A family with three recessive traits and homozygosity for a long 9qh+ chromosome segment.

We report a family in which a mentally retarded, proportionately dwarfed girl had a child from a presumably incestuous mating that had the Ellis van-Creveld syndrome, presumed autosomal recessive hydrocephalus (Dandy-Walker type), and homozygosity for an extremely long 9qh+ chromosomal marker. The mentally retarded mother had normal birth weight, unusual facial appearance, and virtual absence of secondary sexual hair; she developed severe hypoglycemia during pregnancy. Her parents were first cousins, and she may have a previously unreported autosomal recessive syndrome.

Mucosal neuroma, pheochromocytoma and medullary thyroid carcinoma: multiple endocrine neoplasia type 3.

1. Three members of a kindred and a fourth unrelated individual demonstrating the syndrome of mucosal neuroma, bumpy lips, marfanoid habitus, medullary thyroid carcinoma and pheochromocytoma are reported, and the literature pertaining to this syndrome has been reviewed. 2. There are currently 41 definite and 16 additional probable reported cases manifesting the syndrome of mucosal neuroma, bumpy lips, pheochromocytoma and medullary thyroid carcinoma. Mucosal neuroma was present in all patients. Medullary thyroid carcinoma was histologically proved in 38 cases. Pheochromocytoma was documented in 19 patients with a probable diagnois in another 4 patients. Only one patient was noted to have hypercalcemia associated with parathyroid adenoma. Associated abnormalities seen in this syndrome include hypertrophied corneal nerves, skeletal defects and gastrointestinal tract abnormalities. 3. The relationship of this syndrome to other types of multiple endocrine neoplasia syndromes and the phakomatoses is also discussed. This syndrome appears to be distinct from the entity of multiple endocrine neoplasia type 2. We suggest that this syndrome be called multiple endocrine neoplasia type 3, following the classification originally proposed by Steiner et al. 4. MEN type 3 appears to be inherited as an autosomal dominant disorder. Many apparently non-familial cases have been reported, but due to inadequate information regarding family history it may be possible that some of these cases also had other affected family members. 5. This syndrome most likely results from a dysplasia of neuroectodermal tissue. The pathogenesis of this syndrome is discussed and evidence supporting the hypothesis is reviewed. 6. The importance of diagnosing the syndrome at an early stage and of investigating the relatives of a patient manifesting this potentially fatal syndrome are stressed. 7. Plasma calcitonin measurement following calcium infusion is extremely useful as a screening procedure for the diagnosis of medullary thyroid carcinoma, when the patients are completely asymptomatic and routine thyroid function tests are normal. Affected individuals should also be periodically screened for the development of pheochromocytoma.

Hypogandotropic hypogonadism with anosmia: the Kallmann syndrome.

Five cases are presented and the literature reviewed concerning the association of anosmia or hyposmia and hypogonadotropic hypogonadism (Kallmann syndrome). Two of the five cases are sporadic and without associated anomalies, the third is associated with ichthyosis and epilepsy, the fourth has a sister with hypogonadism and cleft lip and palate while the fifth case also has Albright's hereditary osteodystrophy (pseudopseudohypoparathyroidism). It is concluded that "Kallmann syndrome" is present in a wide spectrum of disorders with different genetic etiologies.

Abnormal regulation of adenosine 3',5'-monophosphate and corticosterone formation in an adrenocortical carcinoma.

A spontaneously occurring rat adrenocortical carcinoma which produces corticosterone was maintained by transplantation. The carcinoma appeared to utilize corticosterone biosynthetic steps similar to those of the normal adrenal, but the tumor produced only about 1-10% as much corticosterone per unit tissue weight as nontumorous adrenal glands. The tumor demonstrated little or no increase in corticosterone production in response to adrenocorticotropic hormone (ACTH) either in vivo or in vitro. In normal adrenals, ACTH increases the activity of adenyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to adenosine-3',5'-monophosphate (cyclic AMP), the latter then serving as an intracellular regulator of steroidogenesis. ACTH failed to increase cyclic AMP levels in the tumor in vivo or in slices in vitro, conditions under which there were 50- and 20-fold increases in nontumorous adrenals. However, in homogenates fortified with exogenous ATP, adenyl cyclase activity was comparable in the tumor and adrenals, and cyclic AMP formation was increased 3-fold by ACTH in each. As measured in homogenates, the tumor did not possess a greater ability to destroy cyclic AMP than did normal adrenals. Although ATP levels in the carcinoma were found to be considerably lower than those in normal adrenals, it was not clear that this finding can explain the inability of ACTH to increase cyclic AMP levels in intact tumor cells. While the failure to normally influence cyclic AMP levels in the carcinoma cells could be an important factor in the lack of a steroid response to ACTH, several lines of evidence suggest that the tumor possesses one or more additional abnormalities in the regulation of steroidogenesis. First, in the absence of ACTH stimulation, the tissue concentrations of cyclic AMP were comparable in the tumor and in nontumorous adrenals, but these cyclic AMP levels were associated with a lower level of steroidogenesis in the tumor. Second, tumor slices failed to increase corticosterone production when incubated with cyclic AMP, in contrast to 5-fold increases observed with nontumorous adrenals.

A study of mechanisms by which adrenocorticotropic hormone maintains adrenal steroidogenic responsiveness.

Following hypophysectomy in the rat, there was a progressive decline in the rate of adrenal protein synthesis in vivo during the ensuing 24-48 hr, and an accompanying decrease in the acute corticosterone secretory response to an intravenous injection of ACTH. There was a similar decrease in the in vitro conversion of Delta(5)-pregnenolone, progesterone, and deoxycorticosterone to corticosterone. These in vivo and in vitro effects of hypophysectomy could be reversed by the administration of depot ACTH for an additional 7 hr period. However, if cycloheximide, an inhibitor of protein synthesis, was administered concomitantly with the depot ACTH, then the restorative actions of ACTH on the steroid biosynthetic pathway were prevented. These experiments suggest that ACTH maintains not only the general structure of the adrenal cortex, but also the level of the steroid biosynthetic mechanism, through its effects on adrenal protein synthesis.