Increase of GTP cyclohydrolase I activity in mononuclear blood cells by stimulation: detection of heterozygotes of GTP cyclohydrolase I deficiency.

An assay is described for GTP cyclohydrolase I activity in human mononuclear cells isolated from 20 ml of heparinized blood. The activity of this enzyme was low in unstimulated cells and increased 5-10 times after stimulation by phytohemagglutinin (formation of 0.8-1.3 pmol dihydroneopterin triphosphate/min per mg protein at 37 degrees C, n = 15) or mixed lymphocyte culture. No activity was detected in phytohemagglutinin-stimulated mononuclear cells of a patient with proven GTP cyclohydrolase I deficiency in liver; the samples from the father and mother of the patient showed 30 and 46%, respectively, of the mean of 15 healthy controls. In unstimulated cells, neopterin was the main component of the total intracellular pterins (after oxidation). After stimulation, dihydroneopterin triphosphate, measured as neopterin triphosphate by high performance liquid chromatography, was increased 10-30 times; neopterin and pterin were increased only 2- to 6-fold. Since the immunoreactive cells from this patient were unable to produce pterins and all immunological tests on the patient were normal, it is concluded that neither dihydroneopterin triphosphate, nor one of its metabolites are of primary importance for an immune reaction. The assay described can be used for the detection of heterozygotes of GTP cyclohydrolase I deficiency.

Unilateral mastitis obliterans presented as a palpable breast mass in a patient with long-standing diabetes mellitus.

Mastitis obliterans is an uncommon and late manifestation of ductal ectasia. We report a case of a woman with a long-term type 2 diabetes, referred to us because of a palpable right breast mass. Mammography showed an asymmetry in the palpated area. Ultrasonography was consistent with a an irregular, hypoechoic mass with indistinct margins and linear tracts to the skin. The biopsy showed a fibrotic component surrounding dilated galactophore ducts, which were collapsed by an infiltrate of lymphocytes and histiocytes corresponding to mastitis obliterans. The differential diagnosis should be made between diabetic fibrous mastopathy, granulomatous mastitis and lobular carcinoma. In our opinion, the therapeutic approach should depend on the symptomatology and should be individualized for each patient owing to the lack of information on this pathology, adopting therefore a conservative attitude.

Estrogen-induced weight gain cannot be predicted in individuals.

The effect of high estrogen doses on weight was studied in 36 adolescent girls with familial tall stature treated to reduce adult height. Mean weight gain during the first year was 9.0 +/- 3.6 kg. Thereafter, there was no or minimal gain on continued treatment. The largest weight velocity occurred during the first 6 months. Within that period, it was most marked during the first 5 weeks, probably due to early water retention. The gain (total, in different groups of patients and in treatment periods of different duration) did not correlate with height and weight before treatment expressed in absolute values or standard deviation scores. It is concluded that the weight gain induced by long-term estrogen treatment cannot be predicted quantitatively before treatment in individuals, and that heavy or fat girls do not necessarily gain more weight than light and lean girls.

Testicular adrenal-like tissue (TALT) in congenital adrenal hyperplasia: detection by ultrasonography.

In a consecutive series of 15 male adolescents and young adults with congenital adrenal hyperplasia (CAH), the size, shape, firmness and echostructure of the testes were assessed. The latter was abnormal in 7 patients under long standing treatment with glucocorticoids (group I). In 8, 5 under and 3 off treatment for several years, ultrasonography (US) was normal (group II). On the basis of the US findings the patients were placed in two groups. In group I, the testes had a heterogeneous ultrasonographic pattern; clinically, most felt hard and irregular, although their volume was normal. Sperm count in 3 patients was 5.0 to 14.4 x 10(6)/ml. Five patients have 21-hydroxylase deficiency that was diagnosed in early infancy and had salt-wasting; two have 11-beta-hydroxylase deficiency that was diagnosed late and had no salt-wasting. In group II, testicular volume, shape, firmness and echostructure were normal. All have 21-hydroxylase deficiency, no history of salt-wasting and were diagnosed late. Sperm counts in 3 patients off treatment were 10.5 to 66.0 x 10(6)/ml. In severe cases with a history of salt loss, TALT with deficient spermiogenesis seems likely despite treatment. In mild cases, TALT is absent and spermiogenesis may be normal even without treatment. US is much more accurate in assessing the testes than palpation.

Ovarian steroidogenesis in an adrenalectomized girl with 21-hydroxylase deficiency.

A girl with congenital adrenal hyperplasia due to 21-hydroxylase deficiency could not be controlled by conventional treatment, and was adrenalectomized at age 8.5 years (bone age 13.5 years). After surgery, puberty and menarche occurred. On replacement therapy, her progress was uneventful up to the age of 16 years, when menstruations ceased and signs of virilization reappeared. Testosterone, androstenedione, and 17-hydroxyprogesterone in plasma, and pregnanetriol in urine were high, but DHEA in plasma, and pregnenetriol and pregnanetriolone in urine were low. Oestrogens in plasma were normal. There was no steroid response to ACTH, and marked, but somewhat slow suppression by dexamethasone. HMG induced a strong rise in oestrone and oestradiol. Ethinyloestradiol reduced not only oestradiol in plasma, but also testosterone, androstenedione, and 17-hydroxyprogesterone. With subsequent dexamethasone treatment, menstruation restarted, and the values returned to normal. It is concluded that virilization may reoccur in patients with 21-hydroxylase deficiency even after adrenalectomy, and that the ovaries in this patient contain some tissue, which has properties of adrenal (suppressibility by dexamethasone) and ovarian tissue (suppressibility by ethinyl oestradiol, preference for delta 4-pathway, low steroid 11-oxygenation) at the same time.

Congenital adrenal hypoplasia in a male with gonadotropin deficiency.

We report the case of a boy with adrenal insufficiency diagnosed at the age of 2.5 months. He required immediate therapy with corticosteroids. His two brothers and a cousin died in infancy with vomiting and dehydration. Aged 17.5 years (bone age 13 years), he showed no signs of puberty, a testicular volume of 2 ml, an infantile penis, and no axillary or pubic hair. There was no evidence of a pubertal growth spurt. The low plasma levels of cortisol, 17-OHP, delta-4-A, LH and FSH did not increase after stimulation with ACTH or LHRH respectively. Urinary testosterone levels before and after HCG were extremely low. These factors strongly suggest the diagnosis of a sex-linked type of adrenal insufficiency (cytomegalic form), associated with gonadotropin deficiency.

GTP cyclohydrolase I deficiency, a new enzyme defect causing hyperphenylalaninemia with neopterin, biopterin, dopamine, and serotonin deficiencies and muscular hypotonia.

A 4-year-old patient is described with hyperphenylalaninemia, severe retardation in development, severe muscular hypotonia of the trunk and hypertonia of the extremities, convulsions, and frequent episodes of hyperthermia without infections. Urinary excretion of neopterin, biopterin, pterin, isoxanthopterin, dopamine, and serotonin was very low, although the relative proportions of pterins were normal. In lumbar cerebrospinal fluid, homovanillic acid, 5-hydroxyindoleacetic acid, neopterin and biopterin were low. Oral administration of L-erythro tetrahydrobiopterin normalized the elevated serum phenylalanine within 4 h, serum tyrosine was increased briefly and serum alanine and glutamic acid for a longer time. Urinary dopamine and serotonin excretion were also increased. Administration of an equivalent dose of D-erythro tetrahydroneopterin was ineffective and demonstrated that this compound is not a cofactor in vivo and cannot be transformed into an active cofactor. GTP cyclohydrolase I activity was not detectable in liver biopsies from the patient. The presence of an endogenous inhibitor in the patient's liver was excluded. This is the first case of a new variant of hyperphenylalaninemia in which the formation of dihydroneopterin triphosphate and its pterin metabolites in liver is markedly diminished. Normal activities of xanthine oxidase and sulfite oxidase were apparent since uric acid levels were normal and no increase in hypoxanthine, xanthine, and S-sulfocysteine concentrations could be observed in urine. It is concluded that the molybdenum cofactor of these enzymes may not be derived from dihydroneopterin triphosphate in man. Also, since no gross abnormalities in the patient's immune system could be found, it seems unlikely that dihydroneopterin triphosphate metabolites, such as neopterin, participate actively in immunological processes, as postulated by others. See Note added in proof.

Some comparative aspects of a longitudinal growth study in normal Spanish children and other longitudinal studies.

The differences existing among some european longitudinal growth studies make it necessary to be cautious in the use of standards constructed on different populations. The improvement of the environmental conditions during the last 20 years is probably the most important cause of the "catch-up" phenomenon of the spanish stature. It is probable that racial characteristics also play a role, even in the same country as can be appreciated on comparing two spanish longitudinal studies based on children originally from different regions. All of which indicates the need to use own standards in those countries which, like ours, have lived through a period of intense changes. Even exploratory studies of regional differences in the same country seem necessary.

Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls.

Spontaneous pubertal growth was studied in eight patients with the syndrome of androgen insensitivity to obtain information on the growth-promoting action of estrogens. In one additional patient (who had a gonadectomy before puberty), the effect of exogenous estrogens was studied. Mean age at peak height velocity (12.7 years) was closer to that in normal girls than to that in normal boys. Mean peak height velocity (7.4 cm/yr) was as in normal girls (7.3 cm/yr), but was lower than in normal boys (9.3 cm/yr). Bone age corresponded better to male standards. Mean adult height (172.3 cm) was lower than in normal men (-0.6 SD), but higher than in normal women (+1.4 SD). In the patient who had a gonadectomy, estrogen replacement caused a higher peak height velocity (12 cm/yr), but lower adult height (160.5 cm) than in the patients with intact gonads who received no treatments. We conclude that in normal girls, the pubertal growth spurt also results from the action of estrogens rather than of adrenal androgens. To ensure normal pubertal growth, physiologic estrogen replacement in hypogonadal females should be started at a bone age of about 11 years, and should not be delayed in the hope of achieving a greater mature height.

Kenny syndrome: evidence for idiopathic hypoparathyroidism in two patients and for abnormal parathyroid hormone in one.

We report three unrelated patients with Kenny syndrome. Clinical symptoms included severe dwarfism, with internal cortical thickening and medullary stenosis of the tubular bones, normal bone age, macrocephaly, absent diploic space, delayed closure of the anterior fontanel, and normal intelligence; two of the patients had hyperopia and papillary edema. The patients also had episodic hypocalcemic tetany and low serum levels of magnesium. In two patients the diagnosis of idiopathic hypoparathyroidism was established on the basis of undetectable serum parathyroid hormone (PTH) levels (N- and C-terminal RIAs); one of these had normal urinary cyclic adenosine monophosphate (cAMP) response to exogenous PTH. Circulating calcitonin was undetectable in either patient. In a third patient, who had abnormal body proportions, serum levels of PTH were increased in an RIA detecting predominantly intact PTH (N-RIA) and undetectable in another RIA recognizing carboxy-terminal fragments (C-RIA). Administration of PTH promptly increased urinary cAMP excretion. In this patient, serum levels of calcitonin were increased, whereas values for 25-OHD and 1,25(OH)2D were normal.