Year : 2005 | Volume
: 16 | Issue : 2 | Page : 193--197
Co-Existence of Tuberous Sclerosis and the Fanconi Syndrome in Two Saudi Male Siblings: Report on Two Cases
Abdulla K Al-Hwiesh, Samir H Al-Mueilo, Ibrahim Saeed, Anfal H Barak, Fahd A Al-Muhanna
Department of Internal Medicine, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia
Abdulla K Al-Hwiesh
Department of Internal Medicine, King Fahd Hospital of the University, P.O. Box 40246, Al-Khobar 31952
In this report, we present two cases of familial tuberous sclerosis co-existing with the Fanconi Syndrome. Both cases presented with history of failure to thrive and mental retardation associated with hypokalemic metabolic acidosis. To our knowledge, the association between tuberous sclerosis and the Fanconi Syndrome has not been reported previously.
|How to cite this article:|
Al-Hwiesh AK, Al-Mueilo SH, Saeed I, Barak AH, Al-Muhanna FA. Co-Existence of Tuberous Sclerosis and the Fanconi Syndrome in Two Saudi Male Siblings: Report on Two Cases.Saudi J Kidney Dis Transpl 2005;16:193-197
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Al-Hwiesh AK, Al-Mueilo SH, Saeed I, Barak AH, Al-Muhanna FA. Co-Existence of Tuberous Sclerosis and the Fanconi Syndrome in Two Saudi Male Siblings: Report on Two Cases. Saudi J Kidney Dis Transpl [serial online] 2005 [cited 2020 Sep 27 ];16:193-197
Available from: http://www.sjkdt.org/text.asp?2005/16/2/193/32940
Tuberous sclerosis (TS) is an autosomal dominant disorder in which tumor-like malformations called hamartomas develop in multiple organ systems. TS affects one in about 10,000 individuals. Spontaneous mutations appear to occur at high frequency and are estimated to account for 60-70% of new cases. TS is genetically heterogenous. At least two loci are involved. The first (TSC1) is on chromosome region (9 q 32 - q34), near the ABL oncogene and the second (TSC2), on chromosome region 16p 13 adjacent to pKD1. ,, Both TSC1 and TSC2 have been identified and sequenced. The protein product of TSC2, called Tuberin, has a region of homologue to GTPase - activating protein GAP3.
GTPase - activating protein binds to Ras protein, regulate their activity. Ras protein is involved in the control of cell proliferation and differentiation. The protein product of TSC 1, which has been named hamartin, was more recently identified and its role in cell growth regulation is under investigation.
The most common clinical manifestations of tuberous sclerosis involve central nervous system and the skin. Approximately 80% of affected individuals have seizures and 50% have mental retardation. Kidney involvement occurs frequently in TS. , The principal manifestations include angiomyolipoma, cysts and renal malignancy.
The prevalence of TS among the Saudi population is unknown. The Fanconi Syndrome (FS) refers to dysfunction of the proximal tubule leading to excessive urinary excretion of amino acids, glucose, phosphatase, bicarbonate and other solutes handled by this nephron segment. , Their loss leads to the clinical problems of acidosis, dehydration, and electrolyte imbalance. The co-existence of FS and TS has not been reported previously. Here, we describe two Saudi brothers with TS and mild mental retardation associated with FS. To our knowledge, this is the first report of such an association in the literature.
A 20-year-old Saudi male was diagnosed as having TS with mental retardation since childhood. He presented with febrile convulsions at the age of four. He was maintained on phenarbitol for one year. Since then, he was on regular follow-up at the neurology clinic without medication. Birth details revealed fullterm normal vaginal delivery and his parents are first cousins. He was seen several times in the pediatric clinic for evaluation of failure to thrive, easy fatigability, polyuria, polydypsia and hypokalemic metabolic acidosis. He was diagnosed as having renal tubular acidosis Type II and was treated with potassium (K+) supplements. Two weeks before the current presentation, he reported to the emergency room with history of easy fatigability, myalgia, numbness and tingling of all extremities and inability to walk. Serum potassium measured was 1.9 mmol/L.
Clinical examination revealed signs of mild mental retardation and failure to thrive. His vital signs were as follows: blood pressure 105/55 mmHg, pulse 75/minute regular, afebrile, weight 40 kg, and height 150 cm. He was noted to be pale with multiple facial angiofibromas [Figure 1]. Cardiovascular examination revealed normal heart sounds with no additional sounds or murmurs. He had pigeon chest deformity. Abdomen and lower limb extremities were normal. Fundoscopy was normal. His white blood cell (WBC) count was 5.9 x lO 9 /L with normal differential. The hemoglobin level was 10 g/1 with microcytic hypochromic picture, hematocrit 32% and platelet count was 478,000 mm 3 . Serum electrolytes showed sodium of 140 mmol/L, potassium 1.9 mmol/L, chloride 113 mmol/L, bicarbonate 14 mmol/L and anion gap of 13. The blood urea nitrogen was 29 mg/dL, serum creatinine 0.7 mg/dL, phosphate 3 mg/dL, glucose 90 mg/dL and calcium 8.1 mg/dL. The serum alkaline phosphate was 200 u/L, total protein 7.2 g/dL and serum albumin 3.3 g/dL with the liver enzymes being within normal limits. Urinalysis revealed a specific gravity of 1,010, pH 7.5, trace protein, and glucosuria. Blood glucose was normal (90 mg/dL) at the time of urinalysis. Arterial blood gas analysis showed pH of 7.2, PCo2 40 mm Hg and bicarbonate of 12 mmol/L. Further laboratory studies showed phosphaturia 1400 mg/24 hours (Normal 400-1300 mg/24 hours) and hyperuricosuria 700 mg/dL (Normal 150-600). Screening for cystinosis was negative. Tests for pyruvate kinase deficiency, galactosemia, hereditary fructose intolerance, tyrosinemia, lead, copper levels were within normal limits. Screening for connective tissue disorders including ANA and anti-DNA, Anti-smith antibody, C3; C4 and CH50 were normal. Slit lamp examination of the eyes was normal. CT-scan of brain showed bilateral basal ganglia calcification [Figure 2]. Renal biopsy showed mild tubular atrophy with mesangial expansion [Figure 3].
A 17-year-old male brother of the first case was also diagnosed to have TS with mild mental retardation. Investigations disclosed hypokalemic metabolic acidosis with normal anion gap, glucosuria with normal blood sugar, phosphaturia and uricosuria. Therefore, it was concluded that this sibling also has a combination of TS and the FS. The two affected brothers have five brothers and two sisters, all of whom are normal.
Tuberous sclerosis commonly involves the central nervous system and the skin. Approximately 80% of affected individuals have seizures and 50% have mental retardation. In affected individuals over five years of age, the most common skin lesions are facial angiofibromas, hypomelanotic macules and ungual fibromas. 
Kidney involvement occurs frequently in TS. , The principle manifestations include angiomyolipomas, cysts and renal malignancies. Some of the malignant tumors originally thought to be renal cell carcinoma are now regarded as malignant epithelial angiomyolipoma.  Multiple renal angiomyolipomas are the principal form of hamartoma in TS and occurs very commonly identified in 40-80% of patients at autopsy. Solitary angiomyolipomas are found in the general population, particularly among old women.
Angiomyolipomas in patients with TS are usually multiple and bilateral. They rarely occur before five years of age but increase in frequency and size with age. The clinical manifestations are related to the potential for hemorrhage (gross hematuria, intratumoral or retroperitoneal hemorrhage) and to mass effects (abdominal or flank mass and tenderness, hypertension and renal insufficiency).
Women tend to have more numerous and larger angiomyolipomas than men. Moreover, pregnancy appears to increase the risk of rupture and hemorrhage. , Renal cystic disease is the earliest renal finding in TS and may be the presenting manifestation in infants and children. The co-occurrence of cysts and angiomyolipomas, easily detected by computer tomography (CT), is strongly suggestive of TS. The CT scan of our patients did not show any cysts or angiomyolipomas [Figure 4]. In the absence of angiomyolipomas, the renal cystic disease may be radiographically indistinguishable from adult polycystic kidney disease (ADPKD). Affected children frequently have early onset of severe hypertension and progressive decline in renal function that results in end-stage renal disease during the second or third decade of life.
Renal carcinoma reportedly occurs in patients with TS with higher frequency and at an earlier age than in general population. Renal carcinoma is often bilateral and occurs more commonly in females with a median age of diagnosis at 28 years; 19-50% of these patients die due to metastatic disease. The two male siblings with TS that are presented in this report have evidence of generalized proximal tubular dysfunction in the form of bicarbonaturia, phosphaturia, uricosuria and glucosuria. Other cases of proximal RTA such as multiple myeloma, drugs and cystinosis were excluded in our patients. ,,,,,, The growth retardation in our patients may be in part due to early onset of RTA. A Medline literature search by the authors did not disclose any reports of an association between the FS and TS.
In conclusion, we present two Saudi males with evidence of both tuberous sclerosis and the Fanconi Syndrome. To our knowledge, such association has not been reported previously. The genetic basis of such rare association is not clear and needs to be investigated.
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