Langer-giedion syndrome with renal cyst
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《美国医学杂志》
Department of Pediatrics, JJMMC, Davangere, Karnataka, India
Abstract
Here it is reported a 4-year-old boy with Langer-Giedion syndrome (Trichorhino phalangeal syndrome-II), who had characteristic features of TRP II, associated with multiple renal cysts hitherto unreported. This could be a new association in this syndrome that may serve to support the concept of contiguous gene syndrome in patients with TRP II.
Keywords: Langer-Giedion syndrome; Renal cysts
Tricho-rhino-phalangeal syndrome (TRP-II) also called a ' Langer-Giedion syndrome More Details', was first reported by Langer in 1968[1], followed by Giedion in 1969.[2] Later Hall et al reported five additional cases and delineated the syndrome in 1974.[3]
Tricho-rhino-phalangeal syndrome is characterized by its unique facial features and skeletal abnormalities. A bulbous, pear-shaped nose, elongated philtrum, sparse hairs, cone-shaped epiphyses and mild growth retardation are found in both TRP I and TRP II. TRP II can be distinguished from TRP I when multiple exostoses, redundant skin with or without mental retardation present. Recently TRP II has been reported with severe brachydactly and severe short stature.[4] Although most cases are sporadic, familial cases with autosomal dominant inheritance have been reported.[5],[6]
The current interest is in its association with deletion of long arm of chromosome 8.[7],[8] There have been many associations with this syndrome. Urogenital abnormalities are one among them, which are rarely reported.[9],[8] A case of TRP II with associated renal cysts hitherto unreported is reported.
Case report
A 4-year-old presented with dysmorphic features and recurrent respiratory infections. He was born to a non-consanguineously married couple by cesarean section, with birth weight of 2.5 kg and redundant skin was noted at birth. At one year of age he was operated for congenital dislocation of hip on left side. Child attained all the milestones normally.
On physical examination, his height was 99.5 cm (25th centile, NCHS), with weight of 14 kg (10th centile, NCHS) and head circumference-47cm (5th centile, NCHS). He had distinctive features with microcephaly, sparse hair, receding frontal hairline, wide palpebral fissures with long eye lashes bushy eyebrows, large and low set ears, broad nasal root with bulbous nose, large flat philtrum and broad neck Figure1. He had bony protuberance at both elbows and hips Figure2. Simian crease was present in both hands. There was wide space between 1st and 2nd toes on both sides, with broad great toes.
Skin all over was extremely lax and wrinkled Figure3. He had cryptorchidism. His systemic examination revealed no abnormalities and his blood pressure was 100/60 mm of Hg. He was a friendly, cooperative boy with no appreciable behavioral problems.
Radiological examination revealed cone-shaped on X-ray's of hands Figure4 and dislocation at both elbow joints Figure5. Ultrasound of abdomen revealed right kidney with increase in echopattern of the cortex and moderate loss in corticomedullary difference (Grade 2 nephropathy) whereas left kidney was dysplastic with increase in echopattern and loss of renal contour with few cysts of 2-3mm in size (Grade 4 nephropathy) Figure6. Renal parameters like blood urea, serum creatinine and serum electrolytes were all normal. Karyotype from peripheral lymphocytes showed normal pattern i.e 46,XY.
Discussion
Tricho-rhino-phalangeal syndromes are rare syndromes, reported first by Klingmuller in 1956 with distinctive craniofacial and skeletal abnormalities such as microcephaly, sparse hairs, bulbous nose, long flat philtrum and cone shaped epiphysis.[10] TRP II is distinguished from TRP I by multiple exostoses, redundant skin with or without mental retardation. Exostoses and cone shaped epiphysis appear around 4 years of age.[11] Patients with redundant skin may be misdiagnosed in infancy as Ehler-Danlos syndrome. Recently TRP III has been described with severe brachydactly, short stature but without exostoses.[4] Most cases are sporadic but few familial cases with autosomal dominant inheritance have been reported.[5],[6]
Of additional interest in our patient is the presence of renal cysts, an association that has not been reported previously in patients with TRP II. Urogenital anomalies described in TRP II include small phallus or testes, cryptorchidism, ureteral reflux.[9] Fryns et al and Partington et al described hydrometrocolpos and hematometra as complications of this syndrome.[8],[12] Ramos et al found persistent cloaca and the prune belly sequence in a patient with Langer-Giedion syndrome and interstitial 8q deletion.[13] Lu et al reported a case of TRP II associated with non-Finish type of congenital nephritic syndrome. [14]
The etiology of the different types of TRP can result from either single base pair mutations, or the complete deletion of the TRPI gene, which encodes a zinc finger transcription factor located on chromosomal band 8q24.1.[15] TRP II is a true contiguous gene deletion syndrome in which affected individuals have deletions in both TRP and EXTI genes.[4] Patients with TRP I have a deletion only in the TRP gene which is more centromeric on the long are of chromosome.[8] In TRP II, there is a deletion in the EXTI gene which is more telomeric and localized to the 8q24.11-8q24.13 region.[16] When larger pieces of 8q are deleted, mental retardation is more commonly associated with TRP II.[16] Common features among both types are due to deletion of 8q24.12. Exostoses in TRP II are the result of the effects of the mutations of the EXT 1 gene on enchondral bone growth. EXT 1 gene is thought to be a tumor suppressor gene.[17] Multiple cartilaginous exostoses also occur independently of TRP II as an autosomal dominant disease. There are at least two other loci, EXT 2 locus on chromosome 11q11-p12 and the EXT 3 locus on chromosome 19p11- p13 that are known to cause multiple exostoses.[18],[19] In a recent study on Japanese family, it has been observed that TRP III results from missense mutations in exon 6 of TRP I.[20]
Since there are no previous reports of TRP II associated with renal cysts, this could be a new association in this syndrome that may serve to support the concept of contiguous gene syndrome in patients with TRP II.
References
1. Langer LO. The thoracic-pelvic-phalangeal dystrophy. Birth Defects 1968 ; 4: 55-64.
2. Giedion VA. Dieperiphere dysostose (PD)-em sammelhegriff. Fortnschr Rontgenstr 1969; 110: 595-599.
3. Hall BD, Langer LO, Giedion A, Smikth DW, Cohen MM, Beals RK et al. Langer Giedion syndrome. New York; Alan R. Liss Inc for the National Foundation -March of Dimes, BD: OAS X (12) 1974; 147-164
4. Ludecke HJ, Schaper J, Meinecke P, Momeni P, Gross S, Von Holtum D et al. Genotypic and phenotypic spectrum in tricho-rhinopahlangeal syndrome types I and III. Am J Genet 2001; 68: 81-91
5. Ferrandez A, Remirez J, Saenz P, Calvo M. The trichorhinophalangeal syndrome. Report of 4 familial cases belonging to 4 generations. Helv Pediatr Acta 1980; 35: 559-567
6. Langer LO, Krassikoff N, Laxova R, Scheer-Williams M, Lutter LD, Gorlin RJ et al. The tricho-rhinophalangeal syndrome with exostoses (or Langer-Giedion syndrome): Four Additional patients without mental retardation and review of the literature. Am J Med Genet 1984; 19: 81-111.
7. Buhler EM, Buhler UK, Christen R. Terminal on intestinal deletion in chromosomes 8 Long Arm in Langer- Giedion-Syndrome (TRP-II Syndrome ) Hum Genet 1983; 64: 163-166.
8. Fryns JP, Heremans G, Manien J, Van der Berghe. Langer- Giedion Syndrome and Deletion of the Long Arm of Chromosome 8. Confirmation of the critical segment to 8q 23. Hum Genet 1983; 64: 194-195.
9. Wilson WG, Wyanadt HE, Shah H. Interstitial deletion of 8q. Am J Dis Child 1983; 137: 444-448.
10. Klingmuller G. Uber eigentumliche Konstitution-anomelien bei 2 Schwestern und ihre Beziehungen zu neuerenentwicklungspathologischen. Befungen Hautarzt 1956; 7: 105.
11. Jones KL. Smith's recognizable patterns of human malformation. Pennsylvania; WB Saunders Company; 1997: 290-291.
12. Partington MV, Rae J, Payne MJ. Hematometra in the Langer- Geidion syndrome. J Med Genet 1991; 28: 645-646
13. Ramos FJ. MacDonald-McGinn DM, Emanuel BS, Zackai EH. Tricho- Rhinophalangeal syndrome type II (Langer-Giedion) with persistent Cloaca and prune belly sequence in a girl with 8q interstitial deletion. Am J Hum Genet 1992; 44: 790-794
14. Lu FL, Hou JW, Tsai WS, Teng RJ, Yau KI, Wang TR. Tricho-rhinophalangeal syndrome type II associated with epiglottic aplasis and congenital nephrotic syndrome. J Formos Med Assoc 1997; 96: 217-221.
15. Hilton MJ, Sawyer JM, Gutierrez L, Hogart A, Kung TC, Well TC et al. Analysis of a novel and recurrent mutations responsible for the tricho-rhynophalangeal syndrome. J Hum Genet 2002; 47: 103-106.
16. Ludecke HJ, Wagner MJ, Nardmann J, La Pillo B, Parrish JE, Willem PJ et al. Melocular dissection of a contiguous gene syndrome; locations of the genes involved in the Langer-Geidion syndrome. Hum Mol Genet 1995; 4: 31-36.
17. Ahn J, Ludecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ et al. Cloning of the putative tumor suppresser gene for hereditary multiple exostoses (EXT1). Nat Genet 1995; 11: 137-143.
18. Wuyts W, Ramlakhan S Van Hul W, Hecht W, Van de Ouweland AMW, Raskind et al. Refinement of the multiple exotoses locus (EXT2) to a 3-cM interval on chromosome 11. Am J Genet 1995; 57: 382-387.
19. Le Merrer, Legeai- Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H et al. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet 1994; 3: 717-722.
20. Kobayashi H, Hino M, Shimodahira M, Iwakura T, Ishihara T, Ikekubo K et al. Missense mutation of TRPSI in a family of tricho-rhino-phalangeal syndrome type III. Am J Med Genet 2002; 107: 26-29.(Kulkarni ML, Zaheeruddin )
Abstract
Here it is reported a 4-year-old boy with Langer-Giedion syndrome (Trichorhino phalangeal syndrome-II), who had characteristic features of TRP II, associated with multiple renal cysts hitherto unreported. This could be a new association in this syndrome that may serve to support the concept of contiguous gene syndrome in patients with TRP II.
Keywords: Langer-Giedion syndrome; Renal cysts
Tricho-rhino-phalangeal syndrome (TRP-II) also called a ' Langer-Giedion syndrome More Details', was first reported by Langer in 1968[1], followed by Giedion in 1969.[2] Later Hall et al reported five additional cases and delineated the syndrome in 1974.[3]
Tricho-rhino-phalangeal syndrome is characterized by its unique facial features and skeletal abnormalities. A bulbous, pear-shaped nose, elongated philtrum, sparse hairs, cone-shaped epiphyses and mild growth retardation are found in both TRP I and TRP II. TRP II can be distinguished from TRP I when multiple exostoses, redundant skin with or without mental retardation present. Recently TRP II has been reported with severe brachydactly and severe short stature.[4] Although most cases are sporadic, familial cases with autosomal dominant inheritance have been reported.[5],[6]
The current interest is in its association with deletion of long arm of chromosome 8.[7],[8] There have been many associations with this syndrome. Urogenital abnormalities are one among them, which are rarely reported.[9],[8] A case of TRP II with associated renal cysts hitherto unreported is reported.
Case report
A 4-year-old presented with dysmorphic features and recurrent respiratory infections. He was born to a non-consanguineously married couple by cesarean section, with birth weight of 2.5 kg and redundant skin was noted at birth. At one year of age he was operated for congenital dislocation of hip on left side. Child attained all the milestones normally.
On physical examination, his height was 99.5 cm (25th centile, NCHS), with weight of 14 kg (10th centile, NCHS) and head circumference-47cm (5th centile, NCHS). He had distinctive features with microcephaly, sparse hair, receding frontal hairline, wide palpebral fissures with long eye lashes bushy eyebrows, large and low set ears, broad nasal root with bulbous nose, large flat philtrum and broad neck Figure1. He had bony protuberance at both elbows and hips Figure2. Simian crease was present in both hands. There was wide space between 1st and 2nd toes on both sides, with broad great toes.
Skin all over was extremely lax and wrinkled Figure3. He had cryptorchidism. His systemic examination revealed no abnormalities and his blood pressure was 100/60 mm of Hg. He was a friendly, cooperative boy with no appreciable behavioral problems.
Radiological examination revealed cone-shaped on X-ray's of hands Figure4 and dislocation at both elbow joints Figure5. Ultrasound of abdomen revealed right kidney with increase in echopattern of the cortex and moderate loss in corticomedullary difference (Grade 2 nephropathy) whereas left kidney was dysplastic with increase in echopattern and loss of renal contour with few cysts of 2-3mm in size (Grade 4 nephropathy) Figure6. Renal parameters like blood urea, serum creatinine and serum electrolytes were all normal. Karyotype from peripheral lymphocytes showed normal pattern i.e 46,XY.
Discussion
Tricho-rhino-phalangeal syndromes are rare syndromes, reported first by Klingmuller in 1956 with distinctive craniofacial and skeletal abnormalities such as microcephaly, sparse hairs, bulbous nose, long flat philtrum and cone shaped epiphysis.[10] TRP II is distinguished from TRP I by multiple exostoses, redundant skin with or without mental retardation. Exostoses and cone shaped epiphysis appear around 4 years of age.[11] Patients with redundant skin may be misdiagnosed in infancy as Ehler-Danlos syndrome. Recently TRP III has been described with severe brachydactly, short stature but without exostoses.[4] Most cases are sporadic but few familial cases with autosomal dominant inheritance have been reported.[5],[6]
Of additional interest in our patient is the presence of renal cysts, an association that has not been reported previously in patients with TRP II. Urogenital anomalies described in TRP II include small phallus or testes, cryptorchidism, ureteral reflux.[9] Fryns et al and Partington et al described hydrometrocolpos and hematometra as complications of this syndrome.[8],[12] Ramos et al found persistent cloaca and the prune belly sequence in a patient with Langer-Giedion syndrome and interstitial 8q deletion.[13] Lu et al reported a case of TRP II associated with non-Finish type of congenital nephritic syndrome. [14]
The etiology of the different types of TRP can result from either single base pair mutations, or the complete deletion of the TRPI gene, which encodes a zinc finger transcription factor located on chromosomal band 8q24.1.[15] TRP II is a true contiguous gene deletion syndrome in which affected individuals have deletions in both TRP and EXTI genes.[4] Patients with TRP I have a deletion only in the TRP gene which is more centromeric on the long are of chromosome.[8] In TRP II, there is a deletion in the EXTI gene which is more telomeric and localized to the 8q24.11-8q24.13 region.[16] When larger pieces of 8q are deleted, mental retardation is more commonly associated with TRP II.[16] Common features among both types are due to deletion of 8q24.12. Exostoses in TRP II are the result of the effects of the mutations of the EXT 1 gene on enchondral bone growth. EXT 1 gene is thought to be a tumor suppressor gene.[17] Multiple cartilaginous exostoses also occur independently of TRP II as an autosomal dominant disease. There are at least two other loci, EXT 2 locus on chromosome 11q11-p12 and the EXT 3 locus on chromosome 19p11- p13 that are known to cause multiple exostoses.[18],[19] In a recent study on Japanese family, it has been observed that TRP III results from missense mutations in exon 6 of TRP I.[20]
Since there are no previous reports of TRP II associated with renal cysts, this could be a new association in this syndrome that may serve to support the concept of contiguous gene syndrome in patients with TRP II.
References
1. Langer LO. The thoracic-pelvic-phalangeal dystrophy. Birth Defects 1968 ; 4: 55-64.
2. Giedion VA. Dieperiphere dysostose (PD)-em sammelhegriff. Fortnschr Rontgenstr 1969; 110: 595-599.
3. Hall BD, Langer LO, Giedion A, Smikth DW, Cohen MM, Beals RK et al. Langer Giedion syndrome. New York; Alan R. Liss Inc for the National Foundation -March of Dimes, BD: OAS X (12) 1974; 147-164
4. Ludecke HJ, Schaper J, Meinecke P, Momeni P, Gross S, Von Holtum D et al. Genotypic and phenotypic spectrum in tricho-rhinopahlangeal syndrome types I and III. Am J Genet 2001; 68: 81-91
5. Ferrandez A, Remirez J, Saenz P, Calvo M. The trichorhinophalangeal syndrome. Report of 4 familial cases belonging to 4 generations. Helv Pediatr Acta 1980; 35: 559-567
6. Langer LO, Krassikoff N, Laxova R, Scheer-Williams M, Lutter LD, Gorlin RJ et al. The tricho-rhinophalangeal syndrome with exostoses (or Langer-Giedion syndrome): Four Additional patients without mental retardation and review of the literature. Am J Med Genet 1984; 19: 81-111.
7. Buhler EM, Buhler UK, Christen R. Terminal on intestinal deletion in chromosomes 8 Long Arm in Langer- Giedion-Syndrome (TRP-II Syndrome ) Hum Genet 1983; 64: 163-166.
8. Fryns JP, Heremans G, Manien J, Van der Berghe. Langer- Giedion Syndrome and Deletion of the Long Arm of Chromosome 8. Confirmation of the critical segment to 8q 23. Hum Genet 1983; 64: 194-195.
9. Wilson WG, Wyanadt HE, Shah H. Interstitial deletion of 8q. Am J Dis Child 1983; 137: 444-448.
10. Klingmuller G. Uber eigentumliche Konstitution-anomelien bei 2 Schwestern und ihre Beziehungen zu neuerenentwicklungspathologischen. Befungen Hautarzt 1956; 7: 105.
11. Jones KL. Smith's recognizable patterns of human malformation. Pennsylvania; WB Saunders Company; 1997: 290-291.
12. Partington MV, Rae J, Payne MJ. Hematometra in the Langer- Geidion syndrome. J Med Genet 1991; 28: 645-646
13. Ramos FJ. MacDonald-McGinn DM, Emanuel BS, Zackai EH. Tricho- Rhinophalangeal syndrome type II (Langer-Giedion) with persistent Cloaca and prune belly sequence in a girl with 8q interstitial deletion. Am J Hum Genet 1992; 44: 790-794
14. Lu FL, Hou JW, Tsai WS, Teng RJ, Yau KI, Wang TR. Tricho-rhinophalangeal syndrome type II associated with epiglottic aplasis and congenital nephrotic syndrome. J Formos Med Assoc 1997; 96: 217-221.
15. Hilton MJ, Sawyer JM, Gutierrez L, Hogart A, Kung TC, Well TC et al. Analysis of a novel and recurrent mutations responsible for the tricho-rhynophalangeal syndrome. J Hum Genet 2002; 47: 103-106.
16. Ludecke HJ, Wagner MJ, Nardmann J, La Pillo B, Parrish JE, Willem PJ et al. Melocular dissection of a contiguous gene syndrome; locations of the genes involved in the Langer-Geidion syndrome. Hum Mol Genet 1995; 4: 31-36.
17. Ahn J, Ludecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ et al. Cloning of the putative tumor suppresser gene for hereditary multiple exostoses (EXT1). Nat Genet 1995; 11: 137-143.
18. Wuyts W, Ramlakhan S Van Hul W, Hecht W, Van de Ouweland AMW, Raskind et al. Refinement of the multiple exotoses locus (EXT2) to a 3-cM interval on chromosome 11. Am J Genet 1995; 57: 382-387.
19. Le Merrer, Legeai- Mallet L, Jeannin PM, Horsthemke B, Schinzel A, Plauchu H et al. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet 1994; 3: 717-722.
20. Kobayashi H, Hino M, Shimodahira M, Iwakura T, Ishihara T, Ikekubo K et al. Missense mutation of TRPSI in a family of tricho-rhino-phalangeal syndrome type III. Am J Med Genet 2002; 107: 26-29.(Kulkarni ML, Zaheeruddin )