Generalized muscle weakness is the most common symptom across all types of familial hypophosphatemia, while myalgia and fatigue are invariably present [2] [8]. Additionally, XLH is distinguished by a childhood onset of progressive bowing deformities and short stature [8], as well as calcification of tendons, joint capsules and ligaments (known as enthesopathy) and a limited range of motion at the hips, spine and other larger joints [2] [3]. Dentinal clefts, enlarged pulp chambers, and appearance of dental abscesses are some of the most common dental abnormalities seen in hypophosphatemia patients [7]. In adults, bone pain, osteomalacia and pseudofractures, rachitis-like characteristics (genu valgum, frontal bossing, widening of the ends of long bones), rhabdomyolysis, and and hearing loss were observed.

• Short Stature

  Thus, the short stature in patients with X-linked hypophosphatemia is not due to a GH/IGF-I secretory defect. [ncbi.nlm.nih.gov]

  Bony abnormalities seen in untreated patients include progressive bowing, anteromedial rotational torsion of tibiae and persistent short stature [5]. [austinpublishinggroup.com]

  Symptoms - X-linked hypophosphatemia XLH manifests during childhood with typical clinical features of rickets such as skeletal deformities (bowed legs, genu varum, rachitic rosary...), short stature, and bone pain. [checkorphan.org]

• Pediatric Disease

  The FDA previously designated burosumab as a drug for a “rare pediatric disease”, enabling issuance of a priority review voucher if burosumab is approved. [selectscience.net]

• Surgical Procedure

  Other orthopedic surgical procedures may be needed depending on bone and joint abnormalities Individuals with Familial Hypophosphatemia have a slower bone repair process. [dovemed.com]

• Dental Abscess

  The main outcome measures were the number of enthesopathy sites assessed radiographically and the severity of dental disease, categorized as >5 or ≤5 dental abscesses identified historically. [endocrineweb.com]

  Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. [ncbi.nlm.nih.gov]

  Other features of the disease include dental abscesses, early tooth decay, craniosynostosis and hypertension. Citation: Stevens NM and Hennrikus WL. 3 Cases of Genu Valgum in Medically Treated X-linked Hypophosphatemic Rickets. [austinpublishinggroup.com]

  Good oral hygiene with flossing and regular dental follow-up is encouraged to prevent dental abscesses. [rchsd.org]

• Bone Pain

  Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. [ncbi.nlm.nih.gov]

  In adulthood, therapy is usually continued in symptomatic patients and generally aims at reducing bone pain. Corrective surgery of skeletal deformities may be required in some cases. [orpha.net]

• Muscle Weakness

  Bone pains and proximal muscle weakness improve significantly; however, longitudinal growth in children remains unsatisfactory 1. [casereports.bmj.com]

  Hypotonia and muscle weakness are absent. Causes - X-linked hypophosphatemia Prevention - X-linked hypophosphatemia Not supplied. [checkorphan.org]

  Generalized muscle weakness is the most common symptom across all types of familial hypophosphatemia, while myalgia and fatigue are invariably present. [symptoma.com]

  Muscle weakness and hypotonia are absent. Etiology The disease is caused by various mutations in the PHEX gene (Xp22.1) and is transmitted as an X-linked dominant trait with complete penetrance, but variable expressivity. [orpha.net]

• Rachitic Rosary

  Symptoms - X-linked hypophosphatemia XLH manifests during childhood with typical clinical features of rickets such as skeletal deformities (bowed legs, genu varum, rachitic rosary...), short stature, and bone pain. [checkorphan.org]

  Clinical description XLH manifests during childhood with typical clinical features of rickets such as short stature, bone pain, and skeletal deformities (bowed legs, genu varum, rachitic rosary...). [orpha.net]

  […] views AP and lateral of affected bone findings physeal widening metaphyseal cupping Looser's zones (pseudofracture on the compression side of bone) decreased bone density prominence of rib heads at the osteochondral junction ( rachitic rosary ) bowing [orthobullets.com]

• Dolichocephaly

  0000682 Bowing of the long bones Bowed long bones Bowing of long bones [ more ] 0006487 Delayed eruption of teeth Delayed eruption Delayed teeth eruption Delayed tooth eruption Eruption, delayed Late eruption of teeth Late tooth eruption [ more ] 0000684 Dolichocephaly [rarediseases.info.nih.gov]

  […] valgum) or bowed legs (genu varum) Thick wrists Ribs of the chest may show small knots, similar to beads; this is called rachitic rosary Hip deformities (coxa vara) Short stature Tooth decay and abscess formation; late eruption of teeth Narrow head (dolichocephaly [dovemed.com]

• Proximal Muscle Weakness

  muscle weakness for 8 years. [casereports.bmj.com]

• Psychomotor Retardation

  retardation due to S-adenosylhomocysteine hydrolase deficiency Pterygium colli-intellectual disability-digital anomalies syndrome Ptosis-syndactyly-learning difficulties syndrome Pycnodysostosis Pyknoachondrogenesis Pyle disease Pyruvate dehydrogenase [se-atlas.de]

• Seizure

  More severe cases can present with neurological complaints (altered speech, confusion, seizures, hearing impairment), bone pain, poor teeth status, and fatigue. [symptoma.com]

  […] anomalies syndrome Intellectual disability-seizures-macrocephaly-obesity syndrome Intellectual disability-severe speech delay-mild dysmorphism syndrome Intellectual disability-short stature-hypertelorism syndrome Intellectual disability-sparse hair-brachydactyly [se-atlas.de]

  Acute hypercalcemia (with resulting irritability, confusion, and potential seizures) can occur during treatment. Nephrocalcinosis, the long-term result of aggressive therapy, may be more damaging. [boneandspine.com]

  Hereditary Vitamin D-Dependent Rickets (Type I and II) Rare disorder Clinical features similar to Vitamin D-Deficient Rickets but more severe Clinical characteristics Type I joint pain/deformity, hypotonia, muscle weakness, growth failure, and hypocalcemic seizures [orthobullets.com]

  MEF2C Rhizomelic chondrodysplasia punctata, type 1 PEX7 Rieger-Syndrom PAX6 Roberts-Syndrom ESCO2 Rubinstein-Taybi-Syndrom CREBBP Rubinstein-Taybi-Syndrom EP300 Saethre-Chotzen Syndrom TWIST1 Seckel Syndrom ATR, CEP152, PCNT Segawa-Syndrom TH, GCH1 Seizures [meduniwien.ac.at]

• Abnormal Gait

  Whereas, in the study of Yue et al. [ 25 ], the mutation was found in familial patients with abnormal gait, kyphosis, and hip and knee joint pain. [omicsonline.org]

Clinical suspicion of X-linked hypophosphatemia should be supported by data from patient history and findings during physical examination. A positive family history for similar symptoms or confirmed hypophosphatemia in the presence of skeletal-related complaints in childhood are highly suggestive, in which case laboratory assessment is the next step. Evaluation of serum phosphate, calcium, alkaline phosphatase (ALP), PTH, 1,25 vitamin D3, as well as kidney function tests, urinalysis to detect proteinuria, glycosuria, calciuria, and determination of renal phosphate absorption through the ratio of the maximum rate of tubular phosphate reabsorption to the glomerular filtration rate (TmP/GFR) is recommended in the initial workup [2] [9]. In addition to laboratory workup, imaging studies such as radiography and bone scintigraphy can be used to assess skeletal changes [2]. Although clinical and laboratory clinical findings are usually sufficient to confirm the diagnosis, genetic testing to confirm FGF23 mutations and further molecular studies may be performed [9].

• Hypocalciuria

  Differential Diagnoses Renal tubular acidosis Hereditary hypophosphatemic rickets with hypocalciuria Fanconi syndrome Hereditary Vitamin D Dependent rickets Vitamin D deficient rickets Pseudohypoparathyroidism Lab Studies Serum calcium levels are normal [boneandspine.com]

• Hypophosphatemia

  Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. [ncbi.nlm.nih.gov]

  Causes - X-linked hypophosphatemia Prevention - X-linked hypophosphatemia Not supplied. [checkorphan.org]

• Hypophosphatemia

  Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. [ncbi.nlm.nih.gov]

  Causes - X-linked hypophosphatemia Prevention - X-linked hypophosphatemia Not supplied. [checkorphan.org]

• Parathyroid Hormone Increased

  Biochemical findings include elevated circulating levels of FGF-23 associated with hypophosphatemia, hyperphosphaturia, normal serum levels of calcium and parathyroid hormone, increased or normal plasma levels of alkaline phosphatise, normal plasma calcidiol [orpha.net]

• Alkaline Phosphatase Increased

  Abnormal shape of pelvic girdle bone 0002644 Arthralgia Joint pain 0002829 Bowing of the legs Bowed legs Bowed lower limbs [ more ] 0002979 Elevated alkaline phosphatase Greatly elevated alkaline phosphatase High serum alkaline phosphatase Increased [rarediseases.info.nih.gov]

The goals of therapy are to reduce or abolish symptoms and complaints caused by reduced phosphate concentrations in serum, as directed therapy does not exist yet. Oral phosphorus supplementation, however together with active vitamin D analogs (for ex. alfacalcidiol or calcitriol) can be quite effective and is the mainstay of therapy for all types of hereditary hypophosphatemia [10]. The dosage of oral phosphorus ranges between 30-60 mg/kg [8] [10], while calcitriol is given in doses of 20-30 ng/kg/24h [8], but factors such as age, levels of PTH, body weight, ALP levels and the extent of skeletal changes can lead to marked variations in the dosage, ranging between 10-80 ng/kg/24h for vitamin D and 30-180 mg/kg/24h for phosphorus [10]. Because of rapid changes in phosphate concentrations due to impaired reabsorption, multiple daily doses are recommended [3]. In severe cases, intravenous administration of phosphate is necessary [8]. In addition to supplementation, various surgical, orthopedic and dental procedures may be indicated, depending on the extent of damage caused by hypophosphatemia. Metaphyseal–diaphyseal osteotomies, epiphysiodesis, physiotherapy, applications of topical fluoride on teeth as well as pit and fissure sealants have all been described as potential therapeutic measures [7] [8] [10].

Recognition of hypophosphatemia in early life and determination of the underlying cause is of vital importance in terms of prognosis, as the effects of debilitating sequelae such as growth impairment and dental alterations may be seen [5] [7], but more importantly, severe cases may develop life-threatening cardiorespiratory failure, which illustrates the importance of an early diagnosis.

Genetic mutations affecting regulation of phosphate absorption and excretion in the body are the underlying cause of several forms of familial hypophosphatemia. Inactivating PHEX mutations trigger X-linked hypophosphatemia (XLH), leading to increased FGF23 concentrations, leading to decreased absorption of phosphate in the proximal renal tubules.

XLS, described as the most common form, is seen in approximately 1 in 20,000 individuals [4]. Countries such as Norway, however, report XLS in 1 in 60,000 children [5].

Phosphate is an integral electrolyte of numerous physiological functions and together with calcium, it plays a pivotal role in growth and development of the skeletal system. This electrolyte is absorbed from the gastrointestinal tract by passive and active transcellular pathways, the latter involving sodium phosphate cotransporter 2b, after which it is filtered and reabsorbed in the proximal renal tubule through the activity of two additional sodium phosphate cotransporters - NaPi2a and NaPi2c [6]. This mechanism is tightly regulated by dietary intake of phosphate, PTH, 1,25 vitamin D3, and FGF23, one of the main targets of X-linked hypophosphatemia. Mutations of FGF23 lead to reduced activity of NaPi2a and NaPi2c, causing increased phosphate wasting through urine as they are not able to reabsorb it [6].

Genetic counselling for couples or families in whom a diagnosis of familial hypophosphatemia is made should be carried out, as other prevention strategies are not available.

X-linked hypophosphatemia (XLH) is considered as the most common form of familial hypophosphatemia (seen in 1 in 20,000 children) [1]. XLH arises due to mutations in the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (or PHEX), leading to increased expression of the fibroblast-growth-factor 23 (FGF23), which is responsible for decreased absorption of phosphate in the proximal renal tubules [2]. The onset of lower-extremity bowing, calcification of tendons, joint capsules and ligaments (known as enthesopathy) in the first few years of life is typically encountered [3].

Together with parathyroid hormone (PTH), vitamin D, and calcium, phosphate is one of the most important molecules involved in skeletal growth, but in dozens of other metabolic pathways as well. X-linked hypophosphatemia (XLH) impairs the ability of the body to maintain normal levels of phosphate. Symptoms usually occur in early childhood, most common being generalized muscle weakness and skeletal alterations - short stature, bowing of the limbs, and reduced range of motion in the spine, hips and shoulders. More severe cases can present with neurological complaints (altered speech, confusion, seizures, hearing impairment), bone pain, poor teeth status, and fatigue. The diagnosis can be made by obtaining a thorough patient history that will determine the presence of hypophosphatemia within the family and by observing symptoms and signs during physical examination. Laboratory studies are needed to confirm the disorder, however, and assessment of serum phosphate and calcium levels, parathyroid hormone (PTH), vitamin D, kidney function tests and urinalysis is necessary. In some cases, genetic testing can be conducted. Treatment aims to correct the levels of phosphate through long-term oral supplementation with phosphorus, but it must be administered simultaneously with vitamin D, which is necessary for its adequate absorption. If patients are compliant, treatment can alleviate the majority of symptoms, but an early recognition of hypophosphatemia carries a much better prognosis, emphasizing the need for physicians to consider this group of disorders in the differential diagnosis of skeletal abnormalities in both children and adults.

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