Phosphate wasting ineluctably leads to hypophosphatemia and numerous consequences including mineralization defects. In children, hypophosphatemia is revealed by vitamin D-resistant rickets and results in variable degrees of delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. Symptoms might be present, although to a lesser degree, in adults who underwent the conventional treatment throughout their childhood and adolescence. Causes of phosphate wasting are mostly due to genetic defects in factors necessary for phosphate handling; for a review read 1. They have been summarized in Table 1.

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NCBI Bookshelf. The phenotypic spectrum of X-linked hypophosphatemia XLH ranges from isolated hypophosphatemia to severe lower-extremity bowing. XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes is not manifest until adulthood, as previously unevaluated short stature.

In adults, enthesopathy calcification of the tendons, ligaments, and joint capsules associated with joint pain and impaired mobility may be the initial presenting complaint. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported. Additionally, the normal physiologic response to hypophosphatemia of an elevation of 1,25 OH 2 vitamin D is absent. Serum calcium and hydroxy vitamin D are within the normal range; parathyroid hormone is normal to slightly elevated.

Alkaline phosphatase is characteristically elevated in children, especially during periods of rapid growth, and usually returns to normal in adulthood with or without treatment. Identification of a hemizygous in males or heterozygous in females pathogenic variant in PHEX by molecular genetic testing confirms the diagnosis.

Treatment of manifestations: Pain and lower-extremity bowing improve with frequent oral administration of phosphate and high-dose calcitriol. Children are generally treated from the time of diagnosis until long bone growth is complete. The role of pharmacologic treatment in adults is less clear; such treatment is generally reserved for individuals with symptoms such as skeletal pain, upcoming orthopedic surgery, biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures.

Prevention of primary manifestations: Frequent oral administration of phosphate and high-dose calcitriol to minimize bowing of long bones during growth. Good oral hygiene with flossing, regular dental care, and active strategies to prevent dental abscesses. Evaluation of relatives at risk: Molecular genetic testing if the PHEX pathogenic variant has been identified in the family or biochemical testing of infants at risk to ensure early treatment for optimal outcome.

Pregnancy management: No data are available on the use of phosphate and calcitriol in pregnant women who have XLH. Most women with XLH who are on active therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly.

X-linked hypophosphatemia is inherited in an X-linked manner. Offspring who inherit the pathogenic variant will be affected, but because of the great intrafamilial variation, severity cannot be predicted. Prenatal diagnosis for pregnancies at increased risk is possible if the PHEX pathogenic variant in the family has been identified. X-linked hypophosphatemia XLH should be suspected in an individual with the following clinical findings, radiographic findings, and results of biochemical testing.

It should be noted that this is a dominant X-linked disorder in which males and females are similarly affected. Findings in children include progressive lower-extremity bowing with a decrease in height velocity after the child starts ambulating and the characteristic clinical signs of rickets: rachitic rosary, craniotabes, Harrison's groove a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward , and epiphyseal swelling.

In children the metaphyses may be widened, frayed, or cupped; sometimes rachitic rosary or beading of the ribs results from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage. Although involvement of the metaphyses of the lower limbs is typical, any metaphysis can be involved. The two main laboratory findings characteristic of XLH are low-serum phosphate concentration and reduced tubular resorption of phosphate corrected for glomerular filtration rate.

Low serum phosphate concentration. Normal phosphate concentrations vary with age, with higher values observed in infants; therefore, it is important to use the age-related values.

One widely used data set is reviewed in Table 1. Several studies have reported the normative data for age-related serum phosphate values [reviewed by Meites ]. View in own window. Lockitch et al []. In order to use the nomogram, the tubular resorption of phosphate TRP must first be calculated as follows:.

Note: For the calculation of the TRP the urine should be collected as an untimed urine after an overnight fast. Molecular genetic testing approaches can include single- gene testing , use of a multigene panel , and more comprehensive genomic testing :.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene. Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here. Morey et al []. Holm et al [] , Dixon et al [] , Ichikawa et al [] , Gaucher et al [] , Ruppe et al [].

Some of the reports suggest a lower rate of variant detection in simplex cases i. Two studies utilized multiplex ligation-dependent probe amplification MLPA to detect deletions and duplications [ Clausmeyer et al , Morey et al ].

In contrast, the Clausmeyer study which also utilized both techniques failed to find a pathogenic variant in a subset of individuals tested. Methods that may be used include: quantitative PCR , long-range PCR, multiplex ligation-dependent probe amplification MLPA , and a gene -targeted microarray designed to detect single- exon deletions or duplications. The clinical presentation of X-linked hypophosphatemia XLH ranges from isolated hypophosphatemia to severe lower-extremity bowing.

The diagnosis is frequently made in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood.

Individuals with XLH commonly present with short stature and lower-extremity bowing valgus or varus deformities. Joint pain and impaired mobility associated with enthesopathy, osteophyte formation or other radiologic findings can occur.

Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari malformations. A detailed cephalometric study revealed increased head length, decreased occipital breadth, and a low mean cephalic index the ratio of the maximum width of the head multiplied by divided by its maximum length [ Pronicka et al ]. The incidence of Chiari malformations, which may cause headache and vertigo, has not been determined.

Persons with XLH are prone to spontaneous dental abscesses, which have been attributed to changes in the dentin component of teeth: irregular spaces with defective mineralization in the tooth dentin have been described [ Boukpessi et al ]; panoramic imaging reveals enlarged pulp chambers with prominent pulp horns leading to susceptibility to abscess formation [ Baroncelli et al ].

Sensorineural hearing loss has been reported; the actual prevalence of hearing loss is not known. Radiographic evaluation of a small number of persons with XLH and hearing loss showed generalized osteosclerosis and thickening of the petrous bone [ O'Malley et al ], a finding that has not been evaluated in other cohorts.

The features of X-linked hypophosphatemia are the same in males and females. The severity can differ among members of the same family. The etiology of this variability within the same cohort is not known. Several studies have evaluated genotype-phenotype correlations in XLH. There is no known difference between penetrance in males and females. One instance of discordance for XLH in monozygotic twin girls was reported by Owen et al [] : at age 19 months the girls were diagnosed with XLH based on biochemical findings and family history; no PHEX pathogenic variant was identified in either twin.

One twin was significantly shorter than the other length: The shorter twin had marked bilateral genu varum; the other twin had mild genu valgum. The authors proposed that non- penetrance resulted from discordant X-chromosome inactivation with non-random lack of PHEX expression in critical tissues. X-linked hypophosphatemia or its common abbreviation, XLH is the current and preferable term. Other terms that have been used:. The incidence of XLH is 3. No phenotypes other than those discussed in this GeneReview are known to be associated with pathogenic variants in PHEX.

The rachitic skeletal changes of nutritional and hereditary forms of rickets are indistinguishable. These types of rickets can be distinguished by biochemical testing: in hypophosphatemic rickets, serum concentrations of hydroxy vitamin D and calcium are normal, whereas in vitamin D-deficient rickets the hydroxy vitamin D serum concentration is low and the calcium concentration may be low or normal.

The different forms of hypophosphatemic rickets are distinguished by the presence of hypercalciuria or elevated 1,25 OH 2D. Mode of inheritance and molecular genetic testing help distinguish the different forms of hereditary hypophosphatemic rickets without hypercalciuria of which XLH is the most common. Feng et al [] , Lorenz-Depiereux et al []. Levy-Litan et al [] , Lorenz-Depiereux et al []. Riminucci et al []. Previously referred to as linear sebaceous nevus syndrome or epidermal nevus syndrome.

Hoffman et al []. Kinoshita et al []. White et al []. Brownstein et al []. To establish the extent of disease and needs of an individual diagnosed with X-linked hypophosphatemia XLH , the following evaluations are recommended. In children , treatment generally begins at the time of diagnosis and continues until long bone growth is complete. Treatment for most children consists of oral phosphate administered three to five times daily and high-dose calcitriol, the active form of vitamin D.

Two different regimens have been used, but have not been compared:. Doses are adjusted based on 1 evidence of therapeutic success including reduction in serum alkaline phosphatase activity, changes in musculoskeletal examination, improvement in radiographic rachitic changes, and when possible improved growth velocity; and 2 evidence of therapeutic complications including hyperparathyroidism, hypercalciuria, and nephrocalcinosis see Prevention of Secondary Complications.

Note: Normalization of the serum phosphate concentration is not a therapeutic goal as normal serum phosphate concentration frequently indicates overtreatment and increases the risk for treatment-related complications.

Jehan et al [] described differences in growth during treatment that are associated with different vitamin D receptor promoter haplotypes, providing a possible explanation for some of the clinical variability observed in XLH. After growth is complete, lower doses of the medications can be used to reach the treatment goals. In adults , the role of treatment has not been well studied; treatment is generally reserved for individuals with symptoms such as skeletal pain, upcoming orthopedic surgery, biochemical evidence of osteomalacia with an elevated alkaline phosphatase, or recurrent pseudofractures or stress fractures [ Carpenter et al ].

The calcitriol doses that are frequently employed in adults are in the range of 0. Orthopedic treatment. Despite what appears to be adequate pharmacologic therapy see following Note , some individuals have persistent lower-limb bowing and torsion, which may lead to misalignment of the lower extremity. In these individuals, surgical treatment is frequently pursued. No control trials of the different surgical techniques have been undertaken; the literature consists of case series.

Note: Poor compliance with pharmacologic therapy during childhood and the teen years may be one factor for persistent lower-limb deformities. Note: The risk with this procedure is prematurely stopping growth. In older children and adults, surgical techniques reported include distraction osteogenesis by external fixation, acute correction by external fixation with intramedullary nailing, internal fixation with intramedullary nailing, and acute correction by intramedullary nailing [ Song et al , Petje et al ].

Additionally, total hip and knee arthroplasty is sometimes required because of degenerative joint disease and enthesopathy.


Portal de información de enfermedades raras y medicamentos huérfanos

Hypophosphatemia in critically ill children. E-mail: heitorpl terra. The purpose of this paper is to review clinical studies on hypophosphatemia in pediatric intensive care unit patients with a view to verifying prevalence and risk factors associated with this disorder. Search terms included critically ill, pediatric intensive care, trauma, sepsis, infectious diseases, malnutrition, inflammatory response, surgery, starvation, respiratory failure, diuretic, steroid, antiacid therapy, mechanical ventilation. The search period covered those clinical trials published from January to January Studies concerning endocrinological disorders, genetic syndromes, rickets, renal diseases, anorexia nervosa, alcohol abuse, and prematurity were not included in this review. Out of 27 studies retrieved, only 8 involved pediatric patients, and most of these were case reports.


Clinical Approach to Hypocalcemia in Newborn Period and Infancy: Who Should Be Treated?

Hypocalcemia is a common metabolic problem in newborn period and infancy. There is consensus on the treatment of the symptomatic cases while the calcium level at which the treatment will be initiated and the treatment options are still controversial in asymptomatic hypocalcemia. This review article will cover hypocalcemia with specific reference to calcium homeostasis and definition, etiology, diagnosis, and treatment of hypocalcemia in newborn and infancy period. Early-onset hypocalcemia is generally asymptomatic; therefore, screening for hypocalcemia at the 24th and 48th hour after birth is warranted for infants with high risk of developing hypocalcemia.


Therapeutic management of hypophosphatemic rickets from infancy to adulthood




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