Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease.

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Passive transport of 5,5-dimethyl-2, 4-oxazolidinedione into beef heart mitochondria.

5,5-Dimethyl-2,4-oxazolidinedione is used to estimate intracellular pH. The mechanism of transport of this compound into beef heart mitochondria was investigated to assess the validity of its use for the measurement of intramitochondrial pH. This compound and (14)C-labeled carboxy dextran were simultaneously used to determine the intra- and extramitochondrial compartments and the distribution of the compound, which was passively transported into resting, respiring, and simultaneously respiring and phosphorylating mitochondria. The transport of the compound was neither associated with electron transport nor with oxidative phosphorylation.

Decreased metabolic clearance of endogenous growth hormone and specific alterations in the pulsatile mode of growth hormone secretion occur in prepubertal girls with Turner's syndrome. Genentech Collaborative Group.

We have used deconvolution analysis to test the hypothesis that specific facets of GH secretion and clearance differ in young patients with Turner's syndrome and normal prepubertal girls. To this end, we sampled blood at 20-min intervals for 12 h overnight in 50 girls, 37 of whom had Turner's syndrome and 13 of whom were healthy Tanner stage I controls. Deconvolution analysis revealed that the half-life of endogenous GH in Turner's syndrome was significantly prolonged at 14 +/- 0.93 vs. 11 +/- 0.44 min in normal girls (P = 0.029). The number of significant GH secretory bursts was reduced in Turner's patients to 4.7 +/- 0.27 vs. 6.8 +/- 0.60 events/12 h in healthy girls (P less than 0.01). GH secretory burst half-duration was significantly prolonged in Turner's syndrome, viz. 23 +/- 1.3 vs. 15 +/- 0.87 min (controls; P less than 0.001). The changes in GH secretory burst frequency, duration, and half-life were specific, since neither the mass of GH secreted per burst nor the maximal rate of GH secretion attained per burst (amplitude of the secretion pulse) was significantly different in the 2 study groups. Thus, although 12-h GH secretion rates corrected for body weight were similar (3.9 +/- 0.76 in Turner's patients and 3.3 +/- 0.76 micrograms/L.kg/12 h in the control girls), equivalent GH production rates were achieved by different mechanisms in the 2 groups. We conclude that specific alterations in GH secretory burst frequency and duration and endogenous GH half-life can be documented in young girls with Turner's syndrome.

Hypocalcemic coma following two pediatric phosphate enemas.

Coma, tetany, dehydration, hypotension, tachycardia, and hyperpyrexia developed in a 2 1/2-year-old girl following two hypertonic phosphate pediatric enemas. She had marked hyperphosphatemia, hypocalcemia, hypernatremia, and acidosis. Hypocalcemia due to hyperphosphatemia can explain all of these findings. Calculations indicate that about one third of the phosphorus and sodium contents of the enema were absorbed. Physicians should be aware of the potentially lethal complication of this treatment, which is part of everyday practice.

Cerebral gigantism and primary hypothyroidism: pleiotropy or incidental concurrence.

An 8.5-month-old baby girl had cerebral gigantism and primary hypothyroidism with generalized large muscles (the Kocher-Debré-Semelaigne syndrome). The significance of this association remains to be determined.

Massive edema of the ovary and virilization.

Endocrine studies of a virilized adolescent patient with massive ovarian edema are reported. The histologic features of the affected ovary consisted of diffuse edematous stroma with scattered islands of lutein-like cells and no evidence of recent ovulation. Plasma concentrations of progesterone and 17-hydroxyprogesterone (17-OHP) in the peripheral and left ovarian veins and their ovarian-peripheral vein gradients were above the range observed during normal follicular phase. The considerable increase in the ovarian vein concentrations of both steroids observed after adrenocorticotropic hormone administration was noteworthy as a direct effect of this hormone on the ovarian synthesis of steroids has not previously been observed. Peripheral vein levels of testosterone (T) were increased. The secretion of T by the ovary was demonstrated by its elevated levels in the ovarian vein and in the ovarian-peripheral vein gradient. Unexpectedly, the levels of androstenedione in the ovarian vein were normal, suggesting an alteration in the ovarian biosynthetic pathway for the production of T. Similar findings have been observed in hirsute women with hyperthecosis ovarii. After surgery, the peripheral vein levels of 17-OHP and T returned to normal, pointing toward the ovary as their source of excess. The data indicate that stromal luteinization of the massive ovarian edema may lead to changes in normal ovarian steroidogenesis that would be responsible for the clinical manifestations of this disorder.

Reimplantation of the ampulla of Vater after total pancreatectomy for nesidioblastosis.

Total pancreatectomy is often required to control hypoglycemic seizures in infants with nesidioblastosis. If duodenal devascularization results, reconstruction is difficult because standard biliary-intestinal anastomoses may reflux, or, in infants, become strictured. Therefore, surgeons are loath to perform such procedures. To avoid these complications, the common bile duct and the ampulla of Vater were implanted into the reconstructed duodenum.

Successful spleno-renal shunt and splenectomy in two patients with alpha-1-antitrypsin deficiency.

Recent evidence suggests that the cirrhosis of alpha-1-antitrypsin deficiency is not invariably fatal as it was previously thought. Portal hypertension is often the major determinant of survival. The few reports of porta-systemic venous anastomosis in this disorder have shown poor results or uncertain outcome. Thus, doubts exist as to whether porta-systemic shunts should be performed in alpha-1-antitrypsin deficiency. Two patients with alpha-1-antitrypsin deficiency (PiZZ) and associated portal hypertension, cirrhosis, and hypersplenism underwent splenorenal shunt and splenectomy 8 yr ago, and both have done well. One of the patients has chronic severe headaches, diarrhea, exudative enteropathy, sinusitis, and hematuria, all uncommon in alpha-1-antitrypsin deficiency but possibly related to the antienzyme deficiency. She also has a higher trypsin inhibitory capacity than is generally reported in ZZ individuals. Based on the experience with these 2 patients, it appears that alpha-1-antitrypsin deficiency with cirrhosis is not a valid contraindication to the performance of a portasystemic shunt.

Multiple endocrine neoplasia type 2A: a 25-year review.

BACKGROUND/PURPOSE: Before 1970, treatment decisions for the thyroid lesions in patients with multiple endocrine neoplasia (MEN) were based on physical findings. For the next 20 years, biological markers assumed a preeminent role, and at present, DNA testing is being used to define the need for therapeutic intervention. This report presents a 25-year review of 22 children with MEN-2A, with a mean follow-up of 12.5 years. METHODS: All 22 children underwent a total thyroidectomy, and four (18%) were rendered permanently hypoparathyroid. Since 1976, however, only one patient (6.7%) has lost parathyroid function. Despite the fact that biological screening studies routinely were performed once a year in the majority of our patients and surgery was recommended for any elevation in the serum calcitonin (CT) levels, medullary carcinoma of the thyroid (MTC) developed in 17 children (77%) and only five had C cell hyperplasia (CCH). Thirteen of the 17 had macroscopic tumor described by the pathologist, evidence of recurrent disease (MTC-REC) has developed in four children (24%). RESULTS: There was considerable overlap in both the basal and stimulated CT levels among the five children with CCH, the 13 with localized MTC (MTC-NED), and the four who later had recurrent MTC. The basal calcitonin levels were between 25 and 110 (mean, 58) in the CCH patients, 30 to 1,130 (mean, 184) in the MTC-NED group, and 108 to 201 (mean, 140) in those with recurrent MTC. The corresponding stimulated calcitonin levels were 45 to 417 (mean, 179) in CCH, 111 to 9,510 (mean, 1,407) in MTC-NED, and 449 to 5,093 (mean, 3,383) in MTC-REC. CONCLUSIONS: (1) Basal and pentagastrin-stimulated CT levels did not reliably discriminate between CCH and MTC and should not be used to define the timing of thyroid surgery in children with MEN-2A. (2) Surgical therapy should be undertaken early in childhood on the basis of molecular genetic testing. (3) Postoperative complications are infrequent in the modern era.

[Overgrowth with and without obesity: clinical and molecular principles]. / Hipercrecimientos con y sin obesidad: fundamentos clínicos y moleculares.

Somatic overgrowth is a complex and heterogeneous pathology that is only partially understood, although developments in molecular biology have allowed the discovery of the aetiological basis of some of these conditions. The differential diagnosis of a patient with a possible variant of normality, a chromosomopathy, a dysmorphic syndrome, a metabolic or an endocrine disease is essential. The initial clinical evaluation should include a correct anamnesis and physical examination, as well as complementary laboratory and image analyses that will help to orient the diagnosis. This should include a full blood counts and complete biochemical analysis, determinations of IGF-I, IGFBP-3, free T4, TSH and homocystinuria, as well as a karyotype and an X-ray of the left hand and wrist. These results should be very beneficial in orienting the diagnosis. Additional molecular studies should be performed when a monogenic disease is suspected. Cardiological, ophthalmological, skeletal, psychological and psychiatric studies should be performed if the clinical information and previously mentioned complementary studies so indicate. In this review, the aetiological basis and the diagnostic-therapeutic principles in the most common causes of overgrowth, will be analysed.