□ CASE REPORT □

HDR Syndrome (Hypoparathyroidism, Sensorineural Deafness and Renal Disease) Accompanied by Renal Tubular Acidosis and Endocrine Abnormalities

Abdullah Taslipinar 1, Levent Kebapcilar 1, Mustafa Kutlu 1, Mustafa Sahin 1, Aydogan Aydogdu 1, Gokhan Uckaya 1, Omer Azal 1,ErolBolu1 and Halil !brahim Aydın 2

Abstract

Type 1 (distal) and type 2 (proximal) renal tubular acidosis (RTA) are uncommon disorders, particularly in adults. HDR syndrome (hypoparathyroidism, sensorineural deafness and renal disease) is an autosomal domi- nant condition, defined by the triad hypoparathyroidism, renal dysplasia and hearing loss. Here, we describe a 19-year-old man with HDR syndrome accompanied by renal tubular acidosis and endocrinopathic changes.

Key words: HDR syndrome, renal tubular acidosis, polyendocrine syndrome

(Inter Med 47: 1003-1007, 2008) (DOI: 10.2169/internalmedicine.47.0917)

The presence of Fanconi’s syndrome could be considered in Introduction any patient with phosphaturia, uricosuria, generalized ami- noaciduria, renal glycosuria (5). Hypoparathyroidism, deaf- The renal tubule is responsible for the reabsorption of ness and renal dysplasia (HDR) syndrome is an autosomal more than 99% of the water and sodium in the glomerular dominant disorder characterized by hypoparathyroidism, sen- ultrafiltrate. Congenital or acquired tubular dysfunction can sorineural deafness and renal dysplasia (6). This syndrome therefore readily cause profound electrolyte and volume dis- is primarily caused by haplo-insufficiency of the dual zinc turbance. The tubule also regulates acid-base balance, min- finger transcription factor, GATA3, which is contained on eral homoeostasis, and the excretion of organic anions and the short arm of chromosome 10 (7). drugs. Renal tubular acidosis (RTA) is a medical condition Autoimmune polyendocrine syndromes (APS), first re- that involves an accumulation of acid in the body due to a ported by Neufeld and coworkers, have been defined as a failure of the kidneys to appropriately acidify the urine. heterogeneous group of diseases involving autoimmune dis- Type 1 (distal) and type 2 (proximal) renal tubular acidosis orders associated with multiple endocrine-gland insuffi- (RTA) are uncommon disorders, particularly in adults (1). ciency (8). The syndromes are designated as APS types I, II, Distal renal tubular acidosis (dRTA) is characterized by III and IV. The type-III syndrome consisting of autoimmune impaired renal tubular excretion of acid leading to hyper- disease combined with any autoimmune glandular chloremic acidosis with inappropriately alkaline urine (2). dysfunction apart from adrenal insuffiency and/or hypopara- Most subjects also suffer from recurrent nephrolithiasis (3), thyroidism (9). Herein, we report the combination of HDR musculoskeletal symptoms and markedly reduced bone mass syndrome and renal tubular acidosis with autoimmune poly- early in life (4). endocrine syndrome type III; this is an extremely rare situ- Proximal RTA may occasionally present as an isolated de- ation. fect, but is more commonly associated with generalized proximal tubular dysfunction called the Fanconi’s syndrome.

１Department of Internal , Division of and Metabolism, Gulhane Military Medical Faculty, Ankara, Turkey and ２Depart- ment of , Division of Metabolism, Gulhane Military Medical Faculty, Ankara, Turkey Received for publication January 14, 2008; Accepted for publication February 25, 2008 Correspondence to Dr. Levent Kebapcilar, [email protected]

1003 Inter Med 47: 1003-1007, 2008 DOI: 10.2169/internalmedicine.47.0917

Figure 1. Urine chromatography for amino acids showed generalized aminoaciduria.

Blood chemistry showed AST 16 U/L, ALT 11 U/L, ALP Case Report 461 U/L, LDH 145 U/L, total bilirubin 0.38 mg/dL, urea ni- trogen 50.0 mg/dL, creatinine 1.49 mg/dL, sodium 134 A 19-year-old man was admitted to our hospital to deter- mEq/L, potassium 3.3 mEq/L, chloride 104 mEq/L, uric mine the etiology of recurrent stone formation, muscle acid 1.91 mg/dL, total protein 7.08 g/dL with an albumin weakness, sensorineural deafness and short stature. He was level of 4.13 g/dL. Fasting blood glucose was 75 mg/dL. admitted to hospital at the age of 6 because of poor growth. However, serum levels were within the normal A biochemical investigation revealed acidemia. A diagnosis range, and levels were slightly lower of Fanconi’s syndrome and hypophosphatemic rickets and than normal range. Serum calcium and intact parathyroid normocalciuria were made. The patient was started on a sys- hormone levels were 9.25 mg/dL and 4.2 pg/mL, respec- temic alkali (oral sodium - potassium citrate supple- tively. Serum was 38 ng/mL and protein electro- mentation) to correct acid-base balance and vitamin D for phoresis was normal. hypophosphatemic rickets. At the time of admission he had Arterial blood obtained on room air yielded the following: not been receiving systemic alkali therapy or vitamin D for pH 7.24, partial pressure of carbon dioxide 28.9 mmHg, - 6 years. partial pressure of oxygen 110.4 mmHg, HCO3 20.9 mmol/ When the patient was 8 years old he underwent a routine L. Under the condition, urine pH (7.50) was inappropriately audiological assessment, which showed sensorineural hear- alkaline. The serum anion gap, calculated by Na+-(Cl-+ - ing loss (SNHL) in the right ear and normal hearing in the HCO3 ) was 11.8 mEq/L. left ear. Over the subsequent years, repeated audiologic Urinalysis showed a specific gravity of 1.010, pH of 7.50, evaluations revealed bilateral progressive SNHL. He under- proteinuria of 1.7 g/day, generalized aminoaciduria (Fig. 1), went repeated -pulse , but his hearing loss uricosuria and renal glycosuria of 1.06 g/day. Microscopic did not improve. His parents were cousins, and were examination of urinary sediment revealed 1-2 red blood cells healthy. He has only one sister. The patient’s sister had a per high-power field and no casts. Excretion of 24 hour uri- complaint of progressive hearing loss, but no further investi- nary calcium and phosphorus was 596.25 and 859.50 mg/ gation was done. day, respectively and hypercalciuria was found. His cre- On admission, he was 147.0 cm in height and 47 kg in atinine clearance was 59.3 mL/min. weight, pulse 76 beats/min, blood pressure 115/75 mmHg in From the result of high urinary pH, uricosuria, general- a recumbent position. Auditory brainstem responses were ized aminoaciduria, renal glycosuria with chronic renal in- not observed at 105 dB in the right ear and at a threshold sufficiency, hypoparathyroidism, and formation of nephro- elevation of 80 dB in the left ear. Examination of the blood calcinosis, sensorineural deafness and hypokalemia, hyper- on admission showed red blood cell count 4.68×106/L, he- calciuria, nephrolithiasis suspected HDR syndrome associ- moglobin 13.1 g/dL, hematocrit 39.5%, platelet count 142× ated with dRTA and Fanconi’s syndrome were found in this 3 3 10 /L, white blood cell count 7.2×10 /L with 54% seg- patient. The NH4Cl loading test was omitted because the pa- mented neutrophils, 34.3% lymphocytes, and 7.9% mono- tient had already exhibited overt acidemia. The hypokalemia cytes. The erythrocyte sedimentation rate was 10 mm/h. and metabolic acidosis, hypercalciuria, nephrolithiasis with

1004 Inter Med 47: 1003-1007, 2008 DOI: 10.2169/internalmedicine.47.0917

Table 1. Serum and Urinary Data on Admission

+ normal anion gap at the urine pH of 7.50 strongly indicated urinary NH4 excretion. Therefore, a diagnosis of Type 1 the presence of Type 1 RTA. Urine anion gap (Na++K+-Cl-) RTA was made. A renal ultrasound showed a slightly re- was positive (43 mEq/L), which is suggestive of impaired duced renal cortex and medullary area suggested nephrocal-

1005 Inter Med 47: 1003-1007, 2008 DOI: 10.2169/internalmedicine.47.0917 cinosis. deletion-mapping studies and subsequent mutation analysis. Bone densitometry revealed osteoporosis of both trabecu- In this case it may be necessary to make a comparison of lar and cortical bone (spine 0.619 g/cm2 (T-score-4.0 SD), HDR syndrome with hereditary dRTA. Distal RTA is charac- femoral neck 0.617 g/cm2 (T-score-2.8 SD), whole body terized by a failure of urinary acidification, hypokalaemia 0.686 g/cm2). and hypercalciuria leading to nephrocalcinosis and, poten- Hormonal investigation showed autoimmune thyroid dis- tially, stone formation. Like the present case, a significant function (TSH: 7.58 microIU/mL; free T4 and T3 within number of patients with autosomal recessive distal RTA also normal range, antiTg: 327.7 IU/mL) and thyroid ultra- have sensorineural deafness (12). sonography revealed a nonhomogenous structure of the However, it has not been reported that patients with he- gland. In plasma androgens levels (plasma total testosterone reditary dRTA have accompanying hypoparathyroidism. In 259 ng/dL and free testosterone 3.76 pg/mL) were decreased view of these points, we considered that this patient had and hypergonadotropic hypogonadism (FSH: 81.43 mIU/ HDR syndrome accompanied with hereditary dRTA. To di- mL, LH: 81.05 mIU/mL) was found. We found small testes agnose precisely, mutation analysis may have been neces- in pelvic ultarasonography. We performed chromosomal sary but we were unable to perform this. evaluation to rule our Klinefelter syndrome and normal Although in HDR syndrome serum calcium can be karyotype was found. slightly lower than the normal limit, in the present case the The patient was diagnosed as having APS type III due to calcium level was in the normal range. In this point, we the presence of hypergonadotropic hypogonadism, and thy- considered that continous or intermittent metabolic acidosis roid in the absence of adrenal disease. We caused dissolution of bones leading to osteomalacia such analyzed the cortisol level in response to hypoglycemia to that the serum calcium level was maintained within the nor- rule out adrenal insufficiency in patient. mal range. Additionallly in the present case, we suspected To prevent the progression of nephrocalcinosis and a new hypercalciuria leading to nephrocalcinosis and chronic renal episode of urinary stones, we started administration of four failure. It is well known that recurrent urolithiasis due to hy- tablets of potassium-sodium citrate per day, 25 mg/day percalciuria can significantly affect renal function and lead levothyroxine and testosterone 50 mg/day medication. Tes- to nephrocalcinosis and chronic renal insufficiency (13). tosterone therapy may help enhance secondary sex charec- While other studies have shown that nephrocalcinosis may teristics and prevent osteoporosis and improve general well- develop during vitamin D treatment (14), in the present being. case, it is unlikely that vitamin D intoxication caused neph- rocalcinosis, because he had not been taking a medication of Discussion systemic alkali therapy and vitamin D for six years. In comparison to the usual presentation of HDR syn- Hearing loss in combination with hypoparathyroidism and drome and dRTA, our case exhibited features of the proxi- renal dysplasia was first described in patients in 1977 (10). mal tubule dysfunction, including renal glycosuria, general- Hasegawa et al (11) termed this disease “HDR syndrome” ized aminoaciduria, uricosuria. The mechanisms by which and identified the responsible gene map at chromosome 10p. both functions of proximal and distal tubules were affected Haploinsuffiency or zinc-finger transcription factor glutamyl in the present case remain unknown. amidotransferase-subunit A (GATA 3) or mutations involv- The present case was also complicated by hypergonad- ing GATA 3 gene appears to be underlying cause of this otropic hypogonadism, and autoimmune thyroiditis. Autoim- syndrome (7). mune polyendocrine syndrome was diagnosed in this patient HDR syndrome is an autosomal dominant disorder, char- due to the presence of hypergonadotropic hypogonadism and acterized by hypoparathyroidism, sensorineural deafness and thyroid autoimmunity. In the absence of adrenal disease, the renal dysplasia including abnormal renal imaging, nephrosis, coexistence of autoimmune with other auto- abnormal renal tubular function. The sensorineural deafness immune diseases is defined as APS type III (9). is usually bilateral and hearing loss is typically moderate to In summary, we described a very rare case of proximal severe and present at birth. and distal RTA with HDR syndrome who exhibited endo- The present case was diagnosed as HDR syndrome based crinopathic disorders. Endocrine evaluation may be neces- on the patient’s clinical manifestations unfortanately without sary for these patients especially with HDR syndrome.

References

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