(From the March 2014 Issue of PediatricsOnline)
Rickets is not uncommon in young children, especially breastfed infants. In most cases, treatment with concentrated vitamin D resolves early problems with bone growth and deformity. But when extended vitamin D therapy fails to improve skeletal symptoms of rickets, a patient’s soft, weak bones may be caused instead by a calcium or phosphate deficiency or an underlying genetic disorder.
This is what occurred with a female infant who presented to her pediatrician at 1 year of age with bowed legs. Vitamin D therapy failed to correct her bone growth by the age of 5, at which point she was referred to the Metabolic Bone Clinic at Nationwide Children’s Hospital. Published in December in Case Reports in Pediatrics, the case required physicians in the clinic to correctly identify, treat and resolve hypophosphatemic rickets. The team, comprised of experts from genetics, endocrinology, nephrology and orthopedics, discovered that the patient’s illness was caused by mitochondrial complex I deficiency induced de Toni-Debré-Fanconi (or simply Fanconi) syndrome.
“If bowed legs persist beyond about 2 years of age, the child should be further evaluated radiographically,” explains Allan C. Beebe, MD, an orthopedic specialist at Nationwide Children’s. “It could be Blount’s Disease or an endocrine problem, and specialist referral is important.”
In this case, X-rays showed worsening of the patient’s knees from simple bowed legs at 2 years of age to knock knees at angles of 20 and 24 degrees by the age of 5. Lab tests ordered by the clinic team revealed that the patient had phosphate loss from her kidneys, elevated serum alkaline phosphatase and parathyroid hormone levels and inappropriately normal 1,25 OH vitamin D levels — all classic markers for hypophosphatemic rickets. The patient also had increased thirst and urination and was found to have metabolic acidosis, proteinuria and glycosuria on her urinalysis, which led the clinical team to consider Fanconi syndrome as the rare cause of her hypophosphatemic rickets.
Additional testing confirmed their suspicion and more advanced lab tests, including a muscle biopsy, revealed that the syndrome was due to a mitochondrial disorder — deficiency of complex I and mild loss of complex III activity.
Although the patient’s condition had finally been accurately diagnosed, the metabolic bone team was unsure whether the severe degree of her skeletal deformity would respond to the appropriate medical therapy or if corrective orthopedic surgery would be necessary.
“She needed calcitriol, adequate dosage of phosphate and alkali therapy to heal her rickets and correct her limb deformity,” says Sasigarn A. Bowden, MD, clinical researcher and endocrinologist for the Section of Endocrinology, Metabolism and Diabetes at Nationwide Children’s.
Despite the delay in accurate diagnosis and initiation of treatment, the patient responded well to medical therapy, illustrating that advanced bone disease due to delayed diagnosis of Fanconi syndrome can still respond to medical treatment and may not need surgical correction. Bone deformity does not typically respond to therapy — particularly when initiated late — in other types of hypophosphatemic rickets, such as X-linked hypophosphatemic rickets.
Following proper treatment, the patient’s bone pain resolved completely. By the age of 10, her bone deformity was corrected with angulations of only 4 and 5 degrees, no fractures had occurred, serum phosphate levels were back to normal and a renal ultrasound showed no nephrocalcinosis or kidney stones. The patient remains under the care of endocrinologists, nephrologists and geneticists at Nationwide Children’s for her bone disease, mitochondrial disorder and Fanconi syndrome.
This case serves as a reminder for physicians that things may not always be what they seem, Dr. Bowden says.
“Clinicians should be thorough when evaluating a toddler presenting with bowed legs, investigating a variety of potential causes,” suggests Dr. Bowden. “Proper initial diagnosis will lead to proper treatment and the best outcome.”
Bowden SA, Patel HP, Beebe A, McBride KL. Successful Medical Therapy for Hypophosphatemic Rickets due to Mitochondrial Complex I Deficiency Induced de Toni-Debré-Fanconi Syndrome. Case Reports in Pediatrics. 2013 Dec 10. 354314.
Radiograph of both lower extremities in a standing view. (left) Marked deformity, 24-degree angulation on the left and 20 degrees on the right, was noted at age 5 before phosphate and calcitriol therapy commenced. (right) Marked improvement at age 10, 4-degree angulation on the left and 5 degrees on the right.