Renal rickets or renal dwarfism

RENAL RICKETS OR RENAL DWARFISM* T. LEON HOWARD,

M.D.,

P.A.C.S.

Associate Professor of UroIogy, University of Colorado; Genito-Urinary Surgeon, ChiIdren’s and Mercy Hospitals DENVER, COLORADO

rickets and renal dwarfism are names which have been applied to a most interesting, yet IittIe described disease of chiIdhood and earIy adult Iife. This disease is manifested by rachitic symptoms, asexualism, renaI deficiency, and polyuria. The renaI deficiency simuIates that of a chronic interstitial nephritis, or nephroscIerosis. ApparentIy renaI rickets has no predominant prediIection for one sex. The paucity of reports of this disease in genitourinary Iiterature, except for a paragraph by Hinman6 in his recent book, principles and Practice of Urology, prompts us to Iook to the pediatrician and orthopedist for case reports. According to Pfaundler and SchIossman,‘O it was first recognized by Goodhart in 1872, but A. Graeme MitcheII,s of Cincinnati, credits Stenier and Neureutter in 1870 with the first description. In 1883, Lucas’ described in the Lancet, “A Form of Late Rickets associated with AIbum~nuria.” He was of the opinion that albumin occurred too often in rickets of adoIescence to be a mere chance finding. Hunt! says the average duration of Iife after the appearance of the bone deformity is Iess than two years. Up to 1927 there had been but fifty-three recorded cases, and only seven in American Iiterature. The number stiI1 remains under loo, but uroIogists are probably seeing this interesting disease in certain stages of its deveIopment, and are faiIing to recognize it in its entirety because of the muItipIicity of symptoms. ENAL

R

For this reason, and because one of the three cases reported here is complete, I am presenting some review of the subject. WhiIe I am fuIIy aware that the disease is not confined strictIy to the genitourinary organs, it holds one’s interest because of its diversified symptoms and contradictory manifestations. For instance, it is questionabIe whether, were it not for the renal pathoIogy and bIood chemistry, the roentgenoIogist couId differentiate the bone changes from those of ordinary rickets; consequentIy ordinary dwarfism is often confounded with it. On account of polyuria and ~Iydypsia, it has been mistaken for diabetes insipidus. OnIy the terminal stages of renaI rickets may show hypertension, arterioscIerosis, signs of uremia, convuIsions, edema, failing mentaIity, and coma. Yet we find every condition which is supposed to enter into the production of these symptoms, nameIy, a Iow and fixed urine concentration, high bIood protein, Iow blood caicium with high bIood phosphorus, acidosis, and a urine containing aIbumin with hyaIine casts. I fee1 certain that there is an acquired type of renaI rickets, the cause of which, if not reheved, resuIts in bone changes. AIso, there certainly must be a greater number of chiIdren suffering from this condition than the few reports in the Iiterature wouId indicate. The acquired type is often the resuIt of obstructions anywhere beIow the kidney pelvis. EarIy cases do not have a11 the cardina1 signs, which are manifest in

* Read before the Section of Genito-Urinary Surgery, New York Academy of Medicine, Feb. 17,

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the child who has reached the advanced stq ;e of the rachitic; we often prevent the advrance to the Iater stage by relieving the

FIG. I. .I. S. at the age of 19.

cause without perhaps reaIizing that such a disease process was in progress. MitcheI16 in his most compIete review of the Iiterature, mentions congenita1 diIatation of the urinary passages as a cause, as we11 as acquired postnata1 obstruction. Two of my three cases were secondary to the congenita1 type of urinary obstruction. The diagnosis of renaI rickets is based on the folfowing findings: I. General Appearance. This usuahy conforms to a certain type. The skin is dry and often pigmented a dirty yeIIow. The hair of the head is coarse and brittIe, and if the child has reached the age of adoIescence, the pubic hair is thin but coarse, with a we11 defined Iine of demarcation.

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The face is wrinkIed and expression] .ess, resembling that of a Mongoiian idGot. These, together with characteristic Ieg

FIG. 2. J. S., compared with a normal boy of the same age.

deformities and changes which come with Iack of sex deveIopment, give a dwarfish appearance. (Figs. I, 2 and 3.) 2. Bone C~unge~. As a rule these first attract the parents’ as we11 as the physician’s attention. The child deveIops either a genu vaIgum or a genu varum; confirmation is afforded by the x-ray findings. According to the roentgenoiogist, the changes are about the epiphysea1 areas. There is a greater transIucency and a more spongy appearance in the bones of the renal rachitic than in the chiId with ordinary rickets. The skuI1 picture is characteristic; it has been described by Parson9 as having a wooIIy, stippIed, or honey-

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combed appearance, with great thickness. (Figs. 4, 5 and 6.) I was astounded at the ease with which the skuI1 and the femur

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nephritides, we find a moIecuIar retention, and it is we11 known that the larger the moIecuIe, the quicker and greater wiI1 be

FIG. 4. X-ray of sk;lI, showing wooIIy appearance.

FIG. 3. Pubic hair line of J. S. at the age of rg.

were amputated with the ordinary autopsy knife. According to both the roentgenologist, Dr. F. B. Stephenson, and the pathoIogist, Dr. E. I. Dobos, the skuI1 shows marked thickening, with osteoporosis, and the Iong bones show fauIty caIcification (Figs. 7, 8 and g), with softening at the epiphysis, resuIting in the deformities. The seIIa turcica (Fig. IO) was 6 mm. deep, the minimum for the age, and was g mm. in its anteroposterior diameter. This is smaIIer than,the average for the same age, which is 6 by 12 mm. (Fig. I I .) 3. Blood Ganges. Norma1 chiIdren show a bIood caIcium of g to I I mg., and phosphorus between 3.5 and 5 mg. per IOO C.C. In renaI rickets this ratio changes, the phosphorus increasing and the caIcium decreasing, the opposite of ordinary rickets. The cause of this reversa1 is one of the much discussed questions of the disease, for, as is we11 known, there seems to be throughout Iife a constant attempt to maintain a certain norma baIance between the amounts of caIcium and phosphorus in the body. In renaI rickets, as in a11 true

the retention of the substance which that particuIar moIecuIe goes to make up. According to the theory advanced by MitcheIP when the kidney begins retaining phosphorus, this substance seeks the bowels as a means of eIimination. As it enters the aIimentary tract it immediateIy comes in contact with the food caIcium, and, unfortunateIy for the patient, an insoluble caIcium phosphate is formed. This prevents caIcium from entering the bIood stream, and causes a serious caIcium depIetion. The necessary caIcium must be obtained from some source, and since the exogenous caIcium is not avaiIabIe because of its combination with phosphorus for eIimination via the coIon, bone caIcium is drafted for use. The Ioss of caIcium from the bones resuIts in the bone changes so graphicaIIy shown in the autopsy findings. Reports of cases in which bone changes occur have made very Iittle mention of parathyroid findings. Julian D. Boyd,2 in a report on cIinica1 hyperparathyroidism with the citation of a case, makes the foIIowing statement: “It wouId be easy to make a diagnosis of renaI rickets in a patient with bone changes such as are found together with such in this conditio?,. urinary abnormahtres. However, the two

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conditions can be cIearIy differentiated by the determination of serum, caIcium In renaI rickets, the and phosphorus.

to be markedIy increased in size (Fig. whiIe at the same time there was increase of the bIood phosphorus to

IZ), I

an 1.3

FIG. 6. Photomicrograph from skull, showing bone changes. A, muItinucIeated osteocIasts in Howship’s Iacunae. B, fibrous marrow tissue. c, numerous newly formed trabeculae.

FIG. 5. Photograph of the skuII at autopsy, the extreme thickness.

showing

caIcium is lowered and the phosphorus increased, whiIe in hyperparathyroidism,

FIG. 7. Bony deformities of the knees.

the reverse is true.” As I have stated, this is a disease of contradictions, for in our reported case the parathyroids are shown

mg., with a caIcium reading of 9.4 mg. I suspect that a11 patients of this type, with bone changes, who Iive any Iength of time, have an increase in the size of the parathyroids. Where these gIands do not show a hyperpIasia, there are no bone changes compIicating the nephritis; the case shouId then be cIassed as one of uncomplicated chronic interstitia1 nephritis, a condition aIways ending in an earIy death. The mere fact that bone changes do occur shows that this type of rickets is due to a hyperpIasia

FIG. 8. Deformities

of the wrist joint.

of the parathyroids. (Fig. 13.) It is their hyperactivity which mobiIizes the bone calcium, thus in order to maintain keeping

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up a suflicient amount of bIood serum caicium to prevent, as long as possibIe, uremic convuisions, which certainIy shouId occur earIy in the disease, as there is a marked protein retention as we11 as an acidosis. Edward L. Compere3 states: “ In the aduIt as we11 as in the chiId, the bone sa1t.s are continuaIIy removed and renewed, so that there is a constant Aow of both caIcium and phosphorus away from bone into body &ids, and a redeposition of simiIar saIts which have been absorbed from the intestina1 tract. The ratio must be constant if perfect health is to be obtained.” 4. Sex Development. A Iack of sex deveIopment at the age of puberty is a characteristic phenomenon in every case. On this account the hormones have been implicated. In this condition, as in other kidney Iesions of chiIdhood, Iack of sex deveIopment is found, but in none of the autopsy protocoIs of renaI rickets have I been abIe to find reports of sections of either testicIes or ovaries, though a11 writers mention them as undeveIoped. Of course, the simpIest expIanation wouId be to incIude the undeveIoped sex glands as part of the general picture of dwarfism, but it would be a great dea1 more pIausibIe were we to ascribe the dwarfism to the inactivity of the sex hormones, in spite of the fact that Hurtz was unable to find any endocrine changes. Figure 14 shows the testicIe in our case, and according to the pathoIogist, there was a tota absence of cytogenesis. The Iumen of the acini is partiaIIy or compIeteIy obIiterated, and the interstitia1 ceIIs of Leydig greatIy decreased in number. NevertheIess, this patient at the time of his death was twenty years of age. Can the tubular portion of this testicle produce that gIamorous hormone (inhibin), the absence of which aIIows the anterior pituitary Iobe free sway? The testicIes as a whole appear distinctIy smaIIer than usua1, and upon weighing those of our patient, they were found to be onIy 13.5 Gm. each. The epididymis is essentiaIIy negative.

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5. Renal Changes. It is here that the rea1 diagnosis is made. Up to the present, knowledge of these changes is based onIy

FIG.

faulty

9.

Autopsy calcification

sections through with softening

knees, showing at the epiphysis.

on autopsy reports, which in the fma1 anaIysis are unquestionabIy the most accurate. MicroscopicaIIy, there are scIerotic changes in the interstitia1 tissue, which before death affect the majority of the tubuIes and gIomeruIi. Those tubuIes which are active show a very large Iumen due to one of two conditions, a diIatation from back pressure or a compensatory hypertrophy. Dr. George B. Bader of New York’ gave an accurate description of these renaI changes. The interesting feature about the gIomeruIi that are Ieft is that they show what appears to be hyperpIasia, as though they had made an extra attempt to carry on the work after the interstitial changes had destroyed the majority. Hyalinization has taken pIace in numerous other gIomeruIi with Iymphoid deposits. Bowman’s space in some instances seems as though it had become dilated, making one think that in

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its attempt to excrete urine through the tubuIar system which had become partiaIIy bIocked by connective tissue, back pressure

FIG.

IO.

SeIIa turcica

of J. S. Dimensions g mm.

6 by

had occurred, producing this condition. (ShaII we coin a word and caI1 it hydrobowmanosis?) Something Iike this must have taken pIace in many of the gIomeruIi in which hyaIinization foIIowed. The scarcity of renaI bIood vesse1 pathoIogy is of interest and offers the only pIausibIe reason for the Iow blood-pressure which is so characteristic in these patients. Throughout the entire kidney, caIcium is deposited, but it is confined to the interstitia1 tissue, the tubuIes escaping and the arteries showing very IittIe change. Again the disease is one of paradoxes, for in other parts of the body the arteries show marked caIcium deposits. SeveraI case reports have mentioned renaI caIcuIi, but have not designated the Iocation of the stones. (Figs. 15 and 16.) This type of kidney conceivabIy is produced by two causes, i.e., either congenita1, or acquired. To say what produces the congenita1 type wouId be to dea1 only

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with theories. The acquired type is described more often than any other, and yet some authors do not reaIize that they are

FIG. I I. Normal

selIa turcica. 12 mm.

Dimensions

6 by

dealing with interstitial changes in the kidney produced by Iower tract pathoIogy. ReIief from Iower tract pathoIogy by uroIogic maneuvers is the onIy hope for these sufferers. The first case I am reporting is of the congenita1 type, for which I am indebted to Dr. Roy P. Forbes4 The other two patients came under my observation, but it was Dr. Atha Thomas,l’ an orthopedist, to whom I referred one of these patients on account of a genu valgum, who made the diagnosis. In the case of Dr. Forbes, the diagnosis was compIete with the exception of the genitourinary findings, and Iater, the autopsy report. I was requested to see the patient to examine the renaI tract. The foIIowing case history was obtained from the records of the Chiidren’s HospitaI, where the patient had been under observation at varying intervaIs for the preceding four years.

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CASE

REPORT

J. S., age 16 years, was seen in September 1933, with a diagnosis of renaI rickets. His father was 6 feet talI, and weighed 225 pounds. His mother, brothers, and sisters were of average size. There had been no miscarriages, and there was no history of lues in father or mother; no history of any chronic familia1 diseases. The patient was a fuI1 term baby, deIivered normalIy, with a weight of 6 pounds at birth. He had been breast fed unti1 one year of age. Beginning at six months, orange juice x to I ounce daiIy and lime water were given. Shortly afterward, egg, cereal, and green vegetabIes were added. At one year, EagIe Brand milk was given, but no cod liver oi1 was taken unti1 two years of age. The patient lived on .a farm in Missouri, and had abundant exposure to sunshine. However, from a birth weight of 6 pounds, he gained onIy 6 additiona pounds in two years. Tbe skin bas always bad a bronze color. His first tooth erupted at six months. The fontaneIIe cIosed at the age of one year, according to his mother. She noticed no bony changes in skuII or ribs, but the Iower Iegs were bowed, due to softness of bones (genu varum). The patient began waIking at 1% years, but owing to extreme bowing of Iegs, wore braces for support. Later, he deveIoped knock-knees (genu vaIgum). He began school at the age of 6, but his mother considered him backward in comparison with other children, and at the age of 15, he finaIIy reached the eighth grade. He was out of schoo1 at the age of 6 because of a fracture of the right Ieg (cause of this fracture was not given). Diseases and injuries incIude scarIet fever at 5, with no folIow-up urinaIysis; compound fracture of right tibia at age of 6, which became infected and bone was scraped one year Iater; 0nIy recently a smaI1 amount of drainage recurred; appendectomy at 14. Present Illness. Mother presented the child at Children’s Hospital on the advice of the physician who had treated the oId infection of the Ieg. The chief compIaint was that the chiid had failed to grow and deveIop normally, that his bones were soft, necessitating braces for support. There was no history of growing pains. The symptoms reported were moderate frequency and polyuria; moderate poIydipsia; no headaches; occasiona vomiting and distention relieved by fruit juices and soda water; no con-

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vuIsions; no tetany; sIight edema of the ankIes at times; no hemorrhage tendency; no visua1 disturbance; no paIpitation.

FIG. 12. Autopsy

specimen of parathyroids, enIarged.

greatly

Physical Examination. The patient was a poorIy nourished, poorIy deveIoped white male, apparentIy about 12 years of age, though his rea1 age was 16, Iying quietIy in bed with no apparent distress. His voice was of a chiIdIike quaIity. His skin was loose, dry, and of a saIIow, dirty, bronzed appearance. The scaIp was cIean, with a norma growth of brown hair, coarse in texture. The skuI1 was symmetrical, but the prominent parietal bones made it appear large in reIation to the rest of the body. His facia1 expression was vacant, and his features definitely mongoloid. The ears were negative. The pupiIs reacted normaIIy, with norma fundi and muscIe baIance. There was no obstruction to breathing, and the bucca1 mucous membrane was normaI. The teeth, smaI1 in size, were stained a dirty yellow. The tonsiIs were somewhat enIarged, giving evidence

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of chronic inffammation, but no adenopathy was present. The patient was markedIy pigeonchested. No Harrison groove was noted; the

FIG. 13. Photomicrograph

Rickets BIood chemistry per cent; creatinine caIcium 10.5 mg.

of parathyroid,

percussion note was resonant, and the breath sounds cIear. No apparent enIargement of the heart was noted, and the sounds were of good quaIity. A tendency to pot beIIy with sIight distention was present, but no tenderness was elicited and no organs were palpable. No scoliosis or kyphosis was observed. The extremities were poorIy deveIoped, the joints prominent, but without tenderness. There was a marked exterior bowing of both femurs, most pronounced in Iower third, with miId genu vaIgum and marked genu recurvatum, subluxation of both knee joints, and vaIgus deformity of both ankIes. The genitaIia were smaI1 in size; no pubic or axiIIary hair was present. The reflexes were within norma Iimits. Laboratory Findings. The urine was acid, with a specific gravity of 1.003, a trace of albumin. Sugar and acetone were absent; no casts were noted; there were few white ceIIs and no red ceIIs. The Mosenthal kidney function test showed fixation to 1.004 and 1.007. The bIood hemoglobin was 45 per cent; R. B. C., 2,250,000; W. B. C. 6,400; 62 per cent poIymorphonucIears; 38 per cent Iymphocytes. The basa1 metaboIic rate was pIus 3 per cent.

showed N. P. N. ‘09 4 mg.; phosp iori 1s 6

w. w. ;

showing marked hyperplasia.

The bIood Wasserman was negative. I. Q. was 55 on Psychological Examination. the Binet test and 60 on the Otis. Roentgenologic Examination. X-ray of skuI1 showed the seIIa turcica to be sIightIy smaIIer than norma for a chiId of this age. Tibia and fibuIa showed some cupping of the Iower epiphysis of each Ieg, having the appearance of an oId rachitic condition. Some irreguIarity of outIine appeared at the Iower epiphysis of each uIna and radius, with some cupping, suggestive of rachitic change. In November 1933, x-rays of the hands showed sIightIy increased recaIcification of the Iower epiphysis of the uIna and radius, representing a sIight improvement over Iast examination. In June 1934, a second Iaboratory examination discIosed that the urine was neutral, with a specific gravity of I .006; aIbumin 2 PIUS; sugar and acetone negative. An occasiona pus ceI1 was present. The bIood hemogIobin was 50 per cent; R. B. C. 3,000,000; W. B. C. 6,600; 67 31 per cent per cent poIymorphonucIears; 2 per cent eosinophiIes. Iymphocytes; BIood chemistry at this time gave the foIIowing resu1t.s: N. P. N. 120 mg.; creatinine 12 mg. ; caIcium 9.4 mg.; phosphorus I I .3 mg.

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(Certainly a most interesting bIood chemistry, in the face of the improved bIood counts.) On August 1933 the urine was acid, with a

FIG.

specific

14. Photomicrographs

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In January x936, the chiId was brought to the hospital because of recentIy occurring distention with vomiting. This had occurred

of sections through the testicdar a tota absence of cytogenesis.

gravity of I .OI 4, aIbumin I PIUS, and an occasiona pus ceI1. BIood chemistry showed N. P. N. IOO mg.; creatinine 5.2 mg.; urea 45.0 mg.; caIcium 9.0 mg.; phosphorus 7.0 mg.

American JournaI of Surgery

tubuIe, showing

sometimes after meaIs, but was reIieved by either fruit juices or soda water. Between meaIs, distention was aIso induced by coId water. PhysicaI examination showed no essen-

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tiaI change from the previous chemistry creatinine

records. BIood was as foIIows: N. P. N. IIO mg.; 3.65 mg.; caIcium 6.9 mg.; phos-

FIG. IQZ. Photomicrographs

Rickets

On March 3, 1936, the COz combining power of the bIood plasma was 32. A compIete eye examination was negative in every respect.

of sections through the testicular a total absence of cytogenesis.

8.3 mg. The phorus showed improvement, and 1.014.

MosenthaI fixation varying between

test I .o08

FIG. 15. Photomicrograph of kidneys, showing enormous dilatation of the tubuIar system with an increase in the size of the individua1 gIomeruIi. 28, 1936, the bIood chemistry On February was: N. P. N. 172 mg.; urea nitrogen 53.2 mg.; 10.6 mg.; phoscreatinine 4.6 mg.; caIcium phorus 8.8 mg.; per IOO C.C. of bIood.

Mar, 1938

tubuie, showing

The bIood count was: hemogIobin 36 per cent; R. B. C. 2,500,000; W. B. C. 4,000; 65 per cent poIymorphonucIears; 35 per cent. (Fig. 17.)

FIG. 16. Photomicrograph of kidney, showing calcified deposits in the interstitial tissue.

Course. I was caIIed in consuItation to see this patient January 26, 1936, at which time cystoscopy was done. A No. 21 F. BrownBuerger cystoscope was passed without difflcuIty under a IocaI anesthetic. The bIadder was most interesting on inspection, as it gave one

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the impression of a toneIess sac. The mucosa was extremeIy paIe. The uretera openings were not dilated, but the orifice on the right was

Yoaenth~lPlX.tGiOll Sept..‘33 Jan. co2

'38

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defect except that it was of miniature size, with but two welLdefined major caIices present. There was no deformity of the major caIices,

1004 to Km7 la08 to 1014

Combining Power or Blood Plasma Yuoh

'36

32

FIG. 17. A few of the blood and urine findings in the case of J. S. from September rg33 to February 1936.

larger than normal. No. 5 radiographic catheters were introduced up to each kidney, the right meeting with obstruction about 2.5 cm. up, aIthough the meatus on that side was the Iarger. After some manipuIation, the obstruction was overcome and no further diffIcuIty was encountered. Urines were coIIected from each side, urine from the Ieft coming with more frequent and forcefu1 drops than from the right. Stereo-retrograde pyeIograms were made, using neoiopax as shadow media. (Fig. 18.) The dimensions of these kidneys are measured on the fiIms as foIIows: right, 8 cm. in length, 3 cm. in width; Ieft, 7 cm. in length, 2.5 cm. in width. (Fig. ISA.) Compare these dimensions with those of a 6 months oId infant, whose kidney measures 6 cm. in Iength and 3 cm. in width. (Fig. lg.) made by using a Figure 20 is a cystogram 3.5 per cent soIution of sodium iodide and fiIIing the bladder unti1 a sensation of fullness was compIained of. This occurred after the introduction of 14 ounces of the solution. There is no regurgitation up either ureter. From a uroIogic standpoint, it is inconceivabIe that kidneys of this size are capable of carrying on Iife at a11 in a person even haIf the patient’s size. The onIy cIassification under which they can conceivabIy be pIaced wouId be that of congenita1 hypopIastic kidneys, for they appeared to be perfectIy deveIoped in shape, position and contour. The one on the right had no major calices, the minor caIices springing directly from the kidney peIvis, as so often occurs in a hypopIasia of the kidney of congenita1 origin. The peIvis on the Ieft showed no

FIG.

18~.

PyeIogram

taken

January

26,

1936.

yet it was appartnt that they were not nearIy so we11 deveIoped as those of the 6 months old baby demonstrated. The ureter on the right showed some diIatation, which was probabIy accounted for by the obstruction in the first 2.5 cm. of the ureter. coIIected from each (Fig. 21.) The urines kidney gave the same findings as the combined urines, except for an occasiona pus cell from the Ieft. There was onIy an occasiona urine report which gave an acid reaction; yet the bIood showed that the patient was in a state of acidosis. The prostate feIt by rectum, had two weIIdefined IateraI Iobes with a median suIcus, and to the examining finger there was diminished eIasticity. A vigorous massage given to both vesicIes and pros.tate faiIed to express the slightest secretion. The massage was done on a fuI1 bIadder, fiIIed with distiIIed water which was sent to the Iaboratory after it was voided. No spermatazoa or amyIaceous bodies were found-in fact to the eye, the water was as clear as when introduced into the bIadder. The scrotum was of the Aabby type, seen often in with very sIuggish cremasteric old men, reff exes. Both testicIes were firm, but smaI1 and round, Iike those of a chiId of 3 to 4 years. I was abIe to define the epididymis, and there seemed

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to be a sIight amount of fIuctuation on the head of the one on the right. The vasa were pIainIy paIpabIe.

pIete cystoscopic examination, and certainIy the o&y one in which the seminal vesicies have been x-rayed.

FIG. 18~. Autopsy of kidney, September

On February 27, 1936, another cystoscopy was performed, for I was curious to see with a McCarthy panendoscope, the appearance of the prostatic urethra, and to reinspect the bIadder. There were no notabIe changes in the bIadder from the previous examination, but the ureters were very ciose to the bIadder sphincter, which I find is usuaIIy the case when a patient has, as this one did, a we&defined coIIar neck obstruction, although no residua1 urine was demonstrable at either examination. The verumontanum was large and extremely paIe; the openings of both ejacuIatory ducts was easiIy visualized. the Ieft On March 2, 1936, I catheterized ejacuIatory duct and injected 3 C.C. of neoiopax to see if atrophy of the seminaI vesicles had occurred aiong with that of the testicIes. The vesicle couId be we11 HIed, and the vas couId be folIowed down to the externa1 inguinal ring which proves that a faiIure of (Fig. 22), development of the testicIe does not necessariIy produce an atrophy of the vas and semina1 vesicIes. As far as I am abIe to find, this is the onIy case of renal rickets that has ever had a com-

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IO, 1936.

An intravenous dye of neoiopax, using I 5 c.c., was given, and at the end of thirty minutes nothing had been excreted in sufficient quantity to give the shadow of either kidney, peIvis, ureter, or bIadder. Figure 23 was taken during this period to demonstrate this, and brought out a most interesting finding, nameIy, caIcification of the interna iIiac arteries on both sides. This caIcification has been mentioned by severa writers on the subject, but aIways as an autopsy finding. To me it is hard to expIain why there shouId be caIcification in these arteries and decaicification in the bones. One wouId think that with the bIood so deficient in caIcium, the substance wouId be drawn from any source possibIe; yet these arteries have every appearance of deposits of caIcium saits in their waIIs. This was Iater checked at the autopsy. The changes in the bony peIvis (Fig. 23) are aIso typica of those of renaI rickets. The adrenals may pIay a more important r&e than has hitherto been ascribed to them. Dr. Dobos describes a fatty infdtration of the cortex, with the meduIIary substance essentially negative. (Fig. 24,) As the cortex is the principa1 secretory portion of the gIand, this

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fatty change couId interfere with the physioIogic function, even to the extent of causing the pigmentation in the skin.

Rickets

This patient entered the hospital (walked in) for the last time on August 6, 1936, and the following is taken from the hospita1 record: “This patient, who has been in the hospita1 repeatedIy over a four-year period, entered because of vomiting. He had not been abIe to retain fluids for twenty-four hours. A bIood examination reveaIed: N. P. N. 300 mg.; creatinine 4.9 mg.; caIcium 9 mg.; phosphorus 412; with a blood pi of 10.2 mg.; chIorides 6.95. PhysicaI examination was apparentIy the same as on previous examinations, except that the deformities were more marked.” The patient did we11 for about two days. He then developed a severe stomatitis. The nasa1 cavity and tongue Iooked as if they were covered with a IeukopIakia. The blood-pressure were remained about I 10/40. The eyegrounds normaI. The patient refused feedings, and vomited continuousIy. Intravenous Auids, Hartman’s and gIucose, and a bIood transfusion were given. The patient then compIained of inability to move his Ieft arm and leg, but no paralysis or weakness was noted on physica examination. The course was steadiiy downhiI1. The young man became mentaIIy torpid. The

of Surgery

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Iast two days his fingers became cyanotic and the heart tones poor. Despite st~muIation, he expired September IO, 1936.

FK. FIG. 19. Pyelogram of a 6 months old infant. Compare this with that of the 19 year old patient.

American Journd

20. Cystogram

of J. S., using

3.5 sodium iodide.

Figure 25 shows other bIood examinations during this last iIIness. On several occasions the specific gravity of the urine was between 1.012 and 1.018, which seems incredibIe when one considers the kidney drainage. The vomiting, however, couId account for this concentration. Autopsy. The autopsy findings were recorded by the pathologist, Dr. E. I. Dobos, who also prepared the materia1 from which the Zustrations were made. Autopsy Name: J. S. Age: 19 years Attending Physician: Dr. R. Forbes Prosector: Dr. E. I. Dobos

ProtocoI Case No. 22439 Autopsy held at Children’s Hospital, September IO,

1936.

Present at Autopsy: Forbes, Howard, Graw, Verploeg, House Staff.

Drs. Mcand

The body is that of a poorIy deveIoped and very poorIy nourished white maIe chiId ~35 cm. in Iength. The head appears to be enIarged and out of proportion to the rest of the body. The skin shows marked brownish coIor which appears to be fairIy generaIized. However, there are numerous areas of varying size where the skin appears to be bleached. The genera1

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appearance of the skin cIoseIy resembIes the bronze toIor of Addison’s disease. The subcutaneous tissue has Iost the greatest portion

FIG. 21. X-ray of right kidney, showing no major calices.

of the fat content, and the skin may be Iifted up in extremeIy thin foIds. The skeIeta1 changes are extensive. There is a marked deformity of the spine which appears to be a kyphoscoliosis, with possibIy a Iordotic curve in the thoracic region. The bony waI1 of the chest shows a marked IateraI compression on both sides causing a prominence of the sternum -thus somewhat approximating the shape of a pigeon chest. At the junction of the osseous and cartilaginous portion of the ribs on both sides, prominent sweIIing is noted on a11 ribs. The comparative me~urements are: anteroposterior diameter of the bone portion of the ribs, 7 mm.; anteroposterior diameter of the cartiIaginous portion of the ribs, 6 mm.; anteroposterior diameter at the osteochondral junction, 16 mm. The peIvic frame appears to be usua1 in configuration. Upon examination of the Iower extremities, a marked genu vaIgum is noted. Upon opening the chest, approximateIy 40 C.C. of straw-coIored, cIear ffuid is encountered on both sides of the pleura1 cavities. A few firm, calIous adhesions are encountered on both sides of the pIeural cavity. Otherwise, the pIeural surfaces are essentiaIIy negative. The lung parenchyma is rusty brownish in

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MAY, 1938

color, shows no areas of consoIidation or atelectasis, and on the cut surface a considerabIe amount of straw-coIored, cIear Auid empties on pressure from the aIveoIar spaces. The pericardia1 sac contains the usua1 amount of straw-colored, cIear ffuid. The heart is moderateIy enIarged, and the enIargement is chiefly due to diIatation rather than hypertrophy. The measurements of the myocardium I I mm.; right are: left ventrieuIar myocardium, 3.5 mm. The myoventricular myocardium, cardium is soft and flabby throughout and appears grayish in coIor. Examination of the mura1 and vaIvuIar endocardium faiIs to discIose significant anatomic changes. Upon examination of the large vessefs, severa disseminated atheromatous pIaques are found just above the sinus of VaIsaIva which entireIy disappears in the ascending portion and in the arch of the aorta. No atheromatous changes are found in the puImonary artery or in the coronary vesseIs. The structures of the posterior mediastinum are essentiaIIy negative. The peribronchia1 and hi1u.s Iymphnodes show no evidence of enIargement and are usua1 in shape, coIor, and consistency. The thymus has aImost compIetely disappeared. Upon remova of the upper respiratory passages, the entire Iarynx is dissected and removed. It shows no significant gross anatomic changes. The thyroid gIand is somewhat asymmetric. The Ieft Lobe measures 40 mm. in Iength and 18 mm. in the anteroposterior diameter. The right Iobe measures 46 mm. in Iength and I 7 mm. in the anteroposterior diameter. The isthmus is broad. On the posterior aspect of the thyroid gIand, two tumor masses are found on the Ieft side, and one attached to the right Iobe of the thyroid gland. AI1 those tumor masses are in the anatomic Iocation which corresponds with the usua1 site of the parathyroid gIands. These tumor masses appear as encapsuIated prominent structures attached to, but appafentIy independent of, the thyroid gIand, and differing from the substance of the thyroid in color and consistency. The upper nodule attached to the left Iobe is more gIobuIar in shape and measures I I mm. in diameter, whiIe the tumors attached to the Iower poIe of the thyroid gland, one on each side, are more elliptica in shape, measuring 15 mm. in Iength and 9 mm. in thickness. The weight of these noduIes is estimated as foIIows (I fee1 sure this estimate is too low): Ieft upper noduIe, .67 Gm.; Ieft Iower nodule, 1.02 Gm.; right nodule, .74 Gm.

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The gastrointestina1 tract is removed, opened, and examined, but outside of a moderate injection of the Iower part of the iIeum and

FIG. 22. Injection of the Ieft semina1 vesicIe and Ieft vas, showing normality of both.

of the cecum, no noteworthy changes are enountered. The spIeen is moderateIy enIarged. The capsuIe is smooth and gIistening, and on cross section reveaIs a preponderance of connective tissue; very IittIe scraping is obtainabIe. The weight is I xg Gm. The Iiver is usua1 in size, shape, and appearance, and on cross section shows no noteworthy changes. The pancreas is somewhat smaIIer than usua1, is firm and hard in consistency, but no other changes are observed. Upon the remova of the kidneys, both are found to be considerabIy smaIIer than usua1. The left kidney weighs 38 Gm. and the right kidney 22 Gm. The capsuIe is stripped off easiIy and underneath the capsuIe the cortica1 surface is fineIy granuIar in appearance and contains numerous smaI1 cysts containing straw-coIored, cIear Auid. The average diltmeter of these cysts is 2 mm. On cross section, severa small caIcareous masses are encountered. The entire kidney substance is profoundIy fibrosed, and the markings have aImost entireIy disappeared. The pyramids are not recognizabIe, and the boundaries between the meduIIary substance and cortex are indistinct. The caIices and kidney peIves are

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essentiaIIy negative. Both adrenaIs appear to be greatIy enIarged, weighing 14 Gm. each. ?h e spermatic cord, epididymis, and testes are

FIG. 23. CaMcation of the interna on both sides. Note also the changes.

iIiac arteries peIvic bone

removed. The testes appear distinctIy smaIIer than usuaI, weighing 13.5 Gm. each. Examination of the thoracic and abdomina1 aorta discIoses smaI1 atheromatous pIaques around the orifices of the intercosta1 arteries. At the bifurcation of the iIiac arteries, numerous atheromatous uIcerations and caIcareous deposits are found. Gross examination of the skeIeta1 bones reveaIs a generaIized softening which attains such a degree that a11bones, with the exception of the shafts of the Iong bones, can be easily cut with a knife. Such changes are particuiarly pronounced in the vertebrae, in the epiphysea1 ends of the Iong bones, and in the crania1 vauIt. The fronta bone in the midIine between the two orbita spaces measures 12.5 mm. in diameter, and its consistency is such that it can easiIy be cut with a razor bIade. The fIat bones, the epiphysea1 ends of the Iong bones, as we11 as the shafts, show a Iarge amount of fat accumuIation, which is indicated by the yellowish discoIoration of these areas. The distal end of the femur shows such softening of the bony structure that the axis of the epiphysea1 end forms a go degree angie with the

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An uxicanJournal of Surgery

Photomicrograph

of the suprarenal degeneration.

and in contrast to the fatty infiItration of the epiphysis and diaphysis, this metaphysea1 disc is composed aImost entireIy of hyaIinous cartiIage tissue through which narrow strands of bony tissue are woven through. The articulation surfaces and synovia1 membrane appear Aug. N.P.N.

300.0

20

Aug.

31

300.0

Sept. 300.0

Creatlnln

4.9

0.1

--

Caloium

9.0

--

--

0.95

--

Phosphorus Chloride

10.2 --

412.5

2

--

FIG. 25. Blood findings in the case of J. S. a few days before death.

be as usua1. Bone changes simiIar to those described in the femur are observed in the other long bones. Upon opening the crania1 vault, the brain and meninges are exposed. Upon the remova of those organs, no significant anatomic changes are encountered. The pituitary gIand is somewhat smaIIer than usua1. It weighs 0.4 Gm.

to

1938

Microscopic Examination. Bc me. Ex: rmination of the skeIeta1 bones sho ws exten sive fibrous tissue repIacement of the bc)ny st ruc-

axis of the shaft. On cross section, it appears that the metaphysea1 disc is enormousIy thicl kened, attaining a thickness of 39 mm.;

FIG. 24.

Rickets

,

gland,

showing

marked

fatty

tures. In the fibrous tissue, there are disseminated areas where osteobIasts are present, indicating some degree of new bone formation, whiIe the bone trabecuIae show extensive fragmentation and depIetion of calcium. It shouId be emphasized, however, that no evidence of excessive numbers of osteobIasts is found in any pIace in the sectioned area. Besides the connective tissue, Iarge amounts of adipose tissue deposits are found, especiaIIy in the epiphysea1 ends of the Iong bones, as we11 as in the meduIIary cana1. The metaphysis is composed chiefly of hyaIinous cartilage tissue containing smaI1 bone trabeculae. The periosteum shows a diffuse fibrous thickening. Kidneys. Throughout the entire kidney substance, meduIIary as we11 as cortica1, profound connective tissue proIiferation is encountered. There are severa areas of various sizes where the connective tissue undergoes calcareous changes; there are definite evidences of caIcareous deposits in some of the Iarger vesseIs, and caIcium deposits in the interstitia1 stroma. The gIomeruIi show asphyxiation, and part of the uriniferous tubes are compressed and obliterated, while others are greatIy distended,

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attaining a diameter many times the usua1 size. In the vicinity of the surface, the cortical substance shows numerous foci of round ceI1 infil-

FIG. 26. J. M. (Case II). Ureteropyelogram, showing catheters coiIed in diIated ureters, with a large hydronephrosis of the left kidney peIvis.

tration, which occasionaIIy are perivascuIar, whiIe in other places disseminated in the interstitiaI stroma, there are marked degenerative changes in the tubmar epithelium. Coronary Artery. Extensive atheromatous and caIcareous changes are found in the second Iayer of the intima, accompanied by uIcerations in the first Iayer. Testes. While the apparatus of spermatogenesis is weI deveIoped, no evidences of actua1 cytogenesis can be observed. The Iumina of most of the acini are partiaIIy or compIeteIy obliterated, and the Leydig interstitial ceIIs are greatly decreased in number. The epididymis is essentiahy negative. Thyroid GIand. The acini are unusuaIIy Iarge and are filled with excessive coIIoid materiaf. The interstitia1 stroma is scant, and the bIood suppIy is usua1. The gIanduIar epitheIium is singIe layer cuboid epitheIium. Parathyroids. Microscopic examination of the parathyroid reveaIs dense ceIIuIar structure of IobuIar arrangement. The lobules vary in size considerabIy and are separated from each other by narrow strands of connective tissue fibers. This IobuIar arrangement is more pronounced on the peripheral portion of the gland,

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and toward the center portion ture becomes more confluent. stroma is rather insignificant

339

the ceI1uIar strucThe interceIIuIar throughout the

FIG. 27. Cystogram of same patient, showing a regurgitation of the dye to each kidney.

entire sectioned area. Among the ceIIs, it was noted that the eosinophile ceIIs are strikingIy few in number. However, cIose examination reveals slight eosinophile character in a fairly Iarge number of the ceIIs, but inasmuch as the morphoIogic character does not comply with that of the usual eosinophiIe ceIIs of the parathyroid, they cannot be considered as such. The cells are uniform in shape, size and appearance and show no evidence of adenomatous or maIignant changes. The diagnosis is hyperplasia of the parathyroids. AdrenaI. The adrena cortex shows considerable fatty infiItration especiaIIy of the gIomerular and the fascicular layers. At the junction of the meduIIary and cortica1 substances, several round cell deposits are observed. The meduIlary substance is essentially negative. Myocardium. The myocardium shows no fragmentation of the muscIe fibers, but there is a marked enIargement and thickening of the sarcoplasm. The striation is also disturbed. Pancreas. EssentialIy negative.

that, in my opinion, I wish to reiterate this case represents the congenita1 type of rickets, for every indication points to the

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fact that practicaIIy from birth, this chiId had al1 the criteria that go to make up renaI rickets or renai dwarfism.

FIG. 28. J. M. Regurgitation kidney after a suprapubic

to the right drainage.

CASE II. The next case is one of the acquired type of renaI rickets, and the history Ieads one to beIieve the causes for the bone changes were of Ionger standing than the subsequent findings wouId indicate.

t

CASE

HISTORY

J. M., age II years, maIe, of Saratoga, Wyoming was iirst seen in my office on August was negative, 20, 1931. His famiIy history except that the mother had a right renaI caIcuIus. One sister is living and weI1, and one brother was born prematureIy. Past History. The mother stated that since the age of two, the patient had had troubIe in voiding, and at times would roI1 in agony on the fIoor_ whiIe attempting to urinate. As Iong as she couId remember, the urine had contained pus and had had a foul odor. At the age of four, the boy deveIoped a right inguina1 hernia, for which he was operated on, and strange to say, the operation heId despite the fact that he had to strain with each voiding. He had had measIes

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MAY, 1938

one year previously, but no other Znesses. There was no disturbance of gait; the chiId had been abIe to run up and down stairs

FE.

29. X-ray of Ieft knee in same patient, demonstrating earIy epiphysea1 deformity,

without difhcuIty, pIayed and fished with other boys his age. He was in the sixth grade at schoo1 and very bright. His greatest weight had been one year before (65 pounds). He had aIways been constipated. present Illness. The patient had come in because of increasing di&cuIty in voiding, and persistent pus in the urine. He had no nocturia, but upon arising in the morning, passed Iarge quantities of urine with difEcuIty. He had never compIained of pain over either kidney. On August 21, 1931, at Mercy HospitaI, a cystoscopic examination was done under gas, using a No. 12 cystoscope. The bIadder neck was definiteIy constricted, ineIastic, and fibrous in character. The bIadder itself showed ceIIuIes and each uretera opening was gaping wideIy, typica of a congenital bIadder neck obstruction in which the vaIves of each uretera opening had been destroyed from back pressure. A No. 4 catheter was passed up to each ureter. Figure 26 shows the catheters curIed in the Iower ureters; the ‘injection of uroselectan faiIed to give a satisfactory picture of the peIves of the kidneys because most of it

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regurgitated into the bIadder. Urine coIIected from each kidney contained oniy an occasionaI pus ceI1. The voided bIadder urine had a specific gravity of 1.009, was acid in reaction, had a trace of aIbumin, but no sugar, acetone, or casts. There were many pus ceIIs and many red ceIIs. BIood chemistry showed N.P.N. go mg.; 3.7 mg. sugar 100 mg., urea 50 mg.; creatinine or caIcium per 100 C.C. No bIood phosphorus determinations were done. The patient Ieft the hospita1 the foIIowing day, but was readmitted sixteen days Iater. In the meantime, the bIood chemistry had improved: N.P.N. was 50 mg.; urea nitrogen 30 mg.; creatinine 2.3 mg., per IOO C.C. BIood examination was as foIIows: white and red corpuscles were normaI, hemogIobin was 75 per cent, and coaguIation time two minutes. The P. S. P. excretion was 33 per cent at the end of one hour, which I think is quite interesting when one considers the amount of destruction the kidneys have undergone, as shown in pIates of ten days previously; yet we were unabIe to obtain a pyeIogram with uroseIectan intravenousIy. The patient was pIaced on a urethral catheter drainage which improved the kidney function stiI1 further, and on account of this improvement, I advised a bladder neck resection. The parents objected, however. The patient Ieft the hospita1 October 18, 1931, onIy to return six days Iater with a temperature of 103, the first that he had had. BIood chemistry was again bad. P. S. P. excretion at the end of the first haIf-hour was 3 per cent, and for the hour IO per cent. A cystogram, taken on November g, 1931, is shown in Figure 27. This demonstrates the regurgitation of the dye up the ureters. This x-ray pIate aIs gives a very exceIIent picture of the peIvic bones, and the heads of the femurs, which according to the roentgenoIogist show no rachitic changes. was On November 13, 1931, the bIadder opened suprapubicaIIy and the fibrous neck was resected. The impression on paIpating the bladder sphincter was that of an unyielding meta band. The punch, when cutting through it, made a sound as though it was of a cartiThe wound was cIosed laginous materia1. around a Pezzar catheter, but the suprapubic opening had to be kept for constant drainage up to the time of the patient’s death in the summer of 1936. AIthough when the tube was

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cIamped off, his urinary stream was good, and he emptied his bladder, if this persisted for a few days, he wouId deveIop toxic symptoms.

FIG. 30.

J. M. Changes in the bones of both wrists around the epiphyseal areas.

I judge that the mere act of voiding forced urine up the ureters into the kidney peIvis, for the ureterovesica1 valves never recovered their tone, as we demonstrated many times. (Fig. 28.) FoIIowing this operation, his genera1 condition improved, and on December 2, 193 I, he Ieft the hospita1 for his Wyoming home. On August 3, 1933, a year and seven months after his operation, the patient was brought to the oflice by his mother, who stated he was having considerabIe distress on account of pains around the right knee joint, and because of this waIking was painfu1 as we11 as difEcuIt. He was referred to one of the pediatricians for diagnosis, but the cause of the joint pain was not determined. In June of 1934, aImost a year Iater, the mother returned with him, stating that the condition had grown rapidIy worse and he was waIking with great d&uIty. As has aIready been stated, he was seen by Dr. Atha Thomas, the orthopedist on service at the Children’s HospitaI, but it was not unti1 November 18, 1934, that a definite diagnosis of renaI rickets, based on the bIood caIcium and phosphorus findings, together with x-ray pictures of the

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Iong bones, was made. The bIood chemistry at this time was as follows: N.P.N. 108 mg.; 10.3 mg.; phoscreatinine 3.3 mg.; cakium

FIG. 3 I. B. W. (Case III). Regurgitation of cystographic media to Ieft kidney. 1926.

phorus 6.3 mg. The blood count was: HemoW.B.C. gIobin 80 per cent; R.B.C. 4,480,ooo; I 1,700. Urinalysis deveIoped a specific gravity I pIus; an occasional Ieucoof 1.005; aIbumin cyte present ; occasiona red bIood ceIIs;

FIG. 33. B. W. Uretero-pyeIogram made in 1930.

streptococci on culture. The bone changes are shown in Figures g and 30. Remarks. Were it not for the bony changes in this patient, a: discovered in 1934, it is questionabIe whether the bIood chemistry aIone would have given sufficient evidence to cIassify this case as one of renaI rickets. Yet it might have been suspected aIthough the phosphorus

Rickets

MAY, 1938

did not go above 6.3 mg., and the caIcium showed no decrease from normal limits. I fee1 confident that if the proper diagnosis

FIG. 32. Cystogram of 1936, showing no regurgitation following resection in 1931.

of bIadder neck obstruction had been made at the time of the hernia operation, and the obstruction had been relieved then, the patient wouId not have deveIoped ten years Iater the rachitic symptoms and renaI failure that s10wIy

FIG.

34. Uretero-pyeIogram same patient. 1936.

of

folIowed. Even in the face of the fact that his renaI condition was grave in 193 I, the roentgenoIogist did not suspect any rachitic changes. It is unfortunate that this chiId’s symptoms were masked by the straining through of a hernia in attempts to void, and that the hernia was considered his major probIem instead of the bIadder neck obstruction, though the

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mother was certain that the urine contained pus and was of a fouI odor previous to and during this hernia1 hospitaIization. This patient died at his home in the summer of 1936, and I have been unable to obtain a final history. CASE III. The third patient B. W., age 16, stil1 reports at the offrce, and is at the present time in exceIIent health. He pIays basketbalI, is on his debating team in schoo1, and his only defects are a slight genu vaIgum of the left knee and a Iack of sex deveIopment. His condition is unquestionabIy due to a bladder neck obstruction, which was partiaIIy relieved by an open operation six years ago. The iIIustrations show pyeIograms and cystograms, extending from 1926 to the present time. There is stiI1 evident renaI pathology, but the regurgitation of the Ieft ureter no Ionger exists, aIthough the kidney outIines indicate that both are beIow norma in size. One may note the straight spina! coIumn in the early pictures before the genu valgum occurred, and the one of December 1936 (Fig. 34), showing the compensating scoIiosis foIlowing the genu vaIgum of the Ieft knee. Roentgen pictures of the knee show no bone changes. Before this patient came under my care, the diagnosis was that of a neuroIogic bIadder and urethra. He stiI1 does not quite empty his bladder, and I contempIate the removal of more tissue from the bIadder neck. I fee1 confident that this case wouId have folIowed the other two had not his bladder neck obstruction been removed. As previousIy mentioned, he has one deformed Ieg, Iack of testicuIar development with the other changes that go aIong with this hormona1 deficiency, namely, no facia1 hair, saIIow compIexion, and chiIdIike voice. SUMMARY I. Rena1 rickets is a disease of earIy ad& Iife and is secondary to either unexpIainabIe congenita1 defects or obstructive Iower urinary tract pathoIogy. 2. An earIy and correct diagnosis of the obstructive pathoIogy with correction wiI1 prevent in many patients a fata termination. 3. Patients who deveIop bone changes must show a hyperplasia of the parathyroids.

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4. It is very necessary that a more accurate knowIedge of renal pathoIogy in its reIation to hyperparathyroidism be sought, and vice versa. 5. Those patients who deveIop hypertension and edema earIy wiI1 never reach the rachitic stage and should be cIassed as interstitia1 nephritics. 6. In those cases of continuing low bIood pressure the renaI arteries show no changes. 7. There still remains no satisfactory expIanation as to the Iack of gonada deveIopment. I wish to acknowledge the splendid work done by Mr. Glenn E. MiIIs of the Photographic Department of the University of Colorado in preparing the pIates for this paper. REFERENCES BADER, GEORGE B. Renal

I.

368-379

(March)

rickets.

J.

Pediar.,

4:

1934.

2. BOYD, JULIAN D., MILGFCAM,J. E., and STEARNS, G.

3. 4. 5. 6. 7. 8.

CIinicai hyperparathyroidism. J. A. M. A., 93: 684-688 (Aug. 31) 1929. COMPERE, EDWARD L. Arch. surg., 32: 232-272, 1936. FORBES, ROY P. Personal communications.

HINMAN, FRANK. Principles and Practice of Urology. PhiIa., W. B. Saunders, 1935. HUNT, F. C. Rena1 infantilism. Am. J. Dis. Cbild., 34: 234-248 (Aug.) 1927. LUCAS, R. C. A form of late rickets associated with alhuminuria, rickets of adoIescents. Lancet. I : 993, 1883. . MITCHELL, A. G. Nephrosclerosis (chronic interstitia1 nephritis) in childhood, with special reference to renal rickets. Am. J. Dis. Child., 40:

101; 3451 1930. PARSONS, L. G. Bone changes occurring in renal and coeliac infantilism and their relationship to rickets: renal rickets. Arch. Dis. Cbild.. 2: 1-2~ (Feb.) 1927. A. The Diseases 10. PFAUNDLER,M. and SCHLOSSMANN, of ChiIdren. EngIish TransIation, M. G. Peterman, Vol. 5, page 83. II. THOMAS, ATHA. Personal communications.

9.

DISCUSSION DR. CLYDE LEROY DEMING: Ol.lr COIlCeptiOIl Of

rickets is complicated by a mass of new ideas, for I was brought up in medicine when there was IittIe known about avitaminosis rickets, except a bowing of the tibiae, a few humps on the wrists and ankIes, the rachitic rosary, and so forth. And now we have handed to us rickets of the kidney. My first conception of rickets of the kidney was a bowing of the ureter and some dysfunc-

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tion of the kidney. Perhaps I have been rather backward in accepting the diagnosis of renaI rickets. My conceptions of renal rickets have been further retarded by the Iack of opportunity to see the cases. This is probabIy true aIso of my friends in the audience, because most of these cases have been viewed by the pediatricians and it is onIy recentIy that the pediatrician has feIt that he couId not get aIong without the uroIogist. I fee1 indebted to Dr. Howard for being one of the first uroIogists to bring this subject before our Society and our speciaIty. He has given us a cIean-cut picture of the disease in chiIdren, which is characterized first by renaI deficiency, usuaIIy by a urine with a Iow specific gravity and aIkaIine in reaction or near the neutra1 point, a high non-protein nitrogen, a bIood chemistry picture of Iowered calcium and increased phosphorus, and an which is characteristic of x-ray picture hyperparathyroidism. Before some of these probIems are cIeared up we must know more about the x-ray picture in hyperparathyroidism; we must know more about OsteomaIacia, cystic disease of the bone, the epiphysis in syphiIis and Paget’s disease. Dr. Howard has attempted for the first time to cIassify these cases of renaI rickets. I have never attempted to cIassify them. I do not know who has, and I honor him in his attempt. We have onIy had five cases at the New Haven HospitaI. In trying to cIassify them in the same manner as Dr. Howard, I find I can say that two beIong to the congenita1 type without diIatation of the ureters or any evidence of obstruction. Two cases had obstruction, one at the bladder neck and the other at the Iower ends of the ureters. The fifth case was a puzzIe. It presented a11 of the usua1 bone pictures which have been demonstrated. The urinary picture was compatible, the non-protein nitrogen was high; but the bIood chemistry was normal. There have been a few reports of cases which showed a normal caIcium and a very sIight, if any, eIevation of the bIood phosphorus. That brought to my mind the question as to whether or not there were any phases of this disease during which there was an attempt at recovery and a “speed-up” of certain processes. In reviewing this fifth case of ours, we found that the skuII pIate, instead of being wooIIy in type, or a granuIar skuI1, as our radioIogist wished to expIain this film, there were certain areas which Iooked as though there had been an attempt to deposit caIcium. Some of these patients at times

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have a return to aImost norma bIood caIcium and very IittIe eIevation of bIood phosphorus. Dr. Howard has shown that one of his cases demonstrated this change. These changes in the bIood picture and in the x-ray may signify regressions iti the disease. Whether this conception is true or not, it is a probIem for us to consider. With regard to the definite etioIogy of renaI rickets, there are severa reports by Parsons, Pappenheimer and WiIens, who have shown that a Iong-standing nephritis may be the underIying factor. A low bIood caIcium and a high phosphorus usuaIIy deveIop in a case with interstitia1 nephritis of Iong standing, ‘or in a case with congenita1 nephritis. Dr. Howard, as we11 as other writers, has stated that in an interstitia1 nephritis case the phosphorus may not be put out through the urine, but goes into the intestine and unites with the caIcium, making an unabsorbabIe compound, with the result that there is a depIetion of caIcium. Where there is a Iong depIetion of caIcium, there is probabIy a stimuIation of the parathyroid producing a hyperpIasia of the parathyroid as a compensatory reaction. We then get those changes in caIcium metaboIism which are shown in the x-ray flms. Let us Iook at the opposite side of the caIcium metaboIism picture. Take, if you wiI1, a hyperparathyroid case and aIIow it to exist over a Iong period of time. The patient wiI1 develop a nephritis. Both diseases produce changes in the caIcium metaboIism with practicaIIy the same x-ray bone pictures, but the bIood chemistry for caIcium and phosphorus is reversed. Why do we have in this disease a compIication of hypogonadism ? I am particuIarIy interested in hypogonadism. I beIieve that the thymus, the thyroid, and the pituitary pIay a big part in it. That brings in the question whether or not this picture of renaI rickets is not stiI1 more compIicated than we appreciate. A Iow bIood pressure depends much on the thyroid and the adrenal. May we not, just for the sake of arguing, inject possibIy the thyroid and adrena into this picture? The fatty infiItration of the adrena which has been shown us may be positive evidence of muIti-hormonal invoIvement. But I am not content to expIain this picture whoIIy on the basis of renaI insuffIciency of congenita1 origin or on a hormona1 basis. The acquired type which has been discussed seems acquired onIy to a certain degree. Why shouId

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we bIame an obstruction of the urinary tract for renaI rickets when we see renaI rickets without urinary obstruction? Why do not our prostatic cases, which have an obstruction over a Iong period of time, deveIop simiIar changes in the bIood picture and in the gonads? If we reIy on the kidney aIone, why do not poIycystic kidney cases deveIop more changes in the bIood pictures? These have a long-standing nephritis. I beIieve that we must take one step further back. We have seen injured cord cases deveIop a hydro-ureter and a hydronephrosis without obstruction. Here there is an injury to the sympathetic and parasympathetic nerves. Harvey Cushing has stated in his book on the pituitary that Iesions of the pars intermedia and pars posterior produce a hydro-ureter and hydronephrosis without any evidence of obstruction in the urinary tract. These are associated with hypogonadism, low bIood pressure, and so forth. I wouId Iike to suggest that perhaps these cases of renaI rickets are not due simpIy to a congenita1 malformation of the kidney, but to a congenita1 malformation of the diencephaIon. The prognosis in these cases is bad, according to a11 the Iiterature of the pediatricians. I commend Dr. Howard for bringing before us tonight the fact that he has brought a case of so-caIIed renaI rickets through a period of obstruction up to the age of 16. This patient is in better heaIth than any of the cases I have seen or read about. DR. EDWIN BEER: The onIy adequate excuse I can offer for entering the discussion of this interesting group of cases is to be found in the fact that the first paper I wrote was devoted to a cIoseIy reiated subject-metastatic Iime deposits-as we11 as to the fact that some twenty-two years ago I pubIished a study of a series of cases simiIar to the acquired group referred to by Dr. Howard, and have seen we11 over fifty such cases, many of which are described in our monograph on “Diseases of the Urinary Tract in ChiIdren.” After reading carefuIIy the paper of the evening, I cannot convince myseIf that Case I was anything eIse than a case of infantiIe rickets, and that foIIowing the attack of scarIet fever at five years the patient deveIoped an interstitial and fatal nephritis. MacCaIlum, thirty-two years ago, caIIed attention to the association of renaI diseases and parathyroid enIargement which seems to have been present in this case,

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though in the autopsy notes no mention of the microscopic picture, whether hyperplasia or adenomata, was made. The inabiIity of the badIy diseased kidneys to excrete aIIows of accumuIation of phosphoric acid ions, which may act on the calcium in the bone and as compensation for this upset in the caIcium metabolism, possibIy the parathyroids become enIarged and hyperpIastic. In Case I the disease of the bones seems to have begun before the chiId was 2 years old, so that I cannot agree with Dr. Howard’s concIusion that this was a disease of earIy ad& life. In Cases II and III, the disease also started in earIy Iife, in one surely at 2 years. These cases correspond with the cases that I have been studying for aImost thirty years. They seem to be cases of dysharmony between the detrusor and sphincter muscIes of the bladder, and regularIy deveIop fibrosis with contracture of the bladder neck. The pathoIogy at the neck Ieads to back pressure effects, hypertrophy of the bladder-giving way of the ureter meati and usuaIIy biIatera1 diIatation of the ureters and kidney peIves with atrophy of the parenchyma. When infection develops, they usuaIIy come to the uroIogist. In the Iarge series of cases that I have studied, most of the chiIdren are undersized, poorIy nourished and paIe. They might be cIassified in some instances as infantiIe or dwarfed, but as far as I can recaI1, none showed evidence of rickets. In those cases of contracture of the neck, associated with bone changes, perhaps the parathyroids and poor renaI function are again producing the picture. AIfred Hess says; “It is possibIe that the effect on the metaphysis is due IargeIy to the fact that the nephritis occurs at a time when the bones are in the stage of active growth.” It is of great interest to note that EIIis and Evans collected in the London HospitaI twenty cases in as many years beIonging to the group associated with contractures of the neck, though they seem to have failed to recognize this pathoIogy. Under “ Rena1 Dwarfism,” they describe the same cIinica1 picture of obstruction at the bIadder neck, and in fourteen out of seventeen autopsies in this series they found “varying degrees of diIatation, which in some cases was extreme.” Moreover, they state that “the urinary retention appeared to occur at the IeveI of the urethrovesica1 sphincter. No obvious cause of the obstruction or Iesion of the nervous system was found. A disorder of the neuromuscuIar mechanism control-

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Iing the urethrovesicai sphincter is suggested.” UnfortunateIy the case histories and the autopsy reports are so briefly given that they are of little vaIue in eIucidating our problems, and still more unfortunate, the post-mortem examinations seemed to have reguIarIy avoided the parathyroids, which sureIy are an important factor in the secondary bone changes, as has been again emphasized by SheIling and Remsen in a recent pubIication of a base belonging in this same group of contractures of the bIadder. In this case al1 four parathyroids were hyperpIastic and very Iarge. From these few words it can be readily seen that we are stiI1 rather in the dark concerning what is caIIed renaI rickets, and we a11 are indebted to Dr. Howard for reminding us of this stiI1 obscure cIinica1 picture, so that as opportunities offer, we can delve a IittIe deeper into this borderline group of patients and heIp in their elucidation. F. CAMPBELL: COIlCerIling DR. MEREDUH so-caIIed renaI rickets, so irregular are the pathoIogic and cIinica1 manifestations, as we11 as the Iaboratory findings, notabIy the blood calcium and pIasma phosphorus estimations, that terminoIogy aIone is a matter of no smaI1 moment. Park and EIIiot in Brennemann’s recent “Pediatrics” discuss at considerable Iength why the designation renaI rickets, renaI infantiIism, renaI dwarfism, and so forth should be replaced by that of renaf hyperparathyroidism with osteoporosis (osteitis) fibrosa cystica. The probIem of so-caIIed renaI rickets interests me greatIy because we have here a serious condition which conceivabIy may be prevented by earIy recognition of the usua1 basic etiologic factors, viz., obstruction. The condition is but another which iIIustrates and emphasizes the importance of a thorough uroIogic examination in chiIdren when proper indication exists. Chronic pyuria is often present and in the cases which are not diagnosed as, and interminabIy treated for “chronic pyeIitis,” the diagnosis of chronic interstitia1 nephritis is made. The cIinica1 and Iaboratory picture of chronic interstitia1 nephritis is so often produced by advanced urinary obstruction affecting the total renaI secretory apparatus that it is my feeling, and I am sure it is Dr. LyttIe’s aIso, that patients in whom this diagnosis is made shouId at least be subjected to an_^ excretory urographic _ .study. When the . __ renal function is low and Intravenous urog-

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raphy is therefore of no aid, the urethra1 and/or ureteral catheter may advisedIy be empIoyed, in many cases together with cystography and retrograde pyeIography. In a few chiIdren in this group in whom Dr. LyttIe and I were mutuaIIy interested, onIy a thorough uroIogic examination discIosed the obstruction and urostatic nature of the basic pathoIogy of the “chronic interstitia1 nephritis.” Moreover, it is IikeIy that urologists fai1 to recognize many of these cases of renaI rickets; I think I have correctIy observed five cases, but am sure many more went unrecognized. Three of these cases were seen with Dr. LyttIe and doubtIess he wiI1 discuss them; they came to autopsy. In a 7 year oId boy with renaI rickets, congenita1 biIatera1 renaI hypopIasia existed. Post-mortem, diminutive kidneys were found with a ureter coming from the anterior surface of each organ. In another boy of &$ years, but 2 years in size, advanced biIatera1 hydronephrosis resulted from biIatera1 ureterovesical junction stricture; there is secondary ureteropeIvic anguiation obstruction. This boy appeared and acted Iike a IittIe oId man; he was bow-Iegged, wizened, Iooked worried, and there was beginning baIdness of the anterior third of the scafp. The nonprotein nitrogen was 65 mg. per IOO C.C. of bIood. BiIateraI nephrostomy was performed and the boy was returned to his home. Marked genera1 as we11 as renaI improvement has occurred and we hope eventuaIIy to relieve the obstruction on each side. What appears to be a genuine case of renal rickets was studied at BeIIevue HospitaI in June, 1936. A T-year oId boy weighing onIy 26% pounds was admitted with a diagnosis of congenita1 nephritis. He had been treated at other hospital dispensaries in the past. He had never been weI1, never gained, was constipated, cachectic, and had a brown tint to his skin. This curious skin pigmentation has been noted in severa of the reported cases of renal rickets. The breath was offensive; the lower ribs flared with some beading; the mentality was beIow average, and a serosanguinous ana discharge existed. The bIood pressure ranged between 136/98 and r64/ I 12 mm. Hg. There was a miId Ieucopenia; the red ceI1 count varied between I ,200,000 and I ,700,ooo, with 4;9 per cent hemogIobin despite three transfusions. The phenoIsuIfonphthaIein test showed no dye was excreted. The non-protein nitrogen was 197 mg., 208 mg. and creatinine

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7.3 mg. per IOOC.C.of blood. The urine showed albumin 2 PIUS, occasiona white and red bIood ceIIs. NotabIy, the serum caIcium (diminished) was 5.4 mg. and the plasma phosphorus was 13 mg. (increased). The CO2 estimation was 26.7 voIumes per cent. Intravenous urogram showed no excretion. The cystogram was normal (no reffux or residuum). X-ray of the Iong bones showed no rachitic changes; the upper end of the right humerus showed changes of osteochondritis juvenalis deformans. The treatment employed was three transfusions; saline and 5 per cent glucose; high caIoric diet; 5 c.c. of I0 per cent caIcium gIuconate was given intravenousIy daily for four days. The patient died of renaI faiIure three weeks after admission. No autopsy was obtained; we had withheId retrograde pyeIography under the erroneous impression autopsy permission was obtainabIe. This boy, we beIieve, had true renaI hyperparathyroidism; certainIy the low bIood caIcium and high pIasma phosphorus suggest this. DR. JOHN D. LYTTLE: I think everybody agrees that renaI rickets, renaI dwarfism, and renaI infantiIism, are not good terms for this disease. Rickets is not an obIigatory part of the picture; its presence depends entireIy on the bone age. If growth is compIete, bone changes may occur without dwarfism being present, so that is not necessary; and infantiIism has been present in onIy a few of the cases on record. The term used by Park and EIIiot, and advocated by AIlbright and his co-workers, describes the pathoIogy and the cIinica1 picture. It is renaI hyperparathyroidism with osteoporosis (osteitis) fibrosa cystica. A study of the pathoIogy gives the key to pathogenesis; the primary condition is renal insuffIciency, which can be brought about in more than one way. In some of the cases reported there is a definite renaI hypoplasia. In the first case we studied at the Babies’ HospitaI, the kidneys of an I I-year old boy weighed 20 Gm., the. normal weight for a newborn infant. In addition, the kidneys showed cystic degeneration and fibrosis. Urinary tract obstruction and infection, if they persist long enough, Iead to renaI insuficiency. The obstruction can be due to a neurogenie bIadder, or any one of the uroIogica1 conditions which give rise to vesical outIet obstruction. Infection usuaIIy deveIops, which leads to destruction of the kidney and to fibrosis or nephroscIerosis. Edema, retinitis and

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hypertension are not commonIy found in these chiIdren. The second thing to consider in the pathoIogy is the parathyroid glands. I shouId Iike to ask Dr. Howard about the histopathoIogy of the enIarged parathyroid gIands in the case he showed. I take it the enIargement was simple hyperpIasia, and not an adenoma, as is common in primary hyperparathyroidism. The third pathoIogic change of course is in the bones. In a very young child, where endochondra1 growth is going on, rickets of variabIe severity will be found. In an oIder child there will probabIy be moderate changes in the endochondrium and knock-knees or bow-Iegs are present, and in a stiI1 oIder patient, where endochondra1 growth is compIete, Iittle or no deformity is seen. AnatomicaIIy, the changes are at times rickets, but the essentia1 finding is osteoporosis such as we see in hyperparathyroidism. That hyperparathyroidism is a direct resuIt of renaI insuficiency seems IikeIy. I beIieve that experimenta work and cIinica1 investigation wiI1 prove that definiteIy. Dr. Pappenheimer and Dr. WiIens and others have found that in patients dying of chronic Bright’s disease there is from IOO to 200 per cent increase in parathyroid weight as compared to a contro1 series. These workers have reduced the kidney tissue in animaIs, and have demonstrated hyperparathyroid glands at autopsy. Work recentIy pubIished by Hamilton and Highman indicates that in individuaIs who have advanced renaI disease, hyperparathyroidism is present, as shown by the HamiIton and Schwartz test. It is not known how this renaI insufficiency induces hyperparathyroidism, or what produces the demineraIization which goes on in this disease. Park believes that in renaI insufficiency phosphate retention resuIts in low serum caIcium. This aItered calcium-phosphorus equiIibrium the parathyroid gIands attempt to overcome and they become hypertrophied. The bone changes are a resuIt of the overactivity of the parathyroid glands. IdenticaI changes in the bones are seen in primary hyperparathyroidism and foIIowing experimenta injection of parathyroid extract in animals. But the mechanism by which these bone changes are brought about is stiI1 uncertain. Before discussing treatment I should Iike to ask Dr. Howard about the changes in kidney function as clinica improvement occurred in his third case.

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We wiU a11 agree that the pediatrician and the practitioner see these chiIdren before bone changes occur, when treatment can be effective. It is of Iittle benefit to the patient to estabIish drainage, remove obstruction and fight infection when kidney insufliciency is we11 established and bone changes are present. In patients with chronic urinary tract infection we must not be misIed by good kidney function and by apparent welLbeing, but must constantly bear in mind that changes in the kidney are sIowIy but sureIy progressing and wiI1 eventuaIIy Iead to renaI failure. It is up to us to present these cases to the uroIogist at a time when treatment can be effective. DR. T. LEON HOWARD (closing the discussion): Dr. Deming mentioned the resembIance of the bone changes in renaI rickets to those in Paget’s disease, and there must be a similarity, for I asked one of our pathoIogists to give his opinion of the sIide from which the photomicrograph (Fig. 6) was made, and without hesitation he said it was the bone from a case of Paget’s disease. He frankIy admitted he had never seen the bones of a renaI rachitic. The thymus showed no pathoIogy and in none of the case reports I have seen, has the thymus been described as a possibIe factor. I stiI1 insist it is a disease of paradoxes and offers the widest fieId for research, especiaIIy from a hormona1 standpoint, to say nothing of the renaI and parathyroid reIationship.

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The copy of this paper sent to Dr. Beer unfortunateIy omitted the pathoIogist’s microscopic report on the parathyroids, but I assure him there was no adenomatous change in any of the gIands and their enIargement is due to hyperpIasia, as shown in Figure I3. I mentioned the fact that there was a difference in the blood as we11 as in, the bones in patients having adenomas of the parathyroids, for in this condition the exciting Iesion is in the parathyroid, whiIe in the renaI rachitic the parathyroid change is secondary, and is a physioIogic result of the renaI and bIood pathoIogy. The uroIogist wiI1 be of IittIe benefit in the type of patient I reported in detail, for the bone changes begin earIy in Iife, due to some unknown prenata1 renaI defect. But in the other two cases, if the physician wiI1 aIIow the uroIogist to see this obstructive type earIy enough, I fee1 sure he wiI1 be able to prevent, in a certain percentage, the bone changes which are unquestionabIy secondary to the renaI pathology. Dr. Beer is, of course, correct in that a11 cases of Iower renal obstructive lesions do not go on to the rachitic state, and I didn’t intend to Ieave such an impression. In cIosing, I want to thank the members of the Academy for being aIIowed to present the subject of renal rickets for their consideration and to the discussers for their most generous and frank opinions.