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Persons from four generations of a family with mandibulofacial dysostosis (MFD), known as Treacher Collins (TC) Syndrome, were examined for the presence of clinical signs traditionally associated with this syndrome. In this family, 14 adults, who had been judged trait bearers by an earlier family study were included in this study. Maxillary and mandibular study models were taken of affected and unaffected family members. Panoramic cephalograms and lateral radiographs were taken. The lateral cephalograms were traced and digitized on a computer system and compared. The 117 cephalometric values of the trait bearers were compared with known standard values and nontrait bearing family members. In the trait bearing group, 81 of the 117 values and, in the nontrait bearing group, 72 of the 117 values were significantly different (p0.05) when comparing mean values to the accepted normal range. The interfamily comparison between trait-bearing and nontrait members revealed nine values to be significantly different. This indicates that cephalometric analysis of these patients, some of whom have minimal clinical expression of the gene, may have potential value for screening and further characterization of this condition. The results also suggest that intrafamily comparisons may be of greater value for diagnostic confirmation of TC than comparison with literature norms.

BACKGROUND During the 1980s, the Colorado Department of Health received reports from several high-altitude communities of clusters of the malformation craniosynostosis. In a population-based, case-control study, we examined the association between overall and trimester-specific maternal antenatal altitude exposure and the occurrence of infant craniosynostosis. METHODS We identified case children through a statewide registry and randomly sampled control children from birth records. By telephone interview, each mother provided data on the locations of all antenatal residences and places of employment as well as other factors. Staff mapped all locations and abstracted the corresponding altitudes. RESULTS The odds ratio (OR) of any synostosis for a time-weighted mean antenatal altitude of > or = 2000 metres (high altitude) versus < 2000 metres (low altitude) was 1.4 (lower bound of the one-sided 95% test-based confidence interval (CI): 0.9). The OR was elevated in smokers but not in non-smokers. As compared to non-smokers, the OR of any synostosis for high-altitude smokers was 4.6 (lower bound of the 95% one-sided exact CI: 1.7). Particularly elevated were the corresponding OR of coronal (18.1, 4.4) and metopic synostosis (16.3, 2.8), and OR for high-altitude exposure during the second trimester (any synostosis: 6.4, 1.99; coronal: 28.6, 6.1; metopic: 26.7, 4.1). CONCLUSIONS Antenatal maternal high-altitude exposure and smoking are associated with increased risk of infant craniosynostosis, perhaps through generation of intermittent hypoxaemia.

Points to Consider in Preventing Unfair Discrimination Based on Genetic Disease Risk: A Position Statement of the American College of Medical Genetics

Initially thought to be rare, primary lactic acidemia is diagnosed with increasing frequency. Elevations in lactate and pyruvate are markers for a variety of metabolic blocks. Although there have been great strides made in the diagnosis and treatment of lactic acidemia, much remains to be learned. As laboratory techniques improve, clinicians will be able to make an exact enzymatic diagnosis on an increasing percentage of patients. Specific enzymatic diagnosis also will help clinicians determine inheritance patterns, recurrence risks, and methods of prenatal diagnosis.

The progress of nine maple syrup urine disease patients (eight classical, one possible variant) was reviewed to look for similarities in developmental patterns. A consistent developmental profile of stronger Verbal than Performance IQ and lower than familially expected IQ was seen. Younger age at diagnosis was associated with a milder neonatal course. Those who were asymptomatic or suffered mild complications in the newborn period have higher IQs than children experiencing moderate or severe complications. Children with asymptomatic or mild neonatal course also required less special education services. Overall, a picture of ubiquitous motor, visual-analytic and learning deficits is seen.

The risk of maternal phenylketonuria and hyperphenylalaninemia syndrome, a preventable cause of severe birth defects and retardation with a near 100% recurrence risk if untreated, is increasing in the United States.. The reasons for this are reviewed. Women with hyperphenylalaninemia and those with phenylketonuria diagnosed and treated at birth are intellectually normal, as are some women with undiagnosed phenylketonuria. Both groups are at risk for maternal phenylketonuria syndrome in their offspring if blood phenylalanine levels are not controlled by diet during pregnancy. The problems and pitfalls of suspecting, diagnosing, and managing the condition are discussed. Suggested strategies for reversing the increasing trend include the greater use of genetic registers, increased clinical awareness, and some form of rescreening. The advantages and costs of rescreening a subset of pregnant women or all pregnant women at or before their first registration are examined.

Background: In the late 1980s, evidence of an epidemic of craniosynostosis in Colorado included reports of clusters from selected high-altitude communities and an investigation showing the high and rapidly rising rates of surgically corrected synostosis. Some evidence suggested that local diagnostic practice could account for the epidemic. Objective: To determine the contributions of any excess rates of disease occurrence, surgery-based ascertainment, and diagnosis to the reported epidemic. Design: Population-based birth prevalence study with diagnostic evaluation. Setting: The Colorado Department of Health, April 15, 1986, to July 14, 1989. Patients or Other Participants: Children in the Craniosynostosis Registry or state birth record files. Main Outcome Measures: Birth prevalence was estimated from registry and birth record data; case classification by suture type and malformation patterns were determined by review of radiographs and medical records. Results: The period birth prevalence of radiographically confirmed nonsyndromic synostosis was 14.1 per 10 000 live births. Of a total of 605 children, 307 (51%) had definite radiographic evidence of synostosis, for which the intrarater reliability was good (except for the coronal suture on plain films) and the interrater reliability was fair or good (except for the metopic suture on plain films). Between the first and third years, case reports fell from 347 to 103. Conclusions: Diagnostic criteria strongly influenced the rate of synostosis. The rate of radiographically confirmed synostosis was within the range of published estimates. Low diagnostic thresholds, which changed over time, created the semblance of a severe statewide epidemic and may have obscured excess rates of disease at high altitude. Arch Pediatr Adolesc Med. 1997;151:159-164

Sir. —Phenylketonuria (PKU) is an inborn error of metabolism characterized by the inability to hydroxylate phenylalanine (PHE) to tyrosine (TYR). The condition is diagnosed by documentation of elevated serum PHE levels, and typically leads to moderate to severe mental retardation in its untreated form. Individuals with PKU who undergo early dietary PHE restriction usually achieve a full-scale IQ in the normal range. 1 Serum PHE levels of 120 to 480 μmol/L are the typical target values in treatment and constitute good dietary control. Current clinical recommendations and research findings support the need to maintain dietary control throughout childhood. 2-4 For various reasons, monitoring of serum TYR levels is not routine in many metabolic clinics. In our clinic, approximately 38% of patients with PKU who are younger than age 19 years have below-normal serum TYR concentrations (48 μmol/L). This is not clearly correlated with the kind of medical food or diet

A new assay has been developed for 3-hydroxy-3-methylglutaryl-CoA lyase, the final enzyme in the leucine degradative pathway. The assay was performed by incubating lysates of fibroblasts with [glutaryl-3-14C]( d , l )-3-hydroxy-3-methylglutaryl coenzyme A. The products were analysed by high performance liquid chromatography with continuous liquid scintillation counting. This provided simultaneous identification and quantification of one of the enzymatic products, [3-14C] acetoacetic acid. The mean 3-hydroxy-3-methylglutaryl-CoA lyase activity in fibroblasts from five controls was 732 ± 81 (SD) pmol/min · mg protein. Using this assay, we have studied skin fibroblasts cultured from a patient with 3-hydroxy-3-methylglutaric aciduria and found 3% of normal 3-hydroxy-3-methylglutaryl-CoA lyase activity. The activities in skin fibroblasts cultured from the parents were 46 and 53% of control activity which is consistent with heterozygocity. Kinetic studies of 3-hydroxy-3-methylglutaryl-CoA lyase in skin fibroblasts cultured from two normal subjects yielded Km values of 14.4 and 18.8 μmol/l for 3-hydroxy-3-methylglutaryl-CoA.

3-Hydroxy-3-methylglutaric aciduria was found in a newborn infant whose parents are first cousins. The patient presented at 5 days of life with hyperammonemia, hypoglycemia, and metabolic acidosis. There was no ketonuria. Diagnosis was made by analysis of the pattern of organic acids excreted in the urine. A profound deficiency in activity of 3-hydroxy-3-methylglutaryl-coenzyme A lyase was found in cultured skin fibroblasts. The parents had intermediate levels of enzyme activity.

Summary Methionine adenosyltransferase (MAT) I/III deficiency, caused by mutations in the MAT1A gene, is characterized by persistent hypermethioninemia without elevated homocysteine or tyrosine. Clinical manifestations are variable and poorly understood, although a number of individuals with homozygous null mutations in MAT1A have neurological problems, including brain demyelination. We analyzed MAT1A in seven hypermethioninemic individuals, to provide insight into the relationship between genotype and phenotype. We identified six novel mutations and demonstrated that mutations resulting in high plasma methionines may signal clinical difficulties. Two patients—a compound heterozygote for truncating and severely inactivating missense mutations and a homozygote for an aberrant splicing MAT1A mutation—have plasma methionine in the 1,226–1,870 μM range (normal 5–35 μM) and manifest abnormalities of the brain gray matter or signs of brain demyelination. Another compound heterozygote for truncating and inactivating missense mutations has 770–1,240 μM plasma methionine and mild cognitive impairment. Four individuals carrying either two inactivating missense mutations or the single-allelic R264H mutation have 105–467 μM plasma methionine and are clinically unaffected. Our data underscore the necessity of further studies to firmly establish the relationship between genotypes in MAT I/III deficiency and clinical phenotypes, to elucidate the molecular bases of variability in manifestations of MAT1A mutations.

It has recently been shown that 5-azacytidine (5-azaC) can induce altered replication patterns of the late-replicating X chromosome in normal female cells. This has been demonstrated by bromodeoxyuridine labelling of cells late in the S phase. In the present study the same method was applied to the lymphocytes of a Klinefelter patient (48, XXXY/47, XXY). Significant 5-azaC-induced changes in the replication of the entire inactive X chromosome, from late to early, were found in the lymphocytes of this patient. These results indicate that hypomethylating agents can not only alter the replication of individual bands, but also change the gross replication schedule of multiple inactive X chromosomes in the presence of a Y chromosome.

One of twins was bom with prune belly syndrome and congenital heart defect following exposure to Bendectin and Tigan. Red cell antigens and HLA typing were compatible with monozygosity. The possible associations of the prune belly syndrome to monozygotic twinning or to teratogenic agents is considered in light of this patient and review of the literature.

Si, au debut, le diagnostic et le traitement du syndrome de Reye (SR) et des erreurs hereditaires du metabolisme (ECM) qui lui ressemblent sont identiques, ensuite, les recherches diagnostiques, le traitement, le pronostic varient avec la cause sous-jacente. Revue des caracteristiques cliniques et metaboliques pouvant faire suspecter une ECM devant un tableau de SR

In a 9 month infant with the spinal fluid (CSF) NT abnormalities of biopterin synthesis defect we compared treatment with:BH4 high (20 mg/kg/d) dose only; BH4 low (3 mg/kg/d), moderate (10 mg/kg/d) or high dose with the NT precursors dopa/carbidopa (10/1 mg/kg/d) and 5-hydroxytryptophan (5 mg/kg/d); and NT precusors with phenylalanine (phe) restricted diet. Over 4 months we evaluated clinical status, CSF biopterin, CSF NT major metabolites homovanilic acid (HVA), 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol, and CSF NT minor metabolites 3,4-dihydroxy-phenylacetic acid, vanilmandelic acid, m-hydroxyphenylacetic acid (MHPAA), p-hydroxyphenylacetic acid (PHPAA) and indolacetic acid (IAA). Few control values for CSF biopterin and NT major metabolites and none for minor metabolites are known in children. Clinically the patient was well on NT precursors with or without BH4 and deteriorated on BH4 only. Liver enzymes, which were elevated at 4 months on BH4 only, remained normal and blood phe was in good control. CSF biopterin increased to at or above normal with moderate or high dose BH4 but virtually no response of HVA or 5-HIAA independent of NT precursors was seen. BH4 at any but low dose altered the IAA/5-HIAA ratio and BH4 at any dose increased PHPAA but not MHPAA. In this patient, the first in which NT minor metabolites have been measured on BH4, the CSF major metabolites could be maintained at normal levels only with NT precursors but BH4 modified the patterns of minor metabolites.

LISCH NODULES IN AN UNSELECTED POPULATION: PREVALENCE AND USEFULNESS AS INDICATION OF NEUROFIBROMATOSIS