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Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature.

Billington E, Bernard G, Gibson W, Corenblum B - Case Rep Endocrinol (2015)

Bottom Line: She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III.Discussion.In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology & Metabolism, University of Calgary, 1820 Richmond Road SW, Calgary, AB, Canada T2T 5C7 ; Bone & Joint Research Group, Department of Medicine, University of Auckland, Private Bag Box 92019, Auckland 1020, New Zealand.

ABSTRACT
Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this disease's autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

No MeSH data available.


Related in: MedlinePlus

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.
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fig2: 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.

Mentions: 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 μg/L), and free T4 14.9 (8.0–22.0 pmol/L). Her karyotype was 46, XX. She did not menstruate after a progesterone challenge but did when given the oral contraceptive pill, indicating that she was hypoestrogenized and that she did not have an outflow abnormality. She had no further breast growth while being on the oral contraceptive pill. Pelvic ultrasound showed a small uterus, measuring 4.5 × 3.0 × 1.4 cm, normal endometrium, and small ovaries, measuring 1.5 × 0.9 × 1.1 cm (0.78 cm3) on the left and 1.7 × 2.4 × 1.2 cm (2.56 cm3) on the right (average normal volume 6-7 cm3) [14]. MRI of the sella revealed mildly decreased pituitary bulk. A full MRI of the brain was not obtained at the time of initial evaluation, but a subsequent MRI (see Figure 2) revealed diffuse hypomyelination (i.e., hyperintense white matter on T2 weighted images compared to grey matter structures) [15, 16] as well as a slightly thin corpus callosum and mild atrophy of the cerebellum, predominantly seen at the vermis. 4H leukodystrophy was suspected based on the patient's clinical and radiological features. Subsequent DNA sequencing revealed that she is a compound heterozygote for POLR3B mutations, specifically c.1568T>A (amino acid change p.V523E) and the rare intronic variant c.2817+30T>A [5].


Endocrine Aspects of 4H Leukodystrophy: A Case Report and Review of the Literature.

Billington E, Bernard G, Gibson W, Corenblum B - Case Rep Endocrinol (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4465690&req=5

fig2: 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.
Mentions: 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 μg/L), and free T4 14.9 (8.0–22.0 pmol/L). Her karyotype was 46, XX. She did not menstruate after a progesterone challenge but did when given the oral contraceptive pill, indicating that she was hypoestrogenized and that she did not have an outflow abnormality. She had no further breast growth while being on the oral contraceptive pill. Pelvic ultrasound showed a small uterus, measuring 4.5 × 3.0 × 1.4 cm, normal endometrium, and small ovaries, measuring 1.5 × 0.9 × 1.1 cm (0.78 cm3) on the left and 1.7 × 2.4 × 1.2 cm (2.56 cm3) on the right (average normal volume 6-7 cm3) [14]. MRI of the sella revealed mildly decreased pituitary bulk. A full MRI of the brain was not obtained at the time of initial evaluation, but a subsequent MRI (see Figure 2) revealed diffuse hypomyelination (i.e., hyperintense white matter on T2 weighted images compared to grey matter structures) [15, 16] as well as a slightly thin corpus callosum and mild atrophy of the cerebellum, predominantly seen at the vermis. 4H leukodystrophy was suspected based on the patient's clinical and radiological features. Subsequent DNA sequencing revealed that she is a compound heterozygote for POLR3B mutations, specifically c.1568T>A (amino acid change p.V523E) and the rare intronic variant c.2817+30T>A [5].

Bottom Line: She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III.Discussion.In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

View Article: PubMed Central - PubMed

Affiliation: Division of Endocrinology & Metabolism, University of Calgary, 1820 Richmond Road SW, Calgary, AB, Canada T2T 5C7 ; Bone & Joint Research Group, Department of Medicine, University of Auckland, Private Bag Box 92019, Auckland 1020, New Zealand.

ABSTRACT
Introduction. 4H leukodystrophy is an autosomal recessive RNA polymerase III-related leukodystrophy, characterized by hypomyelination, with or without hypodontia (or other dental abnormalities) and hypogonadotropic hypogonadism. Case Presentation. We describe a 28-year-old female who presented with primary amenorrhea at the age of 19. She had a history of very mild neurological and dental abnormalities. She was found to have hypogonadotropic hypogonadism, and magnetic resonance imaging of the brain showed hypomyelination. The diagnosis of 4H leukodystrophy was made. She was subsequently found to have mutations in the POLR3B gene, which encodes the second largest subunit of RNA polymerase III. She wished to become pregnant and failed to respond to pulsatile GnRH but achieved normal follicular growth and ovulation with subcutaneous gonadotropin therapy. Discussion. Patients with 4H leukodystrophy may initially present with hypogonadotropic hypogonadism, particularly if neurological and dental manifestations are subtle. Making the diagnosis has important implications for prognosis and management. Progressive neurologic deterioration is expected, and progressive endocrine dysfunction may occur. Patients with 4H leukodystrophy should be counseled about disease progression and about this disease's autosomal recessive inheritance pattern. In those who wish to conceive, ovulation induction may be achieved with subcutaneous gonadotropin therapy, but pulsatile GnRH does not appear to be effective.

No MeSH data available.


Related in: MedlinePlus