John S. Dallas

Induction of hyperthyroxinemia in BALB/C but not in several other strains of mice.

We recently expressed the extracellular domain of the human TSHR (ETSHR) protein using a baculovirus expression system and purified it to homogeneity. The ETSHR specifically binds both TSH and antibodies to TSHR. In the present study, C57BL/6J, SJL/J, BALB/cJ and B10BR.SgSnJ mice were immunized with the recombinant ETSHR or an equivalent amount of control antigen. All strains of mice produced high titers of antibody against the TSHR protein which were capable of blocking the binding of TSH to native TSHR. However, only BALB/cJ mice showed significantly elevated levels of thyroxine in their sera compared to the control mice. Similarly, BALB/cJ mice primed with ETSHR and then challenged with thyroid membranes showed significantly elevated levels of thyroxine. In addition, histopathological examination of thyroid glands from affected mice showed morphological changes characterized by hydropic and subnuclear vacuolar changes and focal scalloping, with no apparent inflammation or glandular destruction. Moreover, mice with elevated thyroxine levels showed increased in vivo thyroidal uptake of 131Iodine. Together, these data suggest that BALB/cJ mice are susceptible to the induction of hyperthyroxinemia.

Congenital linear sebaceous nevus syndrome

CONGENTIAL LINEAR SEBACEOUS NEVUS syndrome is characterized by yellow or tan verrucous lesions distributed over the body in a linear pattern. Children with this syndrome may also have seizures, mental retardation, and hypophosphatemic rickets. We report a Caucasian male who was diagnosed with this syndrome at 2 months of age, with linear sebaceous nevi covering 50% of his body surface area (A). However, he had no central nervous system manifestations of the syndrome, nor did he have radiographic evidence of rickets (B) at the time of diagnosis. When he had several nevi removed at age 2.5 years, both his height, 83 cm, and his weight, 10.4 kg, were below the fifth percentile for age, and he had rickets on long bone films (C). Hypophosphatemia (2.5 mg/dl), normocalcemia (ionized calcium 5.24 mg/dl), and normal serum parathyroid hormone concentration by immunoradiometric assay (35 pg/ ml) were observed. Serum levels of 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D were normal, 32.6 ng/ml, and low-normal, 21 pg/ml, respectively. Renal tubular reabsorption of phosphate was slightly decreased, at 79%, and 24-h urinary calcium excretion was only 1 mg. Oral phosphate, calcium, and magnesium intakes were 81, 95, and 125%, respectively, of recommended dietary intake for age. Histology revealed striking acanthosis and papillomatosis, reflecting proliferation of keratinocytes (D), and the presence of numerous rudimentary hair follicles associated with small sebaceous, exocrine, and apocrine glands. This case points out that rickets in congenital linear sebaceous nevus syndrome, like X-linked hypophosphatemic rickets, may not be apparent for the first few months of life. Moreover, in light of the normal circulating levels of 1,25-dihydroxy vitamin D in our patient and in one other reported case, the concept of this syndrome must be expanded to allow for calcitriol levels higher than those originally reported.

Detection of Autoantibodies to the Thyrotropin Receptor

Publisher Summary The thyrotropin (TSH) receptor is a member of the large family of guaninenucleotide-binding (G) protein-coupled receptors. The cDNA encoding the human TSH receptor has recently been cloned and characterized. Like all other G-protein-coupled receptors, the TSH receptor has an extracellular domain, seven transmembrane domains, and an intracellular domain. The TSH and other glycoprotein hormone receptors each have relatively large extracellular domains, and this characteristic differentiates them from the other G-protein-coupled receptors. Recent studies have confirmed that both TSH and autoantibodies to the TSH receptor (TSHrAb) bind to the extracellular domain. The transmembrane and intracellular domains are involved in signal transduction, acting through G-protein to stimulate the cyclic adenosine monophosphate (AMP) and phosphatidol–inositol pathways. Mammalian cell transfection with the cDNA results in expression of the human TSHr protein. Another approach to define structure–function relationships is to use peptides and antipeptide antibodies. It should be apparent from this chapter that there is no general consensus on epitopes of TSHr involved in interactions with TSH or autoantibodies.