Twins with senior-loken syndrome
http://www.100md.com
《美国医学杂志》
Department of Pediatric Nephrology, Institute of Child Health and Hospital for Children, Egmore, Chennai 600008, India
Abstract
Senior-Loken syndrome is a rare entity that combines familial juvenile nephronophthisis with retinal dystrophy. The eye disease may be congenital amaurosis of Leber type or pigmentary retinal degeneration and electroretinogram (ERG) helps in the diagnosis of these varieties. The disease progresses inexorably to chronic renal failure. Here is a case of twins with Senior-Loken syndrome emphasizing the importance of ophthalmic examination in children with renal failure, for determining a correct diagnosis.
Keywords: Senior Loken syndrome; Familial juvenile nephronopthisis; Retinitis pigmentosa
Nephronophthisis is the most frequent genetic cause of renal failure in children. Ten percent of affected individuals have retinitis pigmentosa constituting the Senior-Loken syndrome. Defective urinary concentration leading to polyuria and polydipsia are the earliest presenting signs. Visual impairment may be associated. Ophthalmologic examination usually reveals pigmentary retinal changes, which are confirmed by electroretinogram. The disease progresses to end stage renal disease requiring renal replacement therapy.
Case report
Baby X and Y, 11-year-old female twins born to 2nd degree consanguineous parents, presented with polyuria, failure to thrive and defective night vision for the past 3 years. Twin Y also had breathing difficulty for 2 months. On examination, both were anemic, short statured, had acidotic breathing and no secondary sexual characters. Anthropometry revealed weight and height less than the 3rd percentile for age and sex, although Twin Y was taller than Twin X. The upper segment to lower segment ratio was appropriate for age. In addition, the twins had dysmorphic features like high forehead, depressed nasal bridge, micrognathia, brachydactyly, clinodactyly and sandle gap. Twin Y was also hypertensive.
Investigations revealed similar findings in the twins. Twin X had polyuria (urine output: 4.5ml/Kg/hr) but Twin Y had normal urine output (1.5ml/Kg/hr). They both had severe normocytic normochromic anemia (Twin X - 6 gm/dl; Twin Y - 5 gm/dl) and elevated blood urea and creatinine with low bicarbonate levels. Arterial blood gas analysis showed metabolic acidosis with compensated respiratory alkalosis. Urine analysis revealed low specific gravity and increased urinary electrolytes. X-rays showed that the bone age was about 4 years in both the twins but no skeletal abnormalities were seen. Thyroid profile was normal in both of them. Renal ultrasound showed shrunken kidneys, grade III renal parenchymal disease and bilateral corticomedullary cysts. In addition Twin Y had left ventricular hypertrophy with minimal pericardial effusion. A detailed ophthalmological examination undertaken for defective night vision revealed pale optic disc, attenuated retinal vasculature and striking pigmentary changes, findings suggestive of retinitis pigmentosa, which was subsequently confirmed by a diminished electroretinogram in the twins. A diagnosis of Senior Loken variant of Juvenile Nephronophthisis was made. The twins are now undergoing intermittent peritoneal dialysis.
Discussion
Nephronophthisis (NPHP) comprises a group of autosomal recessive cystic kidney diseases, which constitute the most frequent genetic cause for end-stage renal failure in children and young adults, especially in the first two decades of life. Smith and Graham first reported NPHP in 1945.[1] but the first description has been attributed to Fanconi et al in 1951.[2] Four gene loci for NPHP have been mapped to chromosomes 2q13 (NPHP1), 9q22 (NPHP2), 3q22 (NPHP3), and 1p36 (NPHP4). These variants can be distinguished clinically by age at onset of ESRD.
Ten percent of affected individuals have associated retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome. Other extrarenal manifestations of NPHP include oculomotor apraxia(Cogan type); coloboma, aplasia of cerebellar vermis, polydactyly, and neonatal tachypnea (Joubert syndrome); cranioectodermal dysplasia and electroretinal abnormalities (Sesenbrenner syndrome).
NPHP 1 - 4 have been inconsistently associated with Senior-Loken syndrome but recently mutations in a new locus IQCB1 (also called NPHP5) has been identified as the most frequent cause of Senior-Loken syndrome.[3] IQCB1 codes for a protein, nephrocystin-5, which is expressed in primary renal epithelial cells. Nephrocystin-5 interacts with retinitis pigmentosa GTPase regulator expressed by photoreceptor cilia. This interaction causes ciliary dysfunction, which is central to the pathogenesis of Senior-Loken syndrome.
The first symptom is polyuria, which usually starts at the age of about six years and is accompanied by polydipsia and nocturnal enuresis, and is followed by signs associated with advanced renal disease, such as growth retardation. Anemia is precocious and more severe than in control children affected by renal disease. This has been attributed to a defect in the function or regulation of the cells producing erythropoietin. Urinary abnormalities are limited to the inability to concentrate the urine and salt wasting. Severe forms of Senior Loken syndrome can lead to blindness in infancy, less severe forms show variable damage and progression. In some cases only abnormal ERG has been suggested to be the manifestation of ocular involvement.[4]
Cysts of 1-15 mm diameter located primarily at the cortico-medullary junction and the medulla are seen in 70% of patients. Cysts are reported to occur late in the course of the disease, but can be seen early by current investigations. Computerized Tomography may be the diagnostic procedure of choice[5] but Ultrasound is also helpful is visualizing the cysts.[6],[7] Nevertheless, the lack of cysts, even in the late stage of the illness, does not exclude the diagnosis of NPHP. Hyperechogenic kidneys of slightly reduced or normal size are consistent with the diagnosis of NPHP.[8]
Renal histology is characterized by the triad of interstitial infiltration, renal tubular cell atrophy with cyst development and renal interstitial fibrosis.[9] Progression to end stage renal disease in invariable and all patients eventually require renal replacement therapy including peritoneal dialysis or hemodialysis, or preemptive kidney transplantation.
The presence of dysmorphic features with Senior-Loken syndrome, as seen in the twins, is unreported so far but other skeletal abnormalities in association with Senior Loken syndrome have been described.[10],[11],[12],[13] Brachydactyly, clinodactyly and sandle gap are limb abnormalities that can be seen in Bardet-Biedl syndrome, a multi-system autosomal recessive disorder that can also have retinitis pigmentosa and renal abnormalities, but the absence of other common features like truncal obesity and polydactyly makes the diagnosis of Bardet-Biedl syndrome unlikely.[14]
Retinitis pigmentosa and nephronophthisis can also occur in RHYNS syndrome (retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia), which was excluded by the presence of a normal thyroid profile and absence of any skeletal dysplasia.[13] A normal skeletal survey also excluded the possibility of asphyxiating thoracic dysplasia or Jeune syndrome, which can have similar renal histological findings and retinal degeneration.
Case reports of Senior-Loken syndrome from India are few.[12],[16] To our knowledge there has been no case report of Senior-Loken syndrome in twins. This report highlights the importance of routine ophthalmic examination in any child presenting with chronic renal failure.
References
1. Smith CH and Graham YB. Congenital medullary cystic disease of the kidney with severe refractory anemia. Am J Dis Child 1945; 69 : 369-377.
2. Fanconi G, Hanhart E, von Albertini A, Euhlinger R, Dolivo G, Prader A. Die familiδre juvenile Nephronophthise. Helv Pediatr Acta 1951; 6: 1-9.
3. Otto EA et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 2005; 37(3) : 282-288.
4. Fillastre YP, General J, Riberi P, Marx P, Whitworth JA, Kunh JM. Senior-Loken syndrome (nephronophthisis and tapeto-retinal degeneration): a study of 8 cases from 5 families. Clin Nephrol 1976; 5 : 14-19.
5. McGregor AR, Bailey RR. Nephronophthisis cystic renal medullary complex. Diagnosis by computer tomography. Nephron 1989; 53 : 70-72.
6. Garel LA, Habib R, Paziente D, Broyer M, Sanvegrain J. Juvenile nephronophthisis: sonographic appearance in children with severe uremia. Radiology 1984; 151 : 93-95.
7. Anguillera A, Rivera M, Gallego N, Nogulira Y, Ortuno J. Sonographic appearance of the juvenile nephronophthisis-cystic renal medulla complex. Nephrol Dial Transplant 1997; 12 : 625-626.
8. Blowey DL, Querfeld U, Geary D, Warady BA, Alon U. Ultrasound finding in juvenile nephronophthisis. Pediatric Nephrol 1996; 10 : 22-24.
9. Waldherr R, Lennert T, Weber HP, Fodisch HJ, Scharer K. The nephronophthisis complex: a clinicopathologic study in children. Virchows Arch A Pathol Anat Histol 1982; 394 : 235-254.
10. Mainzer F, Saldino RM, Ozonoff MB, Minagi H. Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 1970; 49 : 556-562.
11. Giedion A. Phalangese conex shaped epiphysis of the hands (PhCSEH) and chronic renal disease. The conorenal syndromes. Pediatric Radiol 1979; 8 : 32-38.
12. Singh NP, Anuradha S, Gupta S, Rizvi SN, Arora R. Senior-Loken syndrome with unusual manifestations. J Assoc Physicians India 1998; 46 : 740-742.
13. Donaldson MDC, Warner AA, Trompeter RS, Haycock GB, Chantler C. Familiae juvenile nephronophthisis, Jeune's syndrome and associated disorders. Arch Dis Child 1985; 60: 426-434.
14. Beales PL, Elcioglu N, Woolf AS, Parker D. and Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: Results of a population survey. J Med Genet 1999; 36 : 437-446.
15. Di Rocco M, Picco P, Arslanian A, Restagno G, Perfumo F, Buoncompagni A, Gattorno M, Borrone C. Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome Am J Med Genet 1997; 73 : 1-4.
16. Janardhanan R, Krishnakumar S. Senior-Loken syndrome. J Assoc Physicians India 1997; 45 : 889-890.(Giridhar S, Padmaraj R, S)
Abstract
Senior-Loken syndrome is a rare entity that combines familial juvenile nephronophthisis with retinal dystrophy. The eye disease may be congenital amaurosis of Leber type or pigmentary retinal degeneration and electroretinogram (ERG) helps in the diagnosis of these varieties. The disease progresses inexorably to chronic renal failure. Here is a case of twins with Senior-Loken syndrome emphasizing the importance of ophthalmic examination in children with renal failure, for determining a correct diagnosis.
Keywords: Senior Loken syndrome; Familial juvenile nephronopthisis; Retinitis pigmentosa
Nephronophthisis is the most frequent genetic cause of renal failure in children. Ten percent of affected individuals have retinitis pigmentosa constituting the Senior-Loken syndrome. Defective urinary concentration leading to polyuria and polydipsia are the earliest presenting signs. Visual impairment may be associated. Ophthalmologic examination usually reveals pigmentary retinal changes, which are confirmed by electroretinogram. The disease progresses to end stage renal disease requiring renal replacement therapy.
Case report
Baby X and Y, 11-year-old female twins born to 2nd degree consanguineous parents, presented with polyuria, failure to thrive and defective night vision for the past 3 years. Twin Y also had breathing difficulty for 2 months. On examination, both were anemic, short statured, had acidotic breathing and no secondary sexual characters. Anthropometry revealed weight and height less than the 3rd percentile for age and sex, although Twin Y was taller than Twin X. The upper segment to lower segment ratio was appropriate for age. In addition, the twins had dysmorphic features like high forehead, depressed nasal bridge, micrognathia, brachydactyly, clinodactyly and sandle gap. Twin Y was also hypertensive.
Investigations revealed similar findings in the twins. Twin X had polyuria (urine output: 4.5ml/Kg/hr) but Twin Y had normal urine output (1.5ml/Kg/hr). They both had severe normocytic normochromic anemia (Twin X - 6 gm/dl; Twin Y - 5 gm/dl) and elevated blood urea and creatinine with low bicarbonate levels. Arterial blood gas analysis showed metabolic acidosis with compensated respiratory alkalosis. Urine analysis revealed low specific gravity and increased urinary electrolytes. X-rays showed that the bone age was about 4 years in both the twins but no skeletal abnormalities were seen. Thyroid profile was normal in both of them. Renal ultrasound showed shrunken kidneys, grade III renal parenchymal disease and bilateral corticomedullary cysts. In addition Twin Y had left ventricular hypertrophy with minimal pericardial effusion. A detailed ophthalmological examination undertaken for defective night vision revealed pale optic disc, attenuated retinal vasculature and striking pigmentary changes, findings suggestive of retinitis pigmentosa, which was subsequently confirmed by a diminished electroretinogram in the twins. A diagnosis of Senior Loken variant of Juvenile Nephronophthisis was made. The twins are now undergoing intermittent peritoneal dialysis.
Discussion
Nephronophthisis (NPHP) comprises a group of autosomal recessive cystic kidney diseases, which constitute the most frequent genetic cause for end-stage renal failure in children and young adults, especially in the first two decades of life. Smith and Graham first reported NPHP in 1945.[1] but the first description has been attributed to Fanconi et al in 1951.[2] Four gene loci for NPHP have been mapped to chromosomes 2q13 (NPHP1), 9q22 (NPHP2), 3q22 (NPHP3), and 1p36 (NPHP4). These variants can be distinguished clinically by age at onset of ESRD.
Ten percent of affected individuals have associated retinitis pigmentosa, constituting the renal-retinal Senior-Loken syndrome. Other extrarenal manifestations of NPHP include oculomotor apraxia(Cogan type); coloboma, aplasia of cerebellar vermis, polydactyly, and neonatal tachypnea (Joubert syndrome); cranioectodermal dysplasia and electroretinal abnormalities (Sesenbrenner syndrome).
NPHP 1 - 4 have been inconsistently associated with Senior-Loken syndrome but recently mutations in a new locus IQCB1 (also called NPHP5) has been identified as the most frequent cause of Senior-Loken syndrome.[3] IQCB1 codes for a protein, nephrocystin-5, which is expressed in primary renal epithelial cells. Nephrocystin-5 interacts with retinitis pigmentosa GTPase regulator expressed by photoreceptor cilia. This interaction causes ciliary dysfunction, which is central to the pathogenesis of Senior-Loken syndrome.
The first symptom is polyuria, which usually starts at the age of about six years and is accompanied by polydipsia and nocturnal enuresis, and is followed by signs associated with advanced renal disease, such as growth retardation. Anemia is precocious and more severe than in control children affected by renal disease. This has been attributed to a defect in the function or regulation of the cells producing erythropoietin. Urinary abnormalities are limited to the inability to concentrate the urine and salt wasting. Severe forms of Senior Loken syndrome can lead to blindness in infancy, less severe forms show variable damage and progression. In some cases only abnormal ERG has been suggested to be the manifestation of ocular involvement.[4]
Cysts of 1-15 mm diameter located primarily at the cortico-medullary junction and the medulla are seen in 70% of patients. Cysts are reported to occur late in the course of the disease, but can be seen early by current investigations. Computerized Tomography may be the diagnostic procedure of choice[5] but Ultrasound is also helpful is visualizing the cysts.[6],[7] Nevertheless, the lack of cysts, even in the late stage of the illness, does not exclude the diagnosis of NPHP. Hyperechogenic kidneys of slightly reduced or normal size are consistent with the diagnosis of NPHP.[8]
Renal histology is characterized by the triad of interstitial infiltration, renal tubular cell atrophy with cyst development and renal interstitial fibrosis.[9] Progression to end stage renal disease in invariable and all patients eventually require renal replacement therapy including peritoneal dialysis or hemodialysis, or preemptive kidney transplantation.
The presence of dysmorphic features with Senior-Loken syndrome, as seen in the twins, is unreported so far but other skeletal abnormalities in association with Senior Loken syndrome have been described.[10],[11],[12],[13] Brachydactyly, clinodactyly and sandle gap are limb abnormalities that can be seen in Bardet-Biedl syndrome, a multi-system autosomal recessive disorder that can also have retinitis pigmentosa and renal abnormalities, but the absence of other common features like truncal obesity and polydactyly makes the diagnosis of Bardet-Biedl syndrome unlikely.[14]
Retinitis pigmentosa and nephronophthisis can also occur in RHYNS syndrome (retinitis pigmentosa, hypopituitarism, nephronophthisis, and skeletal dysplasia), which was excluded by the presence of a normal thyroid profile and absence of any skeletal dysplasia.[13] A normal skeletal survey also excluded the possibility of asphyxiating thoracic dysplasia or Jeune syndrome, which can have similar renal histological findings and retinal degeneration.
Case reports of Senior-Loken syndrome from India are few.[12],[16] To our knowledge there has been no case report of Senior-Loken syndrome in twins. This report highlights the importance of routine ophthalmic examination in any child presenting with chronic renal failure.
References
1. Smith CH and Graham YB. Congenital medullary cystic disease of the kidney with severe refractory anemia. Am J Dis Child 1945; 69 : 369-377.
2. Fanconi G, Hanhart E, von Albertini A, Euhlinger R, Dolivo G, Prader A. Die familiδre juvenile Nephronophthise. Helv Pediatr Acta 1951; 6: 1-9.
3. Otto EA et al. Nephrocystin-5, a ciliary IQ domain protein, is mutated in Senior-Loken syndrome and interacts with RPGR and calmodulin. Nat Genet 2005; 37(3) : 282-288.
4. Fillastre YP, General J, Riberi P, Marx P, Whitworth JA, Kunh JM. Senior-Loken syndrome (nephronophthisis and tapeto-retinal degeneration): a study of 8 cases from 5 families. Clin Nephrol 1976; 5 : 14-19.
5. McGregor AR, Bailey RR. Nephronophthisis cystic renal medullary complex. Diagnosis by computer tomography. Nephron 1989; 53 : 70-72.
6. Garel LA, Habib R, Paziente D, Broyer M, Sanvegrain J. Juvenile nephronophthisis: sonographic appearance in children with severe uremia. Radiology 1984; 151 : 93-95.
7. Anguillera A, Rivera M, Gallego N, Nogulira Y, Ortuno J. Sonographic appearance of the juvenile nephronophthisis-cystic renal medulla complex. Nephrol Dial Transplant 1997; 12 : 625-626.
8. Blowey DL, Querfeld U, Geary D, Warady BA, Alon U. Ultrasound finding in juvenile nephronophthisis. Pediatric Nephrol 1996; 10 : 22-24.
9. Waldherr R, Lennert T, Weber HP, Fodisch HJ, Scharer K. The nephronophthisis complex: a clinicopathologic study in children. Virchows Arch A Pathol Anat Histol 1982; 394 : 235-254.
10. Mainzer F, Saldino RM, Ozonoff MB, Minagi H. Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med 1970; 49 : 556-562.
11. Giedion A. Phalangese conex shaped epiphysis of the hands (PhCSEH) and chronic renal disease. The conorenal syndromes. Pediatric Radiol 1979; 8 : 32-38.
12. Singh NP, Anuradha S, Gupta S, Rizvi SN, Arora R. Senior-Loken syndrome with unusual manifestations. J Assoc Physicians India 1998; 46 : 740-742.
13. Donaldson MDC, Warner AA, Trompeter RS, Haycock GB, Chantler C. Familiae juvenile nephronophthisis, Jeune's syndrome and associated disorders. Arch Dis Child 1985; 60: 426-434.
14. Beales PL, Elcioglu N, Woolf AS, Parker D. and Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: Results of a population survey. J Med Genet 1999; 36 : 437-446.
15. Di Rocco M, Picco P, Arslanian A, Restagno G, Perfumo F, Buoncompagni A, Gattorno M, Borrone C. Retinitis pigmentosa, hypopituitarism, nephronophthisis, and mild skeletal dysplasia (RHYNS): a new syndrome Am J Med Genet 1997; 73 : 1-4.
16. Janardhanan R, Krishnakumar S. Senior-Loken syndrome. J Assoc Physicians India 1997; 45 : 889-890.(Giridhar S, Padmaraj R, S)