Hypergonadotrophic hypogonadism and cerebellar ataxia in an Indian adolescent: A rare report.

Dear Sir,

The association between hypogonadism and cerebellar ataxia was first recognized and described as a distinct, rare, autosomal recessive syndrome by Gordon Holmes in 1907.[1] Gordon Holmes syndrome is a highly heterogenous syndrome with insidious onset. In most patients with Gordon Holmes syndrome, hypogonadism is hypogonadotropic, with a defect in the production or release of gonadotropins by pituitary gland.[2] In some patients, hypogonadism is hypergonadotropic, with a failure at the level of the gonads rather than at the level of the pituitary. Here, we report a 17-year-old girl who came with primary amenorrhea and gait ataxia and was found to have hypergonadotrophic hypogonadism with early-onset cerebellar atrophy which is a rare association.

A 17-year-old girl, born out of nonconsanguineous parentage, with normal perinatal and childhood period, came to us with the history of progressive gait unsteadiness of 3 years duration. There was no nocturnal worsening in gait unsteadiness. She did not have articulation difficulty or incoordination of upper limbs. No family history of ataxia. There were no complaints of night blindness, decreased vision or hearing. She had average scholastic performance. She had primary amenorrhea. Her height and weight was normal. On neurological examination, fundus was normal. She had fine gaze evoked horizontal jerky nystagmus in both eyes. Speech was normal. Cranial nerves were normal. Motor examination showed normotonia, normal power with elicitable deep tendon reflexes in all limbs. Sensory examination was normal. She had mild incoordination of both upper limbs but broad based ataxic gait with impaired tandem gait. Magnetic resonance imaging brain showed pan cerebellar atrophy with no brainstem involvement with periventricular hyperintensities on fluid-attenuated inversion recovery sequence [Figure 1]. Complete hemogram, renal, hepatic and thyroid function tests were normal. Serum Vitamin E, B 12 and folate levels were normal. Plasma lactate and serum creatinine phosphokinase levels were normal. Pure tone audiogram showed normal hearing. Echocardiogram and electrocardiogram were normal. Multimodal evoked potential studies and nerve conduction studies were normal. Karyotype was 46, XX. Endocrinological assessment showed raised serum levels of follicle stimulating hormone: 30.9 (1.4–18.1 mIU/ml), luteinizing hormone: 15.6 (1.5–9.3 mIU/ml) and low estradiol: 10 (20–240 pg/ml); indicating a hypergonadotrophic type of hypogonadism. On ultrasonography of pelvis, the uterus and the ovaries were reduced in size.

Figure 1

Magnetic resonance imaging brain fluid-attenuated inversion recovery images shows (a), (b and d) periventricular hyperintensities (red arrow), (c) cerebellar atrophy (red arrow), (e) T1 sagittal image shows cerebellar atrophy (red arrow)

This case illustrates a syndrome characterized by early onset of cerebellar ataxia, primary amenorrhea, and hypergonadotropic hypogonadism. Gordon Holmes syndrome is associated with ataxia and hypogonadism. Both hyper and hypogonadotropic forms were reported. There is also little understanding of the pathophysiology mechanism of this association. The association of spinocerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy as an autonomous single-gene disorder was described by Boucher and Gibberd in 1969 and Neuhausser and Opitz in 1975 and is designated as Boucher–Neuhauser syndrome.[3] The association of hypergonadotropic hypogonadism in females and sensorineural hearing loss in females and males was first described in 1951 as Perrault syndrome. This is a genetic syndrome inherited in an autosomal recessive manner. Affected females have streak gonads in place of their ovaries with primary amenorrhea. Some patients also have neurological manifestations in the form of mental subnormality and cerebellar involvement. Amor et al. reviewed patients with the rare association of ataxia and hypergonadotropic hypogonadism (AAH) and documented only 15 cases.[4] The onset of ataxia in patients of the above series ranged from 2 to 30 years. Ten patients had primary amenorrhea. We ruled out the ataxia with vitamin E deficiency which is commoner and treatable cause of early onset of cerebellar ataxia with cerebellar atrophy. Our patient may represent a variant of Holmes type ataxia and belongs to a group of AAH. This entity has been rarely reported from Indian subcontinent.

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