Pediatric Nephrology
Pediatr Nephrol (1987) 1:509-518 9 IPNA 1987
Fanconi-Bickel syndrome Friedrich Manz 1, Horst Bickel 2, Johannes Brodehl 4, Dietrich Feist 2, Karl Gellissen 5, Brigitte Geschfill-Bauer 6, Giulio Gilli 7, Erik Harms s, Helmut Helwig 9, Walter Niitzenadel 2, and Riidiger Waldherr 3 Research Institute for Child Nutrition, Heinsttick 11, D-4600 Dortmund 50 2 University Children's Hospital and 3 Department of Pathology, University of Heidelberg, Im Neuenheimer Feld, D-6900 Heidelberg 4 Children's Hospital, Medical School Hannover, D-3000 Hannover 5 Children's Hospital, D-5450 Neuwied, ~Wippertstrasse 3, D-7800 Freiburg 7 Children's Hospital "Florence Nightingale", D-4000 Diisseldorf 8 Children's Hospital of the Technical University, D-8000 Mtinchen 9 Children's Hospital St. Hedwig, D-7800 Freiburg, Federal Republic of Germany
Abstract. Clinical, biochemical, functional and morphological data are presented in nine infants, children and adults, with Fanconi-Bickel syndrome. Long-term follow-up studies show severe growth retardation, partly compensated for by late onset of puberty. Glomerular filtration rate is normal or slightly decreased. Renal tubular dysfunction is characterized by a specific pattern of impaired proximal tubular transport mechanisms, with marked impairment of glucose transport. The utilization of glucose and galactose is defective, whereas fructose metabolism seems to be normal. Glycogenosis of the liver may be an epiphenomenon. Glycogen accumulation in the kidney is limited to the proximal tubule, with maximal levels in the straight part. The Fanconi-Bickel syndrome is a defined clinical entity which is distinguished from other inherited metabolic diseases by complex defects of renal tubular transport and other forms of glycogenosis.
pseudo-phlorizin diabetes [20], hepatic glycogenosis with aminoaciduria and glycosuria [43], and renal glucose losing syndrome [8, 13]. It is a rare autosomal recessive disease, in which an enzymatic defect has not so far been identified. Impaired metabolism of galactose and a characteristic pattern of proximal tubular dysfunction separates this type from other known forms of glycogenosis [251. During the last 20 years we have followed a total of nine patients with Fanconi-Bickel syndrome for periods ranging from 2 to 25 years (mean 14 years). Their clinical, biochemical and morphological data, as well as their long-term follow-up, are reported here. The findings are compared with those in the literature and in other inherited metabolic diseases with complex defects of renal tubular transport in an attempt to delineate the characteristics of this disease.
Key words: transport tabolism sis - Short
Case reports
Fanconi-Bickel syndrome - Renal Renal morphology - Glucose meGalactose metabolism - Glycogenostature
Introduction There are many synonyms for Fanconi-Bickel syndrome [19] such as glycogenose hdpatorbnale avec tubulopathie complexe [38], Fanconi-type glycogenosis [26], hepatic glycogenosis with De ToniDebr6-Fanconi syndrome [2, 3, 22], Fanconi syndrome in glycogen storage disease [32, 33], glycogenosis type VI with Fanconi syndrome [25, 42], Offprint requests to: F. Manz
Case I. Female, born 8 June 1961. Case observed in Freiburg [3]. The first permanent tooth appeared at the age of 10 years, 13 were missing and the others severely misplaced. Acute pancreatitis was observed at the age of 15 and 16 years. Puberty appeared late and menarche was noted at the age of 19.9 years. She suffers from orthopaedic problems as a late consequence of rickets. Adult height is 142.5 cm ( - 3 . 3 SD). Sitting height is 80 cm ( - 1.3 SD) [4]. She is married and works as a children's nurse. The treatment was based on vitamin D and supplementation of water, phosphorus, bicarbonate and potassium. During the later years a diabetic diet was prescribed in addition. Case 2. Female, born 18 October 1960, sister of patient 3. Cases 2 and 3 were observed in Heidelberg [44]. Birth weight was 3.25 kg, supine length 52 cm. Failure to thrive was noted at the age of 5 months. At 15 months the patient presented with severe dystrophy (5.5 kg), psychomotor retardation, hepatomegaly, constipation, polyuria and rickets. She had two
510 spontaneous fractures. Adult height is 131.5 cm. She is working as a secretary. Treatment with vitamin D was supplemented by phosphorus at the age of 12 years. Case 3. Female, born 15 February 1963, sister of patient 2 [44]. Birth weight was 3.25 kg, supine length 48 cm. At 8 years of age she had a fracture of the left tibia. Treatment with vitamin D was continued, resulting in severe vitamin D intoxication. For 3 years she received only supplements of phosphorus before vitamin D was reinstituted. She is working as a secretary. Case 4. Male, born 13 April 1964. Case observed in Bonn and H a n n o v e r [7, 8 11-13, 48]. The great-grandfathers of both father and mother were siblings. Delivery was by caesarian section due to placenta praevia. Birth weight was 3.25 kg. At the age of 5 months he presented with fever, dehydration, growth retardation, rickets, hepatomegaly, proteinuria and glycosuria. Liver biopsy showed no abnormality. Full puberty was reached at the age of 17 years. Adult height is 158 cm. He shows minor orthopaedic problems as a consequence of rickets. He is working as a motor mechanic. Case 5. Female, born 19 June 1966. Case observed in Heidelberg. Birth weight was 3.03 kg and supine length 51 cm. At 8 months of age the patient presented with dystrophy (5.6 kg), fever, rickets and hepatomegaly. Vitamin D and continuous supplementation of a glucose solution by a nasogastric tube resulted in a rapid increase in body weight and catch-up growth. After cessation of the continuous gastric drip a hypoglycaemic episode was noted. Vitamin D intoxication with hypercalcaemia was observed at the ages of 1.4 and 4 years, the latter time u n d e r vitamin D dosage of 3000 I U / d a y . At 11 years teeth were malpositioned. Severe hypertension (200/150 mmHg) was discovered by chance, and could not be controlled efficiently with antihypertensive drugs. Renal arteriography revealed severe stenosis of the right renal artery. The stenotic part of the renal artery was resected at the age of 13 years but the revascularization failed. The stenosis showed fibromuscular hyperplasia. The patient died shortly after surgery. From 5 to 11 years of age the patient received no treatment. Case 6. Male, born 24 May 1967. Case observed in Bonn. At the age of 10 months the boy presented with dystrophy (6.9 kg), hepatomegaly and rickets. The infant received vitamin D, supplements of bicarbonate, water and glucose. The patient was lost to follow-up at the age of 3.1 years. Case 7. Male, born 1 July 1970. Case observed in Freiburg [24]. Birth weight was 2.5 kg, supine length 51 cm. At 9 months the boy showed dystrophy (6.1 kg), glucosuria and ketonuria. Enamel defects and dysplasia of several incisors were noted at the age of 2.4 years. Two malpositioned first teeth were extracted at 4 years of age, and the clavicle was fractured at 9 years. The first permanent tooth appeared at 10 years of age. Treatment with vitamin D was started at the age of 1.25 years. Case 8. Male, born 16 February 1981. This patient and his twin brother (case 9) were observed in Freiburg. Birth weight was 2.51 kg, supine length 45 cm. Glucosuria and an increased serum galactose level were observed at the age of 14 days but activities of the galactose-related enzymes in the erythrocytes were normal. Proteinuria and generalized hyperaminoaciduria were first noted at 6 weeks of age and rickets at 3 months. The boy was treated with vitamin D and was maintained on a galactose-free diet.
Case 9. Male, born 16 February 1981, twin brother of case 8. Birth weight was 1.98 kg and supine length 42 cm. Constant glucosuria has been documented from the 2nd day of life. On the 3rd day an increased serum level of galactose was noted in the Paigen screening test, whereas the Beutler test and the enzyme activities of galactose metabolism of the erythrocytes were normal. A galactose-free diet was instituted. Hypophosphataemia (0.9 mmol/1), proteinuria (63 mg/day) and generalized hyperaminoaciduria were observed at the age of 6 weeks. Two episodes of seizures and coma, possibly due to hypoglycaemia, were noted at the ages of 8 and 17 months. Treatment of rickets with vitamin D was started at 3 months.
Results Blood Serum creatinine and urea remained normal in all cases. Hypophosphataemia (median 0.9 mmol/1, typical range from 0.5 to 1.4 mmol/1) and hypouricaemia (median 71 p.mol/1) were both constant; hyponatraemia (>131 mmol/1), hypokalaemia (>3.1 mmol/1) and a modest metabolic acidosis (standard bicarbonate > 1 6 mmol/l) were frequent findings. Serum levels of calcium were normal, whereas alkaline phosphatase was usually increased. In cases 2 and 3 the serum levels of the trace elements, expressed as 10 -9 g/ml, were normal (Zn 5500, 27300; Se 64, 115; Rb 270, 298; Co 17, 14; Cr 25; Hg 5.9, 6.7; Cs 1.0, 1.5; Sb 1.8, 3.6).
Renal function Glomerular filtration rate remained normal or slightly reduced during the long observation periods (Table 1). There was neither progression to glomerular insufficiency nor deterioration of tubular defects. Detailed clearance studies revealed unimpaired PAH clearance and filtration fraction, grossly increased clearance rates of glucose, phosphorus, uric acid and amino acid with a corresponding reduction in the tubular reabsorption rates of these substrates (Tables 1, 2). Clearance of potassium was in the normal range. In two patients (cases 4 and 8) the mild proteinuria was found to be almost exclusively of tubular origin. The most severe tubular defect was related to renal glucose transport. At normal serum levels, daily urinary glucose excretion was in the range 4 0 - 2 0 0 g/1.73 m 2 (Fig. 1). During the 1st year of life, rates of glucose excretion (corrected to surface area of 1.73 m 2) were lower and increased with age. The ratio of glucose clearance to inulin clearance (C~:CI,) ranged from 0.59 to 1.0
511 Table 1. Renal function in nine patients with Fanconi-Bickel syndrome Patients Age (years) Body surface (m 2)
1
2
3
4
5
21
15
13
12
10
1.27
0.78
0.7
1.0
0.78
6 0.8 0.36
7 12 0.85
8
9
1.5
0.7
0.36
0.28
N o r m a l values mean +- SD; range
References
Clearance of inulin ( m l / m i n / 1 . 7 3 m 2)
50
64
68
104
125
84
70
121 + 18.5
[371
198
507
552
488
648
439
465
598_+81
[371
0.59
0.8 t
0.67
0.74
Clearance o f P A H ( m l / m i n / 1 . 7 3 m 2)
Clearance of glucose Clearance o f inulin
1.0
Clearance of phosphorus ( m l / m i n / l . 7 3 m 2)
39
47
48
43
23
25
34
11.6+-4.2
[371
0.12
0.12
0.22
0.67
1.02
0.77
0.48
1.34+-0.05
[3o]
14
10
13
21
84
19
16
46 b
50
47
6-10
[371
0.76+--0.17
[37]
Tubular reabsorption of phosphorus Clearance of inulin (gmol/ml)
Clearance of potassium ( m l / m i n / 1 . 7 3 m 2)
Clearance of uric acid ( m l / m i n / 1 . 7 3 m 2)
44
Maximum transport of PAH Clearance of inulin (mg/ml)
0.04
0.43 d
0.38 d
0.37 d
0.6t
0.36
Volume (ml/day)
2195
1200
1250
1840
2900
440
1810
0.49
trace
trace
0.46
0.43b
94
172
183
136
118
66
0.2
0.27
0.36
0.26
0.28
0.45
2.2
4.0
4.9
2.8
1.5
2.2
1020
480
0.89
0.19
120
115
90
<0.2
[37]
0.26
0.38
0.39
0.007 - 0.137
[351
2.2
3.8
5.1
0 . 3 6 - 1.4l
[351
3.6
2.8 ~
4.0 ~
0 - 2.46
[35I
Proteinuria (g/day)
Glucosuria ( g / d a y / 1 . 7 3 m 2)
Calciuria (mmol/kg/day)
Organic aciduria (mEq/kg/day)
Net acid excretion (mEq/kg/day) M a x i m u m osmolality (mosmol/l)
> 740 ~
3.4 b
2.8
> 600 c 790 b
> 6 5 0 ~ > 6 0 0 c >800
[49]
a N o 24-h urine collection; b At another time; ~ Spontaneous urinary osmolality d Serum level o f P A H below the range o f m a x i m a l tubular P A H secretion
(Table 1) and did not change during loading with glucose, galactose, calcium or alanine (Fig. 2). Loading with ghtcose and phosphate induced a rise of Cc:Ctn from 0.73 to 0.93. As C c : C m is independent of the blood glucose levels, maximal tubular reabsorption of glucose approached normal values corresponding to renal glucosuria type B
[411. Galactose excretion was 620 mg/day in case 1 on a normal diet and 5 mg/day in case 7. After an oral load with galactose (2 g/kg) the percentage of galactose tubular reabsorption was 10% at a serum level of 105 rag% (case 4).
During i.v. loading with fructose, tubular reabsorption was almost negligible (3%) at a serum fructose level of 106 mg/dl (case 1). The fractional tubular reabsorption of phosphate (Tp/C~n) was decreased in all patients (Table 1). It did not change during loading with calcium, alanine or glucose, but decreased further during combined loading with glucose and phosphate (Fig. 3). Hypercalciuria was a constant finding (Table 1). Urinary calcium excretion increased during metabolic acidosis (case 4) and vitamin D intoxi-
512 Table 2. Values of percentage tubular reabsorption of free amino acids of seven patients with Fanconi-Bickel syndrome Patients
1
Age (years)
5-2l
Number of clearance investigations
3
Taurine Threonine Serine Proline Citrulline Glycine Alanine Valine Cystine Methionine Isoleucine Leucine Tyrosine Phenylalinine Ornithine Lysine Histidine Tryptophan Arginine
71 54 71 71 45 37 72 84 43 92 94 91 64 77 90 60 32 62 84
2
3
15
13
1
1
48 58 42 92 68 32 67 89 75 91 96.2 86 68 78 97.2 81 17 68 91
4 1-14
61 55 48 82 68 23 60 88 70 86 95 84 54 73 92 78 7 62 82
6
11
7
0.8
Normal values (mean • SD)
12
14
1
1
1
82 76 62 96.9 80 59 83 94 59 94 98.6 94 76 85 92 77 44 94
88 95 90 97.4 95.5 80 96.3 99.4 90 97.2 99.0 98.4 94 96. t 99.1 96.2 82 92 97.9
86 75 92 61 91 98.1 88 94 99.0 97.2 89 91 95 88 60 98.0
67 85 70 95 73 56 86 98.1 96.7 98.3 95.5 8l 93 80 45 48 95.7 92
(11)
99.1• 98.0• 99.7• 96.5• 99.3• 99.8• 99.3• 99.3• 99.7• 99.6• 98.3• 98.8• 99.7• 99.0• 92.2• 99.8•
c
18o
Gtucosuria
Mean
n
gt d / 1,73 m 2
= ~x~ o
9
umol/m[
9
9 9
1.0
~ I
9 Normal conditions or phosphate (i.v]
-2 Standard deviation
9 C a l c i u m g l u c o n a t e (i.v.)
100
o
~
ooo%
0.8
§ 60
5
0
o
0 ~3
Patient
Patient
~
o
o ~
I
§ ~
VI VII
o
II
o
Ill
,a Vlil
9
IV
0
IX
V 1
l,
?
10 months
/.
8
12
D Alanine {oral loading) o G l u c o s e (i,v.) ~
"."
0.6
~
~
o
*
04 o
16
20 years
Fig, 1, Glucosuria and age in nine patients with Fanconi-Bickel syndrome
0.2
Serum phosphorus
0:s
1:o
l:s
2:0
m ~ol/t
Fig, 3, Ratio of tubular reabsorption of phosphate to inulin clearance related to the serum level of phosphate in case 4 with Fanconi-Bickel syndrome 1.0-
Glucose
Inuline
clearance clearance
80-
0.6'
9 9 o o
0.z,
Normal conditions or glucose (i~) Calcium gluconate (i.v.) Alanine (orQ[ loading) Phosphate (i.v)
0.2 Blood
s'o
40
i~o
2~o
2~o
glucose
;,g/d~
Fig, 2, Ratio of glucose clearance to inulin clearance in relation to the blood glucose level in case 4 with Fanconi-Bickel syndrome
cation (cases 3 and 5), did not change during oral calcium restriction (case 5) and decreased after the intake of hydrochlorothiazide (case 5). The serum levels and the renal transport of magnesium were normal. Generalized hyperaminoaciduria was observed in all patients. Plasma amino acids were normal or low; therefore, hyperaminoaciduria was of renal origin. The total amount of urinary amino acids as calculated from five 24-h urine
513 specimens in case 4 was 1.6 m m o l / k g per day or 10 g / d a y per 1.73 m 2. The percentage tubular reabsorption of all amino acids was greatly decreased (Table 2). Rickets, hypercalcaemia and phosphate loading increased the hyperaminoaciduria further. Increased excretion of several non-aminated organic acids was observed in four patients. During acid loading, renal citrate excretion was increased at each urine pH level but decreased regularly (cases 2 and 3) [44]. Ketonuria was a frequent finding, especially in the morning. Net acid excretion was increased in the absence of alkali therapy (Table 1). During ammonium chloride loading in cases 2 and 3 minimal urine pH (4.8, 4.7) and maximal excretion of titratable acidity (51,40 g m o l / m i n per 1.73 m 2) were normal, whereas maximal ammonium excretion was increased (163, 193 g m o l / m i n per 1.73 m 2) [14]. Renal bicarbonate threshold was decreased to 18-20 mmol/1 (cases 4 and 5). In case 5 it became normal at the age of 11 years. Polyuria was a constant finding, probably due to osmotic diuresis (Table 1). High urinary osmolality was observed spontaneously in several patients, suggesting normal maximal urinary osmolality.
Kidney size and renal morphology Kidney size at X-ray was enlarged in most patients (Fig. 4). In case 3 interruption of kidney growth was noted after an episode of severe vitamin D intoxication. A renal biopsy (case 5) disclosed a slight variation in the cell height of proximal tubular cells. Glomeruli, interstitium and vessels were normal. By electron microscopy, marked glycogen accumulation was found in some but not in all proximal tubular cells. Megamitochondria were occasionally encountered in these cells. The brush border was normal. Glycogen accumulation seemed
+2SD Right Kidney
I~1
V
Length
,IV
- 2 SD
100
8060-
6'0
8'0
1C)0
1:70
I~0 Body Height cm
Fig. 4. Length of the right kidney related to body height in six patients with Fanconi-Bickel syndrome [29]
to predominate in the straight part of proximal tubules.
Liver and carbohydrate metabolism At birth the size of the liver was found to be normal (case 9) or slightly increased (case 8). The organ enlarged greatly during infancy (cases 8 and 9) when hepatomegaly was present in all patients. The size of the liver then decreased again, especially after the institution of an antiketogenic diet (cases 1 and 5). In computed tomography five of six patients showed an increased density of the liver of 77-100 Hounsfield units compared with 65-75 Hounsfield units in normal children (n = 13). As the density of fat is low and that of glycogen high, the increased density points to a predominant increase of glycogen content [36]. Glycogen accumulation was found in liver biopsy specimens (Table 3). It was reduced after 2 years of dietary treatment (case 5). The serum levels of the liver enzymes were normal or slightly increased. Several enzymes of carbohydrate metabolism, measured in the material of four liver biopsies, showed normal activities (Table 3). In the fasting state, serum levels of glucose were low. Episodes of seizures and coma, possibly
Table 3. Glycogen content and enzymes of carbohydrate metabolism of the liver in two patients with Fanconi-Bickel syndrome (J. Schaub, Kiel) Patient
5
Age (years)
4.4
Liver size Glycogen Glucose-6-phosphatase Phosphorylase Amylo-l,6-glucosidase o:-Glucosidase
(cm) (g/100 g) (~tmol/g/min) (p.mol/g/min) (gmol/g/min) (gmol/g/min)
6 > 15 1.51 21.6
6 4.5 6 > 15 1.58 20.6 2.03 1.39
13.5 5 9 6.3
normal
5.9 5 6.2 29 1.1
<6 2 - 18 12 - 41 0.3 - 1.2 0.25- t.6
514
~ Blood glucose mg/d[ 9
!
160
Oral
glucose ( 7 0 g )
200
Plasma insulin m~E/ml
Plasma
C peptid
ng/mt
~ll.~
C''ll''O
eO
~
8
~ ....
Oral Lactose
Blood
Glucose
9
Goloctose
o
mg/dt
6
B0
50
~0 .(/
0 o
I
610
i
i 12o
i
rnin
30
60
90
rnin
L
Fig. 5. The level of blood glucose, plasma insulin and C-peptide in case 1 with Fanconi-Bickel syndrome after an oral load of glucose
due to hypoglycaemia, were noted in cases 5 and 9. Oral glucose loading resulted in abnormal levels of blood glucose (cases 1, 4, 8 and 9) (Fig. 5). In case 5 normal nutrition (80 kcal/kg per day, fat 2.2 g/kg per day, carbohydrates 9.5 g/kg per day) was replaced by a high-calorie diet for several months (125 kcal/kg per day, fat 3.8 g/kg per day, carbohydrates 18 g/kg per day). Blood glucose levels increased from 96-116 mg/dl to 199-236 mg/dl, urinary glucose excretion from 6.6 to 13.7 g/kg per day and glucose utilization from 2.9 to 4.3 g/kg per day. Intravenous glucose tolerance tests (0.5 g/kg) in case 5 at the ages of 4 and 12 years resulted in a low glucose transfer (0.22; 0.26 mg/g per hour, normal mean for age 0.38; 0.32 mg/g per hour), if glucosuria is ignored, and a very low glucose transfer (<0.06 mg/g per hour), if glucosuria is estimated [18]. HbA~c was normal (case 1). Increased serum levels of galactose were observed in neonatal screening and oral lactose loading (Fig. 6). Oral galactose loading (2 g/kg) in three patients (cases 2, 3 and 4) did not really change the serum levels of glucose or lactate (Aglucose: 0, + 13, + 15 mg/dl; Alactate: +0.6, +2.2 mmol/1), but increased the serum levels of phosphorus (Aphosphorus: 0.23, 0.29 mmol/1) and galactose (Agalactose: 116 mg/dl). In case 4, 20% of the oral intake of galactose was excreted in urine. Intravenous galactose loading in two patients (cases 1 and 4) showed a decreased galactose elimination capacity of 97 mg/min per m 2 (normal adults: 267 mg/min per m 2) and an increased urinary excretion of the load of 33% (normal rate for adults and patients with liver cirrhosis is 10%) [47]. Oral fructose loading in cases 4 and 5 of 1 or 2 g/kg resulted in a slight increase in blood glucose levels (Aglucose: 20, 24 mg/dl), a small increase
Urine
before loading
after
DT.
D.M
D,T
DM
Glucose
gldt
2,2
1,56
0,6
1.65
Go,lactose
g/dl
0,002
0,003
0,74
1,/.2
Fig. 6. Blood levels of glucose and galactose and urinary excretions of glucose and galactose in twins with FanconiBickel syndrome after an oral load with lactose
in serum fructose (up to 15 mg/dl), no change in the serum levels of phosphorus, GOT, and GPT and no fructosuria. Intravenous fructose loading of 0.5 g/kg steeply increased the blood levels of glucose from 80 to 170 mg/dl [3]. During intravenous infusion of fructose (660 mg/min) in case 1 (41.5 kg) fructosuria of 71 mg/min was normal at a serum fructose level of 106 mg/dl [21]. All patients showed symptoms of catabolism, such as hypoglycaemia, ketonuria, ketonaemia, decreased serum levels of the glucoblastic amino acids, increased serum levels of the branched chain amino acids, triglycerides, free fatty acids, phospholipoids, and the corresponding lipoproteins (hyperlipidaemia type IV). Hypoglycaemia and ketonuria were pronounced in the morning. Case 9 showed normal serum levels of lipids and lipoids at the age of 2 months but hyperlipidaemia at 17 months.
Endocrinologicalfindings The serum levels of insulin were within the normal range (case 1). Oral glucose loading steeply increased the serum levels of insulin (Fig. 5), whereas intravenous glucose loading failed to raise the serum levels (case 5). Intravenous injection of insulin decreased the blood glucose levels from 70 to 40 mg/dl within 30 min in case 4 and from 77 to 23 mg/dl within 60 min in case 7. During 24 h the serum levels of C-peptide ranged from 0.1 to 2.7 ~tg/ml (normal values, case I). Oral glucose loading increased the serum levels of C-peptide (Fig. 5). Urinary excretion of C-peptide was increased like that of other small peptides.
515 Ten glucagon tests were performed in five patients. The difference between the maximum blood glucose level 20-60 min after the injection and the basal level was 0 - 1 0 m g / d l in one test, 10-20 mg/dl in five, 20-40 m g / d l in three and more than 50 mg/dl in one. In cases 4 and 6 a concomitant increase of blood glucose (Aglucose: 17, 11 mg/dl) and glucosuria (Aglucosuria: 5.8, 15 mg/min) was observed. In case 4 blood glucose rose from 46 to 62 m g / d l after the injection of tolbutamide and from 70 to 85 m g / d l after the injection of adrenaline. The serum levels of human growth hormone of six patients and the results of follow-up studies during the day in case 1 were normal. Exercise or stress tests induced high serum levels of growth hormone (cases 2-4). Hypoglycaemia did not change the serum levels of growth hormone (case 7). The serum levels of T3, T 4 and TSH (five patients) and the response to TRF tests (cases 5 and 7) were normal. The serum levels of LH and FSH (cases 5 and 7) and prolactin (case 7) were within the normal range and adequately stimulated by LRH considering sexual development. Serum parathormone was normal, whereas 25-hydroxyvitarain D was frequently elevated in accordance with vitamin D treatment. Cortisol in serum showed normal oscillation (cases 1 and 4), whereas urinary excretion of tetrahydrocortisol, tetrahydrocortison and free cortisol were decreased (case 1).
Linear growth, bone and teeth Birth weight was in the lower part of the normal range, short stature was a prominent finding in all patients (Fig. 7) and retardation of bone age was quite variable (Fig. 8). However, the correlation of height age to bone age showed a similar loss of potential height (Fig. 9). Rickets and fractures were common, frequently resulting in deformities. Supplements of phosphorus, calcium and vitamin D were effective in long-term management. Dental eruption was delayed. Absence of permanent teeth, malposition, enamel defects and dysplasia were noted in some patients. Eyes Ophthalmological examinations were done repeatedly in six patients due to raised plasma galactose levels. Cataracts were not noted. Discussion
Fanconi-Bickel syndrome is a well-defined clinical entity. The primary defect is unknown [13]. It is characterized by a typical pattern of proximal
Standard
deviation
Height
§ .1
2
/q
6
8
10
12
14
16
t8
20 years
50th.r
-2
~AZ'~VI
~
Gi(ls
6"~~IX
VII
lllil
Fig. 7. Height (SD of the mean) in nine patients with FanconiBickel syndrome
years 15
RUS Bone age
.->~ /~/
12
I II
~-f~"
..,e 6
~ Boys 9 GiNs
3 Chronotogicat age I
!
i
i
3
6
9
12
1'5
18
years
Fig. 8. Bone age of radius, ulna and short bones (RUS) and chronological age in six patients with Fanconi-Bickel syndrome [46]
years "Height age"
12
6
/ / ~
/
~
~ Boys 9 Girls
3 RUS Bone age ;
;
;2
'years
Fig. 9, "Height age" (age of a normal child growing at the 50th centile with the same height as the patient) related to bone age (RUS) in six patients with Fanconi-Bickel syndrome
tubular dysfunction, impaired utilization of glucose and galactose and hepatorenal glycogenosis. The first case was described by Fanconi and Bickel [19] in 1949 [23]. In the literature 19 more patients have been reported [2, 3, 5, 6, 7-9,
516 11-13, 20, 22, 24-26, 31-33, 38, 42, 43, 48] and 5 further patients are known to the authors (personal communications from W. Blunck, P. Durand, D. Flynn, H. G6tze and H. P. Weber). FanconiBickel syndrome is probably inherited as an autosomal recessive trait. This hypothesis is supported by consanguinity in the families of 5 patients [9, 19, 38] (case 4), the occurrence in siblings [6] (cases 2, 3, 8 and 9) and the proximity of places of residence of case 1 and cases 8 and 9, as well as the patient reported by Rotthauwe [43] and case 4 both originating from the same rural community. The first biochemical findings were glucosuria on the 1st day of life, galactosaemia on the 4th day and hypophosphataemia at the age of 8 weeks. The first symptoms were fever, vomiting, growth failure and rickets at the age of 3-10 months. Later, the patients presented with dwarfism, protuberant abdomen, hepatomegaly, moon-shaped face and fat deposition about the shoulder and abdomen. Cutting of the teeth and puberty were retarded. Fractures and pancreatitis were complications. The coexistence of FanconiBickel syndrome and fibromuscular hyperplasia of the renal artery in case 5 seems to be due to chance, although Bulgarelli and Bruni observed a child with glycogenosis and progressive arterial hypertension [15]. The renal disorder is characterized by a normal or slightly decreased glomerular filtration rate and a typical pattern of proximal tubular dysfunction. The most outstanding feature is the severe impairment of glucose transport, unknown in other types of Fanconi syndrome and most types of renal glucosuria [9, 39]. The defect of glucose transport is characterized by a very low theoretical renal glucose threshold, a constant ratio of glucose clearance to inulin clearance and a normal maximal tubular transport of glucose at very high blood glucose levels. The renal transport of galactose may also be impaired, as in case 4 in whom the percentage of tubular reabsorption to galactose was low compared with published data [21]. Impairment of renal tubular transport of phosphate [19, 22, 26, 32, 38, 43] and amino acids is a constant finding. Renal transport of uric acid is severely impaired [26, 38]. In addition, the urinary excretion of several further non-aminated organic acids is increased [3, 31, 32, 38]. The renal transport of paraaminohippurate is normal or slightly impaired [38]. Proteinuria is slight and of tubular origin. Hypercalciuria is a constant finding [26, 32, 38]. The renal handling of sodium and potassium presents only minor abnormalities. There is a
tendency to hyponatraemia and hypokalaemia [32, 38]. Hyponatraemia may result from osmotic diuresis, increased renal net acid excretion and hyperlipidaemia (pseudohyponatraemia). Hypokalaemia may be due to volume contraction and long-lasting high renal net acid excretion with metabolic acidosis. Mild or moderate polyuria was observed in all patients. In the absence of hypercalcaemia and nephrocalcinosis, renal concentrating capacity seemed to be normal; polyuria is therefore mainly the result of an increased osmotic load. Some patients present mild or moderate metabolic acidosis in the blood [19, 22, 32, 38, 43], whereas others show normal acid base status [26] (case 5). Metabolic acidosis is due to proximal tubular acidosis and an increased renal net acid excretion resulting from the increased renal excretion of organic acids. In Fanconi-Bickel syndrome not only the renal transport, but also the metabolism of glucose and galactose are defective. The presence of glycogenosis, ketonuria and hypoglycaemia in the fasting state point to inadequate glucose mobilization. Prolonged hyperglycaemia after glucose loading indicates decreased utilization of glucose. The cause of this metabolic defect is unknown. It is neither due to inappropriate insulin secretion, since adequate serum levels of insulin and C-peptide were noted after an oral load of glucose, nor to insulin resistance, since the administration of insulin resulted in marked hypoglycaemia in three of our patients and in two patients in the literature [19, 38]. The symptoms of impaired galactose metabolism are galactosaemia and galactosuria. Oral galactose loading tests were abnormal in five of our patients and in six patients in the literature [22, 26, 32, 38, 43]. A normal oral galactose loading test was observed only once [38]. Intravenous loading with galactose resulted in an abnormal response in two of our patients and three patients in the literature [9, 32, 38]. An enzymatic defect of galactose metabolism has not been demonstrated in Fanconi-Bickel syndrome but significant impairment of (1-14C) galactose oxidation was observed in minced liver tissue [9]. The metabolism of fructose seems to be normal. Fructosuria has been noted only incidentally [38]. The response to oral loading with fructose was adequate in two of our patients and three patients in the literature [22, 38]. Diarrhoea resulted in one patient [20]. The intravenous fructose test was normal in case 1 as well as in three patients in the literature, but abnormal in the patient of Houser and Angle [26, 38].
517 The pathophysiological significance o f glycogenosis is still speculative. Glycogenosis o f the liver develops during the 1st year o f life and m a y be i n f l u e n c e d by nutrition. In case 1 huge h e p a t o m e galy and glycogenosis o f the liver were shown in early childhood. At the age o f 21 years the liver was only slightly enlarged and c o m p u t e d tomog r a p h y failed to d e m o n s t r a t e an increased content o f glycogen. A n o r m a l content o f glycogen was also reported by Hers a n d van H o o f in one o f their patients [25]. F u r t h e r m o r e , there are two reports in the literature o f patients with idiopathic F a n c o n i s y n d r o m e and defects o f glucose and galactose metabolism, who show m a n y signs o f Fanconi-Bickel s y n d r o m e but n o glycogenosis [1, 16]. As no e n z y m a t i c defect o f glycogen m e t a b o l i s m has been d o c u m e n t e d in patients with FanconiBickel s y n d r o m e , the hypothesis should be considered that glycogenosis is a s e c o n d a r y p h e n o m e n o n o f defective c a r b o h y d r a t e t r a n s p o r t or metabolism as, for instance, in M a u r i a c s y n d r o m e [28, 341. The diagnosis o f Fanconi-Bickel s y n d r o m e is based on three findings: the characteristic pattern o f the d y s f u n c t i o n o f the p r o x i m a l tubule, the imp a i r e d utilization o f glucose a n d galactose and the h e p a t o r e n a l glycogenosis. Inherited m e t a b o l i c diseases with defects o f c a r b o h y d r a t e m e t a b o l i s m a n d c o m p l e x tubular d y s f u n c t i o n are k n o w n in galactosaemia, h e r e d i t a r y fructose intolerance a n d in a few patients with idiopathic F a n c o n i s y n d r o m e . Fanconi-Bickel s y n d r o m e , galactosaemia and h e r e d i t a r y fructose intolerance were easy to distinguish. T h e r e are two reports o f three patients with idiopathic F a n c o n i s y n d r o m e resembling Fanconi-Bickel s y n d r o m e , but showing no glycogenosis [1, 16]. F u r t h e r m o r e , diabetes mellitus seems to be a characteristic s y m p t o m o f a subg r o u p o f patients with idiopathic F a n c o n i synd r o m e [17, 27, 40, 45]. In Fanconi-Bickel s y n d r o m e specific t h e r a p y is not available. S y m p t o m a t i c r e p l a c e m e n t treatm e n t based on s u p p l e m e n t a t i o n o f water, electrolytes and vitamin D, restriction o f galactose, and a diabetes mellitus-like diet, p r e s e n t e d in f r e q u e n t small meals with an a d e q u a t e calorie intake, considering the high urinary loss o f calories, m a y imp r o v e growth, the well-being o f the patient and the function o f extrarenal organs. L o n g - t e r m medical t r e a t m e n t must be t h o r o u g h l y organized and should be s u p p o r t e d by assistance in social integration. The pathogenesis o f Fanconi-Bickel s y n d r o m e is u n k n o w n . The following hypothesis m a y stimulate further research. The s y n d r o m e m a y be
caused by a defect o f the diffusion carrier facilitating the influx and efflux o f glucose and galactose in the liver and the efflux o f glucose and galactose at the basolateral m e m b r a n e o f the proximal tubule. The hypothesis explains the decreased utilization o f glucose and galactose by the liver a n d perhaps the Mauriac-like clinical status with glycogenosis. The t r a n s p o r t defect at the basolateral m e m b r a n e would i n d u c e high c y t o p l a s m a t i c levels o f glucose. It is highly speculative, but m a y be possible, that the high intracellular glucose c o n c e n t r a t i o n induces p r o x i m a l tubular dysfunction and inhibition o f glycogen degradation.
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