We describe a patient with Gordon Holmes syndrome presenting with a combination of hypogonadotropic hypogonadism, ataxia and progressive cognitive decline, with distinct MRI brain findings. Recent genetic advances allowed the identification of the genetic defects responsible for this rather unusual combination of endocrine and neurological involvement.
- gordon holmes syndrome
- cerebellar ataxia
- hypogonadotropic hypogonadism
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Gordon Holmes (1876–1965) was a British neurologist renown for his groundbreaking research into the cerebellum and the visual cortex. He was appointed as a consultant neurologist to the British Expeditionary Forces during World War I. He had the opportunity to observe the effects of brain lesions on balance, vision and bladder function while working in the field hospital. His experience from such lesions from gunshot wounds strengthened his interest in cerebellar diseases.
He first described the syndrome bearing his name in 1908, an autosomal recessive adult-onset neurodegenerative disease with characteristic clinical features of progressive cognitive decline and variable movement disorders such as ataxia and chorea. This neurological presentation was also linked to hypogonadotropic hypogonadism.
He reported on three brothers and one sister (from a family of eight) who, in their mid-30s, developed symptoms and signs of cerebellar disease with clinical features of sex steroid deficiency. The first symptom was staggering gait, followed by incoordination of upper limbs, and dysarthric speech that later became explosive. These patients later developed tremor and choreiform movements of head and limbs. The tendon reflexes were normal or brisk but without evidence of ankle clonus to suggest involvement of the corticospinal tract. There was no involvement of hearing, vision, sensory modalities or sphincters. The three brothers had small genitalia and scanty facial and body hair, suggesting sex steroid hormone deficiency. All four patients progressively worsened, became bedbound and died.
Based on these observations, he concluded that the clinical features of ataxic gait, dysarthric speech, nystagmus, and prominent tremors of limbs and head—without involvement of hearing, vision, sensation, sphincters and strength—clearly suggested a primarily cerebellar degeneration of familial nature. Additionally, the small genitalia, testes and scanty body and facial hair on the three male patients pointed towards an endocrine component to this syndrome.1
With the availability of endocrine assays, both hypergonadotropic and hypogonadotropic forms of this syndrome have been reported, but most of the patients that Gordon Holmes described were hypogonadotropic, with involvement of the pituitary gland.2 3
A 22-year-old man presented with an 8-month history of difficulty playing football because of poor balance. His mother also noted slurring of speech. Examination at the time showed gaze-evoked nystagmus, limb and gait ataxia, as well as slurred speech. His balance deteriorated rapidly over the next 3 years, resulting in wheelchair dependency. He also developed prominent chorea that proved difficult to control.
Cognitive assessments when aged 25 years showed a neuropsychological profile reflecting global involvement in all aspects of higher mental function. A repeat assessment a year later found significant deterioration with decline in non-verbal performance skills, poor registration and learning of both verbal and visual information; there were significant deficits in motor speed and rate of cognitive processing, as well as reduced initiation speed and response fluency. He had impaired motor executive skills with reduced control of responses and signs of mild motor perseveration. The findings suggested the type of cognitive decline associated with subcortical-type dementia syndromes.
He gradually required more care and became bedbound and doubly incontinent 9 years from onset of symptoms. His chorea and ataxia made it impossible to be able to feed himself, or even to be fed, and he required gastrostomy feeding. He died 13 years after onset of symptoms at the age of 35 years.
His history included cleft palate and orchidopexy at the age of 6 years. He had also been diagnosed with hypogonadotropic hypogonadism at the age of 19 years, which had responded well to human chorionic gonadotropin injections. His initial serum testosterone concentration was 0.9 nmol/L (normal 9.4–37), which increased to 33.7 nmol/L after starting human chorionic gonadotropin injections (3000 units twice weekly).
He had worked as an apprentice butcher for 3 years and then as labourer before having to stop due to his disease. His mother had cleft palate. His father had insulin-dependent diabetes mellitus, and his only sister had hypothyroidism. There was no family history of neurological disease.
He had undergone extensive investigations into the causes of progressive ataxia, including limited genetic tests available at the time; all these investigations were normal.
MR scan of brain at presentation showed high signal intensity within the white matter of both cerebral hemispheres with grey matter lesions in the thalami (figure 1, MRI done 10 years after presentation), as well as demonstrating cerebellar atrophy and high T2 signal in the midbrain (figure 2).
The diagnosis of Gordon Holmes syndrome was suspected due to the rare combination of ataxia and hypogonadotropic hypogonadism. We contacted a research group at Massachusetts General Hospital, USA, who were interested in the genetic characterisation of this condition. They were performing whole-exome sequencing in patients with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes. They were therefore interested in well-characterised neurological and endocrine phenotypes of which this patient was a good example. The family agreed to his inclusion in this genetic research, and 4 years after his death we obtained positive genetic results.
He was found to be compound heterozygous for the following RNF216 mutations: RNF216 c.615_616delG p.E205fsX15, RNF216 c. 1791T>A p.C597X.
The syndrome of hypogonadotropic hypogonadism, ataxia and dementia is caused either by two inactivating mutations in RNF216 or by a combination of mutations in RNF216 and OTUD4 (ie, digenic). These findings link disordered ubiquitin to neurodegeneration and reproductive dysfunction. Abnormalities to this important cellular process can have pathological effects on the various regions of the central nervous system, including cerebral white matter, hippocampus, cerebellum, and pituitary and the hypothalamic parts of the reproductive endocrine system.2 Most patients with this syndrome have impaired pituitary gland release of gonadotropins.2 3
This case represents the classic phenotype of Gordon Holmes syndrome as described in the original 1908 publication. It was almost a century later that advances in genetic characterisation (next-generation sequencing) finally enabled the genetic characterisation of the phenotype. This was one of a series of patients reported by the Harvard group who first identified this genetic link.2 While there are other genetic ataxias associated with hypogonadism (eg, mutations in STUB14), this combination of clinical features that includes rapidly progressive ataxia in the context of hypogonadotropic hypogonadism with striking brain imaging findings should raise the possibility of Gordon Holmes syndrome. This was the only case of Gordon Holmes syndrome among a 1500 cases of progressive ataxia evaluated at the Sheffield Ataxia Centre over the last 20 years.5
Gordon Holmes syndrome, while rare, should be considered in any patient with hypogonadotropic hypogonadism and ataxia.
Cognitive decline is a very prominent feature.
Genetic testing is now available and should be an early consideration when encountering such phenotype.
MR imaging shows very characteristic changes that are not seen in other progressive ataxias.
The authors would like to thank the patient’s family.
Contributors SM produced the first draft of the paper. NH selected the figures and produced the figure legends. MH looked after the patient and identified the genetics lab for screening. All three authors revised the manuscript and read and approved the final version.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed. Reviewed by Simon Hammans, Southampton, UK, and Rajith de Silva, London, UK.
Correction notice This article has been corrected since it was published Online First. ’Dr' has been changed to ’Professor' in the Correspondence section for author ’M Hadjivassiliou'.
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