From the Third Department of Internal Medicine (Drs. Machigashira, Wang, and Osame), School of Medical Sciences (Dr. Yoshida), Faculty of Medicine, Kagoshima University, Sakuragaoka, Kagoshima, Japan.
Address correspondence and reprint requests to Dr. Yoshihiro Yoshida, School of Medical Sciences, Faculty of Medicine, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima, 890-8506, Japan; e-mail: yoshiday{at}health.nop.kagoshima-u.ac.jp
In many short-stature patients with human T-lymphotrophic virustype I–associated myelopathy/tropical spastic paraparesis(HAM/TSP), signs and symptoms were manifested during childhood.Successive investigations revealed 12 of 14 short-stature patientswith pseudohypoparathyroidism (PHP) from the findings of shortmetacarpi, parathyroid hormone infusion test, immunoblottingof erythrocyte membrane, or lymphocytic Northern blotting ofGs. Patients with PHP probably showed HAM/TSP based on theirmodified immunologic status. Human T-lymphotrophic virus typeI infection did not induce PHP, but PHP may be a risk factorfor the occurrence of HAM/TSP.
Human T-lymphotrophic virus type I– (HTLV-I–) associatedmyelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic,slowly progressive myelopathy caused by HTLV-I. The main neurologicfindings are spastic paraparesis and urinary disturbance. Theincidence of HAM/TSP among HTLV-I–infected individualsis estimated to be less than 1%.1 This suggests that occurrenceof HAM/TSP requires additional factors, such as viral factorsand host conditions.
Among 213 patients with HAM/TSP diagnosed at our universitybefore 1993, 172 patients had no history of blood transfusion.Although HTLV-I was mainly transmitted by maternal milk, 151patients did not begin to show symptoms of HAM/TSP until middleor old age. However, 21 of 213 patients presented symptoms atless than 15 years of age. These juvenile-onset patients appearedto have characteristic signs of short stature and hypocalcemia.Among them, three juvenile-onset patients with HAM/TSP and pseudohypoparathyroidismtype Ia (PHP Ia) have already been reported.2
The purpose of the current study was to clarify whether short-staturepatients with HAM/TSP had a tendency to exhibit signs and symptomsduring early age and whether this was related to PHP Ia.
HAM/TSP was diagnosed according to World Health Organizationdiagnostic guidelines. We classified the heights of HAM/TSPpatients using the table of Japanese average height againstsex and ages (1995), and we examined 14 patients with HAM/TSPcomplicated with short stature for PHP Ia ( table 1). We appliedthe following criteria for diagnosis of PHP Ia: 1) serum levelsof calcium, phosphorus, and parathyroid hormone (PTH); 2) shortstature, round face, obesity, slight mental retardation, andshort metacarpi—signs of Albright’s hereditary osteodystrophy(AHO); 3) resistance to PTH loading test (Ellsworth–Howardtest, E-H test); and 4) -subunit of the stimulatory guaninenucleotide-binding protein (Gs) abnormality. We used the WechslerAdult Intelligence Scale (WAIS) to determine IQ.
Table 1. Clinical and laboratory findings of the short stature patients with human T-lymphotrophic virus type 1–(HTLV-1–) associated myelopathy/tropical spastic paraparesis
The renal resistance for external PTH was examined from urinarycAMP excretion in response to 100 units of human recombinantPTH 1–34 (Asahi Chemical Ind., Tokyo, Japan) (E-H test).We set a <1 µmol increase of urinary excretion afterPTH injection for 1 hour as positive. Erythrocyte membrane preparedby Dodge’s procedure was subjected to 10% sodium dodecylsulfate polyacrylamide gel electrophoresis and transferred toa nitrocellulose membrane. Western blotting was conducted withanti-Gs antibody (K-20 antibody; Santa Cruz Biotechnology, Inc.,Santa Cruz, CA) and peroxidase conjugated rabbit anti-IgG antibody(Jackson Immunoresearch Laboratories, West Grove, PA) as a secondaryantibody.
Twenty milliliters of heparinized blood was collected with thepatient’s permission, and lymphocytes were separated usinga Ficoll-Hypaque solution (Mono-Poly Resolving Medium; DainipponPharmaceutical Co., Osaka, Japan). Total cellular RNA was extractedwith 1 mL of RNAzol B (Cinna Biotecx, Houston, TX) per 106.Five micrograms of RNA were subjected to Northern blotting witha [32P]-labeled Gs cDNA.
Among the 294 patients with HAM/TSP who were examined before1995, 51 were found to have short stature (less than -1 x SDagainst Japanese average height). Among them, 34 were adult-onsetpatients and 17 were juvenile-onset patients. Furthermore, amongthe short-stature patients measured against Japanese averageheight, the rate of juvenile-onset patients was significantlyhigher ( table 2). The short-stature patients tended to manifestthe signs and symptoms during early age.
Table 2. Correlation of patients with juvenile-onset human T-lymphotrophic virus type 1–(HTLV-1–) associated myelopathy/tropical spastic paraparesis to short stature
Twenty-nine patients with juvenile-onset HAM/TSP (4 men, 25women) were identified among the 294 patients with HAM/TSP.Their heights are plotted in the figure. These findings showthat juvenile-onset patients were mainly those with short stature.
Figure. The relation of the heights to the age of male (A) and female (B) juvenile-onset patients with human T-lymphotrophic virus type I–associated myelopathy/tropical spastic paraparesis (HAM/TSP). Many juvenile-onset patients were apparently recognized with short stature compared with adult-onset patients and standard Japanese individuals. Japanese average heights against age and sex (1995) are shown by solid lines. Solid diamonds, adult-onset patients with HAM/TSP; open squares, juvenile-onset patients with HAM/TSP.
The clinical features of 14 short-stature patients with HAM/TSPare shown in table 1. Neither round face nor obesity was foundin these patients. A younger brother of Patient 14 (aged 44years, height 150 cm [-3.3 x SD]) and two sisters of Patient2 had HAM/TSP and short stature; however, extensive examinationwas not allowed.
The immunoreactivity of Gs, the 45 kDa molecular weight of humanerythrocyte membrane,3 was reduced in 11 patients and in theyoungest sister (aged 38 years, height 153 cm [-0.6 x SD], juvenile-onsetHAM/TSP) of Patient 5 (table 1).
The mRNA expression of Gs was reduced in Patient 3 and her mother,Patient 4, Patient 7 and his mother, and Patient 13, comparedwith that in normal controls (table 1). Only a few patientswere examined because of the large blood volume collection necessaryfor mRNA preparation.
These findings indicate that eight patients possibly had PHPIa and four patients possibly had pseudopseudohypoparathyroidism(PPHP).
PHP is a metabolic disorder characterized by AHO and resistanceto PTH. PHP Ia and PPHP are genetically the same disease. Thedecreased activity and the low protein levels of Gs are responsiblefor PHP Ia.4 We diagnosed four patients with PPHP who had nohormone resistance despite a Gs deficiency.
Although PHP is clinically diagnosed by the E-H test, we usedthe E-H test for several patients because the current patientshad urinary disturbances. Furthermore, most patients with anormal serum calcium level had normal reactions to PTH in theE-H test.5 We have no method to diagnose PHP Ib (PTH receptorabnormality), PHP Ic (adenylate cyclase deficiency), and PHPtype II. Therefore, we only diagnosed PHP Ia and the variant-typePPHP in the patients with HAM/TSP.
Autosomal dominant transmission is a known inheritance patternof PHP Ia.4 Among the families of 12 patients diagnosed withPHP Ia or PPHP, two of their mothers had PHP Ia or PPHP. Themother of Patient 14 was possibly diagnosed with PPHP becauseof slightly shorter stature (aged 71 years, height 145 cm [-0.6x SD]), WAIS IQ score of 85, and hypocalcemia (serum calciumlevel, 8.6 mg/dL).2 The current findings suggest that thesethree patients inherited the PHP gene from their mothers andthat HTLV-I had been originally transmitted to their mothersby their fathers. Many of the patients’ siblings had slightlyshorter stature, and most of the current patients were the youngerchildren in their families. However, further investigation wasimpeded by the death of the other patients’ parents.
The annual period prevalence of PHP was 3.4 per million peoplein 1997 in Japan. Variable clinical severity possibly calculatesthe number of patients with PHP less than the true number. Resultsof the current examination suggest that PHP is possibly nota rare disease; however, the incidence of PHP in HAM/TSP appearedhigh.
Abnormality of PHP is caused in part by reducing 1,25-dihydroxyvitaminD3 (1,25-(OH)2D3). 1,25-(OH)2D3 is recognized not only as acalcium regulator but also as an immunoregulatory hormone.6Vitamin D deficiency is often accompanied by infections suchas tuberculosis.7,8 1,25-(OH)2D3 has an inhibitory effect onthe release of interleukin-2 (IL-2) and interferon- from peripheralblood mononuclear cells.6 Levels of IL-2 mRNA of peripheralblood mononuclear cells from HAM/TSP patients are significantlyincreased compared with those from asymptomatic HTLV-I carriersand patients with ATL .9 IL-2 activates polyclonal proliferationsof HTLV-I–infected T cells.
1,25-(OH)2D3 inhibited the proliferation of MT-2 cells and theHTLV-I infected T-cell line in a time- and dose-dependent manner.10These findings suggest that patients with PHP had an inappropriateimmune defense system caused by decreased 1,25-(OH)2D3, whichmight be a host factor required for development of HAM/TSP.
Many kinds of diseases have been described in relation to HAM/TSP,such as T-lymphocyte alveolitis, Sjögren syndrome, arthropathy,uveitis, and PHP. These diseases, except for PHP, were probablycaused by infiltrations of HTLV-I–infected T cells tothe target organ. In contrast, HTLV-I infection does not inducePHP, but PHP may be a risk factor for the occurrence of HAM/TSP.
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Received March 20, 2000.
Accepted in final form August 24, 2000.
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Article Abstract
Introduction
. Patients with PHP probably showed HAM/TSP based on their modified immunologic status. Human T-lymphotrophic virus type I infection did not induce PHP, but PHP may be a risk factor for the occurrence of HAM/TSP. 
from peripheral blood mononuclear cells.6 Levels of IL-2 mRNA of peripheral blood mononuclear cells from HAM/TSP patients are significantly increased compared with those from asymptomatic HTLV-I carriers and patients with ATL .9 IL-2 activates polyclonal proliferations of HTLV-I–infected T cells. 
