4H leukodystrophy is one of five overlapping leukodystrophies that have been associated with mutations in the
Previous discussion of the endocrine aspects of 4H leukodystrophy has been limited, and induction of ovulation in patients with 4H leukodystrophy has not been described yet. Here, we report on a female patient who presented for endocrine evaluation with primary amenorrhea and was found to have 4H leukodystrophy. We review the clinical, biochemical, and genetic features of 4H leukodystrophy. In addition, we discuss management of the endocrine manifestations of 4H leukodystrophy, in light of our experience with ovulation induction in this patient.
A 19-year-old female presented to our clinic with primary amenorrhea. Thelarche and pubarche had occurred at the age of 13. She denied any symptoms suggestive of primary ovarian insufficiency, polycystic ovarian syndrome, pituitary pathology, or functional hypothalamic disease. Her history was significant for mild dysarthria since childhood. She had been diagnosed with congenital absence of the lower second bicuspids, and dental X-rays (see Figure
Dental X-rays performed at the age of 6 (a) and the age of 19 (b). The lower second bicuspids are absent. There are two supernumerary teeth underneath her secondary lower incisors, which may represent ectopic, malformed bicuspids.
On examination, her height was 154.3 cm (10th percentile) and her BMI was 27.0 kg/m2. She had no dysmorphic features. She had Tanner stage 5 breast and pubic hair development and no features of pituitary hormone deficiency. Neurological examination revealed gaze-evoked nystagmus, a mildly ataxic gait, and mild spasticity of the upper limbs. She had no dysmetria or dysarthria. She did not have a tremor.
Laboratory investigations included LH < 1 (reference range (RR) 1–13 IU/L), FSH 5 (RR 2–10 IU/L), estradiol 62 (prepubertal range: 0–130 pmol/L), prolactin 25 (0–25
MRI of the brain performed at the age of 28, demonstrating evidence of a hypomyelinating leukodystrophy. Compared to grey matter structures, there is diffuse hyperintensity of the white matter on T2 weighted images (a, b, c), with hyperintense signal on T1 weighted images (d), consistent with hypomyelination. As previously reported, there is characteristic relative preservation of myelination within the following structures: optic radiations (long thin white arrow; a, b), anterolateral nucleus of the thalamus (thick white arrow; a, b), globus pallidus (short thin white arrow; a, b), posterior corpus callosum (white arrow head; b), corticospinal tracts (white arrow; c), and the dentate nucleus (white arrow; e). Sagittal T1 weighted imaging (f) demonstrates thinning of the corpus callosum and mild cerebellar atrophy.
At the age of 24, the patient desired pregnancy and so the oral contraceptive pill was discontinued. Trials of both subcutaneous and intravenous pulsatile GnRH therapies failed to show biochemical evidence of follicular development, with a peak estradiol level of 56 pmol/L. She went on to achieve normal follicular development in response to gonadotropin therapy, with a peak estradiol level of 1581 pmol/L and development of a dominant follicle measuring 1.86 cm. She did not conceive. She decided not to undergo further ovulation induction therapy, and so hormone replacement therapy was reinitiated at physiologic doses.
The patient was reassessed at the age of 27. At that time, she had no clinical evidence of progressive neurological dysfunction or pituitary hormone deficiency. A morning cortisol level was 860 mmol/L, free T4 was 14.3 pmol/L, and serum IGF-1 level was 207 (117–329
Our case demonstrates that patients with 4H leukodystrophy may present for endocrine evaluation due to hypogonadotropic hypogonadism before the diagnosis of Pol III-related leukodystrophy is made. Recognizing the syndrome and making the diagnosis of 4H leukodystrophy are crucial, as they have important genetic, neurological, and reproductive implications. Here, we review the salient features of 4H leukodystrophy with a focus on the endocrine aspects.
4H leukodystrophy is a genetic disorder that displays an autosomal recessive inheritance pattern [
In addition to a mutation in exon 15 of the
The presentation of 4H leukodystrophy is variable, but most patients present in early childhood with motor delay or regression and are often subsequently found to have dental manifestations [
Cerebellar dysfunction is the most frequent neurological abnormality [
Patients with 4H leukodystrophy have delayed puberty, low baseline LH and FSH levels, and no response to pituitary stimulation with GnRH [
Our patient’s presentation is unusual in comparison to reports of other patients with 4H leukodystrophy. Her dental and neurological manifestations were exceptionally subtle and did not lead to diagnosis prior to puberty. She does not have evidence of significant cognitive dysfunction and has not exhibited neurological deterioration during eight years of follow-up. In addition, although she failed to go through menarche, she did have spontaneous thelarche at the age of 13. This indicates that she was estrogenized at that time, strongly suggesting that her gonadotropin insufficiency developed after the age of 13. The relatively mild clinical course of our patient may be explained in part by her intronic variant, which may produce some normal
Diagnosis is made based on a combination of clinical features and characteristic findings on dental X-rays and on magnetic resonance imaging (MRI) of the brain [
We have demonstrated that neurological and dental manifestations may be minimal, and patients with 4H leukodystrophy may present for endocrine evaluation due to hypogonadotropic hypogonadism without a prior diagnosis. By looking for clinical manifestations of hypomyelination and hypodontia in patients who present with hypogonadal hypogonadism without a clear etiology, endocrinologists may be able to facilitate a diagnosis of 4H leukodystrophy. Making this diagnosis has important implications in terms of prognosis, genetic counseling, and management from an endocrine, dental, neurological, and ophthalmological perspective.
Given the broad clinical manifestations of 4H leukodystrophy, most patients will require coordinated care from several subspecialists, including a dentist, neurologist, clinical geneticist, and endocrinologist. The endocrine aspects of management for this disorder include surveillance for progressive endocrine dysfunction, consideration and initiation of hormone replacement therapy, and induction of ovulation or spermatogenesis if the patient desires fertility. Given the rarity of this disorder, the optimal method of surveillance for progressive endocrine dysfunction is unclear. Screening for clinical evidence of ACTH, GH, and TSH deficiency at least every few years may be prudent, as may undertaking biochemical evaluation of pituitary hormone function when suggestive clinical features are present. In terms of correcting reproductive hormone deficiencies, we suggest that the same principles of hormone replacement therapy used in patients with other forms of hypogonadotropic hypogonadism can be applied to patients with 4H leukodystrophy. Orcesi et al. describe a 12-year-old boy with 4H leukodystrophy who did not respond to a GnRH stimulation test. They then treated him with chorionic gonadotropin and noted that his height velocity increased substantially and his testosterone levels normalized [
Fertility treatment in patients with 4H leukodystrophy brings up some considerations that are unique to this disorder, but there is little evidence to guide management. At the time that ovulation induction therapy was initially offered to our patient, neither the inheritance pattern nor the neurological implications of 4H leukodystrophy were well understood. Therefore, she did not receive genetic counseling nor was her partner offered carrier testing. However, with the current state of knowledge of this disorder, we recommend that genetic counseling be offered. Patients should be aware of the propensity for neurologic deterioration in 4H leukodystrophy and the autosomal recessive inheritance pattern. Given the rarity of this disorder, carrier testing in partners has not been described but could be considered as sequencing for the causative mutations becomes more readily available.
In terms of choice of therapy, our patient underwent ovulation induction therapy with both pulsatile GnRH and gonadotropin therapy. She did not exhibit a rise in serum estradiol levels or evidence of follicular development on transvaginal ultrasound while receiving a total of three cycles of pulsatile GnRH therapy, a therapy to which more than 90% of women with hypothalamic amenorrhea will respond [
4H leukodystrophy should be considered in the differential diagnosis of patients who present with hypogonadotropic hypogonadism and no overt cause, particularly if dental or neurological abnormalities are present. Endocrine dysfunction in these patients includes hypogonadotropic hypogonadism and GH deficiency and may be progressive, requiring ongoing surveillance. Progressive neurological deterioration is also a hallmark. The defect causing hypogonadism in 4H leukodystrophy appears to be at the hypophyseal level and precludes the use of pulsatile GnRH for ovulation induction, whereas subcutaneous gonadotropin therapy appears to be effective. Reports of 4H leukodystrophy are rare, and the diagnosis may be missed if clinical manifestations are subtle. However, making the diagnosis is critical for ensuring that appropriate counseling, therapy, and surveillance are initiated.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank the patient and her family, without whom this study would not have been possible. Dr. Bernard has received a Research Scholar Junior 1 of the Fonds de Recherche du Québec en Santé (FRQS). She wishes to thank the Montreal Children’s Hospital and McGill University Health Center Research Institutes, the Fondation sur les Leucodystrophies, the Fondation du Grand Defi Pierre Lavoie, and the Canadian Institutes of Health Research (CIHR, Grant no. MOP-G-287547). The authors would also like to thank the Genome Quebec Innovation Center and McGill University for their services. Dr. Gibson is supported by CIHR Grant no. MOP-119595 and by a CFRI Clinician-Scientist Salary Award.