X-linked Hypophosphatemic Rickets

Overview

Definition

X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets (XLHR) is a rare genetic disorder that causes hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome and resultant clinical rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets.

Epidemiology

• XLHR is the most common variant among inherited hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets.
  • Other forms are rare, with fewer than 100 reported cases collectively:
    • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance 
    • Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance
  • Usually familial, but some cases are sporadic Sporadic Selective IgA Deficiency

• Not clear if both genders are affected equally
• The estimated incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency is 1 in 20,000 live births.

Etiology

• X-linked dominant inheritance X-linked dominant inheritance Sex-Linked Inheritance
• Caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the phosphate-regulating gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics with homology to endopeptidases Endopeptidases A subclass of peptide hydrolases that catalyze the internal cleavage of peptides or proteins. Proteins and Peptides located on the X chromosome X chromosome The female sex chromosome, being the differential sex chromosome carried by half the male gametes and all female gametes in human and other male-heterogametic species. Basic Terms of Genetics (PHEX)

Pathophysiology

• The pathogenesis is not fully understood.
• Gene mutation Gene Mutation Myotonic Dystrophies leads to increased synthesis Synthesis Polymerase Chain Reaction (PCR) of fibroblast growth factor 23 Fibroblast growth factor 23 A family of small polypeptide growth factors that share several common features including a strong affinity for heparin, and a central barrel-shaped core region of 140 amino acids that is highly homologous between family members. Although originally studied as proteins that stimulate the growth of fibroblasts this distinction is no longer a requirement for membership in the fibroblast growth factor family. Electrolytes (FGF23) by osteoblasts Osteoblasts Bone-forming cells which secrete an extracellular matrix. Hydroxyapatite crystals are then deposited into the matrix to form bone. Bones: Development and Ossification and osteocytes Osteocytes Mature osteoblasts that have become embedded in the bone matrix. They occupy a small cavity, called lacuna, in the matrix and are connected to adjacent osteocytes via protoplasmic projections called canaliculi. Bones: Development and Ossification.
• FGF23 inhibits renal tubular reabsorption of phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes → hyperphosphaturia → hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome → clinical bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types and dental symptoms
• FGF23 reduces the circulating levels of 1,25-dihydroxyvitamin D.
• Phosphorus plays a crucial role in:
  • Growth and development
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types formation
  • Acid-base homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death
  • Cellular metabolism Cellular metabolism The chemical reactions in living organisms by which energy is provided for vital processes and activities and new material is assimilated. Thyroid Hormones 
• Phosphorus exists in both organic and inorganic forms in the human body:
  • 85% of the phosphorus in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types is bound to calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes as calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes, which provides structural strength.
  • 14% of the phosphorus is present at the cellular level as a component of lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids, proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, nucleic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, and metabolic and signaling pathways.
  • 1% of the phosphorus is present in the serum and extracellular fluid Extracellular fluid The fluid of the body that is outside of cells. It is the external environment for the cells. Body Fluid Compartments. 
• When phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes is needed for homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death, it is obtained from bone resorption Bone resorption Bone loss due to osteoclastic activity. Bones: Remodeling and Healing.
• High phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes levels are necessary for infants and children to maintain adequate skeletal mineralization; thus, hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome leads to rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets.

Clinical Presentation and Diagnosis

Clinical presentation

The clinical presentation of XLHR may vary from asymptomatic to severely symptomatic. X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets is commonly mistaken for nutritional rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets in infants, and the symptoms include:

• Short stature
• Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
• Genu valgum Genu valgum Genu valgum is a deformation of the knee joint(s) that creates angulation of the lower limb(s) toward the midline in the coronal plane. Children ages 1-5 years are commonly affected. Genu Valgum or genu varum Genu varum Genu varum is a deformation of the knee joint(s) that creates angulation of the lower limb(s) away from the midline in the coronal plane. Children ages 1-5 years are commonly affected. Genu Varum:
  • Results from the “softening” of bones
  • May become more prominent when children begin walking
• Joint stiffness (from calcification of ligaments and tendons)
• Dental pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and tooth abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease

Diagnosis

Family history Family History Adult Health Maintenance:

• Relevant family history Family History Adult Health Maintenance coupled with the screening Screening Preoperative Care of infants allows for the early recognition and management of XLHR.
• Early diagnosis and treatment, initiated prior to walking and the development of leg Leg The lower leg, or just “leg” in anatomical terms, is the part of the lower limb between the knee and the ankle joint. The bony structure is composed of the tibia and fibula bones, and the muscles of the leg are grouped into the anterior, lateral, and posterior compartments by extensions of fascia. Leg: Anatomy deformities, is beneficial.

Lab tests:

• Used to confirm hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome and determine the ratio of tubular maximum reabsorption of phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (TmP) to GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests:
  • Fasting serum phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes 
  • Urine phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes 
  • Creatinine 
• 1,25-dihydroxyvitamin D level is low or normal.
• Normal serum calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes
• PTH levels may be mildly elevated ( secondary hyperparathyroidism Secondary hyperparathyroidism Abnormally elevated parathyroid hormone secretion as a response to hypocalcemia. It is caused by chronic kidney failure or other abnormalities in the controls of bone and mineral metabolism, leading to various bone diseases, such as renal osteodystrophy. Hyperparathyroidism) or normal.
• High serum alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma

Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies:

• Diagnosis is confirmed by identification Identification Defense Mechanisms of the mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations on the PHEX gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, but the detection rate is approximately 65%.
• Testing is generally reserved for:
  • Atypical presentation
  • Genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies

Imaging:

Radiologic evaluation should be performed to rule out physiological bowing and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types dysplasia. Potential X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests findings may include:

• Flaring of the metaphysis Metaphysis Bones: Structure and Types (Erlenmeyer flask deformity Deformity Examination of the Upper Limbs)
• “Rachitic rosary” is seen on chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests: a row of bead-like prominence at the junction of a rib and its cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage: Histology (enlarged costochondral joints), which resembles a rosary

Management and Monitoring

The goals of treatment are to improve osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets and skeletal deformities, improve growth in infants and physical activity in children, and decrease pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways.

Management

• High-dose supplementation:
  • Activated vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies ( calcitriol Calcitriol The physiologically active form of vitamin d. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. Parathyroid Glands: Anatomy) twice daily
  • Phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes supplements: 4–5 doses/day
  • Adherence to therapy may be difficult for young children.
  • Overtreatment with phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes and the development of secondary hyperparathyroidism Secondary hyperparathyroidism Abnormally elevated parathyroid hormone secretion as a response to hypocalcemia. It is caused by chronic kidney failure or other abnormalities in the controls of bone and mineral metabolism, leading to various bone diseases, such as renal osteodystrophy. Hyperparathyroidism could be detrimental and requires monitoring.
• Burosumab:
  • Human anti-FGF23 monoclonal antibody
    • Approved in 2018 
    • Currently, the treatment of choice
  • Minimal side effects and less need for monitoring
  • Indicated for previously untreated children or those who show limited benefits after the use of supplements
  • Should never be given in combination with oral phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes and activated vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies metabolites ( calcitriol Calcitriol The physiologically active form of vitamin d. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. Parathyroid Glands: Anatomy)
• Corrective surgery and dental treatment are possible options.
  • Consider only with severe bowing or if tibial torsion does not improve with medical management
  • Corrective osteotomies are not usually performed in children < 6 years of age who will likely respond to medical treatment; this intervention is reserved for older patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with more severe deformities.
  • Orthopedic surgeons should be actively involved in the management of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with XLHR.

Monitoring

Some adults with XLHR may have minimal medical problems, whereas others may experience persistent discomfort or complications. Monitoring the therapy for potential complications of hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism and nephrocalcinosis is imperative.

• Lab testing is indicated every 3 months:
  • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes 
  • Phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes 
  • PTH to monitor for hypercalcemia Hypercalcemia Hypercalcemia (serum calcium > 10.5 mg/dL) can result from various conditions, the majority of which are due to hyperparathyroidism and malignancy. Other causes include disorders leading to vitamin D elevation, granulomatous diseases, and the use of certain pharmacological agents. Symptoms vary depending on calcium levels and the onset of hypercalcemia. Hypercalcemia, hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis, and secondary hyperparathyroidism Secondary hyperparathyroidism Abnormally elevated parathyroid hormone secretion as a response to hypocalcemia. It is caused by chronic kidney failure or other abnormalities in the controls of bone and mineral metabolism, leading to various bone diseases, such as renal osteodystrophy. Hyperparathyroidism
    • Hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis may lead to nephrocalcinosis as a complication related to the drug dose.
    • Secondary hyperparathyroidism Secondary hyperparathyroidism Abnormally elevated parathyroid hormone secretion as a response to hypocalcemia. It is caused by chronic kidney failure or other abnormalities in the controls of bone and mineral metabolism, leading to various bone diseases, such as renal osteodystrophy. Hyperparathyroidism can be corrected by increasing the dose of calcitriol Calcitriol The physiologically active form of vitamin d. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. Parathyroid Glands: Anatomy or reducing the dose of phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes.
  • Monitor serum alkaline phosphatase Alkaline Phosphatase An enzyme that catalyzes the conversion of an orthophosphoric monoester and water to an alcohol and orthophosphate. Osteosarcoma levels (should decrease with treatment).
• Imaging:
  • Renal ultrasonography is suggested at 2–5-year intervals after treatment initiation for the early detection of nephrocalcinosis.
  • X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests:
    • To evaluate the healing of skeletal deformities 
    • When considering surgical management

Differential Diagnosis

• Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets: a rare syndrome characterized by renal phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes wasting and rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets, which is similar to the X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) form but transmitted in an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance pattern. There is an increase in FGF23 similar to that observed in the X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) form; however, this increase is inconsistent and the levels of serum phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes can wax and wane from normal to low. Iron Iron A metallic element with atomic symbol fe, atomic number 26, and atomic weight 55. 85. It is an essential constituent of hemoglobins; cytochromes; and iron-binding proteins. It plays a role in cellular redox reactions and in the transport of oxygen. Trace Elements deficiency during menses Menses The periodic shedding of the endometrium and associated menstrual bleeding in the menstrual cycle of humans and primates. Menstruation is due to the decline in circulating progesterone, and occurs at the late luteal phase when luteolysis of the corpus luteum takes place. Menstrual Cycle and pregnancy Pregnancy The status during which female mammals carry their developing young (embryos or fetuses) in utero before birth, beginning from fertilization to birth. Pregnancy: Diagnosis, Physiology, and Care can trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation FGF23 increase and result in hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome. About half of the patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship affected with autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets present with symptoms similar to those in XLHR in early childhood, whereas others do not present with symptoms until puberty Puberty Puberty is a complex series of physical, psychosocial, and cognitive transitions usually experienced by adolescents (11-19 years of age). Puberty is marked by a growth in stature and the development of secondary sexual characteristics, achievement of fertility, and changes in most body systems. Puberty or early adulthood. The management of autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets is similar to that of XLHR.
• Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets (ARHR): a condition similar to the X-linked X-linked Genetic diseases that are linked to gene mutations on the X chromosome in humans or the X chromosome in other species. Included here are animal models of human X-linked diseases. Common Variable Immunodeficiency (CVID) and autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance forms, but even rarer. Mutations have been described in 3 different genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure. Autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets presents in late infancy with hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome, rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets, and osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets. These features vary and are mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations specific and age dependent. In addition, some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship develop osteosclerosis Osteosclerosis An abnormal hardening or increased density of bone tissue. Paget’s Disease of Bone and bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types overgrowth, nerve deafness, facial and dental abnormalities, and learning disabilities Learning disabilities Conditions characterized by a significant discrepancy between an individual’s perceived level of intellect and their ability to acquire new language and other cognitive skills. These may result from organic or psychological conditions. Relatively common subtypes include dyslexia, dyscalculia, and dysgraphia. DiGeorge Syndrome. Management of ARHR is similar to that of XLHR.
• Hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets with hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis (HRH): a rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance genetic disorder that can present either in childhood or adulthood. The heterozygous form is less severe and presents with mild hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome, hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis, and nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis without bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types disease. Hypophosphatemic rickets Hypophosphatemic rickets A disorder characterized by hypophosphatemia; rickets; osteomalacia; resulting from lack of phosphate reabsorption by the kidneys and possible defects in vitamin D metabolism. Osteomalacia and Rickets with hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis differs from XLRH in that the hypophosphatemia Hypophosphatemia A condition of an abnormally low level of phosphates in the blood. Bartter Syndrome is not mediated by FGF23 activity, and impairment is limited to phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes transport. Serum vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies levels are normal. Management requires close monitoring to prevent elevated calcitriol Calcitriol The physiologically active form of vitamin d. It is formed primarily in the kidney by enzymatic hydroxylation of 25-hydroxycholecalciferol (calcifediol). Its production is stimulated by low blood calcium levels and parathyroid hormone. Calcitriol increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. Parathyroid Glands: Anatomy and phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes levels. 
• Fanconi syndrome Fanconi Syndrome Renal Tubular Acidosis: a rare autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder that results in a defect in the absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption function of the proximal renal tubule, leading to electrolyte imbalances, hyperphosphatemia Hyperphosphatemia A condition of abnormally high level of phosphates in the blood, usually significantly above the normal range of 0. 84-1. 58 mmol per liter of serum. Hypocalcemia, and excretion of certain amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids in the urine. The clinical presentation can manifest at any age with several symptoms including slow growth, osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets, polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation, dehydration Dehydration The condition that results from excessive loss of water from a living organism. Volume Depletion and Dehydration, weakness, tremors, and fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia. The acquired form results from exposure to chemicals, heavy metals, and medications, or due to amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis and multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma. Diagnosis is based on the clinical presentation and lab results. Management involves the treatment of metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis using alkali therapy.
• Rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets and osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets: disorders arising from decreased bone mineralization Bone mineralization Calcium (Ca2+) and phosphate (PO43–) combine to form hydroxyapatite crystals on the bone matrix. Bones: Development and Ossification, most often due to vitamin D deficiency Vitamin D Deficiency A nutritional condition produced by a deficiency of vitamin D in the diet, insufficient production of vitamin D in the skin, inadequate absorption of vitamin D from the diet, or abnormal conversion of vitamin D to its bioactive metabolites. It is manifested clinically as rickets in children and osteomalacia in adults. Fat-soluble Vitamins and their Deficiencies. Rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets affects the cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage: Histology of the epiphyseal growth plates Growth Plates The area between the epiphysis and the diaphysis within which bone growth occurs. Osteosarcoma in children, whereas osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets affects the sites of bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types turnover in children and adults. Rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets commonly presents with skeletal deformities and growth abnormalities. Diagnosis is made based on a combination of clinical findings, laboratory tests, and imaging. Treatment is with vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies, calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes, and phosphorus supplementation.
• Fibrous Fibrous Fibrocystic Change dysplasia of bones: a rare disorder in which regular Regular Insulin bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types is replaced with fibrous Fibrous Fibrocystic Change, scar-like tissue. Fibrous Fibrous Fibrocystic Change dysplasia of bones is a genetic disorder that causes weakening of bones and eventual development of bowing and other pathologies; however, this condition cannot be inherited. There is no curative treatment and the management is aimed at controlling pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways and stabilizing bones.
• Tumor-induced osteomalacia Osteomalacia Disorder caused by an interruption of the mineralization of organic bone matrix leading to bone softening, bone pain, and weakness. It is the adult form of rickets resulting from disruption of vitamin d; phosphorus; or calcium homeostasis. Osteomalacia and Rickets (osteogenic malacia): a paraneoplastic syndrome characterized by bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, muscle weakness, and bone fractures Bone fractures Breaks in bones. Bones: Remodeling and Healing. Osteogenic malacia occurs due to high levels of FGF23 in the blood, which is secreted by mesenchymal tumors. Treatment includes removal of the tumor Tumor Inflammation if it can be located, and supplementation with active vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies and phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes.