Joubert Syndrome 2

A number sign (#) is used with this entry because of evidence that Joubert syndrome-2 (JBTS2) is caused by homozygous mutation in the TMEM216 gene (613277) on chromosome 11q12.

Mutation in the TMEM216 gene can also cause Meckel syndrome-2 (MKS2; 603194).

For a phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.

Description

Joubert syndrome is a genetically heterogeneous autosomal recessive disorder characterized by a specific hindbrain malformation, which is referred to as the 'molar tooth sign' (MTS) on brain MRI, hypotonia, developmental delay, oculomotor apraxia, and breathing abnormalities. The complex brainstem malformation consists of cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (Maria et al., 1997). Additional features sometimes associated with Joubert syndrome include retinal anomalies, polydactyly, hepatic fibrosis, and renal disease. These related disorders are often referred to as 'cerebellooculorenal syndromes' (CORSs) (Chance et al., 1999; Satran et al., 1999).

Clinical Features

The phenotypic presentation of CORSs is highly heterogeneous. Neurologic features can include ataxia, hypotonia, psychomotor developmental delay, oculomotor disorders (such as oculomotor apraxia and nystagmus), and changes in the respiratory rhythm that appear mainly in the neonatal period. Ocular abnormalities comprise Leber congenital amaurosis, other noncongenital and less specific retinopathies, and chorioretinal colobomas, with a clinical presentation ranging from blindness soon after birth to a mild reduction of visual acuity at a later age. Renal abnormalities consist of either cystic dysplastic kidneys or juvenile nephronophthisis and can be asymptomatic or mildly symptomatic until adolescence (Chance et al., 1999; Satran et al., 1999).

Keeler et al. (2003) studied affected members of 3 families with the oculorenal form of Joubert syndrome. Kidney cysts were present in one family, coloboma in the second, and retinopathy in the third. One family was from Pakistan and the other 2 were from the United Arab Emirates; all were consanguineous.

Valente et al. (2003) studied a large consanguineous family from Sicily in which 3 sibs and a maternal uncle had Joubert syndrome with proven MTI and nephronophthisis but without retinal involvement. All 4 patients presented with nystagmus and oculomotor apraxia, with impairment of smooth pursuit and saccades. Neonatal irregular breathing was not reported. The maternal uncle, age 26 years, developed acute renal failure at the age of 17 years and underwent renal transplantation. The histologic diagnosis of juvenile nephronophthisis was made. All 3 sibs showed signs of reduced renal function.

Valente et al. (2005) reported 2 families with JBTS2. In a Turkish family, the affected child showed severe hypotonia, oculomotor apraxia, and severe respiratory abnormalities. Kidney ultrasound was normal. He had postaxial polydactyly of both hands and feet, with camptodactyly of the third and fourth fingers bilaterally, small genitalia, microphthalmia, and patent foramen ovale. MRI showed absence of the cerebellar vermis and the molar tooth sign. An affected 15-year-old patient of Portuguese origin showed hypotonia, ataxia, psychomotor retardation, oculomotor apraxia, and postaxial polydactyly. He had retinal dystrophy with abnormal electroretinogram and normal kidneys.

Edvardson et al. (2010) reported 13 individuals from 8 Ashkenazi Jewish families with JBTS2 showing linkage to chromosome 11p12. Three of the families belonged to the same kindred. All patients were born at term and presented with neonatal hypotonia, rotary nystagmus, esotropia, and feeding difficulties due to oral motor dysfunction, resulting in failure to thrive. Dysmorphic features included dolichocephaly and frontal bossing in 6 patients, metopic craniosynostosis in 1 patient, and macrocephaly due to noncommunicating hydrocephalus in 1 patient. Two patients had postaxial polydactyly in the upper and lower limbs, and 1 had postaxial polydactyly in the lower limbs only. All 13 patients had delayed psychomotor development and mental retardation. The nystagmus improved over the first years of life, and visual function, funduscopic examination, and visual evoked potentials were normal thereafter. Brain MRI showed the molar tooth sign and other cerebellar abnormalities, including complete absence of the vermis or a dysplastic split vermis. Eight patients had normal renal ultrasound, but the 2 oldest patients (aged 17 and 26 years, respectively), had end-stage renal insufficiency beginning in midadolescence.

Valente et al. (2010) reported 14 families, including 10 Ashkenazi Jewish families, with Joubert syndrome-2. All patients had the molar tooth sign on brain imaging, and 2 also had Dandy-Walker malformation. Nine had oculomotor apraxia/nystagmus, 9 had nephronophthisis, and 9 had polydactyly. None had liver or retinal involvement. Two of the Ashkenazi Jewish patients, a 4-year-old boy and a male fetus, also had tongue tumors and multiple oral frenula, respectively, reminiscent of OFD6 (277170).

Mapping

Keeler et al. (2003) described 3 consanguineous families with an oculorenal form of Joubert syndrome and by linkage analysis identified a locus on 11p12-q13.3 (JBTS2), with a maximum 2-point lod score of 5.2 at marker D11S1915.

In a large consanguineous family from Sicily segregating Joubert syndrome, Valente et al. (2003) demonstrated linkage to the pericentromeric region of chromosome 11. The maximum lod score obtained was 3.96, with a recombination fraction of 0.00, for marker D11S1313 in a haplotype spanning bands 11p11.2-q12.3.

By haplotype analysis of 2 families with Joubert syndrome, Valente et al. (2005) refined the JBTS2 locus to a 13.6-Mb region between D11S4191 and D11S1344, encompassing 5.2 Mb of centromeric DNA.

Molecular Genetics

In 13 affected members of 8 Ashkenazi Jewish families with Joubert syndrome-2, Edvardson et al. (2010) identified a homozygous mutation in the TMEM216 gene (R73L; 613277.0001). The carrier rate in this ethnic group was determined to be 1 in 92.

In affected members of 14 families with Joubert syndrome-2 and 6 families with Meckel syndrome-2 (MKS2; 603194), Valente et al. (2010) identified 7 different homozygous mutations in the TMEM216 gene (see, e.g., 613277.0001-613277.0004). Ten families with Joubert syndrome were of Ashkenazi Jewish descent and shared the common founder mutation, R73L, which had a carrier frequency of 1 in 100. A Turkish family had 2 affected patients: 1 with Joubert syndrome and a fetus with Meckel syndrome, indicating that the 2 clinical disorders are part of the same spectrum.

Nomenclature

Keeler et al. (2003) noted that the form of Joubert syndrome that includes retinal dysplasia and cystic dysplastic kidneys has been differentiated from other forms of Joubert syndrome and called either Joubert syndrome type B or type 2. They suggested the name CORS2 for the locus on 11p12-q13.3, because of the apparently frequent association of oculorenal involvement. Likewise, Valente et al. (2003) proposed the CORS acronym for loci identified in all cerebellooculorenal syndromes sharing the pathognomonic MTI, including Joubert syndrome and incomplete phenotypes such as COGAN (257550) and cerebellorenal syndromes. Both groups used the designations CORS1 for JBTS1 (see 213300) and CORS2 for JBTS2.