The role of an ophthalmologist in the Alström syndrome diagnosis Uloga oftalmologa u dijagnostici Alstromovog sindroma

Introduction. The Alström syndrome (AS) is an extremely rare autosomal recessive genetic disorder, affecting fewer than 1: 1,000,000 people globally. It is a single gene disorder due to the mutation of ALMS1 on chromosome 2 (2p13). The AS affects multiple organs and systems. Approximately 800 affected individuals have been identified worldwide so far. Some cases of the AS may go unrecognized for years as many of the clinical features develop over a longer period of time. As the nystagmus and retinitis pigmentosa are the most consistent findings, usually the first visible sign and present at the early infant period, the main aim of this article is to emphasize the importance of the ophthalmologist in establishing an adequate diagnosis of this rare syndrome. Case report. This article describes a Serbian patient with the Alström syndrome, whose diagnosis was genetically confirmed using the whole exome sequencing. Our patient was a 7-year-old obese male with symptoms of progressive visual impairment, photophobia and nystagmus diagnosed in early childhood. On admission, the bilateral visual acuity was poor, RE 0.06, LE 0.01, the intraocular pressure within range. The funduscopy showed central retinal pigmentation, thus suggesting cone-rod retinal dystrophy with “bull’s eye maculopathy”. The initial laboratory work at the time of the consultation revealed the elevated triglycerides levels and hyperinsulinemia, increased transaminases and gamma-glu-tamyl transpeptidase serum activity, whereas the glucose and glycated hemoglobin (HbA1C) levels were normal. The bilirubin test results were normal. Overall, the clinical manifestations were absent. The patient’s cardiac function was normal and the echocardiography did not indicate any abnormalities at the time. His sensorineural hearing was normal as well. A molecular genetic analysis was performed. Two composite heterozygous mutations were discovered within the ALMS1 gene sequence. In addition to the clinical presentation, the mutation detection confirmed the initial diagnosis of the AS. Conclusion. The Alström syndrome should be kept in mind in case of an obese child with photophobia, nystagmus and visual impairment present from early childhood. Fundus examination by an ophthalmologist may significantly help to establish the diagnosis of this rare genetic syndrome.

Introduction: The Alström syndrome (AS) is an extremely rare autosomal recessive genetic disorder, affecting less than 1: 1,000,000 people globally.It is a single gene disorder, due to the mutation of ALMS1 on chromosome 2 (2p13).The AS affects multiple organs and systems.Approximately 800 affected individuals have been identified worldwide so far.Some cases of the AS may go unrecognized for years as many of the clinical features develop over a longer period of time.As the nystagmus and retinitis pigmentosa are the most consistent findings, usually the first visible sign and that at the early infant period, the main aim of this article is to emphasize the importance of the ophthalmologist in establishing an adequate diagnosis of this rare syndrome.
Case Report: This article describes a Serbian patient with Alström syndrome, whose diagnosis was genetically confirmed using the whole exome sequencing.Our case was a 7year-old male with symptoms of progressive visual impairment, photophobia and nystagmus diagnosed in early childhood.On admission, the bilateral visual acuity was poor, RE 0,06, LE 0,01, the intraocular pressure within range.The funduscopy showed central retinal pigmentation, thus suggesting cone-rod retinal dystrophy with "bull's eye maculopathy".The initial laboratory work at the time of the consultation revealed elevated triglycerides levels and hyperinsulinemia, increased transaminases and gamma-glutamyl transpeptidase serum activity, whereas the glucose and HbA1C levels were normal.The bilirubin test results were normal.Overall, the clinical manifestations were absent.The patient's cardiac function was normal and the echocardiography did not indicate any abnormalities at the time.His sensorineural hearing was normal as well.A molecular genetic analysis was performed.Two composite heterozygous mutations were discovered within the ALMS1 gene sequence.In addition to the clinical presentation, the mutation detection confirmed the initial diagnosis of the AS.

Conclusion:
The Alström syndrome should be kept in mind in the case of an obese child with photophobia, nystagmus and visual impairment present from early childhood.Fundus examination by an ophthalmologist may significantly help establish the diagnosis of this rare genetic syndrome.

INTRODUCTION
The Alström syndrome (AS) is an extremely rare autosomal recessive genetic disorder [1] affecting less than 1: 1,000,000 people globally [2].It is a single gene disorder, due to the mutation of ALMS1 on chromosome 2 (2p13).The AS affects multiple organs and systems.
The characteristic features of this syndrome are cone-rod retinal dystrophy causing juvenile blindness, hearing loss, truncal obesity, hyperinsulinemia and insulin resistance, type 2 diabetes mellitus (T2DM), hypertriglyceridemia, dilated cardiomyopathy, and progressive renal, pulmonary, hepatic and neurological dysfunction with mild seizure activity.These combinations of pathologies lead to the patients requiring multiple subspecialists appointments in order to prevent further complications [3,4].
Approximately 800 affected individuals have been identified worldwide so far [5].
However, some cases of AS may go unrecognized or misdiagnosed as many of the clinical features develop over time, as the child grows.Also, there are wide clinical variations among the affected individuals [6].That makes it difficult to determine the true frequency in the general population.The AS diagnosis is usually made on the basis of established clinical features, depending on the age of the patient [7], often without genetic confirmation.However, in most cases the diagnosis is made retrospectively, usually in the first decade of life, after the development of various extraocular features [8].
Since the nystagmus and retinitis pigmentosa are the most consistent findings, usually present first and in early childhood, the main aim of this article is to emphasize the importance of the ophthalmologist in establishing an adequate diagnosis of this rare syndrome.There are only two cases of Alström syndrome reported in Serbia [3].In this study we want to present the third Serbian patient with Alstrӧm syndrome whose diagnosis was genetically confirmed using the whole exome sequencing.

CASE DESCRIPTION
Our case was a 7-year-old male with symptoms of progressive visual impairment, photophobia and nystagmus noted from early childhood.His preliminary diagnosis was cone-rod retinal dystrophy.The patient was born as a second child of a two-child family, from a normal pregnancy and delivery.His family consists of non-related parents, both alive and healthy, and an older sister who is in good health.This patient underwent complete physical examinations including ophthalmological, neurological, otorhynolaryngological and pediatric evaluations.Biochemical investigations as well as molecular genetic analysis were carried out.On admission, the bilateral visual acuity was poor, RE 0,06, LE 0,01, the intraocular pressure within range.In the neurological examination, both pupils were round in shape and midsize (3.5 mm), with a normal response to light.No abnormalities in the eye movements were detected except the horizontal nystagmus.The fundoscopy showed central retinal pigmentation, thus suggesting cone-rod retinal dystrophy with bull's eye maculopathy (Figure 1, 2).
On physical examination, there was evidence of central obesity (Figure 3, 4) with his height being 119cm, weight 36,9 kg and his body mass index (BMI) 26,1 kg/m2 (percentile > 98 th ).His waist circumference was 78cm.His cardiac function was normal as well as his sensorineural hearing.His blood pressure (BP) was 132/86mmHg (percentile 95 th ) with a regular pulse of 80 beats per minute.
Overall, the clinical manifestations were absent.The abdominal ultrasound showed evidence of steatosis, with normal liver and spleen measurements.Echocardiography did not indicate any pathology at the time.The blood urea nitrogen, creatinine and uric acid were normal.The renal echocardiography did not indicate any abnormalities.His current treatment was low-fat diet and moderate exercise.
As a result of therapy, after six months, the triglyceride level decreased to 1, 1 mmol/l, while HDL-c decreased to 0, 93 mmol/l.Despite the diet correction, the child was not physically active.Adding physical activity helped him to raise HDL cholesterol to 1, 36 mmol/l at the next checkup.
Our patient underwent molecular genetic analysis (Genetic diagnostic laboratory, Strasbourg University Hospitals, France).The coding sequences of exons 16 and 19 of ALMS1 were PCR-amplified, purified, and products were sequenced according to standard methods.Genetic samples were analyzed in order to characterize retinitis pigmentosa on the molecular plane.As a result, two composite heterozygous mutations were discovered in the gene ALMS1: two nucleotide variations in exons 16 and 19 of the gene ALMS1: c.

DISCUSSION
The aim of this article is to highlight the AS as one of the rarest genetic disorders in the world.The Alström syndrome represents a ciliopathy that involves multiple organs and shares mutual clinical characteristics of blindness due to retinal dystrophy, early onset of obesity, diabetes and neurosensorial deafness [9,10].Although the specific role of the ALMS1 protein has not yet been thoroughly investigated, it plays an important role in the cilia function and intraflagellar transport, allowing AS to be classified as a ciliopathy [11].
Therefore, it is pertinent to distinguish the AS from other similar diseases accompanied by childhood obesity and retinal dystrophy, such as the Bardet-Biedl and Laurence-Moon syndromes.Cognitive impairment and distal digit abnormalities separate it from a more common ciliopathy, the Bardet-Biedl, while deafness and the absence of spastic paraparesis differentiate the AS from Laurence-Moon [12].The exact etiology of the disease is unknown, but it is believed to be due to progressive multiorgan fibrosis that leads to organ failure, which is the major cause of morbidity and mortality in AS [6].
As some clinical features of the AS do not become apparent until adolescence, an early diagnosis can be difficult in young children.The Alström syndrome exhibits a great extent of clinical variability, thus creating difficulties for general definition [13].Marshall et al.
set the major and minor criteria according to ages, which help the physician set a diagnosis.On the other hand, a diagnosis of the AS could be confirmed at any age with genetic analysis when two ALMS1 mutations have been identified or one mutated ALMS1 allele found in the context of characteristic clinical signs [10,14].Therefore, genetic testing should be carried out in patients who do not have all of the classic AS characteristics [14] and when the combination of the recommended criteria does not allow a clinical diagnosis [7].There is no treatment that can cure AS, prevent and/or reverse the clinical features.The patients require a thorough initial assessment along with an intensive multidisciplinary approach and follow-ups in order to detect and treat potential complications [7].Only an early diagnosis of the AS allows us a timely and preplanned management in order to avoid undesired complications and thus improve longevity as well as the quality of life of the patients [15].The most common cause of death is hepatic dysfunction and congestive heart failure, while life expectancy rarely exceeds 40 years [7].
Our patient was on a controlled diet and moderate physical exercise that led to the reduction of the body mass index and better lipoprotein values [16].
We suspected the Alström syndrome in our patient according to the criteria from the second group [7].Genetic results confirm the reputed diagnosis of the AS, linked to the locus ALMS1 previously rendered.The Alström syndrome is autosomal recessive, so the parents of the affected child represent heterozygous carriers who do not show any signs of the disease.We assume that one of these mutations comes from the mother, while the other one probably from the father, but this has not been confirmed since the father's sample was unavailable.Mutation of the ALMS1 gene causes cone-rod retinal dystrophy, which is part of the AS spectrum.The fundus examination gains ever-increasing importance because retinal dystrophy represents the earliest and most constant feature of the AS [17].Still, retinal dystrophy is not isolated and is accompanied with multiple organ disorders mentioned above [6,7].Therefore, detailed multidisciplinary approach is recommended [18] including biological exams such as liver and kidney biological functions, search for diabetes, insulin resistance, dyslipidemia, cardiological monitoring, search for deafness and overweight care.Prenatal and predictive diagnosis should be conducted if both mutated alleles are found in the parents [14].

CONCLUSION
In conclusion, the Alström syndrome should be kept in mind while examining an obese child with photophobia, nystagmus and visual impairment present from early childhood.Genetic analysis is quite difficult and expensive so all patients with diabetes or truncal obesity are not able to apply.Fundus examination by an ophthalmologist can be of significant help in pointing out the diagnosis of this rare genetic syndrome especially as there is no cure for this condition and detailed multidisciplinary approach is recommended in order to prevent further complications.

INTRODUCTION
The Alström syndrome (AS) is an extremely rare autosomal recessive genetic disorder [1] affecting less than 1: 1,000,000 people globally [2].It is a single gene disorder, due to the mutation of ALMS1 on chromosome 2 (2p13).The AS affects multiple organs and systems.
The characteristic features of this syndrome are cone-rod retinal dystrophy causing juvenile blindness, hearing loss, truncal obesity, hyperinsulinemia and insulin resistance, type 2 diabetes mellitus (T2DM), hypertriglyceridemia, dilated cardiomyopathy, and progressive renal, pulmonary, hepatic and neurological dysfunction with mild seizure activity.These combinations of pathologies lead to the patients requiring multiple subspecialists appointments in order to prevent further complications [3,4].
Approximately 800 affected individuals have been identified worldwide so far [5].
However, some cases of AS may go unrecognized or misdiagnosed as many of the clinical features develop over time, as the child grows.Also, there are wide clinical variations among the affected individuals [6].That makes it difficult to determine the true frequency in the general population.The AS diagnosis is usually made on the basis of established clinical features, depending on the age of the patient [7], often without genetic confirmation.However, in most cases the diagnosis is made retrospectively, usually in the first decade of life, after the development of various extraocular features [8].
Since the nystagmus and retinitis pigmentosa are the most consistent findings, usually present first and in early childhood, the main aim of this article is to emphasize the importance of the ophthalmologist in establishing an adequate diagnosis of this rare syndrome.There are only two cases of Alström syndrome reported in Serbia [3].In this study we want to present the third Serbian patient with Alstrӧm syndrome whose diagnosis was genetically confirmed using the whole exome sequencing.

CASE DESCRIPTION
Our case was a 7-year-old male with symptoms of progressive visual impairment, photophobia and nystagmus noted from early childhood.His preliminary diagnosis was cone-rod retinal dystrophy.The patient was born as a second child of a two-child family, from a normal pregnancy and delivery.His family consists of non-related parents, both alive and healthy, and an older sister who is in good health.This patient underwent complete physical examinations including ophthalmological, neurological, otorhynolaryngological and pediatric evaluations.Biochemical investigations as well as molecular genetic analysis were carried out.On admission, the bilateral visual acuity was poor, RE 0,06, LE 0,01, the intraocular pressure within range.In the neurological examination, both pupils were round in shape and midsize (3.5 mm), with a normal response to light.No abnormalities in the eye movements were detected except the horizontal nystagmus.The fundoscopy showed central retinal pigmentation, thus suggesting cone-rod retinal dystrophy with bull's eye maculopathy (Figure 1, 2).On physical examination, there was evidence of central obesity (Figure 3, 4) with his height being 119cm, weight 36,9 kg and his body mass index (BMI) 26,1 kg/m2 (percentile > 98 th ).His waist circumference was 78cm.His cardiac function was normal as well as his sensorineural hearing.His blood pressure (BP) was 132/86mmHg (percentile 95 th ) with a regular pulse of 80 beats per minute.
Overall, the clinical manifestations were absent.The abdominal ultrasound showed evidence of steatosis, with normal liver and spleen measurements.Echocardiography did not indicate any pathology at the time.The blood urea nitrogen, creatinine and uric acid were normal.The renal echocardiography did not indicate any abnormalities.His current treatment was low-fat diet and moderate exercise.
As a result of therapy, after six months, the triglyceride level decreased to 1, 1 mmol/l, while HDL-c decreased to 0, 93 mmol/l.Despite the diet correction, the child was not physically active.Adding physical activity helped him to raise HDL cholesterol to 1, 36 mmol/l at the next checkup.
Our patient underwent molecular genetic analysis (Genetic diagnostic laboratory, Strasbourg University Hospitals, France).The coding sequences of exons 16 and 19 of ALMS1 were PCR-amplified, purified, and products were sequenced according to standard methods.Genetic samples were analyzed in order to characterize retinitis pigmentosa on the molecular plane.As a result, two composite heterozygous mutations were discovered in the gene ALMS1: two nucleotide variations in exons 16 and 19 of the gene ALMS1: c.

DISCUSSION
The aim of this article is to highlight the AS as one of the rarest genetic disorders in the world.The Alström syndrome represents a ciliopathy that involves multiple organs and shares mutual clinical characteristics of blindness due to retinal dystrophy, early onset of obesity, diabetes and neurosensorial deafness [9,10].Although the specific role of the ALMS1 protein has not yet been thoroughly investigated, it plays an important role in the cilia function and intraflagellar transport, allowing AS to be classified as a ciliopathy [11].
Therefore, it is pertinent to distinguish the AS from other similar diseases accompanied by childhood obesity and retinal dystrophy, such as the Bardet-Biedl and Laurence-Moon syndromes.Cognitive impairment and distal digit abnormalities separate it from a more common ciliopathy, the Bardet-Biedl, while deafness and the absence of spastic paraparesis differentiate the AS from Laurence-Moon [12].The exact etiology of the disease is unknown, but it is believed to be due to progressive multiorgan fibrosis that leads to organ failure, which is the major cause of morbidity and mortality in AS [6].
As some clinical features of the AS do not become apparent until adolescence, an early diagnosis can be difficult in young children.The Alström syndrome exhibits a great extent of clinical variability, thus creating difficulties for general definition [13].Marshall et al. set the major and minor criteria according to ages, which help the physician set a diagnosis.On the other hand, a diagnosis of the AS could be confirmed at any age with genetic analysis when two ALMS1 mutations have been identified or one mutated ALMS1 allele found in the context of characteristic clinical signs [10,14].Therefore, genetic testing should be carried out in patients who do not have all of the classic AS characteristics [14] and when the combination of the recommended criteria does not allow a clinical diagnosis [7].There is no treatment that can cure AS, prevent and/or reverse the clinical features.The patients require a thorough initial assessment along with an intensive multidisciplinary approach and follow-ups in order to detect and treat potential complications [7].Only an early diagnosis of the AS allows us a timely and preplanned management in order to avoid undesired complications and thus improve longevity as well as the quality of life of the patients [15].The most common cause of death is hepatic dysfunction and congestive heart failure, while life expectancy rarely exceeds 40 years [7].
Our patient was on a controlled diet and moderate physical exercise that led to the reduction of the body mass index and better lipoprotein values [16].
We suspected the Alström syndrome in our patient according to the criteria from the second group [7].Genetic results confirm the reputed diagnosis of the AS, linked to the locus ALMS1 previously rendered.The Alström syndrome is autosomal recessive, so the parents of the affected child represent heterozygous carriers who do not show any signs of the disease.We assume that one of these mutations comes from the mother, while the other one probably from the father, but this has not been confirmed since the father's sample was unavailable.Mutation of the ALMS1 gene causes cone-rod retinal dystrophy, which is part of the AS spectrum.The fundus examination gains ever-increasing importance because retinal dystrophy represents the earliest and most constant feature of the AS [17].Still, retinal dystrophy is not isolated and is accompanied with multiple organ disorders mentioned above [6,7].Therefore, detailed multidisciplinary approach is recommended [18] including biological exams such as liver and kidney biological functions, search for diabetes, insulin resistance, dyslipidemia, cardiological monitoring, search for deafness and overweight care.Prenatal and predictive diagnosis should be conducted if both mutated alleles are found in the parents [14].

CONCLUSION
In conclusion, the Alström syndrome should be kept in mind while examining an obese child with photophobia, nystagmus and visual impairment present from early childhood.Genetic analysis is quite difficult and expensive so all patients with diabetes or truncal obesity are not able to apply.Fundus examination by an ophthalmologist can be of significant help in pointing out the diagnosis of this rare genetic syndrome especially as there is no cure for this condition and detailed multidisciplinary approach is recommended in order to prevent further complications.