1310 Volume 2 . Number 8 . 1992 Idiopathic Fanconi Syndrome in a Family. Part I. Clinical 1 Asad Tolaymat,2 Abdullah Sakarcan, and Richard Neiberger A. Tolaymat, A. Sakarcan, R. Neiberger, University of Florida Health Science Center, Jacksonville Division, Pediatrics Department. Jacksonville, FL (J. Am. Soc. Nephrol. 1992; 2:1310-1317) ABSTRACT Fanconi syndrome is a rare cause of rickets in chil- dren. Only six families with Fanconi syndrome follow- ing an autosomal dominant pattern of inheritance have been reported. In this report, the results of clinical studies performed in three generations of a family of 39 members with autosomal dominant Fan- coni syndrome are presented. Twenty-one members of this family provided blood and urine for biochem- ical evaluation. Many family members have one or more tubular reabsorptive abnormalities; however, the complete Fanconi syndrome was not present in most members. Three children with the complete syndrome all occur in the last generation. When the characteristic features of this family were compared with those of previously reported families with auto- somal dominant Fanconi syndrome, several differ- ences became apparent. Two serious manifesta- tions, diabetes mellitus and renal failure, which occur in previous reports did not occur in this family. This report provides information on apparently the largest number of affected individuals in a single family with Fanconi syndrome. In addition, variable expressivity of tubular reabsorptive defects in a family with Fan- coni syndrome has never been reported. Key Words; Fanconi syndrome. rickets, proximal tubular dys- function, hypophosphatemia. aminoaciduria F anconi syndrome is characterized by decreased reabsorption of phosphate, glucose, amino acids, bicarbonate, and in some cases, citrate, calcium, so- dium , potassium , low-molecular-weight proteins, magnesium. organic acids, and water. The syndrome I Received April 15. 1991. Accepted October 16, 1991. 2 Correspondence to Dr. A. Tolaymat, University of Florida Health Science Cen- for, Jacksonville Division, Pediatrics Department. 655 W. 8th Street, Jacksonville, FL 32209. I0466673/0208- I3 10$03.00/0 Journal of the American Society of Nephrology Copyright C 1992 by the American Society of Nephrology was first described by Lignac in 1 924 (1). Later, DeToni, Debre et a!. , and Fanconi further described the pathophysiobogy (2-5). In 1943, McCune pro- posed the name Fanconi syndrome (6). When no iden- tifiable cause is recognized, the disease is referred to as idiopathic, sporadic, or primary (7,8). Most reported cases of Fanconi syndrome are spo- radic (9). Ten families with Fanconi syndrome have been described in the literature. Six of these families had an autosomab dominant mode of transmission. In this article, we describe the clinical features of another family with autosomal dominant Fanconi syndrome. CASE REPORT The propositus is an 8-yr-old black girl. She was the product of full-term pregnancy and uncompli- cated delivery. At the age of 20/12 yr, she was admit- ted for fever, vomiting, and severe dehydration. Lab- oratory evaluation revealed hyperchboremic meta- bobic acidosis. She was noted to have short stature and genu vanus. Radiographic studies revealed ra- chitic rosary and other changes compatible with rick- ets. The diagnosis of the Fanconi syndrome was made with the following laboratory findings: hypophospha- temia (0.51 mmol/L), increased alkaline phosphatase (600 U/L), hypenchboremic metabolic acidosis, (Cl, 1 14 mmob/L with HCO2, 6.9 mmol/L), generalized aminoacidunia, glucosunia (2.3 mmol/24 h/i .73 m2), hyperphosphatunia (246.4 mmol/24 h/m2), hypercal- ciunia (42.5 mmol/24 h/m2), and low-molecular- weight proteinunia (0.85 g/24 h/m2). Urine protein ebectnophoresis showed an alpha2 and beta band pre- dominance. N-terminal parathyroid hormone and vi- tamin D metabobites were in the normal range, as were serum ceruboplasmin, gamma globulin, tyro- sine, and ammonia. Family history indicated several other family mem- bers had bowed legs and rickets (Figure 1). Subse- quently, other members of the family were studied in an attempt to make a specific diagnosis. Therapy with 1 .25-(OH)2-vitamin D3, potassium phosphate, sodium-potassium citrate, and hydro- chborothiazide was started. The rachitic changes im- proved during the following year. The patient contin- ued to have reduced growth (Figure 2). She has had three additional admissions for dehydration and fe- yen.
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1310 Volume 2 . Number 8 . 1992
Idiopathic Fanconi Syndrome in a Family. Part I. Clinical1
Asad Tolaymat,2 Abdullah Sakarcan, and Richard Neiberger
A. Tolaymat, A. Sakarcan, R. Neiberger, University ofFlorida Health Science Center, Jacksonville Division,Pediatrics Department. Jacksonville, FL
(J. Am. Soc. Nephrol. 1992; 2:1310-1317)
ABSTRACTFanconi syndrome is a rare cause of rickets in chil-dren. Only six families with Fanconi syndrome follow-ing an autosomal dominant pattern of inheritancehave been reported. In this report, the results ofclinical studies performed in three generations of afamily of 39 members with autosomal dominant Fan-
coni syndrome are presented. Twenty-one membersof this family provided blood and urine for biochem-ical evaluation. Many family members have one ormore tubular reabsorptive abnormalities; however,the complete Fanconi syndrome was not present inmost members. Three children with the completesyndrome all occur in the last generation. When thecharacteristic features of this family were comparedwith those of previously reported families with auto-somal dominant Fanconi syndrome, several differ-ences became apparent. Two serious manifesta-tions, diabetes mellitus and renal failure, which occurin previous reports did not occur in this family. This
report provides information on apparently the largestnumber of affected individuals in a single family withFanconi syndrome. In addition, variable expressivity
of tubular reabsorptive defects in a family with Fan-coni syndrome has never been reported.
F anconi syndrome is characterized by decreasedreabsorption of phosphate, glucose, amino acids,
bicarbonate, and in some cases, citrate, calcium, so-dium , potassium , low-molecular-weight proteins,magnesium. organic acids, and water. The syndrome
I Received April 15. 1991. Accepted October 16, 1991.
2 Correspondence to Dr. A. Tolaymat, University of Florida Health Science Cen-
for, Jacksonville Division, Pediatrics Department. 655 W. 8th Street, Jacksonville,FL 32209.
I046�6673/0208- I3 10$03.00/0Journal of the American Society of NephrologyCopyright C 1992 by the American Society of Nephrology
was first described by Lignac in 1 924 (1). Later,DeToni, Debre et a!. , and Fanconi further describedthe pathophysiobogy (2-5). In 1943, McCune pro-posed the name Fanconi syndrome (6). When no iden-
tifiable cause is recognized, the disease is referred toas idiopathic, sporadic, or primary (7,8).
Most reported cases of Fanconi syndrome are spo-radic (9). Ten families with Fanconi syndrome havebeen described in the literature. Six of these familieshad an autosomab dominant mode of transmission.
In this article, we describe the clinical features ofanother family with autosomal dominant Fanconisyndrome.
CASE REPORT
The propositus is an 8-yr-old black girl. She was
the product of full-term pregnancy and uncompli-cated delivery. At the age of 2�0/12 yr, she was admit-ted for fever, vomiting, and severe dehydration. Lab-
oratory evaluation revealed hyperchboremic meta-bobic acidosis. She was noted to have short statureand genu vanus. Radiographic studies revealed ra-chitic rosary and other changes compatible with rick-ets.
The diagnosis of the Fanconi syndrome was madewith the following laboratory findings: hypophospha-temia (0.51 mmol/L), increased alkaline phosphatase
weight proteinunia (0.85 g/24 h/m2). Urine proteinebectnophoresis showed an alpha2 and beta band pre-dominance. N-terminal parathyroid hormone and vi-
tamin D metabobites were in the normal range, aswere serum ceruboplasmin, gamma globulin, tyro-
sine, and ammonia.Family history indicated several other family mem-
bers had bowed legs and rickets (Figure 1). Subse-quently, other members of the family were studied inan attempt to make a specific diagnosis.
Therapy with 1 .25-(OH)2-vitamin D3, potassium
phosphate, sodium-potassium citrate, and hydro-chborothiazide was started. The rachitic changes im-proved during the following year. The patient contin-
ued to have reduced growth (Figure 2). She has hadthree additional admissions for dehydration and fe-yen.
III
I1CR�.�
E0
75th
50th
25th
10th
5th
Tolaymat et a)
Journal of the American Society of Nephrology 1311
Figure 1. Family pedigree of four generations of autosomal dominant Fanconi syndrome. Numbers reflect studied familymember and correspond with those in Tables I through 4.
The propositus with Fanconi syndrome and first-,second- , and third-degree relatives were evaluatedaccording to an outpatient protocol. Twenty-one of39 family members participated in the study.
Twenty-four-hour urine was collected from 21family members (Table 1 ). After the 24-h urine cob-lection, a blood sample was collected. Measurements
of serum sodium, potassium, creatinine, phosphorus,chloride, bicarbonate, BUN, calcium, alkaline phos-phatase, and glucose were obtained with a Technicon
tein, calcium, and glucose were measured in the 24-h urine samples with the Technicon RA 1000. In the
propositus, serum tyrosine was measured by HPLC,and serum ceruboplasmin was measured by nephro-lometny. Urine amino acids were quantitated by au-tomated column chromatography with an ion ex-change resin and pH gradient buffer system. Serum
90th Tampa, FL). Vitamin D metabolites in serum includ-
ing 25-(OH)-vitamin D3 and 1 ,25-(OH)2-vitamin D3were measured by competitive protein binding. Frac-
tional excretion (FE) of phosphate (P1) was calculated
by using the formula:
urine phosphorus x serum creatinine F
serum phosphorus x urine creatinine EPI
Aminoacidunia is defined as amino acid excretionin excess of normal for age as given by a referencelaboratory (Smith-Kline BioScience Laboratories,Ltd.). Glucosunia is defined as urine glucose concen-tration in excess of 1 .7 mmol/24 h/m2. Hypenphos-
phatunic hypophosphatemia is defined as fractionalexcretion of phosphate in excess of 1 5% with serumphosphorus below normal for age (phosphorus, new-
born, 1 .3 to 2.9 mmol/L; 1 yr, 1 .2 to 1 .6 mmol/L; 2to 5 yr, 1 . 1 to 2.2 mmol/L; adult, 1 .0 to 1 .4 mmol/L).Hyperunicunia is defined as uric acid excretion inexcess of 0.47 g/m2/24 h. Tubular proteinunia isdefined as 24-h urine protein excretion of 4 mg/kg/24 h with a predominance of alpha2 and beta bands
on urine protein electrophoresis. Hypercalciunia is
Autosomal Dominant Fanconi Syndrome
1312 Volume 2 . Number 8 . 1992
TABLE 1. Urinary findings in 19 members of a family with idiopathic Fanconi syndrome
.
PatientNo.
. .
Uric Acid(g/day)
CreatinineClear-ance
(mL/S)
24-Hr
Phosphate
�g, y,
FractionalP04 Ex-cretion
(%)
.
Protein
$�y,
24-Hr.
Calcium(mmol/
day)
Glucose(mmol/L/24 h/1.73 m2)
.
Amino AcidsQuantitative
I 0.690 1.12 0.85 47#{176} 0.138 7.48#{176} 30.0#{176} +#{176}
defined as calcium excretion greaten than 4 mg/kg/24 h.
an autosomallinked pattern.
dominant, autosomal recessive, or X-
RESULTS
Laboratory findings and age of 2 1 family members
are presented in Tables 1 and 2. Notice that onlythree patients in this pedigree had full expression ofFanconi syndrome. However, many patients in thefamily exhibited one or more abnormalities in tubularfunction. These results are summarized in Table 3,which indicates qualitatively only normal and abnor-
mal findings. Glucosunia, aminoacidunia, and hypo-phosphatemia were the most common abnormalities.
Many family members did not have bone disease.Calcium, phosphorus, alkaline phosphatase, para-thyroid hormone, and vitamin D metabolites fromfamily members with rickets are shown in Table 4.
Pedigree indicates the clinical involvement of thepropositus and family (Figure 1 ). Genu varus, meta-
physeal widening, rachitic rosary, and x-ray evidence
of rickets were present in eight family members.
DISCUSSION
There are several postulated mechanisms produc-
ing Fanconi syndrome. When a genetic mode of in-henitance is evident, Fanconi syndrome may occur in
EXCLUSION OF SECONDARY CAUSES OF FAN-CONI SYNDROME
Secondary Fanconi syndrome was excluded in this
family clinically or by appropriate laboratory testing.Cystinosts was excluded clinically because it has anautosomab recessive transmission and producesblindness, chronic renal failure, hypothyroidism,and defects in melanin synthesis-all of which areabsent in this family. Slitlamp examinations werenegative for cystine crystals. The genetic defects forLowe’s syndrome probably resides on the X chro-mosome. The disease occurs predominantly amongmales. In addition, it is associated with hypotonia,cataracts, and glaucoma. These characteristics werenot found in any members of this family. Galacto-
semia was excluded because it has an autosomal
recessive transmission and because patients havehepatomegaly, liver failure, and cataracts as impor-tant comorbid factors. Hereditary fructose tnto!er-
ance is transmitted as an autosomal recessive and ischaracterized clinically by liver failure, fructose in-tolerance, and reducing substances in the urine. The
family members presented here have none of theabove findings consistent with fructose intolerance.
�C�#{149}�4 ‘ � � ..�.........
TABLE 2. Serum findings in 21 members of a family with idiopathic Fanconi syndrome
Patient AlkalineNo. Age Sex Sodium Potassium Chloride Bicarbonate Creatinine Calcium Phosphate Phosphatase Glucose
0 Normal values are in parentheses.b Age dependent. See Methods.C Done while on therapy with 1.25-(OH)2-vitamin D3.
Tyrostnemia has autosomal recessive transmission
with hypoglycemia, hepatomegaly, and abnormallyhigh levels of plasma and urine tyrosine. Patients in
this family had no such clinical findings, and theirtyrosine bevels, when measured, were normal. WI!-
son disease is transmitted as autosomab recessive,and patients have Kayser-Fbeischer rings, diabetesmellitus, and increased ceruboplasmin level-char-actenistics that are absent in this family. Medullary
cystic kidney disease was ruled out by renal ultra-sonography. No patients in this family had renalinsufficiency. Multiple myeloma was excluded by
the absence of Bence-Jones proteinunia in these fam-iby members. Heavy metal toxicity seems unlikely
because family members live in different regions ofthe city and some members live out of state. Hyper-
parathyroidism was ruled out by parathyroid hor-mone levels, which were normal in the family mem-bers with hypophosphatemia (Table 4).
CHARACTERISTICS OF THE FAMILY PRESENTED
Growth Retardation
All family members with Fanconi syndrome whowere studied and who had clinically evident rickets
have short stature and/or failure to thrive (5 of 21
patients). Failure to thrive was observed as early asthe first year of life. Hyphosphatemia and acidosis
are known causes of failure to thrive in children, buteven when those two components were corrected, ourpatient continued to fail to grow. Other factors, suchas hypercalciunia, hypokalemia, and extracellularvolume contraction, may play a robe in growth failure.
Parathyroid Hormone
Parathyroid hormone was measured in five of our
patients with Fanconi syndrome and clinical evi-dence of rickets (Table 4). Normal parathyroid hor-mone concentrations in these patients exclude hy-
penparathyroidism as a cause of rickets in this fam-
iby.
The role of parathyroid hormone in Fanconi syn-
drome is not clear. Parathyroid hormone has beenreported to produce a phosphatunic effect in patientswith Fanconi syndrome (7-9). Parathyroid hormone
serum concentration has been reported as normal orelevated in individuals with Fanconi syndrome (10-13).
Phosphate Metabolism
Hypophosphatemia was observed in eight patients
(five children and three adults). Six had clinical evi-
dence of nickets. One of the adult patients, withhypophosphatemia but no clinical evidence of nick-ets, had radiologically evident osteomalacia reportedby two radiologists who were unaware of the patients’condition. In Fanconi syndrome, hypophosphatemiais the result of decreased proximal tubule phosphate
reabsorption. Seven family members out of 1 5 haveincreased fractional excretion of phosphate (frac-
tionab excretion of phosphate greater than 1 5% inthe presence of hypophosphatemia) (Table 1). In pa-tients with hypophosphatemia and/or rickets, the
fractional excretion of phosphate was inappro-pniately high for the degree of hypophosphatemia.
Vitamin D
Vitamin D levels measured in four members withhypophosphatemia were normal (Table 4). VitaminD3 metabolites participate in the regulation of phos-
phate metabolism. Previous reports indicate thatserum concentrations of 1 ,25-(OH)2-vitamin D3 maybe decreased or normal in Fanconi syndrome. Vita-mm D3 concentrations may be inappropriately low
relative to the degree of hypophosphatemia (14-16).
Chesney and Harrison reported that Fanconi syn-drome developed in a patient with vitamin D defi-ciency (13). An abnormality in the conversion of 25-
Tolaymat et a)
Journal of the American Society of Nephrology 1315
(OH)-vitamin D3 to 1 ,25-(OH)2-vltamin D3 may bepresent in some patients with Fanconi syndrome(17).
Hypercalcinuria
Five family members have hypercalciuria. Four ofthese five have radiological evidence of rickets orosteomabacia. Hypercalciuria occurs frequently in pa-
tients with Fanconi syndrome (7, 1 8). Increased cal-cium excretion may occur as a result of phosphatedepletion syndrome produced by dietary phosphate
deprivation or a renal phosphate leak (1 9). Hypercal-cinuria may result from a tubular defect in calcium
reabsorption. Urinary boss of calcium may reduce the
availability of calcium for bone mineralization and
may contribute to bone disease in patients with low
calcium intake. Serum calcium was normal in all butone patient (Table 2). Tieder et a!. described a familywith autosomab recessive Fanconi syndrome and hy-
percalciuria ( 1 1). The hypercalciuria in his patientswas attributed to a normal response of 25-(OH)-vita-
mm D- 1 alpha hydroxybase activity. This in-dicated that the primary defect may exist at a differ-
ent segment of the proximal tubule. Unlike our pa-tients, those patients have elevated levels of 1 ,25-
(OH)2-vitamin D3. Dent and Friedman described two
patients with hypercalciunia, hypophosphatemia, hy-
perphosphaturia, aminoaciduria, and “tubular pro-
teinuria” (1 2). One of them had bow serum bicarbon-ate; both patients had rickets and short stature.Those patients may be similar to the patients re-
ported by Tieder et a!. (1 1). Vitamin D metabolites
could not be measured at that time.
Abnormalities in Water Metabolism
Pobyuria, polydipsia, and frequent episodes of de-hydration are common in patients with Fanconi syn-drome. Three of our patients, admitted for episodes
of dehydration, exhibited a normal ability to concen-trate urine. Their urine sp gr reached 1 .025 in earlymorning specimens. This may indicate that polyuniais related to some mechanism other than impairmentof distal tubular concentration ability.
Uric Acid
Uricosunia was observed in 1 of 2 1 members of thisfamily. Uric acid is filtered at the gbomerulus and is
then both secreted and reabsorbed by the proximaltubule (20). None of these family members had uro-bithiasis.
Prof einuria
Proteinuria, ranging from 0.25 to 2.0 g/m2/24 h,
was present in 4 of 1 0 family members tested.
Twenty-four-hour urine protein electrophoresis
showed increased alpha2 and beta bands in two pa-tients. Proteinunia consists of low-molecular-weightproteins in the 1 ,900 to 30,000 mob wt range. Thispattern of proteinunia has been termed tubular (2 1).
Aminoaciduria
Aminoaciduria was found qualitatively in 1 0 of 19
family members. Three of these had quantitativeamino acid determinations, showing a generalizedincrease in amino acid excretion.
Glucosuria
Glucosunia was found in 7 of 1 9 family members.
The range of glucosuria was from 1 .8 to 30 mmol/24h/i .73 m2. All patients had normal blood sugar de-terminations, indicating reduced renal threshold forglucose absorption.
TREATMENT
No treatment was recommended for patients with-
out rickets. Treatment with calcitrob and phosphatesupplementation, in the three patients with the com-
pbete Fanconi syndrome and rickets (patient nos. 9.
1 0, and 1 2), produced improvement in clinical andradiological bone abnormalities. Treatment did not
correct impaired growth (Figure 2). Growth failure inpatients with Fanconi syndrome is probably multi-factorial.
COMPARISON WITH OTHER AUTOSOMAL DOM-INANT FANCONI SYNDROME REPORTS
Six other families with autosomab dominant Fan-
coni syndrome have been described (22-28) (Table5). In all studies of families including ours, rickets,
osteomalacia, pobyunia, pobydipsia, dehydration, andfever of undetermined origin were the most frequentclinical observations. Diabetes meblitus was de-
scnibed in two members of one family, and ESRDoccurred in two families (Table 5). These two seriouscomplications did not occur in members of the familyreported here.
SUMMARY
1 . Autosomal dominant inheritance of Fanconisyndrome is rare. Only six families appear in the
literature.
2. The family with Fanconi syndrome reportedhere provides information on the largest number ofaffected individuals in a single family with Fanconisyndrome.
3. It is important to note that many family mem-bers have one or more abnormalities in renal reab-
Autosomal Dominant Fanconi Syndrome
1316 Volume 2 . Number 8 . 1992
TABLE 5. Clinical and laboratory data on six families with autosomal dominant Fanconi syndrome
Author(s) (Reference No.)Smith et a!.
(23)Ben-Ishay
(22)Hunt et ci.
(24)Sheldon et a!.
(25)Friedmanet a!.
(26)Wen et a!.
(28).
This Report
No. of Generations 4 3 3 3 2 4Family Members Affected/ 10/15 1 1 4 6/18 14/21
Hypercalciuria 2 2/18Uricosuria 5 1/2 1/21Acidosis 2 2 2 3Hyperphosphaturia with Hy- I I 2 2 1/2 7/19
pophosphatemia
sorptive function but not the complete syndrome.Variable expressivity has been reported previously in
two patients (28).4. Family members of patients with Fanconi syn-
drome should be screened for proximal tubular ab-
normabities.
ACKOWLEDGMENT
The authors acknowledge Elizabeth Patrick for her editorial assist-
ance.
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