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Paper text:
fabry disease ( fd ) is an x - linked recessive disorder caused by lysosomal -galactosidase a 
 deficiency and is characterized by the systemic accumulation of globotriaosylceramide ( 1 ) .
fd is recognized as a multiorgan disease with 
 involvement of the heart , kidney , brain and gastrointestinal system ( 2 ) .
recently , endocrine dysfunctions including subclinical hypothyroidism 
 add to the clinical picture of fd ( 3,4,5,6 ) . in the present study ,
the patient is a boy born to a healthy japanese father and a white american mother .
the 
 mother was diagnosed with autoimmune hypothyroidism at 30 yr of age and was started on 
 thyroid hormone replacement therapy .
he had been doing well until 10 yr of age , but his growth curve indicated 
 stunted growth since then . at 11 yr and 6 mo of age ,
laboratory 
 findings indicated low serum free t3 and t4 and high serum tsh ( table 1 ) .
based on these findings , the patient was 
 diagnosed as suffering from primary hypothyroidism due to autoimmune thyroiditis and was 
 started on levothyroxine ( l - t4 ) replacement therapy at a dose of 100 g / d , to which he 
 responded well , as shown by an increasing height velocity and a decreasing body mass index 
 ( table 1 ) .
table 1   clinical course of the patientchronological agenormal 
 range11 yr 6 mo12 yr 4 mo13 yr 1 mo13 yr 11 mo14 yr 6 moheight ( cm)146.2152.2158.0165.7171.2height sd+0.1 + 0.1 + 0.1 + 0.5 + 0.9weight ( kg)45.846.747.850.754.0bmi ( kg / m)21.420.119.118.518.4tanner stage12234free t3 ( pg / ml)2.23.84.03.63.22.34.3free t4 ( ng / dl)0.61.61.91.31.20.91.7tsh ( u / ml)1150.70.53.07.80.55.0thyroid test1,600<100microsome test100<100l - t4 ( g / d)-100100100100bmi , body mass index ; l - t4 , levothyroxine . 
 
bmi , body mass index ; l - t4 , levothyroxine . at 12 yr and 4 mo of age ,
he 
 recurrently experienced burning pain in his feet since then . at 14 yr and 4 mo of age , he 
 complained of burning pain in his feet when taking a hot bath .
based on these findings , it 
 was suspected that he might suffer from fd , and his -galactosidase a activity was 
 determined in a blood sample spotted on filter paper ( 7 ) ; he had very low activity ( 3.9 units , normal range > 17.0 units ) and thus was 
 diagnosed as having fd . at 14
yr and 6 mo of age , a thyroid function test revealed an 
 elevated serum tsh level ( table 1 ) .
the patient and parents decided to start supplemental 
 enzyme treatment with recombinant -galactosidase a at another university hospital , to which 
 we referred him .
complete blood counts , urinalyses and serum creatinine and urea nitrogen levels were normal 
 during the follow - up period at our hospital .
the recombinant -galactosidase a replacement therapy for fd has been demonstrated to be 
 effective in prevention or alleviation of the progression of tissue damage ( 8,9,10,11 ) . since the 
 replacement therapy is now available in japan ( 12 ) , 
 it has become crucial for a better outcome to make the diagnosis as early as possible . in 
 our patient ,
the burning pain in his feet was the only clue for the diagnosis , and it took 
 us two years to diagnose him as suffering from fd .
the delay in diagnosis was caused , at 
 least in part , by the lack of easy access to the -galactosidase a assay .
therefore , we 
 assume that easier access to the assay should make early diagnosis feasible .
we did not have 
 an opportunity to measure the -galactosidase a activity in his apparently normal younger 
 brother .
measurement of the activity should have helped us to determine whether he suffers 
 from fd or not . since the first report by tojo et al . describing a 48-yr - old male fd 
 patient with primary hypothyroidism and marked globotriaosylceramide accumulation in the 
 thyroid gland ( 3 )
, primary thyroid dysfunction has 
 been well recognized as one of manifestations in fd patients older than 30 yr of age , which 
 is characterized by only mildly elevated serum tsh levels and normal serum free t4 levels , 
 that is , subclinical hypothyroidism ( 4,5,6 ) . in fd 
 patients ,
the thyroid gland is not enlarged , and thyroid autoantibodies are negative ( 3,4,5,6 ) . 

ultrasonography of the thyroid glands has been reported to show no abnormalities ( 4 ) or to reveal high incidence of a mild hypoechoic 
 pattern ( 5 , 6 ) . 
 of note ,
therefore , thyroid dysfunction in fd patients is very 
 likely to be caused by accumulation of globotriaosylceramide in the gland , not by 
 antithyroid autoimmunity .
although we did not have an opportunity to perform ultrasonic examination of the thyroid 
 gland , we diagnosed our patient as suffering from primary hypothyroidism due to autoimmune 
 thyroiditis because of the following findings : 1 ) he had a positive family history of 
 autoimmune hypothyroidism , 2 ) he developed overt hypothyroidism as young as 11 yr of age , 3 ) 
 he had diffusely enlarged goiter and 4 ) he had clearly positive antithyroid autoantibodies . 
 to our knowledge , this is the first fd patient with overt autoimmune hypothyroidism . 

treatment with l - t4 successfully normalized his thyroid function , but his serum tsh level 
 rose again in 3 yr .
the elevation may be attributable to the increase in his body size 
 and/or to the globotriaosylceramide accumulation in the thyroid gland caused by the 
 coexistent fd . in any case
, we described the first patient suffering from fd superimposed on overt 
 autoimmune hypothyroidism .
fabry disease ( fd ) is an x - linked recessive disorder caused by lysosomal -galactosidase 
 a deficiency . 
 fd is characterized by the systemic accumulation of globotriaosylceramide 
 with involvement of the heart , kidney , brain and gastrointestinal system . 
 recently , 
 nonautoimmune thyroid dysfunction was recognized as an additional clinical feature of fd . 
 in the present study 
 , we describe a patient suffering from fd superimposed on overt 
 autoimmune hypothyroidism . 
 the patient was an 11-yr - old boy who presented with goiter and 
 stunted growth , and was diagnosed with primary hypothyroidism due to autoimmune 
 thyroiditis . during levothyroxine replacement therapy , the patient complained of burning 
 pain in his feet and was diagnosed as suffering from fd based on low blood -galactosidase 
 a activity . in conclusion , we have described the first fd patient preceded by overt 
 autoimmune hypothyroidism .