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Pseudovitamin D deficiency rickets—a report from the Indian subcontinent
  1. Abdul Hamid Zargara,
  2. Ambrish Mithalb,
  3. Arshad Iqbal Wania,
  4. Bashir Ahmad Lawaya,
  5. Shariq Rashid Masoodia,
  6. Mir Iftikhar Bashira,
  7. Mohammad Ashraf Ganiea
  1. aDepartment of Endocrinology, Sheri-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, India, bDepartment of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
  1. Professor Abdul Hamid Zargar, Post Box No 1098, GPO, Srinagar 190001, Kashmir, India (e-mail: abdulhamidz{at}vsnl.com)

Abstract

Pseudovitamin D deficiency rickets (also called vitamin D dependent rickets type I) is one of the types of inherited rickets and is caused by a deficit in renal 25-hydroxyvitamin D 1α-hydroxylase. This form of rickets has not been reported from the Indian subcontinent. Three patients with this disorder are presented. These patients were all females aged 3–20 years and presented with growth failure and skeletal deformities. All had florid clinical and radiological rickets. The biochemical abnormalities seen included hypocalcaemia, hypophosphataemia, and hyperphosphatasia. All patients had grossly raised 25-hydroxyvitamin D concentrations and markedly low to undetectable concentrations of 1,25-dihydroxyvitamin D. A disturbing feature of this study was the late referral of the patients.

  • 1α-hydroxylase
  • calcitriol
  • inherited rickets
  • vitamin D dependent rickets

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It is well recognised that it is the casual exposure to sunlight that provides most humans with their vitamin D requirement. A subset of patients with rickets and osteomalacia whose clinical and metabolic abnormalities are resistant to conventional therapeutic doses of vitamin D have been identified. This subset of patients is referred to as having vitamin D resistant rickets or, if pharmacological doses of vitamin D were therapeutically effective, vitamin D dependent rickets.

Pseudovitamin D deficiency rickets (or type I vitamin D dependent rickets) is an autosomal recessive disorder that may be due to impaired activity of 25-hydroxyvitamin D 1α-hydroxylase, the enzyme responsible for conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25-dihydroxyvitamin D (1,25(OH)2D).1 In this report we present the data of three patients with pseudovitamin D deficiency rickets. To our knowledge no such data have been published from the Indian subcontinent.

Case reports

Three patients aged 3–20 years presented to the endocrinology department at the Sheri-Kashmir Institute of Medical Sciences, Srinagar, Kashmir (India) for growth failure, and variable features of rickets and bony deformities.

PATIENT A

A 3 year old girl, product of a consanguineous marriage, was brought to the endocrine clinic with the complaints of failure to thrive and delayed motor milestones. Clinical examination revealed a 71 cm tall, well nourished girl with mild frontal bossing, rachitic rosary, widening of wrists, and knock knees. Examination of respiratory, cardiovascular, gastrointestinal, and neurological systems was normal.

PATIENT B

A 7 year old girl, second in birth order, product of a normal vaginal delivery, was brought to medical attention with the complaint of progressive deformity of lower limbs for two years. Clinical examination revealed widening of wrists and ankles with knock knees. Her systemic examination did not reveal any abnormality. She was 105 cm tall.

PATIENT C

A 20 year old regularly menstruating woman was referred by an orthopaedic surgeon with unusual deformities of both legs and arms. She had sustained a fracture of her left tibia at 3 months of age and fractures twice thereafter, the last one at the age of 12 years. Thereafter, the patient had complained of progressive deformities of both lower limbs. Clinical examination revealed a young woman with normal secondary sexual characteristics. She had anterior bowing of tibia on both sides and deformities in the arms around the elbow joints.

The anthropometric data of the three patients are given in table 1. Full blood count, urinalysis, kidney and liver function tests, serum sodium and potassium, and ammonium chloride test (performed as recommended by Wrong and Davies2) were normal in all the subjects. Detailed radiological screening of these patients revealed marked changes of rickets in long bones of arms and legs in patient A (fig 1); widened, frayed, and deeply cupped epiphyses of radius and ulna in patient B (fig 2); and marked smooth bowing of the long bones in legs and arms in patient C (figs 3 and 4). As shown in table 2, all patients had hypocalcaemia, hypophosphataemia, and hyperphosphatasia. Serum concentrations of 25(OH)D and 1,25(OH)2D, measured by specific radioimmunoassay, were normal to raised and low to undetectable respectively.

Table 1

Anthropometric parameters of patients

Figure 1

Radiograph of wrists (patient A) showing marked rickets.

Figure 2

Radiograph of hands (patient B) showing changes of rickets.

Figure 3

Radiograph of legs (patient C) showing smooth bending of leg bones.

Figure 4

Radiograph of arms (patient C) showing smooth bowing of forearm bones.

Table 2

Biochemical investigations

Discussion

Pseudovitamin D deficiency rickets is an inborn error of vitamin D metabolism. Vitamin D, synthesised in the skin and obtained from dietary sources, is 25-hydroxylated in the liver to 25(OH)D. In the proximal renal tubules, 25(OH)D is converted to 1,25(OH)2D, the biologically active metabolite of vitamin D. Pseudovitamin D deficiency rickets, also known as vitamin D dependent rickets type I, is an autosomal recessive disorder that may be due to impaired activity of 25-hydroxyvitamin D 1α-hydroxylase, a renal cytochromeP-450 enzyme of the vitamin D pathway.1

Patients discussed in this report had developed rickets and other bony abnormalities in the absence of symptoms, signs, or laboratory evidence of malabsorption, hepatic or renal disease. Distal renal tubular acidosis constitutes an important cause of short stature and rickets in the Kashmir valley.3 However, a normal ammonium chloride test excludes that disorder. These patients had low serum calcium, low phosphorus, and low to undetectable 1,25(OH)2D in presence of normal to raised 25(OH)D. This suggests the diagnosis of pseudovitamin D deficiency rickets in all these patients.

Learning points

  • Pseudovitamin D deficiency rickets, an uncommon form of rickets, has not been reported from India before.

  • Biochemical findings include hypocalcaemia, hypophosphataemia, hyperphosphatasia, and low to undetectable concentrations of 1,25(OH)2D in the presence of normal to raised 25(OH)D concentrations.

  • Treatment with calcitriol corrects biochemical abnormalities, induces healing of rickets, and restores the rate of skeletal growth.

Features of pseudovitamin D deficiency include hypocalcaemia, hypophosphataemia, short stature, skeletal deformities of rickets, dental enamel hypoplasia, and frequently marked increases of serum alkaline phosphatase activity; circulating concentrations of 1,25(OH)2D are low or undetectable.4

Before the availability of 1α-hydroxylated vitamin D metabolites, this disorder was treated with vitamin D or 25(OH)D. The doses of vitamin D (40–54.5 mg/kg/day) and 25(OH)D (3–18 mg/kg/day) required to achieve normocalcaemia and healing of rachitic lesions were approximately 100 times than those used for the treatment of dietary vitamin D deficiency.5 6

This disorder is inherited as an autosomal recessive trait. Two other types of inherited rickets include hypocalcaemic vitamin D resistant rickets (also known as type I vitamin D dependent rickets) in which the gene for vitamin D receptor is mutated7-9 and X linked hypophosphataemic vitamin D resistant rickets in which the PEX gene (phosphate regulating gene with homology to endopeptidase on the X chromosome) is mutated.10 Until recently the molecular basis of pseudovitamin D deficiency rickets had remained unclear, even though the disease locus has been mapped to chromosome 12q14 by linkage analysis.11 However, in a recent study inactivating mutations in the 25-hydroxyvitamin D 1α-hydroxylase gene as a cause of pseudovitamin D deficiency rickets have been identified.12

With the availability of 1,25(OH)2D (calcitriol), the treatment of this disorder has become simple; however, early diagnosis of this disorder is imperative to prevent major bony deformities as seen in our older patients.

Learning points

  • Both cortisol and aldosterone bind the mineralocorticoid receptor. In target tissues for mineralocorticoid action, specificity of aldosterone action in the presence of cortisol is mediated by 11β-HSD which converts cortisol into cortisone. The latter is incapable of binding the mineralocorticoid receptor.

  • Inherited defects of 11β-HSD are responsible for endogenous renal cortisol excess associated with the syndrome of AME, a rare form of hypertension in children. Glycyrrhetenic acid, the metabolite of glycyrrhicinic acid in liquorice, is a potent inhibitor of 11β-HSD and liquorice induced hypertension closely resembles AME from a pathogenetic point of view.

  • In hypertensive patients, particularly in young women employed in office jobs and in patients who have recently stopped smoking, inquiring into dietary habits is mandatory in order to identify ingestion of 11β-hydroxysteroid dehydrogenase inhibitors such as liquorice.

References

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