De novo partial duplications 1p: report of two new cases and review.

We describe two de novo intrachromosomal duplications of 1p. One case is a dir ins dup(1)(q21p21p31) in a newborn girl with low birth weight, growth retardation, and tetralogy of Fallot. The other is a 10-month-old girl with developmental delay, craniosynostosis, plagiocephaly, and an inv dup 1p34.1p31. Although, these patients have manifestations in common with previous cases, they do not establish a syndrome. Interestingly, all males with duplications spanning 1p31 had genital anomalies, whereas females with duplications of the same region had normal genitalia. Thus, genes within 1p31 appear to control the development of male genitalia and tentatively exclude effects of tda1, a sex-determining gene in a region of mouse chromosome 4 syntenic to 1p36 in man. However, it is necessary to identify the human tda1 homologue and candidate genes within 1p31 before drawing final conclusions.

Identification of four novel mutations in patients with carnitine palmitoyltransferase II (CPT II) deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency, an autosomal recessive disorder of fatty-acid oxidation, presents as three distinct phenotypes (neonatal, infantile, and adult onset). In order to investigate the molecular basis of these three phenotypes, six patients with CPT II deficiency have been studied. All six unrelated patients in this study experienced the clinical symptoms of CPT II deficiency. Three patients had the neonatal form, one had the milder infantile form, and the remaining two had the adult-onset form with "muscular" symptoms only. Their diagnoses were based upon in vitro analysis of the mitochondrial beta-oxidation pathway in fibroblasts and standard enzyme assays. We devised a method to screen the entire coding sequence and flanking splice junction of the CPT II gene. A total of six different mutations have been identified, including four novel mutations. Among them, the previously reported common mutation, S113L, was only found in 3 of 12 variant alleles. Three of the six mutations have been identified in a few unrelated patients, while the remaining three have been found in single families. This study, as well as those by others, indicates genetic heterogeneity in this disease. In addition to tabulating the mutations, the correlation of mutant genotype to clinical phenotype is briefly discussed.

A novel mutation identified in carnitine palmitoyltransferase II deficiency.

Carnitine palmitoyltransferase II (CPT II) deficiency is an autosomal recessive disorder of mitochondrial fatty-acid oxidation which presents as three distinct phenotypes (neonatal, infantile, and adult onset). CPT II exons from an adult-onset CPT II-deficient patient were amplified and directly sequenced to further investigate the molecular basis of this disorder. A novel mutation, C471T, in exon 4 of the carnitine palmitoyltransferase II gene was found which created a stop codon, TGA, at residue 124 of the protein (R124Stop). This mutation would result in severe protein truncation. This unique mutation was found on one allele while the S113L mutation, previously reported, was present on the other allele.

"De novo" duplication Xq23-->Xq26 of paternal origin in a girl with a mildly affected phenotype.

We report a de novo dup(X)(q23-->q26) in a 3-year-old girl with growth retardation, developmental delay, and minor anomalies. X-inactivation in lymphocytes by BRDU labeling showed the abnormal X was late replicating. The androgen receptor assay (HAR) demonstrated a skewed methylation (88.8%) of the paternal allele and a 11.2% methylation of the maternal allele. These data, which suggest the duplication was paternally inherited, are the first parental-origin identification of a duplication Xq. The mild phenotype of the patient may be related to the size and region of the duplication, the low percentage of a dup(X) active detected by the HAR assay, or a combination of these mechanisms.

Interstitial deletions 4q21.1q25 and 4q25q27: phenotypic variability and relation to Rieger anomaly.

We describe clinical and chromosomal findings in two patients with del(4q). Patient 1, with interstitial deletion (4)(q21.1q25), had craniofacial and skeletal anomalies and died at 8 months of hydrocephalus. Patient 2, with interstitial deletion (4)(q25q27), had craniofacial and skeletal anomalies with congenital hypotonia and developmental delay. These patients shared certain manifestations with other del(4q) patients but did not have Rieger anomaly. Clinical variability among patients with interstitial deletions of 4q may be related to variable expression, variable deletion, or imprinting of genes within the 4q region.

Clasped-thumb mental retardation (MASA) syndrome: confirmation of linkage to Xq28.

We describe a 5-generation Hispanic family with 13 males and 1 female affected with MASA syndrome. The proposita, a 17-year-old female, and her affected male relatives shared many of the cognate manifestations--mental retardation (14/14), aphasia or delayed speech (13/13), shuffling gait (8/13), adduction of thumbs (14/14)--as well as scoliosis (2/13) and increased deep tendon reflexes in the lower extremities (10/13). Southern analysis with the polymorphic DNA probes DXS14 (Xp11), DXS72 (Xq21), and F8C (Xq28) confirmed linkage to the Xq28 region with a maximum lod score of 3.01 for this family.

Faecal steroids and colorectal cancer: steroid profiles in subjects with adenomatous polyps of the large bowel.

In this necroscopy study the relation between carriage and size of colorectal polyps was correlated with luminal steroid concentrations in respect to malignant risk. Of the 92 subjects entered into the study, 68 had adenomatous polyps of the large bowel, of which 19 had adenomas > 0.9 cm in diameter (large adenomas), 26 in the range 0.5-0.9 cm in diameter (medium adenomas) and 23 of 0.4 cm or less in diameter (small adenomas). Sixty-three percent of subjects carrying large adenomas and 26% of persons carrying small adenomas had an abnormal ratio (> 1.0) of lithocholic acid to deoxycholic acid in intestinal contents as compared to 17% of the adenoma-free comparison group (n = 24). These findings support the suggestion that the ratio of lithocholic acid to deoxycholic acid as a faecal marker may be a useful adjunct to screening procedures for colorectal cancer.

Abnormalities of differentiation and maturation in the oesophageal squamous epithelium of patients with tylosis: morphological features.

Tylosis is an autosomal dominant inherited defect of keratinization, associated in two Liverpool families with a high risk of developing oesophageal squamous carcinoma. In 29 individuals, followed by regular endoscopy and biopsy, we have noted several morphological abnormalities of the epithelium in this pre-cancerous condition. A control group of 43 non-tylotic patients with normal oesophageal histology and a further 26 patients with acute oesophagitis was used for comparison. Recognizable dysplasia was confined to the older age range in the tylotic group and was present in four patients. Almost half of the patients showed acute inflammation. Abnormalities of maturation were common, the most frequent being the presence of prominent basophilic inclusions and clear cell acanthosis, with parakeratosis and frank surface keratinization present in smaller numbers. There was, however, no statistically significant difference between the tylotic and inflamed control groups for any of these features. The only feature to show a significant difference between these groups was the presence of individual cell keratinization. The results suggest that in the oesophageal epithelium of the patients with tylosis, inflammation is the predominant abnormality, together with individual cell keratinization, and that these lesions appear in a much younger age group than dysplasia.

Chromosomal deletion 4p15.32----p14 in a Treacher Collins syndrome patient: exclusion of the disease locus from and mapping of anonymous DNA sequences to this region.

Treacher Collins syndrome is an autosomal dominant condition of bilateral craniofacial abnormalities of structures derived from the first and second branchial arches. A patient with severe manifestations of Treacher Collins syndrome and a de novo chromosomal deletion in region 4p15.32----p14 was identified. Anonymous DNA sequences of loci D4S18, D4S19, D4S20, D4S22, and D4S23 were mapped to the deleted region. DNA probes previously mapped to loci on chromosome 4p (D4S10, D4S15, D4S16, D4S26, D4S35, D4S95, D4S144, RAF1P1, QDPR, and HOX7) were not deleted in this patient. Linkage analysis between the D4S18, D4S23, and QDPR loci and Treacher Collins syndrome in eight families excluded the Treacher Collins syndrome locus from the region of the deletion.

Tetrasomy 9p: an emerging syndrome.

An infant with non-mosaic 9p tetrasomy is described. The tetrasomy apparently results from a translocation involving the 9qh region. All the cells analyzed from multiple banding techniques from lymphocyte culture as well as skin fibroblast culture were 9p tetrasomic. The infant, who had the characteristic dysmorphic features of 9p tetrasomy, survived for 2 months. Prominent features included: low birth weight, severe retardation, brachycephaly with large anterior fontanelle, hypertelorism with short bilateral palpebral fissures, beaked nose, bilateral cleft lip and palate, and low-set, malformed ears. Skeletal anomalies, ambiguous genitalia and heart defect were also observed. These features are highly characteristic of the 9p tetrasomy syndrome based on six pure tetrasomy and four cases of tetrasomy that included part of the 9qh region.

A study of medical costs associated with selected genetic disorders in Texas.

We estimated that the payments associated with the 11 selected diseases during 1987 in Texas included $88.2 million from Medicaid and $10.6 million from CIDC for a total of $98.8 million. Patients with these diseases represented 0.83% of Medicaid claims, but 4.68% of Medicaid payments. Medicaid payments for genetic services for patients with these 11 selected disorders in Texas during a nine-month period in 1987 were $10,122, or 0.02% of the total Medicaid payments for these claimants. We conclude that our estimate of the Medicaid payments for these disorders in 1987 of nearly $100 million represents a low estimate of the true medical costs for the care of these patients. This study also indicates that these 11 disorders represent a disproportionate share of Medicaid payments; i.e., these patients show a high ratio of payment per claim. We also conclude from these data that CIDC is a significant source of support for the medical care of these patients in Texas. And, finally, this study suggests that referral for genetic services represents a significant barrier for individuals in need of these services.

Needs assessment for genetic services in Texas.

In summary, we found that the availability of genetic services for the Medicaid patients with the 11 selected disorders follow the general population distribution for Texas. In general, there is no major geographic factor limiting availability of services. We also found that the calculation of Medicaid dollars paid according to the size of the metropolitan area in which the patient resides indicates that there are fewer Medicaid dollars spent on these 11 genetic disorders per person in the population in the larger metropolitan areas. We conclude that preliminary review of these data indicate that the urban poor may have a greater need for medical services that deal with genetic disease.

Effects of a somatostatin analogue (SMS 201-995) on the growth and development of hepatic tumour derived by intraportal injection of Walker cells in the rat.

Administration of a long active analogue of somatostatin, SMS 201-995 (2 micrograms subcutaneously twice a day) for 3 weeks after intraportal administration of Walker cells significantly inhibited their growth and development in the liver. This was not due to a direct cytotoxic effect of the analogue on Walker cells whose growth was stimulated in vitro. Furthermore, SMS 201-995 had no effect on the growth of Walker cells implanted into the thigh of rats suggesting that the inhibitory action of the analogue could be confined to tumour cells growing in the liver. Further studies suggested that the inhibitory effect of SMS 201-995 on the growth of Walker cells in the liver could be related to a marked stimulation of the hepatic reticuloendothelial system, by a reduction in portal venous flow in the early stages of treatment or by a combination of these effects. Further studies are required to delineate more precisely the mechanism whereby SMS 201-995 inhibits the growth of hepatic tumour derived from intraportal administration of Walker cells.

Patterns of colonisation of Campylobacter pylori in the oesophagus, stomach and duodenum.

Thirty five subjects underwent upper gastrointestinal endoscopy and multiple biopsy (30 patients, five normal subjects). A total of 11 biopsies per subject from four sites (oesophagus (three), gastric body (two), antrum (three), duodenum (three] were examined for inflammation and the presence of Campylobacter pylori and using standard methods of culture and by light (LM) and electron microscopy (EM). The organism was cultured from oesophageal biopsies in eight of 30 (27%) patients but could not be identified at this site by LM or EM. There was evidence of oesophageal inflammation in 20 patients which was associated with the local finding of C pylori in five (25%) including two of seven (29%) with Barrett's mucosa. Antral C pylori was present in 22 of 23 (96%) patients with chronic active gastritis. The organism was found in the antrum and oesophagus in four of 22 patients (18%), in the antrum and duodenum in four of 22 patients (18%) and in all three sites in a further two of 22 patients (9%). Antral C pylori was found in five of six patients with peptic ulceration. C pylori was cultured from the duodenum in six patients with confirmation by LN and EM in three, but only on areas of gastric metaplasia. The organism was not found in the normal group. This study indicates that C pylori may be irregularly isolated from the oesophagus and duodenum in patients with antral C pylori and chronic active gastritis. The role of C pylori in the oesophagus is most likely that of a commensal or contaminant.

Changes in the hepatic perfusion index during the development of experimental hepatic tumours.

A model of microscopic liver tumour has been developed in the Fisher rat by intraportal injection of 1.6 x 10(7) Walker 256 carcinosarcoma cells. Rats were studied at 2, 4 and 6 days after the inoculation of live Walker cells. A control group received dead Walker cells. No tumour was visible in control groups at 2, 4 and 6 days after inoculation. Similarly in rats injected with live cells no tumour was visible at 2 days after inoculation but at 4 and 6 days the percentage hepatic replacement was (mean +/- s.d.) 7.0 +/- 2.3 and 27.9 +/- 6.80 respectively. The hepatic perfusion index was significantly raised at 4 and 6 days after inoculation of live cells compared with control animals and those receiving viable cells after 2 days inoculation. Portal flow and portal venous inflow were significantly reduced when the hepatic perfusion index increased but hepatic arterial flow did not alter. Changes in the hepatic haemodynamics were accompanied by increases in the portal and splanchnic vascular resistance and an increase in the amount of arteriovenous shunting through the liver. These findings confirm studies that the hepatic perfusion index is useful in the detection of occult liver metastases but that the change is not a consequence of an increase in the hepatic arterial flow.

Familial transmission of 16p trisomy in an infant.

Based on four reported cases including the present case, 16p trisomic infants have remarkably similar features. These are severe developmental delay, psychomotor retardation, typical facies, and anomalies of extremities.