Hemihyperplasia syndromes
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《美国医学杂志》
Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India,
Abstract
Obective. Hemihyperplasia is a heterogenous group of disorders characterized by asymmetric limb growth. There is considerable confusion regarding their classification and ascertainment into various syndromes. We tried to look into the various aspects of hemihyperplasia syndromes. Methods. Records of 17 consecutive cases of hemihyperplasia were reviewed and were ascertained into various syndromes based on available literature and diagnostic criteria. Results. Of the 17 cases with hemihyperplasia, 3 cases satisfied the diagnostic criteria for Proteus syndrome. One patient each was ascertained as Klippel Trenaunay Weber syndrome and Hemihyperplasia- Multiple lipomatosis. 9 cases were classified as isolated hemihyperplasia. We found two novel associations with hemihyperplasia; namely Ehlers-Danlos syndrome like skin changes and Poland anomaly on the affected side. The remaining 3 cases had miscellaneous disorders with limb asymmetry, namely Neurofibromatosis Type I in 2 cases and Olliers disease in one case. Conclusion. Efforts to diagnose syndromes of hemihyperplasia help in genetic counseling.
Keywords: Hemihyperplasia; Overgrowth; Proteus; Syndrome
Humans have been fascinated by overgrowth since ages. There are ample examples of giant humans in mythology. Although the problems of overgrowth syndromes were appreciated in the nineteenth century, the study of overgrowth syndromes as a clinical field began only in 1980s. A rapid increase in knowledge has occurred in recent past, and with the advent of recent molecular advances, significant breakthroughs can be anticipated in future. But in spite of continued research, molecular mechanisms are known for only a few of the syndromes, namely Beckwith-Weidemann syndrome, Banayan Riley Ruvalcaba syndrome, Simpson Golabi Behmel syndrome and Sotos syndrome.[1] Thus, until molecular mechanisms of other overgrowth syndromes are elucidated, clinical delineation remains essential.
In addition to the generalized overgrowth syndromes, hemihyperplasia, i.e. overgrowth of one or more limbs or body parts is another interesting entity. A number of syndromes associated with hemihyperplasia are described in the literature. In absence of confirmatory laboratory test, the diagnosis of these disorders mainly relies on clinical diagnostic criteria. This makes classification of many cases under specific headings difficult.
Materials and Methods
The records of patients with hemihyperplasia seen over a period of 7 years were reviewed. These patients had attended the clinical genetics out -patient department of our institute. The diagnosis was made by a clinical geneticist. All patients with asymmetric overgrowth were included. Information was obtained from patients regarding age, gender, family history, age of onset, progression, treatment received and surgeries done. A full clinical examination was done to look for extent of overgrowth, associated features, presence of tumours and appropriate anthropometric measurements were done. Clinical photographs were taken with prior consent. Radiological investigations including X-rays of involved extremities, CT-scan, abdominal ultrasound for tumours, color doppler and digital subtraction angiography for vascular malformations were done as and when indicated. Karyotype from blood was done in 4 cases and from skin fibroblasts in one case. The diagnostic labels were given according to the associated clinical features. For Proteus syndrome the diagnostic criteria given by Biesecker et al were used.[2]
Results
A total of 17 patients were ascertained based on the clinical features and investigations. Of these, 10 were males and 7 were females. The age group of patients at presentation ranged from 6 months to 15 years. The clinical features of each of these cases are presented in table1. Of the 17 cases, 2 patients were born out of consanguineous union (case 6 and 10). Almost all patients had overgrowth since birth except for case 11 and 17. Overgrowth was noted at one and 8 years of age in these cases respectively.
Abdominal ultrasound for visceromegaly and renal masses was done in all cases and did not detect any abnormality. None of the patients had any tumor at time of presentation. Karyotype from peripheral blood was done in 4 cases and all were normal and that from skin biopsy from affected area was also normal. Digital subtraction angiography and color doppler investigations were done in cases with prominent superficial veins or hemangiomas. Digital subtraction angiography was done in 3 cases and revealed vascular malformations in 2 patients whereas color Doppler imaging was done in 3 cases and revealed vascular anomalies in two patients table1.
Discussion
Syndromes associated with hemihyperplasia are heterogenous group of disorders characterized by overgrowth of different parts of body. The etiology of most of these disorders remains unknown, although mosaicism for a single gene or chromosomal mutation is a likely cause.
Among the 17 cases in our series, based on clinical features and investigations, we divided the cases in 3 groups. Case 1-3 were grouped as Proteus syndrome according to the diagnostic criteria. Case 4-14 were grouped as Hemihyperplasia group, of which case 6-14 were isolated hemihyperplasia. Case 4 was ascertained as Hemihyperplasia-Multiple lipomatosis syndrome and case 5 as Klippel Trenaunay Weber syndrome More Details. The remaining cases 15-17 as other syndromes associated with discrepancy of growth of limbs.
The clinical features of cases labeled as Proteus are listed against the diagnostic criteria for Proteus syndrome in table2. Among our patients, 3 cases (case 1, 2, and 3) satisfied all general criteria. None of the cases satisfied feature of category A, i.e. connective tissue nevus. Connective tissue nevi are the hallmark of Proteus syndrome.[1],[3] They may be found on feet, hands or abdomen. They are also known as cerebriform connective tissue nevi (CCTN) due to their characteristic appearance. A number of cases have been misreported as Proteus syndrome due to erroneous interpretation of, overgrowth of soft tissue of soles, as connective tissue nevus. Overgrowth of palms and soles has to be differentiated from CCTN. Cohen et al have provided information regarding the utility of the diagnostic criteria to avoid over diagnosis.[3] Case 1 had three features of category B and two of Category C, which included pigmented lesions, disproportionate overgrowth, hyperostosis and dysregulated adipose tissue Figure1a, b, c and d. Case 2 and 3 had two features of category B and one of Category C, including epidermal nevus, disproportionate overgrowth and vascular malformations.
Other cases with hemihyperplasia did not satisfy the criteria for Proteus syndrome and hence were grouped as Hemihyperplasia group. Of these, case 4 and 5 had associated features of multiple lipomas and vascular malformations respectively. Hence case 4 was ascertained as Hemihyperplasia-multiple lipomatosis syndrome and case 5 as Klippel Trenaunay Weber syndrome. Hemihyperplasia-multiple lipomatosis (HHML) has been described by Biesecker et al.[4] This designation may prove useful to classify those patients with moderate asymmetry and overgrowth with subcutaneous lipomata, who do not fully satisfy the criteria for Proteus syndrome. Case 5 was ascertained as Klippel Trenaunay Weber syndrome based on the features of limb enlargement and vascular malformations. Klippel Trenaunay Weber syndrome is characterized by classic triad of cutaneous hemangiomata, hemihyperplasia and varicosities. The rest of the cases (case 6 to 14) could not be grouped into any specific entity and hence were ascertained as isolated hemihyperplasia.
Hemihyperplasia is a heterogenous group of disorders which have hemihyperplasia as a predominant finding, but there may be a number of associated features. Here comes the problem of lumping and splitting. If each of these associations is designated as a syndrome then there will be a large number of syndromes. In contrast, it is very difficult to "lump" the features together as there are a large number of associated findings reported with hemihyperplasia, involving almost each part and system of the body. Among our cases, table3 shows the features associated with hemihyperplasia cases. These include epidermal nevus, pigmentation, skin laxity, macrodactyly, syndactyly, and vascular malformations like capillary and venous malformations. Figure2a, b shows various features associated with hemihyperplasia in our cases.
One of our cases (case 12) had associated skin changes similar to Ehlers Danlos syndrome on the side of hemihyperplasia Figure3a, b. Such a combination of hemihyperplasia and hyper elastic fragile skin changes has never been reported in the past and suggests somatic mosaicism. Chromosomal analysis from skin fibroblasts of the affected and unaffected regions was normal and this makes mosaicism for chromosomal anomaly unlikely. Mosaicism for a gene mutation or a microdeletion is the likely explanation. Another case (case 13) had a left sided Poland anomaly (absence of pectoralis major) in association with hemihyperplasia on same side Figure3c. This association too has not been reported in literature.
There are some other syndromes associated with discrepancy of limb growth. These include Beckwith Weidmann syndrome, neurofibromatosis, McCune Albright syndrome, epidermal nevus syndrome, triploidy, Langer Giedeon syndrome, multiple exostosis, Maffucci syndrome and osteochondromatosis (Ollier's syndrome). Our series had 2 cases of neurofibromatosis type 1 (case 15, 16) and one case of Ollier syndrome (case 17). The plexiform neurofibroma gives rise to limb asymmetry and can be diagnosed clinically. But in case of doubt, associated features like cafι au lait spots, Lisch nodules, axillary freckling and histology of suspected neurofibroma can help in diagnosis. Beckwith Weidemann syndrome needs to be suspected in presence of omphalocele, large tongue, ear creases etc. Molecular diagnosis is possible now. Other syndromes with limb discrepancy involve bones e.g. Multiple exostosis, Maffucci syndrome and Osteochondromatosis (Ollier's syndrome) and radiologic investigations are diagnostic. Our patient with Ollier disease showed multiple enchondromas in long bones on X-rays.
The main diagnostic problems are for Proteus syndrome, Klippel Trenaunay Weber syndrome and isolated hemihyperplasia. Proteus syndrome has always been overdiagnosed.[3] Strict use of diagnostic criteria needs to be followed and in our series three cases justified the diagnosis of Proteus syndrome. Although five out of nine cases in hemihyperplasia group had some features like macrodactyly, pigmented lesions and vascular malformations, none of them fulfilled all the diagnostic criteria for Proteus syndrome.
Association of tumours is an important feature of overgrowth syndromes, but the type of tumour varies based on the disorder. The risk of tumour in neurofibromatosis, Ollier's disease etc. is not of great magnitude, but needs clinical follow up for appropriate symptoms and investigations at low threshold. In Beckwith Weidemann syndrome 7.5% cases develop tumours.[1] The risk of tumours in isolated hemihyper-plasia is 5.9%.[5] The commonly seen tumours are Wilm's tumour, adrenal cell carcinoma and hepatoblastoma. Tumour surveillance protocol suggested is abdominal ultrasound examination every three months till six years and every six months thereafter till puberty.[5] The tumours commonly associated with Proteus syndrome are testicular tumours, ovarian cystadenoma, meningioma and monomorphic adenoma of parotid gland.[1]
The handicap due to limb asymmetry varies from case to case and many cases can be managed by special shoes. Cases of isolated hemihyperplasia rarely have very rapid increase in limb size and most of the patients can be assured that if there is no rapid increase in the size of limbs in early childhood, it is less likely to increase in later part of life. As opposed to this, cases with Proteus syndrome have progressive, distorting and relentless overgrowth. This may hamper function and mobility. Although attempts are made sometimes to amputate the overgrown parts, such attempts may lead to further disfigurement and distortion rather than improve the function. This is very much evident in case 1 of our series Figure1. Vascular anomalies seen in cases of hemihyperplasia may be localized or extensive. Treatment for localized lesions with embolization can be done but the vascular malformation in case 3 and 5 of our series were too extensive to attempt embolization.
Identification of genetic defect may make the classification of these cases an easy task. Some cases of isolated hemihyperplasia may be allelic to Proteus syndrome. Recently Smith et al concluded that mutation in tumor suppressor gene PTEN was present in a case of Proteus syndrome.[6] But the validity of the diagnosis of Proteus syndrome was questioned by Cohen et al[7] Barker et al and Thiffault et al reported that there is no major role of PTEN mutation in Proteus syndrome.[8], [9] Thus the molecular mechanism of Proteus syndrome still remains elusive.
In our series, two cases were born out of consanguinous union. Though most of the cases of hemihyperplasia are sporadic and no recurrence in sibling is reported, the consanguinity suggests one to think of rare possibility of autosomal recessive gene.
Overgrowth syndromes are a heterogenous group of syndromes and as more and more cases are ascertained, the amount of knowledge will grow regarding the proper classification of these syndromes. Efforts to classify cases of hemihyperplasia will help in genetic counseling for these families. Fortunately isolated hemihyperplasia, Proteus syndrome, Beckwith Weidman syndrome are sporadic and there is no risk of recurrence in the siblings of the affected case.
References
1. Cohen MM Jr, Neri G, Weksberg R. Overgrowth Syndromes 1st ed. New York: Oxford University Press, 2002. p. 33.
2. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL et al. Proteus Syndrome: Diagnostic Criteria, Differential Diagnosis, and Patient Evaluation. Clin Genet 1999; 84: 389-395.
3. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of Proteus syndrome literature: Application of diagnostic criteria to published cases. Am J Med Genet 2004; 130A: 111-122.
4. Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S, Schimke N. Clinical differentiation between Proteus syndrome and hemihyperplasia: Description of a distinct form of hemihyperplasia. Am J Med Genet 1998; 79: 311-318.
5. Hoyme HE, Seaver LH, Jones KL, Procopio F, Crooks W, Feingold M. Isolated Hemihyperplasia (Hemihypertrophy): Report of a Prospective Multicenter study of the incidence of neoplasia and review. Am J Med Genet 1998; 79: 274-278.
6. Smith JM, Kirk EPE, Theodosopoulos G, Marshall GM, Walker J, Rogers M et al. Germline mutation of tumour suppressor PTEN in Proteus syndrome. J Med Genet 2002; 39: 937-940.
7. Cohen MM Jr, Turner JT, Biesecker LG. Correspondence. Am J Med Genet 2004; 130A: 216-217.
8. Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J et al. PTEN mutations are uncommon in Proteus syndrome. J Med Genet 2001; 38: 480-481.
9. Thiffault I, Schwartz CE, Kaloustian VD, Foulkes WD. Mutation analysis of the tumour suppressor PTEN and Glypican 3 gene in patients diagnosed with Proteus syndrome. Am J Med Genet 2004; 130A: 123-127.(Dalal Ashwin B, Phadke Sh)
Abstract
Obective. Hemihyperplasia is a heterogenous group of disorders characterized by asymmetric limb growth. There is considerable confusion regarding their classification and ascertainment into various syndromes. We tried to look into the various aspects of hemihyperplasia syndromes. Methods. Records of 17 consecutive cases of hemihyperplasia were reviewed and were ascertained into various syndromes based on available literature and diagnostic criteria. Results. Of the 17 cases with hemihyperplasia, 3 cases satisfied the diagnostic criteria for Proteus syndrome. One patient each was ascertained as Klippel Trenaunay Weber syndrome and Hemihyperplasia- Multiple lipomatosis. 9 cases were classified as isolated hemihyperplasia. We found two novel associations with hemihyperplasia; namely Ehlers-Danlos syndrome like skin changes and Poland anomaly on the affected side. The remaining 3 cases had miscellaneous disorders with limb asymmetry, namely Neurofibromatosis Type I in 2 cases and Olliers disease in one case. Conclusion. Efforts to diagnose syndromes of hemihyperplasia help in genetic counseling.
Keywords: Hemihyperplasia; Overgrowth; Proteus; Syndrome
Humans have been fascinated by overgrowth since ages. There are ample examples of giant humans in mythology. Although the problems of overgrowth syndromes were appreciated in the nineteenth century, the study of overgrowth syndromes as a clinical field began only in 1980s. A rapid increase in knowledge has occurred in recent past, and with the advent of recent molecular advances, significant breakthroughs can be anticipated in future. But in spite of continued research, molecular mechanisms are known for only a few of the syndromes, namely Beckwith-Weidemann syndrome, Banayan Riley Ruvalcaba syndrome, Simpson Golabi Behmel syndrome and Sotos syndrome.[1] Thus, until molecular mechanisms of other overgrowth syndromes are elucidated, clinical delineation remains essential.
In addition to the generalized overgrowth syndromes, hemihyperplasia, i.e. overgrowth of one or more limbs or body parts is another interesting entity. A number of syndromes associated with hemihyperplasia are described in the literature. In absence of confirmatory laboratory test, the diagnosis of these disorders mainly relies on clinical diagnostic criteria. This makes classification of many cases under specific headings difficult.
Materials and Methods
The records of patients with hemihyperplasia seen over a period of 7 years were reviewed. These patients had attended the clinical genetics out -patient department of our institute. The diagnosis was made by a clinical geneticist. All patients with asymmetric overgrowth were included. Information was obtained from patients regarding age, gender, family history, age of onset, progression, treatment received and surgeries done. A full clinical examination was done to look for extent of overgrowth, associated features, presence of tumours and appropriate anthropometric measurements were done. Clinical photographs were taken with prior consent. Radiological investigations including X-rays of involved extremities, CT-scan, abdominal ultrasound for tumours, color doppler and digital subtraction angiography for vascular malformations were done as and when indicated. Karyotype from blood was done in 4 cases and from skin fibroblasts in one case. The diagnostic labels were given according to the associated clinical features. For Proteus syndrome the diagnostic criteria given by Biesecker et al were used.[2]
Results
A total of 17 patients were ascertained based on the clinical features and investigations. Of these, 10 were males and 7 were females. The age group of patients at presentation ranged from 6 months to 15 years. The clinical features of each of these cases are presented in table1. Of the 17 cases, 2 patients were born out of consanguineous union (case 6 and 10). Almost all patients had overgrowth since birth except for case 11 and 17. Overgrowth was noted at one and 8 years of age in these cases respectively.
Abdominal ultrasound for visceromegaly and renal masses was done in all cases and did not detect any abnormality. None of the patients had any tumor at time of presentation. Karyotype from peripheral blood was done in 4 cases and all were normal and that from skin biopsy from affected area was also normal. Digital subtraction angiography and color doppler investigations were done in cases with prominent superficial veins or hemangiomas. Digital subtraction angiography was done in 3 cases and revealed vascular malformations in 2 patients whereas color Doppler imaging was done in 3 cases and revealed vascular anomalies in two patients table1.
Discussion
Syndromes associated with hemihyperplasia are heterogenous group of disorders characterized by overgrowth of different parts of body. The etiology of most of these disorders remains unknown, although mosaicism for a single gene or chromosomal mutation is a likely cause.
Among the 17 cases in our series, based on clinical features and investigations, we divided the cases in 3 groups. Case 1-3 were grouped as Proteus syndrome according to the diagnostic criteria. Case 4-14 were grouped as Hemihyperplasia group, of which case 6-14 were isolated hemihyperplasia. Case 4 was ascertained as Hemihyperplasia-Multiple lipomatosis syndrome and case 5 as Klippel Trenaunay Weber syndrome More Details. The remaining cases 15-17 as other syndromes associated with discrepancy of growth of limbs.
The clinical features of cases labeled as Proteus are listed against the diagnostic criteria for Proteus syndrome in table2. Among our patients, 3 cases (case 1, 2, and 3) satisfied all general criteria. None of the cases satisfied feature of category A, i.e. connective tissue nevus. Connective tissue nevi are the hallmark of Proteus syndrome.[1],[3] They may be found on feet, hands or abdomen. They are also known as cerebriform connective tissue nevi (CCTN) due to their characteristic appearance. A number of cases have been misreported as Proteus syndrome due to erroneous interpretation of, overgrowth of soft tissue of soles, as connective tissue nevus. Overgrowth of palms and soles has to be differentiated from CCTN. Cohen et al have provided information regarding the utility of the diagnostic criteria to avoid over diagnosis.[3] Case 1 had three features of category B and two of Category C, which included pigmented lesions, disproportionate overgrowth, hyperostosis and dysregulated adipose tissue Figure1a, b, c and d. Case 2 and 3 had two features of category B and one of Category C, including epidermal nevus, disproportionate overgrowth and vascular malformations.
Other cases with hemihyperplasia did not satisfy the criteria for Proteus syndrome and hence were grouped as Hemihyperplasia group. Of these, case 4 and 5 had associated features of multiple lipomas and vascular malformations respectively. Hence case 4 was ascertained as Hemihyperplasia-multiple lipomatosis syndrome and case 5 as Klippel Trenaunay Weber syndrome. Hemihyperplasia-multiple lipomatosis (HHML) has been described by Biesecker et al.[4] This designation may prove useful to classify those patients with moderate asymmetry and overgrowth with subcutaneous lipomata, who do not fully satisfy the criteria for Proteus syndrome. Case 5 was ascertained as Klippel Trenaunay Weber syndrome based on the features of limb enlargement and vascular malformations. Klippel Trenaunay Weber syndrome is characterized by classic triad of cutaneous hemangiomata, hemihyperplasia and varicosities. The rest of the cases (case 6 to 14) could not be grouped into any specific entity and hence were ascertained as isolated hemihyperplasia.
Hemihyperplasia is a heterogenous group of disorders which have hemihyperplasia as a predominant finding, but there may be a number of associated features. Here comes the problem of lumping and splitting. If each of these associations is designated as a syndrome then there will be a large number of syndromes. In contrast, it is very difficult to "lump" the features together as there are a large number of associated findings reported with hemihyperplasia, involving almost each part and system of the body. Among our cases, table3 shows the features associated with hemihyperplasia cases. These include epidermal nevus, pigmentation, skin laxity, macrodactyly, syndactyly, and vascular malformations like capillary and venous malformations. Figure2a, b shows various features associated with hemihyperplasia in our cases.
One of our cases (case 12) had associated skin changes similar to Ehlers Danlos syndrome on the side of hemihyperplasia Figure3a, b. Such a combination of hemihyperplasia and hyper elastic fragile skin changes has never been reported in the past and suggests somatic mosaicism. Chromosomal analysis from skin fibroblasts of the affected and unaffected regions was normal and this makes mosaicism for chromosomal anomaly unlikely. Mosaicism for a gene mutation or a microdeletion is the likely explanation. Another case (case 13) had a left sided Poland anomaly (absence of pectoralis major) in association with hemihyperplasia on same side Figure3c. This association too has not been reported in literature.
There are some other syndromes associated with discrepancy of limb growth. These include Beckwith Weidmann syndrome, neurofibromatosis, McCune Albright syndrome, epidermal nevus syndrome, triploidy, Langer Giedeon syndrome, multiple exostosis, Maffucci syndrome and osteochondromatosis (Ollier's syndrome). Our series had 2 cases of neurofibromatosis type 1 (case 15, 16) and one case of Ollier syndrome (case 17). The plexiform neurofibroma gives rise to limb asymmetry and can be diagnosed clinically. But in case of doubt, associated features like cafι au lait spots, Lisch nodules, axillary freckling and histology of suspected neurofibroma can help in diagnosis. Beckwith Weidemann syndrome needs to be suspected in presence of omphalocele, large tongue, ear creases etc. Molecular diagnosis is possible now. Other syndromes with limb discrepancy involve bones e.g. Multiple exostosis, Maffucci syndrome and Osteochondromatosis (Ollier's syndrome) and radiologic investigations are diagnostic. Our patient with Ollier disease showed multiple enchondromas in long bones on X-rays.
The main diagnostic problems are for Proteus syndrome, Klippel Trenaunay Weber syndrome and isolated hemihyperplasia. Proteus syndrome has always been overdiagnosed.[3] Strict use of diagnostic criteria needs to be followed and in our series three cases justified the diagnosis of Proteus syndrome. Although five out of nine cases in hemihyperplasia group had some features like macrodactyly, pigmented lesions and vascular malformations, none of them fulfilled all the diagnostic criteria for Proteus syndrome.
Association of tumours is an important feature of overgrowth syndromes, but the type of tumour varies based on the disorder. The risk of tumour in neurofibromatosis, Ollier's disease etc. is not of great magnitude, but needs clinical follow up for appropriate symptoms and investigations at low threshold. In Beckwith Weidemann syndrome 7.5% cases develop tumours.[1] The risk of tumours in isolated hemihyper-plasia is 5.9%.[5] The commonly seen tumours are Wilm's tumour, adrenal cell carcinoma and hepatoblastoma. Tumour surveillance protocol suggested is abdominal ultrasound examination every three months till six years and every six months thereafter till puberty.[5] The tumours commonly associated with Proteus syndrome are testicular tumours, ovarian cystadenoma, meningioma and monomorphic adenoma of parotid gland.[1]
The handicap due to limb asymmetry varies from case to case and many cases can be managed by special shoes. Cases of isolated hemihyperplasia rarely have very rapid increase in limb size and most of the patients can be assured that if there is no rapid increase in the size of limbs in early childhood, it is less likely to increase in later part of life. As opposed to this, cases with Proteus syndrome have progressive, distorting and relentless overgrowth. This may hamper function and mobility. Although attempts are made sometimes to amputate the overgrown parts, such attempts may lead to further disfigurement and distortion rather than improve the function. This is very much evident in case 1 of our series Figure1. Vascular anomalies seen in cases of hemihyperplasia may be localized or extensive. Treatment for localized lesions with embolization can be done but the vascular malformation in case 3 and 5 of our series were too extensive to attempt embolization.
Identification of genetic defect may make the classification of these cases an easy task. Some cases of isolated hemihyperplasia may be allelic to Proteus syndrome. Recently Smith et al concluded that mutation in tumor suppressor gene PTEN was present in a case of Proteus syndrome.[6] But the validity of the diagnosis of Proteus syndrome was questioned by Cohen et al[7] Barker et al and Thiffault et al reported that there is no major role of PTEN mutation in Proteus syndrome.[8], [9] Thus the molecular mechanism of Proteus syndrome still remains elusive.
In our series, two cases were born out of consanguinous union. Though most of the cases of hemihyperplasia are sporadic and no recurrence in sibling is reported, the consanguinity suggests one to think of rare possibility of autosomal recessive gene.
Overgrowth syndromes are a heterogenous group of syndromes and as more and more cases are ascertained, the amount of knowledge will grow regarding the proper classification of these syndromes. Efforts to classify cases of hemihyperplasia will help in genetic counseling for these families. Fortunately isolated hemihyperplasia, Proteus syndrome, Beckwith Weidman syndrome are sporadic and there is no risk of recurrence in the siblings of the affected case.
References
1. Cohen MM Jr, Neri G, Weksberg R. Overgrowth Syndromes 1st ed. New York: Oxford University Press, 2002. p. 33.
2. Biesecker LG, Happle R, Mulliken JB, Weksberg R, Graham JM Jr, Viljoen DL et al. Proteus Syndrome: Diagnostic Criteria, Differential Diagnosis, and Patient Evaluation. Clin Genet 1999; 84: 389-395.
3. Turner JT, Cohen MM Jr, Biesecker LG. Reassessment of Proteus syndrome literature: Application of diagnostic criteria to published cases. Am J Med Genet 2004; 130A: 111-122.
4. Biesecker LG, Peters KF, Darling TN, Choyke P, Hill S, Schimke N. Clinical differentiation between Proteus syndrome and hemihyperplasia: Description of a distinct form of hemihyperplasia. Am J Med Genet 1998; 79: 311-318.
5. Hoyme HE, Seaver LH, Jones KL, Procopio F, Crooks W, Feingold M. Isolated Hemihyperplasia (Hemihypertrophy): Report of a Prospective Multicenter study of the incidence of neoplasia and review. Am J Med Genet 1998; 79: 274-278.
6. Smith JM, Kirk EPE, Theodosopoulos G, Marshall GM, Walker J, Rogers M et al. Germline mutation of tumour suppressor PTEN in Proteus syndrome. J Med Genet 2002; 39: 937-940.
7. Cohen MM Jr, Turner JT, Biesecker LG. Correspondence. Am J Med Genet 2004; 130A: 216-217.
8. Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J et al. PTEN mutations are uncommon in Proteus syndrome. J Med Genet 2001; 38: 480-481.
9. Thiffault I, Schwartz CE, Kaloustian VD, Foulkes WD. Mutation analysis of the tumour suppressor PTEN and Glypican 3 gene in patients diagnosed with Proteus syndrome. Am J Med Genet 2004; 130A: 123-127.(Dalal Ashwin B, Phadke Sh)