Asphyxiating thoracic dystrophy with facial dysmorphism
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《美国医学杂志》
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India
Here it is reported a male newborn baby with features of asphyxiating thoracic dystrophy (ATD) with facial dysmorphism. The disproportionate rhizomelic short stature, narrow thorax, long fibulae, wide metaphysis and trident acetabule are consistent with diagnosis of ATD. In addition the baby had facial dysmorphism and broad thumbs and great toes similar to Oto-palato-digital syndrome type II (OPD II). The association of these features with ATD is not reported till date.
Keywords: Asphyxiating thoracic dysplasia; Otopalatodigital syndrome; Rhizomelia; Narrow thorax; Broad thumbs
Asphyxiating thoracic dystrophy (ATD) is a lethal skeletal dysplasia with multisystemic manifestations. Oto palato digital syndrome (OPD) type II is a rare, severe, lethal, X- linked skeletal dysplasia. The authors describe a case of asphyxiating thoracic dystrophy with facial dysmorphism and thumb anomalies similar to OPD II.
Case report
The index case was a male baby born at 37 weeks of gestation to a healthy, consanguineous, Indian Muslim couple. This couple had previous seven liveborn children and two first trimester abortions. Three female children were alive and did not have any malformations. Four male children died during neonatal period or infancy. There were no medical records of any of the children. First pregnancy ended at full term vaginal delivery and delivered a male baby who died on the third neonatal day. The parents did not notice any external anomalies. Next pregnancy resulted in a male child who died at three months of age due to cyanotic congenital heart disease. A female baby who is alive followed this. Fourth pregnancy ended at term, delivering a male baby. According to parents the baby had limb shortening, developed respiratory distress on second day of life and died on fourth neonatal day. A live born female infant followed this. The next pregnancy, the mother delivered a male baby with short limbs and cleft palate. The child died at the age of 18 months due to respiratory problems. He had severe developmental delay and growth retardation.
Physical examination of the neonate showed wide anterior fontanel, a flat face with hypertelorism and down slanting palpaberal fissures, low set posteriorly rotated ears, micrognathia with prominent transverse and vertical chin creases and smooth philtrum [Figure - 1]a & b. He had narrow thorax and kyphosis of thoracolumbar spine. Limbs were short with predominant rhizomelic shortening. The thumbs and great toes were short and broad [Figure - 1]c & d. External genitalia were normal. The length of the child at birth was 45 cm (less than third centile) with upper segment to lower segment ratio of 1.9. The occipito frontal circumference was 35 em, normal for the age.
Skeletal survey showed narrow thorax with sinuous ribs [Figure - 2]a. The long bones were short with wide metaphyses [Figure - 2]b. The fibulae were long and the upper ends were protruding out on the lateral aspects of the knees. There was spur formation in the lateral iliac wings leading to trident acetabulae. Metacarpals and phalanges were short. Fundus examination was normal. Cardiac evaluation revealed a small patent ductus arteriosus (PDA). Ultrasonogram of the abdomen was normal. Hematological examination, hepatic, renal functions and calcium and phosphorus levels in serum were normal.
Discussion
The present case has narrow thorax and short limbs with predominant rhizomelic shortening. These features are characteristic of ATD. In addition, the child had facial dysmorphism, sinuous ribs, broad thumbs and great toes similar to OPD II [Table - 1]. Though small thorax is described in OPD II, it is not so narrow as in ATD and the present cases.[1] Various types of anomalies of digits and toes including finger contractures, overlapping of fingers and toes, fanned out toes, and short, thick malformed metacarpals are described in OPD II.[2] The present case did not have these charecteristic hand abnormalities. The present case had broad great toes and thumbs and contractures of the fingers. The other anomalies characteristic of OPD II namely cleft palate, curved long bones and hypoplastic fibula were absent in the present case. The present case had kyphoscoliosis, which is described in OPD II.
ATD and OPD II are usually lethal in neonatal period. Survivors with OPD II have mental retardation while mental function is normal in ATD. One sibling who survived till 18 months had developmental delay and cleft palate, which are described in OPD II. The authors' patient had a congenital heart disease in the form of PDA, which was described earlier with OPD II and ATD. Other rare malformations reported in OPD II are omphalocoele, hydrocephalus and cryptorchidism, which were not present in our patient. Hearing loss usually associated with OPD II, which was not tested in patient.
The mode of inheritance of OPD II is X-linked while that of ATD is autosomal recessive. The pedigree in authors' case is consistent with X linked as well as autosomal recessive inheritance due to affection of only males and consanguinity respectively.
Phenotypic similarities of OPD II, Melnick Needles syndrome (MND) and OPD I was already described.[4],[5] The mutation of filamin A (FLNA) in OPD I, OPD II, MND and fronto dysplasia have proved allelic nature of these disorders.[6] The absence of this mutation in substantial number of cases (40%) in OPD II suggests the possibility of genetic heterogeneity.[7] Some cases with overlapping features of OPD II have phenotypic similarities with Atelestogenisis I / III and Boomerang dysplasia.[8] Similarly overlapping fcatures of ATD, Ellis van craved syndrome, other SRP syndrome and various OFD syndromes also described.[9],[10]
The disproportionate short stature, narrow thorax, long fibula, wide metaphysis, trident acetabulae and spur formations in iliac wings was consistent with diagnosis of ATD. Renal cysts, polydactyly, retinal dysplasia associated with ATD was absent in this case. The present case is the first case of ATD with facial dysmorphism.
References
1.Holder SE, Winter RM, Syndrome of the mouth. Oto-palato-digital syndrome type II. J Med Genet 1993; 30 : 310-313.
2.Savarirayan R, Cormier-Daire V, Unger S et al. Oto-palato-digital syndrome, type II: report of three cases with further delineation of the chondroosseous morphology. Am J Med Genet 2000; 95:193-200.
3.Pries S, Kemperdick H, Majewski F. Oto-palato-digital syndrome type II in two unrelated boys. Clin Genet 45: 154-161.
4.Robertson S, Gunn T, Allen B, Chapman C, Becroft D. Are Melnick-Needles syndrome and oto-palato-digital syndrome type II allelic Observations in four generation kindred. Am J Med Genet 1997; 71 : 341-347.
5.Verloes A, Lesenfants S, Barr M et al. Fronto-otopalatodigital dysplasia: clinical evidence for a single entity encompassing Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2, and frontometaphyseal dysplasia. Am J Med Gent 2000; 90: 407-422.
6.Robertson SP, Twigg SR, Sutherland-Smith AJ et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 2003; 33 : 487-491.
7.Robertson SP. Molecular pathology of filamin A: diverse phenotypes, many functions. Clin Dysmorphol 2004; 13 : 123-131. [PUBMED] [FULLTEXT]
8.Nishimura G, Horiuchi T, Kim OH, Sasamoto Y. Atypical skeletal changes in Otopalatodigital syndrome type II: Phenotypic overlap among Otopalatodigital syndrome type II, Boomerang dysplasia, Atelosteogenesis type I and type III, and lethal male phenotype of Melnick-Needles syndrome. Am J Med Genet 1997; 73 : 132-138. [PUBMED] [FULLTEXT]
9.Ho NC, Francomano C, Van Allen M. Jeune asphyxiating thoracic dystrophy an short-rib polydactyly type III (Verma-Naumoff) are variants of the same disorder. Am J Med Genet 2000; 90 : 310-314.
10.Majewski F, Ozturk B, Gillessen-Kaesbach G. Jeune syndrome with tongue lobulation and preaxial polydactyly, and Jeune syndrome with situs inversus and asplenia: compound heterozygosity Jeune-Mohrand Jeune-Ivemark. Am J Med Genet 1996; 63 : 74-79.(Sankar VH, Phadke Shubha R)
Here it is reported a male newborn baby with features of asphyxiating thoracic dystrophy (ATD) with facial dysmorphism. The disproportionate rhizomelic short stature, narrow thorax, long fibulae, wide metaphysis and trident acetabule are consistent with diagnosis of ATD. In addition the baby had facial dysmorphism and broad thumbs and great toes similar to Oto-palato-digital syndrome type II (OPD II). The association of these features with ATD is not reported till date.
Keywords: Asphyxiating thoracic dysplasia; Otopalatodigital syndrome; Rhizomelia; Narrow thorax; Broad thumbs
Asphyxiating thoracic dystrophy (ATD) is a lethal skeletal dysplasia with multisystemic manifestations. Oto palato digital syndrome (OPD) type II is a rare, severe, lethal, X- linked skeletal dysplasia. The authors describe a case of asphyxiating thoracic dystrophy with facial dysmorphism and thumb anomalies similar to OPD II.
Case report
The index case was a male baby born at 37 weeks of gestation to a healthy, consanguineous, Indian Muslim couple. This couple had previous seven liveborn children and two first trimester abortions. Three female children were alive and did not have any malformations. Four male children died during neonatal period or infancy. There were no medical records of any of the children. First pregnancy ended at full term vaginal delivery and delivered a male baby who died on the third neonatal day. The parents did not notice any external anomalies. Next pregnancy resulted in a male child who died at three months of age due to cyanotic congenital heart disease. A female baby who is alive followed this. Fourth pregnancy ended at term, delivering a male baby. According to parents the baby had limb shortening, developed respiratory distress on second day of life and died on fourth neonatal day. A live born female infant followed this. The next pregnancy, the mother delivered a male baby with short limbs and cleft palate. The child died at the age of 18 months due to respiratory problems. He had severe developmental delay and growth retardation.
Physical examination of the neonate showed wide anterior fontanel, a flat face with hypertelorism and down slanting palpaberal fissures, low set posteriorly rotated ears, micrognathia with prominent transverse and vertical chin creases and smooth philtrum [Figure - 1]a & b. He had narrow thorax and kyphosis of thoracolumbar spine. Limbs were short with predominant rhizomelic shortening. The thumbs and great toes were short and broad [Figure - 1]c & d. External genitalia were normal. The length of the child at birth was 45 cm (less than third centile) with upper segment to lower segment ratio of 1.9. The occipito frontal circumference was 35 em, normal for the age.
Skeletal survey showed narrow thorax with sinuous ribs [Figure - 2]a. The long bones were short with wide metaphyses [Figure - 2]b. The fibulae were long and the upper ends were protruding out on the lateral aspects of the knees. There was spur formation in the lateral iliac wings leading to trident acetabulae. Metacarpals and phalanges were short. Fundus examination was normal. Cardiac evaluation revealed a small patent ductus arteriosus (PDA). Ultrasonogram of the abdomen was normal. Hematological examination, hepatic, renal functions and calcium and phosphorus levels in serum were normal.
Discussion
The present case has narrow thorax and short limbs with predominant rhizomelic shortening. These features are characteristic of ATD. In addition, the child had facial dysmorphism, sinuous ribs, broad thumbs and great toes similar to OPD II [Table - 1]. Though small thorax is described in OPD II, it is not so narrow as in ATD and the present cases.[1] Various types of anomalies of digits and toes including finger contractures, overlapping of fingers and toes, fanned out toes, and short, thick malformed metacarpals are described in OPD II.[2] The present case did not have these charecteristic hand abnormalities. The present case had broad great toes and thumbs and contractures of the fingers. The other anomalies characteristic of OPD II namely cleft palate, curved long bones and hypoplastic fibula were absent in the present case. The present case had kyphoscoliosis, which is described in OPD II.
ATD and OPD II are usually lethal in neonatal period. Survivors with OPD II have mental retardation while mental function is normal in ATD. One sibling who survived till 18 months had developmental delay and cleft palate, which are described in OPD II. The authors' patient had a congenital heart disease in the form of PDA, which was described earlier with OPD II and ATD. Other rare malformations reported in OPD II are omphalocoele, hydrocephalus and cryptorchidism, which were not present in our patient. Hearing loss usually associated with OPD II, which was not tested in patient.
The mode of inheritance of OPD II is X-linked while that of ATD is autosomal recessive. The pedigree in authors' case is consistent with X linked as well as autosomal recessive inheritance due to affection of only males and consanguinity respectively.
Phenotypic similarities of OPD II, Melnick Needles syndrome (MND) and OPD I was already described.[4],[5] The mutation of filamin A (FLNA) in OPD I, OPD II, MND and fronto dysplasia have proved allelic nature of these disorders.[6] The absence of this mutation in substantial number of cases (40%) in OPD II suggests the possibility of genetic heterogeneity.[7] Some cases with overlapping features of OPD II have phenotypic similarities with Atelestogenisis I / III and Boomerang dysplasia.[8] Similarly overlapping fcatures of ATD, Ellis van craved syndrome, other SRP syndrome and various OFD syndromes also described.[9],[10]
The disproportionate short stature, narrow thorax, long fibula, wide metaphysis, trident acetabulae and spur formations in iliac wings was consistent with diagnosis of ATD. Renal cysts, polydactyly, retinal dysplasia associated with ATD was absent in this case. The present case is the first case of ATD with facial dysmorphism.
References
1.Holder SE, Winter RM, Syndrome of the mouth. Oto-palato-digital syndrome type II. J Med Genet 1993; 30 : 310-313.
2.Savarirayan R, Cormier-Daire V, Unger S et al. Oto-palato-digital syndrome, type II: report of three cases with further delineation of the chondroosseous morphology. Am J Med Genet 2000; 95:193-200.
3.Pries S, Kemperdick H, Majewski F. Oto-palato-digital syndrome type II in two unrelated boys. Clin Genet 45: 154-161.
4.Robertson S, Gunn T, Allen B, Chapman C, Becroft D. Are Melnick-Needles syndrome and oto-palato-digital syndrome type II allelic Observations in four generation kindred. Am J Med Genet 1997; 71 : 341-347.
5.Verloes A, Lesenfants S, Barr M et al. Fronto-otopalatodigital dysplasia: clinical evidence for a single entity encompassing Melnick-Needles syndrome, otopalatodigital syndrome types 1 and 2, and frontometaphyseal dysplasia. Am J Med Gent 2000; 90: 407-422.
6.Robertson SP, Twigg SR, Sutherland-Smith AJ et al. Localized mutations in the gene encoding the cytoskeletal protein filamin A cause diverse malformations in humans. Nat Genet 2003; 33 : 487-491.
7.Robertson SP. Molecular pathology of filamin A: diverse phenotypes, many functions. Clin Dysmorphol 2004; 13 : 123-131. [PUBMED] [FULLTEXT]
8.Nishimura G, Horiuchi T, Kim OH, Sasamoto Y. Atypical skeletal changes in Otopalatodigital syndrome type II: Phenotypic overlap among Otopalatodigital syndrome type II, Boomerang dysplasia, Atelosteogenesis type I and type III, and lethal male phenotype of Melnick-Needles syndrome. Am J Med Genet 1997; 73 : 132-138. [PUBMED] [FULLTEXT]
9.Ho NC, Francomano C, Van Allen M. Jeune asphyxiating thoracic dystrophy an short-rib polydactyly type III (Verma-Naumoff) are variants of the same disorder. Am J Med Genet 2000; 90 : 310-314.
10.Majewski F, Ozturk B, Gillessen-Kaesbach G. Jeune syndrome with tongue lobulation and preaxial polydactyly, and Jeune syndrome with situs inversus and asplenia: compound heterozygosity Jeune-Mohrand Jeune-Ivemark. Am J Med Genet 1996; 63 : 74-79.(Sankar VH, Phadke Shubha R)