A 38-year-old woman with intellectual disability (ID), primary amenorrhoea and focal seizures (Fig.1A) described two years of progressive balance difficulties. On examination she had short stature (1.45m), cerebellar ataxia and a visual acuity of 6/60. T2 weighted MR Imaging showed severe cerebellar atrophy, an atrophic corpus callosum and patchy signal change in the corona radiata suggestive of hypomyelination (Fig.1B).
Figure 1. Clinical Features of the 4H syndrome.
A. Electroencephalogram (EEG) showing spike activity centred on the fronto-central region.
B. T2 weighted MRI demonstrating hyperintensity in the corona radiate bilaterally (arrows) suggestive of hypomyelination.
C. Dental radiograph demonstrating hypodontia with the absence of one pre-molar and two lateral incisors.
Given the clinical features, a diagnosis of ‘4H syndrome’ (hypomyelination, hypodontia and hypogonadotrophic hypogonadism) was considered. Genetic sequencing of POLR3B identified compound heterozygous mutations, which segregated with parents. Detailed endocrine assessment confirmed hypogonadotropic hypogonadism (LH/FSH ratio (<0.5 u/L) and low estradiol (<60 pmol/L)), but not growth hormone deficiency (IGF1 = 13nmol/L (NR 6-29)). Contact with the patient’s dentist established the presence of hypodontia (Fig.1C).
4H leukodystrophy typically presents with ID or developmental delay and is associated with motor deterioration, often due to ataxia,1, 2 due to recessive mutations in either POLR3A or POLR3B which code for subunits of RNA polymerase III. Whilst hypomyelination is present in 95% of patients, the extra-neurological features, such as hypodontia and hypogonadism, may be absent and are not essential for diagnosis.1, 2 Seizures occur in a significant minority (19%),1 whilst other features including myopia,1 short stature1 and growth hormone deficiency 3 are also recognised.
A molecular diagnosis led to hormone replacement therapy and vitamin D supplementation to maintain bone mineral density. A definitive diagnosis has obviated the need for ongoing investigation and provided important prognostic information for her family, thereby facilitating appropriate long term care planning.
Acknowledgements
Wellcome Trust (101876/Z/13/Z) (096919Z/11/Z), & Medical Research Council (MC_UP_1501/2).
Footnotes
Conflict of Interest Disclosures
AJCH - none
HES - none
AP - none
YH - none
RQ - none
PFC - none
References
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