bluuebunny/crossref_metadata_2025 huggingface dataset:
Pseudoxanthoma elasticum: High calcium intake in early life correlates with severity
Authors: Renie William A. , Pyeritz Reed E. , Combs James , Fine Stuart L.
Published: June 2005

The characteristic histopathologic lesion of pseudoxanthoma elasticum (PXE) is calcification of the central core of elastic fibers in affected organs; it is correlated with clinical severity. One hypothesis holds that lowering dietary calcium might reduce or prevent tissue injury and minimize clinical effects. This hypothesis would be supported by demonstrating that clinical expression is positively associated with previous calcium intake. We studied 32 unrelated PXE patients (20 men and 12 women, mean age 43 years, SE = 14.2, range = 13–71) by grading their clinical severity and their presumed calcium intake during childhood, adolescence, and adulthood. Overall severity in the study group varied greatly and correlated positively with age (P < 0.001). Overall severity correlated positively with calcium ingestion as an adolescent (P < 0.001, with the other predictor variables held constant). Overall cardiovascular and eye severity were a function of age (P < 0.000001 for both), whereas skin severity was not.

These results confirm that PXE is a highly variable condition that generally worsens with age and support the rationale for a clinical trial to determine the effects of different levels of dietary calcium ingestion in young PXE patients on their subsequent clinical course.
Frontofacionasal dysplasia: Evidence for autosomal recessive inheritance
Authors: Gollop T. R. , Kiota M. M. , Martins R. M. M. , Lucchesi E. A. , Alvarenga F0 E.
Published: June 2005

We report on a 2‐month‐old girl whose parents are first cousins. The patient has severe craniofacial anomalies characterized by: encephalocele, hypertelorism, midface hypoplasia, hypoplasia of frontal bone on the left side, malformed left eye, absent inner eyelashes, irregular S‐shaped palpebral fissures, deformed nostrils, hypoplastic right nasal wing and cleft lip, and clefts of premaxilla, palate and uvula. No other malformations were observed. This association of anomalies suggests the diagnosis of frontofacionasal dysplasia. Parental consanguinity suggests autosomal recessive inheritance.
Börjeson‐Forssman‐Lehmann syndrome: Further delineation in five cases
Authors: Ardinger Holly Hutchison , Hanson James W. , Zellweger Hans U.
Published: June 2005

We have studied five males with Börjeson‐Forssman‐Lehmann syndrome (BFLS) from two unrelated families. They had a characteristic facial appearance with prominent supraorbital ridges, deep‐set eyes, ptosis, and large ears, as well as obesity, severe mental retardation, hypotonia, and hypogonadism. Ophthalmologic, EEG, and skeletal abnormalities were also present. The findings in several presumed or possible heterozygous women were evaluated and suggested a wide range of phenotypic effects varying between apparent normality to mild or moderately evident BFLS manifestations. The observed pattern of occurrence of the BFLS in our two families provides strong support for X‐linked inheritance. In clinically normal female relatives at risk for being carriers of BFLS, we have been unsuccessful in identifying a reliable screening test. The condition in our and previously reported patients was contrasted with other malformation syndromes and our findings support the conclusion that BFLS is a distinct and clinically indentifiable disorder.
A family study of renal dysplasia
Authors: Al Saadi A. A. , Yoshimoto Masanaga , Bree Robert , Farah Jalil , Chang Chung‐Ho , Sahney Shobha , Shokeir M. H. K. , Bernstein Jay
Published: June 2005

A family study was undertaken to investigate genetic involvement in renal dysplasia, which is defined as abnormal metanephric differentiation. Probands were ascertained through the retrospective examination of necropsy records and the reevaluation of available material, which included microscopic examinations of the kidneys, gross descriptions of organs, and gross photographs. We obtained family histories and performed physical examinations and renal ultrasonography on parents and sibs of the 21 probands. In only one family a sibling with renal dysplasia was discovered; both the proband and the previous stillborn sib had renal dysplasia in association with posterior urethral values. Renal dysplasia could have resulted from urinary tract obstruction secondary to the urethral valves, with inheritance of the valves as the primary abnormality. However, we cannot exclude primary inheritance of the renal abnormality, perhaps with multifactorial determination with a threshold. The empiric recurrence risk of 2.1%, calculated from this family study, was statistically not significantly different from zero. We can assume, therefore, that the multicystic and aplastic types of renal dysplasia, which predominated in this study, are sporadic or rarely familial, but certain other types of renal dysplasia, identified in the literature as familial, probably carry a higher recurrence risk.
Prenatal diagnosis: The experience in families who have children
Authors: Black Rita Beck , Furlong Regina
Published: June 2005

Recent investigations have documented the potentially stressful nature of prenatal diagnostic testing but no systematic attention has been paid to the particular experiences of women who already have other offspring in the home. Some evidence suggests an alteration of parent‐child relationships. Further support for need to inquire into this issue can be found in the extensive literature concerned with children's reactions to death and bereavement, as well as to miscarriage. Results are presented from a study of the experiences of families in which mothers used prenatal diagnostic testing. The sample consisted of 112 women drawn from an outpatient population receiving prenatal testing and their 175 living offspring who were 4 years old or older. Over two thirds of the mothers indicated they had told at least one child in the family about the testing, and children's reactions were characterized as very interested, with low to moderate levels of anxiety, worry, or confusion about the testing. More extreme, worrisome reactions were the exception. In a few cases children were reported to have been concerned about the possibilities of harm to the mother and about abortion. Some of the preschool age children seem to have been frightened by overly graphic descriptions of the procedure itself: A few mothers also voiced concerns that as a result of knowing about the testing their children might become frightened and feel less secure about their own imperfections.
Cytogenetic diagnosis using midtrimester fetal blood samples: Application to suspected mosaicism and other diagnostic problems
Authors: Watson Michael S. , Breg W. Roy , Hobbins John C. , Mahoney Maurice J.
Published: June 2005

Cytogenetic studies on fetal blood cells obtained at 18–25 weeks gestation have provided information for decision making in 25 cases identified as being at high risk of having an abnormal fetus. In particular, in the 21 cases studied to consider the possibility of true mosaicism, confirmation in fetal blood was obtained in three, one of which presented as a pseudomosaic on the original amniotic fluid cell study. Fetal blood was also informative in two cases (one positive and the other negative) in which a diagnosis of the fragile X syndrome was being considered. Furthermore, when high risk pregnancies presented late in gestation (21–24 weeks), these methods allowed for a rapid cytogenetic diagnosis. The procedure has proved useful in most of these cases since the couples involved had indicated that they would probably have terminated the pregnancy without the reassurance of normal fetal lymphocyte studies. Since the technique carries a much higher risk of pregnancy loss than does amniocentesis, its use should only be considered when there are compelling indications.
Elaboration of the phenotypic changes of the upper limbs in the Neu‐Laxova syndrome
Authors: Shved I. A. , Lazjuk G. I. , Cherstvoy E. D. , Opitz John M. , Reynolds James F.
Published: June 2005

We present two new cases and data from a detailed study of the upper limbs (structural changes, the state of peripheral nerves, arteries, muscles and bones) of three stillborn infants with the Neu‐Laxova syndrome. The morphogenesis of many of the examined anatomical structures in these fetuses was anomalous. The origin of these anomalies is discussed.
Kindler syndrome in two related Kurdish families
Authors: Hacham‐Zadeh Shoshana , Garfunkel Adi A. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a 19‐year‐old girl with Kindler syndrome. She has suffered from bullae on pressure areas of the skin since birth. These healed with atrophic scars and caused marked atrophy of the skin of the palms and soles and wrinkled and parchment‐like skin of the dorsum of the hands and feet. Since infancy the patient has also suffered from severe photosensitivity on exposed areas and developed poikiloderma on the skin of her face, neck, chest, and upper back. Since age 17 years the patient has been free of bullae but moderate photosensitivity exists. Oral examination showed limitation of mouth opening, ankyloglossia, overjet malocclusions, and atrophy of buccal mucosa with widespread white macules. Results of laboratory tests were within normal limits.

The proposita's parents (family 1) are Jews of Kurdish origin and first cousins. She is the only one affected among five siblings. Family 1 is related to a second family (family 2) through a common great‐grandfather. The parents of family 2 are first cousins and they have three affected children. An autosomal recessive mode of inheritance of Kindler syndrome is suggested in these two related families.
Duplication 5q(5q22→5q33): From an intrachromosomal insertion
Authors: Martin Nicole J. , Cartwright David W. , Harvey Phillip J. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an infant with an as yet undescribed partial duplication 5q(q22→5q33). He had a number of the already recorded manifestations of partial trisomy 5q, namely microcephaly, growth retardation, brachydactyly, long flat philtrum, thin upper lip vermilion and downturned angles of mouth and apparently low set ears. He survived only 6 months. He inherited his duplication from a maternal intrachromosomal insertion; thus he represents a pure dup(5)(q22→5q33).
Odontoonychodysplasia with alopecia: A new pure ectodermal dysplasia with probable autosomal recessive inheritance
Authors: Pinheiro Marta , Freire‐Maia Newton , Gollop Thomaz R. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two Brazilian sisters who have a probably autosomal recessive ectodermal dysplasia of trichodysplasia, dental anomalies, onychodystrophy, skin alterations, and other findings. This appears to be the first full report of this condition for which we propose the name odontoonychodysplasia with alopecia.
Male‐to‐male transmission of the hypertelorism‐hypospadias (BBB) syndrome
Authors: Stoll Claude , Geraudel André , Berland Henri , Roth Marie‐Paule , Dott Béatrice , Holmes Lewis B. , Reynolds James F.
Published: June 2005

A boy and his father with the hypertelorism‐hypospadias (BBB) syndrome are described. This example of male‐to‐male transmission is evidence that the BBB syndrome is not due to an X‐linked gene.
Interstitial deletion of the long arm of chromosome 10: Del(10)(q11.2q21)
Authors: Holden Jeanette J. A. , MacDonald E. Athen , Opitz John M. , Reynolds James F.
Published: June 2005

A de novo interstitial deletion of part of the long arm of chromosome 10 [de(10)(q11.2q21)] was identified by GTG (G‐bands by trypsin using Giemsa) banding in a 9‐year‐old girl with mental retardation and minor anomalies. Only one other case of a similar deletion has been reported [Ray et al, 1980] and the phenotypic findings of the two cases are compared.
Non‐mosaic partial tetrasomy and partial trisomy 9
Authors: Shapiro Steven D. , Hansen Kathryn L. , Littlefield Christine A. , Opitz John M. , Reynolds James F.
Published: June 2005

Partial tetrasomy 9 is a very rare chromosome abnormality. Of the reported cases, most have had tetrasomy only of 9p arising from the formation of an isochromosome. In addition, mosaicism was found in five of the 12 previous cases. We report on a case of non‐mosaic partial tetrasomy 9 involving all of the short arms and asymmetrical segments of the long arms.
The phenotypic and cytogenetic spectrum of partial trisomy 9
Authors: Wilson Golder N. , Raj Anita , Baker Diane , Opitz John M. , Reynolds James F.
Published: June 2005

A new patient with trisomy for the chromosome segment 9pter→q22 is compared to 19 previously reported cases of partial trisomy 9. Manifestations such as microcephaly, prominent nasal root, bulbous nose, and down‐turned corners of the mouth are common to patients with trisomic segments extending from 9p21 to 9q13, while intra‐uterine growth retardation, cleft lip/palate, skeletal anomalies, and heart defects are more common with trisomic segments extending through 9q22‐9q32. A graphic method illustrates this progression in the partial trisomy 9 malformation spectrum as the triplicated chromosome region extends from bands 9q21 to 9q32. More severe and random defects are observed with complete trisomy 9 or tetrasomy 9p, suggesting an extreme excess of material greatly increases developmental variability.
Unbalanced translocation (15;17)(q13;p13.3) with apparent Prader‐Willi syndrome but without Miller‐Dieker syndrome
Authors: Elder F. F. B. , Nichols M. M. , Hood O. J. , Harrison W. R. , Opitz John M. , Reynolds James F.
Published: June 2005

We studied after death a 3‐month‐old girl whose karyotype was 45,XX, − 15, − 17, + der(17),t(15;17)(q13;p13.3) and thus combines abnormalities of chromosome 15 associated with the Prader‐Willi syndrome and of chromosome 17 associated with the Miller‐Dieker syndrome. This infant had several manifestations of the Prader‐Willi syndrome in infancy but none of the Miller‐Dieker syndrome. We propose that essentially no loss of 17p material has occurred and confirm previous reports that the critical region for the production of the Miller‐Dieker phenotype is located subterminally in the 17p13.3 region.
Discordant amniotic band sequence in monozygotic twins
Authors: Donnenfeld Alan E. , Dunn Linda K. , Rose Nancy C. , Opitz John M. , Reynolds James F.
Published: June 2005

Multiple congenital anomalies were identified at 16 weeks gestation in one fetus of an unsuspected twin pregnancy while ultrasound examination was performed before routine genetic amniocentesis. Further sonographic studies documented the amniotic band sequence (ABS) and transient oligohydramnios in the affected fetus. The latter finding supports the theory of amnion rupture followed by amniotic fluid leakage through an ineffective chorion barrier as the pathogenesis of compression related anomalies in this syndrome. Extensive craniofacial involvement including hydrocephalus, encephalocele, and multiple facial clefts in the affected fetus, combined with an erroneous ultrasound diagnosis of ABS in the unaffected twin, created an extremely difficult management and counseling situation. A review of ABS, the embryology of placental membrane development, and a discussion of selective termination procedures are presented.
Osteogenesis imperfecta with unusual skeletal lesions: Report of three families
Authors: Levin L. Stefan , Wright John M. , Byrd D. Lamar , Greenway Guerdon , Dorst John P. , Irani Roshen N. , Pyeritz Reed E. , Young Richard J. , Laspia C. L. , Opitz John M. , Reynolds James F.
Published: June 2005

Thirteen individuals with osteogenesis imperfecta (OI) from three families were evaluated. All examined persons with OI had multilocular radiolucent, radiopaque, or radiolucent‐radiopaque lesions of the maxilla and mandible. In most patients, the lesions involved the tooth bearing areas, but in two, the rami also were involved. Teeth were normal. Radiologic findings in the extragnathic skeleton included marked coarseness of trabeculae and diffuse osteopenia. It is proposed that these patients represent yet another dominantly inherited OI syndrome.
Evaluation of carrier detection of Duchenne muscular dystrophy using carbonic anhydrase III and creatine kinase
Authors: Heath R. , Carter N. D. , Jeffery S. , Edwards R. J. , Watts D. C. , Watts R. L. , Opitz John M. , Reynolds James F.
Published: June 2005

Carbonic anhydrase III (CAIII) and creatine kinase (CK) were measured in plasma samples from a series of females at‐risk as carriers of Duchenne muscular dystrophy and compared with control groups. Both plasma CAIII and CK levels were raised in a proportion of carriers. Although measurement of CAIII and CK was no more successful in identifying carriers than CK alone, CAIII could fulfill a useful confirmatory role, particularly for cases with a marginally elevated CK or where the sample is poorly preserved. The difference between the CK and CAIII results could indicate biochemical heterogeneity in the expression of Duchenne muscular dystrophy.
Prenatal diagnosis of Weyers syndrome (deficient ulnar and fibular rays with bilateral hydronephrosis)
Authors: Elejalde B. Rafael , De Elejalde Maria Mercedes , Booth Carol , Kaye Celia , Hollison Lynne , Opitz John M. , Reynolds James F.
Published: June 2005

A fetus with Weyers oligodactyly was studied after a previous sibling had been born with that condition. Prenatal diagnosis was undertaken using ultrasound to visualize the long bones, which were found to be severely affected by the condition at 19 weeks of gestation. Most notable were the ulnae and fibulae, which were very short; the fetus had bilateral hydronephrosis.
Visualization of the fetal spine: A proposal of a standard system to increase reliability
Authors: De Elejalde Maria Mercedes , Elejalde B. Rafael , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a method for the morphological, developmental, and functional analysis of the fetal spine. Using this system, different types of spina bifida and hemivertebrae have been discovered. A system of quality control and documentation is proposed and cases that were not detected ultrasonographically are described. The results of the analyses of seven abnormal fetuses out of 818 pregnancies examined by us and three referred after birth are presented, including fetuses with caudal regression, spina bifida, hemivertebrae with lordosis and kyphosis, and spina bifida without ultrasonographic or radiologic evidence of bone abnormality. Cases that were not diagnosed ultrasonographically by other observers are presented.
The neurofibromatosis‐Noonan syndrome
Authors: Mendez Heirie M. M. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two patients with clinical evidence of Noonan syndrome and neurofibromatosis. Four hypotheses to explain the simultaneous occurrence of both conditions are discussed.
Osteodysplastic primordial dwarfism: Report of a further patient with manifestations similar to those seen in patients with types I and III
Authors: Winter R. M. , Wigglesworth J. , Harding B. N. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a female infant with low birthweight osteodysplastic microcephalic dwarfism. The child has many manifestations in common with those seen in osteodysplastic primordial dwarfism types I and III. The classification of this heterogeneous group of disorders is discussed in the light of the above case.
Unusual type of brachydactyly associated with short stature and facial anomalies. A new syndrome?
Authors: Richieri‐Costa A. , Colletto G. M. D. D. , Otto P. A. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a 10‐year‐old boy with short stature, mild microcephaly, malar hypoplasia, highly arched palate, prominent upper incisors, micrognathia, and unusual digital anomalies involving the proximal phalanges of fingers 2–5 of both hands. To our knowledge, this is a hitherto undescribed syndrome.
Linear skin atrophy, scarring alopecia, anonychia, and tongue lesion: A “new” syndrome?
Authors: Sequeiros Jorge , Sack George H. , Opitz John M. , Reynolds James F.
Published: June 2005

One of a pair of female monozygotic twins showed skin atrophy with linear alternation of depressed scarlike areas and intervening ridges of normal or nearly normal skin. She was born with friable skin and a vesicular‐bullous eruption which was followed by gradual scabbing. Hypohidrosis in the affected areas, heat intolerance, and febrile convulsions were noted in infancy and childhood. No new skin lesions developed, and the existing ones, the sweating disturbance, and the heat intolerance gradually improved with time. Scarring alopecia, congenital absence of three toenails, and a scarlike lesion of the tongue were also present. Their absence in the other twin supports the view that 1) these manifestations all are part of the same syndrome, and 2) this syndrome is nongenetic.

Histologically, there were no diagnostic or consistent findings, but the number of skin appendages was diminished, and the elastic fibers were reduced in number and size in one biopsy. The calculated probability for the twins being monozygotic was 0.9998.

This family was also remarkable for the presence of alopecia areata in three successive generations with only one instance of apparent nonpenetrance.

We conclude that this may represent a previously undescribed syndrome of congenital fragility of connective tissue which predisposed to damage of the elastica, possibly caused by an early inflammatory phase.
Multiplicity of genetic polymorphisms of blood in the Schmiedeleut Hutterites
Authors: Lewis Marion , Kaita Hiroko , Giblett Eloise R. , Anderson Jeanne , Philipps Sylvia , Steinberg Arthur G. , McAlpine Phyllis J. , Opitz John M. , Reynolds James F.
Published: June 2005

Ninety‐eight alleles in 38 polymorphisms of blood are identified in the Schmiedeleut Hutterites. The study was initiated because of the presence of Wda, an allele found almost exclusively in Hutterites. Eight of the other alleles also have an exceedingly low incidence in a random white population: r″ (.006), R2w (<.001), LWb (<.01), ESD*rare (<.001), GPT*0 (.004), NP*4 (<.001), GOT2*3 (.001), and C6*0 (.002). The occurrence of this many rare alleles in a population with an estimated maximum of 124 ancestral genomes was surprising but consistent with observations in other isolates. The degree of heterozygosity and large family size make the population ideal for genetic linkage studies.
Juvenile cataract in Hutterites
Authors: Shokeir M. H. K. , Lowry R. B. , Opitz John M. , Reynolds James F.
Published: June 2005

Isolated juvenile or congenital cataract is a rare disorder. It occurs commonly as part of a more generalized or systemic condition or as a component of a syndrome. When encountered per se it may be genetically determined. The inheritance then often is autosomal dominant; autosomal recessive transmission of isolated juvenile cataract is rare. Here we present, four sibships from an extensive kindred including nine individuals affected with juvenile (or congenital) cataracts. The kindred belongs to the Lehrerleut Hutterite group from the provinces of Saskatchewan and Alberta in Canada and the state of Montana in the United States. Apart from the cataracts, all the patients were healthy and of normal growth and development. Specifically, no metabolic disorder could be identified. Intellect, hearing and behavior were all normal and the patients were neurologically intact. Furthermore, there were no other ocular lesions aside from the cataracts. In this kindred cataracts appear to be a recessive trait.
Congenital anomalies in the Hutterite population: A preliminary survey and hypothesis
Authors: Lowry R. B. , Morgan K. , Holmes T. M. , Gilroy S. W. M. , Opitz John M. , Reynolds James F.
Published: June 2005

The Alberta Provincial Congenital Anomaly (CA) Surveillance reporting forms were scanned for infants whose surnames and addresses identified them as belonging to the Hutterite Brethren. Death registrations (of infants up to 1 year) and stillbirth registrations were similarly scanned. While the overall percentage of total malformations (5%) and major malformations (2%) was no different from that of the total population of Alberta, closer examination of the actual entities showed a large number of monogenic disorders among the Hutterites. The frequency of multifactorial congenital anomalies was approximately 1 %. The inbreeding coefficients, using a genealogic data base, were computed for each “case baby” and two Hutterite “control babies,” the latter being births preceding and succeeding the case baby. There was no statistical difference in the distribution of inbreeding coefficients between the case and control groups. While the data are based on small numbers and therefore are preliminary, they suggest that the Hutterite lifestyle, of good nutrition (using largely home prepared foods), absence of tobacco and minimal alcohol consumption, may be one factor responsible for fewer multifactorial CAs whose occurrence is environmentally susceptible to such influences. Studies of populations with a low incidence of disorders are just as important as those with a high incidence.
Primary hypogonadism and partial alopecia in three sibs with Müllerian hypoplasia in the affected females
Authors: Al‐Awadi S. A. , Farag T. I. , Teebi A. S. , Naguib K. , El‐Khalifa M. Y. , Kelani Y. , Al‐Ansari A. , Schimke R. N. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe 3 sibs, two females and a male, with hypogonadism, defective Müllerian development in the sisters, and partial alopecia consisting of cranial hair only in the center of the scalp. One sister had absent gonads, the other had streak ovaries; both had markedly hypoplastic internal genitalia. Their brother had hormonal and histologic findings consistent with germinal cell aplasia. In view of the fact that the parents were consanguineous, autosomal recessive inheritance of the syndrome is likely.
Autopsy findings in a stillborn female infant with the Osebold‐Remondini syndrome
Authors: Opitz John M. , Gilbert Enid F. , Reynolds James F.
Published: June 2005

The Osebold‐Remondini syndrome is a bone dysplasia with mesomelic shortness of limbs and, hence, shortness of stature, absence or hypoplasia of second phalanges with synostosis of the remaining phalanges, carpal and tarsal coalitions, and apparently no other anomalies. This is an autosomal dominant condition. In the family described by Osebold et al [1985], a female infant with the Osebold‐Remondini syndrome was still‐born. Cause of fetal death could not be determined, and, at the moment, cannot be assumed to be a pleiotropic manifestation of this gene. The skeletal abnormalities in the infant are described and illustrated. Histologic structure of bone (proximal femur, vertebral bodies, iliac crest, and costal junctions) was studied by light and electronmicroscopy. Several histologic and ultrastructural abnormalities found suggest that the Osebold‐Remondini syndrome may involve more generalized anomalies of bone development than the clinical picture might suggest.
Female relatives in families with the fragile X syndrome
Authors: Partington M. W. , Opitz John M. , Reynolds James F.
Published: June 2005

Three problems–mental retardation, having retarded children, and fear of having retarded children–are described in women in families with the fragile X syndrome. The investigation of one family with a counselling dilemma is presented in detail.
Aortic root dilatation and mitral valve prolapse in the fragile X syndrome
Authors: Loehr James P. , Synhorst David P. , Wolfe Robert R. , Hagerman Randi J. , Opitz John M. , Reynolds James F.
Published: June 2005

Forty patients with fragile X [fra(X)] or Martin‐Bell syndrome, confirmed by chromosome analysis, underwent full cardiac evaluation including physical examination, chest film, electrocardiography (ECG), and M‐mode and 2‐dimensional echocardiography. Thirty‐four males and six females were studied. Although all patients were asymptomatic, seven males were found to have mild aortic root dilatation. All seven also had evidence of mitral valve prolapse. Twenty‐two (55%) of the study patients had mitral valve prolapse with either a click or murmur heard on physical examination and confirmation by M‐mode echocadiogaphy.The frequency of mitral valve prolapse was the same in males and females, but 80% of males older than 18 years had mitral valve prolapse. These findings support the hypothesis of a connective tissue dysplasia in the fra(X) syndrome.
Variability of thymidylate synthase activity in whole blood cultures treated with FUdR
Authors: Sklower Susan L. , Jenkins Edmund C. , Anderson Melba L. , Chan Colin B. , Brown W. Ted , Opitz John M. , Reynolds James F.
Published: June 2005

Induction of some fragile sites including fragile X [fra(X)] depends on the depletion of thymidine monophosphate (TMP) from the culture medium. This can be accomplished by use of inhibitors such as 5‐fluorodeoxyuridine (FUdR) and by culturing cells in medium deficient in folate and TMP. FUdR inhibits the activity of thymidylate synthase (TS), thereby depleting cells of TMP. To determine the degree of FUdR inhibition of TS under routine cytogenetic culture conditions, we modified the tritiated dUMP TS method for use in short‐term whole blood cultures stimulated with phytohemagglutinin. TS inhibition was highly variable across whole blood cultures from 30 individuals exposed to FUdR during the last 24 hours of a 4 day culture. If an additional dose of FUdR was added 12 hours be fore harvest, TS inhibition usually increased. These findings have a potential impact on the use of FUdR for the diagnosis of the fra(X) syndrome.
Differential expression of fragile site Xq27 in cultured fibroblasts from hemizygotes and heterozygotes and its implications for prenatal diagnosis
Authors: Schmidt Angela , Passarge E. , Opitz John M. , Reynolds James F.
Published: June 2005

Expression of the fragile site Xq27 (fraXq27) was studied in metaphases derived from fibroblasts of 8 hemizygotes and 2 heterozygotes, cultured in 2 different media containing reduced concentrations of folic acid. The proportion of fra(X)(q27)‐positive metaphases ranged from 1.0 to 14%, which is considerably lower than in lymphocyte cultures from the same individual, but differed with respect to the culture medium used. Four hemizygotes showed a higher proportion of fra(X)‐positive cells in medium 199 than in methotrexate‐exposed cultures. No fra(X)‐negative cultures were observed when the folic acid inhibitor methotrexate was added to medium 199 . Thus, in all 10 individuals carrying the fra(X), the fragile site could be detected in fibroblast cultures. We conclude that the expression of fra(X)(q27) in cultured fibroblasts should be studied using at least 2 types of culture conditions, because familial, i.e. genetic differences may influence the expression of this fragile site in fibroblasts. The implications for prenatal diagnosis are discussed on the basis of investigations in 15 pregnancies at risk for the trait.
A possible fragile‐site at Yq12: Case report and possible relevance to de novo structural rearrangements of the Y‐chromosome
Authors: Holden Jeanette J. A. , Ridgway Patricia , Smith Anne , Opitz John M. , Reynolds James F.
Published: June 2005

In a routine chromosome study it was noted that cells from a patient had different lengths of Y‐chromosome: 20% of the cells had a Y‐chromosome with about 40% of the normal length of heterochromatin, whereas the majority of cells had an average sizeYq12 region. A break within Yq12 was found in 3–4% of the cells with the long Yq12 chromosome, indicating the presence of a possible new fragile site. The frequency of cells with the 2 different sizes of Y‐chromosomes was unaffected by culture conditions as was the frequency of cells with a break or gap. Possible consequences of a fragile‐site within Yq12 are discussed.
Normal male carriers in the fra(X) form of X‐linked mental retardation (Martin—Bell syndrome)
Authors: Froster‐Iskenius U. , McGillivray B. C. , Dill F. J. , Hall J. G. , Herbst D. S. , Opitz John M. , Reynolds James F.
Published: June 2005

Evidence for the transmission of X‐linked mental retardation through normal male carriers is reviewed in 6 kindreds. In these pedigrees we identified 15 unaffected males who likely had passed the gene on through their daughters. Fifty‐one mentally retarded grandsons or great grandsons descended from these males had 50 daughters with only 2 of them being of low intelligence. Two of the male carriers were recently identified through fra(X)‐ positive results in their mentally normal daughters. Among the sibs of these males, mentally retarded brothers were found in 3 families. This was unexpected since earlier observations suggested that the risk for mental retardation among sibs of non‐manifesting carriers is exceedingly low.
DNA linkage studies in the fragile X syndrome suggest genetic heterogeneity
Authors: Brown W. Ted , Gross Anne C. , Chan Colin B. , Jenkins Edmund C. , Opitz John M. , Reynolds James F.
Published: June 2005

Previsouly we showed genetic heterogeneity for linkage between the fra(X) locus and a factor IX DNA RFLP (Brown et al, 1985). When fra(X) families were predivided into two classes, one containing those with non‐penetrant (NP) males and one with apparent full penetrance (P), evidence of significant heterogeneity was present. We have now extended this analysis by adding DNA linkage information on 2 additional probes, 52A and ST14, studied in 16 fra(X) kindreds. These data were combined with information on 16 published fra(X) families. There were 7 NP families and 25 P families. We confirmed our previous findings of a higher recombination fraction between factor IX and fra(X) in P families (0 = .32 with lod of .67) compared to as NP familes (0 = .06 with lod of 6.11) which was singnificant at p < .01. In comparing recombination fractions for the additional probes, more recombination between 52A and the other loci was consistently seen in P compared to NP familes which suggested that there may be a higher rate of recombination proximal to the fra(X) locus in P kindreds. A strikingly higher recombination fraction between 52A and factor IX was present in comparing all fra(X) families (.18) to normal families (.02) which was significant at p < .001. These results suggest genetic heterogeneity with respect to recombination is present both among fra(X) pedigrees and between fra(X) and normal pedigrees.
Cytogenetic studies in Wiskott‐Aldrich syndrome: Identification of a case with a 6p chromosome abnormality
Authors: Johnson M. P. , Filipovich A. H. , Opitz John M. , Reynolds James F.
Published: June 2005

Lymphocytes from patients with Wiskott‐Aldrich syndrome (WAS) were studied (1) with prometaphase G banding to search for minor chromosome anomalies and (2) in mutagen stress assays to assess the extent of chromosome breakage under these conditions. One patient, a sporadic case of WAS, was found to have a stable inversion of a large segment of one chromosome 6 that involved the region encoding the major histocompatibility complex (MHC). The anomaly was not present in the patient's parents, nor in three other unrelated patients with WAS, all of whom demonstrated X‐linked inheritance (based on family history). None of the four patients showed an excessive number of breaks or radial exchange figures following exposure to mitomycin C or diepoxybutane. Thus chromosome fragility in WAS was not confirmed by these studies. However, the incidental finding of 6p inversion in a sporadic case of WAS suggests that genetic rearrangement involving the MHC can result in clinical immunodeficiency mimicking WAS.
Lethal osteopetrosis with multiple fractures in utero
Authors: Khazen Nabih El , Faverly Daniel , Vamos Esther , Van Regemorter Nicole , Flament‐Durand Jacqueline , Carton Brigitte , Cremer‐Perlmutter Noémi , Opitz John M. , Reynolds James F.
Published: June 2005

Severe osteopetrosis was diagnosed in utero in two successive pregnancies resulting from an intermarriage. Hydrocephaly and skeletal hyperdensity were detected at 18 weeks of gestation, and fractures at 24 weeks. We report on extensive ultrasound, radiological, and pathological findings, including those on brain and bone. The markedly reduced number of osteoclasts observed in these sibs and the very early fetal involvement suggest that this form of osteopetrosis might represent a new entity: autosomal recessive lethal osteopetrosis.
Osteogenesis imperfecta type III. Delineation of the phenotype with reference to genetic heterogeneity
Authors: Sillence D. O. , Barlow K. K. , Cole W. G. , Dietrich S. , Garber A. P. , Rimoin D. L. , Opitz John M. , Reynolds James F.
Published: June 2005

The existence of a rare form of osteogenesis imperfecta, OI type III, has been postulated. This is characertized by autosomal recessive inheritance with neonatal manifestations of bone fragility or deformability. It is usually nonlethal. Studies of some 345 pedigrees of OI in the last 8 years confirm that patients falling into this group are rare. They should be distinguished as a special group within the group of O1 subjects with a progressively deforming O1 phenotype delineated in previous publications [Sillence et al, 1979a, b]. The OI type III phenotype does not necessarily equate with progressively deforming OI, and probably only a proportion of cases with severe deformity and normal scleraehave OI type III. On the other hand, distinction between these patients and those with a milder form of perinatally lethal OI type II might be difficult. Whereas the natural history of skeletal deformity and fractures in patients with OI type III has certain similarities, variable severity between families indicates that OI type III is likely to be genetically heterogeneous.
Subclavian artery supply disruption sequence: Hypothesis of a vascular etiology for Poland, Klippel‐Feil, and Möbius anomalies
Authors: Bavinck Jan N. Bouwes , Weaver David D. , Opitz John M. , Reynolds James F.
Published: June 2005

A hypothesis is presented to explain the pathogenesis of the Poland, Klippel‐Feil, and Möbius anomalies, isolated absence of the pectoralis major with breast hypoplasia, isolated terminal transverse limb defects, and the Sprengel anomaly. We propose that these conditions are the result of an interruption of the early embryonic blood supply in the subclavian arteries, the vertebral arteries and/or their branches, and hypothesize that the occlusions occur at specific locations in these vessels during or around the sixth week of embryologic development and produce predictable patterns of defects. The termsubclavian artery supply disruption sequence(SASDS) is suggested for the group of birth defects represented by the above conditions. Possible causes for interruption of embryonic blood supply are discussed.
A comparison of the availability and content of genetic counseling as perceived by hemophilic men and carriers in the U.S.A., Canada, Scotland, and Greece
Authors: Markova Ivana , Forbes Charles D. , Aledort Louis M. , Inwood Martin , Mandalaki Titika , Miller Connie H. , Pittadaki Jane , Reynolds James F.
Published: June 2005

A survey study was carried out with 211 hemophilic men and 205 carriers of hemophilia at four hemophilia centers in New York; London, Ontario; the West of Scotland; and Athens, Greece. The participants responded to a questionnaire exploring socio‐demographic and medical information, attitudes toward hemophilia, and experience of and attitudes toward genetic counseling. The study shows differences between attitudes of hemophilic men and carriers, differences in perceived problems among patients and carriers in the four centers, and differences in opinions between consumers and professionals. Comprehensive services for hemophilic families available in the New York center facilitate both patient education and satisfaction.
Concurrence of von Willebrand's disease and hemophilia A: Implications for carrier detection and prevalence
Authors: Miller Connie H. , Hilgartner Margaret W. , Harris Michael B. , Bussel James B. , Aledort Louis M. , Reynolds James F.
Published: June 2005

Five families with concurrent von Willebrand's disease (VWD) and classic hemophilia (hemophilia A) are described. Three were ascertained through women undergoing hemophilia carrier testing, one through an obligate carrier who also has VWD, and one through the affected father of a hemophiliac. The VWD probands exhibited Type I VWD with reduced Factor VIII‐related antigen (VIIIR: Ag) and/or von Willebrand factor on more than one occasion, normal VIIIR: Ag on crossed immunoelectrophoresis, and mild symptoms. No male had both disorders, but two obligate hemophilia carriers alos had VWD. Neither was detectable as a carrier by discriminant analysis. Four possible carriers of hemophilia had VWD and would also be classified as noncarriers statistically. These findings suggest that the presence of VWD may invalidate hemophilia carrier testing by conventional methods. The independent entry into the family of the two genes by mating of a hemophilia carrier and a VWD male is documented in two cases and probable in two. The observed frequency of such matings supports the hypothesis that VWD is a common disorder.
Persistent hyperplastic primary vitreous and recessive oculo‐dento‐osseous dysplasia
Authors: Traboulsi Elias I. , Faris Bishara M. , Kaloustian Vazken M. Der , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a patient with oculo‐dento‐osseous dysplasia and bilateral persistence of the hyaloid system. Autosomal recessive inheritance may be the cause of this patient's condition since she was born to unaffected first‐cousin parents. Ocular findings in the recessive variety of this syndrome seem to be more severe than those in the more common dominant form.
Investigation on genetic heterogeneity in Duchenne muscular dystrophy
Authors: Rabbi‐bortolini Eliete , Zatz Mayana , Opitz John M. , Reynolds James F.
Published: June 2005

The preliminary results of a study to investigate possible genetic heterogeneity in Duchenne muscular dystrophy (DMD) are reported. Ninety‐eight patients have been analyzed: 47 were isolated cases; 51 were familial cases. The patients were divided into three groups (normal intelligence, borderline, and mentally retarded) according to mental capacity and a comparison of clinical evolution (onset of clinical signs and loss of ambulation) as well as serum enzyme activities (creatinekinase and pyruvate‐kinase). In addition intrafamilial correlation analysis was done for the same parameters.

The preliminary results did not show a significant difference between DMD patients with normal intelligence and those with mental retardation.
Prenatal diagnosis of the Beckwith‐Wiedemann syndrome
Authors: Winter Susan C. , Curry Cynthia J. R. , Smith J. Charles , Kassel Stephen , Miller Linda , Andrea Janet , Reynolds James F.
Published: June 2005

We report on the prenatal diagnosis of Beckwith‐Wiedemann syndrome (BWS) in a pregnancy monitored because of a previously affected child. The proposita had classical stigmata of BWS including macroglossia, omphalocele, and typical ear creases. Chromosomes were 46,XX. Both parents and the extended maternal family were clinically normal. In a subsequent pregnancy by another father, the mother had serial ultrasound monitoring at 13.5, 18, and 19 weeks gestation which showed an enlarged abdominal circumference and a 2‐cm omphalocele. At termination the female fetus weighed more than two times the expected weight, had striking hypertrophy of skeletal muscles, a protuberant abdomen, and a 2‐cm omphalocele and characteristic facial appearance. Autopsy confirmed generalized organomegaly. This is the first report of the prenatal diagnosis of BWS prior to 20 weeks in an at‐risk family. The recurrence in this family emphasizes the difficulty in providing accurate genetic recurrence risks in BWS and suggests that ultrasonographic prenatal diagnosis should be offered to families even when the case appears to be “sporadic”.
An autosomal recessive mental retardation syndrome with hepatic fibrosis and renal cysts
Authors: Thompson Elizabeth , Baraitser Michael , Opitz John M. , Reynolds James F.
Published: June 2005

Two sisters had developmental retardation and congenital hepatic fibrosis. One, 23 years old, had facial anomalies reminiscent of Smith‐Lemli‐Opitz syndrome, ocular coloboma, and hypoplastic kidneys with a single cyst. The other sister died at 18 months and had an encephalocele and cystically dilated collecting ducts in the renal medulla. Although the manifestations in these two sisters are similar to the Smith‐Lemli‐Opitz and Meckel syndromes respectively, there are sufficient differences to suggest that they had a separate autosomal recessive MCA‐MR syndrome.
Distal deletion of the long arm of chromosome 6: A specific phenotype ?
Authors: Fryns Jean‐Pierre , Bettens Walter , Berghe Herman Van Den , Reynolds James F.
Published: June 2005

We report on an8‐month‐old girl with a de novo 5q/6q autosomal translocation with loss of the distal part of the long arm of chromosome 6 (6q23.3→6qter); clinical manifestations are peculiar craniofacial stigmata, truncal obesity and persisting hypotonia.

The similarity with a previously reported patient with 6q interstitial deletion is discussed.
The differential symptomatology of errors of collagen metabolism: A tentative classification
Authors: Maroteaux Pierre , Frézal Jean , Cohen‐Solal Lola , Opitz John M. , Reynolds James F.
Published: June 2005

We address the confusion in the current classification of inherited disorders of collagen and the excessive extension of the concept of the Ehlers‐Danlos „syndrome”︁ that tends to cover many facts and conditions frequently without strong clinical connection.

We propose to subdivide the collagen disorders into four main classes depending on whether skin, joints, bone, or blood vessels are mainly involved. The class with mainly skin involvement includes the different forms of cutis laxa, Ehlers‐Danlos syndrome types I and II (autosomal dominant), types V and IX (X‐linked recessive), type VI (autosomal recessive), and type VIII (autosomal dominant). The group with mainly articular involvement includes Larsen and related syndromes and other types with a more benign course. The conditions with mainly skeletal involvement include the different forms of osteogenesis imperfecta. The class with mainly blood vessel involvement includes disorders of type III collagen and the Marfan syndrome.

This tentative classification proposes a logical clinical framework that will allow easier integration of molecular biology data.
Distal arthrogryposis type II: A family with varying congenital abnormalities
Authors: Reiss J. A. , Sheffield L. J. , Opitz John M. , Reynolds James F.
Published: June 2005

Five family members with distal arthrogryposis in two generations are reported. Cleft lip and palate, micrognathia, ptosis, webbed neck, kyphoscoliosis, and short stature are seen in one or more affected family members. All individuals with distal arthrogryposis also have trismus. This family does not fit any of the recently proposed five subcategories of type II distal arthrogryposis, nor does it fit any other recognized autosomal dominant condition with distal contractures.