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A case of bilateral congenital hypoplastic testes leading to an unexpected diagnosis of X-linked trichothiodystrophy

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Bilateral congenital hypoplasia of the testes is not frequently encountered in the clinical setting. This case is significant due to the rarity of RNF113A-related trichothiodystrophy, with limited documented cases and no established treatments. It highlights the utility of trio-based exome sequencing in diagnosing patients with complex phenotypes.

Case Presentation
An 18-year-old male was evaluated in general genetics clinic for history of congenital hypoplastic testes, epilepsy, and absent permanent teeth. The patient was a relatively new arrival to the United States and was referred to medical genetics by his primary physician. Patient was noted at birth to have diminutive, undescended testes. He underwent bilateral orchipexies at age 1 year, prior to bilateral orchiectomies for suspected bilateral atrophy. Seizures began at age 3 years and were initially treated with phenytoin, which was discontinued due to an allergic reaction. Treatment was then transitioned to valproic acid, which successfully controlled the seizures. Attempts to wean valproic acid at age 11 led to a recurrence of seizures, but they have not returned since then. After primary dental exfoliation, permanent teeth have never erupted. During the evaluation, the patient's mother endorsed a lifelong history of developmental issues. The patient exhibited developmental delays, including walking at 4 years and speaking at 3 years, with current academic performance at least three years behind. The mother reported that she cannot trust the patient to handle money or make purchases. She worries about others easily taking advantage of him. A normal male karyotype had been previously been obtained. Physical examination revealed head circumference at the 71st centile, no major facial dysmorphisms apart from asymmetrically sized ears, poor dentition, bilateral fifth digit clinodactyly, an empty scrotum, otherwise normal Tanner 5 genitalia, and 3 café-au-lait macules. Skin and hair showed no obvious major abnormalities.

 

Diagnostic Workup
Given the major congenital anomaly of the genitalia, patient underwent renal/bladder ultrasound, which was normal. Additionally, patient had fragile X assay, SNP chromosomal microarray, and trio exome sequencing including samples from both parents. Fragile X assay showed a hemizygous FMR1 alelle with a normal number of CGG repeats. Microarray was consistent with a typical male and no copy number variants were reported. Exome sequencing identified a de novo pathogenic variant in the gene RNF113A, with nomenclature c.890dup:p.(Tyr297Ter) in exon 1.



Polarizing light microscopy was undertaken to look for classic "tiger tail" pattern of hair shafts. 

Treatment and Management
Care involved a multidisciplinary approach, addressing intellectual disability, genital anomalies, and dental issues through tailored interventions. Genetic counseling was provided to the family to explain the condition and its inheritance. While no specific experimental treatments for RNF113A-related disorders are currently established, participation in clinical trials could become a possibility in the future.  Patient was referred to urologist for potential testicular implant placement and dentist for hypodontia. Additionally, patient is now in queue for neuropsychological testing given suspicion for intellectual disability. 

Outcome and Follow-Up
The patient continues on a stable course, though challenges with intellectual and physical limitations have persisted.

Discussion
The identification of a de novo pathogenic variant in RNF113A aligns with literature linking pathogenic variants in this gene to intellectual disability, genital anomalies, and dental abnormalities. This case underscores the critical role of trio exome sequencing in diagnosing rare genetic disorders. Similar cases in the published literature highlight phenotypic variability, emphasizing the need for personalized management. Understanding genotype-phenotype correlations can enhance prognostic accuracy and guide tailored interventions, contributing to improved patient care and expanding genetic knowledge.

Conclusion
This case reveals the importance of precise genetic diagnosis through trio exome sequencing in uncovering rare diagnoses like RNF113A-related trichothiodystrophy. Future research should explore genotype-phenotype correlations and the molecular mechanisms of RNF113A, aiming to develop targeted therapies and improve outcomes for affected individuals.

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