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Familial Hypophosphatemia

Vitamin D-Resistant Rickets

Familial hypophosphatemia is a term encompassing a group of genetic diseases that impair homeostatic pathways of phosphate in the body. Bone pain, fatigue, myopathy, as well as growth and dental abnormalities are usually encountered, whereas cardiac and pulmonary failure may ensue in severe cases. Patient history, clinical examination and complete laboratory studies are necessary to confirm the diagnosis, while oral phosphorus and vitamin D supplementation is the main form of treatment.


Generalized muscle weakness is the most common symptom across all types of familial hypophosphatemia, while myalgia and fatigue are invariably present [4] [10]. Additionally, XLH is distinguished by a childhood onset of progressive bowing deformities and short stature [10], 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 [4] [5]. It is not uncommon, however, for the diagnosis to be made in adulthood, as a delayed onset of symptoms is reported in a small but significant number of individuals [5]. Dentinal clefts, enlarged pulp chambers, and appearance of dental abscesses are some of the most common dental abnormalities seen in hypophosphatemia patients [12]. Chronic and more severe forms of hypophosphatemia present with bone pain, osteomalacia and pseudofractures, rachitis-like characteristics (genu valgum, frontal bossing, widening of the ends of long bones), rhabdomyolysis, and neurological symptoms (dysarthria, sensorineural hearing loss, paresthesias, neuropathy, seizures and altered mental status) [4] [5] [10]. In acute and life-threatening cases, cardiac and respiratory function can be severely diminished, in which case rapid recognition of the underlying cause is mandatory [4].

  • The lack of phosphate in the body, results in the formation of weak bones; this weakening is called osteomalacia Weak bones and abnormal growth of bones in a child results in physical abnormalities, such as deformities of the legs (bowed legs) and short[dovemed.com]
  • Generalized muscle weakness is the most common symptom across all types of familial hypophosphatemia, while myalgia and fatigue are invariably present.[symptoma.com]
  • The patient’s voice may be weak and shaky. Assess the patient’s ability to swallow and the gag reflex. Auscultate the heart; the pulse may be weak and irregular.[medical-dictionary.thefreedictionary.com]
  • Sigh. As I drove away, I started to feel aggravated. What I wish I could have said was, “I was born with a rare disease called x-linked hypophosphatemia. I have noticeable physical characteristics of XLH and then some that aren’t so noticeable.[banjogrrldiaries.wordpress.com]
Dental Abscess
  • In children, the disorder first becomes apparent with the development of rickets, skeletal deformities, short stature, and dental abscesses.[indiana.pure.elsevier.com]
  • Dentinal clefts, enlarged pulp chambers, and appearance of dental abscesses are some of the most common dental abnormalities seen in hypophosphatemia patients.[symptoma.com]
  • Prevalence of dental abscess in a population of children with vitamin D-resistant rickets. Pediatr Dent 1991; 13 (2): 91–96. Shroff D, McWhorter A.[medigraphic.com]
  • Familial hypophosphatemic vitamin D-resistant rickets–prevention of spontaneous dental abscesses on primary teeth: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:525–30. Crossref Google Scholar 9. Pettifor JM.[degruyter.com]
  • Delayed dentition; dental abscesses; deafness; Chiari malformation; extraskeletal calcification of the tendons, ligaments, and joint capsules; and craniosynostosis are occasionally encountered.[emedicine.medscape.com]
Dental Caries
  • The patient had multiple periodontal abscesses, but no evidence of dental caries, trauma, or periodontal disease on the corresponding teeth at the time of his oral examination.[ncbi.nlm.nih.gov]
  • Increased calcium levels in blood, can lead to significant side effects Treating disorders of teeth would help decrease the development of dental caries, which if untreated can result in blood infections Leg deformities may be treated with surgical measures[dovemed.com]
  • caries, delay in eruption of the dentition, enamel hypoplasia, dental abscesses, and gingivitis Data Monitoring Committee An independent DMC that includes members with expertise in metabolic bone disease, cardiology, and nephrology, and the conduct of[clinicaltrialsregister.eu]
Delayed Dentition
  • Delayed dentition; dental abscesses; deafness; Chiari malformation; extraskeletal calcification of the tendons, ligaments, and joint capsules; and craniosynostosis are occasionally encountered.[emedicine.medscape.com]
  • Nevertheless, no gender differences in disease severity were detected in the largest reported series of patients with XLH rickets. 15 Affected patients grow slowly and have delayed dentition, dental abscesses, and early tooth decay.[consultant360.com]
  • Low phosphate levels in children will lead to poor bone health and a variety of clinical symptoms that may include abnormal bone formation, bone pain, lower than normal bone density, fractures, short stature, tooth abscesses, tinnitus, deformities in[ultragenyx.com]
Bone Pain
  • Bone pain, fatigue, myopathy, as well as growth and dental abnormalities are usually encountered, whereas cardiac and pulmonary failure may ensue in severe cases.[symptoma.com]
  • […] due to weak bones.[dovemed.com]
  • They develop bone abnormalities that can interfere with movement and cause bone pain. The most noticeable of these abnormalities are bowed legs or knock knees (a condition in which the lower legs are positioned at an outward angle).[icdlist.com]
  • pain, and tooth abscesses.[icd.codes]
  • In adults, manifestations of XLH include osteomalacia, degenerative joint disease, enthesopathy, bone and joint pain, and continued dental disease.[indiana.pure.elsevier.com]
  • 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.[symptoma.com]
  • The disorder may also cause abnormal bone growth where ligaments and tendons attach to joints (enthesopathy).[icdlist.com]
  • Liang G, Katz LD, Insogna KL, Carpenter TO, Macica CM (2009) Survey of the enthesopathy of X-linked hypophosphatemia and its characterization in Hyp mice. Calcif Tissue Int 85(3):235–246 PubMed CrossRef Google Scholar 7.[link.springer.com]
  • Conventional Therapy in Adults With X-Linked Hypophosphatemia: Effects on Enthesopathy and Dental Disease.[ncbi.nlm.nih.gov]
Rachitic Rosary
  • Growth plate widening with metaphyseal flaying and fraying, bowing of lower limb long bones, rachitic rosary ribs, coxa vara 4 public playlists includes this case Case information rID: 16565 Published: 29th Jan 2012 Last edited: 16th Jul 2018 Inclusion[radiopaedia.org]
  • In infants and children, the signs and symptoms include: Abnormal "waddling" walk due to knock-knees (genu 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[dovemed.com]
  • In addition to her respiratory findings, widespread signs of rickets were found--ie, frontal bossing, rachitic rosary, widening of the wrists, and double maleoli.[consultant360.com]
  • On examination, she had a short stature (146 cm), frontal bossing of the cranium, bulging of the costochondral junctions (rachitic rosary) and bowing of the lower limbs.[pubs.sciepub.com]
Muscle Cramp
  • cramps Bone pain with frequent fractures due to weak bones.[dovemed.com]
  • cramps since 1990 with consecutive abuse of analgesics, frequent psychogenic, and rare epileptic seizures since 1990, iron-deficient normocytic and normochrome anemia since at least 1994 which did not respond to substitution, hyperlipidemia since at[ijpm.info]
Coxa Vara
  • Growth plate widening with metaphyseal flaying and fraying, bowing of lower limb long bones, rachitic rosary ribs, coxa vara 4 public playlists includes this case Case information rID: 16565 Published: 29th Jan 2012 Last edited: 16th Jul 2018 Inclusion[radiopaedia.org]
  • vara) Short stature Tooth decay and abscess formation; late eruption of teeth Narrow head (dolichocephaly) with early fusion of the skull bones (craniosynostosis) Bone pain and weakness, which may result in fractures, weak joints In adults, the signs[dovemed.com]
Abnormal Gait
  • Snapshot A 6-year-old boy is brought to his pediatrician by his parents due to poor growth, weakness, and abnormal gait. On physical exam, there is bowing of the legs and tenderness upon palpation of the lower extremity.[medbullets.com]
Waddling Gait


Clinical suspicion of familial 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 [4] [9]. It must be noted that patients who develop severe acute bone pain and consequent rhabdomyolysis can paradoxically present with hyperphosphatemia, due to the fact that intracellular phosphate is released into the circulation, and can be a significant challenge for the physician [4]. In addition to laboratory workup, imaging studies such as radiography and bone scintigraphy can be used to assess skeletal changes [4]. 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].


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 [6]. The dosage of oral phosphorus ranges between 30-60 mg/kg [6] [10], while calcitriol is given in doses of 20-30 ng/kg/24h [10], 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 [6]. Because of rapid changes in phosphate concentrations due to impaired reabsorption, multiple daily doses are recommended [5]. In severe cases, intravenous administration of phosphate is necessary [10]. 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 [6] [10] [12]. Calcimimetics (cinacalcet), calcitonin and FGF23 neutralizing antibodies are currently being investigated as future therapeutic strategies, but their efficacy is yet to be confirmed [9].


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 [8] [12], 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, whereas autosomal dominant forms (ADHR) arise due to direct mutations of the FGF23 [1]. Moreover, three forms of autosomal recessive hypophosphatemia have been recognized so far, stemming from mutations in dentin matrix protein 1 (DMP1), ecto-nucleotide pyrophosphatese/phosphodiesterase 1 (ENPP1), and FAM20c, respectively [6] [8]. All of the mentioned disorders universally lead to impaired FGF23 concentrations and its activity in serum, but two additional forms that are independent of FGF23 are documented as well - Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Fanconi syndrome, in which sodium-dependent phosphate cotransporter molecules in the renal proximal tubule are mutated and unable to perform their respective function of reabsorbing phosphate in the kidney [7] [9].


Familial syndromes causing hypophosphatemia are considered to be rare in he general population. Denmark reports an overall prevalence rate of 4.8 per 100,000 [11], while XLS, described as the most common form, is seen in approximately 1 in 20,000 individuals [3]. Countries such as Norway, however, report XLS in 1 in 60,000 children [8]. Apart from a positive family history, no other risk factors have been identified, although pregnancy was identified as a precipitating event in the onset of adult ADHR [5] [7].

Sex distribution
Age distribution


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 [7]. This mechanism is tightly regulated by dietary intake of phosphate, PTH, 1,25 vitamin D3, and FGF23, one of the main targets of familial hypophosphatemia. Namely, mutations of FGF23, regardless of the underlying cause, lead to reduced activity of NaPi2a and NaPi2c, causing increased phosphate wasting through urine as they are not able to reabsorb it [7]. This mechanism is responsible for the development of ADHR, ARHR and XLR, and the term "FGF23-dependent" is used to describe the pathophysiological changes that occur in these conditions [7] [9]. In hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Fanconi syndrome, on the other hand, mutations affect sodium phosphate cotransporters directly, and are often termed "FGF23-independent" [7].


Genetic counselling for couples or families in whom a diagnosis of familial hypophosphatemia is made should be carried out, as other prevention strategies currently do not exist. Several steps can be made in reducing the risk for complications of these disorders, including rigorous dental hygiene and regular dental check-ups, periodic assessment of serum phosphate levels and successful compliance with therapy, one of the key factors in ensuring good quality of life.


Familial hypophosphatemia denotes abnormally low phosphate concentrations in the body as a result of hereditary diseases. Mutations of genes and respective proteins that are involved in normal phosphate homeostasis are the underlying cause and several disorders are recognized in literature [1] [2] [3]:

  • X-Linked hypophosphatemia (XLH) - Considered as the most common form of familial hypophosphatemia (seen in 1 in 20,000 children) [2], 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 [4]. 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 [5].
  • Autosomal dominant hypophosphatemic rickets (ADHR) - Mutations of the FGF23 protein are the cause of this familial disorder that can have a delayed clinical course of bone pain, pathological fractures and muscle weakness until adolescence or adulthood, while growth abnormalities are seen if symptoms start during childhood [6] [7].
  • Autosomal recessive hypophosphatemic rickets (ARHR) - Three subtypes of ARHR are described - type I, caused by mutations of dentin matrix protein 1 (DMP1); type 2, in which symptoms appear as a result of ecto-nucleotide pyrophosphatese/phosphodiesterase 1 (ENPP1) gene mutations; and type 3, characterized by family with sequence similarity 20, member C (FAM20c) gene mutations, all leading to increased levels of FGF23 and consequent hypophosphatemia [6] [8].
  • Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Fanconi syndrome - Unlike XLH, ADHR and ARHR, these familial disorders are considered "FGF-23 independent", as their occurrence is related to mutations that do not involve this molecule. Sodium-dependent phosphate cotransporters in the renal proximal tubule (NaPi2a and NaPi2c, respectively) are targets of genetic mutations [7] [9].

In addition to skeletal and soft tissue-related symptoms, patients may suffer from neurological deficits (such as paresthesia, dysarthria, seizures, neuropathies and even altered mental state), rhabdomyolysis, intravascular hemolysis, osteomalacia and most importantly, cardiac and respiratory insufficiency [4]. For this reason, prompt recognition of the disorder in early life is vital. A thorough patient history with an emphasis on familial occurrence of the disease and similar symptoms, a detailed physical examination that will identify findings suggestive of hypophosphatemia, and a complete laboratory workup comprising complete blood counts (CBC), serum levels of phosphate and other electrolytes (calcium, sodium, potassium), parathyroid hormone (PTH), alkaline phosphatase (ALP) 1,25OHD (vitamin D), kidney function tests and urinalysis are essential components [4] [9]. If hypophosphatemia is confirmed, evaluation of FGF23 in serum may be highly useful, as the majority of syndromes are FGF23-related [10]. Simultaneous oral supplementation of calcitriol and phosphate is currently the mainstay of therapy in both children and adults, while various surgical, orthopedic and dental procedures may be necessary to provide symptomatic relief [4] [6] [10]. Newer pharmacologic agents, such as calcimimetics, calcitonin and FGF23 neutralizing antibodies are showing promising results as future therapy, but further studies are necessary to solidify their use in general practice [9].

Patient Information

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. The term familial hypophosphatemia describes a group of genetic diseases that impair the ability of the body to maintain normal levels of phosphate. Specifically, X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and Fanconi syndrome are conditions in which hereditary mutations of various proteins and molecules responsible for phosphate transport reduce the capacity for absorption of this electrolyte from the kidneys, the end-result being chronic loss of phosphate through urine. 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. Symptoms can be mild and chronic in nature, but they may also be rapidly progressive and life-threatening, more commonly in childhood. A small number of cases present in adulthood due to a delayed onset of symptoms, and conditions such as pregnancy was identified as a precipitating factor for their development. 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.



  1. Razali NN, Hwu TT, Thilakavathy K. Phosphate homeostasis and genetic mutations of familial hypophosphatemic rickets. J Pediatr Endocrinol Metab. 2015;28(9-10):1009-1017.
  2. Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y. A clinical and molecular genetic study of hypophosphatemic rickets in children. Pediatr Res. 2005;58(2):329-333.
  3. Pavone V, Testa G, Gioitta Iachino S, Evola FR, Avondo S, Sessa G. Hypophosphatemic rickets: etiology, clinical features and treatment. Eur J Orthop Surg Traumatol. 2015;25(2):221-226.
  4. Imel EA, Econs MJ. Approach to the Hypophosphatemic Patient. J Clin Endocrinol Metab. 2012;97(3):696-706.
  5. Ruppe MD. X-Linked Hypophosphatemia. 2012 Feb 9 [Updated 2014 Oct 16]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.
  6. Linglart A, Biosse-Duplan M, Briot K, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13-R30.
  7. Gattineni J. Inherited Disorders of Calcium and Phosphate Metabolism. Curr Opin Pediatr. 2014;26(2):215-222.
  8. Rafaelsen S, Johansson S, Ræder H, Bjerknes R. Hereditary hypophosphatemia in Norway: a retrospective population-based study of genotypes, phenotypes, and treatment complications. Eur J Endocrinol. 2015;174(2):125-136.
  9. Lee JY, Imel EA. The Changing Face of Hypophosphatemic Disorders in the FGF-23 Era. Pediatr Endocrinol Rev. 2013;10(0 2):367-379.
  10. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A Clinician's Guide to X-linked Hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388.
  11. Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009;160(3):491-497.
  12. Souza MA, Valente Soares Junior LA, dos Santos MA, Vaisbich MH. Dental abnormalities and oral health in patients with Hypophosphatemic rickets. Clinics. 2010;65(10):1023-1026.

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Last updated: 2019-07-11 20:30