Uncommon endemic diseases of the Persian Gulf area

385 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. Vol. 48. No. 5. September, 1954.

U N C O M M O N E N D E M I C DISEASES OF T H E PERSIAN G U L F AREA BY

J. H. W A L T E R S , M.D., M.R.e.P.*

Late Physician at the State Hospital, Kuwait (From the West African Council for Medical Research Laboratories, Lagos, Nigeria)

The successful exploitation of its immensely rich oilfield has brought great wealth to the State of Kuwait, which is situated at the north-west corner of the Persian Gulf. To it, during the last two years, have flocked people of many races in search of employment. Others [KAQ.

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have come from long distances for free medical treatment which has been made available to all by the liberality of the Ruler, His Highness Sheikh Abdulla al Salim al Subah, who has e I am grateful to Dr. Norman Young, Pathologist, Kuwait Oil Company, for much assistance in pathological investigations, to Mr. William Rothwell who carried out splenectomy on two patients, and to Miss J. M. Smith, M.S.R., who took the radiographs. I wish to thank also my colleagues, Drs. Naif Hassan and Jamil Kadar, Paediatricians at the State Hospital, Kuwait, for access to patients, and to Dr. Abdul Latif for much personal assistance. Colonel H. R. D. Dickson of the Kuwait Oil Company also gave me much help from his great store of local knowledge. M y thanks are also due to Ilfords Limited, and especially to Miss K. Clark, for reproductions of radiographs.

386

UNCOMMON

ENDEMIC

DISEASES OF T H E P E R S I A N

G U L F AREA

e s t a b l i s h e d a c o m p r e h e n s i v e m e d i c a l service w i t h fully e q u i p p e d m o d e r n hospitals. K u w a i t has t h u s b e c o m e a c o n v e n i e n t focus f r o m w h i c h to s u r v e y e n d e m i c disease t h r o u g h o u t t h e P e r s i a n G u l f littoral a n d s o u t h - e a s t e r n A r a b i a i n c l u d i n g large t r a c t s of c o u n t r y h i t h e r t o unexplored by modern diagnostic methods. T h e diseases w h i c h have b e e n f o u n d a n d w h i c h a p p e a r w o r t h y of d i s c u s s i o n are s c h i s t o somiasis m a n s o n i , kala-azar, skeletal fluorosis a n d certain t y p e s o f g e n e t i c a n a e m i a a s s o c i a t e d w i t h t h e sickling p h e n o m e n o n . I.

SCHISTOSOMIASIS

MANSONI

T h e h o m e of this infection is t h e e a s t e r n half of Africa, f r o m L o w e r E g y p t , to N y a s a l a n d : f r o m this area it is k n o w n to h a v e o v e r f l o w e d into t h e s o u t h - w e s t e r n t i p of A r a b i a , for e x a m p l e s have b e e n r e p o r t e d f r o m t h e Y e m e n b y GaEWL (1922) a n d b y MALCItI (1924), a n d f r o m t h e A d e n P r o t e c t o r a t e b y PETRIE a n d SEAL (1943). T h e six e x a m p l e s o f this disease e n c o u n t e r e d in K u w a i t w e r e all in n a t i v e s of a small area of c o m p a r a t i v e f e r t i l i t y called M a j m a , s i t u a t e d 125 miles n o r t h west of R y a d h , a l m o s t in t h e c e n t r e o f t h e A r a b i a n p e n i n s u l a r . A b u n d a n t w a t e r is f o u n d in surface wells a n d even in s t r e a m s , w h i c h p e r s i s t t h r o u g h o u t t h e h o t w e a t h e r : n o t h i n g is k n o w n , however, a b o u t t h e i n d i g e n o u s snail p o p u l a t i o n . I t is p r o b a b l e t h a t t h e fluke was i n t r o d u c e d in t h e b o d i e s of N e g r o slaves f r o m E a s t Africa, in a s i m i l a r m a n n e r to t h a t in w h i c h it has b e e n d i s t r i b u t e d t h r o u g h o u t W e s t A f r i c a a n d t h e n c e to t h e islands of t h e C a r r i b e a n . I t is likely t h a t o t h e r foci of t h i s infection await d i s c o v e r y in t h e oases of A r a b i a . Case 1. Nasir Ibrahim el Frih, a boy of 13 years, was brought to hospital by his father, an impoverished tailor. He arrived in a state of grave malnutrition, which had developed over several months, and was accompanied by rectal bleeding and the protusion of a polypoid mass from the anus. He showed general anasarca, bilateral parotid enlargement and severe hypochromic anaemia. The liver was palpably enlarged to two fingers' breadth below the costal margin and was unduly firm, the spleen was palpable to one finger's breadth. The heart was dilated, with a resting rate of t20 per minute and a gallop rhythm: the blood pressure was 98/50 mm.Hg. Investigation showed : R.B.C. 2.9 million per c.mm.; haemoglobin 4.6 g. per 100 ml.; reticulocvtes 11 per cent.; serum protein 7.16 g. per 100 ml. (albumin 1.71 g., globulin 5.45 g.); thymol turbidity 60 units (Maclagan). Urine: No abnormality on repeated examination. Stools: Numerous lateral-spirted ova, typical of S. mansoni, containing viable miracidia. Sigmoidoscopy revealed many large, succulent polypi in the rectum and lower sigmoid colon. Section of a polyp removed at sigmoidoscopy showed ova of S. mansoni enmeshed within the granulation tissue of which it was composed. Treatment with a high protein diet restored a normal state of nutrition, and a course of 27 ml. of stibophen given over 6 weeks reduced the numbers of ova shed in the stools. Following an intensive course of miracil the stools became free from ova. A final sigmoidoscopy showed that the polypi, though still present, were somewhat shrunken and were no longer ulcerated. T h e patient refused to submit to liver biopsy. Case 2. Abdul Aziz bin Abdul Rahman, a boy of 12 years, also came from Majma for treatment of an illness which had begun some 2 years previously. The initial symptoms were headache and progressive weakness; his abdomen began to swell 1 year later. His father was a teacher, and the boy had received a fairly good mixed diet. His nutritional state was fair on admission, but he was obviously anaemic. There was marked gaseous distension of the bowel, with moderate ascites. The liver was enlarged to two fingers' breadth, its surface firm and finely nodular and its edge sharp and elastic. T h e spleen was palpable to three fingers' breadth. T h e results of investigation were : R.B.C. 4.08 million per c.mm.; haemoglobin 6.9 g. per 100 ml.; M C V 70 cu. ~; M.C.H.C. 24 per cent.; serum protein 8.93 g. per 100 ml. (albumin 2.80 g., globulin 6.13 g.); thymol turbidity 16 units (Maclagan). Sigmoidoscopy disclosed scattered small haemorrhagic elevations, suggestive of early schistosomal papillomata: a swab taken from these contained numerous viable ova of S. mansoni. A high protein diet, with iron by mouth, quickly restored his state of nutrition and his haemoglobin level, and as his general health improved his tympanites subsided and his ascites resolved. An in-

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tensive course of miracil eliminated ova of S. mansoni from his stools, and was followed by a marked reduction in the number and size of the lesions in the bowel. The liver and spleen, however, remained unchanged. Sections of a biopsy specimen of the liver obtained before discharge showed a chronic inflammatory reaction with fibrosis, limited to the portal tracts, the lobular architecture and the parenchymal cells being undamaged. Case 3. Lafi bin Kheil, a cultivator of about 45 years of age, had been suffering for 6 months from increasing weakness, anorexia and abdominal distension. His appearance was one of extreme cachexia, for vomiting was easily induced and he could take only extremely small meals. The upper abdomen was distended, and active gastric peristalsis became visible when he drank 10 oz. of water. The liver edge could be felt two fingers' breadth below the costal margin, its consistency was hard, and its edge sharp and elastic. The tip of the spleen was just palpable. Investigation showed evidence of both renal and hepatic damage, and of an intense infestation with S. mansoni. The results were : R.B.C. 2.45 million per c.mm.; haemoglobin 6.4 g. per 100 ml.; serum protein 7.58 g. per 100 ml. (albumin 2.13 g., globulin 5.45 g.); thymol turbidity 32 units (Maclagan); alkalinephosphatase 62 units (King). Urine: albumin present (heavy cloud on boiling), sugar nil, granular casts in abundance, leucocytes present in moderate mtmbers, n o schistosome ova found. Stools: numerous ova of S. mansoni. Alcohol test meal: no free hydrochloric acid secreted. Sigmoidoscopy showed multiple ulcerations of the mucous membrane, each lesion being covered with a greyish-white slough. T h e cause of the obstruction to the outflow of the stomach was uncertain, but it seemed essential to attempt the relief of this most urgent symptom by surgical means. After preparation with blood transfusion, intravenous cashydrol and glucose saline, a laparotomy was carried out by Mr. William ROTHWELL. It was seen that a severe degree of constriction of the 2nd part of the duodenum was being caused by multiple peritoneal adhesions, which also bound the fundus of the stomach firmly to the surface of the spleen. An anterior gastro-jejunostomy was performed with considerable difficulty. The liver was found to be finely nodular, and the spleen much enlarged. The patient did not rally after operation, and died 12 hours later. A limited autopsy was carried out through the operation incision. Acute general peritonitis was evident, from a perforation in the terminal part of the ileum, where a segment of gut, about 12 inches long, was intensely inflamed, oedematous and ulcerated throughout. Sections of the ileum at the site of perforation showed a well marked, subacute inflammatory reaction with ulceration, which involved both mucosa and submucosa: four schistosome ova were seen lying in the submucosa at the base of the ulcer. The colon on section showed an inflammatory reaction involving most intensely the submucosal layer. The liver, in addition to a characteristic portal fibrosis, gave evidence of a developing diffuse fibrosis together with foci of parenchymal necrosis and nodules of regeneration.Case 4. Mohammad Ahmad Hamdan, a cultivator aged about 45 years, had been suffering for 2 months from bouts of fever with abdominal pain and occasional vomiting, and had lost weight. He was in fair condition when first seen, the only notable clinical finding being marked hepatomegaly. The liver was palpable to one hand's breadth below the costal margin ; it was soft, regular and painless. Investigation showed infestation with S. mansoni, and defective liver function. The results obtained were: R.B.C. 3.35 million per c.mm.; haemoglobin 8.4 g. per 100 ml.; serum protein 7.21 g. per 100 ml. (albumin 2.45 g., globulin 4.76 g.); thymol turbidity 46 units (Maclagan); alkaline phosphatase 94 units (King); serum not icteric. Urine : No abnormality. Stools: Ova of S. mansoni present. At sigmoidoscopy a single typical schistosomal papilloma was seen, and was removed for section. This showed a granuloma, with two schistosome ova lying in the tissue. Sections of liver biopsy material showed a chronic inflammatory reaction with fibrosis, limited to the portal tracts. A course of miracil cleared the stools of ova, but did not influence the degree of hepatomegaly.

T h e r e m a i n i n g two examples of this disease p r o v i d e d n o features of special i n t e r e s t : i n both, the lesions were c o n f i n e d to the bowel a n d b o t h r e s p o n d e d w i t h a p p a r e n t success to miracil. Comment

I n Cases 2 a n d 4, the characteristic portal fibrosis was d e m o n s t r a t e d b y liver biopsy,

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U N C O M M O N ENDEMIC DISEASES OF THE PERSIAN GULF AREA

and, although there was no histological evidence of damage to the liver parenchyma, the results of thymol turbidity and alkaline phosphatase estimations suggested that the function of the hepatic cells was indeed impaired. I n the case of Patient 3, the typical portal lesion was overshadowed by grave degenerative changes in the parenchymal cells, leading to a condition of diffuse hepatic fibrosis: this was almost certainly of nutritional origin and had been precipitated by the development of duodenal obstruction. Case 3 presented in addition the interesting and unusual feature of an intense localized schistosomal ileitis, giving rise to a plastic peritonitis and ultimately causing his death from acute peritonitis due to perforation of the affected segment.

II.

KALA-AZAR

Visceral leishmaniasis has only once previously been recognized in the area under review, t h o u g h rare examples have been discovered in Aden, the Yemen, Trans-jordan, Israel and Bagdad, and the disease is well known round the shores of the Caspian Sea (REID, 1950). T h e first case reported from the Persian Gulf area was that of REID (1950) from Abadan; the patient, a child, appeared to have acquired the infection in a town called Kazerun, near Shiraz, in South Persia. Case 1. Nura hint Sayed, a girl of 4 years, was brought to hospital on account of severe epistaxis. Her mother stated that the child had been suffering from irregular fever for 3 months, accompanied by wasting, pallor and progressive enlargement of the spleen. On examination, the child was seen to be cachectic and obviously ill. The spleen filled the left half of the abdomen, and extended medially to the umbilicus. The firm, smooth liver was palpably enlarged to two fingers' breadth below the costal margin. Investigation showed: R.B.C. 1.80 million per c.mm.; haemoglobin 4.6 g. per 100 ml.; W.B.C. 2,400 per c.mm. (polymorphs 46 per cent., lymphocytes 54 per cent.); formolgel test, positive. Smears of the splenic pulp showed many mononuclear cells heavily parasitized by Leishmania. No specific drugs being then in stock, a blood transfusion and haematinics were given pending the arrival of a supply of pentostam. The condition of the child rapidly deteriorated, however, and within 2 weeks cancrum oris and a patch of gangrene on the tip of the nose appeared. A further blood transfusion, of only 50 ml., was given but even this small amount proved sufficient to overload her circulation and precipitated her death from acute left ventricular failure. The child had been born in Kuwait and had remained there until the age of 3 years, when she was taken on a visit lasting 6 months to her grandparents who lived in a coastal village in South Persia, near Bandar Abbas. After her return, she remained in good health for 6 months, when she contracted whooping cough. This illness appeared to have initiated the clinical manifestation of kala azar. Case 2. Hashar Hamood, a boy of 4 years, was brought to Kuwait for treatment of fever and enlargement of the abdomen, from which he had been suffering for the past year. He was found to be running a sustained pyrexia; the abdominal swelling was seen to be due to an enormously enlarged spleen which reached the right iliac fossa, and there was also a generalized enlargement of the palpable lymphatic glands. Investigation showed: R.B.C. 2.21 million per c.mm.; haemoglobin 5.6 g. per 100 ml.; W.B.C. 4,800 per c.mm. (polymorphs 30 per cent., lymphocytes 65 per cent., monocytes 5 per cent.); formolgel test, positive. Smears of the splenic pulp showed numerous intracellular Leishmania. The disease responded rapidly to a course of intramuscular injections of pentostam, comprising 9 ml. over 6 days, which was repeated after a 2 weeks' interval. No follow-up was possible. T h e home of this child was in Dubai, on the Trucial Coast of Arabia, but the parents had taken him with them on the Haj pilgrimage to Mecca. T h e journey lasted for 2 months, and it was on his return that the boy fell ill. T h e locality in which he acquired his infection therefore remains doubtful. Comment

T h e two present subjects, with that of R~D, were all juveniles.

T w o children appear

1. It. WALTE1RS

389

to have been infected in the country bordering the eastern or Persian coast of the Persian Gulf, the third was infected on the western side, probably in Dubai itself, but possibly on the road to Mecca. The disease thus appears to be endemic but of low intensity in these areas, and probably resembles the juvenile Mediterranean form, being transmitted from a canine reservoir by a sandfly of unknown species. No classification or study of species distribution of Phlebotomus has yet been undertaken in these countries. III.

FORMS OF GENETIC ANAEMIA ASSOCIATED WITH THE SlCKLING PHENOMENON

The sickling reaction has only been noted occasi~)nally in Arab peoples, previous reports including that of ARCHIBALD (1926), who diagnosed sickle-cell anaemia in an Arab girl in Omdurman, and of ABBASY(1951) who has described the case of a girl of Algerian stock in whom a chronic haemolytic anaemia was associated with the heterozygous inheritance of the sickle gene. This reaction has been demonstrated however in 5 per cent. of local recruits examined by the Kuwait Oil Company (YOUNG, 1953). It appears to be independent of traces of a Negro ancestry. Three examples of anaemia associated with the sickle-cell anomaly have been investigated. Case 1. Nuriyeh Tahir, a girl 8 years old, of pure Arab features, first came under observation in the summer of 1952. At that time she showed a severe degree of haemolytic anaemia, with numerous target cells and scanty sickle cells in the peripheral blood. When tested by the sodium metabisulpbite reduction method, nearly all the red cells developed the sickle deformity, the majority assuming elongated filinaentous shapes. There was considerable enlargement of both liver and spleen, and an indolent ulcer was present over the left ankle. Blood examination showed R.B.C. 2.40 million per c.mm.; haemoglobin 5.38 g. per I00 ml.; reticulocytes 22 per cent.; 3 normoblasts per 100 leucocytes; W.B.C. 22,800 per c.mm. (polynaorphs 17 per cent., lymphocytes 81 per cent., monocytes 2 per cent.) After 12 months, during which her condition slowly deteriorated, her parents permitted her admission to hospital. The degree of spleno-hepatomegaly was unchanged, but her anaemia was more severe. The progress of the blood picture is summarized in the table. Examination of her serum showed evidence of haemolytic icterus and of liver cell damage, the results being: Total serum bilirubin 3.08 rag. per 100 ml. Direct acting bilirubin 0.35 nag. per 100 ml. Indirect acting bilirubin 2.73 rag. per 100 ml. Serum protein 8.61 g. per 100 nal. (albumin 3.72 g., globulin 4.89 g.) Thymol turbidity 18 units (Maclagan). Kunkel's gamma globulin 27 units. Alkaline phosphatase 15 units (King). Stained blood films showed marked anisocytosis, poikilocytosis and polychromasia, together with target cells, ovalocytes and normoblasts in moderate numbers. The osmotic fragility was diminished. Alkali resistant haemoglobin, presumably foetal, was present in a proportion of 7 per cent. T h e sickling test was still strongly positive, the erythrocytes assuming predominantly the elongated fitimentous shape which is characteristic of the bomozygous form of the disease.

The blood of the father showed slight hypochromia, with a positive sickling reaction. The mother was moderately anaemic and had a positive sickling reaction. In the case of each parent the osmotic fragility was slightly diminished, but their blood contained no haemoglobin of foetal type. The blood group of each parent, and of the child, was A/1. Father's blood Mother's blood

R.B.C. millions 5.27 4.33

Hb. g./100 ml. 13.4 11.1

MCV cu. t* 85 90

M.C.H.C. % 30 29

T h e r e was t h u s clear evidence that the child suffered f r o m sickle-cell anaemia, d u e to the h o m o z y g o u s i n h e r i t a n c e of the sickle-cell trait. I n view of h e r steady d e t e r i o r a t i o n d u r i n g 1 year's observation, it was d e c i d e d to r e m o v e h e r spleen i n a n e n d e a v o u r to e l i m i n a t e the m a j o r focus of haemolysis. F r o m the progress

390

U N C O M M O N ENDEMIC DISEASES OF THE PERSIAN GULF AREA

of he r b l o o d p i c t u r e after o p e r a t i o n (Table), it m a y be seen t h a t s p l e n e c t o m y was f o l l o w e d b y s o m e i m m e d i a t e benefit, t h e h a e m o l y t i c process b e i n g sufficiently ! n h i b i t e d to allow h e r to m a i n t a i n a c o n c e n t r a t i o n of r e d cells and h a e m o g l o b i n b e t w e e n 20 a n d 25 p e r cent. a b o v e TABLE. Nuriyeh Tahir.

Date 1953 4.VII 23 .VII 6.VIII ll.VIII 1.IX 1.IX

Treatment

Progress of Blood Picture.

R.B.C. Hb. millions/ g./100 M . C . V . M.C.H.C. % c.mm. ml. CU.

Normoblasts Retic. per 100 % leucocytes

2.07

4.80

89

26

22

8

2.53 2.36

6.50 7.70

83 112

31 29

18 17

2 42

2.73 3.70 3.69 3.24

7.25 8.20 8.40 8.60

93 86 80 85

28 26 28 31

8 5 11 17

68

Blood transfusion 250 ml. Blood transfusion 500 ml. Splenectomy and blood transfusion 500 ml.

8.IX 19.IX 14.X 8.XI

h e r p r e - o p e r a t i v e level.

2

T h i s d e g r e e of i m p r o v e m e n t was r ef l ect ed in h e r g en er al c o n d i t i o n ,

and in a gain of weight of 5 lb. in the 2 months after operation (despite the removal of a 5 lb. spleen.), compared with a gain of only 1½ lb. in a similar period prior to operation. Case 2. Farida bint Mahommad, a woman of 25 years, has already been the subject of a detailed report (WALTERS and YOUNG, 1954), under the diagnosis of micro-drepanocytic disease. T h e features of her case which are relevant to the present discussion were : (a) a chronic haemolytic state, with a concentration of red cells and haemoglobin stabilized at 3.5 million per c.mm. and 10 g. per 100 ml. respectively. (b) a very strong sickling reaction. (c) moderate microcytic anisocytosis with poikilocytosis and polychromasia, and the presence of target ceils. (d) diminished osmotic fragility. (e) the presence of a proportion of abnormal haemoglobin of two different types, foetal and sickle. (f) following splenectomy, great symptommatic improvement due to marked inhibition of the haemolytic process, and the appearance of very numerous target cells in the peripheral blood. Her father was a case of thalassaemia minor, while her mother carried the sickle-cell trait: the combination of the genes of these two conditions gave rise in the patient to a chronic haemolytic anaemia with a peripheral blood picture which reflected that of both Mediterranean anaemia and sickle-cell disease. Case 3. Abdul Khaliq Said, a man aged 21, suffered from a form of toxic dyshaemopoietic anaemia associated with a positive sickling reaction and the presence of a proportion of foetal haemoglobin. He was of pure Negro blood, though born in Basra. For 1 month before admission he had been suffering from a persistent headache, for which he had taken 8-10 aspirin tablets, daily, and latterly an additional 20 tablets of a French preparation containing aspirin and " amidone." He was in good employment and had been taking a satisfactory mixed diet. His presenting symptom was diarrhoea and the only abnormal clinical findings were fever and marked anaemia: neither liver nor spleen was palpably enlarged. Four days later, though the diarrhoea was controlled, the anaemia had become more severe and his condition appeared grave; there was bleeding from the gums, numerous retinal haemorrhages had developed and the heart had become dilated. T h e blood showed extreme anaemia, granulopoenia and thrombocytopoenia, and a few late megaloblasts were found in the stained smears. T h e details were : R.B.C. 1.20 million per c.mm. ; haemoglobin 3.65 g. per 100 rot. ; M.C.V. 96 cu. tz ; M.C.H.C. 32 per cent.; W.B.C. 1,280 per c.mm. (polymorphs 45 per cent.). An alkali denaturation test revealed the presence of 5 per cent. resistant or foetal type of haemoglobin. T h e osmotic fragility was normal. The bone marrow presented a very cellular but confusing picture. T h e r e was a mixed megaloblastie-

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391

normoblastic hyperplasia, associated with marked maturation arrest of the myeloid series, while megakariocytes could not be found. Treatment was initiated with~a blood transfusion, folic acid and ferrivenin. A reticulocyte crisis of 28 per cent. developed on the 5th day, and recovery rapidly ensued. After 1 month, blood examination showed: R.B.C. 4.63 million per c.mm.; and haemoglobin 11.5 g. per 100 ml. Foetal haemoglobin was still present in a proportion of 15 per cent. After a further month, the findings were: R.B.C. 5.90 million per c.mm. and haemoglobin 15.75 g. per 100 ml.; the sickling test remained positive and 20 per cent. of the haemoglobin was of the foetal type. In this case the anaemia was clearly incidental, being attributable to a toxic depression of the bone marrow by drugs of the antracene series. The interest lies in the final blood picture. The sickling reaction without an associated haemolytic anaemia, together with the " holly leaf" type of deformity assumed by the red cells under conditions of anoxia, indicated that the sickle-cell gene had been derived from only one parent, yet the presence of a proportion of the foetal type of haemoglobin is not consistent with a diagnosis of simple sickle-cell trait. Its occurrence suggests the combination of the sickle-cell gene with that of either thalassaemia or " haemoglobin III " (ITANO and NEEL, 1950). The absence of an abnormal degree of haemolysis, however, appears to exclude the former, for, as illustrated in Case 2 above, this combination of genes is characterized by a chronic haemolytic state. Blood from this patient is under electrophoretic study for the presence o f " haemoglobin I I I " as well as of the characteristic sickle and foetal types of pigment. Comment

It is now well known that the sickling reaction is not a characteristic peculiar to the Negro races, but is to be found among peoples devoid of Negro blood. It appears that in the Arab race there exist genes carrying the sickle anomaly, that of thalassaemia and possibly also that of " haemoglobin I I I . " There is scope for further investigation of this subject in Arabia. IV. ENDEMICFLUOROSIS Foci of chronic fluorine intoxication, as indicated by the high incidence of mottled teeth, are common in the countries bordering the Persian Gulf. Among those born in the town of Kuwait, teeth devoid of mottling are exceptional, for samples of local water obtained from depths down to 450 feet contain 2 to 2.4 parts per millions of fluorine. In addition to this innocuous manifestation, however, examples of advanced skeletal fluorosis have also been encountered. These have originated in two sharply defined loci, the twin towns of Shajah and Dubai, on the Trucial Coast, and the Wadi el Miyah, in the Hassa province of Saudi Arabia (see Map). A pooled sample of water from four surface wells from the former place was found to contain 8 parts per million of fluorine, but it has not yet been possible to obtain samples from the latter. Eight examples of gross skeletal fluorosis have come from Shahjah-Dubai, and one from the Wadi el Miyah. In seven out of these nine subjects, symptoms of their disease other than mottling of the teeth began in the 3rd or 4th decade. This is the usual period that elapses before an insidious ankylosing spondylosis begins to be manifest. (SHORTT, MCROBERT and BARNARD, 1937). Of greater interest, however, were two patients whose skeletal development was seriously impaired from their early years, and who appeared stunted and gravely deformed at the ages of 16 and 20 respectively. A detailed account of these two cases will be given. The radiological changes in the older patients followed the classical pattern. They were most

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U N C O M M O N ENDEMIC DISEASES OF THE PERSIAN GULF AREA

m a r k e d i n t h e vertebral c o l u m n , ribs, pelvis a n d p r o x i m a l b o n e s of t h e limbs. I n films of the affected skeletons the b o n e s showed increased radiological d e n s i t y a n d a p p e a r e d chalky white. T h e c o m p a c t b o n e was increased i n width, a n d t h e t r a b e c u l a r p a t t e r n of the cancellous b o n e was coarsened, w i t h m a r k e d t h i c k e n i n g of i n d i v i d u a l striae. G e n e r a l i z e d periosteal n e w b o n e f o r m a t i o n was evident, especially along the lower m a r g i n s of the ribs. Calcification of t h e anterior a n d lateral spinal ligaments restricted the m o v e m e n t s of the v e r t e b r a l c o l u m n , a n d the sacro-iliac j o i n t s in m o s t cases showed e v i d e n c e of fusion. Calcification of the a t t a c h m e n t of m u s c l e s a n d t e n d o n s a c c e n t u a t e d tile u s u a l ridges on t h e l i m b bones, a n d had e x t e n d e d i n some i n s t a n c e s to the interosseous m e m b r a n e s of arms a n d legs. Figs. 1, 2 a n d 3 illustrate these anomalies. N e u r o l o g i c a l changes were f o u n d i n four out of the eight p a t i e n t s who s u b m i t t e d to a full clinical e x a m i n a t i o n . T h e y were m a r k e d i n b o t h the adolescent patients. T h e changes c o m p r i s e d parasthaesias of the extremities, w i t h o u t objective s e n s o r y i m p a i r m e n t , a n d g e n e r alized spasticity. Case 3 will b e described as a n example of this s y n d r o m e . Case 1. Abdul Rahman Jeel, a youth of 20, came to Kuwait from his home in Shahjah 2 months before admission to hospital. He had never been able to walk or run as freely as other boys and during recent months his gait became so stiff that he was compelled to give up his work as a house servant. He reported that his mother was very short and that his only brother had deformities and a disability similar to his own. His six sisters were all stunted but able to walk well. His appearance is shown in Fig. 4. He was stunted (height 5" 2"), with a large skull, short bowed humeri and femora, bowed tibiae and fibulae and short spade-like hands and feet. Parietal bossing of the skull was a striking feature. Extension of the elbow joints was limited, and flexion of the spine almost completely abolished. The teeth showed large patches of opaque white and brown discolouration. His gait was stiff and clumsy and he was quite unable to run. Fine movements of the hands were defective. All the tendon reflexes were exaggerated and both patellar and ankle clonus could be readily elicited. The Babinski responses were indefinite but the abdominal reflexes were retained. The cranial nerves showed no abnormality and there were no objective sensory or sphincter disturbances. The Kahn reaction was negative in blood and C.S.F. Lumbar puncture gave a clear fluid under normal tension, containing 10 lymphocytes per c.mm., with no other abnormality. The blood count and urine showed no abnormality. Radiological examination showed that changes in the vertebrae were responsible in part for the short stature (Figs. 5 and 6), for, although the disc spaces were of normal width, the centra were compressed by about 30 per cent. as compared with controls, and were considerably widened. The femora showed marked anterior bowing, while the tibiae and fibulae were curved inwards at the lower ends. (Fig. 7). The long bones were heavy and much thickened, with a very coarse trabecular pattern and numerous transverse striae in the metaphyses. The bones of the hands and feet showed a similar pattern. The diploeae of the skull were thickened, the pituitary fossa was completely bridged and there was some basal invagination. Case 2. Munira bint Mahommad, a girl of 16 years, was brought to Kuwait from her home in the Wadi el Miyah because she was unable to walk. Married at 14 years, she had had one child, which had died within a few months of birth. She presented an arresting appearance, for she was very short (height 4' 2"), with bulging forehead, bent foreatwns and marked anterior bowing of the tibiae. She was able to stand with some support, but was unable to take a step. Fine movements of the fingers were very clumsily performed, there was increased tonus of the leg muscles, and all voluntary movements were weak. The tendon reflexes were exaggerated and ankle clonus could be elicited, but the abdominal reflexes were retained and the plantar responses were of flexor type. There were no objective sensory changes. The Kahn reaction was negative, and examination of the urine, C.S.F. and blood showed no significant abnormality. Radiological examination showed characteristic changes in the vertebral eolunm, ribs and pelvis, but the major abnormalities were those present in the forearms, legs and skull (Figs. 8, 9 and 10). The bones of each forearm were unduly thick, with a coarse trabeeular pattern, and were much bowed in the lateral plane. Healing pathological fractures were evident in each ulna. A ridge of periosteal new bone appeared above the lateral epicondyle of each humerus. Each tibia and fibula showed slight anterior bowing, with the formation of periosteal new bone along the posterior aspect of the shaft of each tibia. Healing pathological fractures were found in all four leg bones. The skull was thickened and its bones unusually opaque, especially at the base. The pituitary fossa was bridged. It appeared as though the base had been pushed up into the vault, to produce a mushroom-shaped deformity.

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Fig. 9. Skeletal fluorosis. Case 2. To show deformities of leg bones with pathological fractures.

Fig. 10. Skeletal Auorosis.

Case 2.

To show changes in base of skull.

J. H. WALTERS

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Improvement took place on treatment with a high calcium intake and vitamin D, 150,000 units daily, together with a 2 weeks' course of vitamin B12, 20 mg. daily. She regained the power to walk, though never very freely, and the fractures united. Case 3. Abdulla Faris, a man aged 52, had lived all his life in Shajah until he came to Kuwait for treatment. His symptoms comprised tingling of the extremities, clumsiness of the hands and an increasing difficulty in walking. The parasthaesia, deterioration in handwriting and defect in his gait had been noticed in that sequence some 2 months before he presented himself. The skull was large, with prominent temporal ridges, but the limb bones showed no abnormality and the spine was mobile. There was impairment of fine movements of the hands and fingers; the gait appeared slightly stiff when walking, but marked spasticity was evident when he attempted to run. An active jaw jerk could be elicited, the tendon reflexes in the arms were much exaggerated and a brisk finger jerk was obtained. The activity of the knee and ankle jerks was much increased and both patellar and ankle clonus were readily initiated. The abdominal reflexes were present and the plantar responses were of flexor type. There were no objective sensory changes. Dental fluorosis was well marked and characteristic changes were evident in X-ray pictures of the ribs, vertebrae, pelvis and skull. The Kahn reaction was negative in the serum, and the blood, urine and stools showed no significant abnormality. Comment

Chronic fluorine intoxication affects the physiology of the body in two important ways. It influences adversely the absorption and deposition of certain minerals, notably calcium and phosphorus (RoHOLM, 1937), and inhibits enzyme systems, especially those concerned in cellular respiration (RoHOLM, 1937; GREENWOOD, 1940). In numerous animal experiments it has been demonstrated, by balance tests, that a high fluorine intake diminishes the retention of both calcium and phosphate, the former to a greater extent than the latter. This reaction is influenced, however, not only by the total fluorine intake over a given time, but also by that of calcium, phosphate and vitamin D obtained from the diet during the same period. In practice, a high intake of vitamin D appears to be the most effective antagonist to the action of fluorine. T h e effect of chronic fluorine intoxication on the development and calcification of bone in the experimental animal is complex. T h e normal replacement of osteoid tissue by cancellous bone is disturbed, and the resulting trabecular formation is coarse and irregular: calcium is deposited sparingly and in large irregular particles. At this stage, a porotic condition resembling osteo-malacia develops, but later an excessive deposition of calcium leads to an abnormal thickening and densening of the compact bone. A concurrent periosteal stimulation gives rise to the formation of excessive periosteal new bone, and calcium is also deposited ectopically in muscle attachments, ligaments and interosseous membranes. Foci of skeletal fluorosis of an intensity comparable to that described have been reported from the Nellore district of south India by SHORTT, MCROBERT and ]~ARNARD(1937), and by LYTH (1946) from the Yunnan province of China. Such naturally occurring loci must be rare, but their recognition is of importance since the causal agent may be eliminated without great difficulty. T h e influence of chronic fluorine intoxication on intracellular enzyme systems may lead to degenerative changes in many parenchymatous organs, notably the kidney (SHORTT et al., 1937) and the liver (RoHOLM, 1937). Its effect on the nervous system has received little attention, though a significant experiment was made by ROHOLM (1937) on a group of pigs 8 weeks old. After feeding these animals on a diet containing 15 rag. fluorine per kg. per day for 2 months, they developed a stiff gait with paresis of the hind limbs. T h e neurological changes which were an important feature in the series described by SHORTT et al. (1937) were ascribed by them to compression of the spinal cord by posterior protrusion of osteophytes

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into the spinal canal. In the present series of four patients, however, certain features do not accord with this conception, and suggest rather that the syndrome may result from a generalized toxic degeneration of sensory and pyramidal nerve cells. In the degenerative form of chronic spondylosis of later life, parasthaesia of the limbs is usually accompanied by pain, sensory impairment and some muscular weakness of segmental distribution (DIMSDALE, 1954). These were not evident in the cases under review. A degree of spastic quadriplegia, modified in the upper limbs by the effects of root compression, is also frequently attributable to chronic spondylosis in Great Britain (DIMSDALE, 1954). Although segments may be affected above the highest level at which posterior disc protrusions can be demonstrated in the cervical spine, possibly from interference with the flow in the anterior spinal artery, and from the pull of the denticulate ligament on the displaced cord, such factors could scarcely give rise to spasticity of the temporalis muscle, which was manifested in Case 3 by an active jaw jerk. The development of severe skeletal deformities before adult life is unusual, and was not found in the Nellore cases nor in those reported from China by LYTH (1946). If the degree of conditioned calcium deficiency were sufficiently severe and sustained during the period of growth, the development of pseudo-rachitic deformities, such as those shown in Case 1, could readily be expected: the additional drain on available minerals imposed by pregnancy, as in Case 2, might be expected to precipitate a condition resembling osteo-malacia. It is of interest that the people of Shahjah-Dubai are well aware that their defective water supply is the cause of their common disability, but can find no alternative source which is generally available. SUMMARY (1) An endemic focus of schistosomiasis mansoni has been found at Majma, near Ryadh, in Saudi Arabia. (2) Juvenile kala-azar exists on the Persian Gulf littoral. (3) Examples of sickle-cell anaemia and of other types of genetic anaemia associated with the sickling phenomenon are to be found among Arab peoples. (4) Foci of severe skeletal fluorosis exist in Shahjah-Dubai , on the Trucial Coast, and in the Hassa Province of Saudi Arabia. REFERENCES ABBASY,A. S. (1951). Blood, 6, 555. ARCHIBALD, R. G. (1926). Trans. R. Soc. trop. Med. Hyg., 19, 389. DIMSDALE, HELEN(1954). Proe. R. Soc. Med., 47, 54. GREENWOOD,D. A. (1940). Physiol Rev., 20, 582. GREVEL, S. D. S. (1923). Indianff. reed. Res., 10, 934. ITANO, H. A. ~%NELL, J. W. (1950). Proc. nat. Acad. Sci. Wash., 36, 613. LYTH, O. (1946). Lancet, 1, 233. MALCHI, A. (1924). Harefuah, 1, 75. (Abst. in Trop. Dis. Bull (1925), 22, 866). PETRIE, P. W. R. & SEAL, K. S. (1943). A Medical Survey of the Western Aden Protectorate, 1939-40. London: Colonial Office. 183, 88. ROHOLM,K. (1937). Fluorine Intoxication. Copenhagen: Arnold Busch. REID, H. S. (1952). Trans. R. Soc. trop. Med. Hyg., 46, 555. SHORTT, H. E., McROBERT, G. R. & BARNARD,T. W. (1937). Indian ft. reed. Res., 25, 553. WALTERS, J. H. • YOUNG,N. A. F. (1954). Trans. R. Soc. trop. Med. Hyg., 48, 253. YOUNG, N. A. F. (1954). Personal communication.