MedGen

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. [from GeneReviews]

Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset multisystem disorder characterized by bilateral kidney cysts, liver cysts, and an increased risk of intracranial aneurysms. Other manifestations include: cysts in the pancreas, seminal vesicles, and arachnoid membrane; dilatation of the aortic root and dissection of the thoracic aorta; mitral valve prolapse; and abdominal wall hernias. Kidney manifestations include early-onset hypertension, kidney pain, and kidney insufficiency. Approximately 50% of individuals with ADPKD have end-stage kidney disease (ESKD) by age 60 years. The prevalence of liver cysts increases with age and occasionally results in clinically significant severe polycystic liver disease (PLD), most often in females. Overall, the prevalence of intracranial aneurysms is fivefold higher than in the general population and further increased in those with a positive family history of aneurysms or subarachnoid hemorrhage. There is substantial variability in the severity of kidney disease and other extra-kidney manifestations. [from GeneReviews]

Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma including intramuscular vaccinations. Painful, recurrent soft-tissue swellings (flare-ups) may precede localized heterotopic ossification. Heterotopic ossification can occur at any location, but typically affects regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification impacting joint mobility. Problems with swallowing and speaking can occur with ossification affecting the jaw, head, and neck, and restriction of the airway and breathing may lead to thoracic insufficiency syndrome. [from GeneReviews]

Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by Aker et al., 2012). Genetic Heterogeneity of Autosomal Recessive Osteopetrosis Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (611490), which is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13, and OPTB5 (259720), which is caused by mutation in the OSTM1 gene (607649) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; 259710) is caused by mutation in the TNFSF11 gene (602642) on chromosome 13q14, an intermediate form (OPTB6; 611497) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; 612301) is caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q22. Another form of autosomal recessive osteopetrosis (OPTB8; 615085) is caused by mutation in the SNX10 gene (614780) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; 259730) is caused by mutation in the CA2 gene (611492) on chromosome 8q21. OPTB9 (620366) is caused by mutation in the SLC4A2 gene (109280) on chromosome 7q36. Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, 607634). [from OMIM]

The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. [from GeneReviews]

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 discussion of genetic heterogeneity of rickets due to disorders in vitamin D metabolism or action, see vitamin D-dependent rickets type 1A (VDDR1A; 264700). [from OMIM]

Paget disease is a metabolic bone disease characterized by focal abnormalities of increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Bone lesions in this disorder show evidence of increased osteoclastic bone resorption and disorganized bone structure. See reviews by Ralston et al. (2008) and Ralston and Albagha (2014). Genetic Heterogeneity of Paget Disease of Bone Also see PDB2 (602080), caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q21; PDB4 (606263), mapped to chromosome 5q31; PDB5 (239000), caused by mutation in the TNFRSF11B gene (602643) on chromosome 8q24; and PDB6 (616833), caused by mutation in the ZNF687 gene (610568) on chromosome 1q21. Suggestive linkage of a form of PDB to chromosome 6p (PDB1) was reported by Fotino et al. (1977); however, further studies did not confirm linkage to this site (Moore and Hoffman, 1988; Nance et al., 2000; Good et al., 2001). [from OMIM]

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. [from OMIM]

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). [from OMIM]

Multiple congenital anomalies-hypotonia-seizures syndrome-2 (MCAHS2) is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, early-onset myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (summary by Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability; these features are consistent with a form of developmental and epileptic encephalopathy (DEE) (summary by Belet et al., 2014, Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis. For a discussion of genetic heterogeneity of MCAHS, see MCAHS1 (614080). For a discussion of nomenclature and genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293). [from OMIM]

Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003). Genetic Heterogeneity of Mitochondrial Complex III Deficiency Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12; and MC3DN10 (618775), caused by mutation in the UQCRFS1 gene (191327) on chromosome 19q12. See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene. [from OMIM]

Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type XI is an autosomal recessive form of OI (summary by Alanay et al., 2010). [from OMIM]

In 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.

Another 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).

Researchers 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.

Other 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.

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. [from MedlinePlus Genetics]

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). [from OMIM]

Hereditary hypophosphatemic rickets with hypercalciuria 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). [from OMIM]

Congenital bile acid synthesis defect-3 (CBAS3) is an autosomal recessive disorder characterized by prolonged jaundice after birth, hepatomegaly, conjugated hyperbilirubinemia, elevations in characteristic abnormal bile acids, and progressive intrahepatic cholestasis with liver fibrosis (summary by Setchell et al., 1998 and Ueki et al., 2008). For a general phenotypic description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see 607765. [from OMIM]

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). [from OMIM]

Hyperphosphatasia with impaired intellectual development syndrome-1 (HPMRS1) is an autosomal recessive disorder characterized by mental retardation, various neurologic abnormalities such as seizures and hypotonia, and hyperphosphatasia. Other features include facial dysmorphism and variable degrees of brachytelephalangy (summary by Krawitz et al., 2010). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Hyperphosphatasia with Impaired Intellectual Development Syndrome See also HPMRS2 (614749), caused by mutation in the PIGO gene (614730) on chromosome 9p13; HPMRS3 (614207), caused by mutation in the PGAP2 gene (615187) on chromosome 11p15; HPMRS4 (615716), caused by mutation in the PGAP3 gene (611801) on chromosome 17q12; HPMRS5 (616025), caused by mutation in the PIGW gene (610275) on chromosome 17q12; and HPMRS6 (616809), caused by mutation in the PIGY gene (610662) on chromosome 4q22. Knaus et al. (2018) provided a review of the main clinical features of the different types of HPMRS, noting that some patients have a distinct pattern of facial anomalies that can be detected by computer-assisted comparison, particularly those with mutations in the PIGV and PGAP3 genes. Individuals with HPMRS have variable increased in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between HPMRS and MCAHS (see, e.g., 614080), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified under the more encompassing term of 'GPI biosynthesis defects' (GPIBD). [from OMIM]

Paget disease of bone-5 is an autosomal recessive, juvenile-onset form of Paget disease, a disorder of the skeleton resulting from abnormal bone resorption and formation. Clinical manifestations include short stature, progressive long bone deformities, fractures, vertebral collapse, skull enlargement, and hyperostosis with progressive deafness. There is phenotypic variability, with some patients presenting in infancy, while others present later in childhood (summary by Naot et al., 2014). For discussion of genetic heterogeneity of Paget disease of bone, see 167250. [from OMIM]

The phenotypic spectrum of ATP8B1 deficiency ranges from severe through moderate to mild. Severe ATP8B1 deficiency is characterized by infantile-onset cholestasis that progresses to cirrhosis, hepatic failure, and early death. Although mild-to-moderate ATP8B1 deficiency initially was thought to involve intermittent symptomatic cholestasis with a lack of hepatic fibrosis, it is now known that hepatic fibrosis may be present early in the disease course. Furthermore, in some persons with ATP8B1 deficiency the clinical findings can span the phenotypic spectrum, shifting over time from the mild end of the spectrum (episodic cholestasis) to the severe end of the spectrum (persistent cholestasis). Sensorineural hearing loss (SNHL) is common across the phenotypic spectrum. [from GeneReviews]