Clinical care in craniofacial microsomia: a review of current management recommendations and opportunities to advance research.

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM.

Osteopathia striata congenita with cranial sclerosis and intellectual disability due to contiguous gene deletions involving the WTX locus.

Osteopathia striata congenita with cranial sclerosis (OSCS) is a skeletal dysplasia caused by germline deletions of or truncating point mutations in the X-linked gene WTX (FAM123B, AMER1). Females present with longitudinal striations of sclerotic bone along the long axis of long bones and cranial sclerosis, with a high prevalence of cleft palate and hearing loss. Intellectual disability or neurodevelopmental delay is not observed in females with point mutations in WTX leading to OSCS. One female has been described with a deletion spanning multiple neighbouring genes suggesting that deletion of some neighbouring loci may result in abnormal neurodevelopment. In this cohort of 13 females with OSCS resulting from deletions of WTX, a relationship is observed where deletion of ARHGEF9 and/or MTMR8 in conjunction with WTX results in an additional neurodevelopmental phenotype whereas deletion of ASB12 along with WTX is associated with a good neurodevelopmental prognosis.

Combining cariporide with glyceryl trinitrate optimizes cardiac preservation during porcine heart transplantation.

Sodium-hydrogen exchange inhibitors, such as cariporide, are potent cardioprotective agents, however, safety concerns have been raised about intravenously (i.v.) administered cariporide in humans. The aim of this study was to develop a preservation strategy that maintained cariporide's cardioprotective efficacy during heart transplantation while minimizing recipient exposure. We utilized a porcine model of orthotopic heart transplantation that incorporated donor brain death and 14 h static heart storage. Five groups were studied: control (CON), hearts stored in Celsior; CAR1, hearts stored in Celsior with donors and recipients receiving cariporide (2 mg/kg i.v.) prior to explantation and reperfusion, respectively; CAR2, hearts stored in Celsior supplemented with cariporide (10 mumol/L); GTN, hearts stored in Celsior supplemented with glyceryl trinitrate (GTN) (100 mg/L); and COMB, hearts stored in Celsior supplemented with cariporide (10 mumol/L) plus GTN (100 mg/L). A total of 5/5 CAR1 and 5/6 COMB recipients were weaned from cardiopulmonary bypass compared with 1/5 CON, 1/5 CAR2 and 0/5 GTN animals (p = 0.001). Hearts from the CAR1 and COMB groups demonstrated similar cardiac function and troponin release after transplantation. Supplementation of Celsior with cariporide plus GTN provided superior donor heart preservation to supplementation with either agent alone and equivalent preservation to that observed with systemic administration of cariporide to the donor and recipient.

The effects of hormone resuscitation on cardiac function and hemodynamics in a porcine brain-dead organ donor model.

We compared the effects of hormone resuscitation (HR) with a norepinephrine-based protocol on cardiac function, hemodynamics and need for vasopressor support after brain death in a porcine model. Following brain death induction, animals were treated with norepinephrine and fluids for 3 h. In the following 3 h, they continued on norepinephrine and fluids (control) or received additional HR (triiodothyronine, methylprednisolone, vasopressin, insulin). Data were collected pre-brain death, 3 and 6 h post-brain death. At 6 h, median norepinephrine use was higher in controls (0.563 vs. 0 microg/kg/min; p < 0.005), with 6/8 HR animals weaned off norepinephrine compared with 0/9 controls. Mean arterial pressure was higher in HR animals at 6 h (74 +/- 17 vs. 54 +/- 14 mmHg; p < 0.05). Cardiac contractility was also significantly higher in HR animals at 6 h (stroke work index 1.777 vs. 1.494). After collection of 6 h data, all animals were placed on the same low dose of norepinephrine. At 6.25 h, HR animals had higher stroke work (3540 +/- 1083 vs. 1536 +/- 702 mL.mmHg; p < 0.005), stroke volume (37.2 +/- 8.2 vs. 21.5 +/- 9.8 mL; p < 0.01) and cardiac output (5.8 +/- 1.4 vs. 3.2 +/- 1.2 L/min; p < 0.005). HR in a porcine model of brain death reduces norepinephrine requirements, and improves hemodynamics and cardiac function. These results support the use of HR in the management of the brain-dead donor.

Symbolic shape descriptors for classifying craniosynostosis deformations from skull imaging.

Craniosynostosis is a serious condition of childhood, caused by the early fusion of the sutures of the skull. The resulting abnormal skull development can lead to severe deformities, increased intra-cranial pressure, as well as vision, hearing and breathing problems. In this work we develop a novel approach to accurately classify deformations caused by metopic and isolated sagittal synostosis. Our method combines a novel set of symbolic shape descriptors and off-the-shelf classification tools to model morphological variations that characterize the synostotic skull. We demonstrate the efficacy of our methodology in a series of large-scale classification experiments that contrast the performance of our proposed symbolic descriptors to those of traditional numeric descriptors, such as clinical severity indices, Fourier-based descriptors and cranial image quantifications.

Century of Jackson-Weiss syndrome: further definition of clinical and radiographic findings in "lost" descendants of the original kindred.

Jackson-Weiss syndrome (JWS) is a condition consisting of craniosynostosis characterized by premature fusion of the cranial sutures and/or characteristic radiographic anomalies of the feet. The condition is inherited as an autosomal dominant trait with high penetrance and variable expressivity. Six different mutations in the fibroblast growth factor receptor 2 have been identified in patients with the clinical diagnosis of JWS. Jabs et al. [1994: Nat Genet 8:275-279] identified an Ala344Gly substitution in two branches of the family in which the clinical syndrome was originally described. This is the only publication to document this mutation in a family with the clinical diagnosis of JWS. In this study, we have identified a previously unrecognized branch of the original family with individuals that meet the clinical criteria for the diagnosis of JWS. We demonstrate that a mutation that produces the Ala344Gly substitution is present in affected members. This family illustrates the widely variable expression of the mutation, including a novel phenotype in the proband with a leg-length discrepancy and unilateral absence of the fifth digital ray in her right foot. We identify the clinical and detailed radiographic features of each affected individual and offer considerations when making the diagnosis of JWS.

12-year-old male with Elejalde syndrome (neuroectodermal melanolysosomal disease).

Neuroectodermal melanolysosomal disease, also known as Elejalde syndrome, is a rare syndrome characterized by silvery hair, pigment abnormalities, and profound central nervous system dysfunction. It is similar to the Chediak-Higashi and Griscelli syndromes, although these syndromes are associated with severe immunologic dysfunction. We report on a 12-year-old male with Elejalde syndrome and compare the Elejalde, Chediak-Higashi, and Griscelli syndromes.

Deuterium NMR investigation of an amphotericin B derivative in mechanically aligned lipid bilayers.

The methyl-d(3) amide derivative of the polyene antibiotic amphotericin B was synthesized, assayed for biological activity, incorporated into mechanically aligned bilayers of dipalmitoylphosphatidylcholine (DPPC), and examined by deuterium and phosphorus NMR. The amide derivative has a lesser, but qualitatively similar, biological activity relative to amphotericin B. Incorporation of the amide derivative and ergosterol into aligned DPPC bilayers resulted in a single, stable bilayer phase, as shown by phosphorus NMR of the DPPC headgroups. Deuterium NMR spectra revealed one major (2)H quadrupolar splitting and one major (2)H-(1)H dipolar splitting in the liquid-crystalline phase, consistent with a high degree of alignment and a single, averaged physical state for amphotericin B methyl-d(3) amide in the bilayer. Variations of the quadrupolar and dipolar splittings as a function of macroscopic sample orientation and temperature indicated that the amide derivative undergoes fast rotation about a motional axis that is parallel to the bilayer normal.

Retrospective multicenter study of an anodized, tapered, diminishing thread implant: success rate at exposure.

Performance of a new tapered, threaded implant at exposure was evaluated retrospectively using conservative assessment criteria. The criteria used were intended to ensure that an implant in the early stages of failing as well as those implants that have clearly failed would be identified as such. These results reflect an evaluation preliminary to comparing the performance of the implant at exposure and its performance (i.e., success rate) observed after longer periods (i.e., > or = 1 year) of loaded service. Data from 663 patients treated in the setting of the authors' private practice offices were evaluated to assess the performance of the implant under representative "clinical practice" usage conditions. The implant success/failure criteria were prospectively defined and applied to data obtained in a masked fashion from patients' records. Neither the dentist nor personnel involved in the analysis of the data were aware of which patients were qualified for and included into the study. Of 1100 implants available for evaluation, 15 implants failed at or before exposure. The success rate at exposure was 98.6%. There was no correlation between the anatomical region in which an implant was placed and the incidence of implant failure. Implants placed in fresh extraction sites and/or grafted sites appeared to be more likely to fail at exposure. Conversely, the failure rate of implants placed using a single-stage surgical procedure was comparable to that of implants placed using a conventional two-stage surgical methodology. Immediately loaded implants experienced a success rate comparable to that of implants placed using conventional two-stage surgical procedures. Factors under the clinician's control may play a substantial role in determining implant performance at exposure.

A physical and transcriptional map of the preaxial polydactyly locus on chromosome 7q36.

Preaxial polydactyly is a congenital hand malformation that includes duplicated thumbs, various forms of triphalangeal thumbs, and duplications of the index finger. A locus for preaxial polydactyly has been mapped to a region of 1.9 cM on chromosome 7q36 between polymorphic markers D7S550 and D7S2423. We constructed a detailed physical map of the preaxial polydactyly candidate region. With a combination of methods we identified and positioned 11 transcripts within this map. By recombination analysis on families with preaxial polydactyly, using newly developed polymorphic markers, we were able to reduce the candidate region to approximately 450 kb. The homeobox gene HLXB9, a putative receptor C7orf2, and two transcripts of unknown function, C7orf3 and C7orf4, map in the refined candidate region and have been subjected to mutation analysis in individuals with preaxial polydactyly.

GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease.

Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1.

Chromosome abnormalities in congenital heart disease.

Refinements in cytogenetic techniques have promoted progress in understanding the role that chromosome abnormalities play in the cause of congenital heart disease. To determine if mutations at specific loci cause congenital heart disease, irrespective of the presence of other defects, and to estimate the prevalence of chromosome abnormalities in selected conotruncal cardiac defects, we reviewed retrospectively cytogenetic and clinical databases at St. Louis Children's Hospital. Patients with known 7q11.23 deletion (Williams syndrome), Ullrich-Turner syndrome (UTS), and most autosomal trisomies were excluded from this analysis. Two groups of patients were studied. Over a 6.5-year period, 57 patients with chromosomal abnormalities and congenital heart disease were identified. Of these, 37 had 22q11 deletions; 5 had abnormalities of 8p; and 15 had several other chromosome abnormalities. The prevalence of chromosome abnormalities in selected conotruncal or aortic arch defects was estimated by analysis of a subgroup of patients from a recent 22-month period. Chromosome abnormalities were present in 12% of patients with tetralogy of Fallot, 26% in tetralogy of Fallot/pulmonary atresia, 44% in interrupted aortic arch, 12% in truncus arteriosus, 5% in double outlet right ventricle, and 60% in absent pulmonary valve. We conclude that chromosome analysis should be considered in patients with certain cardiac defects. Specifically, fluorescent in situ hybridization (FISH) analysis of 22q11 is indicated in patients with conotruncal defects or interrupted aortic arch. High resolution analysis should include careful evaluation of the 8p region in patients with either conotruncal or endocardial cushion defects.

Chromosome 18q22.2-->qter deletion and a congenital anomaly syndrome with multiple vertebral segmentation defects.

Multiple vertebral segmentation defects occur in a group of conditions variably associated with anomalies of other organ systems. This report describes a female child in whom a deletion of chromosome 18 (18q22.2-->qter) is associated with congenital anomalies including multiple vertebral segmentation defects resembling sporadic spondylocostal dysplasia. The child also has unilateral renal agenesis and unilateral fibular aplasia. The association of severe multiple vertebral segmentation defects with 18q- in this patient suggests the possibility that a gene important for somite formation or vertebral differentiation maps to this segment of chromosome 18.

Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly.

Holoprosencephaly (HPE) is a genetically and phenotypically heterogenous disorder involving the development of forebrain and midface, with an incidence of 1:16,000 live born and 1:250 induced abortions. This disorder is associated with several distinct facies and phenotypic variability: in the most extreme cases, anophthalmia or cyclopia is evident along with a congenital absence of the mature nose. The less severe form features facial dysmorphia characterized by ocular hypertelorism, defects of the upper lip and/or nose, and absence of the olfactory nerves or corpus callosum. Several intermediate phenotypes involving both the brain and face have been described. One of the gene loci, HPE3, maps to the terminal band of chromosome 7. We have performed extensive physical mapping studies and established a critical interval for HPE3, and subsequently identified the sonic hedgehog (SHH) gene as the prime candidate for the disorder. SHH lies within 15-250 kilobases (kb) of chromosomal rearrangements associated with HPE, suggesting that a 'position effect' has an important role in the aetiology of HPE. As detailed in the accompanying report, this role for SHH is confirmed by the detection of point mutations in hereditary HPE patients.

Mapping human telomere regions with YAC and P1 clones: chromosome-specific markers for 27 telomeres including 149 STSs and 24 polymorphisms for 14 proterminal regions.

A YAC library enriched for telomere clones was constructed and screened for the human telomere-specific repeat sequence (TTAGGG). Altogether 196 TYAC library clones were studied: 189 new TYAC clones were isolated, 149 STSs were developed for 132 different TY-ACs, and 39 P1 clones were identified using 19 STSs from 16 of the TYACs. A combination of mapping methods including fluorescence in situ hybridization, somatic cell hybrid panels, clamped homogeneous electric fields, meiotic linkage, and BLASTN sequence analysis was utilized to characterize the resource. Forty-five of the TYACs map to 31 specific telomere regions. Twenty-four linkage markers were developed and mapped within 14 proterminal regions (12 telomeres and 2 terminal bands). The polymorphic markers include 12 microsatellites for 10 telomeres (1q, 2p, 6q, 7q, 10p, 10q, 13q, 14q, 18p, 22q) and the terminal bands of 11q and 12p. Twelve RFLP markers were identified and meiotically mapped to the telomeres of 2q, 7q, 8p, and 14q. Chromosome-specific STSs for 27 telomeres were identified from the 196 TYACs. More than 30,000 nucleotides derived from the TYAC vector-insert junction regions or from regions flanking TYAC microsatellites were compared to reported sequences using BLASTN. In addition to identifying homology with previously reported telomere sequences and human repeat elements, gene sequences and a number of ESTs were found to be highly homologous to the TYAC sequences. These genes include human coagulation factor V (F5), Weel protein tyrosine kinase (WEE1), neurotropic protein tyrosine kinase type 2 (NTRE2), glutathione S-transferase (GST1), and beta tubulin (TUBB). The TYAC/P1 resource, derivative STSs, and polymorphisms constitute an enabling resource to further studies of telomere structure and function and a means for physical and genetic map integration and closure.

Male-male courtship behavior induced by ectopic expression of the Drosophila white gene: role of sensory function and age.

Male-male courtship behavior was recently reported to be induced in large populations of Drosophila (e.g., 600-1500 flies) by ectopic expression of the white (w) gene. Little is known about the basis of this behavior; in male-female courtship, sensory cues are believed to play an important role. Previous data are consistent with the possibility that misexpression of w causes abnormal reception or processing of sensory information. We show here that w-induced male-male courtship occurs in isolated pairs of flies. Thus the behavior does not depend on sensory cues found only among large populations of flies, or on cues produced only by a small subset of such populations. This finding enabled quantitative analysis of mechanisms that underlie the behavior. Specifically, male-male courtship does not depend on the reception of olfactory information, nor on the reception or generation of auditory cues, as determined by surgical ablation of antennae, maxillary palps, or wings. Although the rapid onset of the behavior following w induction suggested that its basis could lie in a modulation of sensory physiology, we found visual, olfactory, and gustatory function to be normal in physiological or behavioral tests. The only sensory deprivation to produce an effect on male-male courtship was testing under dim red light; the percentage of flies courting another male was reduced to one-fourth of control values. A striking age dependence of the behavior is also documented: courtship between paired male mini-w+ flies was not observed in tests of very young (1-day-old) flies, but occurs at high levels between the ages of 1 and 4 weeks.

Linkage of preaxial polydactyly type 2 to 7q36.

We have characterized a 6-generation North American Caucasian kindred segregating one form of preaxial polydactyly type 2 (PPD-2). We demonstrate linkage to the 7q36 region and describe a submicroscopic telomeric chromosomal deletion in phase with the PPD-2 phenotype. Recently, several kindreds segregating triphalangeal thumb (TPT) with and without associated hand anomalies (syndactyly and/or postaxial polydactyly) have also been linked to the subtelomeric region of chromosome 7q [Heutink et al., 1994: Nat Genet 6:287-291; Tsukurov et al., 1994: Nat Genet 6:282-286]. We demonstrate by haplotype analysis that our North American pedigree represents a PPD allele that is independent of the founder PPD allele present in the previously described kindreds.

An investigation of the ligand-binding site of the glutamine-binding protein of Escherichia coli using rotational-echo double-resonance NMR.

Glutamine-binding protein (GlnBP) is an essential component of the glutamine transport system in Escherichia coli. Rotational-echo double-resonance (REDOR) solid-state nuclear magnetic resonance (NMR) has been used to determine internuclear distances in the complex of GlnBP and its ligand, L-glutamine. REDOR, combined with strategically placed isotopic labels, is effective in obtaining model-independent internuclear distances and thus detailed structural information on the ligand-binding site of GlnBP. The existence of a single histidine residue (His156) in the binding site has provided an excellent probe for distance measurements between protein and ligand. REDOR distances up to 6.3 A have been observed between 13C labels in L-glutamine and 15N labels in His156. These results have unambiguously determined the ligand orientation with respect to the imidazole ring of His156, which is an important first step in refining the ligand-binding-site model of GlnBP in general. The measured distances were also used as constraints in restrained molecular dynamics calculations of the complex using the unliganded crystal structure of GlnBP as the starting point. The simulations clearly show consistency between calculated distances and those measured by REDOR.