bluuebunny/crossref_metadata_2025 huggingface dataset:
Dominant inheritance of syn‐camptodactyly of the second and third toes with foot and lower limb asymmetry and scoliosis
Authors: Halal Fahed , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a family in whom affected persons have the following anomalies in variable combination: camptodactyly of the second and/or third toes, partial syndactyly of second and third toes, foot and lower limb asymmetry, and scoliosis. The condition seems to be an autosomal dominant trait with apparently reduced penetrance and variable expressivity.
Mandibulofacial dysostosis in hutterite sibs: A possible recessive trait
Authors: Lowry R. B. , Morgan K. , Holmes T. M. , Metcalf P. J. , Stauffer G. F. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two sisters with mandibulofacial dysostosis (MFD). Both parents were examined carefully by clinical, radiographic, audiologic, and cephalometric methods. Neither showed evidence of the MFD gene. Photographs of three grandparents and examination of one disclosed no evidence of MFD. The parents are from the Hutterite Brethren and are consanguineous. Examination of the literature on MFD disclosed a number of other families with affected sibs and apparently normal parents. These families raise the possibility of an autosomal recessive form of MFD or some other explanation such as germinal mosaicism, chromosome rearrangement, or delayed mutation. For our family, the recurrence risk is probably 25%, but since germinal mosaicism cannot be excluded, it could be as high as 50%.
Screening for methylmalonic aciduria in alberta: A voluntary program with particular significance for the Hutterite Brethren
Authors: Fowlow S. Beatrice , Snyder Floyd F. , Holmes T. Mary , Morgan Kenneth , Opitz John M. , Reynolds James F.
Published: June 2005

A selective, voluntary urine screening program has been established to facilitate detection and early treatment of infants with methylmalonic acidurias (MMA), a group of rare, potentially lethal, autosomal recessive disorders of organic acid metabolism. The laboratory methods have been modified for newborn infants so that urine specimens can be collected on filter paper in the diaper and tested by the thin‐layer chromatography method. One Hutterite child was previously known to have methylmalonyl‐coenzyme A (MMCoA) mutase deficiency (mut0) which is unresponsive to vitamin B12 but is responsive to diet and other therapeutic measures. No undiagnosed existing cases of MMA were identified by the voluntary screening program among 1,165 Hutterite infants and preschool children.
Disequilibrium syndrome in montana hutterites
Authors: Pallister Philip D. , Opitz John M. , Reynolds James F.
Published: June 2005

This is a preliminary note on the occurrence of the disequilibrium syndrome (DES) in the Dariusleut Hutterites of Montana. Previously the condition was reported in the Dariusleut of Alberta by Schurig et al [1981] as an automosal recessive, non‐progressive neurological disorder with congenital hypotonia, considerable psychomotor retardation, unsteady broadly based gait and stance, increased deep tendon reflexes, and mild to moderate mental retardation. Affected individuals were short. In the Montana family studied by us in 1981, a brother and three sisters are affected.
NOR activity and centromere suppression related in a de novo fusion tdic(9;13)(p22;p13) chromosome in a child with del(9p) syndrome
Authors: Daniel Art , Ekblom Linda , Phillips Sandra , Fitzgerald Joan M. , Opitz John M. , Riccardi Vincent M.
Published: June 2005

A female infant with del(9p) syndrome was found to have the karyotype 45,XX,tdic(9;13)(p22;p13) de novo. In the translocation chromosome, various combinations of AgNOR activity and inactivity were found with suppression of either the 9 or neither centromere. These phenomena of discontinuous centromeric suppression and variation in NOR activity in the one chromosome were scored on AgNOR, GTG, and a combination of AgNOR‐ and GTG‐banded preparations. With AgNOR staining, 15.8% tdic chromosomes were AgNOR‐positive, and this coincided (in preparations with GTG banding only) with 16% tdic chromosomes with a nonstaining gap present at the NOR site. This suggested that when the NOR‐nonstaining gap was present the AgNOR staining would be positive; this was confirmed by the absence of gaps in combination AgNOR–GTG‐banded preparations. In cells with tdic–NOR‐negative chromosomes, equal proportions of cells with the 13 or both centromeres constricted were observed, but in cells with tdic‐AgNOR‐positive chromosomes there was only half the proportion of tdic chromosomes with both centromeres constricted; ie, there was a (significant) tendency towards inactivity of the NOR when both centromeres were constricted in the tdic chromosome. Therefore, the 2 phenomena, variation in NOR activity and centromeric suppression, are interrelated in this case.
Microcephaly, hypergonadotropic hypogonadism, short stature, and minor anomalies: A new syndrome
Authors: Mikati Mohamad A. , Najjar Samir S. , Sahli Itaf F. , Mansour Sylvie , Der Kaloustian Vazken M. , Melhem Rafik E. , Opitz John M. , Reynolds James F.
Published: June 2005

Four sibs, three males and one female, had microcephaly, hypergonadotropic hypogonadism, short stature, and multiple congenital anomalies. They had five normal sibs and consanguineous parents. Findings in the affected sibs also included a narrow forehead, synophrys, micrognathia, abnormally folded pinnae, early loss of teeth in three, cubitus valgus in two, genu valgum, gynecomastia, and undescended testes in one. All sibs had normal chromosomes. Results of tests for growth hormone release and adrenocortical function were normal. Luteinizing hormone releasing hormone (LHRH) and human chorionic gonadotropin (hCG) stimulation tests were consistent with primary gonadal failure. Testicular biopsy, performed on two affected males, was normal in one and showed focal atrophy with decreased spermatogenesis in the other. The patients manifest a phenotype different from all other known types of hypergonadotropic hypogonadism and appear to represent a new MCA/MR syndrome.
Gingival fibromatosis with sensorineural hearing loss: An autosomal dominant trait
Authors: Hartsfield James K. , Bixler David , Hazen Raymond H. , Opitz John M. , Reynolds James F.
Published: June 2005

Gingival fibromatosis is a heterogeneous entity that can occur both as a part of syndromes and as an isolated trait. We describe the second family with a rare, dominantly inherited syndrome of gingival fibromatosis and progressive sensorineural hearing loss.
Phenotypic variation in the del(12p) syndrome
Authors: Kivlin Jane D. , Fineman Robert M. , Williams Marc S. , Opitz John M. , Reynolds James F.
Published: June 2005

Previous reports suggested the existence of a del(12p) syndrome. Phenotypic abnormalities associated with del(12p) appear to be mental retardation, microcephaly, and micrognathia. The patient with del(12p) reported here was normocephalic and large for gestational age. She probably had sclerocornea, a finding not previously associated with del(12p). Phenotypic variation in del(12p) syndrome is probably caused by differences in the size of the deleted segment and/or the presence or absence of mutant genes on the homologous 12p segment.
Prenatal diagnosis of neuronal ceroid‐lipofuscinoses
Authors: Macleod Patrick M. , Dolman Clarissa L. , Nickel Robert E. , Chang Eva , Nag Sukriti , Zonana Johnathan , Silvey Kerry , Opitz John M. , Reynolds James F.
Published: June 2005

We report on the successful prenatal diagnosis of the late infantile “Jansky‐Bielschowsky” variant of the neuronal ceroid‐lipofuscinoses (NCL). The fetus was studied at 16 weeks of gestation because of an affected sib. Uncultured amniotic fluid cells were studied by conventional electron microscopic techniques. About one‐third of a subpopulation of dark, elongated cells contained one or more deposits of curvilinear cytosomes bound by a single unit membrane. These findings were considered typical of the late infantile variant of NCL. After delivery at term, a skin punch biopsy and a buffy coat preparation from the baby were examined and found to have similar characteristic inclusions, which confirmed our prenatal diagnosis.
X‐linked intellectual handicap and precocious puberty with obesity in carrier females
Authors: Hockey Athel , Opitz John M. , Reynolds James F.
Published: June 2005

Precocious puberty (PP) and intellectual handicap were present in 3 males in 2 generations of a Western Australian family. The 2 obligate carrier women were of normal intelligence but were grossly obese; one died of a cardio‐myopathy at 55 years.

The youngest affected male was found to have PP at 3 years. His mother was then pregnant, and because of her family history, was aware of the risk to have an affected male. Her mother had given birth to 2 sons with PP. By school age both of these males were mildly intellectually handicapped and this later became moderate.

Apart from these 3 affected males, the 2 carriers lost 6 of their other 8 offspring, leaving only one normal woman and her unaffected son.

The Fragile X test was negative on all males. This appears to be a new X‐linked mental retardation syndrome, and a condition different from true idiopathic PP, or familial PP affecting both sexes, or PP with X‐linked dominant inheritance.
Cognitive profiles and the spectrum of clinical manifestations in heterozygous fra(X) females
Authors: Kemper Melinda B. , Hagerman Randi J. , Ahmad Razia S. , Mariner Robin , Opitz John M. , Reynolds James F.
Published: June 2005

We investigated the possibility that fra(X) heterozygotes had a distinct or specific set of mental deficits (“cognitive profile”) which would allow for accurate diagnosis. Wechsler Intelligence Scale for Children‐Revised (WISC‐R) subtest scores obtained on 8 fra(X) school age girls were compared with similar scores obtained on 8 “learning‐disabled” non fra(X) gils matched on the basis of Full Scale IQ (FSIQ). The Block Design subtest score was significantly lower in fra(X) girls. In a larger sample of 22 fra(X) females, a characteristic combination of low Arithmetic, Digit Span, and Block Design subtest scores was observed. The mean discrepancy between these 3 subtest scores from the total Verbal or Performance subtest means was significant for the fra(X) group but not for a comparison group of 20 learning‐disabled females. Verbal IQ (VIQ) and Performance IQ (PIQ) discrepancy was not significant in fra (X) females. Percent fra(X) positive cells was negatively correlated with VIQ and FSIQ but not with PIQ.
An analysis of autism in fifty males with the fragile X syndrome
Authors: Hagerman Randi J. , Jackson Alfred W. , Levitas Andrew , Rimland Bernard , Braden Marcia , Opitz John M. , Reynolds James F.
Published: June 2005

Fifty males with the fragile X [fra(X)] syndrome, which we consider synonymous with the Martin‐Bell syndrome, were identified by a chromosome analysis of patients with developmental delays or mental retardation and family studies of known fra(X) pedigrees. These males were evaluated for autism using three criteria: (1) the DSM III diagnostic criteria for Infanti, Autism; 2) the Autism Behavior Checklist (ABC); and 3) the Diagnostic Checklist for Behavior Disturbed Children, Form E2. Sixteen percent of patients fulfilled all of the DSM III criteria for Infantile Autism and an additional 30% fulfilled criteria for Infantile Autism Residual State. Thirty‐one percent of patients had autism using the ABC checklist but none of the patients fit the classical Kanner syndrome as described by the E2 questionnaire. Some autistic traits were seen in almost all of the 50 fra(X) patients, including eye avoidance in 90%, handflapping, handbiting or handstereotypies in 88%, and language delays with language peculiarities, usually echolalic speech, in 96%. A pervasive lack of responsiveness was seen in 18% at their present age and in 44% in earlier childhood only.

Autistic symptoms are common in the fra(X) syndrome. Therefore, any patient with developmental delays and autism or autistic manifestations should have a chromosomal analysis, including fra(X) examination.
Somatic cell hybrid studies of fragile (X) expression in a carrier female and transmitting male
Authors: Ledbetter David H. , Airhart Susan D. , Nussbaum Robert L. , Opitz John M. , Reynolds James F.
Published: June 2005

We have extended our previous studies of fra(X) expressionin somatic cell hydrids to the analysis of a carrier female with a low level of expression and to an unaffected, transmitting male who shows no expression in lymphocytes or lymphoblasts. Optimum conditions for fra(X) expression was treatment with 10−8 M FUdR for 16 hours. In recent experiments, addition of 2.2 mM caffeine 2 hours before harvest was found to increase expression consistently. Two clones from the carrier female containing the far(X) chromiosome but not the normal X showed expression of 2–4%, indicating that expression in heterozygous females is not influenced by the presence or absence of the normal X. Expression rate was increased to 20% by exposure to FUdR plus caffeine. Analysis of hybrids containing only the fra(X) in an inactive state, and after reactivation by 5‐azacytidine, showed no change in the frequency of expression. A hybrid clone from the nonexpressing, transmitting male containing only the X and chromosome 13, showed expression rangine from 2% without caffeine to 12% with caffeine in three different experiments. The ability to induce fra(X) expression n hybrid from this nonexpressing male may be explained in one of several ways: (1) a second mutation has occurred, (2) an autosomal suppressor locus was lost, or (3) the hamster genome or unusually short cell cycle lowers the threshold for expression, particularly in presence of caffeine.
Caffeine enhances fragile (X) expression in somatic cell hybrids
Authors: Ledbetter David H. , Airhart Susan D. , Nussbaum Robert L. , Opitz John M. , Reynolds James F.
Published: June 2005

Yunis and Soreng recently demonstrated enhanced expression of common fragile sites as and of fra(X) when 2.2 mM caffeine is added to FUdR treated lymphocyte cultures 6 hours before harvest. We failed to replicate this finding for fra(X) expression in we do find a consistent increase in expression levels in somatic cell hybrids between a Chinese hamster cell line and 3 unrelated individuals with the fra(X) mutation when caffeine is present for the last 2 hours before harvest. This was particularly true for “low‐expressing” cell lines, in which a 4‐6 fold increase was observed. Using a thymidylate synthase deficient hybrid which could be blocked in the S phase by thymidine deprivation, we found that caffeine significantly reduced the recovery time from thymidine release to mitosis. This produced the highest level of fra(X) expression (48%) only one hour after release from thymidine deprivation. These results show that caffeine does enhance fra(X) expression in at least some cell types. The effect is probably, inhibiting the mitotic delay usually associated with DNA damage.
A rodent‐human hybrid containing Xq24‐qter translocated to a hamster chromosome expresses the Xq27 folate‐sensitive fragile site
Authors: Nussbaum Robert L. , Airhart Susan D. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

A somatic cell hybrid containing a single human X chromosome hearing the Xq27 fragile site was lethally irradiated and re‐hybridized to its HPRT‐ Chinese hamster parent. One of 24 colonies surviving selection for HPRT was found to have retained human G6PD but not PGK. This line, X300‐11 which shows Xq24‐qter translocated to a hamster chromosome by trypsin G‐banding and a single human chromatin fragment corresponding to this segment of the X by G‐11 staining, expresse the fragile site on exposure to 5‐fluorodeoxyuridine. Dot blots using total human DNA suggest that X3000‐11 retains ∼0.2% of the human genome. By Southern blotting, X3000‐11 retains Factor IX, DXS11 and DXS42 but lacks DXYS1, DXS3 and DXS17. This hybrid is being used to construct a cosmid library in the vector pCOS2 from which a sub‐library of 500‐1000 clones of human origin will be isolated using in vivo recombination with cloned Alu and Kpn family repeats. Such a sub‐library will greatly facilitate chromosome walking to the fragile site as well as the testing fo individual clones for their ability ot create a folate‐sensitive fragile by DNA transfer into permissive Chinese hamster recipient cells.
Studies of the fragile (X) syndrome in populations of mentally retarded individuals in Hawaii
Authors: Jacobs Patricia A. , Mayer Martha , Abruzzo Michael A. , Opitz John M. , Reynolds James F.
Published: June 2005

Three populations of retarded individuals were surveyed and the frequency of the fra (X) was found to be 1.9% in males and 0.3% in females.
Population incidence and segregation ratios in the Martin‐Bell syndrome
Authors: Webb Tessa P. , Bundey Sarah E. , Thake Ann I. , Todd June , Opitz John M. , Reynolds James F.
Published: June 2005

A clinical and cytogenetic study of children attending schools for the educationally handicapped has been carried out in the City of Coventry. As a result of this an estimate of the population incidence of the Martin‐Bell syndrome among schoolchildren has been made. Among schoolboys the incidence of mental retardation dur to the fra(X) was found to be 0.73 per 1000 and among schoolgirls 0.48 per 1000. The overall prevalence is 0.61 per 1000. Genetic and cytogenetic analysis of 14 families ascertained in an unbiased manner showed that the expected 50% ratio of affected to unaffected relatives was disturbed, the possible result of a segregation distortion.
The Martin‐Bell syndrome in South Africa
Authors: Venter Philip A. , Hof Johann Op't , Coetzee Dennis J. , Opitz John M. , Reynolds James F.
Published: June 2005

A national screening programme was introduced in 1980 when the first cases with the Martin‐Bell syndrome were diagnosed in South Africa. This survey includes patients from all the major population groups in South Africa. One thousand patients, who include 354 relatives of 21 index cases, were investigated cytogenetically. About 75% of the 354 relatives were either affected males or obligate or possible carriers. The segregation pattern of the fragile site was investigated in 271 offspring of 58 carrier women. At least 30% of the carriers were mildly mentally retarded with most expressing the fragile site. Various other investigations, such as measurements of testes, speech, verbal and IQ evaluations and hormone studies were done on several affected males. No fragile site could be demonstrated in 57 unselected autistic children. The results of this programme show that this syndrome is a common cause of mental retardation and that prevention of mental retardation is possible if all the involved families could be identified.
Neonatal adrenoleukodystrophy: New cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes
Authors: Kelley Richard I. , Datta Nabanita S. , Dobyns William B. , Hajra Amiya K. , Moser Ann B. , Noetzel Michael J. , Zackai Elaine H. , Moser Hugo W. , Opitz John M. , Reynolds James F.
Published: June 2005

Eight new cases of autopsy‐confirmed or suspected neonatal adrenoleukodystrophy (NALD) are presented together with new biochemical data on very‐longchain fatty acids (VLCFA) and plasmalogens and a review of all previously published cases. The clinica biochemical, and histopathologic abnormalities characteristic of this newly recognized form of adrenoleukodystrophy are analyzed in detail and compared to the principal characteristics of the similar disorder, the cerebrohepatorenal syndrome of Zellweger (ZS). Using strict pathologic criteria for the diagnosis of NALD, we find that, despite many clinical resemblances, NALD and the ZS are distinguishable on the basis of histology and peroxisomal biochemistry. Patients with NALD demonstrate adrenal atrophy, systemic infiltration by abnormal lipid‐laden macrophages, and elevations of saturated VLCFA. In contrast, patients with ZS have chondrodysplasia, glomerulocystic disease of the kidney, central nervous system dysmyelination, and elevations of unsaturated as well as saturated VLCFA, but they lack adrenal atrophy. We conclude that NALD and the ZS probably represent at least two different genetic defects.
An association of prune belly anomaly with trisomy 21
Authors: Amacker Elizabeth A. , Grass Frank S. , Hickey Docia E. , Hisley John C. , Opitz John M. , Reynolds James F.
Published: June 2005

We report on two patients wth prune belly anomaly (PBA) and trisomy 21 documented by clinical examination and cytogenetic investigation. The first infant was diagnosed at birth. A distended bladder was detected prenatally by ultrasound in the second, and chromosome studies were performed on cells obtained from fetal “bladdercentesis.” We discuss the importance of cytogenetic studies in cases where fetal surgery is a consideration.
A re‐examination of major locus hypotheses for high density lipoprotein cholesterol level using 2,170 persons screened in 55 Utah pedigrees
Authors: Hasstedt Sandra J. , Ash K. Owen , Williams Roger R. , Reynolds James F.
Published: June 2005

A dominant major locus (allele frequency of .0025 ± .0014), resulting in low levels of high density lipoprotein cholesterol (HDL‐C), was revealed by likelihood analysis on 2,170 persons in 55 Utah pedigrees. This allele was expressed through HDL‐C levels ranging from 20 to 30 mg/dl in seven persons in two pedigrees. Early coronary heart disease was associated with the allele in one pedigree, but not in the other. In the pedigree without associated heart disease, HDL subfractions HDL2 and HDL3 were both low in individuals with the low HDL‐C allele. No other major locus determining either high or low levels of HDL‐C was identified in our sample. Polygenic heritability as part of the mixed model was estimated as .561 ± .035.
Zellweger syndrome: Diagnostic assays, syndrome delineation, and potential therapy
Authors: Wilson Golder N. , Holmes Ronald G. , Custer Joseph , Lipkowitz Jeffrey L. , Stover Joan , Datta Nabanita , Hajra Amiya , Reynolds James F.
Published: June 2005

Patients with the cerebrohepatorenal syndrome of Zellweger lack peroxisomes and certain peroxisomal enzymes such as dihydroxyacetone phosphate acyltransferase in their tissues. Deficiency of this enzyme, which is necessary for glycerol ether lipid synthesis, provides a biochemical method for recognizing patients with subtle manifestations of Zellweger syndrome and suggests the utility of exogenous ether lipid precursors as a therapeutic strategy for these children. We describe the results of glycerol ether lipid supplementation to two children, one with classic Zellweger syndrome and 9% of control fibroblast dihydroxyacetone phosphate acyltransferase activity, and one with mild facial manifestations, wide sutures, hypotonia, developmental delay, hepatomegaly, peripheral retinal pigmentation, and 50% of control fibroblast dihydroxyacetone phosphate acyltransferase activity. An increase in erythrocyte plasmalogen levels following therapy was clearly demonstrated in the milder patient, and neither patient showed evidence of toxicity. Evaluation of therapy by comparison to the usual clinical course of Zellweger syndrome was not helpful because of the variability and incomplete documentation of 90 previously reported cases. The literature survey did provide criteria for classic Zellweger syndrome, which include hypotonia with or without deformation of limbs, large fontanels and split sutures, prominent forehead, flattened facial profile with hypoplastic supraorbital ridges, anteverted nares, highly arched palate, cryptorchidism or labial hypoplasia, hepatomegaly or elevated liver enzymes, peripheral pigmentation of the retina, renal cortical cysts, and characteristic neuropathology involving decreased myelinization, abnormal neuronal migration, and sudanophilic macrophages. Less severe patients, as exemplified by our case 2 and others from the literature, will not have all the classic features and can be recognized only by a growing panel of biochemical indicators. Our patient studies illustrate the complexity of designing comprehensive therapy for Zellweger‐like conditions, suggest other diseases that may involve peroxisomal alterations, and emphasize the need for multicenter, collaborative studies to evaluate biochemical heterogeneity and therapy of peroxisomal disorders.
Interstitial deletion of (17)(p11.2p11.2): Report of six additional patients with a new chromosome deletion syndrome
Authors: Stratton Robert F. , Dobyns William B. , Greenberg Frank , DeSana Jeanne B. , Moore Charleen , Fidone George , Runge Gretchen H. , Feldman Paula , Sekhon Gurbax S. , Pauli Richard M. , Ledbetter David H. , Opitz John M. , Reynolds James F.
Published: June 2005

Recently, a new clinically recognizable syndrome resulting from a small interstitial deletion of 17p [del(17)(p11.2p11.2)] was described in ten unrelated patients. We have identified six additional patients with similar cytogenetic and phenotypic abnormalities. Consistent clinical manifestations include 1) brachycephaly with a broad face and nasal bridge, 2) flat midface, 3) short, broad hands, and 4) mental retardation associated with hyperactivity and often self‐destructive behavior. The craniofacial and hand anomalies are reminiscent of several craniosynostosis syndromes. Most patients also had growth deficiency and several other (more variable) congenital malformations. Chromosome studies with special attention to 17 should be performed in any patient with a similar phenotype.
Acromicric dysplasia
Authors: Maroteaux Pierre , Stanescu Ritta , Stanescu Victor , Rappaport Raphaël , Reynolds James F.
Published: June 2005

We describe a new type of bone dysplasia, the „acromicric dysplasia”︁, based on the study of six patients. This dysplasia is characterized clinically by mild facial anomalies, markedly shortened hands and feet, and growth retardation that is severe in most of cases.

Roentgenograms of the hands are characteristic: the metacarpals and the phalanges are short and stubby, the proximal portion of the last four metacarpals are slightly pointed with an external notch on the 2nd metacarpal and an internal notch on the 5th metacarpal, similar to pseudoepiphyses. The shape of the epiphysis and the metaphysis of the long bones is almost normal, except for a slight deformation of the femoral heads in some patients. No signs of visceral storage were found, which rules out geleophysic dwarfism. The histological, histochemical, and electron microscopical examination of the growth cartilage in two cases showed similar lesions: disorganization of the growth zone with islands of cells, some of them degenerated; abnormal organization of collagen forming thick rims around the cells and wide fibers in the interterritorial matrix; large accumulation of glycogen in most chondrocytes.

Both sexes are affected; all patients are isolated cases from normal families.
Problems in detecting etiological heterogeneity in genetic disease illustrated with retinitis pigmentosa
Authors: Beaty T. H. , Boughman J. A. , Reynolds James F.
Published: June 2005

Simulated data were generated under four etiologic mechanisms for each of 20 different pedigree structures drawn from a study of families ascertained through a proband with retinitis pigmentosa. These simulated data were then used to identify subgroups of pedigrees which best supported each of three genetic mechanisms (autosomal dominant, autosomal recessive, X‐linked recessive with 10% penetrance of disease in heterozygous females) and a non‐genetic, sporadic mechanism. Results of these studies show that pedigrees identified as supporting one genetic model in a “model choice” approach tend to be etiologically homogenous, but are not truly representative of all the phenotypic combinations possible under that mechanism. The problem of etiologic heterogeneity is most acute when dealing with pedigrees less than size 10. Pedigrees lumped under a non‐genetic, sporadic mechanism are extremely heterogeneous and studies of the natural history of diseases where both genetic and non‐genetic mechanisms may be operating (such as with retinitis pigmentosa) should avoid using this group of largely simplex pedigrees.
Maternal hartnup disorder
Authors: Mahon Barbara E. , Levy Harvey L. , Opitz John M.
Published: June 2005

We describe childbearing in two unrelated women with Hartnup disorder, an inborn error of neutral amino acid transport. Two living, unaffected offspring born after untreated and uneventful pregnancies, one from each woman, have had normal growth and development. The older one had an IQ of 92 at 4 years while the younger one at 4 months had a Development Quotient of 107 on the Mental Scale and 102 on the Motor Scale. A third offspring had a neural tube defect complicated by hydrocephalus and died at 3 months. This mother had a family history of major congenital anomalies. We think that this experience supports the view that Hartnup disorder in the mother, unlike phenylketonuria, does not have an adverse effect on the fetus. The presence of normal ratios of the amino acid concentrations between maternal and umbilical veins in one mother also suggests that placental transport of free amino acids, unlike renal transport, may not be reduced in maternal Hartnup disorder.
Chromosomal mosaicism in the Killian/Teschler‐Nicola syndrome
Authors: Raffel Leslie J. , Mohandas T. , Rimoin David L. , Opitz John M. , Reynolds James F.
Published: June 2005

We report a patient with the Killian/Teschler‐Nicola/Pallister mosaic syndrome in association with a cytogenetic abnormality. This patient is the first reported to have lymphocyte mosaicism for an isochromosome of 12p. All other patients with the Killian syndrome have had normal lymphocyte karyotypes, although mosaicism for a similar isochromosome of 12p has been reported in the fibroblasts of most patients with the Killian syndrome.
Restrictive dermopathy: A newly recognized autosomal recessive skin dysplasia
Authors: Witt David R. , Hayden Michael R. , Holbrook Karen A. , Dale Beverly A. , Baldwin Virginia J. , Taylor Glenn P. , Opitz John M. , Reynolds James F.
Published: June 2005

A brother and sister from consecutive pregnancies had rigid and tightly adherent skin in association with generalized contractures, unusual facies, pulmonary hypoplasia, an abnormal placenta, and a short umbilical cord. Both died shortly after birth. Pathologic examination of the skin by light and electron microscopy showed structural abnormalities of the epidermis, dermis, and subcutaneous fat. An abnormal pattern of keratin proteins was determined biochemically using extracted epidermal proteins. Autopsy showed a normal spinal cord and muscle histology. It is postulated that the defective skin severely restricted movement and secondarily led to the other abnormalities. Familial occurrence is most consistent with autosomal recessive transmission. These patients and the primary skin defect are discussed within the framework of the Fetal Akinesia or Hypokinesia Deformation Sequence.
SC phocomelia syndrome, premature centromere separation, and congenital cranial nerve paralysis in two sisters, one with malignant melanoma
Authors: Parry Dilys M. , Mulvihill John J. , Tsai Shien , Kaiser‐Kupfer Muriel I. , Cowan Janet M. , Opitz John M. , Reynolds James F.
Published: June 2005

Two middle age sisters had most manifestations of the SC phocomelia syndrome including postnatal growth retardation, symmetric limb deficiencies with radial aplasia and absent thumbs, facial anomalies with microcephaly, microphthalmia, hypoplastic nasal alae, and borderline to mild mental retardation. Unusual findings included congenital paralysis of some cranial nerves in both patients and malignant melanoma in the proposita. Cultured lymphocytes from both patients, and skin fibroblasts, Esptein Barr virus‐transformed lymphocytes, and tumor cells from the proposita demonstrated premature separation of centromeric heterochromatin (PCS) of many chromosomes, a finding noted previously in the SC phocomelia syndrome and the similar but more severe Roberts syndrome.

Extensive overlap of the phenotypes of the sisters and 15 other patients with either syndrome and PCS confirms that these are either allelic conditions or the same disease—designated Roberts‐SC phocomelia syndrome. The role of PCS in the syndrome(s) remains uncertain since some patients with the characteristic clinical phenotypes are reported to lack it.
Inflammatory linear verrucous epidermal nevus (ILVEN) in a mother and her daughter
Authors: Hamm Henning , Happle Rudolf , Opitz John M. , Reynolds James F.
Published: June 2005

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disease with characteristic clinical and histological changes. The approximately 100 cases so far reported include only one familial occurrence involving a woman and her nephew. We report the occurrence of typical ILVEN in a 47‐year‐old mother and her 17‐year‐old daughter. So far, no clear‐cut genetic interpretation of this observation can be given. Apart from coincidence, various genetic explanations are considered, including X‐linked inheritance with extreme lyonization.
Branchio‐oto‐renal syndrome: Reduced penetrance and variable expressivity in four generations of a large kindred
Authors: Heimler Audrey , Lieber Ernest , Opitz John M. , Reynolds James F.
Published: June 2005

The family on which this report is based is of interest because it contains individuals with 1) the branchio‐oto‐renal (BOR) syndrome who have renal hypoplasia or malformations of the kidney or collecting system including duplication; 2) only branchial and ear anomalies; and 3) apparent nonpenetrance of the syndrome.

This report provides evidence to support the hypothesis that in some families variable expressivity includes duplication of the urinary collecting system in individuals with other manifestations of the BOR syndrome as well as individuals with branchial and ear anomalies who have apparently normal kidneys.
De la chapelle dysplasia
Authors: Whitley Chester B. , Burke Barbara A. , Granroth Gustav , Gorlin Robert J. , Reynolds James F.
Published: June 2005

Since the description by de la Chapelle and colleagues of two sibs with a unique skeletal dysplasia, two additional cases have occurred, one in the original Finnish family and one sporadic patient born to unrelated parents of Belgian descent. The original Finnish family has later had a fourth child, a normal daughter who was found to be unaffected upon radiographic examination in the 19th week of gestation. These additional findings are compatible with recessive inheritance. Physical features common to these four patients include cleft palate, small thorax, moderately severe micromelia with small hands, and equinovarus deformity. In each case, the ulnae and fibulae were reduced to an almost triangular osseous remnant. Other long bones were short and bowed. Neonatal death occurred in all cases and may be attributed to a consistent triad of respiratory tract malformations: laryngeal stenosis, tracheobronchomalacia, and pulmonary hypoplasia. Clinical and radiographic features are sufficiently unique to distinguish de la Chapelle dysplasia from other disorders in the spectrum of neonatal lethal osteochondrodysplasias. Lacunar halos were identified as a distinctive histopathologic feature also observed in achondrogenesis but not in several other skeletal dysplasias.
Hepatic peroxisomes are deficient in infantile refsum disease: A cytochemical study of 4 cases
Authors: Roels Frank , Cornelis Alfons , Poll‐The Bwee Tien , Aubourg Patrick , Ogier Helène , Scotto Jacques , Saudubray Jean‐Marie , Opitz John M. , Reynolds James F.
Published: June 2005

We examined liver biopsies from 4 patients with the infantile form of Refsum disease. No peroxisomes were visualized by light microscopy after cytochemical staining for catalase, a marker enzyme for this organelle. Absence of peroxisomes was confirmed by electron microscopy in 3 patients; in the 4th patient we observed organelles of peculiar size and structure and with minimal catalase activity. Light microscopy also showed birefringent macrophages containing P.A.S.‐positive material; they were abundant in the 3 older children, and rare in the youngest (8 months). Peroxisomes and birefringent macrophages were absent in 2 patients with the cerebrohepatorenal syndrome of Zellweger. The simultaneous presence of these unique light microscopical characteristics may be of diagnostic value.
Maroteaux‐Lamy syndrome in a large consanguineous kindred: Biochemical and immunological studies
Authors: Black Susan H. , Pelias Mary Z. , Miller James B. , Blitzer Miriam G. , Shapira Emmanuel , Opitz John M. , Reynolds James F.
Published: June 2005

We describe a large consanguineous German‐Acadian (“Cajun”) family from a rural area in Louisiana in which 11 persons in two generations had the Maroteaux‐Lamy syndrome. The mutant arylsulfatase B enzyme in this family was similar to the mutant enzyme in previously studied families in its cross‐reactivity with specific antibodies to the enzyme, but it differed in both its electrophoretic mobility and its residual enzymatic activity. These findings indicate that a different mutational event leading to Maroteaux‐Lamy syndrome occurred in this family.
Familial lipoid adrenal hyperplasia: Genetic marker data and an approach to prenatal diagnosis
Authors: Frydman Moshe , Kauschansky Arieh , Zamir Rina , Bonné‐Tamir Batsheva , Opitz John M. , Reynolds James F.
Published: June 2005

Some of the anatomic endocrine, and genetic aspects of lipoid adrenal hyperplasia were studied in an inbred Israeli‐Arab family with two affected sibs. One sib, a genetic female, presented with acute Addisonian crisis. Endocrine studies documented elevated ACTH levels and no detectable steroids of gonadal or adrenal origin. The other patient, a male pseudo‐hermaphrodite, was found at autopsy to have typical lipoid adrenal hyperplasia and ectopic adrenal tissue adjacent to an intra‐abdominal testicle. Complete vagina, uterus, and fallopian tubes were present in addition to the Wolffian structures. This unique observation supports the view that steroids may be necessary for Müllerian inhibitory factor to induce regression of Müllerian structures. The segregation of 27 autosomal markers was studied in one affected and five unaffected sibs. Genetic linkage to HLA, MNS, and GPT is unlikely. In addition, the affected sib is heterozygote for a haplotype of chromosome 1 which includes the Rh, Fy, PGM‐1 systems. Determination of fetal gender by the combined use of ultrasonography and amniocentesis is suggested for prenatal diagnosis and improved risk counselling.
Clinical anthropometry and medical genetics: A compilation of body measurements in genetic and congenital disorders
Authors: Meaney F. John , Farrer Lindsay A. , Opitz John M. , Reynolds James F.
Published: June 2005

Anthropometry has become an important tool in the study of genetic conditions, particularly as a diagnostic aid for the clinical geneticist. However, many practicing physicians do not do anthropometry of patients for several reasons, such as: appropriate measurements in a given situation are unknown; normative reference data are unavailable; or analysis and interpretation of the data are confusing. In this review we present an annotated compilation of informative measurements for hereditary and congenital disorders and a guide to normative anthropometric data of use in evaluation and diagnosis of such disorders. Further development of multivariate approaches will enhance the application of anthropometry as a means of identifying and classifying a syndrome and documenting the natural history of many disorders. Continued cooperation among physicians, geneticists, and anthropologists for the collection and assessment of patient and normative data is essential if these goals are to be realized.
Risk for trisomy 21 in offspring of individuals who have relatives with trisomy 21
Authors: Abuelo Dianne , Barsel‐Bowers Gail , Busch Wendy , Pueschel Siegfried , Pezzullo John , Reynolds James F.
Published: June 2005

This study was performed to determine if sibs and other relatives of individuals with trisomy 21 are themselves at increased risk for having offspring with trisomy 21. The results suggest that the reproductive risk to these relatives is not increased beyond the risk to the general population.
Dermatoglyphics and creases in patients with neurofibromatosis von recklinghausen
Authors: Vormittag Walter , Weninger Margarete , Raff Manfred , Konrad Klaus , Scheiber Viktor , Neri Giovanni
Published: June 2005

Fingerprint and palmar dermatoglyphics and creases were investigated in 60 patients (20 males and 40 females) with generalized neurofibromatosis. Like previous investigators, we found a significantly increased frequency of digital central pocket patterns. Furthermore, affected males and females had an increased frequency of monocentric whorls (P = 0.0037), higher quantitative values on digit II of both hands (P = 0.04), more often a reduction of main line C (P < 0.05) with decreased frequencies of patterns in the 3rd and 4th interdigital area of the left hand (P < 0.05), and a lower ab ridge count (males P < 0.005; females P < 0.001) than control individuals. On the right hand of males the frequency of high endings (5′ or 5″) of line A was decreased (P < 0.05). A significantly increased frequency of Sf1 (Sydney line) was found in female patients (P < 0.001). Male and female patients often showed a high number of secondary creases (P < 0.001).
Probabilistic assessment of the degree of antigen sharing in couples with impaired reproductive performance
Authors: Dawson Deborah V. , Ciftan Elinor A. , Reynolds James F.
Published: June 2005

Increased histocompatibility antigen sharing has been reported in couples experiencing recurrent infertility problems. Mathematical expressions describing the probability distribution of the number of antigens shared by randomly mating couples are derived for a single locus, two linked loci, and multiple independent systems. These theoretical frequencies are applied in concert with conventional statistical procedures to evaluate hypotheses concerning antigen distributions. Extensions for simultaneous consideration of other genetic systems are discussed.
Clinical application of DNA analysis in a family with OTC deficiency
Authors: McClead Richard E. , Rozen Rima , Fox Joyce , Rosenberg Leon , Menke James , Bickers Rex , Morrow Grant , Opitz John M. , Reynolds James F.
Published: June 2005

We describe the clinical application of DNA restriction fragment analysis to the genetic evaluation of a family with a child deficient in ornithine transcarbamylase (OTC). The results of protein loading studies and the interpretation of the DNA haplotype profiles for the human OTC gene are reported. DNA restriction fragment analysis may be a reliable technique for the prenatal diagnosis of OTC deficiency and identification of obligate carriers of this gene.
Distal osteolysis, short stature, mental retardation, and characteristic facial appearance: Delineation of an autosomal recessive subtype of essential osteolysis
Authors: Petit Paul , Fryns Jean‐Pierre , Reynolds James F.
Published: June 2005

We describe the concurrence of severe distal Osteolysis, mental retardation, short stature, and characteristic facial appearance with maxillary hypoplasia and relative exophthalmos in two adult sibs, a 57‐year‐old woman and her deceased brother. Apparently they represent a distinct, autosomal recessive entity in the group of the so‐called essential osteolyses. Furthermore, this observation confirms that the facial changes that may occur in patients with essential osteolysis, ie, maxillary hypoplasia and relative exophthalmos, may be present in all types of osteolysis, independent of their localisation or inheritance.
Animal Model: Genetic Analysis of an Inherited Deficiency of the Third Component of Complement in Brittany Spaniel Dogs
Authors: Johnson John P. , McLean Robert H. , Cork Linda C. , Winkelstein Jerry A. , Prieur David J.
Published: June 2005

Genetically determined C3 deficiency in Brittany spaniel dogs shares a number of biochemical and clinical characteristics with the human disorder. In humans, the gene for C3 deficiency is a null gene that is allelic to the structural gene tor C3 and is not linked to the major histocompatibility locus. The current study used allotype analysis of canine C3 in order to demonstrate that the gene for C3 deficiency in these dogs is also a null gene allelic to the structural gene for C3. In addition, preliminary pedigree analysis suggests that the gene for canine C3 deficiency is apparently not closely linked to the major histocompatibility complex of the dog. Thus, it appears that C3 deficiency in Brittany spaniel dogs not only shares biochemical and clinical features with C3 deficiency in humans, but also shares some genetic characteristics with the human disorder.
Magnetic resonance spectroscopy of normal and diseased muscles
Authors: Chance B. , Younkin D. P. , Kelley R. , Bank W. J. , Berkowitz H. D. , Argov Z. , Donlon E. , Boden B. , McCully K. , Buist N. M. R. , Kennaway N. , Opitz John M. , Reynolds James F.
Published: June 2005

Phosphorus magnetic resonance spectroscopy (P MRS) affords and innovative approach to the study of the oxidative enzyme content of normal and diseased muscles. Examples of the evaluation of the enzyme content of normal muscles by an exercise protoocol are provided. The protocol affords a hyperbolic work/cost profile, the Vmax of which is calculated by the reciprocal plots giving the enzyme content and the “effective Michaelis constant” with an evaluation of the resting metabolism. This steady state protocol clearly illustrates enzyme adaptation, on the one hand, and tissue atrophy particularly in the case of tissue injury, Duchenne's dystrophy, and genetic deletion of specific enzymes, on the other hand. The method is rapid, safe, and affords a quantitative evaluation of the disease process and possibilities for following appropriate therapies. So far, approx 1000 examinations or normal and diseased human limbs have been carried out in our laboratory in over the past four years.
The opitz syndrome: A new designation for the clinically indistinguishable BBB and G syndromes
Authors: Cappa M. , Borrelli P. , Marini R. , Neri G.
Published: June 2005

The BBB and G syndromes are multiple congenital anomaly (MCA) syndromes characterized by a developmental defect of the midline field. Prominent clinical manifestations are hypertelorism and, in males, hypospadias. Transmission is most likely autosomal dominant in both syndromes. Examination of two new cases and scrutiny of the literature led us to conclude that there are no discriminating qualitative differences between the two conditions. Therefore we propose that they both be designated by the common term “Opitz syndrome”.
Prenatal detection of Salla disease based upon increased free sialic acid in amniocytes
Authors: Renlund Martin , Aula Pertti , Opitz John M. , Reynolds James F.
Published: June 2005

Salla disease is an autosomal recessive lysosomal storage disease relatively common in the Finnish population. The main manifestations of more than 70 patients detected to date are severe psychomotor retardation and ataxia of early onset. Intracellular free N‐acetylneuraminic acid (sialic acid) is increased 10–20‐fold and localized in the lysosomes. Four pregnancies at risk were monitored by quantitation of free and total sialic acid in amniocytes and supernatant amniotic fluid by high‐performance liquid chromatography. In 3 children results were normal. Free sialic acid content of the amniocytes from one affected child was 2.6 nmol/mg protein, which was approxi‐mately 5 times higher than that of the 3 unaffected children (0.3 to 0.8) and 14 control samples (0.3 to 0.9). The ratio of free/total sialic acid of the amniocytes also clearly distinguished the affected pregnancy (13.8%) from the unaffected (2.3–4.8%) and control individuals (1.8–5.3%).

This represents the first successful prenatal identification of a patient with Salla disease and indicates that both free sialic acid and free/total sialic acid ratio should be monitored in pregnancies at risk for the disease.