Jarcho-Levin syndrome
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《美国医学杂志》
Department of Pediatrics, JJM Medical College, Davangere, Karnataka, India
Abstract
Jarcho-Levin syndrome is an eponym that represents a spectrum of short trunk skeletal dysplasias with variable involvement of the vertebrae and ribs. Initially considered to be lethal, it is now accepted as compatible with life in its milder presentations. Here are reported two neonates with the lethal variety of this syndrome. One neonate had associated anomalies like hydrocephalus, hydroureteronephrosis and meningomyelocoele while the other had no additional anomalies. Also is reviewed the literature regarding this less understood disorder focusing on the applied clinical aspects that have stemmed out from the recent molecular research.
Keywords: Jarcho-Levin syndrome; Spondylo-thoracic dysplasia; Spondylo-costal dysplasia; Short-trunk dwarfism; Dysostosis.
Jarcho and Levin, in 1938 described a pattern of vertebral and costal anomalies distinctly different from the well-known Klippel-Feil syndrome More Details.[1] Since then, the eponym has been used for cases of this type. The subtype spondylo-thoracic dysplasia (STD) suggests predominant vertebral defects and spondylo-costal dysplasia (SCD) describes the variant with vertebral and intrinsic costal anomalies.[2] Despite being rare, this disorder has been in focus in recent times due to the controversies surrounding it.[3] The purpose of reporting these cases is to bring to clinical understanding this rare disorder and review the emerging current knowledge about it.
Case Reports
Case 1
A female baby was born to an apparently normal consanguineous couple and was severely depressed at birth. The baby failed to respond to the resuscitative measures and died 15 minutes after birth. The first examination showed a short neck and trunk with apparently long appearing limbs, a protruberant abdomen, anal ectopia and mild facial dysmorphism. Figure1. A prenatal ultrasound was not done. The post mortem ultrasound examination of abdomen and cranium was normal.
The infantogram revealed the classical radiologic features of SCD-pebble beach appearance of the vertebrae, posterior fusion of ribs, missing ribs, bifid ribs and abnormal shaped ribs Figure2. The autopsy revealed no major organ abnormalities.
Case 2
This male baby was a product of an uncle-niece marriage and showed a large head, ruptured meningomyelocoele, short neck and thorax, scoliosis, distended abdomen and mildly dysmorphic facies Figure3. The antenatal diagnosis of hydrocephalus with meningomyelocoele had been offered. The postnatal ultrasound revealed bilateral moderate hydroureteronephrosis.
The infantogram showed - scoliosis, multiple hemivertebrae, fused vertebrae, grossly abnormal right ribcage with a few highly malformed ribs Figure4. The child died after 50 hr due to respiratory failure.
Discussion
Jarcho-levin syndrome is a type of short trunk skeletal dysplasia with vertebral and rib anomalies. About 400 cases have been described in the world literature and about 15 in the Indian literature. It has both autosomal dominant and recessive modes of inheritance. The vertebral anomalies seen are - hemivertebrae, absent vertebrae, fused vertebrae, block/ wedge vertebrae, sickle shaped vertebrae due to segmentation and formation defects[2],[4],[5],[6] (pebble-beach appearance). The costal defects noted are 'crab-like' or 'fan-like' appearance of the thorax due to crowded ribs, posterior fusion of the ribs and absent, irregular or bifid ribs.
This disorder has been noted in both consanguineous and non-consanguineous families, especially in Puerto-rico. Most cases reported follow a pattern of autosomal recessive inheritance. In southern India, consanguinity is commonplace. Despite this fact, the disorder is seen uncommonly and reported very rarely from this part of the country.
The two cases reported in the present communication have characteristic clinicoradiologic features of Jarcho-Levin syndrome. These cases represent the severe lethal form of this disorder. In Case 1, the presentation is very classical of SCD with no other major anomalies. Case 2 was associated with neural tube defects, hydrocephalus and hydroureteronephrosis. The anomalies associated with Jarcho-Levin syndrome are minor facial dysmorphism, urogenital and anal anomalies,[7] complex congenital heart disease,[8] limb and digit anomalies etc. Neurologic anomalies are particularly uncommon and include neural tube defects, hydrocephalus[9] etc.
The understanding of Jarcho-Levin syndrome is confounded by its attendant controversies - classification of subtypes, advances in molecular genetics, dilemmas in genetic counseling, prenatal diagnosis and effective management strategies.
Solomon et al[2] classified Jarcho-Levin syndrome into 2 clinical phenotypes based on the extent and distribution of skeletal anomalies, the pattern of inheritance and the prognosis. STD is an autosomal recessive disorder with posterior symmetric fusion of all the ribs at the costovertebral joints bilaterally and segmentation and formation defects of the vertebrae throughout the spine giving a classical 'crab-like' or 'fan-like' appearance to the thorax. The ribs themselves had no defects. In STD, neonatal death or death in infancy may occur due to pneumonias, restrictive lung disease with its attendant pulmonary hypertension. SCD may be inherited in both autosomal dominant and recessive forms. Intrinsic rib anomalies like broadening, bifurcation and asymmetrical fusion are noted. The survival rate in SCD is high after the age of six months (56%).[10] Almost all the patients have normal intelligence and neurological abnormalities are infrequent.[3]
Taking the centerstage now, as regards the academic advances in Jarcho-Levin syndrome is concerned, it is molecular genetics. Patients with SCD are known to have mutations in the delta-like 3 (DLL3) gene on chromosome 19.[11],[12] Patients with STD have no mutations in the DLL3 gene. Bannykh et al[13] analysed protein expression from PAX1 and PAX9 genes in 2 sibs with with this syndrome and compared it with age-matched controls. Immunochemical analysis showed a significant reduction in the levels of protein expression on chondrocytes of the vertebral column. Whittock et al[14] demonstrated a mutation in the MESP 2 gene in 2 sibs affected by a mild variety of SCD.
Prenatal diagnosis by ultrasound can be done as early as 16 weeks of gestation after conception. Ultrasound criteria for diagnosis are unpaired or poorly formed vertebrae, indistinct or fused posterior ribs, irregular short 'pebble-like' appearance of the spine, short trunk, protruberant abdomen, hernias, normal amniotic fluid, normal limb length and normal biparietal diameter.[15]
Counseling the affected family is not a simple task because of the varied presentation and striking intrafamilial variability. The exact clinicoradiologic diagnosis with molecular diagnosis is essential for accurate genetic counseling and prognostication of each individual case.
Management should aim at aggressive neonatal care, prevention and apt treatment of respiratory infections. Surgery of the spine to improve the thoracic volume and hence decrease of the pulmonary restriction has been tried.
References
1. Jarcho S, Levin PM. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp 1938; 62: 216-226.
2. Solomon L, Jimenez RB, Reiner L. Spondylothoracic dysostosis: report of 2 cases and review of the literature. Arch Path Lab Med 1978; 102: 201-205.
3. Cornier AS, Ramirez N, Carlo S, Reiss A. Controversies surrounding Jarcho-Levin syndrome. Curr Opin Pediatr 2003; 15(6): 614-620.
4. Gellis SS, Feingold M. Spondylothoracic dysplasia (costovertebral dysplasia, Jarcho-Levin syndrome). Am J Dis Child 1976; 130: 513-514.
5. Pochaczevsky R, Ratner H, Perles D, Kassner G, Naysan P. Spondylothoracic dysplasia. Radiology 1971; 98(1): 53-58.6. Pamela SK, Deborah D, Susan AB, Mary EMP. Jarcho-Levin syndrome: four new cases and classification of subtypes. Am J Med Genet 1991; 40: 264-270.
6. Murr MM, Waziri MH, Schelper RL, Abu-Youself M. Case of multivertebral anomalies, cloacal dysgenesis, and other anomalies presenting prenatally as cystic kidneys. Am J Med Genet 1992; 42(6): 761-765.
7. Adegboyega PA, Adesokan AA, Sample TG, Nichols MM. Pathological case of the month. Spondylothoracic dysplasia with multiple congenital cardiac anomalies. Arch Pediatr Adolesc Med 1996; 150(2): 221-222.
8. Giacoia GP, Say B. Spondylocostal dysplasia and neural tube defects. J Med Genet 1991; 28: 51-53.
9. Cornier AS, Ramirez N, Arroyo S, Acevedo J, Garcia L, Carlo S et al. Phenotype characterization and natural history of spondylothoracic dysplasia syndrome: a series of 27 new cases. Am J Med Genet 2004; 128A: 120-126.
10. Turnpenny PD, Bulman MP, Frayling TM, Abu-Nasra TK, Garrett C, Hattersley AT et al. A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3. Am J Hum Genet 1999; 65: 175-182.
11. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genet 2000; 24: 438-441.
12. Bannykh SI, Emery SC, Gerber JK, Jones KL, Benirschke K, Masliah E. Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review. Am J Med Genet 2003; 120A: 241-246.
13. Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet 2004; 74: 1249-1254.
14. Marks F, Hernanz-Schulman M, Horii S, Greenland VC, Lustig I, Snyder J et al. Spondylothoracic dysplasia. Clinical and sonographic diagnosis. J Ultrasound Med 1989; 8(1): 1-5.
15. Mortier GR, Lachman RS, Bocian M, Rimoin DL. Multiple vertebral segmentation defects: analysis of 26 new patients and review of the literature. Am J Med Genet 1996; 61: 310-319.(Kulkarni ML, Navaz Sarfar)
Abstract
Jarcho-Levin syndrome is an eponym that represents a spectrum of short trunk skeletal dysplasias with variable involvement of the vertebrae and ribs. Initially considered to be lethal, it is now accepted as compatible with life in its milder presentations. Here are reported two neonates with the lethal variety of this syndrome. One neonate had associated anomalies like hydrocephalus, hydroureteronephrosis and meningomyelocoele while the other had no additional anomalies. Also is reviewed the literature regarding this less understood disorder focusing on the applied clinical aspects that have stemmed out from the recent molecular research.
Keywords: Jarcho-Levin syndrome; Spondylo-thoracic dysplasia; Spondylo-costal dysplasia; Short-trunk dwarfism; Dysostosis.
Jarcho and Levin, in 1938 described a pattern of vertebral and costal anomalies distinctly different from the well-known Klippel-Feil syndrome More Details.[1] Since then, the eponym has been used for cases of this type. The subtype spondylo-thoracic dysplasia (STD) suggests predominant vertebral defects and spondylo-costal dysplasia (SCD) describes the variant with vertebral and intrinsic costal anomalies.[2] Despite being rare, this disorder has been in focus in recent times due to the controversies surrounding it.[3] The purpose of reporting these cases is to bring to clinical understanding this rare disorder and review the emerging current knowledge about it.
Case Reports
Case 1
A female baby was born to an apparently normal consanguineous couple and was severely depressed at birth. The baby failed to respond to the resuscitative measures and died 15 minutes after birth. The first examination showed a short neck and trunk with apparently long appearing limbs, a protruberant abdomen, anal ectopia and mild facial dysmorphism. Figure1. A prenatal ultrasound was not done. The post mortem ultrasound examination of abdomen and cranium was normal.
The infantogram revealed the classical radiologic features of SCD-pebble beach appearance of the vertebrae, posterior fusion of ribs, missing ribs, bifid ribs and abnormal shaped ribs Figure2. The autopsy revealed no major organ abnormalities.
Case 2
This male baby was a product of an uncle-niece marriage and showed a large head, ruptured meningomyelocoele, short neck and thorax, scoliosis, distended abdomen and mildly dysmorphic facies Figure3. The antenatal diagnosis of hydrocephalus with meningomyelocoele had been offered. The postnatal ultrasound revealed bilateral moderate hydroureteronephrosis.
The infantogram showed - scoliosis, multiple hemivertebrae, fused vertebrae, grossly abnormal right ribcage with a few highly malformed ribs Figure4. The child died after 50 hr due to respiratory failure.
Discussion
Jarcho-levin syndrome is a type of short trunk skeletal dysplasia with vertebral and rib anomalies. About 400 cases have been described in the world literature and about 15 in the Indian literature. It has both autosomal dominant and recessive modes of inheritance. The vertebral anomalies seen are - hemivertebrae, absent vertebrae, fused vertebrae, block/ wedge vertebrae, sickle shaped vertebrae due to segmentation and formation defects[2],[4],[5],[6] (pebble-beach appearance). The costal defects noted are 'crab-like' or 'fan-like' appearance of the thorax due to crowded ribs, posterior fusion of the ribs and absent, irregular or bifid ribs.
This disorder has been noted in both consanguineous and non-consanguineous families, especially in Puerto-rico. Most cases reported follow a pattern of autosomal recessive inheritance. In southern India, consanguinity is commonplace. Despite this fact, the disorder is seen uncommonly and reported very rarely from this part of the country.
The two cases reported in the present communication have characteristic clinicoradiologic features of Jarcho-Levin syndrome. These cases represent the severe lethal form of this disorder. In Case 1, the presentation is very classical of SCD with no other major anomalies. Case 2 was associated with neural tube defects, hydrocephalus and hydroureteronephrosis. The anomalies associated with Jarcho-Levin syndrome are minor facial dysmorphism, urogenital and anal anomalies,[7] complex congenital heart disease,[8] limb and digit anomalies etc. Neurologic anomalies are particularly uncommon and include neural tube defects, hydrocephalus[9] etc.
The understanding of Jarcho-Levin syndrome is confounded by its attendant controversies - classification of subtypes, advances in molecular genetics, dilemmas in genetic counseling, prenatal diagnosis and effective management strategies.
Solomon et al[2] classified Jarcho-Levin syndrome into 2 clinical phenotypes based on the extent and distribution of skeletal anomalies, the pattern of inheritance and the prognosis. STD is an autosomal recessive disorder with posterior symmetric fusion of all the ribs at the costovertebral joints bilaterally and segmentation and formation defects of the vertebrae throughout the spine giving a classical 'crab-like' or 'fan-like' appearance to the thorax. The ribs themselves had no defects. In STD, neonatal death or death in infancy may occur due to pneumonias, restrictive lung disease with its attendant pulmonary hypertension. SCD may be inherited in both autosomal dominant and recessive forms. Intrinsic rib anomalies like broadening, bifurcation and asymmetrical fusion are noted. The survival rate in SCD is high after the age of six months (56%).[10] Almost all the patients have normal intelligence and neurological abnormalities are infrequent.[3]
Taking the centerstage now, as regards the academic advances in Jarcho-Levin syndrome is concerned, it is molecular genetics. Patients with SCD are known to have mutations in the delta-like 3 (DLL3) gene on chromosome 19.[11],[12] Patients with STD have no mutations in the DLL3 gene. Bannykh et al[13] analysed protein expression from PAX1 and PAX9 genes in 2 sibs with with this syndrome and compared it with age-matched controls. Immunochemical analysis showed a significant reduction in the levels of protein expression on chondrocytes of the vertebral column. Whittock et al[14] demonstrated a mutation in the MESP 2 gene in 2 sibs affected by a mild variety of SCD.
Prenatal diagnosis by ultrasound can be done as early as 16 weeks of gestation after conception. Ultrasound criteria for diagnosis are unpaired or poorly formed vertebrae, indistinct or fused posterior ribs, irregular short 'pebble-like' appearance of the spine, short trunk, protruberant abdomen, hernias, normal amniotic fluid, normal limb length and normal biparietal diameter.[15]
Counseling the affected family is not a simple task because of the varied presentation and striking intrafamilial variability. The exact clinicoradiologic diagnosis with molecular diagnosis is essential for accurate genetic counseling and prognostication of each individual case.
Management should aim at aggressive neonatal care, prevention and apt treatment of respiratory infections. Surgery of the spine to improve the thoracic volume and hence decrease of the pulmonary restriction has been tried.
References
1. Jarcho S, Levin PM. Hereditary malformation of the vertebral bodies. Bull Johns Hopkins Hosp 1938; 62: 216-226.
2. Solomon L, Jimenez RB, Reiner L. Spondylothoracic dysostosis: report of 2 cases and review of the literature. Arch Path Lab Med 1978; 102: 201-205.
3. Cornier AS, Ramirez N, Carlo S, Reiss A. Controversies surrounding Jarcho-Levin syndrome. Curr Opin Pediatr 2003; 15(6): 614-620.
4. Gellis SS, Feingold M. Spondylothoracic dysplasia (costovertebral dysplasia, Jarcho-Levin syndrome). Am J Dis Child 1976; 130: 513-514.
5. Pochaczevsky R, Ratner H, Perles D, Kassner G, Naysan P. Spondylothoracic dysplasia. Radiology 1971; 98(1): 53-58.6. Pamela SK, Deborah D, Susan AB, Mary EMP. Jarcho-Levin syndrome: four new cases and classification of subtypes. Am J Med Genet 1991; 40: 264-270.
6. Murr MM, Waziri MH, Schelper RL, Abu-Youself M. Case of multivertebral anomalies, cloacal dysgenesis, and other anomalies presenting prenatally as cystic kidneys. Am J Med Genet 1992; 42(6): 761-765.
7. Adegboyega PA, Adesokan AA, Sample TG, Nichols MM. Pathological case of the month. Spondylothoracic dysplasia with multiple congenital cardiac anomalies. Arch Pediatr Adolesc Med 1996; 150(2): 221-222.
8. Giacoia GP, Say B. Spondylocostal dysplasia and neural tube defects. J Med Genet 1991; 28: 51-53.
9. Cornier AS, Ramirez N, Arroyo S, Acevedo J, Garcia L, Carlo S et al. Phenotype characterization and natural history of spondylothoracic dysplasia syndrome: a series of 27 new cases. Am J Med Genet 2004; 128A: 120-126.
10. Turnpenny PD, Bulman MP, Frayling TM, Abu-Nasra TK, Garrett C, Hattersley AT et al. A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3. Am J Hum Genet 1999; 65: 175-182.
11. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES et al. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genet 2000; 24: 438-441.
12. Bannykh SI, Emery SC, Gerber JK, Jones KL, Benirschke K, Masliah E. Aberrant Pax1 and Pax9 expression in Jarcho-Levin syndrome: report of two Caucasian siblings and literature review. Am J Med Genet 2003; 120A: 241-246.
13. Whittock NV, Sparrow DB, Wouters MA, Sillence D, Ellard S, Dunwoodie SL et al. Mutated MESP2 causes spondylocostal dysostosis in humans. Am J Hum Genet 2004; 74: 1249-1254.
14. Marks F, Hernanz-Schulman M, Horii S, Greenland VC, Lustig I, Snyder J et al. Spondylothoracic dysplasia. Clinical and sonographic diagnosis. J Ultrasound Med 1989; 8(1): 1-5.
15. Mortier GR, Lachman RS, Bocian M, Rimoin DL. Multiple vertebral segmentation defects: analysis of 26 new patients and review of the literature. Am J Med Genet 1996; 61: 310-319.(Kulkarni ML, Navaz Sarfar)