Duplication of the distal part of the long arm of chromosome 1.

A case of dup(1)(q42----qter) is reported. A literature review of duplication of the distal third of chromosome 1 with breakpoints at various sites, 1q23, 1q25, 1q32, and 1q42, was undertaken. Clinical similarities and differences based on the size of the duplicated segment and other associated deficiencies are summarized.

Holoprosencephaly: a developmental field defect.

Holoprosencephaly refers to a spectrum of craniofacial malformations including cyclopia, ethmocephaly, cebocephaly, and premaxillary agenesis. Etiologic heterogeneity is well documented. Chromosomal, genetic, and teratogenic factors have been implicated. Recognition of holoprosencephaly as a developmental field defect stresses the importance of close scrutiny of relatives for mild forms such as single median incisor, hypotelorism, bifid uvula, or pituitary deficiency.

Duplication 10q confirmed by DNA in situ hybridization.

Partial duplication of 10q is a recognizable clinical entity. In most of the reported cases, the trisomic segment is identified by a balanced translocation state in a parent. Verification remains a problem in de novo cases. However, the recent availability of whole chromosome probes allows for confirmatory diagnosis of suspected cases. We describe a case of de novo duplication (10q) with verification using DNA in situ hybridization.

Prenatal diagnosis of Meckel syndrome: case reports and literature review.

We report on 2 couples at risk to have Meckel syndrome (MS) offspring. Three pregnancies were monitored by ultrasonography and alpha-fetoprotein (AFP) assay in midtrimester. Of the 2 involving an affected fetus, one was thought to be unaffected. A literature survey was undertaken. Sources of error seem to lie in the heterogeneity of clinical manifestations and the variable onset and rate of progression of clinical components of MS and limitations in ultrasonographic resolution inherent in the scanner or due to the associated oligohydramnios. The following observations/suggestions are made concerning the prenatal diagnosis of MS: 1) Utilize as many tests as are available. 2) Amniotic fluid AFP is more likely to show significant elevation than serum AFP. 3) Ultrasonography should concentrate on presence of oligohydramnios, small head diameter, cystic mass at the occiput, large kidneys, and absent bladder. 4) Use serial AFP and sonographic examination if findings are initially normal or equivocal.

Trisomy 14 mosaicism: case report and review.

Complete or partial trisomy 14 is compatible with life. However, in the former case, mosaicism is probably always present. A case of trisomy 14 mosaicism is reported. Comparisons are made with other trisomy 14, trisomy 14 mosaicism, and duplication 14q cases previously reported. As a group, they share some clinical manifestations. The phenotype consists of multiple congenital anomalies, including microcephaly, broad nose, wide mouth, high or cleft palate, micrognathia, congenital heart disease, intrauterine growth retardation, and mental retardation. The present patient also has asthma, eczema, and developmental asymmetry.

Sex chromosome marker: clinical significance and DNA characterization.

Two patients are described with a virtually identical marker sex chromosome that was so small as to defy classification by conventional cytogenetic studies. DNA hybridization with Y probes allows classification into Y or non-Y, and in situ hybridization with X centromere specific sequences, into X or non-X. One patient was proven to have a Y fragment, and the second, an X fragment. DNA characterization is important since prognosis and clinical management depends on proper identification of the small marker sex chromosome.

Pelizaeus-Merzbacher disease: clinical and DNA-linkage study of an extended family.

We describe a 5-generation family of 6 individuals with Pelizaeus-Merzbacher disease, Type I. DNA linkage study was done to establish carrier status. Two loci, DXS162 and DXYS1, were informative in this family for carrier determination. The highest lod score is that for PMD-DXYS1 (Z = 1.421 at theta = 0). The carrier probability can only be defined as likely or unlikely in the absence of an established recombination frequency.

A newly recognized neuroectodermal syndrome of familial alopecia, anosmia, deafness, and hypogonadism.

We describe a large, three generation kindred in which 16 individuals were affected with alopecia, hyposmia or anosmia, conductive deafness associated with protruding ears, microtia, and/or atresia of the external auditory canal, hypogonadotropic hypogonadism due to LH/FSH deficiency, and a greater than normal tendency to dental caries. Variable manifestations include mild facial asymmetry, mental retardation, congenital heart defect, and cleft palate. This seems to be a previously undescribed pleiotropic autosomal dominant trait with variable expressivity. The manifestations can be explained on the basis of involvement of the ectoderm and neuroectoderm of the first and second branchial arches, of Rathke's pouch, and of the diencephalon.

Martin-Bell syndrome segregating in a large kindred with normal transmitting males: clinical, cytogenetic, and linkage study.

We report on a large kindred with 10 mentally retarded, fra(X) positive males and 2 normal transmitting males. Clinical findings include variable degrees of facial anomalies, macroorchidism, behavioral characteristics, and cognitive deficiencies. The affected grandsons were fra(X) positive while their obligate carrier mothers and transmitting grandfathers were fra(X) negative. DNA-restriction fragment length polymorphism (RFLP) linkage study was undertaken to find informative markers to identify heterozygotes or hemizygotes. The problems encountered in genetic counselling, by the absence of established criteria for diagnosis, are discussed.

FISH detection of Wolf-Hirschhorn syndrome: exclusion of D4F26 as critical site.

Wolf-Hirschhorn syndrome (WHS) is due to a deletion in the terminal band of 4p16.3. Among loci that have been involved in deletions are D4S98, D4S95, D4S125, D4F26, as shown by PCR typing, Southern blot hybridization, and/or fluorescent in situ hybridization (FISH). Currently, FISH detection of WHS is predicted upon the deletion of the D4F26 locus with failure to hybridize to pC847.351, a commercially available cosmid probe. A WHS patient is shown to have an interstitial deletion, by hemizygosity at D4S98 and D4S95 but not at D4F26. This suggests that the tip of 4p, specifically D4F26, is not a critical deletion site for WHS.

Natural history of mosaic trisomy 14 syndrome.

Trisomy 14 mosaicism produces a distinct phenotype. Among the 13 reported and 2 additional patients, the following findings were present in more than 90%: growth retardation (15/15), psychomotor retardation (10/10), broad nose (13/14), "dysplastic" and/or apparently low-set ears (15/15), micrognathia (15/15), short neck (11/12), congenital heart disease (14/15), and micropenis and cryptorchidism (6/6). Other frequent findings were prominent forehead (12/14), hypertelorism (8/13), narrow palpebral fissure (7/9), large mouth (10/14), cleft or highly arched palate (10/14), body asymmetry (8/12), and abnormal skin pigmentation (6/10). Sex ratio was 6M:9F. Four patients died before age 4 months, while at least 2 patients survived through teens. One boy died at age 3 years following cardiac surgery. One girl with tetralogy of Fallot showed a remarkable improvement in health after Blalock-Taussig procedure. Although the surviving patients showed moderate growth and mental retardation, the oldest surviving woman at 29 years demonstrates functional language and appropriate self help skills.

Delimiting the Wolf-Hirschhorn syndrome critical region to 750 kilobase pairs.

Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition characterized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing to the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment previously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an intensive investigation of the developmental role of all the genes contained within it would be daunting and expensive. Further refinement in the definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this study, we have utilized fluorescence in situ hybridization to further characterize a WHS patient previously demonstrated to have an interstitial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating several genes previously proposed as contributing to this syndrome and allows further research to focus on a more restricted region of the genome and a limited set of genes for their role in the WHS syndrome.

Fetal alcohol syndrome: craniofacial and central nervous system manifestations.

Magnetic resonance imaging (MRI) is undertaken on fetal alcohol syndrome (FAS) subjects to document central nervous system (CNS) anomalies. The abnormalities found include agenesis and hypoplasia of the corpus callosum, cavum septi pellucidi, cavum vergae, ventriculomegaly, hypoplasia of inferior olivary eminences, small brain stem, and micrencephaly. Craniofacial anomalies range from the well-recognized FAS physiognomy to the more severe frontonasal "dysplasia" (median cleft face). CNS and craniofacial abnormalities are predominantly symmetric and central or midline. The association of these anomalies becomes self-evident with recognition of the concept of the midline as a special developmental field, vulnerable to adverse factors during embryogenesis and fetal growth and development.

New syndrome of spondylospinal thoracic dysostosis with multiple pterygia and arthrogryposis.

We describe a "new" syndrome of spondylospinal thoracic dysostosis with a short curved spine and fusion of the spinous processes, short thorax with "crab-like" configuration of the ribs, pulmonary hypoplasia, severe arthrogryposis and multiple pterygia, and hypoplastic maxilla and mandible in two siblings. This appears to be an autosomal recessive lethal trait. A literature review revealed two reports of four similar or related cases.

Deletion of the distal long arm of chromosome 1: a definable syndrome.

Based on analysis of 15 cases, there appears to be a characteristic facial appearance and pattern of associated malformations that would allow clinical delineation of deletion of the distal bands of 1q. Characteristic manifestations include round face with prominent "cupid's bow" and downturned corners of the mouth, thin vermilion borders of lips, long upper lip with smooth philtrum, short and broad nose, epicanthal folds, apparently low-set ears, micrognathia, microcephaly, abnormal hands and feet, variable cardiac, genital, and other anomalies, moderate to severe mental retardation, and growth retardation. The deletion includes 1q42 or 1q43----qter and was a de novo defect in nine of 15 cases.

Molecular detection of a 4p deletion using PCR-based polymorphisms: a technique for the rapid detection of the Wolf-Hirschhorn syndrome.

Wolf-Hirschhorn syndrome (WHS) results from a deletion of part of chromosome 4p. The region of 4p consistently deleted in WHS is near the tip of 4p. Two loci in this region D4S95 and D4S125 are associated with highly informative VNTR polymorphisms and were recently converted to allow PCR-based screening. PCR analysis was used successfully to identify a small de novo deletion of 4p in a patient suspected of having WHS. This procedure allows a rapid and accurate confirmation of 4p deletions in cases where cytogenetics alone cannot provide a clear answer.

Uniparental isodisomy of chromosome 14 in two cases: an abnormal child and a normal adult.

Uniparental disomy (UPD) of a number of different chromosomes has been found in associated with abnormal phenotypes. A growing body of evidence for an imprinting effect involving chromosome 14 has been accumulating. We report on a case of paternal UPD of chromosome 14 studied in late gestation due to polyhydramnios and a ventral wall hernia. A prenatal karyotype documented a balanced Robertsonian 14:14 translocation. The baby was born prematurely with hairy forehead, retrognathia, mild puckering of the lips and finger contractures. Hypotonia has persisted since birth and at age one year, a tracheostomy for laryngomalacia and gastrostomy for feeding remain necessary. Absence of maternal VNTR polymorphisms and homozygosity of paternal polymorphisms using chromosome 14 specific probes at D14S22 and D14S13 loci indicated paternal uniparental isodisomy (pUPID). Parental chromosomes were normal. We also report on a case of maternal UPD in a normal patient with a balanced Robertsonian 14:14 translocation and a history of multiple miscarriages. Five previous reports of chromosome 14 UPD suggest that an adverse developmental effect may be more severe whenever the UPD is paternal in origin. This is the second reported patient with paternal UPD and the fifth reported with maternal UPD, and only few phenotypic similarities are apparent. Examination of these chromosome 14 UPD cases of maternal and paternal origin suggests that there are syndromic imprinting effects.

Distinct 15q genotypes in Russell-Silver and ring 15 syndromes.

Individuals with a ring 15 chromosome [r(15)] and those with Russell-Silver syndrome have short stature, developmental delay, triangular face, and clinodactyly. To assess whether the apparent phenotypic overlap of these conditions reflects a common genetic cause, the extent of deletions in chromosome 15q was determined in 5 patients with r(15), 1 patient with del 15q26.1-qter, and 5 patients with Russell-Silver syndrome. All patients with Russell-Silver syndrome were diploid for genetic markers in distal 15q, indicating that Russell-Silver syndrome in these individuals was unlikely to be related to the expression of single alleles at these or linked genetic loci. At least 3 distinct sites of chromosome breakage close to the telomere were found in the r(15) and del 15q25.1-qter patients, with 1 r(15) patient having both a terminal and an interstitial deletion. Although the patient with del 15q25.1-qter exhibited the largest deletion and the most profound growth retardation, the degree of growth impairment among the r(15) patients was not correlated with the size of the deleted interval. Rather, the parental origin of the ring chromosome in several patients was associated with phenotypes that are also seen in patients with either Prader-Willi (PWS) or Angelman (AS) syndromes, conditions that result from uniparental expression of genes on chromosome 15. In fact, unequal representation of chromosome 15 alleles in 1 patient with r(15) suggests the possibility that a mosaic karyotype composed of the constitutional cell line and cell line(s) possibly deficient in the ring chromosome might be present. The PWS-like or AS-like phenotypes could be explained by postzygotic loss of the ring chromosome, leading to uniparental inheritance of the intact chromosome in some tissues of r(15) patients.

Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial.

Patients with the RSH or Smith-Lemli-Optiz syndrome (SLOS) have an inborn error of cholesterol biosynthesis which results in a deficiency of cholesterol and an elevation of the cholesterol precursor, 7-dehydrocholesterol. A treatment protocol consisting of administration of cholesterol +/- bile acids was initiated in an attempt to correct the biochemical abnormalities seen. Fourteen patients (8 female, 6 male: ages 2 months to 15 years) have now been treated for 6-15 months. Three patients received cholesterol alone, while 11 patients received cholesterol and one or more bile acids. Biochemical improvement in sterol levels and in the ratio of cholesterol to total sterols was noted in all patients. The most marked improvement was noted in patients presenting with initial cholesterol levels < 40 mg/dl. No toxicity was observed. Clinical improvement in growth and neurodevelopmental status was also observed.

Activity of single-agent melphalan 220-300 mg/m2 with amifostine cytoprotection and autologous hematopoietic stem cell support in non-Hodgkin and Hodgkin lymphoma.

High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220-300 mg/m(2) plus amifostine (AF) cytoprotection and AHSCT as part of a phase I-II trial. Median age was 51 years (range 24-62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, 'first-line' AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D +100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL+AF+AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median follow-up in these latter patients of D +1163 (range D +824 to D +1630); one of these patients had a nonmyeloablative allograft as consolidation on D +106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure. Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL+AF+AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens.