Short report: Hyperammonaemia in critically ill septic infants.

Three infants with subphrenic abscess, pyonephrosis, and obstructive ureterocoele respectively had grossly increased concentrations of plasma ammonia. This was considered to be a result of infections with urea splitting organisms. All died in spite of intensive care support, including specific measures to reduce plasma ammonia.

Organisation of the human PAX4 gene and its exclusion as a candidate for the Wolcott-Rallison syndrome.

Neonatal diabetes mellitus is a rare condition, the causes of which are mostly unknown. One well defined though very rare entity is the autosomal recessive Wolcott-Rallison syndrome, in which permanent neonatal diabetes, osteopenia, and epiphyseal dysplasia occur. Only five previous families have been reported, and here we describe the second in which parental consanguinity was present. The proband was born to first cousin parents and died at 2 years from the sequelae of poorly controlled diabetes. To test the hypothesis that mutation of PAX4, required in the mouse for pancreatic islet beta cell development, might cause WRS, the structure of the human PAX4 gene was deduced and DNA from two unrelated WRS patients sequenced. No PAX4 mutation was present, though the entire coding region was sequenced in both patients. It therefore appears unlikely that PAX4 is involved in the aetiology of Wolcott-Rallison syndrome, though it remains a good candidate for other forms of neonatal diabetes mellitus.

GNAS1 mutational analysis in pseudohypoparathyroidism.

OBJECTIVE: Mutations of the GNAS1 gene, which is located on chromosome 20q13.11 and encodes the alpha-subunit of the stimulatory GTP-binding protein, have been identified in patients with pseudohypoparathyroidism type Ia (PHPIa) and pseudopseudohypoparathyroidism (PPHP). We have undertaken studies to determine the prevalence of GNAS1 mutations and to explore methods for their more rapid detection. METHODS: Thirteen unrelated families (8 with PHPIa and PPHP patients, and 5 with PPHP patients only) were investigated for GNAS1 mutations in the 1050 base-pair (bp) region spanning exons 2-13 by single-stranded conformational polymorphism (SSCP) and DNA sequence analysis. RESULTS: GNAS1 mutations were detected in 4 of the 8 families with PHPIa patients. These consisted of: two novel de novo missense mutations (Pro115Ser and Glu259Val) in two families and an identical 4 bp deletion of codons 189 and 190 resulting in a frame-shift in two unrelated families. These results expand the spectrum of GNAS1 mutations associated with this disorder and confirm the presence of a mutational hot-spot involving codons 189 and 190. SSCP analysis was found to be a specific and sensitive method that detected all 4 mutations. GNAS1 mutations were not detected in any of the PPHP only families. CONCLUSIONS: The pseudohypoparathyroid disorders appear to represent a heterogeneous group with GNAS1 mutations forming the molecular aetiology in approximately 50% of pseudohypoparathyroidism type Ia families. Such mutations can be reliably identified by single-stranded conformational polymorphism and this will help to supplement the clinical evaluation of some patients and their families, particularly as the disease may not be fully penetrant.

Neurogenic chronic idiopathic intestinal pseudo-obstruction, patent ductus arteriosus, and thrombocytopenia segregating as an X linked recessive disorder.

We present a family with three affected males in two generations with congenital neurogenic chronic idiopathic intestinal pseudo-obstruction (CIIP), patent ductus arteriosus, and large platelet thrombocytopenia apparently segregating as an X linked recessive disorder. The pattern of segregation of DNA markers within the family is consistent with linkage to the previously described neurogenic CIIP (CIIPX) locus at Xq28. This combination may represent a new contiguous gene disorder and appears to have a good prognosis with supportive therapy.

Evolution of pseudohypoparathyroidism: an informative family study.

An adult woman with pseudopseudohypoparathyroidism had a child with normal calcium and parathyroid hormone concentrations and cyclic AMP response to injected parathyroid hormone in infancy. By 2.5 years he had features of pseudohypoparathyroidism with raised parathyroid hormone and 'flat' cyclic AMP response. This is the first documented case of a change in parathyroid hormone responsiveness. The abnormal cyclic AMP response to parathyroid hormone in pseudohypoparathyroidism can evolve during childhood.

Rhizomelic chondrodysplasia punctata with isolated DHAP-AT deficiency.

An infant with the characteristic phenotype of classical rhizomelic chondrodysplasia punctata was found to have an isolated deficiency of the peroxisomal enzyme acyl CoA dihydroxyacetone phosphate acyltransferase (DHAP-AT). All other peroxisomal functions measured were found to be normal. Previously described in one other case report, this confirms the existence of another distinct form of peroxisomal disorder characterised biochemically by a deficiency in de novo plasmalogen biosynthesis only.

Nager acrofacial dysostosis: minor familial manifestations supporting dominant inheritance.

We report on a girl with Nager acrofacial dysostosis, three of whose relatives had variable mild anomalies of the thumb. The possible relationship of such minor features to the radial limb anomalies in the proposita provides further evidence that the Nager syndrome can be the manifestation of a dominantly inherited disorder with very variable expressivity.

Parental consanguinity in the blepharophimosis, heart defect, hypothyroidism, mental retardation syndrome (Young-Simpson syndrome).

In 1987 Young and Simpson reported a child with hypothyroidism, congenital heart disease, severe mental retardation, and striking facial dysmorphism. Two subsequent reports have described patients sharing some of the features of their case, although in both there were enough discordant features to make it uncertain that the same entity was being described. Here we present a female infant with virtually identical features to Young and Simpson's original case. Her Caucasian parents are first cousins, raising the possibility of autosomal recessive inheritance of this new syndrome.

Outcome in tyrosinaemia type II.

Tyrosinaemia type II was diagnosed in a boy with failure to thrive and in his sister on neonatal screening. On diet the outcome, at 12 and 10 years respectively, has been excellent in respect of oculocutaneous sequelae, growth, and psychomotor development, contrasting with the generally unfavourable outcome in most reported cases.

Familial growth hormone releasing factor deficiency in pseudopseudohypoparathyroidism.

A mother with pseudopseudohypoparathyroidism and her short son showed poor spontaneous growth hormone secretion, and provocation tests suggested a deficiency of growth hormone releasing factor. This is the first report of growth hormone releasing factor deficiency in pseudopseudohypoparathyroidism. The boy has responded well to growth hormone treatment over a period of three years.

Plasma cyclic AMP response to intravenous parathyroid hormone in pseudohypoparathyroidism.

Highly purified bovine parathyroid hormone (PTH) was given by intravenous bolus injection to patients being investigated for disorders of mineral metabolism, and to adult volunteer controls. Plasma cyclic AMP measured basally and at 10 min gave reliable discrimination between the normal response and cases of pseudohypoparathyroidism. Infants under 3 months of age tended to have higher basal levels of cAMP and a flatter pattern of response to the dose of PTH used. This simplified test procedure in children offers considerable advantages over previous tests of PTH responsiveness which involve urine collections and multiple blood sampling. It is suitable for selective screening of individuals suspected of pseudohypoparathyroidism on the basis of their family history or physical abnormalities.

Mineral balance in infantile cortical hyperostosis: effects of corticosteroids.

The effects on mineral metabolism of therapeutic doses of corticosteroids were investigated in infantile cortical hyperostosis; in four untreated cases the calcium, phosphorus, and magnesium balances were strongly positive. In one severe case, treatment with prednisolone was associated with an alteration to negative calcium and magnesium balance, and faecal losses of calcium were particularly high. This effect persisted for at least three months after the steroids had been discontinued, and during this period there was pronounced retardation of linear growth. Six months after the treatment had been stopped mineral balance was again positive and there was rapid 'catch up' in growth. In infancy, the negative effect of corticosteroids on calcium, phosphorus, and magnesium metabolism may contribute to inhibition of bone growth and steroid stunting.

Transient neonatal hyperparathyroidism secondary to maternal pseudohypoparathyroidism.

A neonate was found to have normocalcaemic hyperparathyroidism with bone disease. The plasma parathyroid hormone concentration returned to normal by 4 weeks, and healing of the bone lesions was evident by age 5 months. The mother proved to have pseudohypoparathyroidism, previously unsuspected.

C-trisomy in a case of neonatal leukaemia.

A case of neonatal leukaemia of acute myeloid cell type was diagnosed at age 8 weeks and the patient died shortly afterwards with evidence of disseminated intravascular coagulation. An aneuploid malignant cell line 47, XY+C was found, in addition to the infant's normal constitutional karyotype. Eight other cases of congenital or neonatal leukaemia with aneuploid malignant cell lines are reviewed. C-trisomy is a commonly acquired chromosomal abnormality in a wide range of malignant and premalignant haematological disorders, and its possible significance in relation to leukaemogenesis in this case is discussed.

Prostaglandin synthetase inhibitor in an infant with congenital chloride diarrhoea.

Hyper-reninaemia, hypokaluria, and hypokalaemia in an infant with congenital chloride diarrhoea improved during treatment with a prostaglandin synthetase inhibitor, ketoprofen. There was evidence of increased activity of therenin-aldosterone system when ketoprofen was stopped. It is suggested that prostaglandins may be involved in stimulating the renin-aldosterone system in congenital chloride diarrhoea.

Cows' milk allergy in the syndrome of thrombocytopenia with absent radius.

A girl with the syndrome of thrombocytopenia with absent radius had severe diarrhoea and dehydration relieved by withdrawal of cows' milk and aggravated by its reintroduction on three occasions. Deterioration in gastrointestinal symptoms was associated with haematological relapse with thrombocytopenia, leucocytosis, anaemia, and eosinophilia. There appeared to be a correlation between milk exposure and the haematological and gastrointestinal disturbances. Supporting evidence from published reports for such a correlation is reviewed. Cows' milk protein intolerance may be a factor in precipitating haematological relapse in susceptible infants with radius aplasia. Early withdrawal of cow's milk protein should be tried in thrombocytopenia with absent radius, especially in cases with prominent gastrointestinal upset.