Perrault Syndrome 3

A number sign (#) is used with this entry because Perrault syndrome-3 (PRLTS3) is caused by homozygous or compound heterozygous mutation in the CLPP gene (601119) on chromosome 19p13.

Description

Perrault syndrome (PRLTS) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and premature ovarian failure (POF) secondary to ovarian dysgenesis. Affected males have SNHL but show normal pubertal development. A spectrum of additional clinical features, including cerebellar ataxia, learning disability, and peripheral neuropathy, have been described in some affected individuals (summary by Jenkinson et al., 2013).

For a discussion of genetic heterogeneity of Perrault syndrome, see PRLTS1 (233400).

Clinical Features

Ain et al. (2007) reported a consanguineous Pakistani family (PKDF291) in which 4 sisters had profound prelingual hearing loss. Reevaluation of this family by Jenkinson et al. (2013) revealed that all 4 affected sisters also had primary amenorrhea with hormone profiles indicative of hypergonadotropic hypogonadism. The 3 oldest affected sibs each had a rudimentary uterus and small ovaries on pelvic ultrasonography, whereas the youngest affected sib had a small uterus and normal sized ovaries at 15 years of age. An unaffected sister had normal imaging of her uterus and ovaries. There was no evidence of learning disability, microcephaly, short stature, epilepsy, or neurologic deficit in this family.

Jenkinson et al. (2012) studied a consanguineous British Pakistani family (P1) in which 3 sisters had sensorineural hearing loss, ovarian dysgenesis and premature ovarian failure, as well as growth retardation, microcephaly, and neurologic features that included seizures, learning and developmental delay, ataxia, and spastic paraplegia. Jenkinson et al. (2013) provided additional clinical features of this family, which they designated PDF1. All 3 affected sisters had profound congenital SNHL, with a greater than 90-decibel hearing level at all test frequencies. The youngest sister was evaluated for delayed puberty at 15 years of age, at which time pelvic ultrasonography showed streak ovaries and hormone profile was consistent with hypergonadotropic hypogonadism. Jenkinson et al. (2013) noted that the oldest sister had given birth to 2 healthy sons despite the fact that only 1 ovary was detectable on pelvic ultrasound at 22 years of age, demonstrating significant prior ovarian reserve. The sisters also exhibited truncal and cerebellar ataxia, with signs of lower limb spasticity. MRI brain scan of the oldest sister showed abnormally high signal intensity in the deep white matter and corticospinal tract.

Dursun et al. (2016) reported an affected brother and sister from a Turkish family in which the parents came from the same village. The proband was a 16-year-old hearing-impaired girl with secondary amenorrhea. Examination revealed the presence of axillary hair, Tanner stage 5 pubic hair, and breast development at Tanner stage 3. Neurologic evaluation and brain MRI were normal. Pelvic ultrasound showed a small uterus, and ovaries could not be detected; hormone studies revealed hypergonadotropic hypogonadism. Her 21-year-old brother was also hearing-impaired, and exhibited Tanner stage 5 of puberty. Neurologic examination was normal, but he was under treatment for attention-deficit disorder. Neither patient exhibited dysmorphic features.

Mapping

By linkage studies in family PKDF291 with deafness, Ain et al. (2007) localized the hearing loss to chromosome 19p13 (maximum 2-point lod score of 3.01 at D19S1034). Linkage analysis of family PKDF291 by Rehman et al. (2011) obtained a maximum multipoint lod score of 3.35 at D19S391, within a 4.08-Mb interval between D19S216 and D19S916 containing 104 genes. They designated this locus DFNB81.

In 3 affected sisters and 1 unaffected sister from family PDF1 with Perrault syndrome, Jenkinson et al. (2013) performed genomewide homozygosity mapping and found a single region of homozygosity greater than 1 Mb that was shared by the affected sibs but not their unaffected sister: chr19:5,765,869-16,392,163 (GRCh37), a 10.63-Mb interval flanked by SNPs rs4366824 and rs3852916 at 19p13.3-p13.11. In another consanguineous Pakistani family (DEM4395) in which a brother and 2 sisters had profound congenital sensorineural hearing loss, Jenkinson et al. (2013) performed genotyping of DNA samples from 5 family members and found a 15.64-Mb homozygous locus flanked by 19pter and rs1273522, with a maximum multipoint lod score of 2.53. The authors noted that the 2 affected sisters reportedly had normal menstrual cycles at ages 22 and 28 years, respectively, although formal evaluation of hormone profiles was not available; no additional medical problems were self-reported by this family.

Dursun et al. (2016) performed genomewide homozygosity mapping in a Turkish family with Perrault syndrome and identified a 2-Mb region on chromosome 19p13 (chr19:5,469,832-7,472,041) that was homozygous in the 2 affected individuals and heterozygous in their parents. The region contained 64 genes, including CLPP.

Molecular Genetics

Jenkinson et al. (2013) performed exome sequencing in affected individuals with features of Perrault syndrome from 3 unrelated Pakistani families, including a family (PKDF291) reported by Ain et al. (2007) and another (PDF1) reported by Jenkinson et al. (2012). The mapped loci at chromosome 19p13 overlapped in the 3 families, and all 3 were found to be homozygous for mutations in the CLPP gene (601119) that were not present in the NHLBI Exome Variant Server: affected members of families PDF1 and PKDF291 were homozygous for missense mutations in CLPP (T145P, 601119.0001; and C147S, 601119.0002, respectively), whereas the 3 affected sibs in family DEM4395 were homozygous for a splice site mutation (601119.0003). Sanger sequencing of the CLPP gene in 20 additional families with Perrault syndrome did not reveal any mutations. Jenkinson et al. (2013) noted that severe to profound hearing loss was present in all affected individuals from the 3 families with mutations in CLPP, in contrast to the more variable hearing loss described in families with Perrault syndrome due to mutation in the HSD17B4 gene (601860; see PRLTS1, 233400) or the HARS2 gene (600783; see PRLTS2, 614926).

In a Turkish family in which 2 sibs had Perrault syndrome mapping to chromosome 19p13, Dursun et al. (2016) sequenced the candidate gene CLPP and identified homozygosity for a missense mutation (I208M; 601119.0004) that segregated with disease and was not found in controls or in public variant databases. The authors noted that these patients appeared to have a milder phenotype, without neurologic findings.