Hereditary Syndromes Research Articles

Clinicopathological and molecular spectrum of patients with germline SUFU mutations: A case series.

One of the hereditary syndromes associated with multiple early-onset basal cell carcinomas (BCCs) is basal cell nevus syndrome (BCNS), of which a minority is caused by germline SUFU mutations. Germline SUFU mutations show a spectrum of phenotypes, of which multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC) is one. Patients with MHIBCC develop multiple basaloid skin tumors from middle age onwards. Three patients presenting with an MHIBCC phenotype were tested for a germline SUFU mutation. Skin biopsies were assessed by two dermatopathologists. Our study adds three new pathogenic SUFU variants, including a mosaic, to the current literature. Literature suggests a spectrum of phenotypes of patients carrying the same SUFU mutation, which ranges from the MHIBCC phenotype, to BCNS, to patients that develop life-threatening brain tumors. This last risk is significantly higher in germline SUFU mutation carriers when compared to BCNS patients carrying germline PTCH1 mutations. Germline SUFU mutation carriers should be recognized as a distinct group of patients carrying specific health risks, independent of meeting the BCNS criteria. Phenotypic prediction based on the specific SUFU mutation seems unfeasible. It is of utmost importance that the less apparent MHIBCC phenotype is recognized, to provide (second generation) germline SUFU mutation carriers appropriate healthcare.

A Case of Breast Cancer Patient with Li–Fraumeni Syndrome: Psychosocial Implications and Literature Review

Li–Fraumeni syndrome (LFS) is defined by the early emergence of tumors and is associated with mutations in the tumor suppression gene known as tumor protein 53 ( TP53). Information is scarce regarding the psychosocial challenges encountered by individuals with LFS and how it affects their treatment decisions. A 21-year-old woman developed multiple breast tumors over a period of nine years. Genetic testing identified a heterozygous missense substitution in exon 6 of the TP53 gene, specific variant chr17:7578190T>C c.659A>G (p.Tyr220Cys) listed in the dbSNP database. The report also highlights the psychosocial implications of the diagnosis at a young age and the patient’s reluctance to undergo the recommended bilateral mastectomy. The patient exhibited a significantly higher incidence of secondary tumors, underscoring the importance of comprehensive screening and timely diagnosis for managing LFS. This case highlights the challenges faced and the importance of emotional and psychological support after the diagnosis of hereditary syndromes, especially among young women.

Efficacy and safety of riluzole for treating motor function in rare dyskinesia syndromes: a systematic review with meta-analysis.

We conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of riluzole to treat neurodegenerative dyskinesia in patients, using the Cochrane collaboration guidelines. We searched databases including Medline, Embase, and Cochrane without any language filters. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used as a guideline, and the study protocol was registered in PROSPERO (CRD42022354627). Eleven studies involving 1376 patients were included. There was a significant overall effect of riluzole on changes in motor function scores. However, the level of heterogeneity was I2 = 74%. In the subgroup analyses, there were no significant effects of riluzole on motor scores in hereditary ataxia, Parkinson's disease, or Huntington's disease. In the sensitivity analysis, there were no significant effects of riluzole on motor function scores. Furthermore, there were no significant differences in adverse events between the riluzole and placebo groups. Although riluzole may not have significant efficacy for improving motor function in neurodegenerative dyskinesia syndromes compared with placebo, it seems to have an acceptable safety profile. Moreover, it may be effective for hereditary ataxia syndromes, although there was a relatively small effect size and limited quality of evidence.

SGLT2-Inhibition in Patients With Alport syndrome

IntroductionLarge-scale trials showed positive outcomes of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in adults with chronic kidney disease (CKD). Whether the use of SGLT2i is safe and effective in patients with the common hereditary CKD Alport syndrome has not yet been investigated specifically in larger cohorts. MethodsThis observational, multi-center, international study (NCT02378805) assessed 112 patients with Alport syndrome after start of SGLT2i. The study’s primary endpoint was change of albuminuria in albumin/gram creatinine from start of therapy. ResultsCompared to randomized trials investigating the effect of SGLT2i in CKD, the adult patients in this study were younger (38±14 years) and had a better estimated glomerular filtration rate, eGFR, (63±35 ml/min/1.73m2; n=98). Maximum follow up was 32 months. Compared to baseline, at the first three follow-up visits (months 1 to 3, 4 to 8 and 9 to 15) after initiation of SGLT2i-therapy, a significant reduction of albuminuria in milligrams albumin/gram creatinine (>30%) was observed. Mean loss of eGFR was 9±12 ml/min/1.73 m2 almost one year after initiation of SGLT2i-therapy (n=35). At a total of 71 patient-years at risk, 0.24 adverse events per patient year on SGLT2i were reported. ConclusionThis study indicates that, additive to RAS-inhibition, SGLT2i have the potential to reduce the amount of albuminuria in patients with Alport syndrome. Future studies are needed to investigate the long-term effects of SGLT2i on CKD progression in patients with Alport syndrome to assess whether the observed reduction in albuminuria translates to a delay in kidney failure.

Pheochromocytoma - diagnosis and treatment, review of literature

Introduction: Pheochromocytomas are rare tumors originating from the adrenal medulla, which can occur sporadically or as part of hereditary syndromes. Many patients with chromaffin tumors harbor genetic mutations, typically inherited in an autosomal dominant manner, hence genetic testing is recommended for all patients. Symptoms can result from both excessive catecholamine production and the mass effect of the tumor. Diagnosis is confirmed by elevated levels of metanephrines or normetanephrines in the plasma or urine. Radiological imaging aids in tumor localization and assessment of potential local invasion or metastasis. Preoperative preparation of all patients involves the use of α-receptor blockers and/or other medications to control arterial hypertension, arrhythmias, and fluid volume. Surgery remains the treatment of choice, with lifelong follow-up recommended.Objective:The review article aims to provide an overview of chromaffin tumor pathology, their etiology, discuss diagnostic possibilities, and indicate therapeutic options for patients.Materials and Methods:A summary of reports available in medical publications and scientific studies found in databases such as PubMed, CrossRef, Google Scholar, as well as relevant textbooks.Results:Chromaffin tumors are rare but dangerous for patients; adequate pharmacological preparation for surgery, which is usually necessary, is extremely important.Conclusions:The main role is to establish the correct diagnosis, or even suggest and conduct diagnostic tests towards a chromaffin tumor. Patient management involves controlling blood pressure, appropriate premedication, and surgical intervention. After such treatment, patients require continuous monitoring to detect any potential disease recurrence.

Pediatric Cancer Screening in Hereditary Gastrointestinal Cancer Risk Syndromes: An Update from the AACR Childhood Cancer Predisposition Working Group.

Gastrointestinal (GI) polyposis and cancer in pediatric patients is frequently due to an underlying hereditary cancer risk syndrome requiring ongoing cancer screening. Identification of at-risk patients through family history, clinical features of a syndrome, or symptom onset ensures appropriate cancer risk assessment and management in childhood and beyond. In this 2024 perspective, we outline updates to the hereditary GI cancer screening guidelines first published by the American Association of Cancer Research Pediatric Cancer Predisposition Workshop in 2017. These guidelines consider existing recommendations by pediatric and adult gastroenterology consortia to ensure alignment with gastroenterology practices in managing polyposis conditions. We specifically address the recommendations for pediatric screening in familial adenomatous polyposis, Peutz-Jeghers syndrome, and juvenile polyposis syndrome. Further, we emphasize the importance of multidisciplinary care and partnership with gastroenterology, as it is crucial in management of children and families with these conditions.

Hereditary Colorectal Cancer Syndromes and Inflammatory Bowel Diseases: Risk Management and Surveillance Strategies.

Background and aims: Hereditary colorectal cancer syndromes (HCCS), including familial adenomatous polyposis (FAP) and Lynch syndrome (LS), are the two most important high-risk conditions for colorectal cancer (CRC). Inflammatory bowel disease (IBD) increases the risk by two to six times compared with that in the general population. The intersection of these two conditions has rarely been documented in literature. We aimed to summarize the prevalence, pathogenesis, and current evidence-based management of IBD and HCCS and the underlying molecular mechanisms of accelerated carcinogenesis due to combined inflammation and genetic predisposition. Methods: PubMed and Scopus were searched until June 2024 to identify relevant studies investigating the epidemiology, pathogenesis, and management of IBD and coexisting hereditary CRC syndromes. Results: Co-occurrence of IBD and hereditary CRC syndromes is exceptionally uncommon. Individuals with LS and IBD tend to develop CRC at a younger age than those without IBD, with patients with ulcerative colitis facing particularly elevated risks. The interaction between mismatch deficiency and chronic inflammation requires further investigation.

EHLERS–DANLOS SYNDROME — A CASE OF MULTIDIRECTIONAL SHOULDER INSTABILITY REHABILITATION

Introduction: Ehlers–Danlos Syndrome (EDS) is a hereditary and heterogeneous syndrome that affects conjunctive tissue, due to collagen production compromise. Hypermobile EDS (hEDS) is the most common subtype of this syndrome and can cause shoulder joint instability, which can lead to chronic pain and significant functional impairment. Methods: A case report of a patient with hEDS followed in our local health unit was made. The authors describe their clinical insight regarding the case, as well as the rehabilitation program the patient was submitted to. Results: Female patient, 32 years old. Functionally autonomous in every daily living activity. Clinically diagnosed with hEDS in 2013, after reporting bilateral shoulder instability. The patient presented herself in a Physical and Rehabilitation Medicine consultation, 6 months after being submitted to the third surgical intervention of the right shoulder. She presented an overall limited range of motion, decreased muscle strength and positive apprehension and drawer tests. An extensive rehabilitation program was prescribed, focusing on joint mobilization, dynamic stabilizers strengthening and proprioceptive training. After 12 weeks, the patient presented reduced shoulder pain and a better functional status. Conclusion: hEDS compromises the integrity of the static and dynamic stabilizers of the shoulder. Clinical management of these cases involves a multidisciplinary approach with early and adequate rehabilitation care treatments.

Association Between Time to Colonoscopy After Abnormal Fecal Immunochemical Test and Risk of Adenoma, Advanced Colorectal Neoplasia and Colorectal Cancer Incidence

Objective: Colorectal cancer (CRC) is a significant health concern in Thailand, with high incidence and late-stage diagnosis rates. This study investigates the timing of colonoscopy following a positive fecal immunochemical test (FIT) and identifies risk factors for colorectal neoplasms. Material and Methods: A retrospective analysis included Thai patients aged 50-75 with a positive FIT who underwent colonoscopy. Exclusions were made for prior colonoscopy, colorectal surgery history, hereditary syndromes, inflammatory bowel disease, and incomplete pathology reports. Data from January 2018 to December 2021 were assessed for demographics, colonoscopy findings, and pathology outcomes. Results: The study encompassed 2,717 participants with balanced age and gender distributions. Preliminary risk factors associated with the development of adenoma and advanced colorectal neoplasia (ACRN) included age [odds ratio (OR): 1.03, 95% confidence interval (CI): 1.02-1.05, p-value<0.001], gender (OR for males: 1.60 for adenoma, 1.69 for ACRN, p-value<0.001), and smoking (OR: 1.92, p-value=0.001). The timing of colonoscopy within one-year post-FIT did not exhibit statistically significant associations with adenoma, ACRN, or CRC. Conclusion: This study provides valuable insights into CRC screening in Thailand. It suggests that timing within a year of colonoscopy might not be the sole determinant of improved outcomes post-FIT. Preliminary risk factors encompassed age, gender, and smoking. Future studies should focus on larger cohorts to investigate adverse outcomes, such as late-stage CRC and CRC-related mortality.

Targeting MERTK on tumour cells and macrophages: a potential intervention for sporadic and NF2-related meningioma and schwannoma tumours

Meningioma and schwannoma are common tumours of the nervous system. They occur sporadically or as part of the hereditary NF2-related schwannomatosis syndrome. There is an unmet need for new effective drug treatments for both tumour types. In this paper, we demonstrate overexpression/activation of TAM (TYRO3/AXL/MERTK) receptors (TAMs) and overexpression/release of ligand GAS6 in patient-derived meningioma tumour cells and tissue. For the first time, we reveal the formation of MERTK/TYRO3 heterocomplexes in meningioma and schwannoma tissue. We demonstrate the dependence of AXL and TYRO3 expression on MERTK in both tumour types, as well as interdependency of MERTK and AXL expression in meningioma. We show that MERTK and AXL contribute to increased proliferation and survival of meningioma and schwannoma cells, which we inhibited in vitro using the MERTK/FLT3 inhibitor UNC2025 and the AXL inhibitor BGB324. UNC2025 was effective in both tumour types with superior efficacy over BGB324. Finally, we found that TAMs are expressed by tumour-associated macrophages in meningioma and schwannoma tumours and that UNC2025 strongly depleted macrophages in both tumour types.

HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B

Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which—through largely unknown mechanisms—can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.Graphical

Mosaic SUFU mutation associated with a mild phenotype of multiple hereditary infundibulocystic basal cell carcinoma syndrome.

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants.

Germline mutation rate predicts cancer mortality across 37 vertebrate species

Abstract Cancer develops across nearly every species. However, cancer occurs at unexpected and widely different rates throughout the animal kingdom. The reason for this variation in cancer susceptibility remains an area of intense investigation. Cancer evolves in part through the accumulation of mutations and, therefore, we hypothesized that germline mutation rates would be associated with cancer prevalence and mortality across species. We collected previously published data on germline mutation rate and cancer mortality data for 37 vertebrate species. Germline mutation rate was positively correlated with cancer mortality (P-value = 0.0008; R² = 0.13). Controlling for species average parental age, maximum longevity, adult body mass, or domestication did not improve the model fit (ΔAIC < 2). However, this model fit was better than a model controlling for species trophic level (ΔAIC > 2). The increased death rate from cancer in animals with increased germline mutation rates may suggest underlying hereditary cancer predisposition syndromes similar to those diagnosed in human patients. Species with higher germline mutation rates may benefit from close monitoring for tumors due to increased genetic risk for cancer development. Early diagnoses of cancer in these species may increase their chances of overall survival, especially for threatened and endangered species.

Gender-specific differences in the development of colorectal cancer in Lynch syndrome patients-Asystematic review

Lynch syndrome (LS) is the most frequent hereditary tumor syndrome and is associated with an increased risk of colorectal cancer (CRC). While gene-specific and age-specific differences are considered in patient surveillance, gender-specific risks in the development of CRC have been reported in many studies but are not consistently documented. This systematic review aims to investigate gender-specific differences in CRC development among LS patients. Asystematic literature search following PRISMA 2020 guidelines was conducted in the PubMed, Ovid, The Cochrane Library and Web of Science databases. A total of 688 studies were screened, and 41met the inclusion criteria. Men have ahigher risk of CRC and develop CRC earlier compared to women. These findings indicate gender-specific differences in the risk of CRC among LS patients, although they do not currently justify separate surveillance strategies.

Comparing Clinicopathological and Immunohistochemical Features of Colorectal Carcinoma between Young and Old Age Groups.

The incidence of colorectal carcinoma (CRC) is increasing among individuals younger than 50, and some studies suggest the presence of differences in CRC among old and young individuals regarding clinical and histopathological features. The aim of this study was to compare clinicopathological features, mismatch repair protein status, and expression of certain immunohistochemical stains between young and old groups. The study included 180 cases and found significant histological and immunohistochemical differences between the two groups. CRC in the young tends to be more right-sided and has a higher percentage of dMMR proteins, but less expression of p53 mutations. These features are commoner in Lynch syndrome, and more investigations to study the relationship between young-onset CRC and hereditary syndromes are needed. Young-onset CRC also tends to show higher expression of tumor cell PD-L1, which is an expected finding, as dMMR cases are more likely to be immunogenic. Two other significant differences are the higher percentage of mucinous carcinoma and the higher tumor grade in young-onset CRC. These two features suggest a more advanced disease with possibly worse outcomes; however, there is no difference in disease stage between the two age groups.

In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes.

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes.

Generation of an induced pluripotent stem cell line from a Brugada syndrome patient carrying SCN5A/c.3118G>C mutation

Brugada syndrome (BrS) is a hereditary arrhythmia syndrome characterized by right bundle branch block on an electrocardiogram and persistent ST-segment elevation in the right precordial leads. In this study, we describe the establishment of an induced pluripotent stem cell (iPSC) line derived from a BrS patient carrying the novel heterogeneous missense mutation (c.3118G>C; p.G1040R) in the sodium channel protein type 5 subunit alpha (SCN5A) gene. Skin fibroblasts underwent reprogramming using a non-integrated Sendai viral method. Generated iPSC line exhibited embryonic stem cell-like morphology, maintained a normal karyotype, expressed pluripotency markers, and demonstrated the capacity to differentiate into three germ layers.

Anamnestic, clinical, laboratory and molecular genetic characteristics of patients with neonatal diabetes mellitus

BACKGROUND: Currently, there is an increase in the incidence of diabetes mellitus throughout the world, including the steadily increasing number of rare, genetically determined forms of diabetes. Of particular interest are monogenic forms, including neonatal diabetes mellitus, which is a rare heterogeneous disease that manifests, as a rule, in the first 6 months of a child’s life, characterized by a severe labile course and a high risk of complications. Neonatal diabetes mellitus is a rare heterogeneous disease that usually manifests itself in the first 6 months of a child’s life, characterized by a severe, labile course and a high risk of complications. Currently, more than 25 genes are known, mutations in which cause both permanent and transient neonatal diabetes mellitus, as well as syndromic variants of this disease, which are of particular interest due to their severity and polymorphic clinical picture. In this regard, timely verification of the diagnosis is of particular importance. AIM: The aim of this study is to increase the efficiency of diagnosis of neonatal diabetes mellitus based on the analysis of anamnestic, clinical, laboratory and molecular genetic characteristics of patients. MATERIALS AND METHODS: 14 patients with transient and permanent neonatal diabetes mellitus were examined. RESULTS: 11 (78.6%) patients had isolated neonatal diabetes, in three of them the disease was verified in the structure of hereditary syndromes (Wolcott–Rallison syndrome, IPEX syndrome and Donohue syndrome). According to molecular genetic analysis, 14 variants were found in the genes ABCC8, KCNJ11, GCK, GATA6, WFS1, CACNA1D, EIF2AK3, FOXP3, PAX4, INSR, IGF1R, three of which were not previously described in the literature. CONCLUSIONS: The clinical heterogeneity identified in patients is determined primarily by the diversity of verified variants in causative genes. New variants in the CACNA1D and IGF1R genes that may be associated with the development of NDM, remain poorly understood and require further research.

Multi-gene panel analysis in BRCA1/2-negative patients suspected of hereditary breast and ovarian cancer syndrome: Real-world data from a single institution.

Although BRCA1/2 is most frequently associated with hereditary breast and ovarian cancer (HBOC), many other related genes have been implicated. Therefore, we investigated the prevalence of non-BRCA1/2 genes associated with hereditary cancer predisposition in BRCA1/2-negative patients from the Department of Genetic Medicine and Services with breast and ovarian cancer using a multi-gene panel (MGP) analysis. We conducted a retrospective MGP analysis (National Cancer Center Onco-Panel for Familial Cancer; NOP_FC) in BRCA1/2-negative patients with breast, ovarian, and overlapping breast/ovarian cancers who visited our genetic counseling between April 2004 and October 2022. NOP_FC was performed in 128 of the 390 BRCA test-negative cases (117 breast cancer, 9 ovarian cancer, and 2 overlapping breast/ovarian cancer cases). Among the BRCA1/2-negative patients, nine (7.7%) with breast cancer and one (11%) with ovarian cancer had pathogenic variants (PVs) in non-BRCA1/2 genes associated with breast and ovarian cancers, respectively. Five patients had PVs in RAD51D, two in PALB2, one in BARD1, one in ATM, and one in RAD51C. Additional MGP testing of germline genes associated with hereditary cancer predisposition syndrome in BRCA1/2-negative breast and ovarian cancer patients revealed PVs in non-BRCA1/2 breast cancer- and ovarian cancer-related genes in 7.7% of breast cancer and 11% of ovarian cancer. Therefore, additional testing may provide useful information for subsequent risk-reducing surgery and surveillance in BRCA1/2-negative patients.

Evaluation and diagnostic approach in patient with Perrault Syndrome

HIGHLIGHTS 1. The rare hereditary condition Perrault Syndrome is characterized by sensorineural hearing loss (SNHL) and ovarian dysfunction2. Cyclic estrogens and progesterone may be given to adolescents with amenorrhea to induce withdrawal bleeding and mimic the menstrual cycle. ABSTRACT Objectives: A multidisciplinary team, which included a reproductive endocrinologist and an otolaryngologist, identified Perrault Syndrome in a patient with secondary amenorrhea and bilateral sensorineural hearing loss. Case Report: A 16-year-old female presented to the obstetrics and gynecology clinic at a type B hospital with primary amenorrhea for one year. Menarche occurred at age 13, followed by regular menstrual cycles for two years, after which menstruation gradually ceased. She denied dysmenorrhea, constipation, leukorrhea, genital pruritus, growth retardation, and weight loss. The patient expressed concern about potential future infertility. At age 9, she was diagnosed with a viral infection by an ENT specialist due to bilateral hearing loss, leading to emotional disturbances. There was no history of prior medication, family illness, or chronic infections. Born at term via spontaneous vaginal delivery, the patient weighed 3,000 grams. Laboratory tests revealed normal T3 (1.51 ng/dl), FT4 (1.16 ng/dl), prolactin (18.25 ng/ml), estrogen (11 pg/ml), and progesterone (0.1 pg/ml) levels, but elevated FSH (66.46 mIU/ml) and LH (29.97 mIU/ml) levels. Symptomatic treatment included bone conduction hearing aids and estrogen replacement therapy. Conclusion: Perrault Syndrome, a rare hereditary condition, manifests as sensorineural hearing loss (SNHL) and ovarian dysfunction, including primary ovarian insufficiency (POI) and gonadal dysgenesis, in individuals with a 46, XX karyotype. Molecular diagnosis remains challenging. Consultation with a pediatric endocrinologist can guide cyclic estrogen and progesterone therapy to induce withdrawal bleeding in adolescents with amenorrhea. Women at risk of ovarian failure should consider donor eggs or oocyte cryopreservation. Avoiding aminoglycosides and excessive noise is crucial for managing hearing loss.