X-Linked Hypophosphatemia (XLH) is characterized
by impaired renal phosphate reabsorption and diminished Vitamin-D
metabolism. In addition, intestinal calcium and phosphate absorption is also
Familial Hypophosphatemia; Hypophosphatemic Vitamin
D-Resistant Rickets type I; X-Linked Vitamin D-Resistant Rickets; Hereditary
Hypophosphatemia type I; Phosphate Diabetes.
XLH is the most common form of rickets in
industrialized countries. It affects males and females in equal numbers;
however, males are usually more severely affected than females. Worldwide
approximately 1 in 20,000 live births suffers from the disease.
In most cases, XLH is inherited as a
dominant X-linked trait. However, autosomal dominant and recessive traits
have also been reported. The X-linked defect seems to be the result of a
mutation in the PHEX (X-linked phosphate regulating endopeptidase homolog)
gene and has been mapped to Xp22.2-22.1. The autosomal dominant form of
familial hypophosphatemia (sometimes associated with decreased glucose
tolerance) seems to be caused by a mutation of gene 12p13.3.
The two pathogenetic mechanisms involved in this
disorder are the failure of the proximal renal tubule to reabsorb phosphate
and to convert calcidiol (25-hydroxy-cholecalciferol) to calcitriol
(1,25-dihydroxy-choleclaciferol). The defect is characterized by low calcium
serum levels in combination with hypophosphatemia not resulting in increased
levels of calcitriol. Decreased concentration of inorganic phosphate leads
to osteomalacia secondary to impaired function of osteoblasts, since mature
bone formation requires the precipitation of hydroxyapatite, which has a
high phosphate content (chemical formula
2+· 2 OH-).
In the absence of a family history of XLH, the
diagnosis is made clinically. Nevertheless, the diagnosis is sometimes difficult. This
is especially true in the first year of life, since the phosphate levels may
be normal even in an infant with an affected parent. In addition, the range of
normal serum phosphorus levels in children is significantly higher than in
adults. Abnormal bowing of the long bones is usually the first sign, but
does not appear before 12 to 18 months of age. Elevated serum alkaline
phosphatase levels (often the first laboratory sign), mild hypocalcemia, and
moderate hypophosphatemia with significant hyperphosphaturia in the absence
of severe secondary hyperparathyroidism are typical. Serum calcitriol levels
are inappropriately normal. In contrast to Hereditary Vitamin D-Resistant Rickets (HVDRR),
aminoaciduria and bicarbonaturia are not present.
The clinical signs of XLH are quite variable.
Major symptoms of XLH include skeletal malformations, bone pain, abnormally
bowed legs (see below), and generalized, but usually mild muscle weakness.
Affected infants may experience failure to thrive resulting in low weight
and a short, stocky stature (with an adult height of usually less than 165
cm). However, most often the symptoms appear at the age of 12 to 18 months
and affected infants show a waddling gait, bowing of the legs with coxa
vara, genua vara or genus valga (all secondary to the weight-bearing
function). Dolichocephaly, Arnold-Chiari Syndrome, and
sensorineural hearing loss ...