bluuebunny/crossref_metadata_2025 huggingface dataset:
Emotional symptoms in Prader‐Willi syndrome adolescents
Authors: Whitman Barbara Y. , Accardo Pasquale , Opitz John M. , Reynolds James F. , Ledbetter David H.
Published: June 2005

Clinical observations and parental reports on the behavior of Prader‐Willi syndrome (PWS) patients suggest the development of a wide variety of psychiatric disorders as the PWS child enters adolescence. Documentation of these emotional disorders remains unsystematic. Here we describe the results of administering the Survey Diagnostic Instrument (SDI) to the parents of 35 PWS adolescents. The questionnaire data were supplemented by additional selected demographic and clinical data. The SDI is a 134 item questionnaire filled out by one parent. It screens for the DSM‐III criterion‐based diagnostic categories of neurosis (dysphoric, compulsive, anxious), somatization, conduct disorder (antisocial, violent), and hyperactivity. The following diagnostic pattern resulted: neurosis, dysphoric, (1 probable); neurosis, compulsive, 3 (6 probable); neurosis, anxious, 4 (and 10 probable); somatization, 0; conduct disorder, violent 0; conduct disorder, antisocial, 0; hyperactivity, 1 (and 1 probable). An odds ratio algorithm is used to uncover possible predisposing factors, and the results are discussed in the context of organic versus psychiatric causes.
Agenesis of the corpus callosum, combined immunodeficiency, bilateral cataract, and hypopigmentation in two brothers
Authors: Vici Carlo Dionisi , Sabetta Gaetano , Gambarara Manuela , Vigevano Federico , Bertini Enrico , Boldrini Renata , Parisi Saverio Giuseppe , Quinti Isabella , Aiuti Fernando , Fiorilli Massimo , Optiz John M. , Reynolds James F.
Published: June 2005

We describe 2 brothers with a malformation syndrome consisting of agenesis of the corpus callosum, cutaneous hypopigmentation, bilateral cataract, cleft lip and palate, and combined immunodeficiency. The clinical history of both patients was characterized by severe psychomotor retardation, seizures, recurrent severe respiratory infections, and chronic mucocutaneous candidiasis. The children died of bronchopneumonia at age 2 and 3 years, respectively. Immunological investigations showed, in one sib studied, skin anergy to recall antigens, profound depletion of T4+ lymphocytes, and serum IgG2 deficiency. Necropsy showed agenesis of the corpus callosum, hypoplasia of the cerebellar vermis, and profound hypoplasia of the thymus and of the peripheral lymphoid tissue.

The distinctive features of these sibs appear to define a previously undescribed hereditarty MCA/MR syndrome. The clinical and pathological findings seem to indicate, as a pathogenetic mechanism, a defect involving the embryonic organization of the central nervous system and of the immune system.
Parental origin of the extra chromosome in the cat eye syndrome: Evidence from heteromorphism and in situ hybridization analysis
Authors: Magenis R. E. , Sheehy R. R. , Brown M. G. , McDermid H. E. , White B. N. , Zonana J. , Weleber R. , Optiz John M. , Reynolds James F.
Published: June 2005

Two individuals, a boy and girl, with a clinical diagnosis of cat eye syndrome had an extra bisatellited chromosome. In the girl, the diagnosis was made on the basis of coloboma of the right iris, right preauricular pit, and imperforate anus; in the boy, bilateral colobomata of the iris, down‐slanting palpebral fissures, right preauricular skin tag, and right preauricular pit. Multiple staining techniques were used to characterize the extra chromosomes. With G‐banding the extra chromosome usually appeared monocentric with two major G‐positive bands, but with satellites on both ends; with C‐banding, two C‐band positive regions were evident, indicating that the chromosomes were likely dicentric. Silver staining demonstrated the presence of NORs near each end; Q‐banding showed satellites on each end, differing in brightness and size. The chromosomes of the parents were normal; comparisons of Q‐band heteromorphisms of the acrocentric chromosomes of the parents with those of the extra chromosome showed in each case one short arm/satellite region of the extra chromosome identical in appearance to one chromosome 22 of the mother and the other end of the extra bisatellited chromosome identical to the short arm/satellite of the mother's second chromosome 22. This extra chromosome, then, is the result of a maternal meiotic error in each case. In situ hybridization studies using the chromosome 22–derived probe p22/34, which identifies locus D22S9, showed 16% of the cells from the female patient to have silver grains on the proximal long arm of the normal chromosome 22 and 14% on the extra chromosome, while 10% of cells from the male had grains on the normal chromosomes 22 and an equal number on the extra chromosome, confirming the chromosome 22 origin of the extra chromosome in these patients.
A case of ring (9)/del(9p) mosaicism associated with gastroesophageal reflux
Authors: Leung Alexander K. C. , Rudd Noreen L. , Optiz John M. , Reynolds James F.
Published: June 2005

We present a male infant with r(9) and del(9p) mosaicism and chromosome constitution of 46,XY,r(9)(p22;q34)/46,XY,del(9) (p22). This patient also had gastroesophageal reflux with persistent regurgitation and resultant failure to thrive. The association of this syndrome with gastroesophageal reflux is emphasized.
Prenatal sonographic diagnosis of Pena‐Shokeir syndrome type I, or fetal akinesia deformation sequence
Authors: Ohlsson Arne , Fong Katherine W. , Rose Toby H. , Moore Donald C. , Optiz John M. , Reynolds James F.
Published: June 2005

We report on a familial case of Pena‐Shokeir syndrome type I (fetal akinesia deformation sequence) born to healthy parents. The antenatal ultrasound diagnosis was based on hydramnios, restricted limb movements, decreased fetal chest movements, small chest, arthrogryposis, clubfoot, fixed extension of knees, fixed flexion of elbows, camptodactyly, kyphosis of thoracic spine, cryptorchidism, and small muscle bulk. Thymic hyperplasia was noted at autopsy.
Fetal akinesia deformation sequence in previable fetuses
Authors: Davis Jennifer E. , Kalousek Dagmar K. , Optiz John M. , Reynolds James F.
Published: June 2005

We reviewed the morphologic findings of 948 previable fetuses and identified the fetal akinesia deformation sequence (FADS) in 16 cases. In eight fetuses who had joint contractures, micrognathia, and pulmonary hypoplasia, the cause of fetal akinesia could be attributed to an abnormal intrauterine environment restricting fetal movement. The other eight fetuses had pterygia across the immobilized joints, in addition to main manifestations of FADS. Since most of the fetuses with pterygia were of only 8–9 weeks developmental age, we suggest that embryonic onset of immobility interferes with limb development and results in joint fixation and pterygium formation, in contrast to fetal‐onset immobility, which causes joint contractures alone.
A new acro‐cranio‐facial dysostosis syndrome in sisters
Authors: Kaplan Paige , Plauchu Henri , Fitch Naomi , Jéquier Sigrid , Optiz John M. , Reynolds James F.
Published: June 2005

Two sisters born to consanguineous parents had a syndrome of short stature, acrocephaly, hypertelorism, proptosis, ptosis, down‐slanting palpebral fissures, high nose bridge and anteverted nares, short philtrum, cleft palate, micrognathia, abnormal external ears, preauricular pits, sensorineural and conductive deafness, proximally placed first toes and digitalized thumbs, bulbous digits, metatarsus adductus, and pectus excavatum.

Radiological abnormalities included craniosynostosis, increased mandibular angle and antegonial notching of mandible; hypoplastic first metacarpals and metatarsals; hypoplastic distal phalanges; partial duplication of the distal phalanx of the thumb; malformed malleus and incus; tall lumbar vertebrae, increased interpedicular distance, and posterior scalloping; flared iliac wings, narrow supraacetabular regions, acetabular “dysplasia,” and coxa valga.

Autosomal recessive inheritence is suggested.
Distinctive syndrome of short stature, craniosynostosis, skeletal changes, and malformed ears
Authors: Hurst J. A. , Winter R. M. , Baraitser M. , Optiz John M. , Reynolds James F.
Published: June 2005

We report on 2 unrelated boys with a distinctive facial appearance of microtia, atretic external auditory meati, small mandible, and microstomia, who also have a skeletal dysplasia, microcephaly, and joint contractures. The skeletal abnormalities, short stature, and microcephaly led to an initial diagnosis of osteodysplastic primordial dwarfism; however, the birth weight of one of the children is not low enough to firmly establish this diagnosis. The similarities were detected by the matching program of the London Dysmorphology Data‐base.
Genitourinary anomalies are a component manifestation in the ectodermal dysplasia, ectrodactyly, cleft lip/palate (EEC) syndrome
Authors: Rollnick B. R. , Hoo J. J. , Optiz John M. , Reynolds James F.
Published: June 2005

Here we report on 13 individuals with the EEC syndrome from a single craniofacial clinic population. Eight of 13 underwent genitourinary (GU) evaluation; all had abnormal findings. Seven had anomalies of the urinary tract, and 3 had genital anomalies. To our knowldege, this is the first report of GU evaluation of the majority of EEC patients from a single clinic population. Results support the suggestion that GU anomalies are a major component of the EEC syndrome. Genitourinary evaluation of all EEC patients and their first degree relatives seems indicated. The abnormal findings observed to date suggest variable expression of an autosomal dominant gene.
Metacarpophalangeal pattern profile analysis in sotos syndrome: A follow‐up report on 34 subjects
Authors: Butler Merlin G. , Dijkstra Piet F. , Meaney F. John , Gale David D. , Optiz John M. , Reynolds James F.
Published: June 2005

Metacarpophlangeal pattern profile (MCPP) was determined on 34 Sotos syndrome individuals and compared with previous MCPP studies. The mean hand profile contained a major peak in the proximal phalangeal area and a smaller peak in the metacarpal area, while the distal hand bones were relatively short. There appear to be three recognized hand profiles in Sotos syndrome, which suggests heterogeneity of the syndrome, although correlation studies indicate clinical homogeneity of individuals in the younger age groups. Discriminant analysis of Sotos syndrome versus control subjects produced a function of two MCPP variables, plus age, which may be applied as another diagnostic tool.
Two patients with ring chromosome 15 syndrome
Authors: Butler Merlin G. , Fogo Agnes B. , Fuchs David A. , Collins Francis S. , Dev Viathilingam G. , Phillips John A. , Optiz John M. , Reynolds James F.
Published: June 2005

We report on 2 patients (3½ year‐old‐male and 6‐year‐old female) with the ring 15 chromosome syndrome and speech delays and review 25 cases from the literature. The main characteristics of this syndrome include growth retardation (100%), variable mental retardation (95%), microcephaly (88%), hypertelorism (46%), and triangular facies (42%). Other frequent findings include delayed bone age (75%), brachydactyly (44%), speech delay (39%), frontal bossing (36%), anomalous ears (30%), café‐au‐lait spots (30%), cryptorchidism (30%), and cardiac abnormalities (30%). The average age at diagnosis was 8.1 years. The average maternal and parental age at the time of birth was 28 and 31 years, respectively.
The inheritance of intraerythrocytic sodium level
Authors: Hasstedt Sandra J. , Hunt Steven C. , Wu Lily L. , Williams Roger R. , Optiz John M. , Reynolds James F.
Published: June 2005

Intraerythrocytic sodium level (RBC Na) was measured on 1,800 normotensive members of 64 Utah pedigrees ascertained through hypertensive or normotensive probands sibs with early stroke death, or brothers with early coronary disease. Likelihood anaysis provided evidence that RBC Na was determind by four alleles at a single locus. Each allele was reccessive to all alleles associated with a lower mean level. The four resultant distributions occurred in the frequencies; 0.8%, 89.3%, 9.7%, and 0.2% with correspondingg means (mmol/1 RBC) of 4.32, 6.67, 9.06 and 12.19, respectively. The major locus explained 29.0% of the variance in RBC Na; Polygenic inheritance explained another 54.6%. A higher frequency of the genotypes for high RBC Na in pedigrees when the proband was hypertensive than normotesive provided evidence that this major locus increases susceptibility to hypertention.
Sparse hair, short stature, hypoplastic thumbs, single upper central incisor and abnormal skin pigmentation: A possible “new” form of ectodermal dysplasia
Authors: Winter R. M. , Macdermot K. D. , Hill F. J. , Neri Giovanni , Reynolds James F.
Published: June 2005

A family is described where a mother and three sons have an unusual form of ectodermal dysplasia that may have been described in the medical literature only once before.

The unusual manifestations in this family are mild short stature, sparse scalp hair, skin pigmentation and a transient urticarial‐like reaction on the hands and arms. The mother and one son demonstrated a single, upper central incisor and the mother and another son had hypoplastic thumbs. The mother alone had hyperkeratosis of the palms and soles.

The inheritance pattern is most likely autosomal dominant, although X‐linked dominant inheritance cannot be excluded.
Prenatal diagnosis of chromosome abnormalities in the presence of fetal structural defects
Authors: Wladimiroff Juriy W. , Sachs Eva S. , Reuss Annette , Stewart Patricia A. , Pijpers Leen , Niermeijer Martinus F. , Reynolds James F.
Published: June 2005

A chromosomal abnormality was found in 42 (10.9%) out of 386 fetuses with a structural defect. Thirty‐five of these were diagnosed prenatally, following ultrasonic detection of one or more structural anomalies and associated pathology such as marked intrauterine growth retardation and polyhydramnios. Termination of pregnancy was carried out in 16 fetuses aged < 26 weeks, intrauterine and neonatal death occurred in 20 cases, the remaining 6 infants were alive at 3 months.

The poor outcome in these pregnancies emphasizes the need for prenatal chromosome analysis in the presence of a fetal structural defect.
Heterogeneity and recurrence risk for congenital hydrocephalus (Ventriculomegaly): A prospective study
Authors: Váradi Valéria , Tóth Zoltán , Török Olga , Papp Zoltán , Optiz John M. , Reynolds James F.
Published: June 2005

We report on 261 prospectively ascertained pregnancies studied to determine the recurrence risk of congenital hydrocephalus. Our results suggest that couples who have had one previous child with hydrocephalus have a recurrence risk of 4%. Such couples should be offered prenatal diagnosis in the second trimester of all subsequent pregnancies. It is suggested that, apart from the X‐linked recessive cases, ventriculomegaly is mostly multifactorially determined.
An unusual cardiomelic syndrome
Authors: Stratton Robert F. , Koehler Nancy , Morrow W. Robert , Reynolds James F.
Published: June 2005

We report on a patient with pre‐ and postnatal growth regardation, bilateral symmetrical ulnar agenesis with monodactyly, atrial septal defect, two ventricular septal defects, Wolff‐Parkinson‐White conduction abnormality, and abnormal configuration of the pancreas. Although she had some facial features reminiscent of the Brachmann‐de Lange syndrome, relatively normal head size and motor development indicate a distinct syndrome.
Molecular cloning and chromosomal localization of a gene coding for human cardiac myosin heavy‐chain
Authors: Matsuoka Rumiko , Chambers Ailsa , Kimura Misa , Kanda Naotoshi , Bruns Gail , Yoshida Michihiro , Takao Atsuyoshi , Optiz John M. , Reynolds James F.
Published: June 2005

A human cardiac myosin heavy‐chain (MHC) gene, cloned in a charon 4A phage, was isolated using two rat cardiac pCMHC DNA clones (pCMHC26: α‐MHC type; and pCMHC5: β‐MHC type) as probes and shown to correspond to cardiac myosin heavy‐chain of the α‐type. The 4.3‐KB cardiac genomic DNA clone was used as a probe in the Southern analysis of human genomic DNA from human–Chinese hamster or human–mouse somatic cell hybrids. The results show that the human cardiac MHC gene is assigned to chromosome 14 and the human cardiac and skeletal MHC genes do not cosegregate as do the mouse cardiac and skeletal MHC genes.
Agnathia, holoprosencephaly, and situs inversus. Report of a case
Authors: Leech Richard W. , Bowlby Linda S. , Brumback Roger A. , Schaefer G. Bradley , Optiz John M. , Reynolds James F.
Published: June 2005

We present the first documented case of agnathia‐holoprosencephaly (an uncommon form of craniofacial anomaly) associated with situs inversus. This case may represent the concordance of multiple field complex anomalies, but the possibility of a major midline malformation (situs inversus) caused by a timed insult (environmental or genetic) which affects multiple structures and occurs concurrently with a major field defect during early embryogenesis cannot be excluded.
47,XXX chromosome constitution, ovarian dysgenesis, and genito‐urinary malformation
Authors: Spear Gerald S. , Porto Manuel , Optiz John M. , Reynolds James F.
Published: June 2005

We describe the second known reported fetus with 47,XXX chromosome constitution and ovarian dysgenesis, in this instance with an unusual urinary tract malformation, nonimmune fetal ascites and meconium peritonitis.
Deletion mapping of the β‐glucuronidase gene
Authors: Allanson Judith E. , Gemmill Robert M. , Hecht Barbara K. , Johnsen Stanley , Wenger David A. , Optiz John M. , Reynolds James F.
Published: June 2005

GUSB, the gene for β‐glucuronidase, has been localized to the proximal long arm of chromosome 7 between 7q11.2 and 7q22. Deficiency of β‐glucuronidase results in mucopolysaccharidosis type VII (MPS VII, Sly syndrome). The enzymatic defect has been demonstrated in cultured skin fibroblasts, leukocytes and serum of affected patients.

An 8‐yr‐old boy presented with manifestations similar to MPS VII (mental retardation, short stature, “coarse” facial appearance, mild skeletal involvement and recurrent lower respiratory tract infection) but other, discrepant abnormalities, e. g., bilateral iris colobomata and cleft palate. Normal activity of β‐glucuronidase was found in the patient's leukocytes. Chromosome analysis disclosed an interstitial deletion of 7q with one breakpoint at the interface between bands 11.22 and 11.23 and the other breakpoint within band 21.1. DNA from this patient's leukocytes was analyzed for dosage of GUSB sequences. This locus appeared to be present at the normal diploid level.

These findings suggest that GUSB is not in the portion of chromosome 7 deleted in our case, narrowing the smallest region of overlap to 7q21.1 → 7q22. We therefore assign the β‐glucuronidase gene to 7q21.1 → 7q22.
A new autosomal recessive lethal chondrodystrophy with congenital hydrops
Authors: Greenberg Cheryl R. , Rimoin David L. , Gruber Helen E. , DeSa D. J. B. , Reed M. , Lachman Ralph S. , Optiz John M. , Reynolds James F.
Published: June 2005

Two sibs, the offspring of consanguineous parents, presented with severe short‐limb dwarfism and distinct chondro‐osseous, radiologic, and histologic appearance. The first sib presented at 30 wk with severe hydrops following fetal death; the second was detected by ultrasonography at 20 wk. Radiologic abnormalities included an unusual “moth‐eaten” appearance of the markedly short long bones, bizzare ectopic ossification centers, and marked platyspondyly with unusual ossification centers. Marked extra‐medullary erythropoiesis was present in both fetuses, and chondro‐osseous histology was characterized by marked disorganization of tissue with interspersed masses of cartilage, bone, and mesenchymal tissue. These sibs appear to have a distinct previously unreported autosomal recessive skeletal dysplasia, which can present as hydrops fetalis.
Inbreeding in outport Newfoundland
Authors: Bear J. C. , Nemec T. F. , Kennedy J. C. , Marshall W. H. , Power A. A. , Kolonel V. M. , Vurke G. B. , Optiz John M. , Reynolds James F.
Published: June 2005

We investigated inbreeding in 3 outport Newfoundland study areas in which persistent genetic isolation was demonstrated previously. The inbreeding coefficient of every person born in each area was calculated from reconstructed pedigree data. The average inbreeding coefficient for persons born between 1960 and 1979 is 0.0032 in Trepassey Parish (southern Avalon Peninsula), 0.0171 for a group of communities on the west coast of the Great Northern Peninsula, and 0.0007 for southeastern Labrador. Average inbreeding of these populations was higher earlier in this century. Averages are high compared to those reported for other populations, consistent with genetic isolation. Coefficients of kinship were calculated for large samples of pairs of births in each study area, and frequency distributions of inbreeding coefficients compared with frequency distributions of kinship coefficients, to evaluate random and nonrandom mating with respect to consanguinity. These comparisons show that matings between unrelated individuals are more frequent than expected, that matings between first cousins are not strongly avoided in 2 of the 3 study areas, that matings between first cousins once removed are favored, and that matings between distantly related individuals are becoming more frequent. To gain an impression of the potential contribution of inbreeding to the prevalence of recessive disease, we calculated indirect estimates of the expected excess of prereproductive mortality due to inbreeding. These estimates are 15% for Trepassey Parish, 49% for the West Coast study area, and 2% for southeastern Labrador. It is unlikely that genetic isolation of outport Newfoundland populations will decrease. Elevated prevalences of recessive disease, due primarily to matings between persons unaware of their distant consanguinity, therefore require consideration in health care planning in Newfoundland.
Additive congenital anomaly patterns
Authors: Czeizel Andrew , Optiz John M. , Reynolds James F.
Published: June 2005

A family study was conducted on 1,038 index patients with unidentified multiple congenital abnormality (MCA) patterns in the population‐based material of the Hungarian Congenital Malformation Registry (HCMR). Congenital abnormalities (CAs) were detected in 5.1% of fathers and in 4.2% of mothers, respectively. Two fathers had an MCA pattern similar to that in their affected child. One component CA of multimalformed index children occurred in 55.1% of fathers and 52.3% of mothers. Thus, in more than half of affected parent–child pairs, there may be a causal connection between the observed anomalies. The combination of CAs of different parental origin in index patients is called “additive CA pattern.” This group of patients may represent about 5% of unidentified MCA patterns and about 50% of affected parent–childpairs.
Discordance of signs in monozygotic twins concordant for the goldenhar anomaly
Authors: Ryan C. Anthony , Finer Neil N. , Ives Elizabeth , Optiz John M. , Reynolds James F.
Published: June 2005

Concordance for Goldenhar anomaly has been described in monozygotic(MZ) twins on 2 occasions but never in dizygotic (DZ) twins. In both cases the twins were similarly, although not identically, affected. We report on a pair of probably monozygotic twins (8% probability of DZ) who presented with extremely diverse manifestations of this anomaly complex. One of them required a tracheostomy because of obstructive apnea due to severe micrognathia and subsequently died. This twin had a midline lower lip cleft which has not previously been described in the Goldenhar anomaly.
Perfect pitch
Authors: Profita Joseph , Bidder T. George , Optiz John M. , Reynolds James F.
Published: June 2005

Thirty‐five subjects with perfect pitch, representing 19 families, were studied with a Perfect Pitch Questionnaire, which provided information on note‐recognition capacity and musical exposure and training, as well as demographic characteristics. Perfect pitch was found to predominate in females and was detected at a very early age. The significant family incidence of the trait suggests the operation of genetic mechanisms concerning which speculations are presented.
Overgrowth, congenital hypotonia, nystagmus, strabismus, and mental retardation: Variant of dominantly inherited Sotos sequence?
Authors: Goldstein D. J. , Ward R. E. , Moore E. , Fremion A. S. , Wappner R. S. , Optiz John M. , Reynolds James F.
Published: June 2005

We report on 2 patients with macrocephaly, strabismus, esotropia, nystagmus, hypolonia, developmental delay, excessive size, unusual facial appearance, and improvement with age. Many of these abnormalities are present in Sotos sequence. The mothers of both patients share some characteristics with their children. These patients may represent an autosomal dominant form of Sotos sequence.
Relationship between Mayer‐Rokitansky‐Küster (MRK) anomaly and hereditary renal adysplasia (HRA)
Authors: de Cássia M. Pavanello Rita , Eigier A. , Otto P. A. , Optiz John M. , Reynolds James F.
Published: June 2005

We report the results of a study performed in a sample of women with the Mayer‐Rokitansky‐Küster (MRK) anomaly and in their first‐degree relatives. Our results are compatible with a traditional model of multifactorial determination; however, we cannot exclude the hypothesis of autosomal dominant inheritance, with an intermediate degree of penetrance and a highly variable expressivity of a single mutant gene. In this sense, our data seem to support the idea expressed recently by Opitz [1987].
Discordant expression of the G syndrome in monozygotic twins
Authors: Young I. D. , Dalgleish R. , Mackay E. H. , Macfadyen U. M. , Optiz John M. , Reynolds James F.
Published: June 2005

We present clinical manifestations of monozygotic male twins with different degrees of expression of the G syndrome. Monozygosity was confirmed using DNA mini‐satellite “fingerprint” analysis. The findings in these twins suggest that expression of the G syndrome can be strongly influenced by theprenatal developmental environment.
Idiopathic multicentric osteolysis. Report of two new cases and a review of the literature
Authors: Pai G. S. , Macpherson R. I. , Optiz John M. , Reynolds James F.
Published: June 2005

Idiopathic multicentric osteolysis is a rare skeletal disorder, usually presenting in early childhood with a clinical picture mimicking juvenile rheumatoid arthritis. Progressive destruction of the carpal and tarsal bones usually occurs and other bones may also be involved. Chronic renal failure is a frequent component of this syndrome. Mental retardation and minor facial abnormalities have been noted in some patients. We report on 2 unrelated, sporadic cases, one with facial anomalies and the other with nephropathy. Our second patient is the first black child to be diagnosed with this disease. The mode of presentation, differential diagnosis, and natural history of this disorder are briefly reviewed.
Achondropiasia is not caused by mutation in the gene for type II collagen
Authors: Francomano Clair A. , Pyeritz Reed E. , Optiz John M. , Reynolds James F.
Published: June 2005

Achondroplasia is the most common human skeletal dysplasia. It is inherited as an autosomal dominant trait but the underlying biochemical cause is unknown. Genomic DNA from 49 affected individuals and two multiplex families with achondroplasia was studied using probes spanning COL2A1, the structural gene for type II collagen. Two lines of evidence speak against mutationin COL2A1 as the cause of achondroplasia: (1) no gross rearrangements areseen on Southern blot analysis of DNA from probands, and (2) linkage studies in multiplex families demonstrate discordant inheritance of achondroplasia and COL2A1 alleles.
Suggestively increased rate of infant death in children of fra(X) positive mothers
Authors: Fryns Jean‐Pierre , Moerman Philippe , Gilis Filip , d'Espallier Luc , Berghe Herman Van Den
Published: June 2005

A review of the Leuven data on the fragile X syndrome indicates that sudden infant death is frequently observed in the progeny of obligate female carriers. This observation may be another indication of a central nervous dysfunction in infants with this type of X‐linked mental retardation.
Fragile X syndrome and neoplasia
Authors: Phelan Mary C. , Stevenson Roger E. , Collins Jack L. , Trent Howard E.
Published: June 2005

Among 100 males with fragile X [fra(X)] or Martin‐Bell syndrome, two have developed malignancies. The first case, a 57‐year‐old man with fra(X) expression in 12% of peripheral blood lymphocytes, developed a seminoma of the left testis at age 45 years and in the right testis at age 50 years. The second case, a 16‐year‐old white boy with fra(X) expression in 23% of lymphocytes, developed a mucin‐producing adenocarcinoma of the colon at age 14 years. Because of the unusual nature of the tumors observed in these patients and in 2 other patients from the literature, we suggest that individuals with the fra(X) syndrome may be at increased risk of cancer.
Aneuploidy and the fragile X syndrome
Authors: Watson Michael S. , Breg W. Roy , Pauls David , Brown W. Ted , Carroll Andrew J. , Howard‐Peebles Patricia N. , Meryash David , Shapiro Lawrence R.
Published: June 2005

The possibility that female carriers of the fragile X gene(s) are at increased risk for nondisjunctional events leading to aneuploid offspring has been suggested by several investigators. To better address this question we analyzed pedigrees of 117 families in which the fragile X syndrome is segregating.

The 117 pedigrees, originally collected for segregation analyses, included 236 females with offspring whose carrier status was determined by cytogenetic or pedigree analysis or by analyses using flanking DNA markers. These 236 females have had 931 offspring including one 47, XXY and 6 trisomy 21 individuals (1/155). Statistical analysis suggested that the observed rate of trisomy 21 was significantly higher than expected (Fisher's exact test, p 0.05). Assuming a Poisson distribution to calculate the confidence interval for the observed rate of trisomy 21 individuals, we found that the expected rate of 1.6/1000 in this sample fell outside the 99% confidence limits of our observed rate of 1/155. Additional data from a larger sample are needed to replicate these findings.
Growth pattern in boys with fragile X
Authors: Nielsen Karen Brøndum
Published: June 2005

The impression that a proportion of boys with fra(X) may show overgrowth in early infancy was investigated in a small series of 7 boys born after 1970. The fra(X) positive boys had been referred for mental retardation, or were identified in investigations of familial mental retardation. The mean birth weight was increased, and average linear growth was consistently above the mean for Danish boys with the greatest increase in the second year of life. In contrast, the weight measurements were on average below the mean until age 2 years. It is suggested that in fra(X) patients there is a disturbance of early infantile growth.
Anthropometry in Martin‐Bell syndrome
Authors: Loesch Danuta Z. , Lafranchi Maureen , Scott David
Published: June 2005

Thirty anthropometric measurements were analyzed in 147 adults with Martin‐Bell syndrome (MBS) (56 men and 91 women) and in a random sample of 108 normal women and 111 men. Results of the univariate comparison of the age, height, or weight‐adjusted variables between MBS and normal individuals of either sex indicated that a decrease in stature, in upper limb length, and in upper face height, and an increase in jaw length, chest circumference, and waist width occurred in both affected men and in heterozygous women. While the increase in ear height and breadth and in hypermobility of finger joints and decrease in palm width and bigonial diameter occurred only in affected men, increased bispinal and bitrochanteric diameters, upper arm circumference, and palm and wrist widths were characteristic deviations in heterozygous women.

Multivariate analysis in the form of principal components showed some differences in the pattern of interrelationships in individual measures between MBS and normal individuals. In particular, and in contrast with both normal groups, height and weight tended to load on separate components (as did head and midfacial measures) in MBS individuals. A discriminant function based on all body measurements included in this study resulted in almost complete separation of discriminant scores of normal from those of MBS men and in good separation of the scores from normal and heterozygous women. Classification rates based on these functions were from 95% in men to 85% in women. These already high classification rates may be further improved mainly by enlarging the samples and including some other category of traits such as dermatoglyphic measurements.
Preliminary communication: Photoanthropometric analysis of individuals with the fragile X syndrome
Authors: Butler Merlin G. , Allen G. Andy , Singh Dharmdeo N. , Carpenter Nancy J. , Hall Bryan D.
Published: June 2005

A photoanthropometric method, which enables an objective description of facial structures, was used to examine 31 boys with the fragile X or Martin‐Bell syndrome below the age of 12 years. The age range was 1.5 to 12 years with an average age of 6.5 years. Facial parameters were measured from strict frontal and profile photographs of fra(X) syndrome boys and compared with other facial measurements from the same face (e.g. mouth width vs. bizygomatic diameter). We studied 18 photoanthropometric facial parameters following the protocol established by Stengel‐Rutkowski et al [1984]. Fourteen indices were calculated and compared with photoanthropometric index standards for age, established from normal children between 0 and 12 years [Stengel‐Rutkowski et al, 1984]. Two of the fourteen craniofacial indices, broad palpebral fissures and decreased inner canthal distance, were significantly abnormal.
A dermatoglyphic study of a group of Sicilian children with fragile‐X syndrome
Authors: Milone G. , Conti L. , Rizzo R. , Sanfilippo S. , Sammito V. , Romano C.
Published: June 2005

In a dermatoglyphic study of 14 fra(X) boys (compared with a control group of 191 normal schoolboys), we observed the following statistically significant (p<0.01) differences: 1) lower frequency of ulnar loops on the fingertips, particularly on the 2nd and 3rd fingers, with a corresponding increase of whorls; 2) transverse course of main line A; 3) increased frequency of abnormal palmar creases. The log score index of Simpson et al [1984] identified 71.4% of our patients and that of Rodewald et al [1986] 64.2%. The different values of these indexes can probably be attributed to ethnic differences. We think that by combining the results of dermatoglyphic analysis from several centers a more discriminatory log score index can be obtained.
Crown size asymmetry in males with fra (X) or Martin‐Bell syndrome
Authors: Peretz B. , Ever‐Hadani P. , Casamassimo P. , Eidelman E. , Shellhart C. , Hagerman R.
Published: June 2005

We measured the mesio‐distal and bucco‐lingual crown diameters of 13 males with the fra(X) or Martin‐Bell syndrome. Fluctuating crown‐size asymmetry was calculated and compared with values obtained in normal Caucasian children and also with a sample of 19 males with Down syndrome. A statistically significant increased asymmetry was found in the fra(X) males when compared to normal control individuals. In the maxilla, Down syndrome males showed a significantly higher tooth crown asymmetry than fra(X) males. (<0.02); in the mandible, no significant differences were found between the 2 groups. It is suggested that crown size asymmetry be included in the evaluation of fra(X) males.
Fragile X syndrome: Neuropathology center
Authors: Brown W. Ted , Rudelli Raul D. , Wisniewski Henry M.
Published: June 2005

There is an acute need for additional neuropathological information in the fra(X) or Martin‐Bell syndrome. We propose a centralized fra(X) neuropathological research center to promote research and understanding of the underlying neuropathologic changes. Brain specimens can be sent to our center for neuropathological analysis. Reports will be sent to the contributing health professionals. Clinicians and relatives are encouraged to request autopsies and to contact the Center regarding brain donations for purposes of research and understanding.
Prevalence of a novel epileptogenic EEG pattern in the Martin‐Bell syndrome
Authors: Musumeci S. A. , Ferri R. , Colognola R. M. , Neri G. , Sanfilippo S. , Bergonzi P.
Published: June 2005

In this paper, we describe a study aiming at establishing the prevalence, specificity, and the sensitivity of a characteristic sleep EEG pattern in patients with Martin‐Bell syndrome, in comparison with a sample of etiologically different mentally retarded patients. The estimation of the prevalence (11% among the total sample), the specificity, and the sensitivity, allows us to propose this pattern as an important “marker”, useful in the diagnosis of the Martin‐Bell syndrome.
The fragile X syndrome: Variability of expression in carrier females
Authors: Howard‐Peebles Patricia N. , Brown W. Ted
Published: June 2005

The fra(X) expression in heterozygotes varies considerably from family to family. In family D23, 5 carriers express the fra(X) regardless of age. DNA studies using 3 markers were inconclusive as to whether cytogenetic testing is more reliable in this family than in others. III‐2 and III‐5 are the critical individuals in the pedigree; further study with closer probes should resolve this question.
A new X‐linked dysplasia gigantism syndrome: Follow up in the first family and report on a second Austrian family
Authors: Behmel A. , Plöchl E. , Rosenkranz W.
Published: June 2005

We report on a new X‐linked recessive syndrome in 2 unrelated families, consisting of pre‐ and postnatal growth excess, typical facial phenotype allowing diagnosis at birth, and usually normal physical and intellectual development. The minor anomalies seen at birth include a “coarse” face with wide nasal bridge, short nose with upturned nasal tip, wide open mouth, thick lips, midline depression of the lower lip, enlarged tongue, highly arched palate, large maxilla and jaw, and a short broad neck. Voice is hoarse and affected individuals have a plump, stocky body with pectus excavatum, thoracic scoliosis, hepatosplenomegaly, umbilical and/or inguinal hernias, broad short hands and feet, and in some cases preauricular dimples, abnormal ears, postaxial hexadactyly, hypoplastic index finger nails, and abnormal dermatoglyphics. Early postnatal death is frequent and pathogenetically unexplained. During infancy and childhood the leading manifestations are the overgrowth (>97th centile), striking facial appearance, hypodontia and/or malposition of teeth, genua valga, hypoplastic calf muscles, and clumsiness. Adolescent and adult patients have well proportioned “gigantism” of athletic build (192–210 cm), large “coarse” face, and a deep voice. General intellectual and motor development are either normal or mildly delayed.
Simpson‐Golabi‐Behmel syndrome: An X‐linked encephalo‐trophoschisis syndrome
Authors: Neri G. , Marini R. , Cappa M. , Borrelli P. , Opitz J. M.
Published: June 2005

We report on another family with the so‐called “gigantism‐dysplasia syndrome”, an X‐linked condition characterized by pre‐and postnatal overgrowth, characteristic face with apparent coarseness, dysplastic changes in several tissues, and mild intellectual impairment. This condition has been called the Golabi‐Rosen syndrome; however, we agree that is the same entity as that described, in a milder form, by Simpson et al in 1975 and by Behmel et al in 1984. Therefore, we suggest that this entity be designated the Simpson‐Golabi‐Behmel syndrome. The manifestations in affected individuals suggest that this condition represents an X‐linked encephalo‐tropho‐schisis syndrome.
Fragile X expression in normal and mentally retarded subjects: Effect of treatment with an antifolic agent
Authors: Sanfilippo S. , Ragusa R. M. , Scillato F. , Ruggeri M. , Neri G.
Published: June 2005

Expression of the fragile site fra (X) (q27.3) in peripheral lymphocytes was evaluated in mentally retarded patients and in normal control individuals before and after administration of the antifolic agent trimethoprim for 7 days. This treatment was effective in converting the status of some individuals from fra (X)‐negative to fra (X)‐positive. However, the induced level of fra (X) expression was very low and not significantly different in patients and in control subjects and did not increase in those individuals where it was already present before treatment. These data support the contention that fra (X) (q27.3) is a common fragile site and that treatment in vivo with an antifolic agent is not effective in enhancing its degree of expression in vitro. Therefore, such treatment seems to be of no diagnostic value in those cases where the fra (X) syndrome is suspected clinically, but where there is no or very low cytogenetic expression of the fra (X).
A controlled trial of stimulant medication in children with the fragile X syndrome
Authors: Hagerman Randi J. , Murphy Mary A. , Wittenberger Michael D.
Published: June 2005

Attentional deficits and hyperactivity frequently are major problems for fra (X) boys. This study evaluated the effectiveness of 2 stimulant medications, methylphenidate and dextroamphetamine compared to placebo in 15 children (13 males, 2 females) with the fra (X) syndrome. A double‐blind crossover design was used with outcome measures which included parent and teacher behavior checklists, a controlled observation period, continuous performance tasks and an actometer measure of movement. When the children were treated with methylphenidate only, improvement was seen in socialization skills and attention span according to teacher checklists. Ten children were clinically considered responders and treatment was continued after the study was completed.
Fra(X) frequency on the active X‐chromosome and phenotype in heterozygous carriers of the fra(X) form of mental retardation
Authors: Wilhelm Dorothea , Froster‐Iskenius Ursula , Paul Jürgen , Schwinger Eberhard
Published: June 2005

Female heterozygotes of the fra(X) form of mental retardation show variable degrees of mental impairment and phenotype expression of the disorder. This might be an effect of inactivation of the X‐chromosome which carries the fra(X)(q). Prior replication studies in heterozygous carriers gave contradictory results with respect to possible genotype‐phenotype correlation. In the interpretation of these studies it is important to understand the effect of BrdU on the fra(X) (q) expression. In a group of 13 hemizygous patients with fra(X) (q) and 7 heterozygous carriers we studied the effect of BrdU on fra(X) expression. In the heterozygous carriers the use of BrdU resulted in a significant suppression of the fra(X) (q), while in hemizygous patients no difference in fra(X) (q) frequency with or without BrdU could be observed. It can be concluded that BrdU suppresses the fra(X) (q) preferentially on the inactive X‐chromosome. Thus the fra(X) (q) frequency on the active X‐chromosome is of primary importance in phenotype correlation studies among heterozygous carriers. In our group of heterozygous carriers we observed a negative correlation between (IQ) phenotype and fra(X) (q) expression on the active X‐chromosome. This suggests that the gene for the fra(X) (q) form of mental retardation is on the X‐chromosome and undergoes inactivation.
Fragile X expression in short‐term whole blood cultures is affected by cell density
Authors: Krawczun Michael S. , Jenkins Edmund C. , Brown W. Ted , Silverman Wayne P.
Published: June 2005

The effect of cell density on expression of the fragile site at (X)(q27.3) in short‐term whole‐blood cultures from patients with fragile X [fra(X)] or Martin‐Bell syndrome was studied. A significant increase in fra(X) frequency was observed in 7 of 8 samples when cell density was decreased. Higher fra(X) frequency was not always noted at below‐routine density, but in some cases fra(X) expression was depressed at above‐routine density. We conclude that decay of the FUdR effect explains the fact that fra(X) expression is affected by culture density. It is significant that a relationship exists between the two; it suggests that in order to maximize fra(X) expression in cases with low‐percentage fra(X) with standard methods, cell density may have to be adjusted. It is possible that in individuals who are normally nonexpressing, such as some obligate female carriers and nonpenetrant males, fra(X) expression may be sensitive to cell density effects.
In situ nick translation of the fragile X region
Authors: Nolin Sarah L. , Jenkins Edmund C. , Brown W. Ted , Dobkin Carl S.
Published: June 2005

At the present time, the molecular nature of the fragile site at Xq27.3 is not well understood. To examine the sensitivity of this region to DNAase I, in situ nick translation was performed on metaphase chromosomes from a fragile X (fra(X)) positive individual. In this technique DNAase I is used to nick regions of chromosomal DNA that are in “open” conformation. Biotinylated dUTP was incorporated by nick translation at these sites. The incorporation was identified by double antibody labeling and avidin‐horseradish peroxidase staining. Spreads, which had been stained with this technique, were photographed and subsequently trysin‐Giemsa G banded (post‐GTG banded) for chromosome identification. In 36 of 44 (82%) fra(X) positive male cells, the region distal to fra(X) (q27.3) was prominently stained in contrast to its light staining appearance in GTG preparations. The fragile site itself was outlined more clearly than can be achieved by GTG or homogeneous staining. When autosomal fragile sites were induced by the addition of 1.5 μM aphidicolin 17 hours prior to harvest, 24 of 27 (89%) fragile sites on the ends of autosomes were prominently stained in regions distal to the break. Because the fra(X) and autosomal fragile regions behaved similarly, this suggests that they have a similar conformation. Thus, while autosomal and Xq27.3 fragile sites are strongly induced by different means, the organization of these sites and the regions distal to them appear to be similar.
A non‐syndromal form of X‐linked mental retardation (XLMR) is linked to DXS14
Authors: Suthers G. K. , Turner G. , Mulley J. C.
Published: June 2005

An analysis of the linkage of a non‐syndromal form of X‐linked mental retardation (MRX1) with a number of markers on the X chromosome was performed in a large pedigree. The affected males had moderate mental retardation; in all other clinical respects and cytogenetically they were normal. No recombinants were observed between the MRX1 gene and the marker DXS14 (p58.1) located at Xpll‐cen (Z (max.) = 2.12 at = 0.00). Recombination was observed between the MRX1 gene and the markers DXS7 and DXYS1 which flank DXS14. This form of XLMR maps to the centromeric portion of the X‐chromosome.
Improved DNA markers for efficient analysis of fragile X families
Authors: Heilig R. , Oberlé I. , Arveiler B. , Hanauer A. , Vidaud M. , Mandel J. L.
Published: June 2005

We report the characteristics of two new probes that detect Bell RFLPs useful for analysis of fragile X families. With these two probes and a single blot, 34% of women are heterozygous both for the proximal marker DXS105 (closer to the fragile X locus than the factor IX gene) and for the distal markers DXS52 or the factor VIII gene. Combined with the analysis of previously described polymorphic markers, it is possible to have a majority of families fully informative for flanking markers using a limited number of probes and restriction digests.