MedGen

PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs. In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding issues, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased. [from GeneReviews]

Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities); and, commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma. [from GeneReviews]

Thrombocytopenia absent radius (TAR) syndrome is characterized by bilateral absence of the radii with the presence of both thumbs, and thrombocytopenia that is generally transient. Thrombocytopenia may be congenital or may develop within the first few weeks to months of life; in general, thrombocytopenic episodes decrease with age. Cow's milk allergy is common and can be associated with exacerbation of thrombocytopenia. Other anomalies of the skeleton (upper and lower limbs, ribs, and vertebrae), heart, and genitourinary system (renal anomalies and agenesis of uterus, cervix, and upper part of the vagina) can occur. [from GeneReviews]

RPE65-related Leber congenital amaurosis / early-onset severe retinal dystrophy (RPE65-LCA/EOSRD) is a severe inherited retinal degeneration (IRD) with a typical presentation between birth and age five years. While central vision varies, the hallmark of this disorder is the presence of severe visual impairment with a deceptively preserved retinal structure. Vision is relatively stable in the first decade of life, but begins to decline in adolescence. Most affected individuals are legally blind (visual acuity 20/200 and/or visual fields extending <20 degrees from fixation) by age 20 years. After age 20 years, visual acuity declines further and by the fourth decade all affected individuals are legally blind and many have complete loss of vision (i.e., no light perception). Milder disease phenotypes have been described in individuals with hypomorphic alleles. [from GeneReviews]

Joubert syndrome is a clinically and genetically heterogeneous group of disorders characterized by hypoplasia of the cerebellar vermis with the characteristic neuroradiologic 'molar tooth sign,' and accompanying neurologic symptoms, including dysregulation of breathing pattern and developmental delay. Other variable features include retinal dystrophy and renal anomalies (Saraiva and Baraitser, 1992; Valente et al., 2005). Genetic Heterogeneity of Joubert Syndrome See also JBTS2 (608091), caused by mutation in the TMEM216 gene (613277) on chromosome 11q13; JBTS3 (608629), caused by mutation in the AHI1 gene (608894) on chromosome 6q23; JBTS4 (609583), caused by mutation in the NPHP1 gene (607100) on chromosome 2q13; JBTS5 (610188), caused by mutation in the CEP290 gene, also called NPHP6 (610142), on chromosome 12q21; JBTS6 (610688), caused by mutation in the TMEM67 gene (609884) on chromosome 8q21; JBTS7 (611560), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; JBTS8 (612291), caused by mutation in the ARL13B (608922) on chromosome 3q11; JBTS9 (612285), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; JBTS10 (300804), caused by mutation in the CXORF5 gene (300170) on chromosome Xp22; JBTS11 (see 613820), caused by mutation in the TTC21B gene (612014) on chromosome 2q24; JBTS12 (see 200990), caused by mutation in the KIF7 gene (611254) on chromosome 15q26; JBTS13 (614173), caused by mutation in the TCTN1 gene (609863) on chromosome 12q24; JBTS14 (614424), caused by mutation in the TMEM237 gene (614423) on chromosome 2q33; JBTS15 (614464), caused by mutation in the CEP41 gene (610523) on chromosome 7q32; JBTS16 (614465), caused by mutation in the TMEM138 gene (614459) on chromosome 11q; JBTS17 (614615), caused by mutation in the CPLANE1 gene (614571) on chromosome 5p13; JBTS18 (614815), caused by mutation in the TCTN3 gene (613847) on chromosome 10q24; JBTS19 (see 614844), caused by mutation in the ZNF423 gene (604577) on chromosome 16q12; JBTS20 (614970), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; JBTS21 (615636), caused by mutation in the CSPP1 gene (611654) on chromosome 8q13; JBTS22 (615665), caused by mutation in the PDE6D gene (602676) on chromosome 2q37; JBTS23 (616490), caused by mutation in the KIAA0586 gene (610178) on chromosome 14q23; JBTS24 (616654), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; JBTS25 (616781), caused by mutation in the CEP104 gene (616690) on chromosome 1p36; JBTS26 (616784), caused by mutation in the KATNIP gene (616650) on chromosome 16p12; JBTS27 (617120), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; JBTS28 (617121), caused by mutation in the MKS1 gene (609883) on chromosome 17q23; JBTS29 (see 617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; JBTS30 (617622), caused by mutation in the ARMC9 gene (617612) on chromosome 2q37; JBTS31 (617761), caused by mutation in the CEP120 gene (613446) on chromosome 5q23; JBTS32 (617757), caused by mutation in the SUFU gene (607035) on chromosome 10q24; JBTS33 (617767), caused by mutation in the PIBF1 gene (607532) on chromosome 13q21; JBTS34 (see 614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; JBTS35 (618161), caused by mutation in the ARL3 gene (604695) on chromosome 10q24; JBTS36 (618763), caused by mutation in the FAM149B1 gene (618413) on chromosome 10q22; JBTS37 (619185), caused by mutation in the TOGARAM1 gene (617618) on chromosome 14q21; JBTS38 (619476), caused by mutation in the KIAA0753 gene (617112) on chromosome 17p13; JBTS39 (619562), caused by mutation in the TMEM218 gene (619285) on chromosome 11q24; and JBTS40 (619582), caused by mutation in the IFT74 gene (608040) on chromosome 9p21. [from OMIM]

MID1-related Opitz G/BBB syndrome (MID1-OS) is characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 30% of affected males. Cleft lip and/or palate are present in approximately half of affected males. Other malformations (present in <50% of affected males) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only. [from GeneReviews]

An autosomal recessive subtype of Joubert syndrome caused by mutation(s) in the AHI1 gene, encoding Jouberin. [from NCI]

Joubert syndrome is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities. Neuroradiologically, Joubert syndrome is characterized by peculiar malformation of the midbrain-hindbrain junction known as the 'molar tooth sign' (MTS) consisting of cerebellar vermis hypoplasia or aplasia, thick and maloriented superior cerebellar peduncles, and abnormally deep interpeduncular fossa (Romano et al., 2006). For a general phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. [from OMIM]

Axenfeld-Rieger syndrome is primarily an eye disorder, although it can also affect other parts of the body. This condition is characterized by abnormalities of the front part of the eye, an area known as the anterior segment. For example, the colored part of the eye (the iris), may be thin or poorly developed. The iris normally has a single central hole, called the pupil, through which light enters the eye. People with Axenfeld-Rieger syndrome often have a pupil that is off-center (corectopia) or extra holes in the iris that can look like multiple pupils (polycoria). This condition can also cause abnormalities of the cornea, which is the clear front covering of the eye.

About half of affected individuals develop glaucoma, a serious condition that increases pressure inside the eye. When glaucoma occurs with Axenfeld-Rieger syndrome, it most often develops in late childhood or adolescence, although it can occur as early as infancy. Glaucoma can cause vision loss or blindness.

The signs and symptoms of Axenfeld-Rieger syndrome can also affect other parts of the body. Many affected individuals have distinctive facial features such as widely spaced eyes (hypertelorism); a flattened mid-face with a broad, flat nasal bridge; and a prominent forehead. The condition is also associated with dental abnormalities including unusually small teeth (microdontia) or fewer than normal teeth (oligodontia). Some people with Axenfeld-Rieger syndrome have extra folds of skin around their belly button (redundant periumbilical skin). Other, less common features can include heart defects, the opening of the urethra on the underside of the penis (hypospadias), narrowing of the anus (anal stenosis), and abnormalities of the pituitary gland that can result in slow growth.

Researchers have described at least three types of Axenfeld-Rieger syndrome. The types, which are numbered 1 through 3, are distinguished by their genetic cause. [from MedlinePlus Genetics]

RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus. [from GeneReviews]

Joubert syndrome-14 (JBTS14) is an autosomal recessive developmental disorder characterized by severe mental retardation, hypoplasia of the cerebellar vermis and molar tooth sign (MTS) on brain imaging, hypotonia, abnormal breathing pattern in infancy, and dysmorphic facial features. Additional findings can include renal cysts, abnormal eye movements, and postaxial polydactyly (summary by Boycott et al., 2007 and Huang et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. [from OMIM]

Joubert syndrome with renal defect is a rare subtype of Joubert syndrome and related disorders (JSRD, see this term) characterized by the neurological features of JS associated with renal disease, in the absence of retinopathy. [from ORDO]

Joubert syndrome (JBTS) is characterized by a specific hindbrain formation, hypotonia, cerebellar ataxia, dysregulated breathing patterns, and developmental delay. Ciliary dysfunction is a key factor in the pathogenesis (summary by Coene et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300. [from OMIM]

Mitochondrial complex IV deficiency nuclear type 5 (MC4DN5) is an autosomal recessive severe metabolic multisystemic disorder with onset in infancy. Features include delayed psychomotor development, impaired intellectual development with speech delay, mild dysmorphic facial features, hypotonia, ataxia, and seizures. There is increased serum lactate and episodic hypoglycemia. Some patients may have cardiomyopathy, abnormal breathing, or liver abnormalities, reflecting systemic involvement. Brain imaging shows lesions in the brainstem and basal ganglia, consistent with a diagnosis of Leigh syndrome (see 256000). Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110. [from OMIM]

Any Joubert syndrome in which the cause of the disease is a mutation in the TCTN1 gene. [from MONDO]

Any COACH syndrome in which the cause of the disease is a variation in the TMEM67 gene. [from MONDO]

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia, see SRTD1 (208500). [from OMIM]

Nephronophthisis can occur as part of separate syndromes that affect other areas of the body; these are often referred to as nephronophthisis-associated ciliopathies. For example, Senior-Løken syndrome is characterized by the combination of nephronophthisis and a breakdown of the light-sensitive tissue at the back of the eye (retinal degeneration); Joubert syndrome affects many parts of the body, causing neurological problems and other features, which can include nephronophthisis.

About 85 percent of all cases of nephronophthisis are isolated, which means they occur without other signs and symptoms. Some people with nephronophthisis have additional features, which can include liver fibrosis, heart abnormalities, or mirror image reversal of the position of one or more organs inside the body (situs inversus).

Nephronophthisis eventually leads to end-stage renal disease (ESRD), a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively. Nephronophthisis can be classified by the approximate age at which ESRD begins: around age 1 (infantile), around age 13 (juvenile), and around age 19 (adolescent).

Nephronophthisis is a disorder that affects the kidneys. It is characterized by inflammation and scarring (fibrosis) that impairs kidney function. These abnormalities lead to increased urine production (polyuria), excessive thirst (polydipsia), general weakness, and extreme tiredness (fatigue). In addition, affected individuals develop fluid-filled cysts in the kidneys, usually in an area known as the corticomedullary region. Another feature of nephronophthisis is a shortage of red blood cells, a condition known as anemia. [from MedlinePlus Genetics]

Anterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (summary by Cheong et al., 2016). Anterior segment dysgenesis is sometimes divided into subtypes including aniridia (see 106210), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (Gould and John, 2002). Some patients with ASGD3 have been reported with the following subtypes: iridogoniodysgenesis, Peters anomaly, Axenfeld anomaly, and Rieger anomaly. Iridogoniodysgenesis, which is characterized by iris hypoplasia, goniodysgenesis, and juvenile glaucoma, is the result of aberrant migration or terminal induction of the neural crest cells involved in the formation of the anterior segment of the eye (summary by Mears et al., 1996). Peters anomaly consists of a central corneal leukoma, absence of the posterior corneal stroma and Descemet membrane, and a variable degree of iris and lenticular attachments to the central aspect of the posterior cornea (Peters, 1906). In Axenfeld anomaly, strands of iris tissue attach to the Schwalbe line; in Rieger anomaly, in addition to the attachment of iris tissue to the Schwalbe line, there is clinically evident iris stromal atrophy with hole or pseudo-hole formation and corectopia (summary by Smith and Traboulsi, 2012). [from OMIM]

A congenital cortical development anomaly due to abnormal neuronal migration involving neocortical and hippocampal lamination, corpus callosum, cerebellum and brainstem. A large clinical spectrum can be observed, from children with severe epilepsy and intellectual and motor deficit to cases with severe cerebral dysgenesis in the antenatal period leading to pregnancy termination due to the severity of the prognosis. [from SNOMEDCT_US]