- Email: [email protected]
Cystinosis: An “eye opener”
a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 4 3 e4 5
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/apme
Case Report
Cystinosis: An “eye opener” Krishnan Swaminathan a,*, Murugan Jeyaraman b a b
Consultant Endocrinologist, Department of Endocrinology, Apollo Specialty Hospital, 625 020 Madurai, India Consultant Paediatrician, Department of Paediatrics, Apollo Specialty Hospital, 625 020 Madurai, India
article info
abstract
Article history:
A much-quoted aphorism in medicine is “Listen to your patient and they are telling you the
Received 3 January 2014
diagnosis”. Most often, the history reveals the diagnosis and sometimes, it is all that is
Accepted 21 January 2014
required to make the diagnosis. Unfortunately, in this age of modern technology-based
Available online 10 February 2014
medicine, many busy clinicians fail to get a proper history and miss important dots in the history that connect to the diagnosis. This is clinically relevant, as a specific diagnosis
Keywords:
completely alters the nature of treatment and thereby improves prognosis. We present a
Short stature
young boy with infantile cystinosis, who was evaluated in at least three tertiary referral
Cystinosis
centers prior to our review and branded as having “renal rickets due to a posterior urethral
Renal failure
valve”. Two important clues from history that clinched a clinical diagnosis of infantile cystinosis in this boy with renal rickets were the father’s comment that “His elder daughter died at 7 years of age with a similar condition” and the mother’s complaint that “her son cannot see television properly, his eyes become red and tears roll through his eyes”. Our aim is to open the eyes of medical community to this rare but treatable condition, especially in young children presenting with renal rickets, photophobia and short stature. Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
1.
Case report
We report a 6-year-old boy born of consanguineous parents. His birth history was normal. At nine months of age, he presented with polyuria and polydipsia, in the absence of hyperglycemia. For the next five years, he was investigated in three different tertiary referral centers in South India for stunted growth and renal rickets. He was finally branded as having “renal osteodystrophy due to a posterior urethral valve”. Treatment consisted of sodium bicarbonate tablets and calcitriol 0.25 once daily, with poor compliance with both the medications. At our clinic visit, we found a lethargic boy with a height centile of <3% with features of renal rickets and dryness of skin (Fig. 1). Abdomen was distended with mild
hepatomegaly. Further detailed family history revealed that his elder sister had died at seven years of age with stunted growth, rickets and renal failure. Another important piece of history came from the boy’s mother who commented that “the only pastime for him is to watch television but nowadays, he gets severe irritation in his eyes with redness and persistent watering”. A PubMed search with “short stature, renal rickets and photophobia” gave three hits, all pointing towards a diagnosis of infantile cystinosis. Further lab work up revealed severe primary hypothyroidism with a Thyroid stimulating hormone (TSH) > 150 mIU/ L and undetectable free thyroxine (FT4). He had renal impairment with low serum calcium, phosphate, grossly elevated parathormone (PTH) and alkaline phosphatase.
* Corresponding author. Tel.: þ91 8526421150; fax: þ91 4522580199. E-mail address: [email protected] (K. Swaminathan). 0976-0016/$ e see front matter Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2014.01.002
44
a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 4 3 e4 5
apparently homozygous state in exon 7: c.422C > T responsible for the replacement of serine by phenylalanine at position 141 on the protein p.Ser141Phe (Fig. 2), in agreement with a diagnosis of cystinosis. The child was started on supportive measures, indomethacin, phosphate and increased dose of calcitriol. With great difficulty, we managed to get Cysteamine (Cystagon), a drug that directly treats the disease by reducing the intracellular cystine content. This drug is very expensive, not available in India and had to be imported from France (Orphan Europe, http://www.orphan-europe.com). To this date, he has tolerated the drug well. Photophobia has improved remarkably with Cysteamine eye drops (Cystagon 0.5%) six times per day. He has been referred to the regional renal transplant team, who have previous experience with a similar boy aged 7 years with infantile cystinosis. Fig. 1 e Evidence of rickets and dryness of skin due to severe primary hypothyroidism.
2. Serum Insulin like Growth Factor-1 (IGF-1) was within normal limits. An ophthalmologist referral revealed extensive corneal micro deposits. Blood samples were sent for molecular genetic analysis to Groupement Hospitalier Est, France. DNA was extracted from leucocytes (Nucleon BACC3 kiteGE Healthcare). Screening for the common 57-kb deletion as well as direct sequencing after PCR (Polymerase Chain Reaction) amplification of the 12 exons of the CTNS gene was carried out. The child was detected to have a mutation in an
Discussion
We report a case of infantile cystinosis where the main clue to the diagnosis was marked photophobia. An accurate diagnosis resulted in appropriate treatment with marked clinical improvement, genetic counseling and a reason for the family to be at peace to know the reason for their son’s illness and their daughter’s death. Cystinosis is a rare autosomal recessive metabolic disorder characterized by defective lysosomal efflux of cystine. This leads to accumulation of cystine in multiple organs,
Fig. 2 e Mutation in an apparently homozygous state in exon 7: c.422C > T responsible for the replacement of serine by phenylalanine at position 141 on the protein p.Ser141Phe.
a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 4 3 e4 5
progressing to severe organ dysfunction, especially end-stage renal failure.1 The first clinical signs usually appear at three to six months of life and by six months, most children have fullblown renal Fanconi syndrome (glycosuria, aminoaciduria, phosphaturia, metabolic acidosis). The clinical manifestations include polyuria, failure to thrive, growth retardation, developmental delay, rickets, constipation and acute dehydration episodes.2 Predominant extra-renal organs affected by cystine deposition are eyes, thyroid and liver. Cystine deposits in the conjunctivae and cornea cause photophobia, blepharospasm and watering of eyes. The deposits can be easily seen on slit lamp examination. Hemorrhagic retinopathy and visual impairment are late complications of this disease.3 Growth retardation is a common feature of this condition. This may be due in part to severe hypophosphatemia but hypothyroidism may be an additional factor as well, especially in older children, where the rates are close to 70% in children more than 10 years of age. Enlarged Kupffer cells with cystine crystals contribute to hepatomegaly and may lead to portal hypertension.4 Muscular and neurological involvements are late complications of the disease contributing to significant morbidity. Such patients are usually older than twenty years. Presenting features include pseudo bulbar palsy, cerebellar, pyramidal signs and encephalopathy associated with strokelike episodes.5 The definitive treatment of infantile cystinosis includes Cysteamine therapy and renal transplantation for end stage renal disease. Cysteamine therapy should be started as soon as the diagnosis is confirmed. This drug reduces cystine accumulation in cells and when started early, delays the development of renal failure, hypothyroidism and improves growth.6,7 For children up to the age of 12 years, Cystagon (cysteamine) dosing should be based on the body surface area, the recommended dose being 1.30 g/m2/day of the free base divided four times a day. In children over age 12 years and >50 kg in weight, the recommended dose is 2 g/day divided four times a day (Courtesy: Cystagon SPC leaflet, Orphan Europe). The goal of therapy is to keep the leukocyte cystine levels to <1 nmol hemicystine/mg protein. Unfortunately, we do not have access to leukocyte cystine levels and therefore have to continue treatment for our case based on clinical response. It is important to remember not to exceed the dose of cysteamine to higher than 1.95 gm/m2. Renal transplantation is a definitive option for children with end stage renal disease as cystine induced tubular dysfunction does not
45
recur on the graft. However, this has to be balanced against long-term morbidity from immunosuppression and extrarenal cystinosis.8 To summarize, infantile cystinosis can be easily missed. We hope that this instructive case is an “eye opener” for the medical community to think about this rare but treatable disease in the appropriate clinical context.
Conflicts of interest All authors have none to declare.
Acknowledgments We wish to acknowledge Dr. Sujatha Jagadeesh, Consultant Geneticist, Chennai and the molecular genetics work by Dr. C. Vianey Saban and Dr. Cecile Acquaviva, France.
references
1. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347(2):111. 2. Knoepfelmacher M, Rocha R, Salgado LR, et al. Nephropathic cystinosis: report of 2 cases and review of the literature. Rev Assoc Med Bras. 1994;40(1):43. 3. Kaiser-Kupfer MI, Caruso RC, Minkler DS, Gahl WA. Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol. 1986;104(5):706. 4. Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011 Feb;26(2):205e215. 5. Broyer M, Teˆte MJ, Guest G, Berthe´le´me´ JP, Labrousse F, Poisson M. Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine. J Inherit Metab Dis. 1996;19(1):65e75. 6. Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993;328(16):1157. 7. Kimonis VE, Troendle J, Rose SR, Yang ML, Markello TC, Gahl WA. Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. J Clin Endocrinol Metab. 1995;80(11):3257. 8. Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol. 2006;1(3):555.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/apme
Case Report
Cystinosis: An “eye opener” Krishnan Swaminathan a,*, Murugan Jeyaraman b a b
Consultant Endocrinologist, Department of Endocrinology, Apollo Specialty Hospital, 625 020 Madurai, India Consultant Paediatrician, Department of Paediatrics, Apollo Specialty Hospital, 625 020 Madurai, India
article info
abstract
Article history:
A much-quoted aphorism in medicine is “Listen to your patient and they are telling you the
Received 3 January 2014
diagnosis”. Most often, the history reveals the diagnosis and sometimes, it is all that is
Accepted 21 January 2014
required to make the diagnosis. Unfortunately, in this age of modern technology-based
Available online 10 February 2014
medicine, many busy clinicians fail to get a proper history and miss important dots in the history that connect to the diagnosis. This is clinically relevant, as a specific diagnosis
Keywords:
completely alters the nature of treatment and thereby improves prognosis. We present a
Short stature
young boy with infantile cystinosis, who was evaluated in at least three tertiary referral
Cystinosis
centers prior to our review and branded as having “renal rickets due to a posterior urethral
Renal failure
valve”. Two important clues from history that clinched a clinical diagnosis of infantile cystinosis in this boy with renal rickets were the father’s comment that “His elder daughter died at 7 years of age with a similar condition” and the mother’s complaint that “her son cannot see television properly, his eyes become red and tears roll through his eyes”. Our aim is to open the eyes of medical community to this rare but treatable condition, especially in young children presenting with renal rickets, photophobia and short stature. Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved.
1.
Case report
We report a 6-year-old boy born of consanguineous parents. His birth history was normal. At nine months of age, he presented with polyuria and polydipsia, in the absence of hyperglycemia. For the next five years, he was investigated in three different tertiary referral centers in South India for stunted growth and renal rickets. He was finally branded as having “renal osteodystrophy due to a posterior urethral valve”. Treatment consisted of sodium bicarbonate tablets and calcitriol 0.25 once daily, with poor compliance with both the medications. At our clinic visit, we found a lethargic boy with a height centile of <3% with features of renal rickets and dryness of skin (Fig. 1). Abdomen was distended with mild
hepatomegaly. Further detailed family history revealed that his elder sister had died at seven years of age with stunted growth, rickets and renal failure. Another important piece of history came from the boy’s mother who commented that “the only pastime for him is to watch television but nowadays, he gets severe irritation in his eyes with redness and persistent watering”. A PubMed search with “short stature, renal rickets and photophobia” gave three hits, all pointing towards a diagnosis of infantile cystinosis. Further lab work up revealed severe primary hypothyroidism with a Thyroid stimulating hormone (TSH) > 150 mIU/ L and undetectable free thyroxine (FT4). He had renal impairment with low serum calcium, phosphate, grossly elevated parathormone (PTH) and alkaline phosphatase.
* Corresponding author. Tel.: þ91 8526421150; fax: þ91 4522580199. E-mail address: [email protected] (K. Swaminathan). 0976-0016/$ e see front matter Copyright ª 2014, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2014.01.002
44
a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 4 3 e4 5
apparently homozygous state in exon 7: c.422C > T responsible for the replacement of serine by phenylalanine at position 141 on the protein p.Ser141Phe (Fig. 2), in agreement with a diagnosis of cystinosis. The child was started on supportive measures, indomethacin, phosphate and increased dose of calcitriol. With great difficulty, we managed to get Cysteamine (Cystagon), a drug that directly treats the disease by reducing the intracellular cystine content. This drug is very expensive, not available in India and had to be imported from France (Orphan Europe, http://www.orphan-europe.com). To this date, he has tolerated the drug well. Photophobia has improved remarkably with Cysteamine eye drops (Cystagon 0.5%) six times per day. He has been referred to the regional renal transplant team, who have previous experience with a similar boy aged 7 years with infantile cystinosis. Fig. 1 e Evidence of rickets and dryness of skin due to severe primary hypothyroidism.
2. Serum Insulin like Growth Factor-1 (IGF-1) was within normal limits. An ophthalmologist referral revealed extensive corneal micro deposits. Blood samples were sent for molecular genetic analysis to Groupement Hospitalier Est, France. DNA was extracted from leucocytes (Nucleon BACC3 kiteGE Healthcare). Screening for the common 57-kb deletion as well as direct sequencing after PCR (Polymerase Chain Reaction) amplification of the 12 exons of the CTNS gene was carried out. The child was detected to have a mutation in an
Discussion
We report a case of infantile cystinosis where the main clue to the diagnosis was marked photophobia. An accurate diagnosis resulted in appropriate treatment with marked clinical improvement, genetic counseling and a reason for the family to be at peace to know the reason for their son’s illness and their daughter’s death. Cystinosis is a rare autosomal recessive metabolic disorder characterized by defective lysosomal efflux of cystine. This leads to accumulation of cystine in multiple organs,
Fig. 2 e Mutation in an apparently homozygous state in exon 7: c.422C > T responsible for the replacement of serine by phenylalanine at position 141 on the protein p.Ser141Phe.
a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 4 3 e4 5
progressing to severe organ dysfunction, especially end-stage renal failure.1 The first clinical signs usually appear at three to six months of life and by six months, most children have fullblown renal Fanconi syndrome (glycosuria, aminoaciduria, phosphaturia, metabolic acidosis). The clinical manifestations include polyuria, failure to thrive, growth retardation, developmental delay, rickets, constipation and acute dehydration episodes.2 Predominant extra-renal organs affected by cystine deposition are eyes, thyroid and liver. Cystine deposits in the conjunctivae and cornea cause photophobia, blepharospasm and watering of eyes. The deposits can be easily seen on slit lamp examination. Hemorrhagic retinopathy and visual impairment are late complications of this disease.3 Growth retardation is a common feature of this condition. This may be due in part to severe hypophosphatemia but hypothyroidism may be an additional factor as well, especially in older children, where the rates are close to 70% in children more than 10 years of age. Enlarged Kupffer cells with cystine crystals contribute to hepatomegaly and may lead to portal hypertension.4 Muscular and neurological involvements are late complications of the disease contributing to significant morbidity. Such patients are usually older than twenty years. Presenting features include pseudo bulbar palsy, cerebellar, pyramidal signs and encephalopathy associated with strokelike episodes.5 The definitive treatment of infantile cystinosis includes Cysteamine therapy and renal transplantation for end stage renal disease. Cysteamine therapy should be started as soon as the diagnosis is confirmed. This drug reduces cystine accumulation in cells and when started early, delays the development of renal failure, hypothyroidism and improves growth.6,7 For children up to the age of 12 years, Cystagon (cysteamine) dosing should be based on the body surface area, the recommended dose being 1.30 g/m2/day of the free base divided four times a day. In children over age 12 years and >50 kg in weight, the recommended dose is 2 g/day divided four times a day (Courtesy: Cystagon SPC leaflet, Orphan Europe). The goal of therapy is to keep the leukocyte cystine levels to <1 nmol hemicystine/mg protein. Unfortunately, we do not have access to leukocyte cystine levels and therefore have to continue treatment for our case based on clinical response. It is important to remember not to exceed the dose of cysteamine to higher than 1.95 gm/m2. Renal transplantation is a definitive option for children with end stage renal disease as cystine induced tubular dysfunction does not
45
recur on the graft. However, this has to be balanced against long-term morbidity from immunosuppression and extrarenal cystinosis.8 To summarize, infantile cystinosis can be easily missed. We hope that this instructive case is an “eye opener” for the medical community to think about this rare but treatable disease in the appropriate clinical context.
Conflicts of interest All authors have none to declare.
Acknowledgments We wish to acknowledge Dr. Sujatha Jagadeesh, Consultant Geneticist, Chennai and the molecular genetics work by Dr. C. Vianey Saban and Dr. Cecile Acquaviva, France.
references
1. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347(2):111. 2. Knoepfelmacher M, Rocha R, Salgado LR, et al. Nephropathic cystinosis: report of 2 cases and review of the literature. Rev Assoc Med Bras. 1994;40(1):43. 3. Kaiser-Kupfer MI, Caruso RC, Minkler DS, Gahl WA. Long-term ocular manifestations in nephropathic cystinosis. Arch Ophthalmol. 1986;104(5):706. 4. Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN. Cystinosis: practical tools for diagnosis and treatment. Pediatr Nephrol. 2011 Feb;26(2):205e215. 5. Broyer M, Teˆte MJ, Guest G, Berthe´le´me´ JP, Labrousse F, Poisson M. Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine. J Inherit Metab Dis. 1996;19(1):65e75. 6. Markello TC, Bernardini IM, Gahl WA. Improved renal function in children with cystinosis treated with cysteamine. N Engl J Med. 1993;328(16):1157. 7. Kimonis VE, Troendle J, Rose SR, Yang ML, Markello TC, Gahl WA. Effects of early cysteamine therapy on thyroid function and growth in nephropathic cystinosis. J Clin Endocrinol Metab. 1995;80(11):3257. 8. Ueda M, O’Brien K, Rosing DR, et al. Coronary artery and other vascular calcifications in patients with cystinosis after kidney transplantation. Clin J Am Soc Nephrol. 2006;1(3):555.