Researchers have described several forms of hereditary hypophosphataemia’s, which are distinguished by their pattern of inheritance and genetic cause. The most common form of the disorder is known as X-linked hypophosphataemia (XLH). It has an X-linked dominant pattern of inheritance. XLH affects globally approximately 1 in 90,000[1] new births each year.

[1]Prevalence and Mortality of Individuals With X-Linked Hypophosphatemia: A United Kingdom Real-World Data Analysis

X-linked, dominant, hypophosphataemia (XLH) is a rare genetic disorder caused by inactivating mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidase on the X chromosome). XLH, first described by Albright in 1937, is the most frequent form of hypophosphataemia, with a prevalence of 1/90.000.

Chronic low serum phosphorus levels lead to defective bone mineralisation and, consequently, to rickets in children and osteomalacia in adults. During the first 1–2 years of life, children with XLH may present bowing of the weight-bearing extremities, frontal bossing, and short stature. Others clinical manifestations, such as joint pain, arthritis, enthesopathy (calcification of ligaments and their attachment to bone), dentin malformation, and recurrent spontaneous abscesses of the teeth may occur with increasing age. Radiographic features include: genu varum, widened metaphyses, bilateral femoral distal metaphysis epiphyseal line blurred, and a general decrease in bone density.

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X-linked recessive hypophosphataemia (XLRH), autosomal dominant hypophosphataemic rickets (ADHR), and autosomal recessive hypophosphataemia rickets (ARHR) of the disorder are much rarer.

Another rare type of the disorder is known as hereditary hypophosphataemic rickets with hypercalciuria (HHRH). In addition to hypophosphatemia, this condition is characterised by the excretion of high levels of calcium in the urine (hypercalciuria).

Phosphate wasting is also a prominent feature of tumour-induced osteomalacia (TIO), which is caused by rare, mostly benign mesenchymal tumours that overexpress fibroblast growth factor 23 (FGF23)

Besides these well-defined conditions, there may be further mosaicism or mendelian hypophosphataemia’s, such as hypophosphataemic bone disease and autosomal recessive hypophosphatemia without hypercalciuria.

In children the first thing that is noticed is that there is some bowing of the legs.  It can be missed initially as normal toddlers can have a degree of normal ‘physiological’ bowing but this is normally mild.  There are other clues however.  The children may walk late or have pain in their legs.  There may be swelling of the ankles, knees and wrists and they may start to walk with a waddling gait.  These are all signs of rickets and many times children are misdiagnosed as having vitamin D deficiency rickets.

Normally the diagnosis of rickets is made by radiographs.  Once rickets is diagnosed and vitamin D deficiency is ruled out then the diagnosis of hypophosphataemic rickets is confirmed using paired urine and blood tests.  This looks at how much phosphate is being lost in the urine on the background of a low blood phosphate level (inappropriate phosphate wasting).  Other clues to the diagnosis is that the children often have tooth abscesses or there may be affected family members.

The key to making the diagnosis is the doctor thinking about this as a possibility.  Sometimes the phosphate can be in the lower part of the normal range and children can go for many months and years before someone looks more closely.

After establishing the clinical diagnosis, the genetic diagnosis can be made.  Most of the time it is due to a mutation in PHEX but there are other genetic causes of hypophosphataemia.

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Autosomal Dominant Hypophosphataemia (ADH) is a rare genetic disorder of phosphate homeostasis, caused by heterozygous point mutations at amino acid residues 176 or 179 in fibroblast growth factor 23 (FGF23). ADH is characterised by impaired mineralisation of bone, rickets and/or osteomalacia, suppressed levels of calcitriol (1,25-dihydroxyvitamin D3), renal phosphate wasting, and low serum phosphate. This disease is the less common form of hypophosphatemia, and has an incomplete penetrance and variable age of onset. Fluctuations in FGF23 concentration correlate with disease severity. Recent studies have revealed that iron could be one of the factors contributing to the regulation of FGF23 expression. Low iron levels were shown to correlate negatively with FGF23 levels in ADHR patients.

Treatments for ADH include: daily oral administration of phosphate and calcitriol, which prevents secondary hyperparathyroidism. Moreover, it is recommended a frequent monitoring of height, calcium, alkaline phosphatase, parathyroid hormone, and phosphate serum levels, urinary calcium and creatinine. In some cases, corrective surgery of skeletal deformities may be necessary.

Autosomal recessive hypophosphataemic rickets (ARHR) is an extremely rare disease, characterised by hypophosphatemia resulting from renal phosphate wasting. It has been described in few families of Middle Eastern and European origins. Clinical manifestations include: short stature, lower-extremity deformities, pathologic fractures, dental defects, and, in some patients, also enthesopathy. Patients also show hypophosphataemia, low levels of serum 1,25-dihydroxyvitamin D, whereas serum calcium, parathyroid hormone, urinary calcium excretion are normal, and high circulating levels of FGF23. ARHR is subdivided in two subtypes: Autosomal recessive hypophosphataemic rickets type 1 (ARHR1) and type 2 (ARHR2). ARHR1 is caused by homozygous loss-of-function mutations in the DMP1 (Dentin matrix protein 1) gene. DMP1 is a noncollagenous extracellular protein, highly expressed in osteoblasts and osteocytes, in bone and teeth. It plays critical roles in bone mineralisation, phosphate homeostasis and odontogenic differentiation.

Autosomal recessive hypophosphataemia (ARHR) is an extremely rare disease, characterised by hypophosphataemia resulting from renal phosphate wasting (See also ARHR1). Autosomal recessive hypophosphataemic rickets type 2 (ARHR2) is caused by homozygous loss-of-function mutation in the ENPP1 gene. ENPP1 encodes a protein called ectonucleotide pyrophosphatase/ phosphodiesterase 1 (NPP1), which is a major generator of extracellular pyrophosphate (PPi). Because PPi inhibits calcification (hydroxyapatite crystal deposition and growth), homozygous inactivating mutations in ENPP1 gene are also responsible for generalized arterial calcification of infancy (see also GACI). In patients with ARHR2, high circulating levels of FGF23 have been described. FGF23 is a secreted protein, which reduces expression of sodium-phosphate co-transporters, NPT2a and NPT2c, resulting in renal phosphate wasting, diminishs the renal 1α-hydroxylase and increases the 24-hydroxylase activity. Moreover, FGF23 acts at the parathyroid gland to decrease parathyroid hormone synthesis and secretion. Currently, it is unclear how mutations in ENPP1 gene results in high FGF23 levels.

Vitamin D hydroxylation-deficient type 1A (VDDR1A) is a rare autosomal recessive disorder caused by mutations in the CYP27B1 gene, resulting in 1α-hydroxylase enzyme deficiency. Two forms of vitamin D exist: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Both forms of vitamin D need two-step hydroxylation to become biologically active. The first step occurs in the liver where vitamin D is hydroxylated to 25-hydroxyvitamin D 25(OH)D by several hepatic enzymes having 25-hydroxylase activity, and CYP2R1 is the major enzyme. The second step of hydroxylation occurs mainly in the kidney, where 25(OH)D is hydroxylated by the mitochondrial 25-OHvitamin D-1α-hydroxylase to the biologically active hormone 1,25-(OH)2D. The 1,25-(OH)2D plays a central role in calcium homeostasis, bone metabolism, and on cell proliferation and differentiation of a variety of tissues. Alteration of vitamin D metabolism causes defects in the growth plate and bone demineralisation, resulting rickets in children and osteomalacia in adults. Clinical manifestations of VDDR1A include: hypotonia, short stature, muscle weakness, hypocalcaemic seizures in early infancy and rickets. Until now, over 60 mutations have been described in different ethnic groups. Certain mutations are more frequent in certain ethnic groups. Radiographic findings include: widening of the distal physis, fraying and widening of the metaphysis, and angular deformities of the arm and leg bones.

Treatment: Consists of administration of large doses of vitamin D and calcitriol. The potential complications of therapy are: nephrocalcinosis, hypercalciuria, and hypercalcemia. Therefore, regular checks monitoring of physical and biochemical examination, and renal ultrasound are required.

Vitamin D hydroxylation-deficient type 1B (VDDR1B) is due to a defect in vitamin D 25-hydroxylation, and is caused by mutation in the CYP2R1 gene. The synthesis of bioactive vitamin D requires hydroxylation at the 1 α and 25 positions by cytochrome P450 enzymes in the kidney and liver, respectively. The mitochondrial enzyme CYP27B1 catalyzes 1 α-hydroxylation in the kidney, and the CYP2R1 is the major enzyme for hydroxylation of vitamin D to 25-hydroxyvitamin D. See also VDDR1A.

Vitamin D-dependent type 2A (VDDR2A) is an autosomal recessive disorder caused by mutation in the gene encoding the vitamin D receptor (VDR). Signalling via this receptor regulates gene expression in 1,25 OHvitamin D3-responsive cells. It is characterised by hypocalcemia, due to reduced intestinal absorption of calcium, with secondary hyperparathyroidism and hypophosphataemia. Hypocalcemia and hypophosphataemia impair normal bone mineralisation leading to childhood rickets. Other clinical manifestations include muscle weakness and convulsions caused by hypocalcaemia, and in many cases alopecia.

Vitamin D-dependent type 2B (VDDR2B) is an unusual form of Vitamin D-dependent rickets due to abnormal expression of a hormone response element binding protein that interferes with the normal function of the VDR, without mutations in the VDR coding region. Hormone resistance resultes from constitutive overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) that competed with a normally functioning VDR-retinoid X receptor (RXR) dimer for binding to the vitamin D response element (VDRE).

Tumour-induced Osteomalacia (TIO) is an ultra rare disease caused by typically benign, slow-growing tumors that produce excess levels of FGF23, which is involved in phosphate reabsorption. Patients with TIO can experience symptoms including severe hypophosphataemia (low levels of phosphate in the blood), osteomalacia (softening of the bones), muscle weakness, fatigue, bone pain and fractures. There are an estimated 500 to 1,000 people in the United States with TIO, and approximately half of all cases are believed to be inoperable. The tumours can arise in bone or soft tissue, occur from head to toe, and are typically very small in size, locating these tumors is often quite challenging. In patients for whom the tumour or lesion is inoperable, the current treatment consists of oral phosphate and/or active vitamin D replacement. Efficacy of this management is often limited, and its benefits must be balanced with monitoring for potential risks.