CASE REPORT

J Clin Res Pediatr Endocrinol 2010; 2: -
Received Date:
Accepted Date:
*

Vitamin D Deficiency Rickets Mimicking Pseudohypoparathyroidism

 


Vitamin D deficiency rickets (VDDR) is a disorder biochemically characterized

by elevated serum alkaline phosphatase (ALP) activity, normal or

decreased serum calcium (Ca) and inorganic phosphate concentrations,

secondary hyperparathyroidism and decreased serum 25-hydroxyvitamin

D (25(OH)D) levels. In stage 1 VDDR, urinary amino acid and phosphate

excretion are normal with minimal or no findings of rickets on 

radiographs. Pseudohypoparathyroidism (PHP) is an inherited disorder

characterized by end-organ resistance to parathormone (PTH). VDDR

occasionally resembles PHP type 2 in clinical presentation and biochemical

features, creating difficulties in the differential diagnosis of these two

entities. Here we report an infant diagnosed with VDDR. In addition to

inadequate vitamin D intake, usage of antiepileptic drugs (AED) may have

led to the worsening of the vitamin D deficiency. The patient presented

with a history of febrile convulsions, for which he received phenobarbital

treatment. The initial findings of hypocalcemia, hyperphosphatemia and

normal tubular reabsorption of phosphate,  mimicking PHP 2, responded

well to vitamin D and oral Ca treatment with normalization of serum Ca,

phosphorus (P), ALP and PTH level

 

Introduction

Vitamin D deficiency rickets (VDDR) remains to be a

common disorder in developing countries. In a recent 

study, it was shown that after the nationwide vitamin D 

supplementation campaign in 2005, the prevalence of 

VDDR declined from 6.09% to 0.099% in children aged

between 0-3 years in Turkey  (1). There are some studies

reporting the resurgence of this disorder in developed 

countries (2,3).

Pseudohypoparathyroidism (PHP) is an inherited 

disorder characterized by an end-organ resistance to

parathormone (PTH). Children with PHP present with

hypocalcemia and normal or elevated serum phosphorus (P)

concentrations despite elevated serum PTH levels. The 

disorder is subdivided into several distinct entities. PHP type

1 is differentiated from PHP type 2 by reduced urinary cAMP

excretion in response to administration of PTH. 

Pediatricians in developed countries have limited 

experience in treating children with VDDR  (4). PHP 

and VDDR can be mistaken for one another because of 

similarity in their presentation and biochemical features. 

Here we report a 23-month-old male patient presenting

with recurrent febrile convulsions and diagnosed 

as antiepileptic drug (AED)-induced VDDR. The initial levels

of serum Ca, P, PTH and tubular phosphate reabsorption

were suggestive of PHP.

Case Report 

A 23-month-old male was brought to our clinic for 

evaluation of fever. He was born at term with a birth weightof 2500g to nonconsanguineous parents. He had a 

convulsion for the first time at age 8 months and,

antiepileptic phenobarbital treatment was started. The

patient had had febrile convulsions on 7 different occasions

since then. He was breastfed only until 6 months of age

and received complementary feedings thereafter. The

infant was given 400 U/day vitamin D supplementation only

in the first two months of life. His neurodevelopment was

appropriate for age. The patient had a history of frequent

infections. He had been hospitalized due to pyelonephritis

at the age of 16 months. 

On physical examination, his height was 84 cm 

(25

th

-50

th

percentile), weight 12.5 kg (50

th

percentile), head

circumference 48 cm (50

th

percentile). Mild enlargement of

the wrists was noted bilaterally. Interpopliteal distance was

5.5 cm (N:<4.5 cm). Rachitic rosary, craniotabes, caput

quadratum, and leg deformities (O-/X-bine) were not 

present. He had also no signs suggestive of Albright’s

hereditary osteodystrophy (AHO), such as short hands,

round face, central obesity or dental hypoplasia.

Initial laboratory investigations showed the following

levels:  glucose 104 mg/dL, Na 134 mmol/L, K 4.5 mmol/L,

BUN 8 mg/dL, creatinine 0.4 mg/dL, Ca 6.4 mg/dL (N: 8.8-

10.8), P 6.7 mg/dL (N: 3.8-6.5), Mg 0.9 mmol/L (N:0.6-0.95),

alkaline phosphatase (ALP): 436 IU/L (N:145-420), total 

protein 6.5 g/dL (N:6.1-7.9), albumin 4.4 g/dL (N:3.5-5), PTH

390.7 pg/mL (N:11.1-79). Left hand and wrist X-ray showed

no findings of rickets. Upon these results, PHP or VDDR

was suspected. Urinary Ca/creatinine ratio was 0.26

(N:<0.6). Tubular reabsorption of phosphate was 0.99

(N:>0.90). Aminoaciduria was absent. EEG was normal. Ca

replacement was started in a dose of 50 mg/kg/day. 

The level of serum 25-hydroxyvitamin D [(25(OH)D] was

low-4.5 ug/L. A diagnosis of vitamin D deficiency was made

and, oral 300 000 U vitamin D was started. In 

addition, oral Ca was given for 15 days. Three weeks later,

serum Ca level was 9.2 mg/dL, P 6 mg/dL, ALP 354 U/L.

The level of PTH had decreased to 37 pg/mL, thus, the

diagnosis of PHP was excluded. Vitamin D in a dose of 

400 IU/day was prescribed. Regular follow-up, including

measurement of serum 25(OH)D levels, was recommended.

Discussion 

VDDR is a disorder biochemically characterized by 

elevated serum ALP activity, normal or decreased serum 

Ca and inorganic phosphate concentrations, secondary

hyperparathyroidism and decreased serum 25(OH)D levels.

Fraser et al (5) described three stages of VDDR on the basis

of clinical and laboratory data. Stage 1 is characterized by

hypocalcemia, normal P, normal urinary amino acid and

phosphate excretion with minimal or no findings of rickets

on radiographs. Stage 2 is associated with normal serum Ca

and low P concentrations in the presence of phosphaturia

and aminoaciduria and mild to moderate rickets findings on

X-rays. Stage 3 is similar to stage 2 but associated with

hypocalcemia and advanced rickets. In this original study,

which is based on the classical teaching of rickets staging,

hypocalcemia was attributed to lack of PTH secretion in the

first stage of VDDR. The earlier studies also showed normal

PTH levels in this stage (6). Later on, it was shown that PTH

levels were actually increased in stage 1 of VDDR at a time

when the phosphaturia or aminoaciduria were still absent. It

was also shown that the regulation and action of PTH were

disturbed in vitamin D deficiency, and restored after 

vitamin D treatment (7). Srivastava (4) was the first to draw

attention to the possibility that the elevated PTH levels

associated with hypocalcemia and normal P indicate an 

element of end-organ resistance to PTH, mimicking PHP. 

PHP is a genetic disorder associated with increased

secretion of PTH and target-tissue unresponsiveness to 

the biological actions of PTH. In PHP patients, biochemical

findings (hypocalcemia and hyperphosphatemia) are 

consistent with hypoparathyroidism. PHP type 1a is 

characterized by hormone resistance in addition to a 

peculiar constellation of developmental and somatic

defects that are collectively termed as AHO. The AHO 

phenotype consists of short stature, round face, obesity,

brachydactyly, subcutaneous ossifications, and rarely dental

defects and sensorineural abnormalities. Our patient had

none of these findings. Similar to patients with PHP type 2,

patients with PHP type 1b present with only PTH resistance

in the absence of features of AHO. The mutations 

of GNAS1, a gene encoding the alpha- subunit of the G

stimulatory protein, are responsible for the two main 

subtypes of PHP, namely types 1a and 1b. Type 1c, 

the rarest subtype, is characterized by AHO as well as

resistance to PTH and other hormones associated with 

normal Gs α activity. In our patient, the clinical findings and

initial laboratory results suggested PHP type 2 or PHP type 1b. 

There are several studies reporting on the difficulty in

differentiating stage 1 VDDR from PHP (4,8,9). Serum PTH

levels cannot be relied on to differentiate between these

two disorders. A detailed history should be taken, including

vitamin D intake, sun exposure and use of drugs that 

interfere with vitamin D metabolism. In our patient, vitamin

D support was inadequate and phenobarbital treatment

probably aggravated the deficiency. Evidence of rickets on

physical and radiological examination is also important in

the differential diagnosis, although clinical signs may be

minimal or absent in stage 1 VDDR. On the other hand, PHP

may present with bony deformities resembling rickets (10).

The hallmark of VDDR is vitamin D depletion (low serum 25

(OH)D), since serum Ca, P and 1,25 (OH)2D levels can be

variable  (7). Nevertheless, if the differential diagnosis 

cannot be made properly in marginal cases, showing the

normalization of biochemical and physical abnormalities

after vitamin D treatment may help in clarifying the diagnosis

(4). Although the clinical and radiological findings were

vague in our patient, the 25 (OH)D level was found low 

174

Ak›n L et al.

Rickets Mimicking Pseudohypoparathyroidismand stoss therapy (300 000 IU vitamin D, orally) led to 

normalization of serum Ca, P, ALP and PTH in three weeks.

Febrile seizures, a common and usually benign 

complaint in infancy and early childhood, are not known to

be associated with rickets. Hoecker et al (11) reported 

that recurrent febrile convulsions might be an unusual 

presentation of nutritional rickets. Since vitamin D is 

reported to have an important role in immune defense

mechanisms  (12), it may be speculated that the febrile 

convulsions triggered by fever during frequent infections in

this patient could be attributable to vitamin D deficiency.

There are several studies reporting that decreased

serum 25(OH)D and altered bone metabolism were 

associated with AED treatment in children (13). Many AEDs

are known to be inducers of hepatic cytochrome P450

metabolism, resulting in increased hepatic metabolism of

vitamin D. Some authors recommend monitoring of the

vitamin D status in children taking AEDs, especially those

receiving polypharmacotherapy  (14). In our patient, we

thought that in addition to inadequate vitamin D intake,

usage of AED may have led to the worsening of the vitamin

D deficiency.

In conclusion, reporting this case we desire to emphasize

that VDDR can be mistaken for PHP in some cases. 

The demonstration of normalization of phosphocalcic

parameters (i.e. serum Ca, P, ALP and PTH) after vitamin D

treatment may be useful in the differentiation of these two

disorders. Vitamin D deficiency should be kept in mind in

the differential diagnosis of hypocalcemia in children, 

especially those being treated with AEDs. 

References

1. Ozkan B, Doneray H, Karacan M, Vançelik S, Yildirim ZK, Ozkan

A, Kosan C, Aydin K. Prevalence of vitamin D deficiency rickets

in the eastern part of Turkey. Eur J Pediatr 2009;168:95-100.

[Abstract] / [PDF]

2. Pal BR, Shaw NJ. Rickets resurgence in the United Kingdom:

improving antenatal management in Asians. J Pediatr 2001;

139:337-338. [Abstract]

3. Kreiter SR, Schwartz RP, Kirkman HN Jr, Charlton PA, Calikoglu

AS, Davenport ML. Nutritional rickets in African American

breast-fed infants. J Pediatr 2000;137:153-157. [Abstract] / 

[Full Text] / [PDF]

4. Srivastava T, Alon US. Stage I vitamin D-deficiency rickets

mimicking pseudohypoparathyroidism type II. Clin Pediatr

(Phila) 2002;41:263-268. [Abstract] / [PDF]

5. Fraser D, Kooh SW, Scriver CR. Hyperparathyroidism as 

the cause of hyperaminoaciduria and phosphaturia in human

vitamin D deficiency. Pediatr Res 1967;1:425-435. [Abstract] 

6. Bonnici F. Functional hypoparathyroidism in infantile 

hypocalcaemic stage I vitamin D deficiency rickets. S Afr Med

J 1978;54:611-612. [Abstract]

7. Kruse K. Pathophysiology of calcium metabolism in children

with vitamin D-deficiency rickets. J Pediatr 1995;126:736-741.

[Abstract] / [Full Text] / [PDF]

8. Robinson D, Flynn D, Dandona P. Hyperphosphataemic rickets

in an Asian infant. Br Med J (Clin Res Ed) 1985;290:1318-1319.

[Full Text] / [PDF]

9. Kapoor D, Agrawal NK, Aggarwal R, Sahoo AK, Singh SK.

Vitamin D deficiency masquerading as pseudohypoparathyroidism

type 2. J Assoc Physicians India 2005;53:999-1000. [Full Text] /

[PDF]

10. Bajpai A, Sharma J, Hari P, Bagga A. Pseudohypoparathyroidism

presenting with bony deformities resembling rickets. Indian J

Pediatr 2004;71:345-348. [Abstract] / [PDF]

11. Hoecker CC, Kanegaye JT. First place winner. Recurrent febrile

seizures: an unusual presentation of nutritional rickets. J

Emerg Med 2002;23:367-370. [Abstract] / [Full Text] / [PDF]

12. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin

D: modulator of the immune system. Curr Opin Pharmacol

2010;10:482-496. [Abstract] / [Full Text] / [PDF]

13. Mintzer S, Boppana P, Toguri J, DeSantis A. Vitamin D levels

and bone turnover in epilepsy patients taking carbamazepine or

oxcarbazepine. Epilepsia. 2006;47:510-515. [Abstract] / 

[Full Text] / [PDF]

14. Nettekoven S, Ströhle A, Trunz B, Wolters M, Hoffmann S,

Horn R, Steinert M, Brabant G, Lichtinghagen R, Welkoborsky

HJ, Tuxhorn I, Hahn A. Effects of antiepileptic drug therapy on

vitamin D status and biochemical markers of bone turnover in

children with epilepsy. Eur J Pediatr 2008;167:1369-1377.

Home Archive Search Menu