Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (summary by Muller et al., 2006). Amelogenesis imperfecta may also be present in some patients (Bardet et al., 2016). A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement. For a discussion of phenotypic and genetic heterogeneity of familial hypomagnesemia, see HOMG1 (602014).

Amelogenesis imperfecta type IB is an autosomal dominant disorder of tooth enamel biomineralization resulting in enamel hypoplasia (summary by Brookes et al., 2017).

Hypocalcified amelogenesis imperfecta is characterized by enamel of normal thickness on newly erupted and unerupted and unresolved teeth. The enamel is soft and may be lost soon after eruption leaving the crown composed only of dentin. The enamel has a cheesy consistency and can be scraped from the dentin. An anterior open bite has been recorded in over 60% of the cases observed. The hypocalcification type is the most frequent type of enamel dysplasia, occurring in about 1 in 20,000 individuals (Witkop and Sauk, 1976). Large masses of supragingival calculus become deposited on the teeth, and this is frequently associated with severe gingivitis or periodontitis (Winter and Brook, 1975).

Kohlschutter-Tonz syndrome (KTZS) is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Impaired intellectual development is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (summary by Schossig et al., 2012 and Mory et al., 2012). See also Kohlschutter-Tonz syndrome-like (KTZSL; 619229), caused by heterozygous mutation in the SATB1 gene (602075) on chromosome 3p23.

Junctional epidermolysis bullosa 2C (JEB2C), also known as laryngoonychocutaneous syndrome (LOCS), is an autosomal recessive disorder characterized by skin erosions, nail dystrophy, dental anomalies, and excessive vascular granulation tissue of the conjunctiva and larynx. Onset is characterized by a hoarse cry soon after birth. Beginning in infancy, chronic skin ulcers and conjunctival lesions appear. Patients may die in childhood secondary to acute or chronic respiratory obstruction. Long-term survivors have visual loss and often require tracheostomy (McLean et al., 2003). For a discussion of genetic heterogeneity of the subtypes of JEB, see JEB1A (226650). Reviews Has et al. (2020) reviewed the clinical and genetic aspects, genotype-phenotype correlations, disease-modifying factors, and natural history of epidermolysis bullosa.

Dental anomalies and short stature (DASS) is characterized by significant short stature with brachyolmia as well as hypoplastic amelogenesis imperfecta with almost absent enamel (Huckert et al., 2015). Some patients exhibit valvular and/or vascular defects, including mitral valve prolapse, aortic root dilation, and aortic as well as other arterial aneurysms (Dugan et al., 2015; Guo et al., 2018). Inter- and intrafamilial variability has been reported.

An amelogenesis imperfecta associated with mutation in a gene in the Xq22-q28 region.

Amelogenesis imperfecta is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988).

Any amelogenesis imperfecta in which the cause of the disease is a mutation in the DLX3 gene.

Autosomal recessive amelogenesis imperfecta pigmented hypomaturation type is characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989). Genetic Heterogeneity of the Hypomaturation Type of Amelogenesis Imperfecta See also AI2A2 (612529), caused by mutation in the MMP20 gene (604629); AI2A3 (613211), caused by mutation in the WDR72 gene (613214); and AI2A4 (614832), caused by mutation in the C4ORF26 gene (614829).

Amelogenesis imperfecta is a disorder of tooth development. This condition causes teeth to be unusually small, discolored, pitted or grooved, and prone to rapid wear and breakage. Other dental abnormalities are also possible. These defects, which vary among affected individuals, can affect both primary (baby) teeth and permanent (adult) teeth.\n\nResearchers have described at least 14 forms of amelogenesis imperfecta. These types are distinguished by their specific dental abnormalities and by their pattern of inheritance. Additionally, amelogenesis imperfecta can occur alone without any other signs and symptoms or it can occur as part of a syndrome that affects multiple parts of the body.

Autosomal recessive amelogenesis imperfecta pigmented hypomaturation type is characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1988).

Immunodeficiency-10 (IMD10) is an autosomal recessive primary immunodeficiency characterized by onset of recurrent infections in childhood due to defective T- and NK-cell function, although the severity is variable. Affected individuals may also have hypotonia, hypohidrosis, or dental enamel hypoplasia consistent with amelogenesis imperfecta (summary by Parry et al., 2016).

Immunodeficiency-9 (IMD9) is an autosomal recessive disorder characterized by early onset of recurrent infections due to defective T-cell activation. Affected individuals also have congenital myopathy resulting in muscle weakness as well as features of ectodermal dysplasia, including soft dental enamel (summary by McCarl et al., 2009).

Any amelogenesis imperfecta in which the cause of the disease is a mutation in the WDR72 gene.

Amelogenesis imperfecta and gingival fibromatosis syndrome is an autosomal recessive condition characterized by mild gingival fibromatosis and dental anomalies, including hypoplastic amelogenesis imperfecta, intrapulpal calcifications, delay of tooth eruption, hypodontia/oligodontia, pericoronal radiolucencies, and unerupted teeth (Martelli-Junior et al., 2008).

CDG2K is an autosomal recessive disorder with a variable phenotype. Affected individuals show psychomotor retardation and growth retardation, and most have short stature. Other features include dysmorphism, hypotonia, eye abnormalities, acquired microcephaly, hepatomegaly, and skeletal dysplasia. Serum transferrin analysis shows a CDG type II pattern (summary by Foulquier et al., 2012). For a general discussion of CDGs, see CDG1A (212065) and CDG2A (212066).

Any amelogenesis imperfecta in which the cause of the disease is a mutation in the ODAPH gene.

Hypoplastic amelogenesis imperfecta IA is characterized by enamel that may not develop to normal thickness. The enamel may have pits on the labial or buccal surfaces that are often arranged in rows and columns (see Witkop, 1989).

Autosomal recessive amelogenesis imperfecta of the pigmented hypomaturation type is characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989).

Developmental and epileptic encephalopathy-25 with amelogenesis imperfecta (DEE25) is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in early infancy. Most patients present with seizures in the neonatal period, which is often associated with status epilepticus. However, there is phenotypic variability, and some patients have onset of seizures later in infancy. Affected individuals show global developmental delay with intellectual disability and poor speech and communication. The seizures may remit somewhat with age, but there are persistent neurologic symptoms, including ataxia, spasticity, and abnormal involuntary movements. In addition to neurologic deficits, patients also have dental anomalies with amelogenesis imperfecta (summary by Thevenon et al., 2014 and Schossig et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Amelogenesis imperfecta type IH is characterized by hypoplastic and hypomineralized tooth enamel that may be rough, pitted, and/or discolored (Wang et al., 2014 and Poulter et al., 2014).

Heimler syndrome, which represents the mildest end of the peroxisomal biogenesis disorder spectrum (see PBD1A, 214100), is a rare autosomal recessive disorder characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities (Ratbi et al., 2015). For a discussion of genetic heterogeneity of Heimler syndrome, see HMLR1 (234580).

Amelogenesis imperfecta type IF (AI1F) is characterized by hypoplastic enamel of the primary and secondary dentition. The teeth may appear rough and discolored, and the tooth enamel may be absent, pitted, or of varying thickness (Poulter et al. (2014)).

Amelogenesis imperfecta is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988).

Autosomal recessive amelogenesis imperfecta of the pigmented hypomaturation type is characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989).

Bone marrow failure syndrome-3 is an autosomal recessive disorder characterized by onset of pancytopenia in early childhood. Patients may have additional variable nonspecific somatic abnormalities, including poor growth, microcephaly, and skin anomalies (summary by Tummala et al., 2016). BMFS3 has a distinct phenotype and may include features that overlap with Shwachman-Diamond syndrome (SDS1; 260400), such as pancreatic insufficiency and short stature, and with dyskeratosis congenita (see, e.g., DKCA1, 127550), such as dental and hair abnormalities and shortened telomeres. In addition, some patients may have joint and skeletal abnormalities, impaired development, and retinal dysplasia (summary by D'Amours et al., 2018). For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).

Specific granule deficiency-2 (SGD2) is an autosomal recessive immunologic disorder characterized by recurrent infections due to defective neutrophil development. Bone marrow findings include paucity of neutrophil granulocytes, absence of granule proteins in neutrophils, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. The disorder is apparent from infancy, and patients may die in early childhood unless they undergo hematopoietic stem cell transplantation. Most patients have additional findings, including delayed development, mild dysmorphic features, tooth abnormalities, and distal skeletal defects (Witzel et al., 2017). For a discussion of genetic heterogeneity of SGD, see SGD1 (245480).

Hypomineralized amelogenesis imperfecta type IIIB (AI3B) is characterized by enamel that is reduced in mineral density and is thin, chipped, and absent in places (Smith et al., 2016).

Heimler syndrome-1 (HMLR1), which represents the mildest end of the peroxisomal biogenesis disorder spectrum (see PBD1A, 214100), is a rare autosomal recessive disorder characterized by sensorineural hearing loss, enamel hyoplasia of the secondary dentition, and nail abnormalities (Ratbi et al., 2015). Genetic Heterogeneity of Heimler Syndrome Another form of Heimler syndrome (HMLR2; 616617) is caused by mutation in the PEX6 gene (601498) on chromosome 6p21.

HOMG5 is an autosomal recessive disorder characterized by severe renal magnesium wasting, progressive renal failure, nephrocalcinosis, and severe visual impairment (Konrad et al., 2006). Amelogenesis imperfecta may also be present in some patients (Yamaguti et al., 2017). For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014.

Short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS)is characterized by disproportionate short stature, defective tooth enamel formation, and skeletal dysplasia with severe scoliosis in some patients. Variable features include facial dysmorphism, moderate hearing impairment, and mildly impaired intellectual development (Ashikov et al., 2018).

Amelogenesis imperfecta type IIIC is characterized by hypocalcified enamel in both the primary and secondary dentition. The enamel is rough and yellow-brown; under normal use, the enamel disintegrates from occlusal surfaces of the molars, leaving a ring of intact enamel remaining on the sides. Some affected individuals have anterior open bite (Kim et al., 2019).

Den Hoed-de Boer-Voisin syndrome (DHDBV) is characterized by global developmental delay with moderately to severely impaired intellectual development, poor or absent speech, and delayed motor skills. Although the severity of the disorder varies, many patients are nonverbal and have hypotonia with inability to sit or walk. Early-onset epilepsy is common and may be refractory to treatment, leading to epileptic encephalopathy and further interruption of developmental progress. Most patients have feeding difficulties with poor overall growth and dysmorphic facial features, as well as significant dental anomalies resembling amelogenesis imperfecta. The phenotype is reminiscent of Kohlschutter-Tonz syndrome (KTZS; 226750). More variable features of DHDBV include visual defects, behavioral abnormalities, and nonspecific involvement of other organ systems (summary by den Hoed et al., 2021).

Amelogenesis imperfecta type 1K (AI1K) is characterized by hypoplastic enamel of all teeth. In some individuals, the pulp chambers may be enlarged and some molars may exhibit taurodontism (summary by Kim et al., 2021).