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Identification of a Novel RPS6KA3 Variant in a Female Child with Features of Coffin-Lowry Syndrome: A Case Study

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Coffin-Lowry Syndrome (CLS) is a rare X-linked disorder characterized by developmental delay, intellectual disability, short stature, kyphoscoliosis, pectus deformity, seizures, and progressive spasticity.  Affected individuals often present with widely spaced eyes, hearing and vision loss, sleep apnea, and distally tapered fingers. Males typically exhibit severe symptoms, while females have milder forms. Diagnosis is confirmed through molecular genetic testing for pathogenic variants in RPS6KA3. CLS is often sporadic, with de novo variants seen in 70-80% of cases.

Case Presentation
A 9-year-old female was referred to genetics for obesity, developmental, and learning delays. She also has gross motor delays with spasticity in her hips and problems with depth perception. At school, she has an IEP with support in math, reading, speech, and occupational and physical therapy. She previously saw endocrinology for premature pubarche starting at 5.5 years old with breast and pubic hair development. Her weight was at the 99th percentile, height at the 97th percentile, and BMI at the 99th percentile.  On exam, she has typical facial features of CLS with hypertelorism, broad columella, thick vermillion of the lips, and tapered fleshy fingers. She has Tanner stage 5 pubic hair, Tanner 2-3 breast development, but has not started her period. Of note, patient data was collected through a retrospective chart review. Parental consent was obtained, and all patient data was de-identified to maintain confidentiality.

Diagnostic Workup
Initial workup revealed normal labs including thyroid hormones, gonadotropins, androgen levels, and bone age. Her A1C was elevated (6%). Leptin was mildly increased as expected in obesity, but not suggestive of leptin resistance. An obesity panel ordered after grossly negative workup revealed a likely pathogenic frameshift variant leading to premature protein termination in RPS6KA3 (c.718_721del, p.Val240Ilefs*17) consistent with CLS.

Treatment and Management
She is followed by multiple specialists in addition to genetics, including endocrinology, neurology, and ophthalmology, for ongoing symptom management. She had a normal echocardiogram, renal ultrasound, and pelvic ultrasound.

Outcome and Follow-Up
The patient is currently well-managed without any medications, and her obesity is being addressed through lifestyle changes with improvement in A1C (5.6%). She may have had a stimulus-induced drop attack once, but this is unconfirmed. She continues to struggle with depth perception. She denies seizures, kyphoscoliosis, or hearing loss; however, there is a low threshold for spine imaging. Audiology and sleep clinic referrals were offered given her diagnosis of CLS, but she remains asymptomatic in these regards.

Discussion
To date, more than 200 patients with CLS have been reported, but there has only been one case report of a female with central precocious puberty and advanced bone age. Our patient is the second case of CLS with precocious puberty.  CLS has generally been associated with delayed puberty, delayed bone age, and short stature. It is also associated with increased risk for obesity, especially in females due to a combination of short stature, hypotonia, and low activity level. However, our patient was at the 97th percentile for height. Obesity is a well-known cause of precocious puberty. At this time it is unclear if there is a direct or indirect effect that CLS may have on precocious puberty.

Conclusion
Precocious puberty is a relatively new finding associated with CLS, and with limited evidence in the literature to suggest a causative link between CLS and precocious puberty, it is important to highlight the potential association. Raising awareness of this possible link may encourage further investigation and ultimately expand our understanding of the condition. Given the unique presentation of our patient from previously documented cases of CLS, there is a lot to be learned about the possible association between CLS and precocious puberty through continued follow up.

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