Pseudohypoparathyroidism, type Ia (PHP-Ia), is a dominantly inherited endocrine disorder characterized by resistance to hormones that act by stimulating adenylyl cyclase. It is caused by inheritance of an autosomal mutation that inactivates the ␣ subunit (␣ s ) of G s , the stimulatory regulator of adenylyl cyclase. In three members of a family, the PHP-Ia phenotype is associated with a mutation (R231H) that substitutes histidine for an arginine at position 231 in ␣ s . We assessed signaling function of ␣ s -WT versus ␣ s -R231H transiently transfected in HEK293 cells. Hormone receptor-dependent stimulation of cAMP accumulation in cells expressing ␣ s -R231H is reduced by ϳ75% in comparison to cAMP accumulation in cells expressing ␣ s -WT. A second mutation, ␣ s -R201C, inhibits the GTPase turnoff reaction of ␣ s , thus producing receptor-independent stimulation of cAMP accumulation. The double mutant, ␣ s -R231H/ R201C, stimulates cAMP accumulation almost as well (ϳ80%) as does ␣ s -R201C itself, indicating that the R231H mutation selectively impairs receptor-dependent signaling. In three-dimensional structures of G protein heterotrimers, Arg-231 is located in a region, switch 2, that is thought to interact with the ␤␥ subunit rather than with the hormone receptor. Thus, the R231H phenotype suggests that switch 2 (perhaps in concert with ␤␥) mediates G protein activation by receptors at a site distant from the receptor-G protein contact surface.Heterotrimeric G proteins relay information from receptors for extracellular stimuli to effector enzymes and ion channels that mediate cell responses. Receptors interact with the G protein ␣/␤␥ complex, causing release of GDP bound in the guanine nucleotide binding pocket of the G protein ␣ subunit and its replacement by GTP. GTP-induced conformational changes cause G␣GTP to dissociate from the ␤␥ dimer, allowing both subunits to interact with effectors. Effector stimulation is then terminated by the intrinsic GTPase activity of G␣, followed by reassociation of G␣GDP and ␤␥. With respect to this cycle, recently published crystal structures have revealed details of GTP-induced conformational change in G␣ (1-3), a plausible structure for the catalytic intermediate in the GTPase reaction (4, 5), and three-dimensional structures for the G␣␤␥ heterotrimer (6, 7). Because we do not have the structure of a receptor-G␣␤␥ complex, however, we cannot yet describe in molecular detail the pivotal event in receptor-G protein signaling, receptor-triggered release of GDP from G␣.At present we can try to understand this event by interpreting effects of instructive mutations. A potential source of such mutations is an inherited disease of G protein signaling, pseudohypoparathyroidism, type Ia (PHP-Ia) (8). PHP-Ia patients inherit a defect in one of the two autosomal alleles of the gene for ␣ s , the ␣ subunit of G s , the stimulatory regulator of adenylyl cyclase. Although G s mediates effects of many hormones, the ϳ50% decrease in G s activity produced by loss of an autosomal allele cau...

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An evaluation of intellectual, personal and social functioning was made in 16 young patients with craniopharyngioma. No changes were found in the overall IQ verbal and performances scores before and after operation, however, discrepancies between verbal and performance scores suggest that one of the manifestations of craniopharyngioma in children are disturbance in cognitive functions. The decrease in the quality of life of the patients and their families manifested through the deterioration of familial and social relationships and the decrease in scholastic achievements lead to the conclusion that children with craniopharyngioma and their families require close psychological supervision and counselling both before and after surgery.

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A female newborn infant with ambiguous genitalia was found to have hypertension (121/82 mm Hg) immediately after birth. The plasma testosterone (T) (0.73 nmol/l), delta 4-androstenedione (delta 4-A) (5.9 nmol/l), dehydroepiandrosterone (DHEA) (8.9 nmol/l), as well as 17 OH-hydroxyprogesterone (17 OHP) (152 nmol/l) were elevated. The diagnosis of 11 beta-hydroxylase deficiency was finally established on the basis of elevated plasma eleven-deoxycortisol (compound S) (greater than 0.6 mumol/l) and confirmed by the normalisation of the blood pressure during hydrocortisone therapy. Our case is probably the youngest patient with 11 beta-hydroxylase deficiency in whom the hypertension was found at birth.

An obese 15-year-old boy of Jewish Iranian origin who is the offspring of consanguineous parents was found to have very low levels of total cortisol in the plasma. Investigation of the family revealed a complete lack of cortisol-binding-globulin (CBG) in the proband and a sister, evidently the first cases of total CBG deficiency to be reported. The parents and a brother were found to have half the normal levels. This study indicates that CBG deficiency, a benign condition, is compatible with a codominant or recessive autosomal trait inheritance.

Head circumference was measured before and during hGH therapy in fourteen children with isolated growth hormone deficiency (IGHD) and in twenty-one children with multiple pituitary hormone deficiencies (MPHD). In both groups there was a retardation in growth of the neurocranium, more marked in the children with IGHD, which was less than the retardation in linear height. In the group with IGHD, initiation of hGH therapy before a chronological age of 5 and a bone age of 3 had been reached led to a rapid catch-up in cranial growth with normalization of the head size. In older children the induction of head growth was similar to that achieved by the long bones but without a true catch-up phenomenon. In three adults with hereditary IGHD without therapy or with irregular treatment during late puberty, the head circumference was below normal range. In view of the possible role played by development of brain tissue upon cranial size, the importance of early diagnosis and initiation of therapy in infants and young children with a deficiency of hGH is stressed.

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