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The Fanconi syndrome
Review THE
FANCOSI
SYKDROME
From the Pediatric Dioision. Baltimore City Hospital, and Department of Pediatrics, Johns Hopkins Liniversity, School of Medicine (Received
T
HE
TRIAD
consisting
(bj generalized
termed
directly
or indirectly
The
Fanconi
syndrome
may result renal
(a)
syndrome.
stem
functional
of
has multiple may
also result
disorder
fluid is rickets
malacia
in adult
if it occurs there
The rickets
is a disproportion
necessary
of renal
of renal
to
functions. tubule
or acquired,
syndrome.
of manifestations
The
functions
other
As a result
the
but have in common
from a deficient!.
linear
association
of the bones
the formation
of renal
of crystals
glycosuria
In by
of bone salt at the rate re-
with
hypophosphatemia
of pediatricians
by vitamin D treatment, values. There were other
of severe
matrix
matrix.
to the attention
this child but the renal glycosuria case from examples
or osteo-
has ceased.
of organic
b>r de Toni,l
although earlier reports of probably similar cases are on record. the case of a child with arrest of growth, marked hypophosphatemia which was not influenced with normal blood glucose
phosphate
is growing,
of this matrix. Because of the deficiency of exphosphate cannot be concentrated in the matrix
for the formation
brought
of inorganic
individual
growth
between
normall\~ the organic
specific was first
tubule
disorders
in disturbances
if the affected
life after
bone cells and the calcification tracellular inorganic phosphate, to calcify
renal
congenital
part of the Fanconi
which results
in the extracellular
to the extent
since
either
is now generallq
can be considered
triad listed above.
The skeletal
quired
of hypophosphatemia,
of specific
etiologies
of causes,
cases may show a wide variety
case,
lesion
manifestations
from disturbances
from a variety
lesion
the characteristic
either
skeletal
and (c) renal glycosuria
A411of these
than those which are by definition individual
the
renal aminoaciduria,
the Fanconi
function
for publication No\,. 20, 1957. i
He presented with rickets
and glycosuria associated evidences of renal injury in
and the hypophosphatemia
renal disease
and in 1933,
with glomerular
differentiated insufficiency,
this chronic
acidosis, dwarfism, and the associated defect of skeletal calcification sometimes termed renal rickets, since these latter patients exhibit hyperphosphatemia. In the next few ?.ears other cases of intractable rickets associated with glycosuria 346
FANCONI
SYNDROME
347
In 1936, Fancon? described a patient with a syndrome which he were reported. termed “infantile nephrotic glycosuria, dwarfism and hypophosphatemic rickets.” Fanconi’s description was thus not the original report, but he pursued the problem vigorously, discovered other cases, and presented a theory of the pathogenesis of this entity so that his name has been given to the syndrome. Fanconi suggested that renal tubular injury might be the basic problem and also noted that these infants excreted an excessive amount of organic acids which he did not identify. McCune, Mason, and Clarke3 investigated this aspect of the problem and found that an extraordinarily great excretion of amino acids accounted for the large organic acid output. It was thought that renal tubular dysfunction could account for both the aminoaciduria and the glycosuria, and attention was directed to the hypophosphatemia to see if it might also be explained on this basis. It had already been indicated by Harrison and Harrison4 that the hypophosphatemia of vitamin D deficiency rickets was associated with reduced renal tubular reabsorption of phosphate and that administration of vitamin D increased tubular reabsorption of this ion. It seemed probable that the hypophosphatemia of the Fanconi syndrome was also due to renal phosphaturia on the basis of renal tubular defect of phosphate reabsorption associated in this instance with defects of glucose and of amino acid reabsorption. This thesis of the mechanism of hypophosphatemia in refractory rickets was espoused by Robertson, Harris, and McCune,5 reaffirmed more recently by Dent,6 and is generally accepted at the present time. The demonstration of the aminoaciduria in infants with the Fanconi syndrome was followed by the observation that cystine crystals could be found in the tissues of these infants. Freudenberg7 examined this association and connected these findings with an earlier report by Lignac* who had studied 3 infants with retardation of growth and rickets whose tissues were found post mortem to be infiltrated with cystine deposits. It then became apparent that cystinosis (or cystine storage disease, as the disease was also termed) was one of the possible causes of the Fanconi syndrome and perhaps the most important cause of the infantile variety. Cases of Fanconi syndrome without demonstrable cystine accumulation in tissues were also discovered in children and adults. Stowers and Dent9 reported a detailed metabolic study of an adult with the picture of hypophosphatemic osteomalacia, generalized aminoaciduria, and glycosuria. Although this was the first case in which generalized aminoaciduria in association with osteomalacia was demonstrated, there had been cases of osteomalacia with renal glycosuria reported much earlier, and these almost certainly represent examples of the adult form of the Fanconi syndrome. One of these cases had been reported by MilkmanlO in his original report of osteomalacia with x-ray evidences of multiple symmetric pseudofractures (Looser-Milkman zones). The term Milkman’s syndrome has been used to describe osteomalacia with these particular roentgenographic findings. The Fanconi syndrome is but one of the several causes of osteomalacia, and if the Looser-Milkman zones are demonstrated b! x-ray the term Milkman’s disease might be applied. There is, therefore, a considerable amount of confusion in t.he literature due to the multiplicity of names which have been used in the description of one or more varieties of the Fanconi syndrome and of osteomalacia.
348
J. (‘hron.
l)is.
April, iY59
The generalized aminoaciduria which is one of the hallmarks of the I;;tncolli syndrome was not readily detected until the method of paper chrornatograph!. was applied 1,~. Dent ‘I to studies of urine aminoacid colltent. This method permits the qualitative detection of the individual amino acids a11(1;LII estimation of the quantit>. of each present. Following introduction of this technique the classification of abnormal amilloacidul-ice bec;me more Iwacticable,‘” ;lnd I he recognition of the l;anconi syndrome was facilitated. It is not surprising, therefore, that more cases have been diagnosed ill recent >‘ears. More exact studies of the aminoacidtlri,t of the l;anconi q,ndrome have also led to a11 explanation of the mechanism of the aminoaciduria and to a11 understanding of the pathogenesis of the h!,(,ophosphatemi~~ and osteomalacia. Simultaneous determinations of plasim amino acid coweritrations and urillc amino acid excretions showed that the plasm;~ levels were norma despite increase(l urine excretion so that amino acid clearantes \vere high.‘” III the normal indivitlual most of the amino acid content of the glomcrular filtrate is reabsorbed h,. the renal tubules so that oiil~, ;I small fraction of 1he tiltered amilio acids appears in the urine excreted. 111 patients with the l;anconi s\,ndrome it can be shown that a much smaller fraction of filtered amino acids is reabsorbed ;lcc.ountillg for the The ph>.siologic defect is thus in the renal excess of amino ~wicls in the urine. tubule cells. The gl~~cosuria also fits iu Lvith this concept since blood sugar levels :u-e normal and the appearance of glwose in uriile is the result of diminished The same t!ye of stud?- led to the espla~~ation tubular reabsorption of glucose. of the h~pophosphatemia, which is me of the major ph>-siologic. disturbances. [Jnder conditions in which adequate amounts of phosphorus are available to the we determined bh. the relationship body the serum phosphorus concentrations between phosphate filtered through the glomeruli and that reabsorbed 1~~. the In the uncomplicated case ot’ the Fancoui s!-ndrome the glomerul:u renal tubules. frltratioll rate is normnl but the rellxl tubular reabsorption of phosph:~tc is reduced just as is the renal tubular reabsorplion oi amino acids and glucose. .As a result phosphate in considerable qu;ultit\, is e.xcrcted in the urine despite pcrsistentl\low levels of phosphate in plasma and other extracellular fluids. Other disturbances of renal tubular functiorl may occur along \vith the aforcmentioned deficiencies of tubular re;tbsorptioll of amino acids, glucose, and phosphate. Potassium ma\. be lost in excess ill the urine due to clisturb;~uce in the mechanism which regulates the exchange of potassium for sodium ;u~d hydrogen ion, and potassium deficit with h~yokalerni:l results.14 This ma). be severe enough to produce episodes of severe muscle weaktless spolltalleousl\., or as the result of injection of glucose intravenously in the performance of a glucose tolerance test. Impairment of the renal mechanism for regulation of the pH of urine has also been found which is manifested bl- a metabolic acidosis a*ith h~~perchloremia associated with the excretion of urine which is neutral or slightly, alkaliuc ill Fiuall>~, a defect of water reabsorption with failure of formation of it reaction. concentrated urine C;LII occur with resultant lwl~wria resembling the 1’ic.ture of As ill the latter s>~ndrome, the c-otlcellt ratio11 of nephrogenic diabetes insipidus. solutes in urine and the volume of urine is not affected 1~~.injection of pitressin since the defect is in the tubule cell. The clinical picture of the Fanconi s)wdrome
Volume 7 Number 4
FANCONI
STNDKOME
349
can thus include a variety of manifestations associated with disturbances of water and electrolyte balance resulting from the various disturbances of renal tubule In some instances there may be difficult,- in differentiating variants of function. the Fanconi syndrome from renal tubular acidosis with hypophosphatemia and In the latter syndrome aminoaciduria is not a constant feature osteomalacia. Calcification of renal tubules and nephrocalcinosis is an important complication. does not occur in the Fanconi syndrome. Not: only are there variations in the clinical phpsiology of this syndrome, but It is now evident the etiology of the Fattconi syndrome may also be quite diverse. that the same general t)rpe of renal tubule dysfunction ma!. occur either on the basis of genetic defect or as the result of acquired injury, and that diverse injurious agents, some known and some as yet unknown, may be responsible for the acIn the following section various forms of the quired forms of this syndrome. Fattconi syndrome will be separated on the basis of the possible pathogenesis of the disorder. The fundamental tnauifestations which must be present in all instances are hypophosphatemia with rickets or osteomalacia, generalized aminoaciduria and renal glycosuria. The last of the three may be quite mild and in some cases the qualitative test for urine glucose may be so slightly positive at times as to be considered of no significance unless a diagnosis of the Fanconi syndrome is being entertained. The marked generalized aminoaciduria along with failure to respond to ordinary vitamin D therapy are the salient features in the differentiation of the Fanconi syndrome from other types of rickets and osteomalacia with similar defortnity and x-ray findings.
The original reports of the Fanconi syndrome were of cases which started in infancy with rickets unresponsive to usual vitamin D therapy, renal glycosuria, and growth retardation. The disease in most instances progressed to a fatal outcome. These cases are now recognized as examples of cystinosis and this disease entity has been thoroughly reviewed by Bickel and his associates.t5 It is hereditary, and the transmission is that of an autosomal recessive gene. The infants are apparently normal at birth and show no disturbances during the first few months of life. Subsequently, they may manifest the nonspecific evidences of a metabolic disturbance-failure of growth, anorexia, lethargJ7, and weakness. In other instances, rachitic deformities, appearing at the age of a year or 18 months despite usual vitamin D intake, ma)- be the first signs. Further stud), reveals the triad of the Fanconi syndrome, i.e., hypophosphatemin, generalized aminoaciduria, and glycosuria. In addition the other manifestations of renal tubular dysfunction such as metabolic acidosis, hypokalemia, and polyuria ma>be present. The distinguishing feature of cystinosis is the accumulation of cystine crystals in large phagoc>.tic cells in many body tissues. They are found tnost readily in the reticuloendothelial system (bone marrow, spleen, lymph nodes, and liver) but may also be found in kidney and subcutaneous tissue. These crystals are likewise fount1 in the cornea, and since the)- can be detected in this tissue by slit-lamp microscopy, this latter procedure is therefore a useful diagnostic technique. Examination of bone marrow spreads or lymph node biopsies will
350 reveal
the characteristic
cystine
flat hexagonal
has been found to crystallize
hexagonal
plates.
deposited
It is important
in the tissues
acids is a generalized
ornithine amino
acids
results
The course ‘The disorder fairly
metabolic
administration
citrate
bJ_ these
methods
and potassium
which
in injut-).
cl\.sfunction
hypophosphatemia perphosphatemia destruction
and
of the kidneys. tnore
initial as
the death
of the patient.
may, stage
glomerular phase,
such as sodiun?
primary
secondat-\.
with
c.\.stinosis
underlying
disorder
therefore,
and
is unknown
to eventual
renal
often
tit rhosis
be progressive
insufficiency.
ma!- be superseded insufficiency
h>~pocalcemia,
If a bJ.
improved
of the
in tissues
ma). occur as in an\. form of severe
infant
so that
This
b!y treatment per day).
and growth
leading
progressive
In this termittal
infections
mixture
mechanism
cells
There
important,
h>~perkalemia
and anemia
poorI\- nourished
The b>- hy-
results
refractory
from meta-
renal insufficiency.
is also particularly-
susceptible
infections have often been a contributor). Sot all infants \vith q.stinosis, however,
to
factor in show this
downhill course, and it appears that the prognosis is not uniforml> We have observed a child with c-ystinosis, proved b,. the presence
progressive unfavorable. of q.stine
tubule
and unfavorable.
the!, can be treated
precipitation
b\- treatment. renal
of the uncomplicated
of nephrons.
bolic acidosis, The
and,
:~11d
in the
associated
syndrome.
units
be healed the
to cystine
ameliorated
of the liver and to fibrosis hepatic
leads
to hepatic
can
and
of these
cystine
be corrected
to 50,000
function,
arginine,
is not
of the Fanconi
alkalittizing
However,
of treatment.
disorder
soluble
cystinuriu
are also present
rickets
has some-
amounts
is usuall~~ progressive
11 (10,000
deficit
The
solution.*
and is ttot necessarily results
of vitamin
lysine,
of large
can frequently
of ;t l’otassium-contaiiiillg
potassium metabolic
metabolism
amounts
acidosis
lesions
with cystinosis
of phosphate
of cystine,
Essential
or the skeletal
in the urine in excess (:ystinosis
of the poorly
calculi.
is
of amino
of renal tubular
to excretion
Crystallization
cystine
only
reabsorption
of c)-stine.
reabsorption
leading
in cl-stine
of infants
large
although
tubular
fortn of disturbance
limited
in the urine.t6
tract
that
of renal
excretion
in which tubular
with h4.pophosphatemia
with
urinary
with another
are specifically
urinar),
In some instances as well as in the more typical
one so that all amino acids are excreted
been confused
essential cystinuria
of qstine.
to emphasize
the disturbance
and there -is no preponderant times
crystals
in fine needles
crJ.stals
been benign.
The
in bone marrow initial
biopsies
manifestations
and in the cornea,
whose
in this child wet-e the bony
course
has
deformities
of rickets
which were first noticed at about 1 year of age. Subsequent studies marked generalized aminoaciduria, and revealed persistent hl.pophosphatemia, mild glyc‘osurin. Treatment with vitamin I1 in doses of 12,500 units daily plus sodium and potassium citrate solution resultecl in elevation of serum phosphorus levels, complete healing of rickets, and resumption of normal growth although the *A solution
which we have used for this purpose has tlw following composition: Citric acid, 70 Gm. Sodium citrate, 98 Cm. Potassium citrate, 108 Gm. Made up to 1 liter in fruit-flavored syrup base. This solution provides 1 mEq. each of sodium and potassium per milliliter. Thirty to forty milliThe liters per day in divided doses has corrected the acidosis of children with the Fanroni syndrome. dosage is regulated by determinations of the Ievnl of bicarbonate in t,he serum and that amount is aivrn which will restore the bicarbonate concentration to the normal range.
F.~N(‘ONI
3.51
S1-NDROME
The child has continued to grow aminoaciduria was not appreciably lessened. at a normal rate and shows no obvious untoward manifestations at the age of 5 years. The relationship of the disturbance in cystine metabolism to the renal tubule Clay, Darmady, and Hawkins” studied the injury in this disease is unsolved. kidneys of patients with cystinosis by the technique of tubule microdissection. They concluded that there was an anatomic abnormality of the tubule which they described as a long narrow swan-neck-like segment of tubule between the glomerulus and the proximal convoluted tubule with shortening of the true convoluted segment. Histologically the convoluted tubule cells in this condition The study of inhave also been shown to be lacking in alkaline phosphatase. fants with cystinosis by Bickel’* suggests, however, that the primary metabolic abnormality is not in the renal tubule but that the disturbance of renal tubule function appears only after several months and is preceded by evidences of cystine deposition in tissues. The tubule dysfunction could be considered to be secondary to the hereditary but as yet unidentified metabolic disorder which leads to accumulation and precipitation of cystine in the tissues. FANCONI
SYNDROME
OF UNKNOWN
PATHOGENESIS
IN CHILDREN
AND ADULTS
As techniques have been developed for differentiating the varieties of rickets and osteomalacia not due to vitamin D deficiency, a number of cases of the Fanconi syndrome have been reported in older children and adults.1gp20 In these patients, examinations of the bone marrow, cornea, or other tissues for cystine crystals have been negative, differentiating them from the cases of cystinosis. In addition, in many of these patients, there has been no striking familial story with the definite hereditary pattern of a recessive characteristic as seen in cystinosis. It is true that a few cases of Fanconi syndrome in adults have given a family story of glycosuria or bone deformities in relatives suggestive of a familial trait,21 but in most instances there have been no documented cases of the complete triad in other members of the family. The story in these patients is usually one of rachitic bone deformity, dwarfism, bone pains due to fractures, and muscle weakness starting either in childhood or adult life with progressive manifestations until the diagnosis is finally made on the basis of x-ray evidences of rickets and osteomalacia. In the adults with osteomalacia Looser-Milkman zones are frequently found. In addition to hypophosphatemia, generalized aminoaciduria, and glycosuria these patients ma-) also show a mild hyperchloremic acidosis, polyuria, and sometimes hypokalemia. The aminoaciduria is generalized and is similar to that found in the infants and children with cystine storage disease. Treatment of these patients with large amounts of vitamin D varying from 50,000 to 300,000 units or more a day has usually resulted in elevation of the serum phosphorus, recalcification of the rachitic and osteomalacic bone, and symptomatic improvement.16 Addition of a sodium citrate or sodium and potassium citrate mixture has been of additional value in those patients with reduced serum bicarbonate levels. The prognosis in a number of these patients has been good when vitamin D therapy was continued and carefully controlled so that hypervitaminosis D was avoided. Since this is probably a heterogenous
352
lI;\KHlSOS
group
of problems
response
D therapy.
has uot ouly
resultctl
aciduria
gl>.cosuria
and
ant!
;L toxic
marked
hypophosphatemia
effect
by Milkmat1.
that
and
aminoacicluria
the
and
of supposedly* metal
due
generalized treatment
produce
the possibi!it!-
tlw
,
ric!;cts
exists
that
from further
although
of
no additional
that renal tubular
be caused
citrate
manifestations
damage
of the Fanconi
some of the cases of IPanconi
might
renal
and
oral sodium
and
healed
had
least one
at
This child responded
a!! of the
It seems evident
paint
and
of removal
injection,
occur
and lead.‘”
amilloaciduri;L,
some or a!! of the manifestations
pathogenesis
may
of lead-containing
consisting
t reatmellt
illjur)*
cadmium,
in the bones,‘” renal
ca!(.iunl
and
\vas emplo\-et!.
unknown
tubular
uranium,
of rickets
cdathanii!
resolved,
ma)’
to renal
including
I~o!!owii~~ prolonget!
D treatment
of cases of osteomalacia
in a chilt! with Icatl !x~isoning.“5
of his lent! poisonillg,
due to heav!- met;L!s syndrome,
bone
tlue to ingestion
rickets,
to leat!, !)arentera!
I;;~tw~rli s>w!rome
vitamin
patients.
incidence WAS so high as to factor. These patients had changes with the pseudofractures
evitlences
has been re!)orted
administration.
in some
a number
severe
c!>ring oi lead poisoning
to treatment exposure
acidosis
reportec!
gl~~cosuria
ant!
of hg.pophosphaten7ic.
case
in the
factor?..
to heav!T metals
been found to show histologic glycosuria
aud
Clqcosuria \V;LSnot detected, md studies of aminoacidat this time. In more recent J-ears, however, it has been
as the result of exposure Children
course
The as the etiologic
of cadmium
uria were not available found
metabolic
in a cadmium
suggest
in the
interest that vitamin D therap!. !>ut has also diminished the amino-
oi rickets
the
associates””
md
in \vorkers
clescribed
is to !)e expected
It is of particulitr
in healing
1942, Sicautl
In
occurring
variation
some
to vitamill
syndrome
by unrecognized
heavy
poisoning.
The
observation
in hepatolenticular has been
that
frequentI>.
the basic defect
generalized
degeneration
The
confirmed.
is ii congenital
aminoaciduria
was made current
deficient)
is a fair!!,
b,- 1Jzman theory
and
uniform
of Wilson’s
of the copper-binding
finding
Denn~~-Browrlz6 disease
protein
and
is that
in plasma,
C’oppcr is absorbed ant! retained in excessive amounts in the ceruloplasmin. tissues with resultant liver anti basal ganglion cell injury. The aminoacidurin has been ascribed
to renal tubule
injur>- due to copper accumulation
in the tubule
111 a few patients with \\~‘i!son’s disease the nminoaciduria has cells. rompanied 1~4’ renal glycosuri;~, ll?.pophosI’hatcmia, and osteomalncia,
been i.e.,
ac-
the
Fanconi syntlrome. The resemblance of this picture to that seen in poisoning with However, ill most patients with Wilson’s disease cadmium or lead is obvious. the h!-po!‘hosphatemia has Ilot been marked, and osteomalacic changes have been slight.
‘I’wo
been
cases
of the
reported.“7,‘b:
Fancotli
syndrome
In the patient
in p:itients
described
with multiple
by Engle”8
sections
myeloma
have
of the kidne).
FANC‘ONI
post
mortem
cells,
the
myeloma tients
revealed
nature
was
and the full-blown
suggests
injury
reduced
potassium
of the Fanconi
loss,
syndrome
may also produce
of renal
These
acids.
in the cytoplasm of renal tubule The coexistence of multiple
determined.
myeloma
in disturbances
and amino excess
inclusions not
picture
that multiple
resulting
glucose, lation,
rod-shaped
of which
353
SYNDROME
tubular
patients
of phosphate,
disturbances
of uric acid
two pa-
renal tubular
reabsorption
also showed
and a disturbance
in these
the specific
of pH regu-
reabsorption
with
uric acid levels in serum. DISCUSSION
It seems probable tubular
that
reabsorption
produced
by poisoning
glycosuria,
and
stereoisomer
of fumaric
combination
exist without
disturbance
old female who
has
normal
curves.
This
patient
similar
to that
of the bones cosuria
were
the renal tubular reabsorption
vitamin
D deficiency
slowly.
In patients
cause an increase of phosphate
normally ment
Small but
upon
reduce
vitamin
of vitamin
aminoaciduria progress
and glyWhether
so that
tubular
of hypophospha-
import
syndrome
amounts
syndrome,
reabsorption
in the Fanconi
of vitamin
injurious
whatever
of amino syndrome
correct
responds
the cause,
more
large doses
will in most instances tubular acids
reabsorption
excreted
It would seem that are those
functioning
agents
bl
the hype..
D rapidly
aminoaciduria
D for their proper
the defect
of phosphate
accompanies
due to more complete range.
that
can be overcome
due to true nutritional
aminoaciduria
the amount
by diverse D.
she
and roentgenograms
with development
the renal
to the normal
mechanisms
by large amounts
of renal
of renal tubular
in serum phosphorus
dependent
of these
and
tolerance
However,
and osteomalacia
generalized
affected
glucose
syndrome. levels,
50 to 100 times the usual requirement,
mechanisms
is not
aminoaciduria
as well as practical
regulation
not usually
linder
lesion
by 1,uder and Sheldon.31
with the Fanconi
is a defect
and will often
although
skeletal
at the moment.
with the Fanconi
D, perhaps
the tubular
impaired
and its bone lesion.
of phosphate
of vitamin
urine,
there
a
generalized
may eventually
In rickets
acids so that
of phosphate.
normal
Fanconi
disorder
theoretical in patients
D in large amounts.
the defect
the
and
marked
combination
becomes
vitamin
phosphatemia
with
is unknown
regulation
and also of amino
to have
in such patients
It is of considerable of phosphate
acid,
can occur with-
since the age of 10 years
levels
of serum phosphorus
This
of phosphate
aminoaciduria,
of maleic
and renal glycosuria can also We have studied a 30-yearmetabolism.
sugar
as a familial
and osteomalacia
reabsorption
to have glycosuria
blood
in subjects
defect
injection
aminoaciduria
was also found
normal.
generalized
by
and its consequent
of phosphate
of regulation
agents may interfere with has been, for example,
renal aminoaciduria
tubular
of renal
has been reported
temia
of renal
fasting
found
no defect
caused
Generalized
who has been known had
exhibited
been
hypophosphatemia
The
of injurious Aminoaciduria
Experimentally,
have
acid.30
impairment
such circumstances,
acids.
with creso1.2g
phosphaturia
out associated found.
a wide variety
of amino
in the
certain which
of are
and the impair-
can be in part
overcome
It is now customaq,
phatemia
(rickets
as the Fanconi
syndrome.
from impairment reabsorption
from injury
enous
of renal tubule
toxic
origin
syndrome
Cystine
in infanc\T and early
hood and adult
life is usually
Heavy
metal
poisoning
factors
of the
Fanconi
renal
tubule
phate
levels
vitamill
vitamill
and multiple
the
The
disturbance
of the rachitic other
so that
Studies
renal
can
ol refr;lctoqy
rickets
classifietl
sillre marked
generalized
of the Fanconi
in late child-
by
or osteomalacia aminoaciduria
is lessened in the ii the
etiologic of the
of serum large
phos-
amounts
and more normal
bone can be achieved.
d~.sfunctions
exrretion
pathogenesis.
mechanism
of regulation
or osteomalacic
disturb-
the possible the
can be corrected
tubular arid
instances
be overcome
the aminoacidurin
of ;imino
syndrome
are among
in most
syndrome
all cases
chararteristics
myeloma
ma)
cause of the Fanconi
and rnz?- be of diverse
but
These
or ma\- be exog-
is an hereditaq.
Fanconi
systems
can probabl?
of agents.
disorders
which
The
the hypophosphatemia
1) therapy
is improved.
childhood.
not hereclitar!.
is unknown.
and growth
instances,
metabolic
results
with tubular and poI)-uria
syndrome
gene is the most common
syndrome
in the Fanconi
D so that
cification some
injur)’
hypokalemia,
Fanconi
disease
glycosuria
Other renal tubular
cells by a wide variet). storage
by a recessive
renal
disturbances
are concerned
acidosis, The
due to hereditar!.
substances.
transmitted
which
amino acids, and glucose. triad.
and
of physiologic
mechanisms
the main
lesions of hypophos-
aminoaciduria,
so that hyperchloremic with
be of endogenous
renal
combination
tubule
of phosphate,
map- be associated
ance
This
of renal
ma>’ also be affected result
to refer to the triad of the skeletal
or osteomalacia),
are also
ameliorated
xnd the chronic urine
problem
should
of cul-
In by
acidosis
be made
in
is to be accurateI>
is one of the constant
diagnostic
s!.ndrome.
de Toni, G.: Remarks Upon the Relations Between Renal Rickets (Renal Dwarfism) and Renal Diabetes, Acta paediat. 16:479, 1933. Der friihinfantile nephrotisch-glykosurische Zwergwuchs mit hypophospha2. Fanconi, G.: tzmischer Rachitis, Jarb. f. Kinderh. 147:299, 1936. Hypophosphatemic Rickets 3. hIcCune, D. J., Mason, H. H., and Clarke, H. T.: Intractable With Renal Glycosuria and Acidosis (The Fanconi Syndrome), Am. J. Dis. Child. 65:81, 1943. Rela4. Ilarrison, H. E., and Harrison, H. C.: The Renal E*;cretion of Inorganic Phosphatein tion to the Action of Vitamin D and F’arathproid Hormone, J. Clin. Invest. 20:47, 1941. Mechanism of 5. Robertson, B. R., Harris, R. C., and McCune, I). J.: Refractory Rickets: Therapeutic Action of Calciferol, .%m. J. Dis. Child. 64:948, 1942. 6. I)cnt, C. E.: Rickets and Osteomalacia From Renal Tubule Defects, J. Bone 8: Joint Surg. 34-B:266. 1952. E.: Cystinosis: Cystine Disease (Lignac’s Disease) in Children. Advances 7. Freudenberg, in Pediatrics, New York, 1949, Interscience Publishers, vol. 4, p, 26.5. Ueber StGrung des Cvstinstoffwechsels bei Kindern. Deutsches Arch. 8. Lipnac. G. 0. E.: clin. Med. 145:139, 1924. ” _ 9. Stowers, J. M., and Dent, C. E.: Studies on the Mechanism of the Fanconi Syndrome, Quart. J. Med. 16:275, 1947. 10. Milkman, L. A.: Multiple Spontaneous Idiopathic Symmetrical Fractures, Am. J. Roentgenol. 32:622, 1934. 11. Dent. C. E.: A Studv of the Behavior of Some Sixtv Amino Acids and Other Ninhvdrinreacting Substances on Phenol-“Collidine”-Filtkr-paper Chromatograms With ‘Notes as to the Occurrence of Some of Them in Biological Fluids, Biochem. J. 43:169, 1948. 1.
G
FANCONI
12. 13. 14. 15.
16. 17. 18. 19. Z: 22.
23. 21. 25. 26. 27. 28. 29. 30. 31.
SYNDROME
355
Harrison, H. E., and Harrison, H. C.: Aminoaciduria in Relation to Deficiency Diseases and Kidney Function, J.A.M.A. 164:1.571, 1957. Quantitative Study With Ion Evered, D. F.: Excretion of Amino Acids by the Human: Exchange Chromatography, Biochem. J. 62:416, 1956. Mime, M. D., Stanbury, S. W., and Thomson, A. E.: Observations on the Fanconi Syndrome and Renal Hyperchloremic Acidosis in the Adult, Quart J. Med. 21:61, 1952. Bickel, H., Smallwood, W. C., Smellie, J. M., and Hickman, E. M.: Cystine Storage Disease With Aminoaciduria and Dwarfism (Lignac-Fanconi Disease), Clinical Description, Factual Analysis and Treatment of Lignac-Fanconi Disease, Acta paediat. (supp. 90) 42:27, 1952. Dent, C. E., and Rose, G. A.: Aminoacid Metabolism in Cystinuria, Quart. J. Med. 20:205, 1951. Clay, R. D., Darmady, E. M., and Hawkins, M.: Nature of Renal Lesion in Fanconi Syndrome, J. Path. & Bact. 65:551, 1953. Bickel, H.: Die Entwicklung der biochemischen L&ion bei der Lignac-Fanconischen Krankheit, Helvet. paediat. acta. 10:259, 19.55. Salassa, R. M., Power! M. H., Ulrich, J. A., and Hayles, A. B.: Observations on the Metabolic Effect of Vitamin D in Fanconi’s Syndrome, Proc. Staff Meet. Mayo Clin. 29:214,1954. Wallis, L. A., and Engle, R. L., Jr.: The Adult Fanconi Syndrome, Am. J. Med. 22:13, 1957. Dent, C. E.. and Harris, H.: Hereditary Forms of Rickets and Osteomalacia, J. Bone & Joint Surg. 3%B:204, 1956. Nicaud, P., Lafitte, A., Gras, A., and Gautier, J. P.: Les lesions osseuses de 1’ intoxication chronique par le cadmium. Aspects radiologique Q type de syndrome de Milkman. Efficacite du traitement calcique et vitaminique (vitamin D), Bull. et mCm. Sot. med. hap. Paris 19:204,1942. Clarkson, T. W., and Kench, J. E.: Urinary Excretion of Amino Acids by Men Absorbing Heavy Metals, Biochem. J. 62:361, 1956. Follis, R. H., Jr., Jackson, D., Eliot, M. N., and Park, E. A.: Prevalence of Rickets in Children Between 2 and 14 Years of Age, Am. J. Dis. Child. 66:1, 1943. Chisolm, J. J., Jr., Harrison, H. C., Eberlin, W. R., and Harrison, H. E.: Aminoaciduria, Hypophosphatemia and Rickets in Lead Posioning, Am. J. Dis. Child. 89:159, 1955. Uzman, L., and Denny-Brown, D.: Aminoaciduria in Hepatolenticular Degeneration (Wilson’s Disease), Am. J. M. SC. 215:599, 1948. Sirota, J. H., and Hamerman, D.: Renal Function in an Adult Subject With Fanconi Syndrome, Am. J. Med. 16:138, 1954. Engle, R. L., Jr., and Wallis, L. A.: Multiple Myeloma and the Adult Fanconi Syndrome, Am. J. Med. 22:5, 1957. Gross Aminoaciduria Following a Lysol Burn, Lancet Spencer, A. G., and Franglen, G. T.: 1:190, 1952. Harrison, H. E., and Harrison, H. C.: Experimental Production of Renal Glycosurla, Phosphaturia and Aminoaciduria by Injection of Maleic Acid, Science 120:606, 1954. Luder, J., and Sheldon! W.: Familial Tubular Absorption Defect of Glucose and Amino Acids, Arch. Dls. Child. 30:160, 1955.
FANCOSI
SYKDROME
From the Pediatric Dioision. Baltimore City Hospital, and Department of Pediatrics, Johns Hopkins Liniversity, School of Medicine (Received
T
HE
TRIAD
consisting
(bj generalized
termed
directly
or indirectly
The
Fanconi
syndrome
may result renal
(a)
syndrome.
stem
functional
of
has multiple may
also result
disorder
fluid is rickets
malacia
in adult
if it occurs there
The rickets
is a disproportion
necessary
of renal
of renal
to
functions. tubule
or acquired,
syndrome.
of manifestations
The
functions
other
As a result
the
but have in common
from a deficient!.
linear
association
of the bones
the formation
of renal
of crystals
glycosuria
In by
of bone salt at the rate re-
with
hypophosphatemia
of pediatricians
by vitamin D treatment, values. There were other
of severe
matrix
matrix.
to the attention
this child but the renal glycosuria case from examples
or osteo-
has ceased.
of organic
b>r de Toni,l
although earlier reports of probably similar cases are on record. the case of a child with arrest of growth, marked hypophosphatemia which was not influenced with normal blood glucose
phosphate
is growing,
of this matrix. Because of the deficiency of exphosphate cannot be concentrated in the matrix
for the formation
brought
of inorganic
individual
growth
between
normall\~ the organic
specific was first
tubule
disorders
in disturbances
if the affected
life after
bone cells and the calcification tracellular inorganic phosphate, to calcify
renal
congenital
part of the Fanconi
which results
in the extracellular
to the extent
since
either
is now generallq
can be considered
triad listed above.
The skeletal
quired
of hypophosphatemia,
of specific
etiologies
of causes,
cases may show a wide variety
case,
lesion
manifestations
from disturbances
from a variety
lesion
the characteristic
either
skeletal
and (c) renal glycosuria
A411of these
than those which are by definition individual
the
renal aminoaciduria,
the Fanconi
function
for publication No\,. 20, 1957. i
He presented with rickets
and glycosuria associated evidences of renal injury in
and the hypophosphatemia
renal disease
and in 1933,
with glomerular
differentiated insufficiency,
this chronic
acidosis, dwarfism, and the associated defect of skeletal calcification sometimes termed renal rickets, since these latter patients exhibit hyperphosphatemia. In the next few ?.ears other cases of intractable rickets associated with glycosuria 346
FANCONI
SYNDROME
347
In 1936, Fancon? described a patient with a syndrome which he were reported. termed “infantile nephrotic glycosuria, dwarfism and hypophosphatemic rickets.” Fanconi’s description was thus not the original report, but he pursued the problem vigorously, discovered other cases, and presented a theory of the pathogenesis of this entity so that his name has been given to the syndrome. Fanconi suggested that renal tubular injury might be the basic problem and also noted that these infants excreted an excessive amount of organic acids which he did not identify. McCune, Mason, and Clarke3 investigated this aspect of the problem and found that an extraordinarily great excretion of amino acids accounted for the large organic acid output. It was thought that renal tubular dysfunction could account for both the aminoaciduria and the glycosuria, and attention was directed to the hypophosphatemia to see if it might also be explained on this basis. It had already been indicated by Harrison and Harrison4 that the hypophosphatemia of vitamin D deficiency rickets was associated with reduced renal tubular reabsorption of phosphate and that administration of vitamin D increased tubular reabsorption of this ion. It seemed probable that the hypophosphatemia of the Fanconi syndrome was also due to renal phosphaturia on the basis of renal tubular defect of phosphate reabsorption associated in this instance with defects of glucose and of amino acid reabsorption. This thesis of the mechanism of hypophosphatemia in refractory rickets was espoused by Robertson, Harris, and McCune,5 reaffirmed more recently by Dent,6 and is generally accepted at the present time. The demonstration of the aminoaciduria in infants with the Fanconi syndrome was followed by the observation that cystine crystals could be found in the tissues of these infants. Freudenberg7 examined this association and connected these findings with an earlier report by Lignac* who had studied 3 infants with retardation of growth and rickets whose tissues were found post mortem to be infiltrated with cystine deposits. It then became apparent that cystinosis (or cystine storage disease, as the disease was also termed) was one of the possible causes of the Fanconi syndrome and perhaps the most important cause of the infantile variety. Cases of Fanconi syndrome without demonstrable cystine accumulation in tissues were also discovered in children and adults. Stowers and Dent9 reported a detailed metabolic study of an adult with the picture of hypophosphatemic osteomalacia, generalized aminoaciduria, and glycosuria. Although this was the first case in which generalized aminoaciduria in association with osteomalacia was demonstrated, there had been cases of osteomalacia with renal glycosuria reported much earlier, and these almost certainly represent examples of the adult form of the Fanconi syndrome. One of these cases had been reported by MilkmanlO in his original report of osteomalacia with x-ray evidences of multiple symmetric pseudofractures (Looser-Milkman zones). The term Milkman’s syndrome has been used to describe osteomalacia with these particular roentgenographic findings. The Fanconi syndrome is but one of the several causes of osteomalacia, and if the Looser-Milkman zones are demonstrated b! x-ray the term Milkman’s disease might be applied. There is, therefore, a considerable amount of confusion in t.he literature due to the multiplicity of names which have been used in the description of one or more varieties of the Fanconi syndrome and of osteomalacia.
348
J. (‘hron.
l)is.
April, iY59
The generalized aminoaciduria which is one of the hallmarks of the I;;tncolli syndrome was not readily detected until the method of paper chrornatograph!. was applied 1,~. Dent ‘I to studies of urine aminoacid colltent. This method permits the qualitative detection of the individual amino acids a11(1;LII estimation of the quantit>. of each present. Following introduction of this technique the classification of abnormal amilloacidul-ice bec;me more Iwacticable,‘” ;lnd I he recognition of the l;anconi syndrome was facilitated. It is not surprising, therefore, that more cases have been diagnosed ill recent >‘ears. More exact studies of the aminoacidtlri,t of the l;anconi q,ndrome have also led to a11 explanation of the mechanism of the aminoaciduria and to a11 understanding of the pathogenesis of the h!,(,ophosphatemi~~ and osteomalacia. Simultaneous determinations of plasim amino acid coweritrations and urillc amino acid excretions showed that the plasm;~ levels were norma despite increase(l urine excretion so that amino acid clearantes \vere high.‘” III the normal indivitlual most of the amino acid content of the glomcrular filtrate is reabsorbed h,. the renal tubules so that oiil~, ;I small fraction of 1he tiltered amilio acids appears in the urine excreted. 111 patients with the l;anconi s\,ndrome it can be shown that a much smaller fraction of filtered amino acids is reabsorbed ;lcc.ountillg for the The ph>.siologic defect is thus in the renal excess of amino ~wicls in the urine. tubule cells. The gl~~cosuria also fits iu Lvith this concept since blood sugar levels :u-e normal and the appearance of glwose in uriile is the result of diminished The same t!ye of stud?- led to the espla~~ation tubular reabsorption of glucose. of the h~pophosphatemia, which is me of the major ph>-siologic. disturbances. [Jnder conditions in which adequate amounts of phosphorus are available to the we determined bh. the relationship body the serum phosphorus concentrations between phosphate filtered through the glomeruli and that reabsorbed 1~~. the In the uncomplicated case ot’ the Fancoui s!-ndrome the glomerul:u renal tubules. frltratioll rate is normnl but the rellxl tubular reabsorption of phosph:~tc is reduced just as is the renal tubular reabsorplion oi amino acids and glucose. .As a result phosphate in considerable qu;ultit\, is e.xcrcted in the urine despite pcrsistentl\low levels of phosphate in plasma and other extracellular fluids. Other disturbances of renal tubular functiorl may occur along \vith the aforcmentioned deficiencies of tubular re;tbsorptioll of amino acids, glucose, and phosphate. Potassium ma\. be lost in excess ill the urine due to clisturb;~uce in the mechanism which regulates the exchange of potassium for sodium ;u~d hydrogen ion, and potassium deficit with h~yokalerni:l results.14 This ma). be severe enough to produce episodes of severe muscle weaktless spolltalleousl\., or as the result of injection of glucose intravenously in the performance of a glucose tolerance test. Impairment of the renal mechanism for regulation of the pH of urine has also been found which is manifested bl- a metabolic acidosis a*ith h~~perchloremia associated with the excretion of urine which is neutral or slightly, alkaliuc ill Fiuall>~, a defect of water reabsorption with failure of formation of it reaction. concentrated urine C;LII occur with resultant lwl~wria resembling the 1’ic.ture of As ill the latter s>~ndrome, the c-otlcellt ratio11 of nephrogenic diabetes insipidus. solutes in urine and the volume of urine is not affected 1~~.injection of pitressin since the defect is in the tubule cell. The clinical picture of the Fanconi s)wdrome
Volume 7 Number 4
FANCONI
STNDKOME
349
can thus include a variety of manifestations associated with disturbances of water and electrolyte balance resulting from the various disturbances of renal tubule In some instances there may be difficult,- in differentiating variants of function. the Fanconi syndrome from renal tubular acidosis with hypophosphatemia and In the latter syndrome aminoaciduria is not a constant feature osteomalacia. Calcification of renal tubules and nephrocalcinosis is an important complication. does not occur in the Fanconi syndrome. Not: only are there variations in the clinical phpsiology of this syndrome, but It is now evident the etiology of the Fattconi syndrome may also be quite diverse. that the same general t)rpe of renal tubule dysfunction ma!. occur either on the basis of genetic defect or as the result of acquired injury, and that diverse injurious agents, some known and some as yet unknown, may be responsible for the acIn the following section various forms of the quired forms of this syndrome. Fattconi syndrome will be separated on the basis of the possible pathogenesis of the disorder. The fundamental tnauifestations which must be present in all instances are hypophosphatemia with rickets or osteomalacia, generalized aminoaciduria and renal glycosuria. The last of the three may be quite mild and in some cases the qualitative test for urine glucose may be so slightly positive at times as to be considered of no significance unless a diagnosis of the Fanconi syndrome is being entertained. The marked generalized aminoaciduria along with failure to respond to ordinary vitamin D therapy are the salient features in the differentiation of the Fanconi syndrome from other types of rickets and osteomalacia with similar defortnity and x-ray findings.
The original reports of the Fanconi syndrome were of cases which started in infancy with rickets unresponsive to usual vitamin D therapy, renal glycosuria, and growth retardation. The disease in most instances progressed to a fatal outcome. These cases are now recognized as examples of cystinosis and this disease entity has been thoroughly reviewed by Bickel and his associates.t5 It is hereditary, and the transmission is that of an autosomal recessive gene. The infants are apparently normal at birth and show no disturbances during the first few months of life. Subsequently, they may manifest the nonspecific evidences of a metabolic disturbance-failure of growth, anorexia, lethargJ7, and weakness. In other instances, rachitic deformities, appearing at the age of a year or 18 months despite usual vitamin D intake, ma)- be the first signs. Further stud), reveals the triad of the Fanconi syndrome, i.e., hypophosphatemin, generalized aminoaciduria, and glycosuria. In addition the other manifestations of renal tubular dysfunction such as metabolic acidosis, hypokalemia, and polyuria ma>be present. The distinguishing feature of cystinosis is the accumulation of cystine crystals in large phagoc>.tic cells in many body tissues. They are found tnost readily in the reticuloendothelial system (bone marrow, spleen, lymph nodes, and liver) but may also be found in kidney and subcutaneous tissue. These crystals are likewise fount1 in the cornea, and since the)- can be detected in this tissue by slit-lamp microscopy, this latter procedure is therefore a useful diagnostic technique. Examination of bone marrow spreads or lymph node biopsies will
350 reveal
the characteristic
cystine
flat hexagonal
has been found to crystallize
hexagonal
plates.
deposited
It is important
in the tissues
acids is a generalized
ornithine amino
acids
results
The course ‘The disorder fairly
metabolic
administration
citrate
bJ_ these
methods
and potassium
which
in injut-).
cl\.sfunction
hypophosphatemia perphosphatemia destruction
and
of the kidneys. tnore
initial as
the death
of the patient.
may, stage
glomerular phase,
such as sodiun?
primary
secondat-\.
with
c.\.stinosis
underlying
disorder
therefore,
and
is unknown
to eventual
renal
often
tit rhosis
be progressive
insufficiency.
ma!- be superseded insufficiency
h>~pocalcemia,
If a bJ.
improved
of the
in tissues
ma). occur as in an\. form of severe
infant
so that
This
b!y treatment per day).
and growth
leading
progressive
In this termittal
infections
mixture
mechanism
cells
There
important,
h>~perkalemia
and anemia
poorI\- nourished
The b>- hy-
results
refractory
from meta-
renal insufficiency.
is also particularly-
susceptible
infections have often been a contributor). Sot all infants \vith q.stinosis, however,
to
factor in show this
downhill course, and it appears that the prognosis is not uniforml> We have observed a child with c-ystinosis, proved b,. the presence
progressive unfavorable. of q.stine
tubule
and unfavorable.
the!, can be treated
precipitation
b\- treatment. renal
of the uncomplicated
of nephrons.
bolic acidosis, The
and,
:~11d
in the
associated
syndrome.
units
be healed the
to cystine
ameliorated
of the liver and to fibrosis hepatic
leads
to hepatic
can
and
of these
cystine
be corrected
to 50,000
function,
arginine,
is not
of the Fanconi
alkalittizing
However,
of treatment.
disorder
soluble
cystinuriu
are also present
rickets
has some-
amounts
is usuall~~ progressive
11 (10,000
deficit
The
solution.*
and is ttot necessarily results
of vitamin
lysine,
of large
can frequently
of ;t l’otassium-contaiiiillg
potassium metabolic
metabolism
amounts
acidosis
lesions
with cystinosis
of phosphate
of cystine,
Essential
or the skeletal
in the urine in excess (:ystinosis
of the poorly
calculi.
is
of amino
of renal tubular
to excretion
Crystallization
cystine
only
reabsorption
of c)-stine.
reabsorption
leading
in cl-stine
of infants
large
although
tubular
fortn of disturbance
limited
in the urine.t6
tract
that
of renal
excretion
in which tubular
with h4.pophosphatemia
with
urinary
with another
are specifically
urinar),
In some instances as well as in the more typical
one so that all amino acids are excreted
been confused
essential cystinuria
of qstine.
to emphasize
the disturbance
and there -is no preponderant times
crystals
in fine needles
crJ.stals
been benign.
The
in bone marrow initial
biopsies
manifestations
and in the cornea,
whose
in this child wet-e the bony
course
has
deformities
of rickets
which were first noticed at about 1 year of age. Subsequent studies marked generalized aminoaciduria, and revealed persistent hl.pophosphatemia, mild glyc‘osurin. Treatment with vitamin I1 in doses of 12,500 units daily plus sodium and potassium citrate solution resultecl in elevation of serum phosphorus levels, complete healing of rickets, and resumption of normal growth although the *A solution
which we have used for this purpose has tlw following composition: Citric acid, 70 Gm. Sodium citrate, 98 Cm. Potassium citrate, 108 Gm. Made up to 1 liter in fruit-flavored syrup base. This solution provides 1 mEq. each of sodium and potassium per milliliter. Thirty to forty milliThe liters per day in divided doses has corrected the acidosis of children with the Fanroni syndrome. dosage is regulated by determinations of the Ievnl of bicarbonate in t,he serum and that amount is aivrn which will restore the bicarbonate concentration to the normal range.
F.~N(‘ONI
3.51
S1-NDROME
The child has continued to grow aminoaciduria was not appreciably lessened. at a normal rate and shows no obvious untoward manifestations at the age of 5 years. The relationship of the disturbance in cystine metabolism to the renal tubule Clay, Darmady, and Hawkins” studied the injury in this disease is unsolved. kidneys of patients with cystinosis by the technique of tubule microdissection. They concluded that there was an anatomic abnormality of the tubule which they described as a long narrow swan-neck-like segment of tubule between the glomerulus and the proximal convoluted tubule with shortening of the true convoluted segment. Histologically the convoluted tubule cells in this condition The study of inhave also been shown to be lacking in alkaline phosphatase. fants with cystinosis by Bickel’* suggests, however, that the primary metabolic abnormality is not in the renal tubule but that the disturbance of renal tubule function appears only after several months and is preceded by evidences of cystine deposition in tissues. The tubule dysfunction could be considered to be secondary to the hereditary but as yet unidentified metabolic disorder which leads to accumulation and precipitation of cystine in the tissues. FANCONI
SYNDROME
OF UNKNOWN
PATHOGENESIS
IN CHILDREN
AND ADULTS
As techniques have been developed for differentiating the varieties of rickets and osteomalacia not due to vitamin D deficiency, a number of cases of the Fanconi syndrome have been reported in older children and adults.1gp20 In these patients, examinations of the bone marrow, cornea, or other tissues for cystine crystals have been negative, differentiating them from the cases of cystinosis. In addition, in many of these patients, there has been no striking familial story with the definite hereditary pattern of a recessive characteristic as seen in cystinosis. It is true that a few cases of Fanconi syndrome in adults have given a family story of glycosuria or bone deformities in relatives suggestive of a familial trait,21 but in most instances there have been no documented cases of the complete triad in other members of the family. The story in these patients is usually one of rachitic bone deformity, dwarfism, bone pains due to fractures, and muscle weakness starting either in childhood or adult life with progressive manifestations until the diagnosis is finally made on the basis of x-ray evidences of rickets and osteomalacia. In the adults with osteomalacia Looser-Milkman zones are frequently found. In addition to hypophosphatemia, generalized aminoaciduria, and glycosuria these patients ma-) also show a mild hyperchloremic acidosis, polyuria, and sometimes hypokalemia. The aminoaciduria is generalized and is similar to that found in the infants and children with cystine storage disease. Treatment of these patients with large amounts of vitamin D varying from 50,000 to 300,000 units or more a day has usually resulted in elevation of the serum phosphorus, recalcification of the rachitic and osteomalacic bone, and symptomatic improvement.16 Addition of a sodium citrate or sodium and potassium citrate mixture has been of additional value in those patients with reduced serum bicarbonate levels. The prognosis in a number of these patients has been good when vitamin D therapy was continued and carefully controlled so that hypervitaminosis D was avoided. Since this is probably a heterogenous
352
lI;\KHlSOS
group
of problems
response
D therapy.
has uot ouly
resultctl
aciduria
gl>.cosuria
and
ant!
;L toxic
marked
hypophosphatemia
effect
by Milkmat1.
that
and
aminoacicluria
the
and
of supposedly* metal
due
generalized treatment
produce
the possibi!it!-
tlw
,
ric!;cts
exists
that
from further
although
of
no additional
that renal tubular
be caused
citrate
manifestations
damage
of the Fanconi
some of the cases of IPanconi
might
renal
and
oral sodium
and
healed
had
least one
at
This child responded
a!! of the
It seems evident
paint
and
of removal
injection,
occur
and lead.‘”
amilloaciduri;L,
some or a!! of the manifestations
pathogenesis
may
of lead-containing
consisting
t reatmellt
illjur)*
cadmium,
in the bones,‘” renal
ca!(.iunl
and
\vas emplo\-et!.
unknown
tubular
uranium,
of rickets
cdathanii!
resolved,
ma)’
to renal
including
I~o!!owii~~ prolonget!
D treatment
of cases of osteomalacia
in a chilt! with Icatl !x~isoning.“5
of his lent! poisonillg,
due to heav!- met;L!s syndrome,
bone
tlue to ingestion
rickets,
to leat!, !)arentera!
I;;~tw~rli s>w!rome
vitamin
patients.
incidence WAS so high as to factor. These patients had changes with the pseudofractures
evitlences
has been re!)orted
administration.
in some
a number
severe
c!>ring oi lead poisoning
to treatment exposure
acidosis
reportec!
gl~~cosuria
ant!
of hg.pophosphaten7ic.
case
in the
factor?..
to heav!T metals
been found to show histologic glycosuria
aud
Clqcosuria \V;LSnot detected, md studies of aminoacidat this time. In more recent J-ears, however, it has been
as the result of exposure Children
course
The as the etiologic
of cadmium
uria were not available found
metabolic
in a cadmium
suggest
in the
interest that vitamin D therap!. !>ut has also diminished the amino-
oi rickets
the
associates””
md
in \vorkers
clescribed
is to !)e expected
It is of particulitr
in healing
1942, Sicautl
In
occurring
variation
some
to vitamill
syndrome
by unrecognized
heavy
poisoning.
The
observation
in hepatolenticular has been
that
frequentI>.
the basic defect
generalized
degeneration
The
confirmed.
is ii congenital
aminoaciduria
was made current
deficient)
is a fair!!,
b,- 1Jzman theory
and
uniform
of Wilson’s
of the copper-binding
finding
Denn~~-Browrlz6 disease
protein
and
is that
in plasma,
C’oppcr is absorbed ant! retained in excessive amounts in the ceruloplasmin. tissues with resultant liver anti basal ganglion cell injury. The aminoacidurin has been ascribed
to renal tubule
injur>- due to copper accumulation
in the tubule
111 a few patients with \\~‘i!son’s disease the nminoaciduria has cells. rompanied 1~4’ renal glycosuri;~, ll?.pophosI’hatcmia, and osteomalncia,
been i.e.,
ac-
the
Fanconi syntlrome. The resemblance of this picture to that seen in poisoning with However, ill most patients with Wilson’s disease cadmium or lead is obvious. the h!-po!‘hosphatemia has Ilot been marked, and osteomalacic changes have been slight.
‘I’wo
been
cases
of the
reported.“7,‘b:
Fancotli
syndrome
In the patient
in p:itients
described
with multiple
by Engle”8
sections
myeloma
have
of the kidne).
FANC‘ONI
post
mortem
cells,
the
myeloma tients
revealed
nature
was
and the full-blown
suggests
injury
reduced
potassium
of the Fanconi
loss,
syndrome
may also produce
of renal
These
acids.
in the cytoplasm of renal tubule The coexistence of multiple
determined.
myeloma
in disturbances
and amino excess
inclusions not
picture
that multiple
resulting
glucose, lation,
rod-shaped
of which
353
SYNDROME
tubular
patients
of phosphate,
disturbances
of uric acid
two pa-
renal tubular
reabsorption
also showed
and a disturbance
in these
the specific
of pH regu-
reabsorption
with
uric acid levels in serum. DISCUSSION
It seems probable tubular
that
reabsorption
produced
by poisoning
glycosuria,
and
stereoisomer
of fumaric
combination
exist without
disturbance
old female who
has
normal
curves.
This
patient
similar
to that
of the bones cosuria
were
the renal tubular reabsorption
vitamin
D deficiency
slowly.
In patients
cause an increase of phosphate
normally ment
Small but
upon
reduce
vitamin
of vitamin
aminoaciduria progress
and glyWhether
so that
tubular
of hypophospha-
import
syndrome
amounts
syndrome,
reabsorption
in the Fanconi
of vitamin
injurious
whatever
of amino syndrome
correct
responds
the cause,
more
large doses
will in most instances tubular acids
reabsorption
excreted
It would seem that are those
functioning
agents
bl
the hype..
D rapidly
aminoaciduria
D for their proper
the defect
of phosphate
accompanies
due to more complete range.
that
can be overcome
due to true nutritional
aminoaciduria
the amount
by diverse D.
she
and roentgenograms
with development
the renal
to the normal
mechanisms
by large amounts
of renal
of renal tubular
in serum phosphorus
dependent
of these
and
tolerance
However,
and osteomalacia
generalized
affected
glucose
syndrome. levels,
50 to 100 times the usual requirement,
mechanisms
is not
aminoaciduria
as well as practical
regulation
not usually
linder
lesion
by 1,uder and Sheldon.31
with the Fanconi
is a defect
and will often
although
skeletal
at the moment.
with the Fanconi
D, perhaps
the tubular
impaired
and its bone lesion.
of phosphate
of vitamin
urine,
there
a
generalized
may eventually
In rickets
acids so that
of phosphate.
normal
Fanconi
disorder
theoretical in patients
D in large amounts.
the defect
the
and
marked
combination
becomes
vitamin
phosphatemia
with
is unknown
regulation
and also of amino
to have
in such patients
It is of considerable of phosphate
acid,
can occur with-
since the age of 10 years
levels
of serum phosphorus
This
of phosphate
aminoaciduria,
of maleic
and renal glycosuria can also We have studied a 30-yearmetabolism.
sugar
as a familial
and osteomalacia
reabsorption
to have glycosuria
blood
in subjects
defect
injection
aminoaciduria
was also found
normal.
generalized
by
and its consequent
of phosphate
of regulation
agents may interfere with has been, for example,
renal aminoaciduria
tubular
of renal
has been reported
temia
of renal
fasting
found
no defect
caused
Generalized
who has been known had
exhibited
been
hypophosphatemia
The
of injurious Aminoaciduria
Experimentally,
have
acid.30
impairment
such circumstances,
acids.
with creso1.2g
phosphaturia
out associated found.
a wide variety
of amino
in the
certain which
of are
and the impair-
can be in part
overcome
It is now customaq,
phatemia
(rickets
as the Fanconi
syndrome.
from impairment reabsorption
from injury
enous
of renal tubule
toxic
origin
syndrome
Cystine
in infanc\T and early
hood and adult
life is usually
Heavy
metal
poisoning
factors
of the
Fanconi
renal
tubule
phate
levels
vitamill
vitamill
and multiple
the
The
disturbance
of the rachitic other
so that
Studies
renal
can
ol refr;lctoqy
rickets
classifietl
sillre marked
generalized
of the Fanconi
in late child-
by
or osteomalacia aminoaciduria
is lessened in the ii the
etiologic of the
of serum large
phos-
amounts
and more normal
bone can be achieved.
d~.sfunctions
exrretion
pathogenesis.
mechanism
of regulation
or osteomalacic
disturb-
the possible the
can be corrected
tubular arid
instances
be overcome
the aminoacidurin
of ;imino
syndrome
are among
in most
syndrome
all cases
chararteristics
myeloma
ma)
cause of the Fanconi
and rnz?- be of diverse
but
These
or ma\- be exog-
is an hereditaq.
Fanconi
systems
can probabl?
of agents.
disorders
which
The
the hypophosphatemia
1) therapy
is improved.
childhood.
not hereclitar!.
is unknown.
and growth
instances,
metabolic
results
with tubular and poI)-uria
syndrome
gene is the most common
syndrome
in the Fanconi
D so that
cification some
injur)’
hypokalemia,
Fanconi
disease
glycosuria
Other renal tubular
cells by a wide variet). storage
by a recessive
renal
disturbances
are concerned
acidosis, The
due to hereditar!.
substances.
transmitted
which
amino acids, and glucose. triad.
and
of physiologic
mechanisms
the main
lesions of hypophos-
aminoaciduria,
so that hyperchloremic with
be of endogenous
renal
combination
tubule
of phosphate,
map- be associated
ance
This
of renal
ma>’ also be affected result
to refer to the triad of the skeletal
or osteomalacia),
are also
ameliorated
xnd the chronic urine
problem
should
of cul-
In by
acidosis
be made
in
is to be accurateI>
is one of the constant
diagnostic
s!.ndrome.
de Toni, G.: Remarks Upon the Relations Between Renal Rickets (Renal Dwarfism) and Renal Diabetes, Acta paediat. 16:479, 1933. Der friihinfantile nephrotisch-glykosurische Zwergwuchs mit hypophospha2. Fanconi, G.: tzmischer Rachitis, Jarb. f. Kinderh. 147:299, 1936. Hypophosphatemic Rickets 3. hIcCune, D. J., Mason, H. H., and Clarke, H. T.: Intractable With Renal Glycosuria and Acidosis (The Fanconi Syndrome), Am. J. Dis. Child. 65:81, 1943. Rela4. Ilarrison, H. E., and Harrison, H. C.: The Renal E*;cretion of Inorganic Phosphatein tion to the Action of Vitamin D and F’arathproid Hormone, J. Clin. Invest. 20:47, 1941. Mechanism of 5. Robertson, B. R., Harris, R. C., and McCune, I). J.: Refractory Rickets: Therapeutic Action of Calciferol, .%m. J. Dis. Child. 64:948, 1942. 6. I)cnt, C. E.: Rickets and Osteomalacia From Renal Tubule Defects, J. Bone 8: Joint Surg. 34-B:266. 1952. E.: Cystinosis: Cystine Disease (Lignac’s Disease) in Children. Advances 7. Freudenberg, in Pediatrics, New York, 1949, Interscience Publishers, vol. 4, p, 26.5. Ueber StGrung des Cvstinstoffwechsels bei Kindern. Deutsches Arch. 8. Lipnac. G. 0. E.: clin. Med. 145:139, 1924. ” _ 9. Stowers, J. M., and Dent, C. E.: Studies on the Mechanism of the Fanconi Syndrome, Quart. J. Med. 16:275, 1947. 10. Milkman, L. A.: Multiple Spontaneous Idiopathic Symmetrical Fractures, Am. J. Roentgenol. 32:622, 1934. 11. Dent. C. E.: A Studv of the Behavior of Some Sixtv Amino Acids and Other Ninhvdrinreacting Substances on Phenol-“Collidine”-Filtkr-paper Chromatograms With ‘Notes as to the Occurrence of Some of Them in Biological Fluids, Biochem. J. 43:169, 1948. 1.
G
FANCONI
12. 13. 14. 15.
16. 17. 18. 19. Z: 22.
23. 21. 25. 26. 27. 28. 29. 30. 31.
SYNDROME
355
Harrison, H. E., and Harrison, H. C.: Aminoaciduria in Relation to Deficiency Diseases and Kidney Function, J.A.M.A. 164:1.571, 1957. Quantitative Study With Ion Evered, D. F.: Excretion of Amino Acids by the Human: Exchange Chromatography, Biochem. J. 62:416, 1956. Mime, M. D., Stanbury, S. W., and Thomson, A. E.: Observations on the Fanconi Syndrome and Renal Hyperchloremic Acidosis in the Adult, Quart J. Med. 21:61, 1952. Bickel, H., Smallwood, W. C., Smellie, J. M., and Hickman, E. M.: Cystine Storage Disease With Aminoaciduria and Dwarfism (Lignac-Fanconi Disease), Clinical Description, Factual Analysis and Treatment of Lignac-Fanconi Disease, Acta paediat. (supp. 90) 42:27, 1952. Dent, C. E., and Rose, G. A.: Aminoacid Metabolism in Cystinuria, Quart. J. Med. 20:205, 1951. Clay, R. D., Darmady, E. M., and Hawkins, M.: Nature of Renal Lesion in Fanconi Syndrome, J. Path. & Bact. 65:551, 1953. Bickel, H.: Die Entwicklung der biochemischen L&ion bei der Lignac-Fanconischen Krankheit, Helvet. paediat. acta. 10:259, 19.55. Salassa, R. M., Power! M. H., Ulrich, J. A., and Hayles, A. B.: Observations on the Metabolic Effect of Vitamin D in Fanconi’s Syndrome, Proc. Staff Meet. Mayo Clin. 29:214,1954. Wallis, L. A., and Engle, R. L., Jr.: The Adult Fanconi Syndrome, Am. J. Med. 22:13, 1957. Dent, C. E.. and Harris, H.: Hereditary Forms of Rickets and Osteomalacia, J. Bone & Joint Surg. 3%B:204, 1956. Nicaud, P., Lafitte, A., Gras, A., and Gautier, J. P.: Les lesions osseuses de 1’ intoxication chronique par le cadmium. Aspects radiologique Q type de syndrome de Milkman. Efficacite du traitement calcique et vitaminique (vitamin D), Bull. et mCm. Sot. med. hap. Paris 19:204,1942. Clarkson, T. W., and Kench, J. E.: Urinary Excretion of Amino Acids by Men Absorbing Heavy Metals, Biochem. J. 62:361, 1956. Follis, R. H., Jr., Jackson, D., Eliot, M. N., and Park, E. A.: Prevalence of Rickets in Children Between 2 and 14 Years of Age, Am. J. Dis. Child. 66:1, 1943. Chisolm, J. J., Jr., Harrison, H. C., Eberlin, W. R., and Harrison, H. E.: Aminoaciduria, Hypophosphatemia and Rickets in Lead Posioning, Am. J. Dis. Child. 89:159, 1955. Uzman, L., and Denny-Brown, D.: Aminoaciduria in Hepatolenticular Degeneration (Wilson’s Disease), Am. J. M. SC. 215:599, 1948. Sirota, J. H., and Hamerman, D.: Renal Function in an Adult Subject With Fanconi Syndrome, Am. J. Med. 16:138, 1954. Engle, R. L., Jr., and Wallis, L. A.: Multiple Myeloma and the Adult Fanconi Syndrome, Am. J. Med. 22:5, 1957. Gross Aminoaciduria Following a Lysol Burn, Lancet Spencer, A. G., and Franglen, G. T.: 1:190, 1952. Harrison, H. E., and Harrison, H. C.: Experimental Production of Renal Glycosurla, Phosphaturia and Aminoaciduria by Injection of Maleic Acid, Science 120:606, 1954. Luder, J., and Sheldon! W.: Familial Tubular Absorption Defect of Glucose and Amino Acids, Arch. Dls. Child. 30:160, 1955.