Accelerated Skeletal Maturation in Disorders of Retinoic Acid Metabolism: A Case Report and Focused Review of the Literature.

Nutritional excess of vitamin A, a precursor for retinoic acid (RA), causes premature epiphyseal fusion, craniosynostosis, and light-dependent retinopathy. Similarly, homozygous loss-of-function mutations in CYP26B1, one of the major RA-metabolizing enzymes, cause advanced bone age, premature epiphyseal fusion, and craniosynostosis. In this paper, a patient with markedly accelerated skeletal and dental development, retinal scarring, and autism-spectrum disease is presented and the role of retinoic acid in longitudinal bone growth and skeletal maturation is reviewed. Genetic studies were carried out using SNP array and exome sequencing. RA isomers were measured in the patient, family members, and in 18 age-matched healthy children using high-performance liquid chromatography coupled to tandem mass spectrometry. A genomic SNP array identified a novel 8.3 megabase microdeletion on chromosome 10q23.2-23.33. The 79 deleted genes included CYP26A1 and C1, both major RA-metabolizing enzymes. Exome sequencing did not detect any variants that were predicted to be deleterious in the remaining alleles of these genes or other known retinoic acid-metabolizing enzymes. The patient exhibited elevated plasma total RA (16.5 vs. 12.6±1.5 nM, mean±SD, subject vs. controls) and 13-cisRA (10.7 nM vs. 6.1±1.1). The findings support the hypothesis that elevated RA concentrations accelerate bone and dental maturation in humans. CYP26A1 and C1 haploinsufficiency may contribute to the elevated retinoic acid concentrations and clinical findings of the patient, although this phenotype has not been reported in other patients with similar deletions, suggesting that other unknown genetic or environmental factors may also contribute.

Catch-up growth: cellular and molecular mechanisms.

In mammals, after a period of growth inhibition, body growth often does not just return to a normal rate but actually exceeds the normal rate, resulting in catch-up growth. Recent evidence suggests that catch-up growth occurs because growth-inhibiting conditions delay progression of the physiological mechanisms that normally cause body growth to slow and cease with age. As a result, following the period of growth inhibition, tissues retain a greater proliferative capacity than normal, and therefore grow more rapidly than normal for age. There is evidence that this mechanism contributes both to catch-up growth in terms of body length, which involves proliferation in the growth plate, and to catch-up growth in terms of organ mass, which involves proliferation in multiple nonskeletal tissues.

Evaluation of the use of automatic external defibrillation in out-of-hospital cardiac arrest in Hong Kong.

A retrospective 6-month audit of out-of-hospital cardiac arrests in Hong Kong following the introduction of automatic external defibrillators is presented. During the 6-month period from 1 July 1995 to 31 December 1995, resuscitation was attempted on 754 patients. Of the 744 patients with cardiac arrest whose records were available, 53.6% had a witnessed arrest. Few cardiac arrest patients (8.9%) received bystander cardiopulmonary resuscitation (CPR) and the majority (80%) of arrests occurred at home. Six hundred and forty-three (86.4%) patients were declared dead on arrival at hospital or in the Accident and Emergency department; 89 (12%) died in hospital and only 12 (1.6%) were discharged alive. The average ambulance response interval (call receipt to arrival of ambulance at scene) was 6.42 min. The average arrest-to-first-shock interval was 23.77 min. Factors predicting survival included initial rhythm and arrest-to-first-shock interval. The survival rate of 1.6% is low by world standards. To improve the survival rates of people with out-of-hospital cardiac arrest, the arrest-to-call interval must be reduced and the frequency of bystander CPR assistance increased. Once these changes are in place, a beneficial effect from the use of pre-hospital defibrillation might be seen.