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BRIEF REPORT |
Departments of Endocrinology and Metabolic Diseases (P.M., N.A.T.H., S.E.P.) and Clinical Genetics (S.G.K.), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Address all correspondence and requests for reprints to: Socrates E. Papapoulos, M.D., Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. E-mail: m.v.Iken{at}lumc.nl.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsDiscussionReferences |
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Objective: Our objective was to describe long-term observations of a family with XLH due to a novel mutation of the PHEX gene with unusual clinical features, including normal growth.
Patients: The mother and her two sons were followed in the same institution for nearly 30 yr.
Results: The mother had hypophosphatemia and normal height (Z score, –0.6) without ever receiving any treatment. Her two sons achieved final heights of 183.7 cm (Z score, –0.01) and 182.7 cm (Z score, –0.18), respectively, despite late initiation of treatment with phosphate and low serum phosphate levels. In addition, they had reversible proximal myopathy that took about 7 yr to resolve in one of them. Direct sequencing of the PHEX gene revealed a new splice site mutation in intron 4 of the gene (IVS4+6T
C) resulting in skipping of exon 4.
Conclusions: Three members of a family with XLH due to a novel mutation of the PHEX gene had a normal growth pattern despite late diagnosis and treatment of the two boys and no treatment at all of their mother. The pathophysiological basis of this phenotype-genotype association warrants further investigation.
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Introduction |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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We report here long-term observations, covering a 30-yr span, of three members of a family with XLH due to a novel mutation of the PHEX gene presenting with unusual clinical features, including normal linear growth and proximal myopathy.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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A 31-yr-old male was diagnosed at the age of 20 months with vitamin D-resistant hypophosphatemic rickets, and he was treated with vitamin D2 up to 30,000 IU/d. He developed vitamin D intoxication that resolved slowly after discontinuation of vitamin D.
He was referred to our Department of Pediatrics at the age of 3.4 yr for evaluation of difficulty in walking. On examination, the most prominent clinical feature was proximal myopathy, confirmed by electromyography and a muscle biopsy. Height was normal for age (101.8 cm, Z score, –0.53). Serum calcium was 2.53 mmol/liter (normal, 2.2–2.6 mmol/liter), phosphate 1.06 mmol/liter (normal for age,1.2–1.8 mmol/liter), phosphate clearance 21.8 ml/min·1.73 m2 (normal, 11.2 ± 5.9ml/min·1.73 m2), 25-hydroxyvitamin D (25-OHD) 200 nmol/liter (normal, 30–120 nmol/liter), PTH 70 pg/ml (normal, 9–90 pg/ml), alkaline phosphatase (ALP) 232 U/liter (normal, 145–420 U/liter), and creatine phosphokinase normal. Skeletal x-rays showed no evidence of rickets, but the boy had mild genu varum requiring an osteotomy and bilateral medial epiphysiodesis of proximal tibiae at the age of 14.5 yr. He was treated with dihydrotachysterol (0.2–0.8 mg/d) and phosphate (2 g/d) in four divided doses.
Normal linear growth was maintained over the following years (Fig. 1
), and there was a slow progressive improvement in his myopathy, which took about 7 yr to completely resolve. Serum phosphate, on treatment, fluctuated between low and low-normal values (Fig. 1).
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Analysis of DNA, obtained after informed consent of the patient, revealed a new donor splice site mutation (http://www.phexdb.mcgill.ca/) in intron 4 of PHEX gene (IVS4 + 6TC). This was not a single-nucleotide polymorphism. There were no mutations of the FGF23 gene.
Case 2
The 33-yr-old brother of case 1 was diagnosed at the age of 3 yr with vitamin D-resistant hypophosphatemic rickets and he was treated with vitamin D2 up to 60,000 IU/d.
At the age of 5 yr, he was referred to the Department of Pediatrics with difficulty in walking and symptoms suggestive of hypercalcemia. Clinically, he had proximal myopathy, normal height (109 cm; Z score, –0.36), signs of a rachitic rosary, bowing of the tibiae, and multiple dental abscesses. Electromyography was normal. Serum calcium was 3.22 mmol/liter, phosphate 1.11 mmol/liter, 25-OHD 181 nmol/liter, and phosphate clearance 34.6 ml/min·1.73 m2; PTH was low, ALP was 210 U/liter, and creatine phosphokinase was normal. Rehydration and a course of prednisone led to rapid normalization of serum calcium concentrations. Two months later, he was started on dihydrotachysterol 0.4 mg/d and phosphate 2 g/d in divided doses. In the following years, the dose of dihydrotachysterol varied from 0.2–0.6 mg/d. Myopathy subsequently resolved after 8 months, and his serum phosphate on treatment was on a few occasions within the reference range. He continued to grow at a normal rate (Fig. 2).
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), despite persistent mild impairment of renal function. BMD measured at the age of 25 yr was high (L1–L4 T-score, +7.19; femoral neck T-score, +4.50). After informed consent, DNA analysis revealed the same mutation in the PHEX gene as his brother. RT-PCR of total RNA from peripheral blood leukocytes as template, with primers located in exons 2 and 5, showed a single shortened product. Sequencing of this product revealed skipping of exon 4, which is predicted to result in an in-frame deletion of 87 nucleotides.
Case 3
The mother of the two patients was first seen in our department at the age of 46 yr. She complained of tiredness but had no other specific complaints. She had never received any bone-specific treatment. She had a strong family history of XLH (grandfather, mother, two of her three brothers, her two sisters, and two of her three sons). The height of her unaffected son was 182.1 (midparental height prediction, 176.5 ± 8.5 cm) and that of her husband was 180.1 cm.
Clinical examination was unremarkable. There were no phenotypic features of XLH, and height was 160 cm (Z-score, –0.6) (9). Serum phosphate was 0.64 mmol/liter and remained low during frequent sampling over 24 h, TmP/GFR was 0.50 mmol/liter, serum 25-OHD was 54 nmol/liter, and serum 1,25-DHD varied between 39 and 54 pmol/liter. A transiliac bone biopsy showed bone with normal lamellar structure, normal turnover, small areas with increased osteoid thickness, and diffuse tetracycline uptake with only small areas of vague double labeling, findings consistent with focal osteomalacia.
During 17 yr of follow-up, the patient had no bone complaints, but she progressively developed joint pains, with, however, no radiological evidence of osteoarthritis or enthesiopathy, serum phosphate remained low or at the lower end of the reference range, and she did not receive any treatment with calcitriol or phosphate. BMD 3 yr after the menopause was high (L1–L4 T-score, +2.34; femoral neck T-score, +1.95). The patient did not consent to DNA analysis.
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Discussion |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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The most striking clinical feature of this family, with a documented mutation of the PHEX gene, was their normal linear growth. This occurred despite the relatively late start of treatment and the generally low serum phosphate levels on treatment in the two male patients and the absence of treatment in their mother. Linear growth failure is a hallmark of XLH (13). Time of diagnosis and treatment are considered major determinants of linear growth, and it has been reported that patients treated during the first year of life grew better than these treated later. In addition, growth failure occurs almost always in patients diagnosed after the age of 3 yr despite adequate treatment.
In our male patients, the diagnosis was made at the ages of 1.8 and 3 yr, respectively, and phosphate supplements were added to treatment at the ages of 3.5 and 5 yr, respectively. This relatively late diagnosis and treatment had no impact on the final height of the patients, which was within the norms of the Dutch population. In addition, both patients developed no body disproportionality. This unusual presentation is further underlined by the fact that both patients were male. In most reported series, boys are more severely affected than girls (14, 15, 16, 17), and this is also our experience. However, a distinguishing feature of the two patients described here was their normal height both at diagnosis and at initiation of therapy, supporting the contention that the best predictor of growth is height at start of treatment (11, 15, 18). In addition, their mother grew normally without ever receiving any therapy. These observations, which exclude hypophosphatemia as a major determinant of growth in this family, suggest that the normal growth pattern may be related to the mutation detected in the PHEX gene, resulting possibly from some retained biological activity of the shortened PHEX protein. Treatment, although essential for healing rickets, does not appear to play a major role in linear growth. Previous reports have already suggested that genetic environment may be the major determinant of final height and body proportions in XLH patients (17, 19, 20).
An additional intriguing clinical feature was the reversible proximal myopathy that was more severe in case 1 and took about 7 yr to resolve. Hypophosphatemia is a known cause of muscular weakness that can be associated with abnormal electromyographic and histological findings, but the mechanism is unknown. This abnormality has not been described in patients with XLH (5). Furthermore, myopathy resolves within days or weeks after vitamin D treatment in patients with vitamin D deficiency or after tumor resection in patients with tumor-induced osteomalacia. In our cases, we do not have an adequate explanation for the muscular weakness observed before treatment and during vitamin D intoxication and its persistence independently of treatment or serum phosphate levels. In addition, the mother had no symptoms or signs of myopathy at presentation at the age of 46 yr.
Finally, all three cases had high BMD, as frequently seen in such patients (5), reinforcing the potential discrepancy between BMD measurements and bone material and structural properties depending on the underlying cause of the bone disease.
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Acknowledgments |
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Footnotes |
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First Published Online February 5, 2008
Abbreviations: ALP, Alkaline phosphatase; BMD, bone mineral density; 1,25-DHD, 1,25-dihydroxyvitamin D; 25-OHD, 25-hydroxyvitamin D; TmP/GFR, transport maximum of phosphate per glomerular filtration rate; XLH, X-linked hypophosphatemic rickets.
Received June 11, 2007.
Accepted January 29, 2008.
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References |
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TopAbstractIntroductionPatients and MethodsDiscussionReferences |
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This article has been cited by other articles:
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  J. Kim, K. H. Yang, J. S. Nam, J. R. Choi, J. Song, M. Chang, and K.-A Lee A Novel PHEX Mutation in a Korean Patient with Sporadic Hypophosphatemic Rickets Ann. Clin. Lab. Sci., January 1, 2009; 39(2): 182 - 187. [Abstract] [Full Text] [PDF]
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