Expanding the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to XX gonadal dysgenesis.

Homozygous variants in PPP2R3C have been reported to cause a syndromic 46,XY complete gonadal dysgenesis phenotype with extragonadal manifestations (GDRM, MIM# 618419) in patients from four unrelated families, whereas heterozygous variants have been linked to reduced fertility with teratozoospermia (SPGF36, MIM# 618420) in male carriers. We present eight patients from four unrelated families of Turkish and Indian descent with three different germline homozygous PPP2R3C variants including a novel in-frame duplication (c.639_647dupTTTCTACTC, p.Ser216_Tyr218dup). All patients exhibit recognizable facial dysmorphisms allowing gestalt diagnosis. In two 46,XX patients with hypergonadotropic hypogonadism and nonvisualized gonads, primary amenorrhea along with absence of secondary sexual characteristics and/or unique facial gestalt led to the diagnosis. 46,XY affected individuals displayed a spectrum of external genital phenotypes from ambiguous genitalia to complete female. We expand the spectrum of syndromic PPP2R3C-related XY gonadal dysgenesis to both XY and XX gonadal dysgenesis. Our findings supported neither ocular nor muscular involvement as major criteria of the syndrome. We also did not encounter infertility problems in the carriers. Since both XX and XY individuals were affected, we hypothesize that PPP2R3C is essential in the early signaling cascades controlling sex determination in humans.

Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM).

Perrault syndrome is a rare heterogeneous condition characterised by sensorineural hearing loss and premature ovarian insufficiency. Additional neuromuscular pathology is observed in some patients. There are six genes in which variants are known to cause Perrault syndrome; however, these explain only a minority of cases. We investigated the genetic cause of Perrault syndrome in seven affected individuals from five different families, successfully identifying the cause in four patients. This included previously reported and novel causative variants in known Perrault syndrome genes, CLPP and LARS2, involved in mitochondrial proteolysis and mitochondrial translation, respectively. For the first time, we show that pathogenic variants in PEX6 can present clinically as Perrault syndrome. PEX6 encodes a peroxisomal biogenesis factor, and we demonstrate evidence of peroxisomal dysfunction in patient serum. This study consolidates the clinical overlap between Perrault syndrome and peroxisomal disorders, and highlights the need to consider ovarian function in individuals with atypical/mild peroxisomal disorders. The remaining patients had variants in candidate genes such as TFAM, involved in mtDNA transcription, replication, and packaging, and GGPS1 involved in mevalonate/coenzyme Q10 biosynthesis and whose enzymatic product is required for mouse folliculogenesis. This genomic study highlights the diverse molecular landscape of this poorly understood syndrome.

LARS2-Perrault syndrome: a new case report and literature review.

BACKGROUND: Perrault syndrome is a rare recessive and genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and gonadal dysgenesis in females. Mutations in seven different genes have been identified: HARS2, HSD17B4, CLLP, C10orf, ERAL1, TWNK and LARS2. To date, 19 variants have been reported in 18 individuals with LARS2-Perrault syndrome. CASE PRESENTATION: Here we describe the case of an 8-year-old girl with compound heterozygous missense mutations in the LARS2 gene. We identified two missense mutations [c.457A > C, p.(Asn153His) and c.1565C > A, p.(Thr522Asn)] and subsequent familial segregation showed that each parent had transmitted a mutation. CONCLUSIONS: These results have implications for genetic counseling and provide insight into the functional role of LARS2. This case highlights the importance of an early diagnosis. Systematic genetic screening of children with hearing loss allows the early identification of a Perrault syndrome in order to ensure specific endocrinological surveillance and management to prevent secondary complications. Clinical data are compared with the other cases reported in the literature.

Middle-age-onset cerebellar ataxia caused by a homozygous TWNK variant: a case report.

BACKGROUND: The TWNK gene encodes the twinkle protein, which is a mitochondrial helicase for DNA replication. The dominant TWNK variants cause progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, while the recessive variants cause mitochondrial DNA depletion syndrome 7 and Perrault syndrome 5. Perrault syndrome is characterized by sensorineural hearing loss in both males and females and gonadal dysfunction in females. Patients with Perrault syndrome may present early-onset cerebellar ataxia, whereas middle-age-onset cerebellar ataxia caused by TWNK variants is rare. CASE PRESENTATION: A Japanese female born to consanguineous parents presented hearing loss at age 48, a staggering gait at age 53, and numbness in her distal extremities at age 57. Neurological examination revealed sensorineural hearing loss, cerebellar ataxia, decreased deep tendon reflexes, and sensory disturbance in the distal extremities. Laboratory tests showed no abnormal findings other than a moderate elevation of pyruvate concentration levels. Brain magnetic resonance imaging revealed mild cerebellar atrophy. Using exome sequencing, we identified a homozygous TWNK variant (NM_021830: c.1358G>A, p.R453Q). CONCLUSIONS: TWNK variants could cause middle-age-onset cerebellar ataxia. Screening for TWNK variants should be considered in cases of cerebellar ataxia associated with deafness and/or peripheral neuropathy, even if the onset is not early.

Disgenesia gonadal pura 46 XX, una causa infrecuente de hipogonadismo: presentación de un caso / Pure gonadal dysgenesis 46 XX, an ucommon cause of hypogonadism: case presentation

El término disgenesia gonadal pura hace referencia a mujeres fenotípicas con infantilismo sexual, amenorrea primaria, hábito eunucoide y un cariotipo 46, XX o 46, XY sin anomalías cromosómicas. Puede asociarse a complicaciones como osteoporosis y síndrome metabólico, elevando el riesgo cardiovascular. Se presenta una paciente femenina de 16 años y 8 meses de edad que acude a consulta de endocrinología por presentar amenorrea primaria.

The term pure gonadal dysgenesis refers to phenotypic women with sexual infantilism, primary amenorrhea an d the eunucoid habit and a 46, XX or 46, XY karyotype without chromosomal abnormalities. It can be associated with complications such as osteoporosis and metabolic syndrome, increasing cardiovascular risk. We present a female patient of 16 years and 8 months of age who attended endocrinology clinic for presenting primary amenorrea.

Coexistence of Gonadal Dysgenesis and Mullerian Agenesis in a Female with 46 XX Karyotype: A Case Report.

Gonadal dysgenesis is a rare genetically heterogeneous disorder characterized by underdeveloped ovaries with consequent, impuberism, primary amenorrhea, and hypergonadotropic hypogonadism. Mullerian agenesis or Mayer­Rokitansky­Kuster­Hauser syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in a woman with normal development of secondary sexual characteristics and a normal 46 XX karyotype. The association of gonadal dysgenesis and Mayer-Rokitansky-Kuster-Hauser syndrome is very rare and appears to be coincidental. We report a case of a 24-years old woman who presented with primary amenorrhea. The endocrine study revealed hypergonadotrophic hypogonadism. The karyotype was normal, 46,XX. Internal genitalia could not be identified on the pelvic ultrasound and pelvic MRI. There were no other morphological malformations. Keywords: Gonadal dysgenesis; Mayer Rokitansky Kuster Hauser syndrome; Mullerian agenesis; primary amenorrhea; 46,XX.

Perrault syndrome with amenorrhea, infertility, Tarlov cyst, and degenerative disc.

Perrault syndrome is a rare autosomal recessive disorder that affects both males and females. The syndrome causes deafness in males, however females display gonadal dysgenesis along with sensorineural hearing loss. Herein, we present a 27-year-old female patient who is deaf and mute along with primary amenorrhea. Hormonal assays revealed hypergonadotropic hypogonadism and the karyotype was 46 XX. Pelvic ultrasound described a hypoplastic uterus and streak ovaries. MRI of the spine showed degenerative discs and Tarlov cysts. Whole exome sequencing identified a LARS2 mutation and the patient was diagnosed with Perrault syndrome type four (PRLTS4).

Perrault syndrome type 3 caused by diverse molecular defects in CLPP.

The maintenance of mitochondrial protein homeostasis (proteostasis) is crucial for correct cellular function. Recently, several mutations in the mitochondrial protease CLPP have been identified in patients with Perrault syndrome 3 (PRLTS3). These mutations can be arranged into two groups, those that cluster near the docking site (hydrophobic pocket, Hp) for the cognate unfoldase CLPX (i.e. T145P and C147S) and those that are adjacent to the active site of the peptidase (i.e. Y229D). Here we report the biochemical consequence of mutations in both regions. The Y229D mutant not only inhibited CLPP-peptidase activity, but unexpectedly also prevented CLPX-docking, thereby blocking the turnover of both peptide and protein substrates. In contrast, Hp mutations cause a range of biochemical defects in CLPP, from no observable change to CLPP activity for the C147S mutant, to dramatic disruption of most activities for the "gain-of-function" mutant T145P - including loss of oligomeric assembly and enhanced peptidase activity.

A homozygous missense variant in HSD17B4 identified in a consanguineous Chinese Han family with type II Perrault syndrome.

BACKGROUND: Perrault syndrome is a rare multisystem disorder that manifests with sensorineural hearing loss in both sexes, primary ovarian insufficiency in females and neurological features. The syndrome is heterogeneous both genetically and phenotypically. CASE PRESENTATION: We reported a consanguineous family (two affected sisters) with Perrault syndrome. The proband had the characteristics of Perrault syndrome: ovarian dysgenesis, bilateral hearing loss and obvious neurological signs. Target genetic sequencing and triplet repeat primed PCR (TP-PCR) plus capillary electrophoresis was conducted to detect causative mutations in the proband. The detected variant was further confirmed in the proband and tested in other family members by Sanger sequencing. Both the proband and her sister were found homozygous for the novel variant HSD17B4 c.298G > T (p.A100S) with their parents heterozygous. Detected by western blot, the protein expression of HSD17B4 mutant was much lower than that of the wild type in SH-SY5Y cells transfected by HSD17B4 wild type or mutant plasmid, which indicated the pathogenicity of the HSD17B4 mutation. CONCLUSIONS: Our findings supported that HSD17B4 was one of the genes contributing to Perrault syndrome with the likely pathogenic variant c.298G > T (p.A100S). Special manifestations of cerebellar impairment were found in cases caused by HSD17B4 mutations. Besides, attention should be paid to distinguish Perrault syndrome from D-bifunctional protein deficiency and hereditary ataxia.

Clinical features and management of 33 patients with 46,XX pure gonadal dysgenesis.

The objective of the study is to summarize the clinical characteristics of 33 patients' cohort (46,XX pure gonadal dysgenesis, 46,XX PGD), discuss the management, and propose treatment suggestions. Patients' information, medical history, and medical records were obtained. All patients were closely followed up. At the time of diagnosis, the patients presented 19.53 ± 3.60 years old, 165 ± 6.49 cm height, breast development of Tanner stage I, and infantile female genitalia. High level of follicle-stimulating hormone (87.41 ± 21.50 mIU/mL) and LH (27.10 ± 8.47 mIU/mL) and low level of E2 (8.85 ± 6.13 pg/mL) were observed. Individualized hormone replacement therapy (HRT) was initiated after diagnosis. After 2 years of treatment, all patients had obvious breast development; the uterus showed (2.38 ± 0.60) × (1.38 ± 0.70) × (1.38 ± 0.55) cm growth. The incidence of osteopenia changed from 69.70% to 22.22% and that of osteoporosis changed from 18.18% to 0. Dysgeminoma was found in one patient. We concluded that gonadal dysgenesis in 46,XX PGD causes secondary sexual characteristic absence, tendency of taller, osteoporosis, infertility, and sexual health problems. There is minor chance of tumor occurrence for the patients. Optimal care including HRT and close follow-up are required.

"It's Part of Me, Not All of Me": Young Women's Experiences of Receiving a Diagnosis Related to Diverse Sex Development.

STUDY OBJECTIVE: To understand young women's experiences of receiving a diagnosis related to diverse sex development. DESIGN: A qualitative narrative analysis of interviews. SETTING: Karolinska University Hospital. PARTICIPANTS: Nine women (aged 20-26 years) with complete androgen insensitivity syndrome, XY or XX gonadal dysgenesis. INTERVENTIONS: Semistructured interviews. MAIN OUTCOME MEASURES: A narrative approach was used to analyze the interviews. This involved identification of individual narratives of receiving the diagnosis, as well as identification of key issues that were common across interviews. RESULTS: The analysis showed how participants' prediagnosis life experiences framed how medical information was perceived upon diagnosis. All participants had been informed about their condition before the study, but not all remembered the name of their diagnosis. Participants described positive characteristics of health professionals, such as being flexible and able to adapt to patients' individual needs. Clinicians' strategies, such as normalizing patients' experiences, were usually perceived as supportive, but were not always considered helpful. After the diagnosis, participants were worried about potential social, practical, and philosophical issues. CONCLUSION: This research highlighted the importance of clinicians taking an exploratory and individualized approach to the sensitive process of disclosing a diagnosis related to diverse sex development to young adults. There are various strategies health professionals can use that might help young people to develop their knowledge about their condition: (1) repeating information to help the patient remember; (2) using language that is not too medicalized; and (3) communicating in a way that is meaningfully connected to patients' everyday lives.

Overview of genetics of disorders of sexual development.

PURPOSE OF REVIEW: Disorders of sexual development (DSD) are a genetic and phenotypic heterogeneous group of congenital disorders. This review focuses on the genetics of DSD and aims to recognize and contextualize, in a systematic way, based on the classification and the genetic mechanisms, the latest developments in the field of DSD diagnostics. RECENT FINDINGS: Due to the current diagnostic armamentarium, during the past decade, the field of DSD diagnostics has changed dramatically from the recognition of few genes and cytogenetic abnormalities, to the identification of multiple genes and a wide arrange of genetic mechanisms involved in the genesis of DSD. In addition, the phenotypes associated with the genetic mechanism have expanded tremendously. SUMMARY: Despite the current diagnostic limitations, the landscape for genetics of DSD is encouraging due to discovery of new genes, their interactions, and the recognition of the variety of mechanisms involved.

Serendipity or prepared mind? Recollections of the KOP translocation (1967) and of one form of Perrault syndrome.

The human X/autosome translocation, designated KOP, was discovered by Dr. Philip D. Pallister in Montana in 1967 in a young man with apparent Klinefelter syndrome. Collaboratively it was possible to elucidate the genetic nature of his unprecedented chromosome rearrangement and its developmental effects in mother and son. In retrospect, these clinical and genetic studies at the height of the somatic cell genetics era (Ruddle, Siniscalco, etc.) presented human genetics with a highly productive opportunity to begin gene mapping of autosomes and the X chromosome. The late Victor McKusick considered the discovery of the KOP translocation, as he determined personally in Montana, one of the major transforming events in human genetics. The Perrault syndrome evaluated in two families in Montana and one in Sicily for familial deafness, primary amenorrhea and neurologic impairment (progressive in some), turned out to be heterogeneous. In the "hands" of Dr. M.-C. King of Seattle four forms of Perrault syndrome have been identified. The autosomal recessive mutation present in the P family studied with Dr. Pallister in Helena, turned out to affect the mitochondrial histidyl tRNA synthetase gene present in prokaryotes, annelids, fungi and mammals, hence, must already have been present in LUCA some 3.8 billion years ago.

Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features.

OBJECTIVE: To identify the genetic cause in 2 families of progressive ataxia, axonal neuropathy, hyporeflexia, and abnormal eye movements, accompanied by progressive hearing loss and ovarian dysgenesis, with a clinical diagnosis of Perrault syndrome. METHODS: Whole-exome sequencing was performed to identify causative mutations in the 2 affected sisters in each family. Family 1 is of Japanese ancestry, and family 2 is of European ancestry. RESULTS: In family 1, affected individuals were compound heterozygous for chromosome 10 open reading frame 2 (C10orf2) p.Arg391His and p.Asn585Ser. In family 2, affected individuals were compound heterozygous for C10orf2 p.Trp441Gly and p.Val507Ile. C10orf2 encodes Twinkle, a primase-helicase essential for replication of mitochondrial DNA. Conservation and structural modeling support the causality of the mutations. Twinkle is known also to harbor multiple mutations, nearly all missenses, leading to dominant progressive external ophthalmoplegia type 3 and to recessive mitochondrial DNA depletion syndrome 7, also known as infantile-onset spinocerebellar ataxia. CONCLUSIONS: Our study identifies Twinkle mutations as a cause of Perrault syndrome accompanied by neurologic features and expands the phenotypic spectrum of recessive disease caused by mutations in Twinkle. The phenotypic heterogeneity of conditions caused by Twinkle mutations and the genetic heterogeneity of Perrault syndrome call for genomic definition of these disorders.

A rare case of 46, XX SRY-negative male with approximately 74-kb duplication in a region upstream of SOX9.

The 46, XX male disorder of sex development (DSD) is a rare genetic condition. Here, we report the case of a 46, XX SRY-negative male with complete masculinization. The coding region and exon/intron boundaries of the DAX1, SOX9 and RSPO1 genes were sequenced, and no mutations were detected. Using whole genome array analysis and real-time PCR, we identified a approximately 74-kb duplication in a region approximately 510-584 kb upstream of SOX9 (chr17:69,533,305-69,606,825, hg19). Combined with the results of previous studies, the minimum critical region associated with gonadal development is a 67-kb region located 584-517 kb upstream of SOX9. The amplification of this region might lead to SOX9 overexpression, causing female-to-male sex reversal. Gonadal-specific enhancers in the region upstream of SOX9 may activate the SOX9 expression through long-range regulation, thus triggering testicular differentiation.

Hernia uteri inguinalis in a case of ovotesticular disorder of sexual differentiation.

An 18-year-old phenotypic male presented with an irreducible left inguinal mass, gynecomastia, and hypospadias. This mass on exploration was found to be a nonfunctional uterus with ipsilateral ovary and was excised. Further investigation confirmed the presence of a contralateral testis and a genotype of 46, XX. This confirmed the diagnosis of ovotesticular disorder of sexual differentiation (formerly true hermaphroditism) with obstructed hernia uteri inguinalis. The patient was raised as a male. Subcutaneous mastectomy for gynecomastia and neourethra construction with full thickness skin graft for hypospadias were performed. Hernia uteri inguinalis is rarely seen in this condition with only 2 cases being reported worldwide thus far, including our case.

A report of two novel NR5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression.

OBJECTIVE: NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus-specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms. DESIGN AND METHODS: We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localization and transactivation assays. RESULTS: We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localization and impaired transcriptional activation without dominant-negative effects in both mutations. CONCLUSIONS: We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations.