bluuebunny/crossref_metadata_2025 huggingface dataset:
A mild autosomal recessive form of osteopetrosis
Authors: Kahler Stephen G. , Burns Jane A. , Aylsworth Arthur S. , Opitz John M.
Published: June 2005

We report on four individuals in one kindred with relative or absolute short stature: increased upper/lower segment ratio with decreased arm span; mandibular prognathism and dental abnormalities; fractures following minimal trauma; mild to moderate anemia with extramedullary hematopoiesis; and radiographic changes of osteopetrosis, including sclerosis of the cranial base, generally increased bone density, sclerosis of the vertebral end plates, and transverse bands and poor diaphyseal modelling of the long bones. There is intrafamilial variability of clinical and radiographic findings in individuals with this mild, autosomal recessive form of osteopetrosis. We summarize ten families from the literature, which include 18 cases of mild recessive osteopetrosis. The manifestations of many are similar to those of the individuals reported here.

Two other types of recessive osteopetrosis have been reported previously: osteopetrosis associated with renal tubular acidosis, and severe osteopetrosis with hepatosplenomegaly, pancytopenia, and early death. Autosomal dominant osteopetrosis is variable but usually mild. Pedigree analysis is currently the only reliable method of determining the patternof inheritance in mild osteopetrosis.
Heterogeneity of prenatal onset hydrocephalus: Management and counseling implications
Authors: Williamson Roger A. , Schauberger Charles W. , Varner Michael W. , Aschenbrener Carol A. , Opitz John M.
Published: June 2005

We have evaluated 30 cases of congenital hydrocephalus, most with a presumed early prenatal onset. The ten cases delivered in 1982 were studied prospectively. In 18 of the 25 nonsurvivors, no cause was apparent and many had multiple anomalies. The heterogeneity seen in this series is discussed in relation to intrauterine treatment.
In utero brain destruction resulting in collapse of the fetal skull, microcephaly, scalp rugae, and neurologic impairment: The fetal brain disruption sequence
Authors: Russell Laura J. , Weaver David D. , Bull Marilyn J. , Weinbaum Marc , Opitz John M.
Published: June 2005

Three infants are reported with a recognizable pattern of defects consisting of severe microcephaly, overlapping sutures, prominence of the occipital bone, and scalp rugae. This condition, which we think represents microhydranencephaly, appears to be produced by partial brain destruction during the second or third trimester, diminution in intracranial hydrostatic pressure, and subsequent collapse of the fetal skull. Several different causes for this condition have been suggested including partial disruption of the blood supply to the brain and prenatal viral infection.
Aarskog syndrome: Full male and female expression associated with an X‐autosome translocation
Authors: Bawle E. , Tyrkus M. , Lipman S. , Bozimowski D. , Opitz John M.
Published: June 2005

We describe a male infant with the Aarskog syndrome and his equally prominently affected mother. The propositus and his mother have a balanced X‐autosome translocation which originated in her. We postulate that the mother's translocation resulted in a presumed de novo point mutation for the Aarskog locus and that she has nonrandom inactivation of her structurally normal X. The full expression of the syndrome in the mother is compared to the partial expression in reported females. It is concluded that the Aarskog syndrome is an X‐linked disorder and that the locus for the syndrome is at Xq13.
Interstitial del(13q) associated with blindness and mental retardation
Authors: Juberg Richard C. , Mowrey Philip N. , Opitz John M.
Published: June 2005

Blindness due to congenital falciform retinal folds and severe mental retardation were present in a male with an interstitial deletion, 46,XY, del(13) (q31.2q32.3).
Cytogenetic findings in 318 couples with repeated spontaneous abortion: A review of experience in British Columbia
Authors: Pantzar J. Tapio , Allanson Judith E. , Kalousek Dagmar K. , Poland Betty J.
Published: June 2005

We studied G‐banded chromosome complements on 318 couples with 2 or more spontaneous abortions. Seven chromosome abnormalities were detected. Three women and one man were identified as carriers of balanced Robertsonian translocations, t(13;14), t(13;14), t(13;21), and t(14;22), respectively. Aneuploidy: 47,XXX; 47,XX, +marker; and 45,X/46,XX/47,XXX were found in the other 3 women. The overall aberration frequency was 2.2% of couples. When a stringent criterion of ≥ 3 consecutive spontaneous abortions was used, the frequency was 4.2%. In this series no chromosome aberrations were identified in couples with 2 spontaneous abortions and a live‐born child with congenital anomalies; 1 of 22 couples with 2 spontaneous abortions and a still‐born infant showed a chromosomal abnormality. Findings from the recent literature are compared with those from this study.
Two chromosome aberrations in the child of a woman with systemic lupus erythematosus treated with azathioprine and prednisone
Authors: Ostrer H. , Stamberg J. , Perinchief P. , Opitz John M.
Published: June 2005

A boy with microcephaly, unusual facial features, micropenis, and growth retardation was born to a 30‐year‐old woman who took azathioprine and prednisone before and during pregnancy for systemic lupus erythematosus. The child has two apparently de novo chromosomal abnormalities: an apparently balanced translocation between chromosomes 6 and 14 and an interstitial deletion of chromosome 7. The karyotype is 46,XY,del(7)(q21);t(6;14)(q21;q12). Use of azathioprine and prednisone in pregnancy has been associated with intrauterine growth retardation, congenital malformations, and transient chromosome breaks in the blood of newborns. To our knowledge, this is the first report of de novo constitutional chromosome abnormalities in such an infant. We suggest that the assessment of infants born to parents treated with azathioprine should include a chromosome study, even if the infants seem to be normal.
Incontinentia pigmenti in a father and his daughter
Authors: Sommer Annemarie , Liu Paul H. , Opitz John M.
Published: June 2005

We present two cases of incontinentia pigmenti in a father and his daughter and discuss possible modes of inheritance. The mode of inheritance in our patients is known.
Psychological aspects of genetic counseling. III. Management of guilt and shame
Authors: Kessler Seymour , Kessler Hilda , Ward Patricia , Opitz John M.
Published: June 2005

Reactions of guilt and shame are conspicuous in the context of genetic counseling, and the relief of their distressing aspects is a widely held goal of genetic counselors. They are in a unique position to accomplish this; however, guidelines as to how one might proceed are not readily available. We have considered guilt and shame responses and have attempted to differentiate them, dynamically and developmentally, and have pointed out how each might be manifested in the course of genetic counseling. The major counseling tactics by means of which the alleviation or reduction of feelings of guilt and shame might be achieved are outlined and case illustrations are provided in which actual and potential counseling situations are explored and discussed.
Ethical considerations in medical genetics–the prenatal diagnosis of hemophilia B
Authors: Smurl James F. , Weaver David D. , Jarmas Audre , Padilla Lillie‐Mae , Optiz John M.
Published: June 2005

A couple is presented who underwent prenatal counseling and amniocentesis for sex determination because the wife was an obligate carrier of hemophilia B. Although the fetus was determined to be male, the parents elected not to have further testing to determine if he had hemophilia or not.

The difficulties in the in utero diagnosis of hemophilia B are presented and discussed. In addition, the moral reasoning and decision‐making process that this couple went through regarding the decision not to have further fetal testing and to continue the pregnancy is presented and analyzed. These moral decisions appear to be based on family and personal ties, and bonding to the fetus after perception of fetal movement. They combine considerations of the duties and rights involved in such situations, and attend to the anticipated consequences as well.
The dynamics of quantifiable homeostasis. III: A linear model of certain metrical diseases
Authors: Renie William A. , Murphy Edmond A.
Published: June 2005

A generalization of the linear, lagged, homeostatic process shows that whether a displacement of the trait function dies out with time, continues indefinitely, or shows a steadily amplifying (wild) oscillation depends on the value assumed by the product of the lag time and the restoration constant. Moreover, it is shown that if a steady displacing force is used rather than an instantaneous displacement, a new homing value results which is given by the ratio of the displacing force to the restoration coefficient. Combining these two developments furnishes grounds for determining whether or not an overshoot will occur when administration of a drug is stopped (for instance, the rebound thrombosis on discontinuing heparin). Further developments of these ideas show how the diabetes that begins in mature patients can be wholly accounted for by the well‐known prolongation of the lag in insulin response that occurs in that disorder. If wild oscillation is to be avoided as the lag time increases, the restoration constant must be weakened (evidently by a systematic reduction in insulin receptors) and this weakening means that the homing value is displaced. Thus the hyperglycemia in this diabetes is to be seen as the price paid for avoiding wild oscillation. Provided that the therapeutic use of exogenous insulin is systematic and regular, rather than cybernetic, its success where endogenous (cybernetic) insulin secretion has failed is readily understood. The point is illustrated by a familiar analogy of a car driver with slow responses. The genetic and evolutionary implications of these ideas are outlined.
Trigonocephaly: A new familial syndrome
Authors: Frydman Moshe , Kauschansky Arieh , Elian Ezra , Opitz John M.
Published: June 2005

Trigonocephaly was found in six relatives through three generations of one family. The propositus was ascertained at birth because of omphalocele. In addition to trigonocephaly, he had minor ear, vertebral, and genital abnormalities. His father had mild microcephaly, and both had minor eye abnormalities. None of the other four affected individuals had any other malformations. In this family, trigonocephaly is an autosomal dominant trait. The ratio of affected males to affected females was 5 to 1, and although the paucity of affected females is not statistically significant, we speculate that it may reflect variable expressivity or sex limitation of the trait. We conclude that the condition in this family represents a unique syndrome in which trigonocephaly is not associated with functional brain abnormalities and where craniosynostosis is limited to the metopic region.
The natural history of Huntington disease: Possible role of “aging genes”
Authors: Farrer Lindsay A. , Conneally P. Michael , Yu Pao‐Io
Published: June 2005

In this paper we consider a model in which genetic factors that control aging also modify expression of the Huntington disease (HD) gene. Significant correlation coefficients were obtained for age‐at‐onset (AO) and age‐at‐death (AD) between affected parents and their affected offspring. However, more relevant to our hypothesis, the correlations between mean AD in normal sibs and AD in the affected parent (r =.57) and mean AD in their affected sibs (r =.54) are also significant. When onset is used instead of death for affected individuals the coefficients are.46 and.52, respectively. Also, AD in the normal parent is significantly correlated with AD in his affected (r =.39) and normal (r =.36) offspring.

Current genetic theories on aging and related trends in HD are discussed. Our results and evidence from gerontological studies support the hypothesis that HD gene carriers with “superior” aging genes manifest symptoms later in life and have increased longevity over those with “inferior” aging genes.
Cyclopia and cebocephaly in two newborn infants with unbalanced segregation of a familial translocation rcp (1;7)(q32;q34)
Authors: Schinzel A. , Opitz John M.
Published: June 2005

This is a report of a family with a balanced reciprocal translocation, rep (1;7)(q32;q34). Among pregnancies from translocation carriers, there were several miscarriages, and two unbalanced offspring with dup(1q32→qter) and del (7q34→qter) who died perinatally. One was a male cyclops with additional brain malformations and hydronephrosis, the other was a cebocephalic female with multiple additional malformations of heart, kidneys, and skeleton. In both pregnancies, the brain and renal anomalies were detected prenatally by ultrasound, in the cyclops during the 32nd and in the cebocephalic fetus during the 28th week of gestation.
A new lipid storage myopathy observed in individuals with the Ruvalcaba‐Myhre‐Smith syndrome
Authors: DiLiberti J. H. , D'Agostino A. N. , Ruvalcaba R. H. A. , Schimschock J. R. , Opitz John M.
Published: June 2005

Four patients with the Ruvalcaba‐Myhre‐Smith syndrome (primary macrocephaly with associated anomalies including pigmented macules on the penis in affected males, hamartomatous intestinal polyps, and lipomas) had evidence of delayed psychomotor development and/or hypotonia in childhood. Electromyography in 3 patients showed evidence of a myopathic process. Muscle biopsy in all four demonstrated a lipid storage myopathy with increased numbers of neutral lipid droplets—predominatly in type 1 fibers. The type 2 fibers were consistently smaller than expected. Electron microscopy was unremarkable except for evidence of lipid accumulation. Muscle carnitine and carnitine palmityl transferase levels were normal in one patient. This appears to be a previously unreported type of lipid storage myopathy characteristic of the Ruvalcaba‐Myhre‐Smith syndrome, a probable autosomal dominant trait.
Developmental pathogenesis of chromosome disorders: Report on two newly recognized signs of down syndrome
Authors: Langenbeck U. , Blum Ellen , Wilkert‐Walter Cornelia , Hansmann I.
Published: June 2005

Testing the hypothesis of amplified developmental instability in autosomal trisomies as proposed by Shapiro we predicted and found an increased frequency of symphalangies in the toes of patients with Down syndrome. In our X‐ray study of the feet of 71 adults with trisomy 21 we also detected a greater than normal number of sesamoid bones.

A corollary to Shapiro's hypothesis is a dependence on ethnic origin of the frequency of symptoms in Down syndrome. Compared to data from Europe, toe symphalangies are more prevalent in Japan. We predict this anomaly to occur even more often in Japanese patients with trisomy 21.
Pyruvate kinase in fetal plasma and amniotic fluid unsuccessful for the prenatal diagnosis of Duchenne muscular dystrophy
Authors: Edwards R. J. , Rodeck C. H. , Watts D. C.
Published: June 2005

A specific spectrophotometric assay of muscle‐pyruvate kinase (M‐PK) was used to measure the activity of this isozyme in fetal muscle, fetal plasma and amniotic fluid at about 17–24 wk of gestational age to assess its predictive value for the prenatal diagnosis of Duchenne muscular dystrophy (DMD). Fetal muscle obtained after termination was found to contain a high M‐PK specific activity. No significant activity was detected in amniotic fluid from normal or at‐risk fetuses. Pure fetal blood was obtained in utero by fetoscopy; significant plasma levels of M‐PK activity were measured in a series of control samples, but at‐risk fetal plasma contained no higher levels. We conclude that M‐PK is of no use for the prenatal diagnosis of DMD.
The dynamics of quantifiable homeostasis. V: Homeostasis of higher order
Authors: Renie William A. , Murphy Edmond A.
Published: June 2005

The properties are explored of a cybernetic process with lag L and force of restoration equal to the size of displacement one lag unit earlier, raised to any arbitrary positive power (w > 1), multiplied by the restoration constant b, the sign being opposite to that of the displacement at that time. No closed‐form solution is available, but a converging Taylor series expansion is presented that gives a solution of arbitrary precision. Unlike the linear system previously discussed, the amplitude of the displacement (A) is germane, and it is shown that the criterion that the effect of a perturbation be damped out is whether or not LbAw−1 exceeds a constant, kw, that depends only on w. The counterpart of this pattern of higher‐order homeostasis is closer to the biological behavior of many forms of homeostasis than the scaled invariance characteristic of the linear process. kw is shown to be bounded between π/2 and 2, and increases monotonically with w. Exactly computed values and large‐sample approximations are given for the critical values below which no overshoot at all occurs. It is shown that where it does not, the minimum expected cost decreases with increasing w and reaches a minimum at infinite w. However, this evolutionary gain is vitiated where large displacements are involved, and may need to be redressed by a change in the restoration constant. Thus, the dynamic balance becomes much more subtle than with lower‐order processes. Several brief clinical illustrations of these ideas are presented.
Hereditary pyropoikilocytosis: Report of two cases from Saudi Arabia
Authors: Mallouh Ahmad , Sa'di A. Rahman , Ahmad M. S. , Salamah M. , Opitz John M.
Published: June 2005

Hereditary pyropoikilocytosis is a rare type of congenital hemolytic anemia reported only in American black children. We report the first two occurrences in Saudi children. This is an autosomal‐recessive trait as proved by normal parents and two affected children. A pathogenetic and probably causal relationship with apparent elliptocytosis seems clear as three sibs have that condition.
Familial external genital ambiguity due to a transformation defect of androgen‐receptor complexes that is expressed with 5α‐dihydrotestosterone and the synthetic androgen methyltrienolone
Authors: Kaufman Morris , Pinsky Leonard , Bowin Adria , Au Mary W. S.
Published: June 2005

We have studied various properties of the binding of 5α‐dihydrotestosterone (DHT) or the synthetic, nonmetabolizable androgen methyltrienolone (R1881; 17β‐hydroxy‐17α‐methylestra‐4, 9,11‐trien‐3‐one) to the androgen receptor of genital skin fibroblasts (GSF) from controls and a subject with familial, receptor‐positive, partial androgen insensitivity. The mutant cells form R1881‐receptor complexes that dissociate 7 times more rapidly than normal at 30°C, and they do not increase their specific R1881‐receptor activity in response to a 72‐hr period of incubation with R1881, whereas the cells from normal individuals do so two‐ to three‐fold. As previously reported [Pinsky et al, 1981; Kaufman et al, 1981], the mutant cells have similar abnormalities with DHT as with R1881. When the patient's cells are incubated for 120 min with varying concentrations (0.05‐3 nM) of R1881 or DHT, Scatchard analysis shows that their androgen‐receptor activity has an apparent equilibrium dissociation constant (Kd) for each ligand that is sixfold greater than that of normal cells (∼0.2 nM). Normal GSF have higher, more variable values of Kd (0.3–1.8 nM) for either ligand after 30 compared to 120 min of incubation, and the 60‐min values are intermediate. This explains why we previously reported that the patient's cells had a 30‐min Kd for DHT in the normal range [Pinsky et al, 1981]. Sucrose gradient centrifugation of mutant GSF cytosol incubated with DHT in the presence of 10 mM sodium molybdate yields a normal 6.5–8S peak of DHT‐receptor complexes.

From these data we conclude that (i) normal GSF form initial, low‐affinity androgen‐receptor complexes that are transformed into one (or more) higher affinity (? activated) states by a process that depends on time and initial concentration of androgen; (ii) the subject's GSF can form low‐affinity androgen‐receptor complexes but cannot generate the normal high‐affinity state of the complexes, and this lack precludes augmentation of their androgen‐receptor activity in response to prolonged incubation with either androgen; and (iii) failure of molybdate to stabilize the androgen‐receptor activity in GSF cytosol is not a more sensitive indicator of structurally altered androgen‐receptor proteins than are other qualities described heretofore.
Bone marrow transplantation for severe combined immune deficiency in an infant with chimerism due to intrauterine‐derived maternal lymphocytes: Donor engraftment documented by chromosomal marker studies
Authors: Borzy Michael S. , Magenis Ellen , Tomar Diane
Published: June 2005

Chromosomal heteromorphisms defined by the quinacrine banding technique were used to identify the maternal origin of 46,XX lymphocytes present in the blood of a male infant with severe combined immune deficiency disease. These chromosomal markers were also used to document the engraftment by donor lymphocytes from the sister and the concurrent disappearance of maternal lymphocytes after a successful bone marrow transplantation. Donor lymphocytes were detected by this technique 6 days after transplantation, earlier than is usually possible with other marker systems and before definite evidence of immunoreconstitution. Maternal lymphocytes persisted in the patient's peripheral blood for a prolonged period of time, being detectable 172 days after transplantation. Analysis of T‐lymphocyte‐and B‐lymphocyte‐enriched populations after transplantation documented lymphoid chimerism with T‐lymphocytes of donor origin and B‐lymphocytes of both patient and donor origin, demonstrating prolonged persistence of patient B‐lymphocytes and suggesting that the patient's immune defect is primarily at the T‐lymphocyte level.
The Meckel syndrome: Clinicopathological findings in 67 patients
Authors: Salonen Riitta , Opitz John M. , Reynolds James F.
Published: June 2005

A nationwide study on the Meckel syndrome (MS) was carried out covering retrospectively the years 1970–1979 and prospectively the years 1980–1981. Sixty‐seven cases from 48 Finnish families were found. The clinical and pathological findings were studied. Cystic dysplasia of the kidneys was present in all the cases where sufficient information was available. In all 41 cases with specimens available from the liver, a typical fibrotic change with proliferation and dilatation of the bile ducts was found. This series and a review of the literature give convincing evidence that cystic dysplasia of the kidneys with fibrosis of the liver is a constant finding in the “true” Meckel syndrome. In conclusion, it is proposed that cystic dysplasia of the kidneys with fibrotic changes of the liver and occipital encephal‐ocele or some other central nervous system malformation are considered as minimal diagnostic criteria of MS. Thus, a histologic investigation of the kidneys and liver is essential in diagnosing MS in doubtful cases. Heterozygote manifestations were not found.
The tricho‐rhino‐phalangeal syndrome(s): Chromosome 8 long arm deletion: Is there a shortest region of overlap between reported cases? TRP I and TRP II syndromes: Are they separate entities?
Authors: Bühler Erica M. , Malik Naseem J.
Published: June 2005

Critical cytogenetic (re)evaluation of 2 of our own cases of tricho‐rhino‐phalangeal syndrome II (TRP II), or Langer‐Giedion syndrome (LGS), and 10 cases from the literature, suggests that the shortest region of overlap of the 8q deletion is a part of band q24. 1. This region is assumed to be causally related to this syndrome, and possibly also to TRP I syndrome which, therefore, may not be a causally separate entity.
Segregation analysis in reciprocal translocation carriers
Authors: Petrosky Dorene L. , Borgaonkar D. S.
Published: June 2005

Segregation analysis of the offspring of balanced translocation carriers was performed on 327 pedigrees collated from published sources and personal communications. Correction was made for bias of ascertainment. Translocations studied involved chromosome arms 1p, 4q, 6p, 6q, 7p, 8p, 10p, 10q, 11q, 14q, 16q, and 17p. Findings included similar rates of occurrence of abnormal liveborn offspring in male and female carriers except for a reduction of risk in male carriers of translocations segregating by 3:1 mode; an elevated risk of fetal loss (spontaneous abortions and stillbirths) in female carriers of 6q, 11q, and 16q translocations compared to male carriers of these translocations; a fetal loss rate exceeding general population estimates in female carriers of 6q and 10q translocations and in male carriers of 6p, 8p, 10q, and 14q translocations including a rate of nearly 50% among female 6q translocation carriers; a higher than expected number of balanced carriers among liveborn offspring; and a low risk of abnormal liveborn children among carriers ascertained by means other than through unbalanced probands. We propose that some translocation carriers may be helped by consideration of more specific empiric risk figures than have traditionally been used.
Interstitial deletion of chromosome 3p: Report of a patient and delineation of a proximal 3p deletion syndrome
Authors: Neri Giovanni , Reynolds James F. , Westphal Joan , Hinz Jeffrey , Daniel Art
Published: June 2005

We report on a patient with a de novo interstitial deletion of the proximal portion of the short arm of chromosome 3 (p12 → 14.2). The deleted portion excludes the constitutive fragile site assigned to band 3p14. The phenotype of the patient, together with that of three previously reported cases, seems to be sufficiently characteristic to allow the delineation of a proximal 3p deletion syndrome.
The Perlman syndrome: Familial renal dysplasia with Wilms tumor, fetal gigantism and multiple congenital anomalies
Authors: Neri Giovanni , Martini‐Neri Maria Enrica , Katz Ben E. , Opitz John M.
Published: June 2005

We describe a familial syndrome of renal dysplasia, Wilms tumor, hyperplasia of the endocrine pancreas, fetal gigantism, multiple congenital anomalies and mental retardation. This condition was previously described by Perlman et al [1973, 1975] and we propose to call it the “Perlman syndrome.” It appears to be transmitted as an autosomal recessive trait. The possible relationships between dysplasia, neoplasia and malformation are discussed.
A high frequency of structural chromosome abnormalities in a south central texas cytogenetics laboratory
Authors: Young Robert S. , Hansen Kathryn L. , Shapiro Steven D. , Jorgenson Ronald J.
Published: June 2005

Abnormalities of chromosome number, such as the autosomal trisomies and sex chromosome aneuploidies, are considered to be sporadic events with low and constant recurrence risk across populations. On the other hand, abnormalities of chromosome structure can be generated by environmental agents and also transmitted in families and therefore may accumulate in certain populations. Evidence from several geographically diverse newborn infant screening studies and from clinical cytogenetics laboratories (including our own) supports the hypothesis that the frequency of structural abnormalities varies among populations, whereas the frequency of numerical abnormalities remains relatively constant among populations. The data from our laboratory, based on 1,201 patients over a 6‐year period, suggest a two‐ to nearly fourfold higher frequency of structural defects over that of other populations (8.8% vs 4.2% and 2.5% of samples tested). Some of the problems associated with making comparisons among the published data sets are discussed, along with alternative explanations for the variability in the frequency of structural defects reported in different populations.
Sensorineural deafness in the FG syndrome: Report on four new cases
Authors: Neri Giovanni , Blumberg Bruce , Miles Paul V. , Opitz John M.
Published: June 2005

We report on four new cases of FG syndrome with typical manifestations of this X‐linked inherited condition and note a hitherto undescribed sign, sensorineural deafness. The association between sensorineural deafness and imperforate anus is likely to represent more than a chance occurrence, given its presence also in the Townes‐Brocks syndrome.
Late‐childhood‐onset spinal muscular atrophy in three Melanesian families in Papua New Guinea
Authors: Scrimgeour Euan M. , Mastaglia Frank L.
Published: June 2005

Late‐childhood‐onset spinal muscular atrophy (SMA) with rapid progression from proximal to distal muscle groups and leading to severe incapacity or death in adolescence or early adult life, was studied in two Melanesian families in Papua New Guinea. Probable SMA with cardiomyopathy was observed in a 12‐year‐old boy in a related family. The pattern of inheritance in the study group did not conform to any of the conventional Mendelian modes and it was conjectured that the disease was expressed in heterozygote carriers of the SMA gene only when an allelomorphic activator gene was present.
X‐linked inheritance of ocular albinism with late‐onset sensorineural deafness
Authors: Winship Ingrid , Gericke George , Beighton Peter
Published: June 2005

We have investigated a large Afrikaner kindred in which seven males had ocular albinism and late‐onset sensorineural deafness (OASD). The pattern of inheritance of OASD is X‐linked recessive. To the best of our knowledge, this association has not previously been reported and in order to establish syndromic identity we describe and discuss the condition in this article.
Trisomy 13 in the child of two carriers of a 13/15 translocation
Authors: Mori M. A. , Huertas H. , Pinel I. , Giralt P. , Martínez‐Frías M. L. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an infant girl with trisomy 13 resulting from an inherited 13–15 Robertsonian translocation identified in a family from a small Spanish village of only 2,100 inhabitants. Both parents and several other relatives had a balanced 13–15 translocation.
Fetal plasma carbonic anhydrase III in prenatal diagnosis of duchenne muscular dystrophy
Authors: Heath Robert , Carter Nicholas D. , Jeffery Stephen , Edwards Robert J. , Watts David C. , Watts Rosemary L. , Rodeck Charles , Opitz John M. , Reynolds James F.
Published: June 2005

Carbonic anhydrase III (CAIII), a skeletal‐muscle‐specific enzyme which is elevated in the plasma of Duchenne muscular dystrophy (DMD) patients, was measured by radioimmunoassay in fetal plasma in order to evaluate its application to prenatal diagnosis of DMD. Using fetoscopy, pure fetal blood samples were taken at 17–24 weeks gestation from 25 fetuses at risk for DMD and from 78 control fetuses. Care was taken in the handling and storage of all samples. Normal sons were born in eight cases at risk for DMD. The CAIII levels in the infants were not significantly different from those of the control infants. Pregnancies were terminated in the remaining 17 at‐risk cases. The CAIII levels in the fetuses were significantly different (p = 0.0034) from those of the control fetuses, although the distributions overlapped. Based on prior maternal risk, seven affected fetuses were expected in the terminated group; five had CAIII levels at or above the 95th centile of the control range. It is suggested that measurement of CAIII achieves partial discrimination between affected fetuses and their normal at‐risk brethren.
Syndrome of telecanthus, hypertelorism, strabismus, and pes cavus in father and son
Authors: Krauss Celeste M. , Herman Thomas E. , Holmes Lewis B. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on a father and son who have telecanthus, hypertelorism, strabismus, and pes cavus. In addition, the son has hypospadias, bilateral inguinal hernia, clinodactyly and camptodactyly of fingers bilaterally, a small tissue mass on the tip of his nose, and radiographic findings including flared metaphyses of long bones and osteopenia.
Dup(3)(p2→pter) in two families, including one infant with cyclopia
Authors: Gimelli Giorgio , Cuoco Cristina , Lituania Mario , Cordone Massimo , Aricò Maurizio , Bianchi Elena , Maraschio Paola , Zuffardi Orsetta , Opitz John M. , Reynolds James F.
Published: June 2005

We report on 2 unrelated cases of duplication of distal 3p due to balanced maternal translocation t(3;6)(p23;q27) and t(2;3)(p25;p23) respectively.

One family was ascertained through the unbalanced offspring and the other through echographic examination of the balanced carrier mother. These cases confirm that dup(3)(p2→pter) results in a characteristic syndrome with distinctive facial appearance. In family 2 inspection of a photograph of a deceased sib was sufficient to connclude that he was affected. The patient in family 2 had cyclopia. Since holoprosencephaly was also reported by Martin and Steinberg [1983], we conclude that this anomaly appears to be a sign of the syndrome.

The duplication usually derives from a maternal balanced translocation, in most cases from adjacent‐1 segregation. However, family 2 was ascertained through a balanced female carrier who inherited the translocation from the father. We have noted that the second chromosome (which varies without apparent preferences) involved in these translocations is broken consistently at a distal band.
Reproductive counselling for multiple sclerosis patients
Authors: Sadovnick A. D. , Baird P. A. , Opitz John M. , Reynolds James F.
Published: June 2005

The diagnosis of multiple sclerosis (MS) is frequently made during the reproductive years, and there is increasing evidence that it has a genetic causal component. An increasing number of couples are concerned about recurrence and they request reproductive counselling at genetic clinics or from their physicians. Here we outline factors to be considered in the reproductive counselling of such individuals. These include (1) empiric recurrence risks, (2) the effect of pregnancy and delivery on maternal MS, (3) overall pregnancy outcome, (4) longterm prognosis for the affected parent, and (5) the possibility of sexual dysfunction in couples trying to conceive a child.
Computerized tomography of the foramen magnum: Achondroplastic values compared to normal standards
Authors: Hecht Jacqueline T. , Nelson F. William , Butler Lan J. , Horton William A. , Scott Charles I. , Wassman E. Robert , Mehringer C. Mark , Rimoin David L. , Pauli Richard M. , Opitz John M. , Reynolds James F.
Published: June 2005

Computerized tomographic dimensions of the foramen magnum of 63 achondroplastic individuals were compared to standards established for nonachondroplastic individuals. The size of the foramen magnum in patients with achondroplasia was small at all ages, particularly in those with serious neurologic problems. The data suggest that measurement of the foramen magnum may identify achondroplastic individuals at high risk of developing neurologic complications.
Marker Chromosomes: Cytogenetic characterization and implications for prenatal diagnosis
Authors: Mohandas T. , Canning N. , Chu W. , Passage M. B. , Anderson C. E. , Kaback M. M. , Opitz John M. , Reynolds James F.
Published: June 2005

Satellited marker chromosomes were identified in four individuals from unrelated families; one was first encountered in cultured amniotic fluid cells obtained for prenatal diagnostic studies. We present cytogenetic characterization of these marker chromosomes and clinical findings in the individuals carrying them. Identification of a marker chromosome in amniotic fluid cell cultures presents problems in genetic counseling, as it is often difficult to determine the clinical significance of such a finding. Chromosome‐banding techniques now allow the precise identification of satellited marker chromosomes originating from chromosome 15. Presence of a supernumerary bisatellited der(15) marker chromosome containing the proximal long arm of 15 has been associated with mental and developmental retardation. Application of chromosome‐banding techniques was useful in characterization of the marker chromosomes and providing prenatal genetic counseling.
Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in down syndrome: A stochastic model
Authors: Kurnit David M. , Aldridge John F. , Matsuoka Rumiko , Matthysse Steven , Opitz John M. , Reynolds James F.
Published: June 2005

Based on the finding that fetal trisomy 21 fibroblasts explanted from lungs and endocardial‐cushion‐derived structures appear more adhesive in vitro than those from normal control individuals, we present a stochastic model for atrioventricular (AV) canal malformations in Down syndrome (DS). Computer simulations were performed to model the normal anatomic sequences of cushion‐to‐cushion and cushion‐to‐septum fusion in AV canal development. In these simulations, randomwalking endocardial cells were allowed to migrate, divide, and adhere with programmable probabilities. Low values of intercellular adhesiveness engendered simulations resembling normal AV canal development; higher values of adhesiveness yielded deficiencies of AV canal development as seen in DS. Moderately high levels of adhesiveness resulted in abnormalities in only a proportion of multiple, independently performed simulations. The model successfully predicts the temporospatial sequence of anatomic events in cushion‐to‐septum fusion, clinical variability among individuals with the same genotype based on chance alone, and amplified developmental instability as observed in individuals with DS.
Sixty‐four patients with Brachmann–de Lange syndrome: A survey
Authors: Hawley Pamela P. , Jackson Laird G. , Kurnit David M. , Opitz John M. , Reynolds James F.
Published: June 2005

We surveyed 64 individuals with the diagnosis of Brachmann–de Lange syndrome (BDLS) to determine the natural course and cause of the disorder. The 64 individuals were ascertained through membership in a national organization, the Cornelia de Lange Syndrome (CDLS) Foundation, comprised of families who have a relative with BDLS. We surveyed 64 families by questionnaire and personally examined 24 of the 64. Our data suggest that lower birth weight correlates with a more severe phenotype, specifically including severe upper limb malformations and greater psychomotor retardation. The lower birth weight group showed a significant excess of females. The miscarriage rate was normal and there were no recurrences reported in the 64 families we surveyed. Major management problems included feeding problems and projectile vomiting, behavioral problems including frequent tantrums, hearing and dental difficulties, and recurrent respiratory tract infections. The oldest, teenaged subjects in our study entered puberty; although pregnancy has not been reported in the syndrome, it is likely that people with BDLS are fertile. Though most BDLS children reared at home survive through adolescence, a significant degree of psychomotor retardation and difficult medical management problems still occur.
The clinical spectrum of α‐L‐iduronidase deficiency
Authors: Roubicek M. , Gehler J. , Spranger J. , Opitz John M. , Reynolds James F.
Published: June 2005

We present five patients with α‐L‐iduronidase deficiency who do not have the typical Hurler or Scheie phenotypes; they are compared to 28 similarly atypical cases from the literature. Phenotypic differences are pointed out and intrafamilial similarities stressed. Among the various possible explanations for this situation, the existence of genetic compounds seems acceptable for some of the cases, but others seem to be caused by different mutations. The elucidation of these alternative possibilities from recent biochemical research is discussed.
Factors influencing maternal estimates of genetic risk
Authors: Ekwo Edem E. , Seals Brenda F. , Kim Jae‐On , Williamson Roger A. , Hanson James W. , Opitz John M. , Reynolds James F.
Published: June 2005

The relationship between the objective and subjective estimates of genetic risk was studied in 202 women accepting and 50 women not accepting amniocentesis. All women were at risk of having a child with congenital anomalies either because of maternal age at pregnancy or family history of Down syndrome (DS) or other congenital anomalies. Only 28.6% of the women rejecting and 44.4% of the women accepting amniocentesis remembered correctly their objective odds. The correlations between the objective risk estimates and the subjective risk estimates were low overall (r = 0.089, p = 0.08); for women rejecting (r = 0.024, p = 0.44) or accepting (r = 0.082, p = 0.12) amniocentesis. The psychosocial and sociodemographic variables relating to either objective or subjective risk estimates were different for both groups of women. The study provides information on variables that should be taken into consideration in formulating a general theory to predict individual perceptions of genetic risk.
Study of H‐Y antigen in abnormal sex determination with monoclonal antibody and an ELISA
Authors: Moreira‐Filho Carlos A. , Wachtel Stephen S. , Opitz John M. , Reynolds James F.
Published: June 2005

A newly developed enzyme‐linked immunosorbent assay (ELISA) has been applied to the study of H‐Y antigen in cases of XY, XYY, and X,dic Y gonadal dysgenesis, testicular feminization syndrome, XXXXY syndrome, and XX true hermaphroditism. Monoclonal H‐Y antibody was absobed with cells from each of eight patients and from normal male and female controls, and then reacted with a plated antigen source in a system subsuming the addition of biotinylated secondary antibody, avidin‐biotin‐enzyme complex and substrate, and thereby the generation of a color. Positive absorption decreased the reaction, and this allowed sensitive measurement of H‐Y phenotype in an electronic optical density reader. The ELISA obviates many of the technical difficulties encountered in complement‐mediated cytotoxicity systems and can be used in the study of clinical cases of aberrant sex determination and in the evaluation of current models of the genetics of sex determination.
Tetraphocomelia in the syndrome of Thrombocytopenia with Absent Radii (TAR syndrome)
Authors: Anyane‐Yeboa K. , Jaramillo S. , Nagel C. , Grebin B. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on an infant with the syndrome of Thrombocytopenia with Absent Radii (TAR) with severe lower‐limb involvement. Amegakaryocytic thrombocytopenia was detected at 6 days when the platelet count was 11,000/μL. The platelet count increased steadily to 100,000/μL at 3 years. The patient required bilateral aboveknee amputations for femorotibial synostoses. We recommend postponement of all elective operations until platelet counts are normal.
Azoospermia and duplication 3qter as distinct consequences of a familial t(X;3) (q26;q13.2)
Authors: Cantú José María , Díaz Miguel , Möller Melba , Jiménez‐Sáinz Martha , Sandoval Lucila , Vaca Gerardo , Rivera Horacio , Opitz John M. , Reynolds James F.
Published: June 2005

A t(X;3) (q26;q13.2) was found in three generations of a family. Female carriers exhibited normal reproductive function, whereas all three postpuberal male carriers showed spermatogenesis arrest at meiosis I. Additionally, a 2 3/12‐year‐old girl had duplication 3qter resulting from an adjacent‐1 segregation.
Prenatal diagnosis of persistent common cloaca with prune belly and anencephaly in the second trimester
Authors: Holzgreve Wolfgang , Opitz John M. , Reynolds James F.
Published: June 2005

We report the prenatal diagnosis of a fetus with persistent cloaca, prune belly swquence, and anencephaly. This fetus resembles the recently reported patient with prune beily and anencephaly. A syndromic diagnosis was not possible in either case, but the likelihood of a chance association also has to be regarded as low.
Survival analysis of the severely and profoundly mentally retarded
Authors: Kaveggia Francis F. , Opitz John M. , Reynolds James F.
Published: June 2005

Life‐table analyses were performed on 1,915 severely/profoundly retarded institutionalized persons. Data on probability of death and hazard rates are presented according to sex and previously described diagnostic/etiologic categories. The median remaining lifetime for a resident of Central Wisconsin Center on admission was found to be greater than 25 years. The average age of admission was 7.3 years with a range of 0–66 years. The highest death rate was noted in residents with inborn errors of metabolism; the lowest death rate was in residents with primary seizure disorders. On admission, the median remaining lifetime was 8.81 ± 4.16 years (95 % confidence interval) for residents with inborn errors of metabolism, 18.56 ± 4.26 years for residents with primary CNS malformations, and 24.66 ± 4.05 years for residents with known syndromes. Residents of all other diagnostic/etiologic categories had a median remaining lifetime of greater than 25 years.
Prenatal diagnosis of Pena‐Shokeir syndrome type 1
Authors: MacMillan R. Hunt , Harbert Guy M. , Davis William D. , Kelly Thaddeus E. , Opitz John M. , Reynolds James F.
Published: June 2005

This report describes the sonographic diagnosis of the Pena‐Shokeir syndrome type 1 during the second trimester of a pregnancy which was electively terminated. The mother had previously delivered a macerated, hydropic infant with multiple congenital anomalies. The diagnosis was based on the recurrence of hydramnios and nonimmune hydrops in a fetus with normal chromosomes, normal amniotic fluid alpha‐fetoprotein, normal fetal echocardiography, and lack of evidence of a lysosomal storage disease. These observations suggest that serial sonography during the second trimester in pregnancies at risk may allow for the prenatal diagnosis of the Pena‐Shokeir syndrome type 1. Without further experience, it would not be prudent to suggest to couples at risk that the prenatal diagnosis of a recurrence can be assured with a high degree of accuracy.
Wolf‐hirschhorn syndrome owing to 1:3 segregation of a maternal 4;21 translocation
Authors: Bauer Kristine , Howard‐Peebles Patricia N. , Keele Doman , Friedman J. M. , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a child with Wolf‐Hirschhorn syndrome with the karyotype 45,XY,inv(9)(pllq13)pat, −4, −21, +der(4),t(4;21)(p15.3;q11.2)mat. This is the second case known to us of Wolf‐Hirschhorn syndrome caused by 1:3 segregation of a parental rearrangement. This mode of segregation can be predicted in both cases by a pachytene‐diagram model. It is uncertain whether or not the proximal 21q monosomy in this case has affected the phenotype.
Nuchal cysts syndromes: Etiology, pathogenesis, and prenatal diagnosis
Authors: Elejalde B. Rafael , De Elejalde Maria Mercedes , Leno John , Opitz John M. , Reynolds James F.
Published: June 2005

We examined 10 fetuses with nuchal cysts and compared the findings with 32 cases from the literature. Based on their characteristics, we propose that nuchal cysts are signs of four causally and pathogenetically different entities: 1) cystic nuchal blebs present in otherwise normal fetuses as a postmortem change; 2) 45,X fetuses who have a particular appearance and multiple congenital malformations; 3) an apparently autosomal recessive syndrome of multiple cysts (that extend into deep muscular planes), generalized edema, cleft palate, peculiar skeletal characteristics, acutely angulated ribs (producing a bell‐shaped rib cage), and shortened long bones; and 4) in fetuses with syndromes that are inherited (multiple pterygium, Roberts) and chromosomal (trisomy 13, trisomy 21) as an unspecific sign representing both primary and secondary lesions.
A distinctive facial appearance in neurofibromatosis von recklinghausen
Authors: Kaplan Paige , Rosenblatt Bernard , Opitz John M. , Reynolds James F.
Published: June 2005

Three children with neurofibromatosis from two unrelated families have unusual facial appearance due to telecanthus, antimongoloid slant of the palpebral fissures, broad nose, and tapering chin. The two boys have large hands and feet, and one is very tall. There were some facial and dermatoglyphic similarities to individuals with the Noonan syndrome, but the manifestations in the children reported here are sufficiently different to suggest the presence of a different type of neurocristopathy in these individuals.