- Email: [email protected]
Dominant SUR1 mutation causing autosomal dominant type 2 diabetes
COMMENTARY
Dominant SUR1 mutation causing autosomal dominant type 2 diabetes See page 301 Type 2 diabetes mellitus is common and increasing rapidly in incidence and prevalence. The disease has a strong genetic component; however, attempts to identify genes that contribute to the risk of the common polygenic form have met with little success. By contrast, major success has been achieved in identifying genes (six so far1) responsible for the rarer monogenetic forms of type 2 diabetes, particularly maturity onset diabetes of the young. Mutations in any of these genes result in primary -cell defects but not defects in insulin action, long considered the hallmark of type 2 diabetes. This finding is not surprising since defective -cell function is now considered an essential element of type 2 diabetes.2 Thus any monogenic defect that causes type 2 diabetes must primarily affect the  cell. By contrast, genetic defects that increase the risk of type 2 diabetes but do not in themselves cause disease may act by either decreasing insulin action or by compromising -cell function. In this issue of The Lancet, Hanna Huopio and colleagues describe another genetic association with autosomal dominant type 2 diabetes which presented between the ages of 39 and 60 years, a similar age range to that seen in the polygenic form. The phenotype in these patients was unique, however, in that the initial clinical signs began in childhood and included hypoglycaemia. The SUR1 mutation responsible was initially identified during a study of autosomal dominant hyperinsulinism of infancy.3 It was only after older members of these families were studied that the connection between the mutation and type 2 diabetes became apparent. The connection between hyperinsulinism of infancy and type 2 diabetes has been proposed in the past. In one family with hyperinsulinism of infancy due to an activating mutation of glucokinase, the eldest affected member of the family developed type 2 diabetes at age 48.4 Patients with hyperinsulinism of infancy caused by recessive SUR1 mutations who undergo partial pancreatectomy almost invariably develop diabetes. Patients who do not undergo pancreatectomy enter clinical remission that is associated with markedly abnormal glucose and insulin response to oral or intravenous glucose stimulation, although it is not yet clear whether they will develop full-blown diabetes later in life.5,6 This progressive loss of -cell function has been explained by the finding of increased levels of apoptosis in  cells of patients with hyperinsulinism of infancy.7 However, patients heterozygous for these same recessive SUR1 mutations do not appear to have impaired glucose tolerance or deterioration of glucose tolerance over time.8,9 The findings reported by Huopio and colleagues suggest a progressive decrease in -cell function in patients with hyperinsulinism of infancy and dominant SUR1. In the postnatal period, increased insulin secretion results in fasting hypoglycaemia. First-phase insulin release becomes defective by puberty. However, sufficient insulin secretion is maintained, presumably stimulated by amplifying mechanisms independent of the KATP channel, and hyperglycaemia is prevented. Eventually this insulin secretion appears to deteriorate, bringing with it the onset of frank diabetes. The mechanism of this slow deterioration of insulin secretion is not clear. Efanova et al10 suggest that chronic membrane-depolarisation results in increased intracellular calcium which in turn activates apoptosis pathways. Alternatively chronic 272
hypersecretion may result in endoplasmic reticulum stress, also initiating apoptosis pathways.11 In either case, these findings may have important implications for long-term use of long-acting sulphonylureas, which act by closing -cell KATP channels, essentially mimicking the physiological defect in these patients. In-vitro studies have suggested that tolbutamide may increase apoptosis,10 whereas long-term clinical studies have failed to demonstrate an increased rate of -cell failure in patients treated with sulphonylureas.12 Huopio and colleagues have identified a novel genetic mechanism causing autosomal dominant type 2 diabetes, and suggest that SUR1 should be considered a seventh gene in maturity onset diabetes of the young. Although the age at diagnosis was clearly more consistent with the common form of type 2 diabetes than with maturity onset diabetes of the young, Huopio and colleagues clearly demonstrate that the -cell defect can be detected years before the onset of clinical disease. Furthermore the age of diagnosis is largely dependent on awareness of the genetic syndrome and testing of asymptomatic relatives. Even in the original family described by Fajans et al,13 the age of diagnosis of the older generations was 40–60 years. Only when younger family members were screened was the disease usually diagnosed before the age of 25. Similarly, in one of the two families described with NEUROD1 mutations (the sixth gene in maturity onset diabetes of the young), the average age of diagnosis was 40 years.14 The term maturity onset diabetes of the young is typically used to indicate autosomal dominant non-insulindependent diabetes diagnosed below the age of 25. However, there is an increasing incidence of polygenic type 2 diabetes in childhood and adolescence, and patients with gene mutations characteristic of maturity onset diabetes of the young often present with clinical diabetes later in life. Therefore perhaps it is appropriate to abandon the term maturity onset diabetes of the young and substitute the term autosomal dominant type 2 diabetes just as the terms maturity onset diabetes and non-insulindependent diabetes have been abandoned for describing polygenic type 2 diabetes. The group of genes causing autosomal dominant type 2 diabetes includes all of those previously associated with maturity onset diabetes of the young. The findings reported by Huopio and colleagues indicate that SUR1 clearly qualifies as the seventh gene associated with autosomal dominant type 2 diabetes, causing a new clinically unique subgroup of type 2 diabetes. Further studies will show if this mechanism of progressive -cell dysfunction plays an important role in the pathogenesis of the more common polygenic form of type 2 diabetes. Benjamin Glaser Endocrinology and Metabolism Service, Internal Medicine Department, Hebrew University Hadassah Medical Center, 91120 Jerusalem, Israel (e-mail: [email protected]) 1
2
3
4
5
Velho G, Robert JJ. Maturity-onset diabetes of the young (MODY): genetic and clinical characteristics. Horm Res 2002; 57 (suppl 1): 29–33. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulindependent diabetes mellitus: problems and prospects. Endocr Rev 1998; 19: 477–90. Huopio H, Reimann F, Ashfield R, et al. Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 2000; 106: 897–906. Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998; 338: 226–30. Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, Landau H. Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: incidence of diabetes mellitus and persistent -cell
THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
6
7
8
9
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13 14
dysfunction at long-term follow-up. J Clin Endocrinol Metab 1995; 80: 386–92. de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, et al. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999; 340: 1169–75. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 2000; 49: 1325–33. Grimberg A, Ferry RJ Jr, Kelly A, et al. Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 2001; 50: 322–28. Huopio H, Vauhkonen I, Komulainen J, Niskanen L, Otonkoski T, Laakso M. Carriers of an inactivating beta-cell ATP-sensitive K(+) channel mutation have normal glucose tolerance and insulin sensitivity and appropriate insulin secretion. Diabet Care 2002; 25: 101–06. Efanova IB, Zaitsev SV, Zhivotovsky B, et al. Glucose and tolbutamide induce apoptosis in pancreatic beta-cells: a process dependent on intracellular Ca2+ concentration. J Biol Chem 1998; 273: 33501–07. Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 2002; 51 (suppl 3): S455–61. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281: 2005–12. Fajans SS, Bell GI, Bowden DW, Halter JB, Polonsky KS. Maturityonset diabetes of the young. Life Sci 1994; 55: 413–22. Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999; 23: 323–28.
In-vitro fertilisation and retinoblastoma See page 309 In today’s Lancet, Annette Moll and colleagues report retinoblastoma in five children born after in-vitro fertilisation (IVF) in the Netherlands. These investigators say that 1·0–1·5% of children in the Netherlands are conceived by IVF. With the assumption that all new retinoblastoma cases between November, 2000, and February, 2002, had been diagnosed, Moll’s group calculate relative risks of 4·9–7·2 for developing this tumour in children born after IVF in the Netherlands. This is an unprecedented and alarming increased risk. A high frequency of cytogenetic abnormalities and errors in cell-cycle regulation are detected in oocytes generated from IVF or intracytoplasmic sperm injection.1,2 Some of these aberrations, especially in regulatory genes, may lead to the development of cancer in some children born after assisted reproductive technologies. An increased risk of developing neuroblastoma3,4 and leukaemia5,6 among offspring of women treated with infertility drugs has been reported. However, the few large and comparative cohort studies in various countries found either a slight7 or no increase8 in the incidence of cancer among children born after IVF. Looking specifically at the occurrence of retinoblastoma among children born after assisted reproductive technologies, the latest findings of Moll and colleagues appear less amenable to reconciliation with the relevant and available literature. From the many published papers about the incidence of malignancies in large cohorts of children born after assisted reproductive technologies, none has reported the incidence or prevalence of retinoblastoma. In fact, ocular manifestations among such children were largely overlooked. In 1994, after what appeared to be an unusual increased incidence of ocular malformations in children born after IVF, our group9 started routine questioning of the parents, specifically about whether the THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
child was conceived normally or not. We soon realised that most mothers did not volunteer information about undergoing IVF. In some instances (including the one case diagnosed with retinoblastoma), this information was obtained only on subsequent follow-up visits. Our observations and the finding of one child with retinoblastoma were published in 2001. A year later another case of retinoblastoma was reported by Moll’s group.10 What could explain these surprising observations? One possibility, although unlikely, is recent increased use of a new (or a combination of multiple) ovulation-inducing drug(s) having a specific influence on the retinoblastoma gene during IVF. The nationwide cohort study in the same country8 in women undergoing IVF during 1980–95 did not find any case of retinoblastoma. It is not clear from the present study by Moll and colleagues whether the IVF technique in the Netherlands has changed substantially during 1996–2000, the period covered by their study. Could the association of ocular manifestations, especially retinoblastoma, with IVF have been missed during earlier years? After the successful delivery of a long-awaited child and the concern of parents for ocular problems in their infants, the fact that the child was conceived after IVF may not be volunteered, especially if the treating ophthalmologist has no reason to inquire. Possibly, our paper9 enhanced awareness for this potential association, which could explain the “sudden” emergence of many retinoblastoma cases in children born after IVF. However, this explanation cannot account for five new cases lacking a family history of retinoblastoma. A thorough survey of the retinas in these family members for possible retinomas is necessary. Two of the five affected children were one of a twin pair; it remains to be seen whether any of the two healthy twins will develop a retinoma or retinoblastoma. Might the five new cases be an example of clustering? This type of clustering, detected by an “interested” observer, has been reported in retinoblastoma11 and may also occur with other “hot” diagnoses. Indeed Klip et al8 said that: “In 4 years [prior to the published study], one of the authors observed at least eight malignancies in children born after hormone stimulation for IVF and 11 malignancies in children born after insemination techniques and/or other use of fertility drugs”. During the nationwide study by Klip et al, however, and a follow-up for an average 6 years, cancers were detected in “only” seven children born after IVF. Moll and colleagues assume that 1·0–1·5 % of children are conceived after IVF in the Netherlands. Is this correct? Other researchers from the Netherlands estimated that in 1992: “almost 2·5% of all live births result from assisted reproductive technologies”.8,12 Is it possible that during the period studied by Moll 3·0 or 3·5% of live births in the Netherlands were conceived after assisted reproductive technologies (ie, not 1·0–1·5%)? If so, the relative risks for retinoblastoma would be much lower than the 4·9–7·2 reported by Moll and colleagues. Whatever the “true” incidence of retinoblastoma is after IVF, there is little doubt that a heightened awareness and a multidisciplinary approach with a closer follow-up of children conceived with assisted reproductive technologies are needed. The question recently voiced by Winston and Hardy—“Are we ignoring potential dangers of in vitro fertilization and related treatments?”—is pertinent and timely.13 An open debate on this issue is necessary to frame it in its proper 273
For personal use. Only reproduce with permission from The Lancet Publishing Group.
Dominant SUR1 mutation causing autosomal dominant type 2 diabetes See page 301 Type 2 diabetes mellitus is common and increasing rapidly in incidence and prevalence. The disease has a strong genetic component; however, attempts to identify genes that contribute to the risk of the common polygenic form have met with little success. By contrast, major success has been achieved in identifying genes (six so far1) responsible for the rarer monogenetic forms of type 2 diabetes, particularly maturity onset diabetes of the young. Mutations in any of these genes result in primary -cell defects but not defects in insulin action, long considered the hallmark of type 2 diabetes. This finding is not surprising since defective -cell function is now considered an essential element of type 2 diabetes.2 Thus any monogenic defect that causes type 2 diabetes must primarily affect the  cell. By contrast, genetic defects that increase the risk of type 2 diabetes but do not in themselves cause disease may act by either decreasing insulin action or by compromising -cell function. In this issue of The Lancet, Hanna Huopio and colleagues describe another genetic association with autosomal dominant type 2 diabetes which presented between the ages of 39 and 60 years, a similar age range to that seen in the polygenic form. The phenotype in these patients was unique, however, in that the initial clinical signs began in childhood and included hypoglycaemia. The SUR1 mutation responsible was initially identified during a study of autosomal dominant hyperinsulinism of infancy.3 It was only after older members of these families were studied that the connection between the mutation and type 2 diabetes became apparent. The connection between hyperinsulinism of infancy and type 2 diabetes has been proposed in the past. In one family with hyperinsulinism of infancy due to an activating mutation of glucokinase, the eldest affected member of the family developed type 2 diabetes at age 48.4 Patients with hyperinsulinism of infancy caused by recessive SUR1 mutations who undergo partial pancreatectomy almost invariably develop diabetes. Patients who do not undergo pancreatectomy enter clinical remission that is associated with markedly abnormal glucose and insulin response to oral or intravenous glucose stimulation, although it is not yet clear whether they will develop full-blown diabetes later in life.5,6 This progressive loss of -cell function has been explained by the finding of increased levels of apoptosis in  cells of patients with hyperinsulinism of infancy.7 However, patients heterozygous for these same recessive SUR1 mutations do not appear to have impaired glucose tolerance or deterioration of glucose tolerance over time.8,9 The findings reported by Huopio and colleagues suggest a progressive decrease in -cell function in patients with hyperinsulinism of infancy and dominant SUR1. In the postnatal period, increased insulin secretion results in fasting hypoglycaemia. First-phase insulin release becomes defective by puberty. However, sufficient insulin secretion is maintained, presumably stimulated by amplifying mechanisms independent of the KATP channel, and hyperglycaemia is prevented. Eventually this insulin secretion appears to deteriorate, bringing with it the onset of frank diabetes. The mechanism of this slow deterioration of insulin secretion is not clear. Efanova et al10 suggest that chronic membrane-depolarisation results in increased intracellular calcium which in turn activates apoptosis pathways. Alternatively chronic 272
hypersecretion may result in endoplasmic reticulum stress, also initiating apoptosis pathways.11 In either case, these findings may have important implications for long-term use of long-acting sulphonylureas, which act by closing -cell KATP channels, essentially mimicking the physiological defect in these patients. In-vitro studies have suggested that tolbutamide may increase apoptosis,10 whereas long-term clinical studies have failed to demonstrate an increased rate of -cell failure in patients treated with sulphonylureas.12 Huopio and colleagues have identified a novel genetic mechanism causing autosomal dominant type 2 diabetes, and suggest that SUR1 should be considered a seventh gene in maturity onset diabetes of the young. Although the age at diagnosis was clearly more consistent with the common form of type 2 diabetes than with maturity onset diabetes of the young, Huopio and colleagues clearly demonstrate that the -cell defect can be detected years before the onset of clinical disease. Furthermore the age of diagnosis is largely dependent on awareness of the genetic syndrome and testing of asymptomatic relatives. Even in the original family described by Fajans et al,13 the age of diagnosis of the older generations was 40–60 years. Only when younger family members were screened was the disease usually diagnosed before the age of 25. Similarly, in one of the two families described with NEUROD1 mutations (the sixth gene in maturity onset diabetes of the young), the average age of diagnosis was 40 years.14 The term maturity onset diabetes of the young is typically used to indicate autosomal dominant non-insulindependent diabetes diagnosed below the age of 25. However, there is an increasing incidence of polygenic type 2 diabetes in childhood and adolescence, and patients with gene mutations characteristic of maturity onset diabetes of the young often present with clinical diabetes later in life. Therefore perhaps it is appropriate to abandon the term maturity onset diabetes of the young and substitute the term autosomal dominant type 2 diabetes just as the terms maturity onset diabetes and non-insulindependent diabetes have been abandoned for describing polygenic type 2 diabetes. The group of genes causing autosomal dominant type 2 diabetes includes all of those previously associated with maturity onset diabetes of the young. The findings reported by Huopio and colleagues indicate that SUR1 clearly qualifies as the seventh gene associated with autosomal dominant type 2 diabetes, causing a new clinically unique subgroup of type 2 diabetes. Further studies will show if this mechanism of progressive -cell dysfunction plays an important role in the pathogenesis of the more common polygenic form of type 2 diabetes. Benjamin Glaser Endocrinology and Metabolism Service, Internal Medicine Department, Hebrew University Hadassah Medical Center, 91120 Jerusalem, Israel (e-mail: [email protected]) 1
2
3
4
5
Velho G, Robert JJ. Maturity-onset diabetes of the young (MODY): genetic and clinical characteristics. Horm Res 2002; 57 (suppl 1): 29–33. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulindependent diabetes mellitus: problems and prospects. Endocr Rev 1998; 19: 477–90. Huopio H, Reimann F, Ashfield R, et al. Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1. J Clin Invest 2000; 106: 897–906. Glaser B, Kesavan P, Heyman M, et al. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998; 338: 226–30. Leibowitz G, Glaser B, Higazi AA, Salameh M, Cerasi E, Landau H. Hyperinsulinemic hypoglycemia of infancy (nesidioblastosis) in clinical remission: incidence of diabetes mellitus and persistent -cell
THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
COMMENTARY
6
7
8
9
10
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dysfunction at long-term follow-up. J Clin Endocrinol Metab 1995; 80: 386–92. de Lonlay-Debeney P, Poggi-Travert F, Fournet JC, et al. Clinical features of 52 neonates with hyperinsulinism. N Engl J Med 1999; 340: 1169–75. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 2000; 49: 1325–33. Grimberg A, Ferry RJ Jr, Kelly A, et al. Dysregulation of insulin secretion in children with congenital hyperinsulinism due to sulfonylurea receptor mutations. Diabetes 2001; 50: 322–28. Huopio H, Vauhkonen I, Komulainen J, Niskanen L, Otonkoski T, Laakso M. Carriers of an inactivating beta-cell ATP-sensitive K(+) channel mutation have normal glucose tolerance and insulin sensitivity and appropriate insulin secretion. Diabet Care 2002; 25: 101–06. Efanova IB, Zaitsev SV, Zhivotovsky B, et al. Glucose and tolbutamide induce apoptosis in pancreatic beta-cells: a process dependent on intracellular Ca2+ concentration. J Biol Chem 1998; 273: 33501–07. Harding HP, Ron D. Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes 2002; 51 (suppl 3): S455–61. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999; 281: 2005–12. Fajans SS, Bell GI, Bowden DW, Halter JB, Polonsky KS. Maturityonset diabetes of the young. Life Sci 1994; 55: 413–22. Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999; 23: 323–28.
In-vitro fertilisation and retinoblastoma See page 309 In today’s Lancet, Annette Moll and colleagues report retinoblastoma in five children born after in-vitro fertilisation (IVF) in the Netherlands. These investigators say that 1·0–1·5% of children in the Netherlands are conceived by IVF. With the assumption that all new retinoblastoma cases between November, 2000, and February, 2002, had been diagnosed, Moll’s group calculate relative risks of 4·9–7·2 for developing this tumour in children born after IVF in the Netherlands. This is an unprecedented and alarming increased risk. A high frequency of cytogenetic abnormalities and errors in cell-cycle regulation are detected in oocytes generated from IVF or intracytoplasmic sperm injection.1,2 Some of these aberrations, especially in regulatory genes, may lead to the development of cancer in some children born after assisted reproductive technologies. An increased risk of developing neuroblastoma3,4 and leukaemia5,6 among offspring of women treated with infertility drugs has been reported. However, the few large and comparative cohort studies in various countries found either a slight7 or no increase8 in the incidence of cancer among children born after IVF. Looking specifically at the occurrence of retinoblastoma among children born after assisted reproductive technologies, the latest findings of Moll and colleagues appear less amenable to reconciliation with the relevant and available literature. From the many published papers about the incidence of malignancies in large cohorts of children born after assisted reproductive technologies, none has reported the incidence or prevalence of retinoblastoma. In fact, ocular manifestations among such children were largely overlooked. In 1994, after what appeared to be an unusual increased incidence of ocular malformations in children born after IVF, our group9 started routine questioning of the parents, specifically about whether the THE LANCET • Vol 361 • January 25, 2003 • www.thelancet.com
child was conceived normally or not. We soon realised that most mothers did not volunteer information about undergoing IVF. In some instances (including the one case diagnosed with retinoblastoma), this information was obtained only on subsequent follow-up visits. Our observations and the finding of one child with retinoblastoma were published in 2001. A year later another case of retinoblastoma was reported by Moll’s group.10 What could explain these surprising observations? One possibility, although unlikely, is recent increased use of a new (or a combination of multiple) ovulation-inducing drug(s) having a specific influence on the retinoblastoma gene during IVF. The nationwide cohort study in the same country8 in women undergoing IVF during 1980–95 did not find any case of retinoblastoma. It is not clear from the present study by Moll and colleagues whether the IVF technique in the Netherlands has changed substantially during 1996–2000, the period covered by their study. Could the association of ocular manifestations, especially retinoblastoma, with IVF have been missed during earlier years? After the successful delivery of a long-awaited child and the concern of parents for ocular problems in their infants, the fact that the child was conceived after IVF may not be volunteered, especially if the treating ophthalmologist has no reason to inquire. Possibly, our paper9 enhanced awareness for this potential association, which could explain the “sudden” emergence of many retinoblastoma cases in children born after IVF. However, this explanation cannot account for five new cases lacking a family history of retinoblastoma. A thorough survey of the retinas in these family members for possible retinomas is necessary. Two of the five affected children were one of a twin pair; it remains to be seen whether any of the two healthy twins will develop a retinoma or retinoblastoma. Might the five new cases be an example of clustering? This type of clustering, detected by an “interested” observer, has been reported in retinoblastoma11 and may also occur with other “hot” diagnoses. Indeed Klip et al8 said that: “In 4 years [prior to the published study], one of the authors observed at least eight malignancies in children born after hormone stimulation for IVF and 11 malignancies in children born after insemination techniques and/or other use of fertility drugs”. During the nationwide study by Klip et al, however, and a follow-up for an average 6 years, cancers were detected in “only” seven children born after IVF. Moll and colleagues assume that 1·0–1·5 % of children are conceived after IVF in the Netherlands. Is this correct? Other researchers from the Netherlands estimated that in 1992: “almost 2·5% of all live births result from assisted reproductive technologies”.8,12 Is it possible that during the period studied by Moll 3·0 or 3·5% of live births in the Netherlands were conceived after assisted reproductive technologies (ie, not 1·0–1·5%)? If so, the relative risks for retinoblastoma would be much lower than the 4·9–7·2 reported by Moll and colleagues. Whatever the “true” incidence of retinoblastoma is after IVF, there is little doubt that a heightened awareness and a multidisciplinary approach with a closer follow-up of children conceived with assisted reproductive technologies are needed. The question recently voiced by Winston and Hardy—“Are we ignoring potential dangers of in vitro fertilization and related treatments?”—is pertinent and timely.13 An open debate on this issue is necessary to frame it in its proper 273
For personal use. Only reproduce with permission from The Lancet Publishing Group.