Following dietary exposure to fructose, sucrose, or sorbitol, untreated hereditary fructose intolerance (HFI) is characterized by metabolic disturbances (hypoglycemia, lactic acidemia, hypophosphatemia, hyperuricemia, hypermagnesemia, hyperalaninemia) and clinical findings (nausea, vomiting, and abdominal distress; chronic growth restriction / failure to thrive). While untreated HFI typically first manifested when fructose- and sucrose-containing foods were introduced in the course of weaning young infants from breast milk, it is now presenting earlier, due to the addition of fructose-containing nutrients in infant formulas. If the infant ingests large quantities of fructose, the infant may acutely develop lethargy, seizures, and/or progressive coma. Untreated HFI may result in renal and hepatic failure. If identified and treated before permanent organ injury occurs, individuals with HFI can experience a normal quality of life and life expectancy.

The Murk Jansen type of metaphyseal chondrodysplasia is characterized by severe short stature, short bowed limbs, clinodactyly, prominent upper face, and small mandible. Hypercalcemia and hypophosphatemia occur despite the lack of parathyroid abnormalities (summary by Cohen, 2002).

Vitamin D-dependent rickets is a disorder of bone development that leads to softening and weakening of the bones (rickets). There are several forms of the condition that are distinguished primarily by their genetic causes: type 1A (VDDR1A), type 1B (VDDR1B), and type 2A (VDDR2A). There is also evidence of a very rare form of the condition, called type 2B (VDDR2B), although not much is known about this form.\n\nThe signs and symptoms of vitamin D-dependent rickets begin within months after birth, and most are the same for all types of the condition. The weak bones often cause bone pain and delayed growth and have a tendency to fracture. When affected children begin to walk, they may develop abnormally curved (bowed) legs because the bones are too weak to bear weight. Impaired bone development also results in widening of the areas near the ends of bones where new bone forms (metaphyses), especially in the knees, wrists, and ribs. Some people with vitamin D-dependent rickets have dental abnormalities such as thin tooth enamel and frequent cavities. Poor muscle tone (hypotonia) and muscle weakness are also common in this condition, and some affected individuals develop seizures.\n\nHair loss (alopecia) can occur in VDDR2A, although not everyone with this form of the condition has alopecia. Affected individuals can have sparse or patchy hair or no hair at all on their heads. Some affected individuals are missing body hair as well.\n\nIn vitamin D-dependent rickets, there is an imbalance of certain substances in the blood. An early sign in all types of the condition is low levels of the mineral calcium (hypocalcemia), which is essential for the normal formation of bones and teeth. Affected individuals also develop high levels of a hormone involved in regulating calcium levels called parathyroid hormone (PTH), which leads to a condition called secondary hyperparathyroidism. Low levels of a mineral called phosphate (hypophosphatemia) also occur in affected individuals. Vitamin D-dependent rickets types 1 and 2 can be grouped by blood levels of a hormone called calcitriol, which is the active form of vitamin D; individuals with VDDR1A and VDDR1B have abnormally low levels of calcitriol and individuals with VDDR2A and VDDR2B have abnormally high levels.

Autosomal dominant hypophosphatemic rickets (ADHR) is characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D3 (calcitriol) levels. Patients frequently present with bone pain, rickets, and tooth abscesses. In contrast to X-linked dominant hypophosphatemic rickets (XLH; 307800), ADHR shows incomplete penetrance, variable age at onset (childhood to adult), and resolution of the phosphate-wasting defect in rare cases (Econs et al., 1997). See also hypophosphatemic bone disease (146350). Genetic Heterogeneity of Hypophosphatemic Rickets Other forms of hypophosphatemic rickets include autosomal recessive forms, i.e., ARHR1 (241520), caused by mutation in the DMP1 gene (600980) on chromosome 4q21, and ARHR2 (613312), caused by mutation in the ENPP1 gene (173335) on chromosome 6q23. An X-linked dominant form (XLHR; 307800) is caused by mutation in the PHEX gene (300550), and an X-linked recessive form (300554) is caused by mutation in the CLCN5 gene (300008). Clinical Variability of Hypophosphatemic Rickets Hypophosphatemic rickets can be caused by disorders of vitamin D metabolism or action (see VDDR1A, 264700). A form of hypophosphatemic rickets with hypercalciuria (HHRH; 241530) is caused by mutation in the SLC34A3 gene (609826), and there is evidence that a form of hypophosphatemic rickets with hyperparathyroidism (612089) may be caused by a translocation that results in an increase in alpha-klotho levels (KLOTHO; 604824).

Vitamin D-dependent rickets type 2A (VDDR2A) is caused by a defect in the vitamin D receptor gene. This defect leads to an increase in the circulating ligand, 1,25-dihydroxyvitamin D3. Most patients have total alopecia in addition to rickets. VDDR2B (600785) is a form of vitamin D-dependent rickets with a phenotype similar to VDDR2A but a normal vitamin D receptor, in which end-organ resistance to vitamin D has been shown to be caused by a nuclear ribonucleoprotein that interferes with the vitamin D receptor-DNA interaction. For a general phenotypic description and a discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700).

Opsismodysplasia (OPSMD) is a rare skeletal dysplasia involving delayed bone maturation. Clinical signs observed at birth include short limbs, small hands and feet, relative macrocephaly with a large anterior fontanel, and characteristic craniofacial abnormalities including a prominent brow, depressed nasal bridge, a small anteverted nose, and a relatively long philtrum. Death in utero or secondary to respiratory failure during the first few years of life has been reported, but there can be long-term survival. Typical radiographic findings include shortened long bones with delayed epiphyseal ossification, severe platyspondyly, metaphyseal cupping, and characteristic abnormalities of the metacarpals and phalanges (summary by Below et al., 2013 and Fradet and Fitzgerald, 2017).

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.

Neonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (summary by Egbuna and Brown, 2008).

Any familial hypocalciuric hypercalcemia in which the cause of the disease is a mutation in the AP2S1 gene.

Vitamin D hydroxylation-deficient rickets type 1B (VDDR1B) is caused by a defect in vitamin D 25-hydroxylation (Molin et al., 2017). The major function of vitamin D is to maintain calcium and phosphate levels in the normal range to support metabolic functions, neuromuscular transmission, and bone mineralization. Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (summary by Liberman and Marx, 2001). Rickets can occur because of inadequate dietary intake or sun exposure or because of genetic disorders. Vitamin D3 (cholecalciferol) is taken in the diet or synthesized in the skin from 7-dehydrocholesterol by ultraviolet irradiation. For vitamin D to be active, it needs to be converted to its active form, 1,25-dihydroxyvitamin D3. Vitamin D is transported in the blood by the vitamin D binding protein (DBP; 139200) to the liver, where vitamin D 25-hydroxylase (CYP2R1; 608713) is the key enzyme for 25-hydroxylation. Vitamin D 25(OH)D3, the major circulating form of vitamin D, is then transported to the kidney, where 25(OH)D3 is hydroxylated at the position of carbon 1 of the A ring, resulting in the active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) (summary by Christakos et al., 2010).

Low molecular weight proteinuria with hypercalciuria and nephrocalcinosis is a form of X-linked hypercalciuric nephrocalcinosis, a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrocalcinosis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009.

Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.

X-linked recessive hypophosphatemic rickets (XLHRR) is a form of X-linked hypercalciuric nephrolithiasis, which comprises a group of disorders characterized by proximal renal tubular reabsorptive failure, hypercalciuria, nephrocalcinosis, and renal insufficiency. These disorders have also been referred to as the 'Dent disease complex' (Scheinman, 1998; Gambaro et al., 2004). For a general discussion of Dent disease, see 300009.

Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.

Raine syndrome (RNS) is a neonatal osteosclerotic bone dysplasia of early and aggressive onset that usually results in death within the first few weeks of life, although there have been some reports of survival into childhood. Radiographic studies show a generalized increase in the density of all bones and a marked increase in the ossification of the skull. The increased ossification of the basal structures of the skull and facial bones underlies the characteristic facial features, which include narrow prominent forehead, proptosis, depressed nasal bridge, and midface hypoplasia. Periosteal bone formation is also characteristic of this disorder and differentiates it from osteopetrosis and other known lethal and nonlethal osteosclerotic bone dysplasias. The periosteal bone formation typically extends along the diaphysis of long bones adjacent to areas of cellular soft tissue (summary by Simpson et al., 2009). Some patients survive infancy (Simpson et al., 2009; Fradin et al., 2011).

Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum.

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006).

Mitochondrial HMG-CoA synthase deficiency (HMGCS2D) is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (summary by Aledo et al., 2006).

Cystinosis comprises three allelic phenotypes: Nephropathic cystinosis in untreated children is characterized by renal Fanconi syndrome, poor growth, hypophosphatemic/calcipenic rickets, impaired glomerular function resulting in complete glomerular failure, and accumulation of cystine in almost all cells, leading to cellular dysfunction with tissue and organ impairment. The typical untreated child has short stature, rickets, and photophobia. Failure to thrive is generally noticed after approximately age six months; signs of renal tubular Fanconi syndrome (polyuria, polydipsia, dehydration, and acidosis) appear as early as age six months; corneal crystals can be present before age one year and are always present after age 16 months. Prior to the use of renal transplantation and cystine-depleting therapy, the life span in nephropathic cystinosis was no longer than ten years. With these interventions, affected individuals can survive at least into the mid-forties or fifties with satisfactory quality of life. Intermediate cystinosis is characterized by all the typical manifestations of nephropathic cystinosis, but onset is at a later age. Renal glomerular failure occurs in all untreated affected individuals, usually between ages 15 and 25 years. The non-nephropathic (ocular) form of cystinosis is characterized clinically only by photophobia resulting from corneal cystine crystal accumulation.

Any Fanconi syndrome in which the cause of the disease is a mutation in the SLC34A1 gene.

Fanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Manz et al., 1987). Because no underlying enzymatic defect in carbohydrate metabolism had been identified and because metabolism of both glucose and galactose is impaired, a primary defect of monosaccharide transport across the membranes had been suggested (Berry et al., 1995; Fellers et al., 1967; Manz et al., 1987; Odievre, 1966). Use of the term glycogenosis type XI introduced by Hug (1987) is to be discouraged because glycogen accumulation is not due to the proposed functional defect of phosphoglucomutase, an essential enzyme in the common degradative pathways of both glycogen and galactose, but is secondary to nonfunctional glucose transport.

Any Fanconi syndrome in which the cause of the disease is a mutation in the HNF4A gene.

Infantile hypercalcemia is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis (summary by Schlingmann et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypercalcemia, see HCINF1 (143880).

Hereditary hypophosphatemic rickets is a disorder related to low levels of phosphate in the blood (hypophosphatemia). Phosphate is a mineral that is essential for the normal formation of bones and teeth.\n\nIn most cases, the signs and symptoms of hereditary hypophosphatemic rickets begin in early childhood. The features of the disorder vary widely, even among affected members of the same family. Mildly affected individuals may have hypophosphatemia without other signs and symptoms. More severely affected children experience slow growth and are shorter than their peers. 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. These abnormalities become apparent with weight-bearing activities such as walking. If untreated, they tend to worsen with time.\n\nOther signs and symptoms of hereditary hypophosphatemic rickets can include premature fusion of the skull bones (craniosynostosis) and dental abnormalities. The disorder may also cause abnormal bone growth where ligaments and tendons attach to joints (enthesopathy). In adults, hypophosphatemia is characterized by a softening of the bones known as osteomalacia.\n\nResearchers have described several forms of hereditary hypophosphatemic rickets, which are distinguished by their pattern of inheritance and genetic cause. The most common form of the disorder is known as X-linked hypophosphatemic rickets (XLH). It has an X-linked dominant pattern of inheritance. X-linked recessive, autosomal dominant, and autosomal recessive forms of the disorder are much rarer.\n\nAnother rare type of the disorder is known as hereditary hypophosphatemic rickets with hypercalciuria (HHRH). In addition to hypophosphatemia, this condition is characterized by the excretion of high levels of calcium in the urine (hypercalciuria).

Fanconi renotubular syndrome-5 (FRTS5) is a mitochondrial disorder characterized by proximal renotubular dysfunction from birth, followed by progressive kidney disease and pulmonary fibrosis. It occurs only in individuals of Acadian descent (Crocker et al., 1997 and Hartmannova et al., 2016). For a discussion of genetic heterogeneity of Fanconi renotubular syndrome, see FRTS1 (134600).

Vitamin D-dependent rickets-3 (VDDR3) is characterized by early-onset rickets, reduced serum levels of the vitamin D metabolites 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and deficient responsiveness to the parent molecule as well as activated forms of vitamin D (Roizen et al., 2018). For discussion of genetic heterogeneity of vitamin D-dependent rickets, see 264700.

Combined oxidative phosphorylation deficiency-55 (COXPD55) is characterized by global developmental delay, hypotonia, short stature, and impaired intellectual development with speech disabilities in childhood. Indolent progressive external ophthalmoplegia phenotype has been described in 1 patient (summary by Olahova et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare.