Endocrine Journal 1996, 43(3), 339-343

NOTE

Early Detection of D Resistant Rickets

Infants with

(HDRR)

Hypophosphatemic Vitamin

KANSHI MINAMITANI, MASANORI MINAGAWA, TosHIYuKI YASUDA, AND HIRoo NIIMI

Department of Pediatrics, Chiba University School of Medicine, Chiba 260, Japan

Abstract. The onset of physical signs in infants with hypophosphatemic vitamin D resistant rickets

(HDRR) has generally been considered to be at the age of 12 months, but the time of appearance of hypophosphatemia and rachitic signs on radiographs remains unclear. We report a prospective study in three neonates whose mothers were HDRR. At birth, despite a low maternal serum inorganic

phosphorus (Pi) level, the serum Pi level was normal together with a negligible renal Pi leak in one neonate. At age 3 months, their serum Pi levels, percentages of tubular reabsorption of Pi, and renal tubular maximal rates of Pi reabsorption in relation to the glomerular filtration rate were low except for one infant. Radiographically, their rickets were not apparent at birth but at age 3 months in all. A

premature born infant, born at 28 weeks' gestation weighing 1240 g, was diagnosed as HDRR based on hypophosphatemia due to low renal tubular maximal rate of phosphorus reabsorption in relation to the

glomerular filtration rate (TmP/GFR) and normal urine Ca excretion at age 5 months. They were initially treated with 1a-hydroxyvitamin D3 (1a OHD3) and later with 1a OHD3 in combination with Pi, which results in healing of the rickets and a normal increase in height. Thus, early detection and treatment of patients born from mothers with HDRR before physical signs of bow-leg and short stature is possible, but the outcome of early treatment requires further study.

Key words: Hypophosphatemic vitamin D resistant rickets

phosphorus, Early detection

, Percentage of tubular reabsorption of

(Endocrine Journal 43: 339-343,1996)

THE ONSET of physical signs in infants with hy-

pophosphatemic vitamin D resistant rickets (HDRR) has generally been considered to be at the age of 12 months, at the time of weight bearing when leg deformities and progressive departure

from the normal growth rate become sufficiently striking to attract attention and make the parents

seek a medical opinion [1, 2]. We report three babies with infantile HDRR whose mothers were

HDRR.

Received: October 18, 1995 Accepted: February 6, 1996 Correspondence to: Dr. Kanshi MINAMITANI, Department of Pediatrics, School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260, Japan

Materials and Methods

Three neonates born from HDRR mothers were evaluated regularly from birth except for one start-ing age 3 months. Blood was analyzed for calcium

(Ca) [Normal value for infants; 9.0-10.5 mg/dl], inorganic phosphorus (Pi) [4.5-7.0 mg/dl], creati-nine (Cre) and alkaline phosphatase (Al-p) [450-800 IU/l]. Urine was analyzed for Ca, Pi and Cre. The percentage of tubular reabsorption of phos-

phorus (%TRP) was calculated and the renal tubular maximal rate of phosphorus reabsorption in relation to the glomerular filtration rate (TmP/ GFR) [Normal value for infants; 4.5-6.0 mg/dl] was determined by using the nomogram of Walton and Bijvoet [3]. Radiographs of the wrist and knee were also evaluated.

340 MINAMITANI et al.

All our studies were approved by the Chiba Uni-

versity Hospital Ethics Committee, and informed

consent was obtained from the patients' parents.

growth is normal at age 8 yr [height SD score; -1.0 SD] and without leg deformity.

Case 2

Case 1

Results

A boy, whose mother has HDRR with severe

osteomalacia, dwarfism [height SD score; -4.6] and leg deformities and had been treated during infan-

cy with vitamin D2 and whose elder sister was known to have a hereditary form of HDRR and

had been treated with combined 1u-hydroxyvita-min D3 (1a OHD3) and inorganic P since age 1 yr,

had been observed since age 3 months. He was fed a standard cow milk-based formula. At age 3

months, the results of a physical examination were normal, and laboratory data were within the nor-

mal range except for a slightly reduced Pi level and slightly high Al-p level. At age 4 months ap-

parent reductions in %TRP, TmP/GFR and Pi were revealed: 85% 2.6 mg/dl and 3.0 mg/dl, respec-tively (Table 1). Renal function parameters, urine

amino acids, urine gravity, urine pH, plasma bi-carbonate and plasma pH were all normal. At age

1 yr, the Al-p level was very high (1311 IU/l). Se-rum midportion parathyroid hormone (PTH-M) level was normal. Retrospectively, knee and wrist

radiographs at age 3 months showed cortical spurs and irregular metaphyseal ends (Fig. 1). He has

been treated with 0.2 , tg/kg of 1a OHD3 and 0.5 g of inorganic P since age 1 yr. The patient's linear

A boy, whose mother has HDRR with severe osteomalacia, dwarfism [height SD score - 3.6 SD],

and leg deformities and had received osteotomy

to correct bow-leg at age 10 yr, had been observed since birth. At birth, the serum Pi level in the cord

blood was normal and no renal Pi waste was ob-served, despite the presence of severe

hypophosphatemia in his mother (Table 2). The knee radiograph was also normal at that time (Fig.

2A). He was breast fed. At age 2 months, reduc-tions in %TRP, TmP/GFR and serum Pi and high

Al-p were observed: 83%, 3.0 mg/dl, 3.6 mg/dl and 1140 IU/l, respectively. At that time, knee

and wrist radiographs showed overt rickets (Fig. 2B). Serum PTH-M level was 1168 pg/ml, but se-

rum Ca and uCa/Cre were normal. He has been treated with 0.2 jig/kg of 1a OHD3 since age 2

months, and also with 1 a OHD3 and 0.5 g of inor-

ganic P since age 6 months. Serum PTH-M level and Al-p level normalized at age 6 months and at

age 2 yr (datum is not shown), respectively. At age 3 yr, the patient's height is -1.7 SD without

leg deformity.

Case 3

A girl, whose mother has HDRR with severe leg

deformity and dwarfism [height SD sore; -3.2 SD] and had received osteotomy at age 14-15 yr, and

Table 1. Laboratory and radiographic findings in Case 1

EARLY DETECTION OF D RESISTANT RICKETS 341

Fig. 1. Knee and wrist radiographs at age 3 months in

cortical spurs and irregular metaphyseal ends.patient 1. There are

Table 2. Laboratory and radiographic f indings in Case 2

Fig. 2. Knee an d wrist radiographs in patient 2 at birth (A) and at age 2 months (B).

342 MINAMITANI et al.

whose elder sister was known to have a hereditary

form of HDRR with rickets, dwarfism and leg de-formities and had been treated with combined 1a

OHD3 and inorganic P since age 1 yr 6 months, was born at 28 weeks' gestation and weighed 1270

g. She was immediately admitted to the neonatal intensive care unit. No abnormalities were noted at the initial biochemical examination when con-

sidering the premature baby and bone radiograph

(Table 3). From age 7 days, she was fed a stan-dard cow milk-based formula. She had been treated with 0.05 ,ug/kg of 1a OHD3 since age 2

months. At age 5 months, hypophosphatemia due to decreased TmP/GFR and normal urine Ca ex-cretion confirmed the diagnosis of HDRR. Serum

PTH-M level was normal. We have treated the

patient with 0.2 ,ug / kg of 1 a OHD3 and 0.5 g of inorganic P since age 8 months. At age 1 yr 3 months, rachitic signs disappeared on bone radio-

graphs, and at age 1 yr 6 months, serum Al-p normalized. At age 2 yr 9 months, the patient height is -1.9 SD without leg deformity.

Discussion

Familial HDRR is usually diagnosed in the sec-

ond year of life or later, by which time growth is compromised and severe leg deformity is evident

[1, 2]. There are, however, only a few reports on the early biochemical and radiographic findings in familial HDRR [4-7]. Schoen et al. and Moncrieff

reported that hypophosphatemia develops by age 2 months and rachitic changes develop by age 6

months [4, 7]. We extended their study and

showed that there is negligible renal Pi leak in fa-milial HDRR immediately after birth to give rise

to a normal Pi level in cord blood, and that the

serum Pi level becomes low by the age of 2-3 months with/without an increased serum Al-p lev-el, by which time there are the radiographic rachitic

signs. The difference in the Al-p level during the infantile period may be related to the P supply

through milk, since case 1 was fed a standard cow milk-based formula with approximately two-fold

higher P content than human breast milk and avoided an increase in the Al-p level at the age of 3 months, whereas case 2, who was fed breast milk,

had increased Al-p at age 2 months. These results

probably indicate the beneficial effect of a greater P supply in infants with HDRR. Most familial HDRR is inherited as an X-linked

dominant; the babies born from parents with this condition have a 50% chance of being affected, which necessitates serial assessment of these ba-

bies. Our study and others therefore demonstrate that the diagnosis of familial HDRR, based on 1)

hypophosphatemia due to renal Pi leakage detect-ed by calculating the %TRP or TmP/GFR, and 2)

normal urine Ca excretion, is made by age 2-3

months. We showed that, at this time, the patient may have a normal Al-p level. Furthermore, we

have had the opportunity to follow a HDRR baby born prematurely, and showed that we could dif-

ferentiate HDRR from rickets due to Pi depletion in a premature baby since the latter condition usu-

ally showed a negligible urine Pi leak and high

urine Ca excretion by calculating urine Ca excre-tion and %TRP.

As for relatively high PTH-M levels noted in two cases at diagnosis, the mechanism is unknown. In

mouse HDRR model (HYP [X-linked hypophos-

phatemic rickets] mouse), they showed high PTH level because of relatively low serum Ca level [2].

Table 3. Laboratory find ings in Case 3

EARLY DETECTION OF D RESISTANT RICKETS 343

The presence of a humoral "hypophosphatemic factor" which may control renal tubular phosphate handling and regulate the serum Pi level has been suggested [2]. After submitting this manuscript, the HYP (X-linked hypophosphatemic rickets = HDRR) Consortium reported that they have isolat-ed a candidate gene named PEX (phosphate regulating gene with homologies to endopeptidase, on the X chromosome) from the HDRR region in Xp22.1, which seems to be a family of endopepti-dase genes [8]. Intragenic deletions and mutations have been detected in all the HDRR patients they examined. Judging from a homology to endopep-tidase genes, PEX may be involved in the degradation or activation of peptide hormone(s). They suggested that PEX may act enzymatically on the humoral factor. The measurement of factor(s) produced by PEX in sera in HDRR pa-tients may therefore be useful for early detection of infants with HDRR in future studies. We consider that the patients should benefit from early treatment before severe rachitic changes be-

come evident [7]. 1,25(OH)2D3/1a OHD3 and Pi

combined is an effective treatment for familial HDRR, and we followed this regimen though there

was a delay in treatment until age 12 months in one case [9]. Before completion of the weaning

period, we found that it is easier to establish a P supplement, which should be beneficial. We can't

yet predict what kind of treatment and what amount of P supplement is required to treat HDRR during the infantile period.

In conclusion, babies born from mothers with HDRR should be serially followed, because the di-

agnosis of HDRR before the emergence of physical signs is possible and early treatment may then be recommended.

Acknowledgements

The authors thank Drs. H. Ohnishi and T. Nish-

ioka for their initial management of case 1.

References

1. Fraser D, Scriver CR (1989) Hereditary rickets and osteomalacia associated with abnormalities in vita-

min D metabolism (calcipenic rickets) or phosphate homeostasis (phosphopenic rickets). In: Degroot LJ

(ed) Endocrinology. W. B. Saunders Company, 1080-1094.

2. Glorieux FH (1993) Hypophosphatemic vitamin D resistant rickets. In: Favus MJ (ed) Primer on the

Metabolic Bone Diseases and Disorders of Mineral Metabolism. Raven Press, New York, 279-282.

3. Walton RJ, Bijvoet OLM (1975) Nomogram for deri- vation of renal threshold phosphate concentration. Lancet 2: 309-310. 4. Moncrieff MW (1982) Early biochemical findings in

familial hypophosphatemic, hyperphosphaturic rickets and response to treatment. Arch Dis Child 57: 70-72.

5. Roza M, Miguel MA, Galbe M, Mejido L, Mencia C

(1983) Early treatment of familial hypophos-

phatemic rickets. Arch Dis Chid 58:1020-1022. 6. Stickler GB (1969) Familial hypophosphatemic vi-

tamin D resistant rickets. The neonatal period and infancy. Acta Paediatr Scand 58: 213-219.

7. Schoen EJ, Reynolds JB (1970) Severe familial hypophosphatemic rickets: Normal growth follow-

ing early treatment. Am J Dis Child 120: 58-61. 8. The HYP Consortium (1995) A gene (PEX) with

homologies to endopeptidases is muated in patients with X-linked hypophosphatemic rickets. Nature

Genetics 11:130-136. 9. Petersen DJ, Boniface AM, Schranck FW, Rupich RC, Whyte MP (1992) X-linked hypophosphatemic

rickets: A study (with literature review) of linear

growth response to calcitriol and phosphate therapy. J Bone Miner Res 7: 583-597.