Triple H Syndrome: A Novel Autoimmune Endocrinopathy Characterized by Dysfunction of the Hippocampus, Hair Follicle, and Hypothalamic-Pituitary-Adrenal Axis

I. Sadaf Farooqi1, M. Keston Jones, Marc Evans, Stephen O’Rahilly2 and John R. Hodges

University Departments of Medicine and Clinical Biochemistry (I.S.F., S.O.R.) and Neurology (J.R.H.), and Medical Research Council Cognition and Brain Sciences Unit (J.R.H.), Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom; and Department of Medicine, Singleton Hospital (M.K.J., M.E.), Swansea SA2 8QA, United Kingdom

Address all correspondence and requests for reprints to: Prof. Stephen O’Rahilly, University Departments of Medicine and Clinical Biochemistry, Box 157, Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk


    Introduction
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 Introduction
 Case Reports
 Discussion
 References
 
We describe two unrelated adult Caucasian females who developed the previously unreported triad of isolated ACTH deficiency, impairment of anterograde memory and alopecia areata. In one of these women the abnormalities were severe, with marked hypocortisolemia, alopecia universalis, and incapacitating, irreversible memory loss associated with radiological abnormalities in the hippocampus. In the other subject disturbances in all systems were less profound, and the alopecia and memory impairment were transient. The similarity between these two cases, and the uncommon nature of the component abnormalities suggest that they represent a novel syndrome, probably of autoimmune origin.

Other than the very rare encephalopathy associated with Hashimoto’s thyroiditis, there are few examples where the central nervous system is a target organ in the context of autoimmune endocrine disease. The highly specific nature of the central nervous system involvement in this novel syndrome suggests the involvement of a molecular target for autoimmunity shared among the hippocampus, the hair follicle, and the hypothalamus and/or corticotroph. We suggest that the term triple H syndrome may serve to alert clinicians to this previously undescribed triad.


    Case Reports
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 Introduction
 Case Reports
 Discussion
 References
 
Subject A

Subject A, a British Caucasian woman, presented to a dermatologist in 1990 at the age of 41 yr with progressive alopecia, which, over the subsequent 2 yr, resulted in total loss of body hair (Fig. 1AGo). She was also noted to have patchy, symmetrical vitiligo (Fig. 1BGo). In 1992 she was referred to a psychiatrist because of complaints of fatigue and memory loss. Endogenous depression was diagnosed, and antidepressant medication was commenced. At that time the results of a tetracosactrin test were reported as normal. Over the subsequent year her symptoms failed to improve, and further laboratory investigations included a random plasma cortisol of 50 nmol/L. She was referred to an endocrinologist (M.K.J.).



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Figure 1. Photograph of subject A, demonstrating alopecia (A) and vitiligo (B).

 
Endocrine evaluation. Other than fatigue, anxiety, and impaired memory, subject A had no specific symptoms referable to endocrine dysfunction. She had two children, aged 13 and 7 yr, and had a regular menstrual cycle. Her maternal grandfather suffered from Addison’s disease, and a maternal aunt had Graves’ disease.

On examination, she was a mildly obese Caucasian female who was fully alert and cooperative, but appeared vague and easily distracted. She had alopecia universalis and widespread scattered vitiligo. Blood pressure was 90/60 mm Hg with no postural fall. The results of relevant endocrine studies are shown in Table 1Go. During an insulin tolerance test she achieved an inadequate peak cortisol of 159 nmol/L despite adequate hypoglycemia. Isolated ACTH deficiency was confirmed by the demonstration of an absent ACTH response during a CRF-41 test and a normal response to depot tetracosactrin (1 mg); pituitary function was otherwise normal. A computed tomographic scan of the brain was normal. Circulating antibodies to thyroid microsomal antigen were detectable, and a test for gastric parietal cell antibodies was weakly positive. Antiadrenal, antigliadin, and antiendomysin antibodies were negative. Hydrocortisone replacement therapy was commenced. Although hydrocortisone therapy led to an improvement in her fatigue, the memory problems became more severe, and she was referred to Cambridge for formal neuropsychological testing. By this time she was severely functionally disabled, being unable to recall the directions to nearby shops and forgetting to undertake basic household tasks and personal hygiene measures.


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Table 1. Results of endocrine evaluation in subject A

 
Neuropsychological evaluation. Neuropsychological evaluation demonstrated a severe, but isolated, amnesic syndrome, with zero recall of prose material and marked impairment on recognition-based tests of anterograde episodic memory, but normal performance on tests of general intellectual ability (WAIS-R), language [Graded Naming Test (1)], and visuo-spatial and perceptual ability [Visual Object and Space Perception Battery (2)], summarized in Table 2Go. Despite the profound anterograde amnesia, she also performed normally on tests of remote episodic memory (Autobiographical Memory Interview) and tests of semantic knowledge, including famous person and event identification (3, 4).


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Table 2. Summary of cognitive function tests in subjects A and B

 
A HMPAO-SPECT (single photon emission computed tomography) scan demonstrated hypoperfusion of the medial temporal region, more marked on the left. A three-dimensional magnetic resonance imaging (MRI) scan with coronal reconstruction showed mild hippocampal atrophy (Fig. 2Go). Cerebrospinal fluid (CSF) analysis was positive for oligoclonal bands, although CSF total protein levels were normal (0.2 g/L). A diagnosis of autoimmune limbic encephalitis was made. Anti-Purkinje cell, antineuronal, and cardiolipin antibodies were negative.



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Figure 2. MRI scans of subject A compared to those of a control subject. Coronal section, T1-weighted images through the temporal lobes at the level of 1) amygdala and 2) anterior hippocampus, showing atrophy of the hippocampus with enlargement of the temporal horn of the lateral ventricle (indicated by arrows).

 
A trial of high dose corticosteroids and azathioprine was undertaken. After 9 months of treatment, there was no objective improvement in memory, although there was some regrowth of hair. At this time a follow-up HMPAO-SPECT scan was unchanged, although CSF oligoclonal bands became undetectable. Immunosuppressive therapy was discontinued. Despite the discontinuation of high dose glucocorticoids the patient’s spouse has noted a marked increase in appetite and food-seeking behavior. Subject A’s body weight has increased markedly from 60 kg in 1991 to 98 kg in 1999. Neuropsychological evaluation 3 yr post onset showed stability of the amnesic syndrome, with no progression to involve other cognitive domains (Table 2Go).

Subject B

A 39-yr-old British Caucasian female presented in 1991 with a 5-month history of progressive fatigue and lethargy, such that she was unable to perform routine household tasks. She also gave a history of forgetfulness, which had become so marked that she would forget to pick up her children from school. She subsequently developed alopecia areata of her scalp with typical clinical features, including exclamation mark hairs. She was menstruating normally and had no previous or family history of endocrine disease. The only past medical history was of atopic asthma, for which she had taken inhaled corticosteroids in the past. No inhaled steroids had been used in the 6 months before presentation. Clinical examination was unremarkable, with normal body habitus and body hair, no abnormality of skin pigmentation, and no postural fall in blood pressure.

Endocrine evaluation. To investigate the possibility of adrenocortical insufficiency a short tetracosactrin (0.25 mg) test was performed. The 30-min cortisol concentration was slightly subnormal at 500 nmol/L. Over the subsequent months two further short tetracosactrin tests were performed, which demonstrated a progressive reduction in 30 min cortisol response (420, then 310 nmol/L). In response to the injection of 1 mg depot tetracosactrin, her plasma cortisol was more than 1000 nmol/L, indicating that the adrenal insufficiency was central in origin. An insulin tolerance test was performed, which resulted in an inadequate peak cortisol of 340 nmol/L despite adequate hypoglycemia. There was no other endocrine abnormality. A MRI scan of the hypothalamus and pituitary was normal.

Neuropsychological evaluation. Neuropsychological evaluation showed a mild, but definite, impairment in both verbal and nonverbal anterograde episodic memory, with preservation of other cognitive abilities (Table 2Go).

She was commenced on hydrocortisone replacement therapy, with considerable improvement in fatigue. Over the subsequent 1–2 yr the alopecia areata resolved, and there was subjective and objective improvement in her memory. The patient’s body weight has remained stable. Attempts to gradually withdraw hydrocortisone replacement have not been tolerated due to the recurrence of fatigue. Repeat neuropsychological evaluation 15 months after presentation showed objective improvement on memory scores (Table 2Go).


    Discussion
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 Introduction
 Case Reports
 Discussion
 References
 
Isolated ACTH deficiency is an uncommon endocrine disorder (5). The relatively nonspecific nature of the symptoms and signs of chronic glucocorticoid deficiency frequently result in long periods of ill health before diagnosis. The clinical and biochemical features of both of our subjects, although different in severity, are typical of the disorder, with a diminished cortisol response to hypoglycemia accompanied in subject A by low ACTH levels that failed to respond to CRH administration, and with a normal cortisol response to depot tetracosactrin in subject B (6). In both subjects symptoms of fatigue and malaise improved markedly with glucocorticoid replacement.

The occurrence of isolated ACTH deficiency in association with Hashimoto’s thyroiditis (7), insulin-dependent diabetes (8), or as part of a generalized autoimmune polyglandular syndrome (9), and the presence of circulating autoantibodies to endocrine cells strongly suggest that the majority of cases are autoimmune in etiology (10). Subject A had vitiligo and alopecia universalis, and subject B had alopecia areata, diseases of the integument that are often associated with polyglandular autoimmunity. In addition, subject A had circulating antibodies to thyroid microsomal antigen and gastric parietal cells. In surveys of patients with isolated ACTH deficiency, primary autoimmune hypothyroidism is the most common reported autoimmune condition (5, 11), but neither alopecia nor vitiligo has specifically been reported.

The most striking aspect of these cases is the presence of a marked disturbance of memory. The nature of the defect in central nervous system function was highly specific, affecting anterograde, but not retrograde, memory. In neither subject was there any evidence of a general decline in cognitive function. The pattern of cognitive deficit seen in the two patients is very unusual and suggests a pathological process limited to the hippocampal-fornix system (12, 13). A remarkable feature of the amnesia in subject A was the dissociation between severely impaired anterograde and preserved retrograde memory. In subject A the amnesia was permanent and extremely disabling, whereas in subject B, like her alopecia, it was a transient phenomenon. SPECT scanning in subject A revealed severe bilateral hypoperfusion in the hippocampal areas, and MRI scanning showed loss of volume in the medial areas of the hippocampus known to be involved in anterograde episodic memory. This pattern is identical to that seen in patients with other causes of circumscribed medial temporal lobe damage of the type described in autoimmune limbic encephalitis associated with remote neoplasm (14), in some patients with herpes simplex virus encephalitis (although most of these patients have more extensive cognitive deficits) and after anoxic brain damage (15, 16).

What possible mechanism could lead to this selective hippocampal damage? Its occurrence in subjects with other known or presumed disorders of immune dysregulation (alopecia areata, vitiligo, and isolated ACTH deficiency) is highly suggestive of an autoimmune etiology. This is further supported by the finding of oligoclonal bands in the CSF of subject A. The coexistence of several uncommon autoimmune disorders in the same subjects suggests the possible coexistence of shared autoimmune targets in hair follicle, hippocampus, and hypothalamus. POMC, the precursor of ACTH, is expressed in the hair follicle, the corticotroph, and the hypothalamic neurons, but there are no reports of POMC-expressing cell bodies in the hippocampus (17, 18). In this regard, POMC concentrations in the CSF, which are thought to be derived from hypothalamic neurons of subject A, were within the normal range (White, A., personal communication), suggesting the preserved integrity of that neuronal population. Receptors for CRH are expressed in pituitary corticotrophs, hair follicle, and hippocampus (19). Additionally, CRH has been reported to have profound effects on memory retention in rodents (20). We attempted to examine whether any circulating autoantibodies to CRH receptors are present in subject A, but her serum did not inhibit signaling through cloned CRH-1 or CRH-2 receptors (Brennand, J., personal communication). Similar studies with cloned melanocortin receptors were also negative (Mountjoy, K., personal communication). The absence of circulating antibodies to these components does not exclude them as potential autoimmune targets, as cell-mediated, rather than humoral, autoimmunity may be involved.

The development of severe hyperphagia and severe obesity in subject A is also of interest. This is unlikely to be due to high dose corticosteroid treatment alone, as this problem has persisted after the discontinuation of immunosuppressive doses of steroids. Although the patient has no conscious memory of eating her last meal, such "food amnesia" appears to be an unlikely explanation for her weight gain, as this is not seen in other cases of amnesia due to hippocampal damage despite more profound amnesia than that of subject A. We hypothesize that hypothalamic neurons expressing a shared autoimmune target may also have been subject to immune destruction. Given the known roles of both POMC-derived peptides and corticotropin-releasing factors and their receptors in the hypothalamic regulation of appetite (21), these would be attractive candidates for such a molecular target.

Autoimmune dysfunction of the central nervous system occurring as part of a syndrome of endocrine autoimmunity is a rare phenomenon. To our knowledge, only the occasional association of thyroid autoimmunity with Hashimoto’s encephalopathy or chorea represent well established examples (22, 23). The coexistence of this unusual form of amnesia with isolated ACTH deficiency in two patients is highly unlikely to be a chance finding. It is perhaps surprising that there are no previous reports of this association. Although it is unlikely that an amnesic state as severe as that seen in subject A would not be detected, the more subtle memory disturbances exhibited by subject B could readily be overlooked in a subject with a range of other nonspecific symptoms secondary to hypocortisolemia.

We suggest that memory be assessed more thoroughly in patients presenting with isolated ACTH deficiency, particularly if accompanied by autoimmune conditions such as alopecia areata or vitiligo. To aid the recognition of this unusual triad of features, we suggest that the term triple H syndrome accurately reflects the simultaneous dysfunction of hippocampus, hair follicle, and hypothalamic-pituitary-adrenal axis.


    Acknowledgments
 
We are indebted to the late Dr. Kristin Breen for expert neuropsychological evaluation. We thank Kathy Mountjoy for studies of melanocortin receptor antibodies, John Brennand for assays of CRH receptor antibodies, and Ann White for measurement of POMC in cerebrospinal fluid.


    Footnotes
 
1 Wellcome Trust Training Fellow. Back

2 Supported by the WellcomeTrust. Back

Received December 6, 1999.

Revised March 24, 2000.

Accepted April 1, 2000.


    References
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 Introduction
 Case Reports
 Discussion
 References
 

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