MedGen

Bardet-Biedl syndrome is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism (summary by Beales et al., 1999). Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014). Genetic Heterogeneity of Bardet-Biedl Syndrome BBS2 (615981) is caused by mutation in a gene on 16q13 (606151); BBS3 (600151), by mutation in the ARL6 gene on 3q11 (608845); BBS4 (615982), by mutation in a gene on 15q22 (600374); BBS5 (615983), by mutation in a gene on 2q31 (603650); BBS6 (605231), by mutation in the MKKS gene on 20p12 (604896); BBS7 (615984), by mutation in a gene on 4q27 (607590); BBS8 (615985), by mutation in the TTC8 gene on 14q32 (608132); BBS9 (615986), by mutation in a gene on 7p14 (607968); BBS10 (615987), by mutation in a gene on 12q21 (610148); BBS11 (615988), by mutation in the TRIM32 gene on 9q33 (602290); BBS12 (615989), by mutation in a gene on 4q27 (610683); BBS13 (615990), by mutation in the MKS1 gene (609883) on 17q23; BBS14 (615991), by mutation in the CEP290 gene (610142) on 12q21, BBS15 (615992), by mutation in the WDPCP gene (613580) on 2p15; BBS16 (615993), by mutation in the SDCCAG8 gene (613524) on 1q43; BBS17 (615994), by mutation in the LZTFL1 gene (606568) on 3p21; BBS18 (615995), by mutation in the BBIP1 gene (613605) on 10q25; BBS19 (615996), by mutation in the IFT27 gene (615870) on 22q12; BBS20 (619471), by mutation in the IFT172 gene (607386) on 9p21; BBS21 (617406), by mutation in the CFAP418 gene (614477) on 8q22; and BBS22 (617119), by mutation in the IFT74 gene (608040) on 9p21. The CCDC28B gene (610162) modifies the expression of BBS phenotypes in patients who have mutations in other genes. Mutations in MKS1, MKS3 (TMEM67; 609884), and C2ORF86 also modify the expression of BBS phenotypes in patients who have mutations in other genes. Although BBS had originally been thought to be a recessive disorder, Katsanis et al. (2001) demonstrated that clinical manifestation of some forms of Bardet-Biedl syndrome requires recessive mutations in 1 of the 6 loci plus an additional mutation in a second locus. While Katsanis et al. (2001) called this 'triallelic inheritance,' Burghes et al. (2001) suggested the term 'recessive inheritance with a modifier of penetrance.' Mykytyn et al. (2002) found no evidence of involvement of the common BBS1 mutation in triallelic inheritance. However, Fan et al. (2004) found heterozygosity in a mutation of the BBS3 gene (608845.0002) as an apparent modifier of the expression of homozygosity of the met390-to-arg mutation in the BBS1 gene (209901.0001). Allelic disorders include nonsyndromic forms of retinitis pigmentosa: RP51 (613464), caused by TTC8 mutation, and RP55 (613575), caused by ARL6 mutation. [from OMIM]

Smith-Lemli-Opitz syndrome (SLOS) is a congenital multiple-anomaly / cognitive impairment syndrome caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase. It is characterized by prenatal and postnatal growth restriction, microcephaly, moderate-to-severe intellectual disability, and multiple major and minor malformations. The malformations include distinctive facial features, cleft palate, cardiac defects, underdeveloped external genitalia in males, postaxial polydactyly, and 2-3 syndactyly of the toes. The clinical spectrum is wide; individuals with normal development and only minor malformations have been described. [from GeneReviews]

Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. There is extensive clinical variability and controversy as to the minimum diagnostic criteria. Early reports, including that of Opitz and Howe (1969) and Wright et al. (1994), stated that the classic triad of Meckel syndrome comprises (1) cystic renal disease; (2) a central nervous system malformation, most commonly occipital encephalocele; and (3) polydactyly, most often postaxial. However, based on a study of 67 patients, Salonen (1984) concluded that the minimum diagnostic criteria are (1) cystic renal disease; (2) CNS malformation, and (3) hepatic abnormalities, including portal fibrosis or ductal proliferation. In a review of Meckel syndrome, Logan et al. (2011) stated that the classic triad first described by Meckel (1822) included occipital encephalocele, cystic kidneys, and fibrotic changes to the liver. Genetic Heterogeneity of Meckel Syndrome See also MKS2 (603194), caused by mutation in the TMEM216 gene (613277) on chromosome 11q12; MKS3 (607361), caused by mutation in the TMEM67 gene (609884) on chromosome 8q; MKS4 (611134), caused by mutation in the CEP290 gene (610142) on chromosome 12q; MKS5 (611561), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; MKS6 (612284), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; MKS7 (267010), caused by mutation in the NPHP3 (608002) gene on chromosome 3q22; MKS8 (613885), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; MKS9 (614209), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; MKS10 (614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; MKS11 (615397), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; MKS12 (616258), caused by mutation in the KIF14 gene (611279) on chromosome 1q32; MKS13 (617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; and MKS14 (619879), caused by mutation in the TXNDC15 gene (617778) on chromosome 5q31. [from OMIM]

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. [from GeneReviews]

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. [from GeneReviews]

GLI3-related Pallister-Hall syndrome (GLI3-PHS) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild GLI3-PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with GLI3-PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency. [from GeneReviews]

Typical Greig cephalopolysyndactyly syndrome (GCPS) is characterized by macrocephaly, widely spaced eyes associated with increased interpupillary distance, preaxial polydactyly with or without postaxial polydactyly, and cutaneous syndactyly. Developmental delay, intellectual disability, or seizures appear to be uncommon manifestations (~<10%) of GCPS and may be more common in individuals with large (>300-kb) deletions that encompass GLI3. Approximately 20% of individuals with GCPS have hypoplasia or agenesis of the corpus callosum. [from GeneReviews]

Ellis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (summary by Ruiz-Perez et al., 2000). The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002). [from OMIM]

BBS2 is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. [from GeneReviews]

BBS12 is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by Stoetzel et al. (2007) and Harville et al. (2010) met the diagnostic criteria of Beales et al. (1999), which required the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features (e.g., developmental delay, ataxia, cataracts). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

This autosomal recessive disorder is designated Meckel syndrome type 7 (MKS7) based on the classic phenotypic triad of (1) cystic renal disease; (2) a central nervous system abnormality, and (3) hepatic abnormalities, as defined by Meckel (1822), Salonen (1984), and Logan et al. (2011). According to these criteria, polydactyly is a variable feature. Herriot et al. (1991) and Al-Gazali et al. (1996) concluded that Dandy-Walker malformation can be the phenotypic manifestation of a central nervous system malformation in MKS. For a general phenotypic description and a discussion of genetic heterogeneity of Meckel syndrome, see MKS1 (249000). [from OMIM]

BBS9 is an autosomal recessive disorder characterized by obesity, polydactyly, renal anomalies, retinopathy, and mental retardation (Abu-Safieh et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of Bardet-Biedl syndrome, see BBS1 (209900). [from OMIM]

Weyers acrofacial dysostosis (WAD) is an autosomal dominant disorder with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar disorder, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease (summary by Howard et al., 1997). [from OMIM]

Meckel syndrome is an autosomal recessive pre- or perinatal lethal malformation syndrome characterized by renal cystic dysplasia and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly (summary by Smith et al., 2006). For a more complete phenotypic description and information on genetic heterogeneity of Meckel syndrome, see MKS1 (249000). [from OMIM]

Synpolydactyly (SPD), or syndactyly type II, is defined as a connection between the middle and ring fingers and fourth and fifth toes, variably associated with postaxial polydactyly in the same digits. Minor local anomalies and various metacarpal or metatarsal abnormalities may be present (summary by Merlob and Grunebaum, 1986). In some families with SPD, the foot anomalies are characterized by preaxial as well as postaxial polydactyly, and appear to be fully penetrant. The more severe features of classic SPD, involving 3/4 synpolydactyly in the hands and 4/5 synpolydactyly in the feet, also occur, but at reduced penetrance. This foot phenotype is not seen in patients with classic SPD due to HOXD13 polyalanine tract expansions (Goodman et al., 1998). Malik (2012) reviewed the syndactylies, noting that the extreme phenotypic heterogeneity observed in SPD families consists of approximately 18 clinical variants that can be 'lumped' into 3 categories: typical SPD features, minor variants, and unusual phenotypes. Genetic Heterogeneity of Synpolydactyly See also SPD2 (608180), caused by mutation in the fibulin-1 gene (FBLN1; 135820) on chromosome 22q13, and SPD3 (610234), which has been mapped to chromosome 14q11.2-q12. [from OMIM]

Because of their serious health problems, most individuals with Meckel syndrome die before or shortly after birth. Most often, affected infants die of respiratory problems or kidney failure.

Other signs and symptoms of Meckel syndrome vary widely among affected individuals. Numerous abnormalities of the brain and spinal cord (central nervous system) have been reported in people with Meckel syndrome, including a group of birth defects known as neural tube defects. These defects occur when a structure called the neural tube, a layer of cells that ultimately develops into the brain and spinal cord, fails to close completely during the first few weeks of embryonic development. Meckel syndrome can also cause problems with development of the eyes and other facial features, heart, bones, urinary system, and genitalia.

Meckel syndrome is a disorder with severe signs and symptoms that affect many parts of the body. The most common features are enlarged kidneys with numerous fluid-filled cysts; an occipital encephalocele, which is a sac-like protrusion of the brain through an opening at the back of the skull; and the presence of extra fingers and toes (polydactyly). Most affected individuals also have a buildup of scar tissue (fibrosis) in the liver. [from MedlinePlus Genetics]

Meckel syndrome is a disorder with severe signs and symptoms that affect many parts of the body. The most common features are enlarged kidneys with numerous fluid-filled cysts; an occipital encephalocele, which is a sac-like protrusion of the brain through an opening at the back of the skull; and the presence of extra fingers and toes (polydactyly). Most affected individuals also have a buildup of scar tissue (fibrosis) in the liver.

Other signs and symptoms of Meckel syndrome vary widely among affected individuals. Numerous abnormalities of the brain and spinal cord (central nervous system) have been reported in people with Meckel syndrome, including a group of birth defects known as neural tube defects. These defects occur when a structure called the neural tube, a layer of cells that ultimately develops into the brain and spinal cord, fails to close completely during the first few weeks of embryonic development. Meckel syndrome can also cause problems with development of the eyes and other facial features, heart, bones, urinary system, and genitalia.

Because of their serious health problems, most individuals with Meckel syndrome die before or shortly after birth. Most often, affected infants die of respiratory problems or kidney failure. [from MedlinePlus Genetics]

Meckel syndrome is a disorder with severe signs and symptoms that affect many parts of the body. The most common features are enlarged kidneys with numerous fluid-filled cysts; an occipital encephalocele, which is a sac-like protrusion of the brain through an opening at the back of the skull; and the presence of extra fingers and toes (polydactyly). Most affected individuals also have a buildup of scar tissue (fibrosis) in the liver.

Other signs and symptoms of Meckel syndrome vary widely among affected individuals. Numerous abnormalities of the brain and spinal cord (central nervous system) have been reported in people with Meckel syndrome, including a group of birth defects known as neural tube defects. These defects occur when a structure called the neural tube, a layer of cells that ultimately develops into the brain and spinal cord, fails to close completely during the first few weeks of embryonic development. Meckel syndrome can also cause problems with development of the eyes and other facial features, heart, bones, urinary system, and genitalia.

Because of their serious health problems, most individuals with Meckel syndrome die before or shortly after birth. Most often, affected infants die of respiratory problems or kidney failure. [from MedlinePlus Genetics]

Hydrolethalus syndrome is an autosomal recessive embryonic lethal disorder characterized by hydrocephaly or anencephaly, postaxial polydactyly of the upper limbs, and pre- or postaxial polydactyly of the lower limbs. Duplication of the hallux is a common finding. HLS2 is considered a ciliopathy (summary by Putoux et al., 2011). Acrocallosal syndrome (ACLS; 200990) is an allelic disorder with a less severe phenotype. For a discussion of genetic heterogeneity of hydrolethalus syndrome, see 236680. [from OMIM]