bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural tube defects and maternal hyperthermia in early pregnancy: Epidemiology in a human embryo population
Authors: Shiota Kohei , Opitz John M.
Published: June 2005

A causal relationship between neural tube defects and maternal febrile illness in early pregnancy was investigated retrospectively using human embryo data from Japan. The frequency of febrile illness was compared with corresponding data from normal controls, and holoprosencephalic and polydactylous embryos. Within the group of neural tube defects, the prevalence of maternal hyperthermia was significantly higher than in normal control and holoprosencephaly mothers. The association was constant and highly significant specifically for exencephaly, which is an embryonic forerunner of anencephaly. The correlation with myeloschisis (without exencephaly) was not significant. In eight out of the ten cases in which the timing of the fever was known, it occurred during the clinically determined critical period of neural tube closure in human embryos. These results support the hypothesis that maternal hyperthermia in early pregnancy can cause neural tube defects in man, especially anencephaly.
Mucolipidosis IV
Authors: Crandall Barbara F. , Philippart Michel , Brown W. Jann , Bluestone David A.
Published: June 2005

We review all reported cases of Mucolipidosis IV, add a new one, and present evidence for a generalized phospholipid storage. All phospholipids were increased in the liver, skin fibroblasts and urine. Lysobisphosphatidic acid which was markedly elevated in these samples was the only lipid stored in muscle. A slowly progressive neurological disease with mental retardation and corneal opacities, but lacking mucopolysaccharide excretion, skeletal changes and organomegaly should raise the suspicion of this disease. At this time, the diagnosis is made by EM studies of skin or conjunctiva which should be done if results of tests on serum or bone marrow for lysosomal diseases are normal. We found some of the typical inclusions in skin fibroblasts from an obligate carrier, which suggests that distinction between the homozygote and heterozygote may be difficult. Despite this, two succeeding pregnancies with normal outcomes were successfully monitored.
Genetic heterogeneity of I‐cell disease is demonstrated by complementation of lysosomal enzyme processing mutants
Authors: Shows T. B. , Mueller O. T. , Honey N. K. , Wright C. E. , Miller A. L.
Published: June 2005

I‐cell disease (mucolipidosis II) is a fatal childhood disorder affecting the expression of multiple lysosomal acid hydrolases. The disorder is characterized by clinical and biochemical heterogeneity which may reflect different mutants with a similar phenotype. Genetic complementation studies demonstrating genetic heterogeneity within this disorder are described utilizing cultured fibroblasts from 11 different patients. Fibroblasts from I‐cell disease (ICD) and from five different lysosomal storage diseases with single structural gene enzyme deficiencies were fused in different combinations, and fractions enriched for multinucleated heterokaryons were isolated and tested for acid hydrolase activity and electrophoretic mobility. In fusions of ICD fibroblasts and various single lysosomal enzyme‐deficient fibroblasts, the activity of the deficient enzyme and of the other ICD hydrolases were restored, demonstrating that ICD is not a lysosomal enzyme structural gene defect and that the ICD defect, and not just the single enzyme deficiency, is corrected. In fusions involving only I‐cell fibroblasts, at least two complementation groups were identified by the recovery of activities of all lysosomal enzymes tested in heterokaryons. These results demonstrate the existence of genetic heterogeneity within the disorder and suggest that different mutations can result in the I‐cell clinical and biochemical phenotype. The data support an altered post‐translational processing of lysosomal enzymes as the cause of ICD and suggest that at least two genes participate in this pathway.
Occasional essay: Jewish perspective on prenatal diagnosis and selective abortion of affected fetuses, including some comparisons with prevailing catholic beliefs
Authors: Fineman Robert M. , Gordis David M.
Published: June 2005

Prenatal diagnosis and selective abortion of affected fetuses are controversial subjects for many individuals. Much of the controversy centers around religious beliefs. In this paper we present prevailing Jewish and Catholic beliefs concerning these two subjects. We hope to resolve some of the controversy and emphasize the fact that physicians counsel and patients often make decisions based on their religious persuasion.
Limb pterygium syndromes: A review and report of eleven patients
Authors: Hall Judith G. , Reed Susan D. , Rosenbaum K. N. , Gershanik J. , Chen H. , Wilson K. M.
Published: June 2005

Conditions with limb pterygia and congenital contractures were reviewed as part of a study of over 350 infants with arthrogryposis. Emphasis was placed on inheritance and variability of distinct pterygium conditions. Eleven patients with limb pterygia were recognized in our study and are described here.

Seven of the 350 patients with congenital contractures had the autosomal recessively inherited multiple pterygium syndrome (Patients 1–7). Three of the seven are sibs, a fourth was born to consanguineous parents, and three were chance isolated cases. These seven had multiple joint webs, unusual finger contractures, syndactyly, rocker bottom feet, ptosis, antimongoloid slant of palpebral fissures, epicanthal folds, highly arched palate, scoliosis, and short stature. There is intrafamilial variability.

Three patients from one family had a lethal multiple pterygium syndrome. Two were monozygotic twins. They had webbing and contractures of the elbows, knees, neck, and fingers, calcaneovalgus deformity of the feet, and an unusual facial appearance: hypertelorism, flat nose, antimongoloid slant of palpebral fissures, apparently low‐set ears. One had a cleft palate. Internal malformations included: bilateral pulmonary hypoplasia, small heart, absence of the appendix, and attenuation of the ascending and transverse colon.

One sporadic case of lethal popliteal pterygium with facial clefts was studied. Multiple anomalies included: ankyloblepharon filiforme adnatum, upslanting palpebral fissures, hypoplasia of nasal cartilages, frenula, clefts into the oropharynx lateral to the mouth, apparently low‐set ears with slit‐like canals, large popliteal pterygia, syndactyly with fusion of all digits in hands and feet, and hypoplastic labia.
Spondylohumerofemoral hypoplasia (giant cell chondrodysplasia): A neonatally lethal short‐limb skeletal dysplasia
Authors: Sillence D. O. , Lachman R. S. , Jenkins T. , Riccardi V. M. , Rimoin D. L.
Published: June 2005

We report two sporadic cases with a previously undescribed skeletal dysplasia lethal in the neonatal period. The syndrome is characterised clinically by striking rhizomelic shortness of the limbs and radiographically by absence or hypoplasia of the humeri, hypoplastic vertebrae, absent fibulae and ossification in only the distal phalanges of the hands. Morphologic studies show hypocellular areas of growth plate cartilage containing occasional multinucleated giant cells.
Association of del(11)(p15.1p12), aniridia, catalase deficiency, and cardiomyopathy
Authors: Gilgenkrantz S. , Vigneron C. , Gregoire M. J. , Pernot C. , Raspiller A. , Opitz John M.
Published: June 2005

We report another patient with del(11p) and aniridia, catalase deficiency, and cardiomyopathy. This association is confirmed from a review of previously reported cases. Since other dysplasias are known in this syndrome, the hypertrophic cardiomyopathy in del(11p) children may also represent an abnormality of tissue development.
Metaphyseal dysplasia with maxillary hypoplasia and brachydactyly
Authors: Halal Fahed , Picard Jean‐Louis , Raymond‐Tremblay Danielle , de Bosset Philippe , Opitz John M.
Published: June 2005

We report the familial occurrence in a French Canadian family of metaphyseal dysplasia associated to short stature and previously undescribed facial and acral anomalies. Facial manifestations include beaked nose, short philtrum, thin lips, maxillary hypoplasia, and dystrophic yellowish teeth. Acral changes include bilateral shortness of metacarpal 5 and/or 2nd middle phalanx of fingers 2 and 5. Dermatoglyphics show low TRC, distal or absent axial triradius, absent triradius C, and radial loop on digit 4. The syndrome appears to be an autosomal dominant trait.
Branchial arch malformations in infants of diabetic mothers: Two case reports and a review
Authors: Johnson John P. , Fineman Robert M. , Opitz John M.
Published: June 2005

We describe two infants of diabetic mothers (IDMs) with branchial arch, vertebral, cardiovascular, and central nervous system malformations. Our observations support the hypothesis of Grix et al [1982] that branchial arch abnormalities may occur with increased frequency in children of diabetic mothers. Two other IDMs (a literature case with hemifacial microsomia and caudal regression, and a child we evaluated with ear abnormalities and the femoral hypoplasia‐unusual facies syndrome) reinforce this suggested association. The latter two patients also demonstrate concurrence of branchial arch abnormalities with caudal regression and/or femoral hypoplasia, field defects known to be strongly associated with maternal diabetes mellitus. Genetic counseling for maternal diabetes mellitus probably should include information regarding all of these developmental abnormalities.
The fragile X(q27) form of X‐linked mental retardation: FUdR as an inducing agent for fra(X)(q27) expression in lymphocytes, fibroblasts, and amniocytes
Authors: Brookwell Ross , Daniel Art , Turner Gillian , Fishburn Jane , Opitz John M.
Published: June 2005

The effect of FUdR on the expression of fra(X)(q27) was examined in lymphocytes and/or fibroblasts from 16 affected males and 5 carriers from 10 families; six different culture media were used: F10, 5% serum, pH 7.3(37°C); medium 199, 5% serum, pH 7.6(37°C); folate‐free 199, 5% serum, pH 7.6(37°C), and these three media with FUdR (0.05 μm). In lymphocytes there was no significant difference in the percentage of fra(X) expressing cells between any of the FUdR‐containing media. The highest percentage of expressing cells seen in lymphocytes with FUdR was 56%. The average enhancement in males with FUdR in the 199 and folate‐free 199 media was 30%. This relative enhancement with FUdR was very much higher in a few blood specimens delayed in transit and FUdR may prevent some of the false‐negative results obtained from mailed specimens. FUdR did not induce the marker in four obligate carriers with previously negative results. The fibroblasts from affected males were grown in the six specific media for the last 48 hr. Two of the six media yielded reproducibly positive results. These were 199‐FUdR and folate‐free 199‐FUdR with mean percentages of expressing cells of 12.8 ± 7.1% and 11.3 ± 6.1%, respectively. F10‐FUdR, which contains thymidine, did not permit expression of the marker in fibroblasts and there was no difference in the percentage of fra(X) expression in 199‐FUdR media with or without folate. It was concluded that FUdR shows promise as an agent to permit prenatal diagnosis of the condition and to enhance the detection of the marker in lymphocyte cultures.
Administration of iduronate sulfatase by plasma exchange to patients with the hunter syndrome: A clinical study
Authors: Brown Frank R. , Hall Clara W. , Neufeld Elizabeth F. , Munoz Louis L. , Braine Hayden , Andrzejewski Stanley , Camargo Edwaldo E. , Mark Shirley A. , Richard James M. , Moser Hugo W. , Herrmann Jürgen
Published: June 2005

The Hunter syndrome (MPS II) is the only mucopolysaccharidosis in which there is appreciable activity of the deficient enzyme in normal plasma. We performed enzyme‐replacement treatment by plasma exchange in five Hunter syndrome children. Carefully monitoring the cardiovascular status, we administered monthly single plasma volume exchanges for a 3 to 8 mo period. The results indicate a substantial gain of enzyme activity, persisting with a t50% = 19 ± 5 hr. The maximal level and persistence of increased enzyme activity did not change after repeated exchanges, suggesting that immune responses were not elicited. Despite this, no demonstrable clinical benefit was apparent when the study group was compared with an age‐matched control group of Hunter syndrome patients.
Prune belly syndrome in an anencephalic male
Authors: Hodes M. E. , Butler Merlin G. , Keitges Elisabeth A. , Mirkin L. David , Wills Edward R.
Published: June 2005

We describe a postmature anencephalic infant with atrophy of the abdominal musculature (prune belly syndrome). Other associations of these conditions are noted.
Familial amniotic bands
Authors: Lubinsky Mark , Sujansky Eva , Sanger Warren , Salyards Phyllis , Severn Charles , Herrmann Jürgen
Published: June 2005

Amniotic bands can cause a wide variety of deformities and mutilations. They are generally considered sporadic. Two families are presented with apparent familial amniotic band anomalies. Additional cases in the literature are reviewed. These aggregations may be coincidental, and recurrence risk is apparently low. However, amniotic band malformations may be an indication for caution in the use of amniocentesis in future pregnancies.
A new short rib syndrome: Report of two cases
Authors: Beemer Frits A. , Langer Leonard O. , Klep‐De Pater Johanna M. , Hemmes Anne M. , Bylsma Jan B. , Pauli Richard M. , Myers Terry L. , Haws Claude C. , Opitz John M.
Published: June 2005

We describe two unrelated malformed infants who died shortly after birth and who had multiple congenital anomalies including hydrops and ascites, facial abnormalities (with median cleft of the upper lip), narrow thorax, protuberant abdomen, and short, bowed limbs.

Postmortem radiographs showed very short ribs and disproportionately short long tubular bones; no metaphyseal abnormalities were present.

Comparison with earlier described short‐rib/short‐rib‐polydactyly syndromes suggest that the disorder present in our two cases is a new type of short‐rib syndrome. One of our patients was born to a consanguineous couple; in a subsequent pregnancy, real‐time ultrasonography in the second trimester showed that the female fetus had the same abnormalities as its sib. Diagnosis was confirmed after elective abortion. This suggests that this short‐rib syndrome may be an autosomal recessive disorder.
Duplication 10p in a girl due to a maternal translocation t(10;14) (p11:p12)
Authors: Gonzalez Claudette H. , Billerbeck Ana Elisa C. , Takayama Luiza C. , Wajntal Anita , Opitz John M.
Published: June 2005

We present a dup (10p) due to a t(10;14) (p11;p12)mat with a malformation syndrome in a girl. The analysis of 37 published cases shows that 31 patients (16 ♂; 15 ♀) had either a mother or a father carrying a balanced translocation; one case was due to a paternal and another due to a maternal pericentric inversion; two cases were due to de novo translocations; one case had a partial duplication of 10p; and one case had a supernumerary ring chromosome composed of 10p material.

The phenotypic spectrum of the condition was analyzed. It is a specific multiple congenital anomalies/mental retardation (MCA/MR) syndrome which includes characteristic facial appearance (dolichocephaly, frontal bossing, short nose with a broad root, highly arched and upswept eyebrows, long philtrum, and thin lips), postnatal growth retardation, severe mental and psychomotor retardation, and several major and minor anomalies. Pseudohermaphroditism seems to be an important anomaly being present in 15 to 20% of affected males. A hypothenar crease together with a transverse crease forming a “crease triangle” seems a helpful sign in the clinical diagnosis of duplication 10p.
Historical background and evidence for dominant inheritance of the Klein‐Waardenburg syndrome (type III)
Authors: Klein David , Opitz John M.
Published: June 2005

The story of the Klein‐Waardenburg syndrome begins with the presentation before the Swiss Society of Genetics in Geneva in August 1947 of a 10‐year‐old girl, who showed, in addition to deafmutism, partial albinism of the hair and over the whole body, dystopia canthorum, blue hypoplastic irides, broad and prominent nasal root, absence of the frontonasal angle, and blepharophimosis. Waardenburg, impressed by the complex clinical picture of our proposita whom he saw in Geneva in 1948, subsequently undertook a systematic investigation in several Dutch institutions for the deaf. He was able to confirm from his study that several manifestations of our patient, principally the palpebro‐irido‐auditory complex, represented a well‐defined syndrome transmitted as a dominant trait with variable penetrance and expressivity. Since arthromyodysplasia did not figure among the clinical signs of his patients, Waardenburg suggested at first the possibility of either a homozygous state of the same mutation or the effect of a different allele as the cause of the accompanying gross skeletal and muscular defects. However, later on he completely questioned the nosologic placement of our case within the framework of his syndrome, having never encountered such extensive bone anomalies in more than one hundred observations.

Meanwhile four other cases with similar hypoplastic upper limb anomalies have been recorded and show an astonishing degree of resemblance to our original proposita with regard to specific bone alterations and their location. However, until recently there were still no observations concerning the inheritance of this complex syndrome.

The follow‐up examination of a French family where the father manifested the complete Klein‐Waardenburg syndrome including muscular and skeletal defects of the upper limbs, and his 12‐year‐old son who had apparently a typical Waardenburg syndrome (but with Sprengel deformity), enabled for the first time the postulation of a common genetic basis for both types with an autosomal‐dominant inheritance of incomplete penetrance and variable expressivity. Further investigations are however needed before this type of inheritance can be considered as firmly established for the Klein‐Waardenburg syndrome.
A boy with ring chromosome 15 derived from a t(15q;15q) robertsonian translocation in the mother: Cytogenetic and biochemical findings
Authors: Neri Giovanni , Ricci Roberta , Pelino Alessandro , Bova Renato , Tedeschi Bruna , Serra Angelo , Opitz John M.
Published: June 2005

We describe a boy with a ring chromosome 15, showing the manifestations characteristic of this condition, ie, growth deficiency and unusual facial appearance with minor anomalies. The ring was derived from a t(15q;15q) chromosome of the mother, who had also had four spontaneous abortions. The respective karyotypes were 45, XX, −15, −15, +t(15q;15q) (mother) and 46,XY, − 15, + r(15q;15q)mat (15q13 → cen → 15q26)(son). The ring chromosome lacked the short arms of the two translocated chromosomes 15 and was duplicated for a portion of the long arms near the centromere, probably cen → q13. Data from enzyme assays suggest that this duplicated region carries the α‐mannosidase gene.
Duplication 6q24 → 6qter in an infant from a balanced paternal translocation
Authors: Chase T. R. , Jalal S. M. , Martsolf J. T. , Wasdahl W. A. , Opitz John M.
Published: June 2005

Duplication of 6q24 → 6qter was identified by GTG banding in an infant girl whose father was a balanced translocation carrier 46,XY,t(3;6)(p26 → q2402). At birth and at 4 mo she had proportionate short stature, microcephaly, asymmetric micrognathia, bow‐shaped upper vermilion, long upper lip, submucous cleft palate, antimongoloid slant of palpebral fissures, telecanthus, prominant eyes, short neck with anterior and lateral webbing, short sternum, overlapping toes, wrist contractures, and hypertonicity. Later she was noted to have psychomotor retardation. Eleven previously published cases and our patient suggest that duplication of 6q (involving at least 6q25 → 6qter) produces a highly characteristic syndrome.
A high incidence of maternal cell contamination of amniotic fluid cell cultures
Authors: Benn Peter A. , Schonhaut Amy G. , Hsu Lillian Y. F. , Karp Laurence E.
Published: June 2005

Maternal cell contamination (MCC) of amniotic fluid cell cultures was detected as an admixture of male and female cells in 15 out of 3,000 cases. Allowing for undetected cases (in which the fetal karyotype is female), the true incidence of MCC may be as high as 1%. Cultures affected by MCC were, in general, established from fluid samples without obvious blood contamination. No common obstetrical or amniocentesis procedural factors could be recognized among those cases affected by MCC. The proportion of maternal cells was highly variable and in some instances maternal cells were present in multiple cultures.

In this series, MCC has not led to any cytogenetic misdiagnoses. MCC may pose its greatest danger for prenatal biochemical diagnoses where the properties of an entire cell population are determined.
Del(X) (q26) in a phenotypically normal woman and her daughter who also has trisomy 21
Authors: Taysi Kutay , Opitz John M.
Published: June 2005

We present a phenotypically normal woman with del(X)(q26) with no evidence of mosaicism, who had two pregnancies resulting in two live‐born infants. Her first child had trisomy 21 Down syndrome and the del(X)(q26). To our knowledge, this woman is the first known case of presumably nonmosaic del(Xq) producing live‐born infants. This finding can be explained on the basis of persistence into adulthood of germ cells in ovaries of the rare del(Xq) individuals. The normal phenotype in this woman supports the hypothesis that the absence of genes of middle Xq segment.(q13 → q26) is responsible for the somatic manifestations of the Ullrich‐Turner syndrome.

Our finding suggests that prenatal diagnosis should be offered not only to pregnant women with numerical X chromosome abnormalities, as suggested previously, but also to those with structural X chromosome abnormalities, because of the possibility of chromosome aberrations in the offspring of such women.
Skeletal dysplasia with short, angulated femora (kyphomelic dysplasia)
Authors: Maclean Ronald N. , Prater William K. , Lozzio Carmen B. , Opitz John M.
Published: June 2005

We report on an infant with broad and severely angulated short femora as the most salient manifestation of a generalized skeletal dysplasia. Other findings include congenital bowing of other long bones, narrow thorax, platyspondyly, micrognathia, and skin dimples. A marked improvement of the bowing and of the irregular flare of the metaphyses was noted over a period of 6 mo. Congenital bowing of long bones can be an isolated finding or associated with other anomalies, so the purpose of reporting all cases is important for further nosologic and pathogenetic elucidation. Because of the severity of the femoral involvement, the condition has been called kyphomelic dysplasia. It may be an autosomal recessive trait. recessive trait.
Familial neonatally lethal syndrome of hypoplastic left heart, absent pulmonary lobation, polydactyly, and talipes, probably Smith‐Lemli‐Opitz (RSH) syndrome
Authors: Kohler H. G.
Published: June 2005

Two siblings, one a male pseudohermaphrodite and the other female, died on the first day of life. In both instances pregnancy was complicated by polyhydramnios. At autopsy each was found to have multiple abnormalities, some concordant, others discordant. The concordant ones were hypoplastic left‐heart complex, absent pulmonary lobation, polydactyly, bilateral talipes, and, on microscopic examination, some large atypical cells in the pancreatic islets.

Chromosome cultures failed to grow. As far as is known parents were unrelated. Autosomal recessive inheritance is considered a possible cause, and the infants are thought to have the most severe form of the so‐called Smith‐Lemli‐Opitz (RSH) Syndrome.
Chromosome studies of patients with Alzheimer disease
Authors: Moorhead Paul S. , Heyman Albert , Opitz John M.
Published: June 2005

Ten patients with either the familial or sporadic form of Alzheimer disease (AD) were studied cytogenetically to confirm reports of aneuploidy and “long acentric fragments” associated with the disease. Findings in leukocytes of patients were compared with those in eight unaffected relatives and seven persons of similar age. Observations from encoded slides involving 3,800 conventionally stained and 1,396 G‐banded metaphases (one patient) showed no significant increase in aneuploidy. The frequency of cells with hypermodal counts, a reliable measure of aneuploidy, was 4.2% and 1.1%, respectively, in women and men with familial AD and 4.0% and 2.3%, respectively, in women and men with the sporadic form of the illness. Similar frequencies of hypermodal cells occurred in female (2.6%) and in male (2.0%) control subjects.

In contrast to the lack of aneuploidy, a small but significant number of false “long acentric fragments” was found in cells of women with AD (P <.05). These aberrations are thought to represent premature centromere division (PCD) in intact chromosomes, primarily supernumerary Xs. Often in multiple copies, PCD occurred in 2.8% of their cells and in 0.6% of cells from control women. PCD occurred in 3.6% of cells of women with the familial form and in 1.7% of cells of women with the sporadic type of dementia. Among unaffected relatives PCD increased with age. The rarity of PCD in G‐banded metaphases from an affected female (3/1,396) suggests that metaphase spreading techniques also may affect observable frequency. Thus PCDs occur more frequently in, but are not unique to, AD and may represent an epiphenomenon of aging, a process also characterized by the occurrence of neurofibrillary tangles and senile plaques in the cerebral cortex.
Dicentric i(Yq) chromosome and azoospermia
Authors: Ataya Khalid M. , Dudin Gertrud , Mroueh Adnan
Published: June 2005

We have studied a 43‐year‐old man with azoospermia. Chromosome analysis, using G‐, Q‐, and C‐banding techniques, showed a dicentric 46,X,i(Yq) chromosome abnormality. The clinical, cytogenetic, endocrine, and testicular histologic findings are presented. The case is discussed in relation to the pertinent literature. This represents the first phenotypic male with this karyotype ever reported.
Origin of a paternal (13q; 15q) translocation leading to dup(13q) in two half sibs
Authors: De Los Cobos Luis F. , Opitz John M.
Published: June 2005

We report on two half‐sibs, a male and a female with dup(13)(q1405 → qter) that resulted from a der(15),t(13;15)(15qter → 15q25::13q1405 → 13qter), h +, pat. Their manifestations were similar to those with duplication of the distal half 13q. The father was a balanced de novo translocation carrier. Since the der(15) had a long secondary constriction, it was possible to trace the site of the mutation to the germ cell of the patients paternal grandmother who had this distinctive long secondary constriction in one of her normal 15 chromosomes.
Congenital heart anomalies in the trisomy 18 syndrome, with reference to congenital polyvalvular disease
Authors: Matsuoka Rumiko , Misugi Kazuaki , Goto Akiko , Gilbert Enid F. , Ando Masahiko , Opitz John M.
Published: June 2005

Congenital polyvalvular disease (CPVD) is seen in trisorny 18 and other aneuploidy syndromes. However, its extent and nature have not been studied. Gross pathologic and histologic aspects of the heart were studied in 15 autopsied cases of trisomy 18. All had CPVD; other congenital defects included membranous ventricular septal defect (87%), patent ductus arteriosus (73%), and high takeoff of the right coronary ostium (80%). With a scoring system, histologic findings of the valves of all trisomy 18 cases were compared with those of 30 normal hearts of comparable age in order to determine the degree of morphologic abnormality. This included the presence of blood cysts, derangement of the spongiosa and fibrosa, vascular degeneration of the spongiosa, and defective elastic fibers. There were distinct differences between the changes seen in CPVD with trisomy 18 syndrome and those seen in the normal individuals. The most severe changes were present in the tricuspid and mitral valves with derangement of the spongiosa and fibrosa and defective elastic fibers. The valve tissue had a similar histologic appearance and structure to that of low birth weight infants (gestational age, 25 weeks). The valvular changes observed therefore are of fetal type and represent errors in tissue differentiation occurring as last as the third trimester.
Fragile (X) X‐linked mental retardation I: Relationship between age and intelligence and the frequency of expression of fragil (X)(q28)
Authors: Chudley Albert E. , Knoll Joan , Gerrard John W. , Shepel Lawrence , McGahey Ellen , Anderson Jo , Opitz John M.
Published: June 2005

Members of eight Saskatchewan families with fragile (X) X‐linked mental retardation were studied in an attempt to relate frequency to age and intelligence. The mean IQ of 37 affected men was 35 (range 10–66). The mean IQ of 32 carriers was 88 (range 57–119), and the mean IQ of 13 females who remain at risk for being carriers, have no affected sons, and who failed to demonstrate the fra(X) was 100 (range 78–126). We demonstrated a significant inverse relationship between age and frequency of the fra(X) in carriers and in affected males. However, we demonstrated a more highly significant inverse relationship between frequency of the fra(X) and IQ in carriers but to a lesser extent in affected males. Of 32 carriers, only 3 (9.4%) did not demonstrate the fra(X) after addition of 5‐fluoro‐2′‐deoxyuridine (FUdR) to the folic acid and thymidine‐reduced culture medium.

From these data we would recommend that chromosome studies in individuals at risk for fra(X) X‐linked mental retardation be carried out at the youngest age and that the addition of FUdR to culture medium is useful in carrier identification. It is clear that, in at least the carriers, a lower expression of the fra(X) is highly significantly correlated to higher intelligence.
Panostotic fibrous dysplasia: A congenital disorder of bone with unusual facial appearance, bone fragility, hyperphosphatasemia, and hypophosphatemia
Authors: Cole David E. C. , Fraser F. Clarke , Glorieux Francis H. , Jequier Sigrid , Marie Pierre J. , Reade Theresa M. , Scriver Charles R. , Opitz John M.
Published: June 2005

We report a boy with unusual facial appearance, melanotic patches (“coast‐of‐Maine” type), myelofibrosis, recurrent femoral fractures, and widespread fibrous dysplasia of bone. Biochemical findings included raised serum alkaline phosphatase (bone isozyme) and 1,25‐(OH)2 vitamin D, and low serum phosphorus levels. Elevated urinary excretion rates of total hydroxyproline, glycylproline, and γ‐carboxyglutamic acid indicated increased turnover of bone matrix. Transiliac bone biopsy showed a dearth of marrow elements, greatly increased bone turnover, and absence of normal trabecular organization. Serial radiographs showed progressive cortical thinning and loss of bony trabeculae. Calcitonin and etidronate treatments had no lasting effect on the progressive bone disease. The term “panostotic fibrous dysplasia” is suggested for this condition.
Two children with de novo del(9p)
Authors: Young Robert S. , Bader Patricia , Palmer Catherine G. , Kaler Stephen G. , Hodes M. E. , Opitz John M.
Published: June 2005

We describe two patients with characteristic manifestations of the del(9p) syndrome. Among the prominent manifestation are moderate mental retardation, trigonocephaly, flat nasal bridge, anteverted nostrils, long philtrum, square and hyperconvex nails, and apparently long digits. The metacarpophalangeal pattern profiles of the patients showed that the clinical impresion of long fingers may be due to relative shortness of the metacarpals rather than to elongation of the phalanges.
Brachymesomelia‐renal syndrome
Authors: Langer Leonard O. , Nishino Rikio , Yamaguchi Atsuko , Ito Yoshimoto , Ueke Tsuyoshi , Togari Hajime , Kato Toshiyuki , Opitz John M. , Gilbert Enid F. , Maroteaux Pierre , Spranger Jürgen
Published: June 2005

We have studied a male Japanese infant with severe upper limb brachymesomelia, glomerulocystic renal dysplasia, abnormalities of the cranium and face, corneal opacities, and a possible congenital heart defect. He was born at term and died on the 10th day of heart and kidney failure. Review of the literature failed to show a similar case.

Glomerulocystic renal dysplasia has been reported in association with a variety of the nonskeletal malformations but has not previously been described in association with bony malformations.
Segregation of HLA in families with oral clefts: Evidence against linkage between isolated cleft palate and HLA
Authors: Van Dyke Don C. , Goldman Allen S. , Spielman Richard S. , Zmijewski Chester M. , Opitz John M.
Published: June 2005

In an earlier study of amilies with two or more sibs affected with a cleft of the lip with or without clefts of the palate, we found no evidence for close linkage of HLA with this malformation. In the present study, we confime our attention to isolated cleft palate, an entity that is genetically distinct from clet palate associated with cleft lip. In 15 sibships with two or more effected sibs, cleft palate, and parental HLA haplotypes assorted independently in the affected sibs, providing evidence against close linkage of this phenotype.
Chromosome abnormalities in infants with prune belly anomaly: Association with trisomy 18
Authors: Frydman Moshe , Magenis R. Ellen , Mohandas T. K. , Kaback Michael M. , Opitz John M.
Published: June 2005

Two infants are described with “prune belly anomaly” (PBA) and concomitant trisomy 18. Severe abdominal distention was detected prenatally in one by ultrasonographic study, and in the second child at birth. Other chromosome abnormalities previously associated with PBA also are reviewed. The prune belly anomaly constitutes a malformation sequence that is causally nonspecific and which may occur in diverse aneuploidy syndromes. Aneuploidy is important to detect in prenatally diagnosed cases in which intrauterine fetal treatment is being considered.
A genetic study of hyper‐alpha‐lipoproteinemia
Authors: Rao D. C. , Lalouel J. M. , Suarez B. K. , Schonfeld G. , Glueck C. J. , Siervogel R. M. , Opitz John M.
Published: June 2005

Because of its association with longevity and reduced incidence of coronary heart disease, it becomes important to find out how elevated HDL‐cholesterol levels are determined. Analyses of family data from Cincinnati initially suggested environmental factors common to sibs; however, some form of dominant inheritance could not be ruled out. Reanalysis of the Cincinnati data by Iselius and Lalouel concluded against a major locus, but did identify three families as possibly segregating for a major locus. Analysis of an additional 26 kindreds from the same population in Cincinnati by Siervogel and associates concluded that a major gene could be causing familial aggregation of high density lipoprotein in white kindreds. In this analysis, we pooled all the white Cincinnati kindreds (n = 31), and investigated the familial transmission using complex segregation analysis. We failed to obtain clear evidence for major locus determination. Under the parsimonious hypothesis of no major locus, the polygenic heritability and common sibling environmental correlation were estimated as 0.531 and 0.263, respectively, consistent with other evidence.
Hemifacial microsomia and variants: Pedigree data
Authors: Rollnick Beverly R. , Kaye Celia I. , Opitz John M.
Published: June 2005

Ear malformations occur per se or together with other congenital anomalies. Many syndromes with ear malformations have been described. We have studied propositi with hemifacial microsomia (HFM) or Goldenhar syndrome (GS), also called oculoauriculovertebral “dysplasia” (OAV). In addition to ear malformations some individuals may have a small and/or malformed mandible, epibulbar, or conjunctival lipodermoids and anomalies of the cervical spine. Other malformations may also be seen. At present, the cause of these disorders is unclear.

Here we present pedigree data on 97 propositi, 44 of whom had a family history of the same or similar anomaly. First‐degree relatives were most often affected (35/433, 8%). Of 176 sibs tabulated, 11 (6%) were considered affected. The pattern of occurrence in many families suggested multifactorial determination, although other interpretations are possible. The occurrence of differing anomalies within a family suggests that the disorders constitute a single entity. The most frequent anomaly was a mild ear malformation (preauricular node or tag). This suggests a broad phenotypic spectrum. These data are useful for purposes of genetic counseling.
Acrofacial dysostosis (Nager syndrome): Synopsis and report of a new case
Authors: Pfeiffer R. A. , Stoess H. , Opitz John M.
Published: June 2005

Acrofacial dysostosis is noted in a stillborn female with mandibulofacial abnormality without cleft palate and with bilateral radial hemimelia, duplication of the left great toe, and aplasia of the right kidney. Synopsis of the published cases shows that the various degrees of mandibulofacial dysostosis frequently characterized by cleft palate and atresia of the auditory meatus are not closely correlated with the malformation of the upper limb. Formal genetics are unknown.
Risk of down syndrome among second‐ and third‐degree relatives of a proband with trisomy 21
Authors: Tamaren Janet , Spuhler Karen , Sujansky Eva
Published: June 2005

Previous studies indicate that parents who have had one child with trisomy 21 have an increased risk of having another affected child. To establish whether sibs, aunts, uncles, and cousins of an index case with trisomy 21 are also at increased risk for having an affected child, 219 kindreds of trisomy 21 probands were surveyed and compared with a control group of 247 kindreds. Control kindreds were ascertained through a child with a nonchromosomal disorder. Empiric risks were obtained and a risk interval calculated for each type of relationship. The results of this study suggest that for most families who have had a child with trisomy 21, the risk to second‐ and third‐degree relatives is increased somewhat but still low (less than 1 %). Analysis of those rare families who present with one or more affected second‐ or third‐degree relative with trisomy 21 in addition to the proband suggests that they represent a small subpopulation with a markedly increased risk. Sibs and second‐degree relatives in such families should be offered the option of amniocentesis, regardless of maternal age.
The syndrome of anosmia with hypogonadotropic hypogonadism: A genetic study of 18 new families and a review
Authors: White Beverly J. , Rogol Alan D. , Brown Kenneth S. , Lieblich Jeffrey M. , Rosen Saul W. , Opitz John M.
Published: June 2005

Among 18 NIH probands with anosmia and hypogonadotropic hypogonadism (AHH), seven had affected relatives and three had consanguineous parents. Both sexes were equally affected and parents were phenotypically normal. Parental age was not increased. Cleft lip and palate occurred in both eugonadal and hypogonadal persons, a previously reported association that may represent variable expression of AHH. Diabetes mellitus, usually insulin‐dependent, was frequent in probands and their families. Other common traits included obesity, cryptorchidism, and hearing loss. All probands were chromosomally normal. The frequency of some dermatoglyphic traits of probands differed from normal, but no trait was unique to AHH.

Segregation analysis of our proband sibships was consistent with a hypothesis of autosomal‐recessive inheritance with variable expression. However, genetic heterogenety was apparent when previous reports of familial AHH were surveyed. An X‐linked or male sex‐limited autosomal‐dominant form with unilateral renal agenesis, mental retardation, and hypotelorism has been observed. The infrequent reports of direct male‐to‐male transmissionn limit characterization of an autosomal‐dominant form of AHH.

Our phenotypic analysis suggests that the traits of mental retardation, renal anomalies, hypotelorism, diabetes, and hearing loss may help to distinguish various forms of AHH, whereas cryptorchidism, clefts, and obesity appear in several types of families. At present, genetic counseling is dependent upon establishing inheritance pattern after examination for the known associated anomalies.
A convenient method for measuring receptor‐cyclase coupling activity in whole blood: Application to Duchenne muscular dystrophy
Authors: Bourne Henry R. , Steinberg Florence , Golbus Mitchell S. , Farfel Zvi , Opitz John M.
Published: June 2005

Activity of the guanine nucleotide‐binding regulatory (N protein) component of adenylate cyclase can be measured in extracts of whole blood, using a modification of an assay previously applied to erythrocyte membranes. N protein activities in the blood of three patients with Duchenne muscular dystrophy and eight heterozygous carriers of the disease did not differ significantly from activities measured in blood of seven normal subjects. In contrast, the modified assay showed a 50% deficiency of N protein activity in blood of four patients with pseudohypoparathyroidism, type I, in whom erythrocyte studies had previously demonstrated a comparable degree of N deficiency.
Ruvalcaba‐myhre‐Smith syndrome: A case with probable autosomal‐dominant inheritance and additional manifestations
Authors: Diliberti John H. , Weleber Richard G. , Budden Sarojini , Opitz John M.
Published: June 2005

We report on a 7 1/2‐year‐old boy with macrocephaly, hamartomatous intestinal polyps, and café‐au‐lait spots on the penis. These abnormalities were reported in two other individuals thought to have the Sotos syndrome. We think that this triad of abnormalities represents a new disorder, the Ruvalcaba‐Myhre‐Smith syndrome. Prominent Schwalbe lines, prominent corneal nerves, and lipid storage myopathy also appear to be part of the syndrome. Macrocephaly, similar facial appearance, and a hamartomatous polyp in the mother suggest dominant inheritance.
Ullrich‐turner syndrome in monozygotic twins
Authors: Al‐Awadi S. A. , Cuschieri A. , Farag T. I. , Naguib K. , Teebi A. S. , Al‐Othman S. A. , Bahig A. H.
Published: June 2005

We report on the Ullrich‐Turner syndrome in monozygotic twin sisters. The first twin had the syndrome with a 45,X chromosome constitution. The second twin had only minor manifestations of the syndrome with 46,XX/45,X mosaicism.

The literature on the Ullrich‐Turner syndrome in twins is reviewed.
Occurrence of neural tube defects among first‐, second‐, and third‐degree relatives of probands: Results of a United States study
Authors: Toriello Helga V. , Higgins James V. , Opitz John M.
Published: June 2005

Data on the occurrence of neural tube defects in first‐, second‐, and third‐degree relatives of probands were collected in a United States study. The proportions of affected individuals were 3.2%, 0.5%, and 0.17% respectively. These findings are compared to those from other recent North American studies, and differences are discussed. It is pointed out that accurate recurrence risk figures may not be available, and that caution should be used when counseling families with relatives who are affected with NTD.
On the nature of folic‐acid‐sensitive fragile sites in human chromosomes: An hypothesis
Authors: Krumdieck Carlos L. , Howard‐Peebles Patricia N. , Opitz John M.
Published: June 2005

The methyl groups of thymine and 5‐methylcytosine exposed along the major groove of the DNA double helix are involved in the binding of specific proteins to specific DNA regions. It is hypothesized that folate‐sensitive fragile sites on chromosomes appear as a result of heritable defects of DNA methylation along a region normally binding a folding protein involved in chromosome condensation. Impairment of DNA‐folding‐protein interaction would result. A superimposed folate deficiency, or any condition leading to impaired thymidylate biosynthesis, would promote misincorporation into DNA of uracil in place of thymine, thus producing a further loss of methyl groups at the fragile site and eventually precluding a full DNA‐folding‐protein interaction. A localized collapse of the chromosome structure would follow.
Possible new autosomal recessive syndrome with unusual renal histopathological changes
Authors: Allanson Judith E. , Pantzar J. T. , Macleod P. M.
Published: June 2005

We report a couple with repeated pregnancy loss—two spontaneous first trimester abortions and two stillbirths with diffuse hypoplasia of the renal tubules. Both parents have been investigated to exclude occult unilateral renal agenesis. We raise the possibility that this is a new autosomal recessive condition.
Carrier detection in Hunter syndrome
Authors: Archer Irene M. , Young Ian D. , Rees Derek W. , Oladimeji Adebayo , Wusteman Frederick S. , Harper Peter S.
Published: June 2005

We have studied the carrier state of the Hunter syndrome using a series of obligate carriers, females at high genetics risk, and normal control women. Specific odds of a female being a carrier of Hunter syndrome were based on serum levels of iduronate 2‐sulphate sulphatase activity. These, together with the prior genetic odds, may be used in calculating the overall odds of a woman being a carrier. Iduronate 2‐sulphate sulphatase levels were found to increase significantly with age. Obligate carriers from families of severe cases had significantly lower enzyme levels compared with those from families of mild cases. In contrast, enzyme levels in sera of mild and severe cases were not significantly different. With the accumulation of more data the effect of age of the potential carrier and the severity of the disease may have to be taken into consideration in the risk calculation.

Hair‐root analysis was more reliable in the detection of carriers than estimation of serum enzyme levels, but some individuals could not be classified with confidence by hair‐root analysis alone. Carrier detection was most reliable when hair‐root analysis and serum enzyme levels were taken together.
Segregation of chromosomes into the spermatozoa of a man heterozygous for a 14;21 Robertsonian translocation
Authors: Balkan Wayne , Martin Renée H. , Opitz John M.
Published: June 2005

Twenty‐four spermatozoa from a man heterozygous for a Robertsonian translocation (45,XY,‐14,‐21,+t(14q;21q) were studied cytogenetically in order to determine the meiotic segregation of the translocation. When compared to the expected 1:1 ratio we observed a greater number of chromosomally normal sperm than sperm with the balanced translocation. Three sperm carried the translocation in an unbalanced form.
The genetics of quantitative plasma Lp(a): Analysis of a large pedigree
Authors: Hasstedt Sandra J. , Wilson Dana E. , Edwards Corwin Q. , Cannon Wayne N. , Carmelli Dorit , Williams Roger R. , Opitz John M.
Published: June 2005

Likelihood analysis using the mixed model of quantitative plasma Lp(a) measurements on members of a large pedigree provided evidence that high levels of Lp(a) are inherited as a dominant major gene with polygenic background. The dominant allele frequency was estimated as 0.10. The major gene and polygenic components together accounted for 95% of the variation seen in the measurements. The major gene index and OBP plots, methods that do not allow for the presence of both components, favored the polygenic model over the major gene model as the mode of inheritance. No association was found with any of the lipids, lipoproteins or apolipoproteins considered.
Brachyolmia, recessive type (Hobaek): A clinical, radiographic, and histochemical study
Authors: Horton William A. , Langer Leonard O. , Collins Debra L. , Dwyer Carmen
Published: June 2005

Brachyolmia recessive type (Hobaek) is a rare bone dysplasia characterized by short trunk dwarfism that becomes evident during childhood. The radiographic manifestations are primarily limited to the spine, and consist of universal platyspondyly with lateral extension of the vertebral bodies beyond the pedicles and irregularity of the vertebral end plates. Histologic changes seen on growth plate biopsy permit the diagnosis to be confirmed. The inheritance pattern appears to be autosomal‐recessive.