Background/objective: 4H syndrome is a rare form of leukodystrophy characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. In 95% of cases, hypomyelination is present, but other clinical features, such as hypodontia and hypogonadotropic hypogonadism, are not always present and may not be necessary for diagnosis. Hypogonadotropic hypogonadism is the most common endocrine complication that can occur in 4H syndrome. Other endocrine abnormalities are short stature and growth hormone deficiency.
Case report: We present a 19-year-old female with 4H syndrome due to POLR3B gene mutations who presented with primary amenorrhea. She was referred to our endocrinology clinic by her primary care physician. She was diagnosed with 4H syndrome at age 15 by her pediatrician when she initially presented with primary amenorrhea, ataxia, and tremors and underwent karyotyping and confirmatory genetic tests. However, she received no endocrine care before coming to our clinic at 19. Neurologic exam revealed slight tremors in outstretched hands. A brain MRI study revealed no intracranial abnormalities. We subsequently placed her on Loestrin birth control, an estrogen/progestin combination contraceptive, and she begun having her menstrual periods.
Discussion: The prevalence of POLR3-related leukodystrophy is currently unknown. It can appear during childhood or later in life. Early onset increases the risk of mortality in young adulthood. Endocrine care entails hormone replacement therapy and monitoring for dysfunction over time.
Conclusion: Early diagnosis of hypogonadotropic hypogonadism in women, with or without other hormonal deficiencies caused by 4H syndrome, is crucial for effective treatment. Treatment should be multidisciplinary and aimed mainly at correcting low estrogen levels.
Keywords: 4H Leukodystrophy; POLR3-Related Leukodystrophy; POLR3B gene mutation.
© 2024 AACE. Published by Elsevier Inc.