Edition 63 - 2017, May / Images

Images in Pediatric Endocrinology: Familial Hypophosphatemic Rickets – Ed. 63

Gisela Viterbo and Valeria De Dona

Servicio de Endocrinología. Hospital de Pediatría Juan. P Garrahan, Buenos Aires, Argentina


Figure:   (A) Left hand and wrist X-Ray film showing mild low bone mineral density with severe metaphyseal flaring and widening. (B) Cupping in radius and ulna (full-line arrow) Bilateral lower limbs with severe metaphyseal flaring in distal tibias and in distal and proximal fibulas, and moderate in distal femurs (full-line arrows) with bowing of both tibias (arrow head). (C) Skull radiograph film with increased digital impressions and premature fusion of cranial sutures. (D) Computed tomography confirmed these findings (dashed-line arrow).


Clinical Case

A 2.7-year-old boy was referred to our hospital because of abnormal gait. He was born pre-term (36 weeks), with normal birth weight (3000 g), by cesarean section because of cephalopelvic disproportion. His personal history included delayed walking (around 24 months of age), without any other delay in his development milestones. Radiographs from the long bones were requested and the patient was referred for further assessment.

Family history: he was the first child of non-consanguineous parents. He had a healthy father, height 176.9 cm (0.60 SDS). His mother had been diagnosed with rickets during infancy. She had underwent multiple surgical corrections (osteotomies), no medical treatment was given. Height: 146.2 cm (-2.37 SDS).

Physical examination on admission revealed weight 17. 2  kg (+1.7 SDS), height 94 cm (-0.3 SDS), head circunference 53 cm (+ 2 SDS), weight to height ratio 125%, Sitting height/height index was in the 90-97 percentile. Widening of both wrist, knees and ankles were found and four incisors teeth were loose. Waddling gait was noticed. He had a rich diet in dairy products, no other treatment or vitamins were given.

Laboratory test showed normal serum calcium 9.2 mg/dl (RV 8.6-10.6); hypophosphatemia 2.4 mg/dl (4.4-6.8); normal serum levels of magnesium 2 mg/dl (1.6-2.4); creatinine 0.28 mg/dl (<0.9); PTH: 50 pg/ml (12-72) and vitamin  D: 28 ng/ml (20-50), high serum levels of alkaline phosphatase (ALP) 873 UI/l (up to 300). Renal tubular phosphate re-absorption was 80% (>85), without any other renal- wasting.

The X-ray profile showed mild low bone mineral density with severe metaphyseal flaring and widening in hands and wrist. Cupping in radius and ulna (figure A).Lower limbs X-ray (figure B) showed bilateral severe metaphyseal flaring in distal tibias and distal and proximal fibulas and moderate in distal femurs with bowing of both tibias.

The association of hypophosphatemia with isolated renal phosphate-wasting, with normal levels of serum calcium, PTH, vitamin D, normal renal function, generalized metaphyseal involvement, elevated ALP and maternal history suggested the diagnosis of familiar hypophosphatemic rickets.

He was started on calcitriol and oral phosphate supplements. After initial therapy, the patient did well, with great improvement in walking and he achieved new motor milestones. ALP levels decreased to 442 UI/l after 30 months of treatment. X –ray also revealed great improvement in metaphyses.

During follow-up, skull x- ray film (figure C) was performed showing increased digital impressions and premature fusion of sutures. Computed tomography confirmed these findings. Eye fundus was performed with no pathological signs were found.


Rickets is a disorder characterized by a defective mineralization or calcification of bones before epiphyseal closure. Many classifications have been proposed but the most useful distinguished between:

Nutritional rickets:

– Primary types: due to vitamin D, calcium or phosphorus deficiencies (the last one is very rare)

-Secondary to renal tubular diseases, nephrotic syndrome, liver-biliary diseases, malabsorption syndromes, drugs causing enzymatic inhibition

Hereditary rickets:

-Familial hypophosphatemic rickets (FHR)

– Vitamin D-dependent rickets caused by mutations of the 25-hydroxyvitamin D 1alpha-hydroxylase (1alpha-hydroxylase, CYP27B1) gene.

-Vitamin D -resistant rickets due to VDR (vitamin D receptor) mutations

-Hypophosphatasia that causes defective mineralization

FHR is an inherited disorder characterized by hypophosphatemia due to renal-phosphate wasting and a defective vitamin D metabolism, rickets and growth failure. High levels of serum ALP are usually found, particularly during periods of rapid growth such as infancy or adolescence. The most common is the dominant-X -linked  hypophosphatemic rickets, but also dominant and recessive autosomal forms of inheritance are described.

The broad fenotypical spectrum of FHR includes from isolated persistent hypophosphatemia without any other sign or clinical symptom up to severe short stature due to growth failure and misalignment of lower limbs. Age at presentation is usually during the first 2 years of life with walking impairment, waddling gait, bone pain and genu varum. However, when symptoms are mild, a delayed diagnosis may occur and is suspected when patients present with short stature.

Treatment consists in oral phosphate supplements and calcitriol. With treatment, bone pain and walking difficulties improve, height velocity increases and afterwards, leg bowing may diminish or correct. In a high number of patients, with good compliance, surgical corrections may be avoided. When final height is reached with physeal closure, treatment is only indicated in cases of disabling skeletal pain, recurrent fractures, pending orthopedic procedures or during pregnancy or breastfeeding.

It is important to consider that patients with FHR may also associate craniosynostosis. It usually develops around 18 months of life. It could be subclinical or may also associate Arnold Chiari malformation. It has no relationship to treatment compliance. It is recommended to measure head circumference regularly, to perform an skull radiograph annually until 6 years of life, an eye fundus in the first visit and then yearly until 3 years-old and/or a computed tomography if required.


– Carpenter TO, Imel E, Holm IA et al. A Clinician´s guide to x linked hypophosphatemia. J Bone Miner Res. 2011 26 (7): 1381-1388

– Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3: R13-30

– Primer on the Metabolic Bone Diseases and Disorders of the Mineral Metabolism, 8th Edition. Clifford J. Rosen (Editor-in-Chief), Roger Bouillon (Senior Associate Editor), Juliet E. Compston (Senior Associate Editor), Vicki Rosen (Senior Associate Editor) August 2013, Wiley-Blackwell.

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