Perrault Syndrome
Summary
Clinical characteristics.
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.
Diagnosis/testing.
The diagnosis of Perrault syndrome is based on the clinical findings of SNHL in men and women and ovarian dysfunction in women with a 46,XX karyotype. The diagnosis is confirmed by the presence of biallelic pathogenic variants in one of six genes (CLPP, ERAL1, HARS2, HSD17B4, LARS2, or TWNK); however, in approximately 60% of individuals with Perrault syndrome identified to date, a molecular diagnosis cannot be established.
Management.
Treatment of manifestations: Hearing loss should be assessed and treated by a multidisciplinary team including an audiologist and otolaryngologist. Possible interventions for those with hearing loss include special educational resources, hearing aids, vibrotactile devices, and cochlear implantation. Cochlear implantation is an option for children older than 12 months with severe-to-profound hearing loss. Primary amenorrhea is treated in adolescents in collaboration with a pediatric endocrinologist in the usual manner, first to induce puberty and then to mimic the menstrual cycle and maintain bone health. Assisted reproduction through in vitro fertilization using donor eggs is a consideration for women with gonadal dysgenesis; oocyte cryopreservation can be considered in women at risk for POI.
Surveillance: Routine audiologic assessments when hearing loss is mild to moderate; no follow up or audiologic assessments when hearing loss is profound. For children with hearing impairment: monitor development
For women with primary amenorrhea: during induction of puberty, follow up every three months for staging of pubertal development and adjustment of estrogen dose. For women on maintenance estrogen replacement therapy: annual follow up as well as assessment of bone density approximately every five years.
Agents/circumstances to avoid: Avoid: ototoxic medication (e.g., aminoglycosides) if alternative medications are available; exposure to loud noise, which can exacerbate hearing loss.
Evaluation of relatives at risk: It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early interventions (e.g., in young children with profound hearing loss; estrogen replacement to facilitate pubertal development in females with ovarian involvement; and potential oocyte cryopreservation if POI is an issue).
Genetic counseling.
Perrault syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the pathogenic variants in the family are known, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.
Diagnosis
No formal diagnostic criteria have been published for Perrault syndrome.
Suggestive Findings
Perrault syndrome should be suspected in individuals with the following clinical findings and family history.
Clinical findings
- Sensorineural hearing loss (SNHL) in men and women. SNHL is bilateral and ranges in severity from moderate with early-childhood onset to profound with prelingual (congenital) onset. The hearing threshold increase can be variable. When presenting in early childhood, hearing loss can be progressive.
- SNHL may be apparent from birth in infants who fail neonatal screening tests.
- In older children SNHL can be demonstrated on an audiogram, which will show similar hearing thresholds for both bone and air conduction.
- Ovarian dysfunction in women with a 46,XX karyotype. The spectrum of ovarian dysfunction extends across a continuum from primary ovarian insufficiency (POI) to ovarian dysgenesis.
- POI is defined as cessation of menses before age 40 years, with raised levels of follicle stimulating hormone (FSH) and reduced serum estrogen concentration.
- Ovarian dysgenesis is a developmental disorder characterized by loss of germ and supportive cells (e.g., granulosa and theca cells, respectively) in the gonads. The ovaries are dysplastic, streak, or absent. Serum concentration of estrogen is decreased with a consequent elevation in serum concentration of the two gonadotropins, lutenizing hormone (LH) and follicle stimulating hormone (FSH) (i.e., with hypergonadotropic hypogonadism). The uterus is rudimentary and prepubertal on ultrasound examination.
Family history is consistent with autosomal recessive inheritance including the possibility of parental consanguinity.
Establishing the Diagnosis
The diagnosis of Perrault syndrome is established:
- Either by clinical findings, family history, and exclusion of other possible diagnoses with findings similar to Perrault syndrome (see Differential Diagnosis);
- Or by identification of biallelic pathogenic variants in one of the six associated genes (see Table 1) in a person with Suggestive Findings.
Clinical Findings and Family History
- SNHL that is bilateral and ranges in severity from moderate with early-childhood onset to profound with prelingual (congenital) onset
- Ovarian dysfunction in women with a 46,XX karyotype
Note: Sensorineural hearing loss is usually the initial manifestation of Perrault syndrome. The diagnosis will not be considered, based on clinical findings alone, in males who do not have an affected sister. The initial diagnosis will not be made in females based on clinical findings alone until delayed pubertal development is noted, usually in the teenage years.
Molecular Genetic Testing
The diagnosis of Perrault syndrome is molecularly confirmed by the presence of biallelic pathogenic variants in one of six genes: CLPP, ERAL1, HARS2, HSD17B4, LARS2, and TWNK (see Table 1).
Note: To date biallelic pathogenic variants in these six genes do not account for all individuals with clinically confirmed Perrault syndrome (Table 1) [Demain et al 2017].
Due to the heterogeneous nature of this disorder, molecular genetic testing approaches can include gene-targeted testing (through a multigene panel) or comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved).
- A multigene panel that includes CLPP, ERAL1, HARS2, HSD17B4, LARS2, and TWNK and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- Comprehensive genomic testing is the best option when the diagnosis of Perrault syndrome has not been considered because an individual has atypical phenotypic features. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Perrault Syndrome
| Gene 1, 2 | Proportion of Perrault Syndrome Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| CLPP | 7/42 | 7/7 | None reported |
| ERAL1 | 3/42 | 3/3 | None reported |
| HARS2 | 3/42 | 3/3 | None reported |
| HSD17B4 | 3/42 | 3/3 | None reported |
| LARS2 | 8/42 | 8/8 | None reported |
| TWNK | 5/42 | 5/5 | None reported |
| Unknown 6 | 13/42 | NA | |
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
When multigene panel testing that includes most/all of the known genes is used, approximately 60% of individuals with Perrault syndrome have not had pathogenic variants [Lerat et al 2016, Demain et al 2017]. Failure to detect pathogenic variants in one of these genes suggests either the presence of a variant in a gene region not sequenced (e.g., enhancer, promoter, intron), pathogenic variants in an as-yet-unidentified gene, or inaccurate clinical diagnosis (see Differential Diagnosis).
Clinical Characteristics
Clinical Description
Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females.
Significant inter- and intrafamilial phenotypic variability has been observed [Jenkinson et al 2012]. Of note, the variable age of onset and degree of deafness do not depend on the sex of the affected individual.
SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. There is no evidence of impaired vestibular function.
Affected females have gonadal dysfunction. Although the ovarian findings in Perrault syndrome were originally described as primary ovarian failure due to absent or streak gonads, subsequent reports identified a spectrum of ovarian dysfunction ranging from gonadal dysgenesis presenting as primary amenorrhea (also known as primary ovarian failure) to primary ovarian insufficiency (POI) (presenting as secondary amenorrhea) which is defined as cessation of menses before age 40 years. One woman with Perrault syndrome had children prior to the onset of ovarian insufficiency [Jenkinson et al 2013].
Fertility in affected males is usually reported as normal, although the number of reported affected males is limited. Males with variants in CLPP have been noted to be azoospermic [Demain et al 2017].
Other features. Some individuals have been reported to have additional clinical features. No consistent pattern has been observed with these additional features, which have been reported in more than one individual [Jenkinson et al 2012].
Neurologic features are present in some individuals with Perrault syndrome. Members of families with CLPP-related Perrault syndrome and LARS2-related Perrault syndrome have been reported with or without neurologic features [Jenkinson et al 2013, Pierce et al 2013, Kosaki et al 2018]:
- Learning difficulties and developmental delay [Jenkinson et al 2012, Lerat et al 2016, Demain et al 2017]
- Cerebellar ataxia [Jenkinson et al 2012, Lerat et al 2016, Demain et al 2017]
- Motor and sensory peripheral neuropathy [Jenkinson et al 2012, Lerat et al 2016, Demain et al 2017]
Skeletal features reported in some individuals include high-arched palate, positive thumb and wrist signs, and marfanoid habitus [Zerkaoui et al 2017]
Phenotype Correlations by Gene
Sensorineural hearing loss (SNHL) in Perrault syndrome resulting from biallelic pathogenic variants in ERAL1, HARS2, HSD17B4, or LARS2 can be congenital and profound or progressive with varying degrees of severity; onset is usually in early childhood and a range of frequencies are affected.
CLPP. In families reported to date with biallelic CLPP pathogenic variants, SNHL is severe to profound with congenital or early childhood onset [Jenkinson et al 2013, Ahmed et al 2015, Lerat et al 2016, Demain et al 2017].
TWNK. All individuals reported to date with biallelic TWNK variants have had associated neurologic features including ataxia and peripheral neuropathy [Morino et al 2014, Lerat et al 2016, Demain et al 2017, Ołdak et al 2017].
Genotype-Phenotype Correlations
Low-frequency SNHL resulting in an upsloping audiogram has been associated with the LARS2 pathogenic variant c.1565C>A in either the homozygous state or in a heterozygous state in trans to another pathogenic LARS2 variant. Other variants in LARS2 have not been associated with low-frequency SNHL [Pierce et al 2013, Demain et al 2017].
Nomenclature
Perrault syndrome has also been referred to as ovarian dysgenesis with sensorineural deafness or XX gonadal dysgenesis with deafness.
Prevalence
Perrault syndrome is rare; approximately 100 affected individuals have been reported to date [Lerat et al 2016]. However, underascertainment is likely as males without an affected sister will be diagnosed with nonsyndromic deafness rather than Perrault syndrome. For example, the authors are aware of males with SNHL and prepubertal girls with SNHL with variants in Perrault syndrome-related genes.
Differential Diagnosis
For individuals with a clinical diagnosis of Perrault syndrome in whom a molecular basis has not been identified, other causes of sensorineural hearing loss and ovarian dysfunction need to be excluded before a clinical diagnosis of Perrault syndrome can made with confidence.
Sensorineural hearing loss (SNHL) is genetically heterogeneous. See Hereditary Hearing Loss and Deafness Overview for a detailed differential diagnosis.
XX gonadal dysgenesis and primary ovarian insufficiency are genetically heterogeneous.
- XX gonadal dysgenesis. For individuals with primary ovarian failure, defined by primary amenorrhea with low estrogen and raised gonadotropins, Turner syndrome (45, X) or other abnormalities of the X chromosome should be excluded by karyotype analysis or chromosomal microarray (also known as array CGH). Hearing loss is present in approximately 50% of women with Turner syndrome [King et al 2007], but tends to be mild to moderate at higher frequencies [Oliveira et al 2013].
- Testing of genes in which pathogenic variants have been reported to cause ovarian dysgenesis (including BMP15, FSHR, MCM9, PSMC3IP, and SOHLH1) is appropriate (OMIM PS233300).
- Other causes of primary ovarian failure include 17α-hydroxylase deficiency and 17,20-lysase deficiency (OMIM 202110); which can be excluded by measurement of 11-deoxycorticosterone and androstenedione levels.
- Primary ovarian insufficiency (POI). Multiple genetic causes of POI are known. Analysis of a limited number of genes is available by routine clinical testing.
- Premutation carriers of an expanded FMR1 allele are at increased risk for ovarian insufficiency; see FMR1-Related Disorders.
- Many females with BPES (blepharophimosis, ptosis, epicanthus inversus syndrome), caused by pathogenic variants or deletions of FOXL2, have POI. BPES can be distinguished from Perrault syndrome by the presence of marked blepharophimosis and ptosis in BPES.
- Ovarian antibodies are increased in polyglandular autoimmune syndrome type 1 (OMIM 240300) and type 2 (OMIM 269200).
SNHL and POI
- RMND1-associated mitochondrial disease, which has a wide phenotypic range including SNHL, hypotonia, developmental delay, lactic acidemia, and renal dysfunction [Ng et al 2016] can present with features consistent with a diagnosis of Perrault syndrome [Demain et al 2018].
- The authors described a novel and likely rare cause of Perrault syndrome in a female who did not have pathogenic variants in any of the known Perrault syndrome-related genes [Faridi et al 2017]. She manifested SNHL and POI as a result of inheriting homozygous pathogenic variants in each of two distinct unlinked genes: CLDN14 and SGO2. CLDN14 is a well-known cause of autosomal recessive SNHL. Her POI was attributed to inactivating variants in SGO2, a gene not known to cause any human disorder but essential for meiosis and strongly implicated in infertility by studies in murine models. The variants of both CLDN14 and SGO2 were segregating in her multigenerational family; her parents were documented to be heterozygous for variants in both genes. Although relatives either manifested SNHL or were heterozygous for the CLDN14 variant, she was the only female who had both SNHL and POI.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Perrault syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Perrault Syndrome
| System/Concern | Evaluation | Comment |
|---|---|---|
| ENT 1 | Audiologic assessment | To define the degree & frequency range of hearing impairment by audiometry & physiologic tests (summarized in Hereditary Hearing Loss and Deafness Overview) |
| Neurologic 1 | Neurologic assessment | Determine if ataxia, peripheral neuropathy, &/or learning disability is present. |
| Endocrine 2 | Serum estrogen & gonadotropin (LH & FSH) concentrations | In women w/relatively intact ovarian function, serum anti-müllerian hormone concentrations may provide evidence of incipient ovarian failure. 3 |
| Pelvic imaging | Ultrasound scan or magnetic resonance imaging to define the presence of ovaries & antral follicle count | |
| Miscellaneous/ Other 1 | Consultation w/clinical geneticist &/or genetic counselor |
- 1.
Men and women
- 2.
Women only
- 3.
De Vos et al [2010]
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Perrault Syndrome
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Hearing loss | Possible interventions:
|
|
| Ovarian insufficiency | In adolescents presenting w/primary amenorrhea, induction of puberty w/incremental doses of estrogen |
|
| Assisted reproduction through in vitro fertilization |
|
- 1.
Cochlear implantation can be considered in children age >12 months with severe-to-profound hearing loss.
Surveillance
Table 5.
Recommended Surveillance for Individuals with Perrault Syndrome
| System/Concern | Evaluation | Frequency |
| Hearing |
| Annually |
| Musculoskeletal | Assess bone density in women on maintenance estrogen replacement therapy. | Every ~5 yrs |
| Endocrine |
| Every 3 mos |
| Women on maintenance estrogen replacement therapy: assessment of withdrawal bleeding & well being | Annually |
Agents/Circumstances to Avoid
For individuals with hearing loss, avoid:
- Ototoxic medication such as aminoglycosides if alternatives are available;
- Exposure to loud noise, which may contribute to deterioration of hearing.
Evaluation of Relatives at Risk
It is appropriate to evaluate the older and younger sibs of a proband in order to identify as early as possible those who would benefit from early interventions (e.g., in young children with profound hearing loss, estrogen replacement to facilitate pubertal development in females with ovarian involvement, and potential oocyte cryopreservation if primary ovarian insufficiency is an issue). See Treatment of Manifestations.
- If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs.
- If the pathogenic variants in the family are not known, screening of sibs should include audiologic assessment in males and females and baseline measurements of serum LH and FSH in females.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.