Isolated congenital ACTH deficiency: a cleavage enzyme defect?

The pro-opiomelanocortin (POMC) gene encodes adrenocorticotrophin (ACTH) which is derived from precursors by proteolytic cleavage. Congenital, isolated ACTH deficiency is rare but may be familial and fatal. The aetiology is unknown though defects at both hypothalamus and adenohypophysis have been postulated. We have studied a female presenting with hypoglycaemia in the neonatal period. When studied at 6 weeks of age, ACTH was unmeasurable even after injection of corticotrophin releasing hormone (CRH1-41). ACTH precursors, quantitated by two-site immunoradiometric assay, were clearly measurable prior to treatment and were stimulated by CRH1-41 and suppressed by glucocorticoid administration. Concentrations of POMC, N-terminal pro-opiocortin (N-POC) and beta-endorphin (beta-EP) were within the normal adult range during glucocorticoid replacement therapy; ACTH and beta-lipotrophin remained undetectable. The secretion of glucagon, measured by radioimmunoassay, in response to hypoglycaemia was normal. By sequencing polymerase chain reaction products from the patient's genomic DNA, the entire coding region of the POMC gene was established to be normal. The results are compatible with a cleavage enzyme defect.     

ACTH receptor, ACTH receptor anomaly, and familial glucocorticoid deficiency

Familial glucocorticoid deficiency (FGD) is an autosomal recessive syndrome with hereditary adrenocortical unresponsiveness to ACTH. After the cloning of ACTH receptor or melanocortin-2 receptor (MC-2R) cDNA, several kinds of mutations in the receptor genes have been reported. However, the apparently normal ACTH receptor gene in some affected children suggests that the etiology of FGD is heterogeneous. In this short review, we describe the recent advances in the molecular biology of ACTH receptor genes, its post-receptor signal transduction in the adrenocortical cells, and the molecular genetics of the FGD and a related syndrome, Allgrove syndrome. We also discuss that this kind of work will help us to understand better about the molecular mechanism of the glucocorticoidogenesis in the human being.     

Genetic heterogeneity of adrenocorticotropin (ACTH) resistance syndromes: identification of a novel mutation of the ACTH receptor gene in hereditary glucocorticoid deficiency

Hereditary primary adrenal insufficiency syndromes due to ACTH resistance include hereditary glucocorticoid deficiency (HGD) and Allgrove's syndrome (AS). Patients with both conditions present in childhood with failure to thrive, weakness, and fatigue or adrenal crisis; patients with AS in addition have alacrima and achalasia (triple A syndrome). We studied four kindreds with HGD and four kindreds with AS for abnormalities of the ACTH receptor (ACTHR) gene. The ACTHR coding sequence in all AS kindreds and two HGD kindreds was normal. Analysis of the ACTHR gene of the proband in one of the HGD kindreds showed him to be homozygous for the previously described G221T transition causing a Ser74Ile substitution of the protein, which has been shown to inactivate the ACTHR in signal transduction. The proband in another HGD kindred was found to be a compound heterozygote with the G221T transition in one allele and a novel C818A transition in the other allele of ACTHR. The C818A transition caused the substitution of the highly conserved Pro273 by His in the receptor protein. In vitro expression of the mutated ACTHR in mouse melanoma M3 cells showed that at a medium ACTH concentration of 3 nM, cells transfected with the wild-type ACTHR produced twofold and threefold, respectively, of the amount of intracellular cAMP when compared to cells transfected with the ACTHR carrying the Pro273His and the Ser74Ile mutation, respectively, confirming that HGD in this kindred is caused by loss-of-function mutations of the ACTHR. These results showed that the genetic cause of the ACTH-resistant syndromes is heterogeneous.     

Isolated biotin-resistant 3-methylcrotonyl-CoA carboxylase deficiency: long-term outcome in a case with neonatal onset

A patient with early-onset 3-methylcrotonyl coenzyme A carboxylase (MCC) deficiency showing a severe clinical course is described. Abnormal eye and head movements suggestive of seizures were noticed soon after birth. Tonic convulsions at the age of 10 weeks led to admission. Urinary organic acid analysis using gas chromatography-mass spectrometry at 3 months of age revealed elevated concentrations of 3-hydroxyisovaleric acid (3HIVA) and 3-methylcrotonylglycine but normal levels of lactate, 3-hydroxypropionate and methylcitrate suggesting isolated MCC deficiency. This was confirmed by enzyme assays in lymphocytes and cultured skin fibroblasts: MCC activity was virtually undetectable whereas activities of propionyl-CoA and pyruvate carboxylases were within the normal range. A low protein (0.8-1.5 g/kg/day) diet supplemented with a leucine-free amino acid mixture resulted in a marked decrease of 3HIVA excretion. L-Carnitine and biotin administration had no effect on the clinical condition or metabolite excretion. Supplementation with glycine resulted in only a temporary fall of 3HIVA excretion and was therefore discontinued. L-Carnitine therapy was reintroduced later because of secondary carnitine deficiency. Compliance with treatment was poor until the age of 27 months resulting in a severe episode with seizures and coma. The general clinical condition of the patient was always good but his psychomotor development was delayed and seizures were not continuously under good control due to poor therapy compliance. The boy is now 10.5 years old and attending a school for children with learning handicaps. Conclusion: Isolated MCC deficiency of early-onset is a rare condition exhibiting a more severe clinical course than the later-onset form described in most other cases. The prognostic value of 3 HIVA measurements in CSF and serum should be evaluated in future cases.     

Simultaneously found transient hypothyroidism due to Hashimoto's thyroiditis, autoimmune hepatitis and isolated ACTH deficiency after cessation of glucocorticoid administration

We present a 42-year-old woman with concomitant transient hypothyroidism due to Hashimoto's thyroiditis, autoimmune hepatitis and isolated ACTH deficiency. Two months after ceasing prednisolone (5 mg/day) for uveitis, she was discovered incidentally to have liver dysfunction with hypergammaglobulinemia, later diagnosed as autoimmune hepatitis by histological examination of the biopsied liver. In addition, primary hypothyroidism due to Hashimoto's thyroiditis and secondary hypocortisolism due to isolated ACTH deficiency were revealed by endocrinological examination. Although not treated, her liver dysfunction and hypothyroid state recovered simultaneously, and the isolated ACTH deficiency was restored six months later. We concluded, after a needle-biopsy of the thyroid, that the transient hypothyroidism was due to Hashimoto's thyroiditis and the reversible ACTH deficiency was probably due to autoimmune hypophysitis. This case shows that cessation of steroid treatment may transiently exacerbate the polyglandular autoimmune syndrome.     

Iron deficiency and educational deficiency

Existing data suggest that iron deficiency anemia (IDA) is a risk factor for poor educational performance in schoolchildren. The synergistic effect of IDA in combination with other forms of malnutrition and other risk factors may affect educational performance more strongly. Thus, IDA and its effect on educational performance should be studied in the context of other risk factors.     

Isolated colonic tuberculosis

Two cases of colonic tuberculosis (TB) isolated in two elderly, not HIV seropositive women, presenting unspecific clinical manifestations (constitutional syndrome, fever, abdominal pain and diarrhea) and stenosis of the colon in diagnostic imaging techniques are presented. In the second case, endoscopy showed stenosis of the colonic lumen and inflammatory mucosa, the biopsy of which demonstrated granulation tissue with no signs of specificity (in the first case, technical problems did not allow the colonoscopy to reach the affected site). In both cases, diagnosis was performed postoperatively by study of the surgical pieces. Biopsy showed granulomas with acid-alcohol resistant bacilli. Both patients responded favorably to tuberculostatic treatment.     

Isolated mesenteric fibromatosis

Isolated mesenteric fibromatosis is a rare form from the group of intraabdominal fibromatoses which often accompany Gardner's syndrome. It consists in a benign proliferation of fibroblasts with infiltration of muscles and fat tissue. It is diagnosed by ultrasound and CT-scans. The treatment of choice is the total surgical extirpation of the tumor. We report about a 19 year old patient with an isolated mesenteric fibromatosis following a normal pregnancy without previous surgical interventions.     

Vitamin deficiency and marginal vitamin deficiency

Fat-soluble vitamin deficiency and marginal deficiency of this type of vitamin will be discussed. The trias of vitamin A deficiency is composed of nyctalopia, xerophthalmia and hyperkeratosis follicularis. Vitamin D deficiency causes rachitis and osteomalacia. In Japan, vitamin D deficiency is more often caused by impaired vitamin D activation due to renal failure, than by a lack of sunbathing or insufficient ingestion of vitamin D from diet. At present, it is quite rare that the physician encounters patients with deficiency of vitamin E or other vitamins. According to surveys of occult vitamin deficiency, the prevalence of marginal fat-soluble vitamin deficiency was lower than that of marginal water-soluble vitamin deficiency. Marginal vitamin deficiency seems to be absent or very rare among healthy individuals. In patients, however, marginal vitamin deficiency is sometimes observed. Since marginal vitamin deficiency can modify the underlying disease or trigger complications, the physician should take adequate measures to prevent the onset of marginal vitamin deficiency in managing patients with various diseases.