Perrault Syndrome 4

A number sign (#) is used with this entry because of evidence that Perrault syndrome-4 (PRLTS4) is caused by homozygous or compound heterozygous mutation in the LARS2 gene (604544) on chromosome 3p21.

Description

Perrault syndrome is characterized by premature ovarian failure (POF) in females and by progressive hearing loss in both females and males (summary by Pierce et al., 2013).

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

Clinical Features

Pierce et al. (2013) reported a consanguineous family of Palestinian ancestry in which the 17-year-old female proband presented with primary amenorrhea and postmenopausal levels of follicle-stimulating hormone and luteinizing hormone (FSH and LH; see 118850). Her uterus was prepubertal in size, and her ovaries were not visualized on abdominal ultrasound. The proband and her 2 brothers were all diagnosed with sensorineural hearing loss at 3 to 5 years of age. Hearing loss in the brothers was severe at lower frequencies and less severe at higher frequencies, resulting in unusual upsloping audiograms. The proband had a similar pattern of hearing loss in her right ear, resulting in an upsloping audiogram, whereas hearing loss remained mild in her left ear; she did not use a hearing aid. Pierce et al. (2013) also studied a second family, of Slovenian ancestry, in which the proband presented with POF and severe hearing loss. She had apparently normal menarche at age 13 years and regular menses until age 18 years, but she had no cycles between ages 19 and 30 years, and her FSH levels at age 30 years were high. Both probands had 46,XX karyotypes, normal neurologic function, and normal intelligence.

Solda et al. (2016) reported a sister and brother, born of unrelated Italian parents, with Perrault syndrome. Both had profound congenital sensorineural hearing loss and received cochlear implants. The sister had normal menarche, but presented with premature ovarian failure at age 31. Abdominal ultrasound showed a bicornuate uterus, hypoplastic left ovary, and probable dysgenesis of the right ovary.

Inheritance

The transmission pattern of Perrault syndrome in 2 families reported by Pierce et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a consanguineous family of Palestinian ancestry with Perrault syndrome, Pierce et al. (2013) performed exome sequencing followed by filtering and identified only 1 homozygous variant, a missense mutation in the LARS2 gene (T522N; 604544.0001), that segregated with disease. In a similarly affected proband from a family of Slovenian ancestry, they identified compound heterozygosity for a missense mutation (T629M; 604544.0002) and a 1-bp deletion (604544.0003) in the LARS2 gene. None of the mutations was found in 239 Palestinian or 362 Slovenian controls, or in 6,500 controls of European American or African American ancestry in the NHLBI Exome Variant Server.

In a sister and brother, born of unrelated Italian parents, with PRLTS4, Solda et al. (2016) identified compound heterozygous missense mutations in the LARS2 gene (T300M, 604544.0004 and E638K, 603544.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional studies and studies of patient cells were not performed.