohzeki Takehiko , Hanaki Keiichi , Motozumi Hiroko , Ohtahara Hiroko , Shiraki Kazuo , Yoshioka Kimiko
Published: June 2005

We report on a Japanese girl and her mother with brachydactyly. Their 2nd and 5th middle phalanges were short and the latter was fused with the distal phalanx in one of the patients. Length and shape of proximal and distal phalanges as well as metacarpals seemed normal. These findings are consistent with brachydactyly type 4‐A, which is a rare subtype and has not been adequately documented. Short stature was reported only in some cases of brachydactyly type A‐1, A‐6, C, and E, but not in the other subtypes. Our patients with type A‐4 brachydactyly also had short stature. © 1993 Wiley‐Liss, Inc.
Renal findings in 40 individuals with Williams syndrome
Authors: Pober Barbara R. , Lacro Ronald V. , Rice Cynthia , Mandell Valerie , Teele Rita L.
Published: June 2005

We tabulated the frequency of renal abnormalities in 40 Williams syndrome individuals presenting for medical and/or developmental assessment to a multi‐disciplinary Williams syndrome program. The average age at time of assessment was 72/12 years. Seven individuals (7/40 = 18%) had abnormalities detected, including nephrocalcinosis = 2; marked asymmetry in kidney size = 2; small kidneys = 1; solitary kidney = 1; and pelvic kidney = 1.

Renal function was also assessed. Two individuals had evidence of renal dysfunction, one secondary to nephrocalcinosis and the second due to hypercalcemia and interstitial nephritis of unclear pathogenesis.

We examined the frequency of renal artery stenosis in 9 individuals who underwent abdominal angiography during cardiac catheterization. We found unilateral or bilateral mild renal artery narrowing in 4 individuals and normal renal arteries in the remaining 5. Persistent hypertension occurred in only 2 individuals and did not correlate with renal artery status.

We conclude that intrinsic renal anomalies, as well as problems secondary to hypercalcemia, occur with sufficient frequency to warrant baseline renal screening in all individuals with Williams syndrome. © 1993 Wiley‐Liss, Inc.
Apparent dominant transmission of the Rubinstein‐Taybi syndrome
Authors: Marion Robert W. , Garcia Diana M. , Karasik Jeffrey B.
Published: June 2005

The cause of the Ruinstein‐Taybi syndrome (RTS), a multiple congenital anomalies/mental retardation (MCA/MR) syndrome first described in 1963, remains obscure. Recently, a deletion of chromosomal material at 16p13.3 has been found in some patients with the disorder, but no such deletion can be identified in the majortity of affected individuals. Although the disorder has been well documented to be concordant in at least 7 monozygotic twin pairs and in one non‐twin sib pair, only one clear‐cut case of parent‐to‐child transmission has been reported previously. We present here a mother and daughter, both of whom appear to be affected with RTS, strongly suggesting either autosomal or X‐linked dominant transmission. The paucity of previous cases of parent‐to‐child transmission may be related to either decreased fertility or decreased fitness in affected individuals. © 1993 Wiley‐Liss, Inc.
Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: Prenatal and postnatal late replication studies
Authors: Zori Roberto T. , Gray Brian A. , Bent‐Williams Angela , Driscoll Daniel J. , Williams Charles A. , Zackowski Joleen L.
Published: June 2005

We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation [46,X,t(X;9)(p22.1;q32)mat] inherited from a previously diagnosed mosaic translocation carrier mother [46,XX/46,X,t(X;9)(p22.1;q32)]. Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical break‐points and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome. © 1993 Wiley‐Liss, Inc.
Effect of fragile X on physical and intellectual traits estimated by pedigree analysis
Authors: Loesch Danuta Z. , Huggins Richard M. , Chin Wai Fong
Published: June 2005

A maximum likelihood scoring technique for analysis of pedigree data, which allows for estimation of random effects (variance components) concurrently with other “fixed” effects in a quantitative trait, was applied to establish the effect of the fragile X condition in the variation of intellectual and physical traits. In 52 fragile X families, intellectual status was represented by measures of vocabulary knowledge (PPVT) and of nonverbal visuospatial skills (BDT), and physical status by a combined physical (anthropometric) score, and jaw length. The fixed effects included fragile X and sex and their interaction on the mean and covariances between relatives for the intellectual and physical scores. The random effects included environmental (common and individual) and genetic (additive and dominance) components. Different genetic models were tested by the likelihood ratio criterion, and the maximum likelihood parameters for each of the three scores were based on the most appropriate models.

The effect of fragile X on the mean values was found to be significant for all the traits, and much more conspicuous in male than in female individuals, the effects in the PPVT and the anthropometric score being intercorrelated. The effect of fragile X on growth of a single physical trait relative to height was demonstrated using jaw length as an example. We have also demonstrated an effect of fragile X on genetic (additive) variance, as well as on the mean of the BDT score, and the effect of age on the nongenetic variance of PPVT, and jaw length. © 1993 Wiley‐Liss, Inc.
Confirmation of trisomy 22 in two cases using chromosome painting: Comparison with t(11;22)
Authors: Slater H. R. , Voullaire L. E. , Vaux C. E. , Bankier A. , Pertile M. , Choo K. H. A.
Published: June 2005

We present a nonmosaic case of trisomy 22 in a liveborn, abnormal infant and a second case of a fetus who died in utero. Both have been verified cytogenetically and confirmed by in situ hybridisation with a centromeric alphoid probe and chromosome painting. The accuracy of the combined cytogenetic and molecular cytogenetic approaches in the karyotype determination is highlighted by comparison with a case showing partial translocation of chromosome 22 in t(11;22) (q23;q11). © 1993 Wiley‐Liss, Inc.
Assessment of subcutaneous fat using ultrasonography in the Ullrich–Turner syndrome
Authors: Ohzeki Takehike , Hanaki Keiichi , Motozumi Hiroko , Ohtahara Hiroko , Urashima Hiroshi , Shiraki Kazuo
Published: June 2005

Subcutaneous fat was measured using an ultrasonic method (SF‐US) in girls with Ullrich–Turner syndrome (UTS) and in height and weight‐matched controls. The method is not influenced by changes in cutaneous compressibility, which is frequently abnormal in UTS especially at a younger age. SF‐US in the arms was significantly less in UTS patients (ulnar SF‐US: P < 0.05; triceps SF‐US: P < 0.005) than in the control girls. Results in suprailiac SF‐US measurement was also similar (P<0.05). Though the mean SF‐US in the subscapular region was less in UTS patients than the control girls, there was no statistically significant difference. It is demonstrated that subcutaneous fat in UTS patients is less in their arms than in girls without UTS and that trunkal fatness is not increased but rather decreased in the UTS. The ratio of lean body mass to weight seems higher in UTS patients than in girls with similar weight and height. © 1993 Wiley‐Liss, Inc.
Steinfeld syndrome: Report of a second family and further delineation of a rare autosomal dominant disorder
Authors: Nöthen Markus M. , Knöpfle Gisela , Födisch Hans‐Jörg , Zerres Klaus
Published: June 2005

We report on a fetus with alobar holoprosencephaly, microphthalmia, midline cleft lip and palate, absent nose, dysplastic ears, radial defects, pentalogy of Fallot, unilateral renal aplasia, absent gallbladder, vertebral anomalies, and absence of ribs. The father had a cleft palate, bilateral colobomas of the iris and retina, a bifid uvula, vertebral anomalies, and unilateral congential hearing loss. His sister had a cleft lip. On the basis of this family and the family reported by Steinfeld [1982], this malformation syndrome can be defined as a rare autosomal dominant syndrome whose main component manifestations are holoprosencephaly, predominantly radial limb deficiency, heart defects, kidney malformations, absence of gallbladder, and vertebral anomalies. © 1993 Wiley‐Liss, Inc.
Genetic epidemiological studies of early‐onset deafness in the U.S. school‐age population
Authors: Marazita Mary L. , Ploughman Lynn M. , Rawlings Brenda , Remington Elizabeth , Arnos Kathleen S. , Nance Walter E.
Published: June 2005

Profound, early‐onset deafness is present in 4–11 per 10,000 children, and is attributable to genetic causes in at least 50% of cases.

Family history questionnaires were sent to 26,152 families of children with profound, early‐onset deafness not known to be related to an environmental cause. The probands were ascertained through the 1988–89 Gallaudet University Annual Survey of Hearing Impaired Children and Youth. The analysis is based on the responses that were received from 8,756 families.

Classical segregation analysis was used to analyze the family data, and to estimate the proportions of sporadic, recessive and dominant causes of deafness in the families. These data were consistent with 37.2% of the cases due to sporadic causes, and 62.8% due to genetic causes (47.1% recessive, and 15.7% dominant). An earlier study using the 1969–70 Annual Survey found 49.3% sporadic cases and 50.6% genetic, demonstrating that the proportion of sporadic cases of early‐onset deafness has significantly decreased since 1970. © 1993 Wiley‐Liss, Inc.
Aarskog syndrome: Report of a family with review and discussion of nosology
Authors: Teebi Ahmad S. , Rucquoi J. K. , Meyn M. S.
Published: June 2005

Five individuals in one family, including dizygotic male twins, a half brother and their mother, had Aarskog syndrome (AS). Phenotypic variability is wide not only between mother and sons but also between sibs. Collectively, the affected relatives have the full spectrum of findings seen in AS. Based on analysis of this family and others from the literature, we derive primary and secondary diagnostic criteria for AS. Primary criteria include: short stature, hypertelorism, short nose with anteverted nares, maxillary hypoplasia, a crease below the lower lip, mild interdigital webbing with short and broad hands, short fifth finger with clinodactyly, and shawl scrotum. Secondary criteria include: abnormal auricles with fleshy lobules, posteriorly angulated ears, widow's peak, ptosis downward slant of palpebral fissures, joint hyperextensibility, broad feet with bulbous toes, cryptorchidism, inguinal hernia, and prominent umbilicus. Literature pertaining to the clinical manifestations and genetics of AS is reviewed and nosology of similar syndromes is discussed. © 1993 Wiley‐Liss, Inc.
Precise mapping of a de novo duplication 18(q21→q22) utilizing cytogenetic, biochemical, and molecular techniques
Authors: Wolff Daynna J. , Schwartz Marcia F. , Cohen Maimon M. , Schwartz Stuart
Published: June 2005

We describe the first de novo inverted duplication of 18q. Due to the difficulty of identifying de novo chromosome abnormalities based solely on cytologic studies, precise definition of the 18q duplication was attempted by integrating cytogenetic and clinical findings with biochemical and molecular dosage studies. The combined results demonstrated that the proposita had a duplication of 18q21→q22 with a karyotype of 46,XX,–18,+inv dup(18) (pter→q12.1::q22→q21::q12.1→qter). The duplication of this specific chromosome region does not result in the typical 18 phenotype, supporting the hypothesis that various loci on chromosome 18 may interact to produce the manifestations of this syndrome. © 1993 Wiley‐Liss, Inc.
Congenital heart disease associated with sporadic Kallmann syndrome
Authors: Cortez Alan B. , Galindo Alvaro , Arensman Frederick W. , van Dop Cornelis
Published: June 2005

A 17‐year‐old boy with Kallmann syndrome had complex congenital heart disease that included double‐outlet right ventricle, d‐malposition of the great arteries, right aortic arch, and hypoplastic main pulmonary artery. He had neurosensory hearing loss and mental retardation. The 7 previously reported patients with Kallmann syndrome and cardiac abnormalities were short with height ≥2 standard deviations below the mean for age (5/7), lacked a family history of Kallmann syndrome (6/6), and were mentally retarded (4/4). Patients presenting with Kallmann syndrome and congenital heart defects appear to represent a distinct subgroup of patients with Kallmann syndrome. The cause of this association is unclear, but may involve either autosomal recessive inheritance, sporadic dominant mutation, or a shared teratogenic event during the first trimester of gestation. © 1993 Wiley‐Liss, Inc.
Macrosomia, obesity, macrocephaly and ocular abnormalities (MOMO syndrome) in two unrelated patients: Delineation of a newly recognized overgrowth syndrome
Authors: Moretti‐Ferreira Danilo , Koiffmann Célia P. , Listik Márcia , Setian Nuvarte , Wajntal Anita
Published: June 2005

We describe 2 unrelated patients, a boy and a girl, with an overgrowth syndrome and the following common characteristics: macrocrania, obesity, ocular abnormalities (retinal coloboma and nystagmus), downward slant of palpebral fissures, mental retardation, and delayed bone maturation. Both cases are of sporadic occurrence with no consanguinity between the parents. We suggest that this syndrome is due to a new autosomal dominant mutation and propose to designate it with the acronym of “MOMO syndrome” (Macrosomia, Obesity, Macrocrania, Ocular anomalities). © 1993 Wiley‐Liss, Inc.
Simpson‐Golabi‐Behmel syndrome: Congenital diaphragmatic hernia and radiologic findings in two patients and follow‐up of a previously reported case
Authors: Chen Emily , Johnson John P. , Cox Victoria A. , Golabi Mahin
Published: June 2005

This report suggests the association of congenital diaphragmatic hernia in Simpson‐Golabi‐Behmel syndrome by describing two unrelated males with this malformation. One male was the maternal half‐nephew of our previously reported 8‐year‐old boy with this syndrome.

Review of the skeletal roentgenograms of these 2 affected males, and those of the previously reported 8‐year‐old, documents flare of the iliac wings, narrow sacroiliac notches, and the presence of two carpal ossification centers as a newborn (“advanced bone age”).

We also report the follow‐up of the 8‐year‐old boy, now 16 years old, who continues to have significant overgrowth and speech, dental, developmental, and adjustment problems. © 1993 Wiley‐Liss, Inc.
Pericentric inversion of chromosome 6 in a patient with cleidocranial dysplasia
Authors: Nienhaus H. , Mau U. , Zang K. D. , Henn W.
Published: June 2005

We describe a male patient with a pericentric inversion of chromosome 6 and classic cleidocranial dysplasia (CCD), mild to moderate mental retardation, hearing deficiency, and unusual facial appearance. We conclude that there is a causal relationship between the chromosomal disorder and the CCD. © 1993 Wiley‐Liss, Inc.
Decrease in thyrocalcitonin‐containing cells and analysis of other congenital anomalies in 11 patients with DiGeorge anamaly
Authors: Palacios José , Gamallo Carlos , García Marcial , Rodríguez José Ignacio
Published: June 2005

Experimental studies have demonstrated that the DiGeorge anomaly is due to cranial neural crest abnormalities. In the present study, the quantitation of thyrocalcitonin immunoreactive cells (C‐cells) has been used to evaluate whether cells derived from the cranial neural crest are or are not present in normal proportions in patients with this anomaly. Thyroid sections from 11 such patients and 11 control patients were studied imnmunohistochemically at autopsy in order to determine the number and distribution of thyrocalcitonin containing cells. Patients with DiGeorge anomaly showed thymic and parathyroid aplasia/hypoplasia and cardiovascular defects, such as type B interrupted aortic arch, truncus arteriosus and tetralogy of Fallot. Other associated defects were alobar holoprosencephaly and meningocels (previously unreported defects in this anomaly), arhinencephaly, renal cystic dysplasia, ureterohydronephrosis, esophageal atresia with tracheoesophageal fistula, and cleft lip and palate. The volume density of C‐cells (1.187%) and the mean number of C‐cells per follicle (1.42) was significantly lower in patients with DiGeorge anomaly than in control patients (3.475% and 2.367, respectively). These results indicate a decrease in cells derived from the neural crest in patients with DiGeorge anomaly, and support the hypothesis of a neural crest disturbance as the pathogenetic factor responsible for this anomaly. © 1993 Wiley‐Liss, Inc.
Genomic imprinting: Summary of an NICHD conference
Authors: Wilson Golder N. , Hall Judith G. , de la Cruz Felix
Published: June 2005

Compelling evidence for genomic imprinting as a pathogenetic mechanism in humans mandates re‐evaluation of every genetic or multifactorial disease for parent‐of‐origin effects. In an expanding list of malformation syndromes, cancers, growth abnormalities, and chromosomal disorders, phenotypes may be determined by source rather than content of transmitted DNA. A multidisciplinary conference held on April 13–14, 1992, reviewed the substantial impact of genomic imprinting in mouse development and discussed in role in human pregnancy, childhood cancers, chromosomal translocations, X‐inactivations, and several disorders associated with mental retardation. Topics for future research include the mechanism, timing, reversibility, and homology of the imprinting process. © 1993 Wiley‐Liss, Inc.