JOINT HYPERMOBILITY SYNDROME

A CONGENITAL EMERGENT DISEASE, THAT COULD BE CAUSED

BY A LACK OF FOLIC ACID DURING THE PERICONCEPTIONAL PERIOD.

Even though it is difficult to evaluate with accuracy, the incidence of joint hypermobility apparently has increased. In the adult population, using the Beighton criteria, Grahame ¹ in London in 1986 found that 2% of 9.275 patients in a rheumatological clinic had Joint Hypermobility (JH). Larsson ² in 1987 in New York reported 4.5%. Now the prevalence in Western populations is about 10% ³. It is more noticeable in females than in males and in children than adults. Orientals have more mobile joints than Negroes and these more than Caucasians. Al-Rawi ⁴ reported^. 25 % in Iraqi students . When people with JH develop symptoms, we call the disease Joint Hypermobility Syndrome (JHS) ⁵.

In Santiago, Chile, from January 2001 till January 2003 we have diagnosed 211 JHS, looking carefully for them (high index of suspicion) and using the Brighton criteria ⁶. The old Beighton criteria evaluated only few joints, but now besides those joints, the Brighton criteria takes into account many other affected tissues. Is unfortunate that these names are so similar , because frequent confusion arises. The JHS patients are forme frustes ³ of a broader group, namely the Hereditary Diseases of the Collagen Tissues (HDCT). JHS accounts for 34% of our rheumatological patients at Clinica Arauco⁷. JHS is a disease with very high prevalence, but is not usually diagnosed ⁸ , not even by good rheumatologists. Grahame has called attention to the lack of recognition of this condition in the United Kingdom ⁹. In these patients we have found frequently congenital malformations. We have seen hip displacia, scoliosis, spina bifida occulta, spondylolisthesis, transitional vertebrae, hernias, gastro-esophageal reflux, mitral valve prolapse, anomalies of feet, hands, knees, limbs, etc. Less frequently we have seen association of HDCT with renal malformations (Prune Belly Syndrome, VATER Syndrome, etc) congenital cardiopathies, abnormal coronary arteries, cornual uterus, etc. This really is an emergent disease, which when looked for, has been noted worldwide. Guma in Barcelona, Spain has reported lately, joint hypermobility in 25% of their rheumatological patients ¹⁰.

The HDCT includes the classical forms of Ehlers-Danlos, Marfan Syndrome and Osteogenesis Imperfecta, as well as forme frustes. They have Autosomal Dominant inheritance, but this by itself can not explain the tremendous increase in prevalence, in the last several decades. We have proposed ⁶ that like other congenital malformations, most likely the increased prevalence of JHS is due to lack of folic acid (FA) during pregnancy. It is well known that this is an important cause of Neural Tube defects and other congenital abnormalities ¹¹. It is probable that the development of these abnormalities is caused by the alteration of the collagen tissues. This would produce JHS, which to most authors, is the same as Hypermobile Ehlers-Danlos or EDS type III ¹². It is easy to understand, that the lack of FA during the periconceptional period can produce gene mutations, since it is essential in the synthesis of purinic and pyrimidinic bases of diverse amino acids and consequently is necessary for the synthesis of DNA and RNA. The lack of dihydrofolate-reductase enzyme of some mothers, which interferes with folic acid action, could also contribute to the production of congenital malformations. Furthermore FA antagonists, that act as dihydrofolate-reductase inhibitors (Triamterene, Sulfazalazine, anti-epileptics, etc.) when used during the periconceptional period, can have the same effect as lack of FA ¹³. As rheumatologists we know that Methotrexate reduces FA and is teratogenic. We should remember that Sulfazalazine too can do the same.

We need to keep in mind that the pathophysiology of Homocystinuria as well as that of Marfan Syndrome, is due to an alteration of fibrillin and both have similar phenotype. Homocystinuria is treated with FA. This same vitamin is also used to treat other cases of hyperhomocisteinemia, when there is danger of thrombosis due to alteration of the vascular endothelium, specially in the prevention of coronary thrombosis. Recently Cagnacci ¹⁴ noted the association of folate deficiency with osteoporosis.

Besides the role of FA, it is less likely, but also possible, that lack of other vitamins (thiamine or others) or concurrent toxic exposures during the periconceptional period my contribute to mutations that could lead to JHS. Possible ones could be: radiations, ozone, smog, cigarette smoking, alcohol, stress, etc. We have already mentioned medications, but toxic chemicals (industrial or insecticides) could also be concurrent agents.

It is interesting to remember that in the XV century seamen developed Scurvy due to lack of Vitamin C. Later in the XVII century (1652) two Dutch shipboard physicians, Bontius and Tulp did the first clinical description of Beriberi, while studying a strange neurological disease in the Far East, which could cause paralysis. Two hundred years later Beriberi was found to be caused by thiamine (Vit.B-1) deficiency, which is contained in the outer coat of rice. In animal studies it has been shown that shortage of thiamin in the diet can cause birth defects. At present in the East, Beriberi is related to the consumption of milled rice and is still endemic in Indonesia.

It appears that now, for the last century (four generations at least), the problem has been the lack of folic acid in the diet, during the periconceptional period, situation that as been proven to cause severe congenital malformations ¹¹. The problem with milled wheat is a little different than that of rice. When wheat is milled, it looses the outer coat and looses some folates. Wheat does not have a high concentration of folates to begin with and these are not well absorbed by humans. The cause then is not the loss of the outer coat of wheat. The problem started when in 1870, steam mills began producing enormous amounts of wheat flour, which became a very high percentage of the diet of millions of people. By eating mainly wheat flour, the percentage of “protector foods” was very small. These are foods that would provide the nutrients and vitamins that the wheat flour did not have. The wheat flour is enriched with FA in higher amounts than what is originally found in wheat, since this is low and not enough to prevent congenital malformations. Synthetic FA is used because it is better absorbed by humans than folates. It is added to wheat flour and not to other foods, because is easy to added a vitamin to flour and this can be done at big mills rather than at small factories. Also because wheat flour has become the most popular staple food in the world, surpassing rice and maize.

It is amazing how many years need to go by to realize the effect that a lack of a certain vitamin can do. Now is known that the lack of FA interferes in the genesis of DNA and RNA and gives rise to congenital malformations. Most likely the worldwide high frequency of malformations is due to the use of purified flour as the major food in the diet. This could have affected not only humans, but animals as well (congenital hip displacia in dogs, hernias in hogs, etc) and probably birds fed mainly with bread, like doves. Fortunately now since January 1998 FA flour enrichment is mandatory in USA and Canada. It is now mandatory also in many other countries, including Chile, since January 2000. Cortes ¹⁵ and Hertrampf ¹⁶ reported a decrease of 42 % in Neural Tube Defects, in Chile, comparing 60.000 newborns before wheat flour fortification with 60.000 newborns after fortification. The average consumption of bread per person was 240 gm a day, which after enrichment provided 486 microgm of FA daily. After fortification, mean serum folate level increased from 4.3 +/- 1.9 to 16.4 +/- 4.2. The intake of bread in Santiago, Chile is very high and in the low socioeconomic level, represents 90% of total consumption of wheat flour. Chile with 96 Kg of bread per person per year, is the second highest bread consumer in the world, second only to Germany. It is important to realize that serum folate levels being so low before FA flour enrichment in Chile, probably explains the high prevalence of congenital defects and probably the high prevalence of JHS. Unfortunately only 28 of the 189 countries in the planet have voluntary or mandatory wheat flour FA enrichment programs. As a consequence of this only 15 % of the wheat flour consumed in the world is enriched. There are 500.000 cases of NTDs per year worldwide, the same numbers as Polio before it was eradicated. Seventy percent of those cases, 350.000 NTDs, and many other congenital malformations could be avoided if all wheat flour could be enriched.

In summary, it is our belief that this emergent disease, the Joint Hypermobility Syndrome (JHS), which is characterized by weak collagen tissues (HDCT) associated to congenital malformations, is a result of mutations during the periconceptional period, due to lack of folic acid in the diet. It appears to have then, the same pathogenesis as the other more usual congenital malformations.

Fortunately, now by enriching flour and giving extra FA to women during the fertile years, we will see a reduction not only of Neural Tube defects and other congenital abnormalities (cardiac, renal, etc) but if our hypothesis is correct, we will also see a reduction in the prevalence of the Joint Hypermobility Syndrome. This is a fertile area for research.

References:

1.- Grahame R. Clinical manifestations of the joint hypermobility syndrome. Reumatologia (USSR) 1986;2:20-4.

2.- Larsson LG, Baum J,and Mudholkar GS. Hypermobility: features and differential incidence between the sexes. Arth & Rheum 1987;30:1426-30.

3.- Grahame R. Joint hypermobility and genetic collagen disorders: are they related ?

Arch Dis Child February 1999; 80: 188-91.

4.- Al-Rawi ZS, Al-Aszawi AJ, Al-Chalabi T. Joint mobility among university students in Iraq. Br J Rheumatol 1985; 24: 326-31.

5.- Mishra MB, Ryan P, Atkinson P, Taylor H, Bell J, Calver D et al. Extra-articular features of benign joint hypermobility syndrome. Br J Rheumtol 1996; 35: 861-66.

6.- Grahame R, Bird HA, Child A et al. The British Society for Rheumatology Special Interest Group on Heritable Disorders of Connective Tissue criteria for the benign joint hypermobility syndrome. The revised (Brighton 1998) criteria for the diagnosis of BJHS. J Rheumatol 2000; 27: 1777-79

7.- Bravo JF, Arteaga MP, Coello L. Utility of Bone Scintigraphy in the study of Hereditary Disorders of the Connective Tissues (HDCT). Alasbimn J 6(22): October 2003. http//www.alasbimnjournal.cl/revistas/22/bravo esp.html

8.- Grahame R. Editorial: Time to Take Hypermobility Seriously (in Adults and Children). Rheumatology 2001;40:485-491.

9.- Grahame R, Bird HA. British consultant rheumatologists perceptions about the hypermobility syndrome: a national survey. Rheumatology 2001; 40: 560-3.

10.- Guma M, Olivé A, Holgado S, Casado E, Roca J, Forcada J, Duró JC y Tena X. Una estimación de la laxitud articular en la consulta externa. Rev Esp Reumatol 2001; 28: 298-00.

11.- Mulinare J, Cordero JF, Erickson JD, Berry RT. Periconceptional use of multivitamins and the occurrence of Neural Tube Defects. JAMA 1988;260:3141.

12.- Beighton P, DePaepe A, Steinmann B, Tsipouras P , Wenstrup RJ. Ehlers-Danlos Syndromes: revised nosology, Villefranche, 1977. Am J Med Gen 1998; 77: 31-37.

13.- Hernandez-Diaz S, Werler MM, Walker AM, Mitchel AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000;343: 1608-14.

14.- Cagnacci A, Baldassari F, Rivolta G Arangino S and Volpe A. Relation of homocysteine, folate, and vitamin B (12) to bone mineral density of postmenopausal women. Bone2003;33: 956-5.

15.- Cortes F, Hertrampf E, Mellado C, Freire W, Castillo S, Erickson E. Impact of wheat flour fortification with folic acid on the frequency of neural tube defects in Chile: preliminary results. Rev Chil Pediatr 2002; 73(6):644.

16.- Hertrampf E, Cortes F, Erickson D, Freire W. Effect of folic acid fortification of wheat flour on folate status of women of fertile age in Chile. Experimental Biology 2002. New Orleans, Louisiana (USA), April 20-24, 2002. Faseb J 2002;16(4):A269 (Abstract 217.16)

Key message: Joint Hypermobility Syndrome is a very frequent, but seldom diagnosed, emergent disease, usually associated to congenital malformations. It appears to be caused by lack of folic acid during the periconceptional period.

Jaime F Bravo MD

Revised : January 11, 2004