Comorbid Bipolar Disorder and Benign Joint Hyper Mobility Syndrome (BJHS): More than a Mere Coincidence?

Sir,

Benign Joint Hypermobility Syndrome (BJHS) is thought to be an inherited connective tissue disorder with an autosomal dominant pattern, clinically characterized by hypermobility and pain in multiple joints in the absence of systemic rheumatologic disorder.[1] There is no consensus on whether this as an independent disorder or a milder variant of well-known Ehler-Danlos syndrome (type-III).[1] Although perceived as a rare condition, BJHS is common, with a prevalence of 5%-38% depending on age, sex, and race.[2] The syndrome appears to be due to an abnormality in collagen or the ratio of collagen subtypes. Mutation in the Fibrillin gene has also been identified in families with BJHS, and recently, mutations in a non-collagenous molecule, Tenascin-X, have also been identified in a subset of patients with BJHS.[1] An increased prevalence of psychological disturbances, such as anxiety, depression, agoraphobia, panic disorder, and attention deficit hyperkinetic disorder (ADHD) has been found in patients with BJHS.[13] Here, we describe a young male with BJHS comorbid with bipolar affective disorder (BPAD). To the best of our knowledge, BPAD comorbidity in BJHS has not been reported till date.

We report a 29-year-old male patient, an unmarried graduate, referred by the neurologist who was treating him for pain in multiple joints for more than a year. The patient had the first episode of depression at 21 years of age, followed by another episode within 4 years. Recently, he had manic episode followed again by depression and was treated with lithium carbonate 800 mg/day, olanzapine 5 mg/day, and escitalopram 2.5 mg/day. He was referred to us due to a partial response to the current treatment with persistent social withdrawal, suspiciousness, and reduced sleep and appetite. Mental status examination revealed referential and persecutory delusions, thought broadcasting, and depressed affect. His physical examination had several significant findings. He had marfanoid habitus such as tall stature, upper segment less than lower segment (<0.89 ratio) and arm span to height ratio of 1.20 (normal value is <1.05). He had hypermobile joints with a Beighton score of 6 [Figures 1–4]. Neurological and cardiovascular examinations were within normal limits. He was diagnosed with BJHS according to Brighton criteria: Beighton score of >4 and arthralgia for longer than 3 months in four or more joints.[4] He had no history of drug or alcohol abuse. His mother was diagnosed with BPAD. He did not have any relative with BJHS. No abnormality was detected in his routine biochemistry and hemogram screen. We raised olanzapine up to 10 mg/day and stopped escitalopram. During the next follow-up after 2 weeks, he reported improvements in his symptoms.

Figure 1

Passive dorsiflexion of the metacarpophalangeal joint to 90°

Figure 4

Apposition of the thumb to the flexor aspect of the forearm

Forward flexion of trunk with knees extended and hands touching the floor

Hyperextension of the elbow beyond 90° (neutral)

This case illustrates the co-occurrence of BPAD with psychotic features in the presentation and BJHS in a male with a family history of BPAD but not of connective tissue disorders. Our patient had a significant disability due to the BJHS that he seldom played with friends and rather stayed back at home most of the time during his adolescent age. He presented with a history of predominantly depressive episodes with a single manic episode and responded well to a combination of lithium and olanzapine.

BJHS has a well-known association with psychological problems. A recent meta-analysis exploring the relationship between BJHS and psychological distress found greater perceptions of fear and more intense fear among patients with BJHS.[5] Furthermore, they have a higher probability of demonstrating agoraphobia, anxiety, depression and panic disorders than those without BJHS. Studies have observed a higher prevalence of autism spectrum disorders, BPAD, ADHD, depression and attempted suicide among patients with hypermobility syndromes (including different variants of Ehler-Danlos syndrome) when compared with matched controls.[16] A relationship was determined between five potentially pathophysiologically linked domains: anxiety disorders, joint laxity, chronic pain disorders, immune dysfunction, and mood disorders.[7] A recent study exploring psychiatric and somatic phenotype of BPAD with co-morbid anxiety disorder found hypermobile joints in 41% of the sample, and it was significantly associated with somatosensory amplification.[8] The commonly used medications for these symptoms, such as antidepressants for anxiety symptoms and steroids for pain symptoms, can have a negative impact on the course of BPAD. Hence, clinicians need to be careful in managing patients with BJHS at risk for BPAD.

The pathophysiology by which BJHS precipitates various psychiatric disorders is not yet clear. This could partly be due to the fear and anxiety associated with potential re-injuries. Moreover, the disease load in BJHS can contribute to poor quality of life and an increased risk of depression and suicide attempt.[2] However, such explanations could not clarify the association between BJHS and BPAD, a progressive, chronic, and episodic psychiatric disorder with multifactorial etiology and strong heritability. BPAD occurring in association with BJHS may be attributed to psychosocial stressors secondary to BJHS or maybe a chance association.

Another possible etiological link between BJHS and BPAD seems to be genetic. Recent evidence suggests that BPAD arises not merely due to neurotransmitter imbalances — rather, it is the result of an impaired synaptic modulation and neural plasticity in crucial pathways that mediate cognitive and affective functions.[9] It can be hypothesized that mutation in the fibrillin gene may predispose patients with BJHS to neurodevelopmental abnormalities which may manifest as psychiatric disorders such as BPAD. A recent genome-wide association study based on single-nucleotide polymorphisms also indicated that polymorphic FBN1 increases the susceptibility to BPAD.[10] Though BJHS is not considered primarily an inflammatory condition, a recent analysis of electronic medical records showed its association with autoimmune/inflammatory disorders.[11] As neuroinflammation is being recognized as an important mediator of the etiopathogenesis of BPAD,[12] the possibility of a shared inflammatory process needs consideration.

In conclusion, our case highlights the co-morbidity of BJHS with BPAD. Such co-occurrences of heritable disorders help us to further understand the neurobiology of both the disorders, especially the role of genes associated with BJHS and the role of connective tissue proteins, in the pathophysiology of BPAD.

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Conflicts of interest

There are no conflicts of interest.