'Deletion rescue' by mitotic 11q uniparental disomy in a family with recurrence of 11q deletion Jacobsen syndrome.

We describe a family with recurrent 11q23-qter deletion Jacobsen syndrome in two affected brothers, with unique mosaic deletion 'rescue' through development of uniparental disomy (UPD) in the mother and one of the brothers. Inheritance studies show that the deleted chromosome is of maternal origin in both boys, and microarray shows a break near the ASAM gene. Parental lymphocyte chromosomes were normal. However, the mother is homozygous in lymphocytes for all loci within the deleted region in her sons, and presumably has UPD for this region. In addition, she is mosaic for the 11q deletion seen in her sons at a level of 20-30% in skin fibroblasts. We hypothesize that one of her #11 chromosomes shows fragility, that breakage at 11q23 occurred with telomeric loss in some cells, but 'rescue' from the deletion occurred in most cells by the development of mitotic UPD. She apparently carries the 11q deletion in her germ line resulting in recurrence of the syndrome. The older son is mosaic for the 11q cell line (70-88%, remainder 46,XY), and segmental UPD11 'rescue' apparently also occurred in his cytogenetically normal cells. This is a novel phenomenon restoring disomy to an individual with a chromosomal deletion.

Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination.

We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes. Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations. Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE. One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation. We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame deletion of 12 amino acids. The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect (one case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation.

Potential growth and drought tolerance of eight desert grasses: lack of a trade-off?

Eight perennial C-4 grasses from the Jornada del Muerto Basin in southern New Mexico show five-fold differences in relative growth rates under well- watered conditions (RGRmax). In a controlled environment, we tested the hypothesis that there is an inverse relationship (trade-off) between RGRmax and the capacity of these species to tolerate drought. We examined both physiological (gas exchange) and morphological (biomass allocation, leaf properties) determinants of growth for these eight species under three steady-state drought treatments (none=control, moderate, and severe). When well watered, the grasses exhibited a large interspecific variation in growth, which was reflected in order-of-magnitude biomass differences after 5 weeks. The species had similar gas-exchange characteristics, but differed in all the measured allocation and morphological characteristics, namely tiller mass and number, root:shoot ratio, dry-matter content, and specific leaf area (SLA). Drought affected tillering, morphology, and allocation, and reduced growth by 50 and 68% (moderate and severe drought, respectively) compared to the well-watered controls. With the exception of SLA, none of these variables showed a significant species-by-treatment interaction. We calculated three indices of drought tolerance, defined as the ratio in final biomass between all the possible "dry"/"wet" treatment pairs: severe/moderate, moderate/control, and severe/control. We found no significant correlation between these drought tolerance indices, on the one hand, and three indices of growth potential (greenhouse RGRmax, final biomass in the control treatment, and final:initial biomass ratio in controls), on the other. Based on these controlled-environment results, we hypothesize that the commonly reported correlation between plant growth potential and drought tolerance in the field may in some cases be explained by differential effects of plants on soil-water content rather than by differences in species responses to drought.

Polytopic anomalies with agenesis of the lower vertebral column.

We describe clinical, pathological and radiological findings in 15 cases of sporadic and familial lower spine agenesis with additional anomalies of the axial skeleton and internal organs and speculate about the cause and pathogenesis of this malformation complex. We show that all of these findings are defects of blastogenesis, originate in the primary developmental field and/or the progenitor fields, thus representing polytopic field defects. This concept appears applicable in our cases and makes such terms such as "caudal regression syndrome" or "axial mesodermal dysplasia spectrum" redundant.

The syndromes of Sotos and Weaver: reports and review.

The syndromes of Sotos and Weaver are paradigmatic of the daily nosologic difficulties faced by clinical geneticists attempting to diagnose and counsel, and to give accurate prognoses in cases of extensive phenotypic overlap between molecularly undefined entities. Vertebrate development is constrained into only very few final or common developmental paths; therefore, no developmental anomaly seen in humans is unique to ("pathognomonic" of) one syndrome. Thus, it is not surprising that prenatal overgrowth occurs in several syndromes, including the Sotos and Weaver syndromes. Are they sufficiently different in other respects to allow the postulation of locus (rather than allele) heterogeneity? Phenotypic data in both conditions are biased because of ascertainment of propositi, and the apparent differences between them may be entirely artificial as they were between the G and BBB syndromes. On the other hand, the Sotos syndrome may be a cancer syndrome, the Weaver syndrome not (though a neuroblastoma was reported in the latter); in the former there is also remarkably advanced dental maturation rarely commented on in the latter. In Weaver syndrome there are more conspicuous contractures and a facial appearance that experts find convincingly different from that of Sotos individuals. Nevertheless, the hypothesis of locus heterogeneity is testable; at the moment we are inclined to favor the hypothesis of allele heterogeneity. An international effort is required to map, isolate, and sequence the causal gene or genes.

Non-steroidal anti-inflammatory drugs fail to enhance healing of acute hamstring injuries treated with physiotherapy.

The effects of two non-steroidal anti-inflammatory drugs (NSAIDs), meclofenamate and diclofenac, in combination with physiotherapy modalities on the rate of healing of acute hamstring muscle tears were studied in a double-blind, placebo-controlled trial. Fourty-four of the 75 patients with this injury recruited were assessed and randomly allocated to one of three treatment groups: meclofenamate (100 mg 3 times a day), diclofenac (50 mg 3 times a day) and placebo. All patients received the same intensive physiotherapy treatment over the 7-day treatment period. Patient assessments were performed on days 1, 3 and 7 of the 7-day study period and included pain assessment (visual analogue scale), swelling measurement (thigh circumference measurement at the site of the muscle tear) and isokinetic muscle performance testing. Treatment produced a significant improvement in all measurements in all groups, but there was no difference in any measurement between groups. However, when only the more severe injuries were analysed, the reported pain score at day 7 was significantly lower in the placebo group than in either the meclofenamate group or the diclofenac group (P < 0.05). Hence this study did not find any additive effect on the healing of acute muscle injuries when meclofenamate or diclofenac was added to standard physiotherapeutic modalities. The study therefore does not support the use of NSAIDs in the treatment of acute hamstring muscle injuries.

Effects of plant size and water relations on gas exchange and growth of the desert shrub Larrea tridentata.

Larrea tridentata is a xerophytic evergreen shrub, dominant in the arid regions of the southwestern United States. We examined relationships between gasexchange characteristics, plant and soil water relations, and growth responses of large versus small shrubs of L. tridentata over the course of a summer growing season in the Chihuahuan Desert of southern New Mexico, USA. The soil wetting front did not reach 0.6 m, and soils at depths of 0.6 and 0.9 m remained dry throughout the summer, suggesting that L. tridentata extracts water largely from soil near the surface. Surface soil layers (<0.3 m) were drier under large plants, but predawn xylem water potentials were similar for both plant sizes suggesting some access to deeper soil moisture reserves by large plants. Stem elongation rates were about 40% less in large, reproductively active shrubs than in small, reproductively inactive shrubs. Maximal net photosynthetic rates (Pmax) occurred in early summer (21.3 µ mol m-2 s-1), when pre-dawn xylem water potential (XWP) reached ca. -1 MPa. Although both shrub sizes exhibited similar responses to environmental factors, small shrubs recovered faster from short-term drought, when pre-dawn XWP reached about -4.5 MPa and Pmax decreased to only ca. 20% of unstressed levels. Gas exchange measurements yielded a strong relationship between stomatal conductance and photosynthesis, and the relationship between leaf-to-air vapor pressure deficit and stomatal conductance was found to be influenced by pre-dawn XWP. Our results indicate that stomatal responses to water stress and vapor pressure deficit are important in determining rates of carbon gain and water loss in L. tridentata.

The Noonan-CFC controversy.

The Noonan syndrome and the cardio-faciocutaneous (CFC) syndrome have been described as phenotypically and genetically distinct entities. However, the resemblance between them led some authors to question the validity of this separation. We review available clinical evidence to support the opposite view, namely, that the Noonan and CFC syndromes are indeed distinct and separate conditions, both falling within the broad and causally heterogeneous spectrum of the Noonan/congenital lymphedema phenotype.

Biological feedbacks in global desertification.

Studies of ecosystem processes on the Jornada Experimental Range in southern New Mexico suggest that longterm grazing of semiarid grasslands leads to an increase in the spatial and temporal heterogeneity of water, nitrogen, and other soil resources. Heterogeneity of soil resources promotes invasion by desert shrubs, which leads to a further localization of soil resources under shrub canopies. In the barren area between shrubs, soil fertility is lost by erosion and gaseous emissions. This positive feedback leads to the desertification of formerly productive land in southern New Mexico and in other regions, such as the Sahel. Future desertification is likely to be exacerbated by global climate warming and to cause significant changes in global biogeochemical cycles.

Factors influencing carbon fixation and water use by mediterranean sclerophyll shrubs during summer drought.

Mediterranean sclerophyll shrubs respond to seasonal drought by adjusting the amount of leaf area exposed and by reducing gas exchange via stomatal closure mechanisms. The degree to which each of these modifications can influence plant carbon and water balances under typical mediterranean-type climate conditions is examined. Leaf area changes are assessed in the context of a canopy structure and light microclimate model. Shifts in physiological response are examined with a mechanistically-based model of C3 leaf gas exchange that simulates progressive reduction of maximum photosynthesis and transpiration rates and increasingly strong midday stomatal closure over the course of drought. The results demonstrate that midday stomatal closure may effectively contribute to drought avoidance, increase water use efficiency, and strongly alter physiological efficiency in the conversion of intercepted light energy to photoproducts. Physiological adjustments lead to larger reductions in water use than occur when comparing leaf area index 3.5 to 1.5, extremes found for natural stands of sclerophyll shrubs in the California chaparral. Reductions in leaf area have the strongest effect on resource capture and use during non-water-stressed periods and the least effect under extreme drought conditions, while shifts in physiological response lead to large savings of water and efficient water use under extreme stress. An important model parameter termed GFAC (proportionality factor expressing the relation of conductance [g] to net photosynthesis rate) is utilized, which changes in response to the integrated water stress experimence of shrubs and alters the degree to which stomata may open for a given rate of carbon fixation. We attempt to interpret this parameter in terms of physiological mechanisms known to modify control of leaf gas exchange during drought. The analysis helps visualize means by which canopy gas exchange behavior may be coupled to physiological changes occurring in the root environment during soil drying.

Atypical phenotype associated with deletion (15) (pter----q11::q13----qter).

We report on a 10-year-old boy with an interstitial deletion within the region of bands 15q11----q13. Authors have associated the manifestation of the Prader-Willi syndrome (PWS) with variable deletions involving the bands q11----q13. Our patient had atypical manifestations not usually associated with PWS, ie, normal stature, proportionally sized hands and feet, normal genitalia, and was nonambulatory and severely mentally retarded. This case emphasized the clinical diversity seen in proximal 15q deletions in the region considered to be correlated with the PWS.

Isochromosome 12p mosaicism (Pallister mosaic aneuploidy or Pallister-Killian syndrome): report of 11 cases.

We report on 11 cases of isochromosome 12p mosaicism (or Pallister mosaic aneuploidy syndrome) in which the isochromosome is usually absent in cultured lymphocytes but present in fibroblasts. The patients range in age from a 22-week-gestation fetus to a 45-year-old man. They have a distinct pattern of anomalies which enables one to make a diagnosis based on clinical manifestations alone. Craniofacial manifestations include "coarse" face with prominent forehead, sparsity of scalp hair, hypertelorism, epicanthal folds, flat bridge of nose, and highly arched palate. Affected newborn infants are profoundly hypotonic with sparsity of scalp hair especially bitemporally and a prominent forehead. Most have accessory nipples. Birthweight and growth parameters are usually normal; however, some newborn infants are unusually large. In infancy, the facial appearance becomes "coarse," hypotonia persists, and seizures may occur. As adults, growth may be normal, scalp hair is thicker and the mandible becomes prominent. Most have a generalized pigmentary dysplasia which may be evident with a Wood's lamp only. All cases have been sporadic and there is no consistent pattern of advanced parental age.

The Montana Fetal Genetic Pathology Program and a review of prenatal death in humans.

Western medicine is being sensitized to the enormous extent of prenatal death in humans at a time when such deaths, occurring after the first missed period, involve to an ever increasing degree wanted pregnancies conceived by women with rising mean maternal age, decreasing mean fertility, and ever greater desire and intention to assure a good pregnancy outcome. Available data suggest that about two-thirds of human ova, embryos, and fetuses fail to reach birth or the end of the first year of life, with infant mortality of 1.06%, stillbirth rate of 8/1,000, abortion rate of about 15%, and death rate around the time of implantation estimated at 34%. Based on limited data on sperm, ova aspirated from Graafian follicles in infertile women, direct observation of a few implanting ova, the low rate of human fecundity, and the high failure rate of in vitro fertilization, it seems reasonable to suppose that about 30% of human ova perish at the time of fertilization and before implantation. Most of this prenatal death is attributable to chromosome abnormalities (aneuploidy and polyploidy), estimated to be present at the beginning of development in about half of all human ova or embryos. Parent's anguish about prenatal death and their desire to understand its causes and to prevent recurrence is putting the medical profession under severe pressure to provide diagnostic and counseling services and make available prenatal diagnosis and preventive approaches; this comes at a low point in the ability of Western medicine to respond adequately, especially in the fields of embryology and developmental genetics, clinical teratology, anatomical pathology, and genetic pathology. Unless drastic ameliorative measures are taken, the situation is likely to get much worse, since health insurance pays for only a minute fraction of costs involved and the number of pediatric pathologists devoting major effort to this work in North America has dwindled to a small number without great hope for replacement from younger ranks, primarily as a result of the lack of incentive by the tertiary centers to make fetal genetic pathology ("morphology") an attractive field to work in. Here we report an effort by a secondary care center to provide such a service--presently more on demand than as systematic effort to reach all at need--in a huge, underpopulated state with birthrate of less than 13,000 and lacking any specially trained pathologist with a strong interest in the field.(ABSTRACT TRUNCATED AT 400 WORDS)

New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome.

Eight patients (4 males, 4 females) were affected with a previously undefined multiple congenital anomalies/mental retardation syndrome which was designated the Cardio-Facio-Cutaneous (CFC) syndrome and which includes congenital heart defects, characteristic facial appearance, ectodermal abnormalities, and growth failure. Cardiac defects were variable, the most common being pulmonic stenosis and atrial septal defect. Typical facial characteristics were high forehead with bitemporal constriction, hypoplasia of supraorbital ridges, antimongoloid slant of palpebral fissures, depressed bridge of nose, and posteriorly angulated ears with prominent helices. The hair was usually sparse and friable. Skin changes varied from patchy hyperkeratosis to a severe generalized ichthyosis-like condition. All cases were sporadic in occurrence, there was no family history of consanguinity, and chromosomes were normal. Although presumed to be genetic, the cause of the CFC syndrome remains unknown.

Hemifacial microsomia, ipsilateral facial palsy, and malformed auricle in two families: an autosomal dominant malformation.

Hemifacial microsomia, ipsilateral facial palsy and anomalies of the auricle were observed in father and son in two families. This combination of anomalies is a causally heterogeneous developmental field defect which may occur rarely as an autosomal dominant trait.

A new autosomal dominant acrofacial dysostosis syndrome.

We report on a family in which a previously undescribed acrofacial dysostosis syndrome is segregating as an autosomal dominant trait. Craniofacial manifestations are those of mild mandibulofacial dysostosis and are quite constant among affected relatives. The acral abnormalities are quite variable, affecting predominantly the radial ray. Variability extends from thumb duplication in one patient to mild hypoplasia of the first metacarpal and first proximal phalanx in most affected individuals. Mandibulofacial dysostosis is a causally nonspecific malformation and as such represents an apparently monotopic developmental field defect. Its occurrence with acral anomalies in several conditions of different cause represents a polytopic developmental field defect.