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2012-02-01-09 Case of the week # 318 © Fabrice Cuillier www.TheFetus.net

 Case of the week #318

May 10th , 2012 -  May 24th , 2012

 

Fabrice Cuillier ,MD.1, Arrazola G.,MD.2, Cartault F.,MD.3, Alessandri J.L.,MD.4 

1 Service de Gynécologie, Hôpital Félix Guyon, 97400 Saint-Denis, La Réunion. France. 

2 Service de Gynécologie, Hôpital , 97400 Saint-Denis, La Réunion. France. 

3  Service de Génétique, Hôpital Félix Guyon, 97400 Saint-Denis, La Réunion. France. 

4 Cabinet d’Echographie, 10 Route de Moufia, 97490 Sainte-Clotilde. La Réunion. France. 


Case report:

A 41-year-old healthy woman (G6P3) was referred to our antenatal unit for 12-gestational-week sonographic examination. Their family and medical histories were remarkable. The parents were consanguineous. Her second child, affected with Ellis-van Creveld syndrome (EVCS), died at 13 months because of respiratory deficiency. She had three miscarriages.
 
 
At 12 weeks the nuchal translucency thickness was 4,4 mm (CRL 60 mm) (Image 1); Biparietal diameter was consistent with 12 weeks, but the lengths of humerus (5 mm), radius (4 mm), femur (6 mm) and tibia (5 mm), (all long bones) were one standard deviation below the normal mean values.
Hexadactyly was confirmed on the feet and hands (Image 2-5).
The thoracic diameter and circumference were within normal ranges. Sagittal and coronal views showed a normal thorax relative to the size of the abdomen and head (Image 10). Ribs were not particularly short. A ventricular septal defect was also noted (Image 5-8). Facial profile was normal (Image 9). Theses anomalies were confirmed at 13 weeks.

The biometry was abnormal at 29 weeks and at 32 weeks (Image 11-12). All bony structures were of normal echogenicity, without fracture. The spine was unremarkable. The volume of amniotic fluid was normal. The posterior uterine wall placenta was of normal appearance. The triple test was 1:10. Chromosome analysis showed a numerically and structurally normal karyotype (46 XY). 
 
The patient’s previous history of a child with Ellis-van Creveld syndrome and these ultrasound findings suggested diagnosis of Ellis-van Creveld syndrome.
 
The couple decided to continue the pregnancy. 
 
Spontaneous labor at 37 weeks led to the vaginal delivery of 2.5 kg female infant without a narrow thorax, but with shortened limbs, postaxial polydactyly and hypoplastic nails in the extremities (image 13-15). Fingernails were inconspicuous. The postnatal radiographic features of the skeleton confirmed the diagnosis. The X-ray babygram did not show a narrow thorax, but a cylindrical chest without short ribs (Image 16-17) The spine appeared normal. Radiologically, the hand showed postaxial hexadactyly, hypoplasia of the terminal phalanges bilaterally. All long bones were markedly shortened, especially the humerus and the femur. There was trident configuration over the acetabulum. X-rays obtained immediately after birth: A markedly narrow thorax with short and horizontally oriented abnormal left ribs. Short iliac bones with round lateral wings trident were seen.
 
The diagnosis of Ellis-van Creveld was confirmed.
 
 
Postnatal view of the hand showed hexadactyly and hypoplastic nails.   
Here are the images we had:
 
Image 1: Nuchal translucency thickness

 

Image 2-5:
Hexadactyly

   

Image 6-8: Ventricular septal defect on Doppler ultrasound.

 


Image 9: Normal facial profile 

  

Image 10:
 Sagittal and coronal views showed a normal thorax relative to the size of the abdomen and head 



Image 11-12: Abnormal biometry






Image 13-15: Xray findings

 




Image 16-17:
Postnatal appearance with postaxial polydactyly and hypoplastic nails in the extremities 


 

See also another case of 
Ellis-van Creveld Syndrome by clicking here. 




Ellis-van Creveld Syndrome

Fabrice Cuillier ,MD.1, Arrazola G.,MD.2, Cartault F.,MD.3, Alessandri J.L.,MD.4 

Definition

Approximately 200 cases of different osteochondrodysplasia (CDD) have been described in the literature. Short Rib Polydactyly Syndrome (SRPDS) is a possible lethal form of osteochondrodysplasia which is categorized by the International classification of osteochondrodysplasia into six subtypes (Horigone (1997)1-2
 
SRP type I: Sandino-Noonan syndrome, 
 
SRP type II: Majewski syndrome, 
 
SRP type III: Verma-Naumoff syndrome, 
 
SRP type IV: Beemer-Langer syndrome, 
 
Asphyxiating thoracic dysplasia: Jeune’s syndrome and 
 
Ellis-Van-Creveld Syndrome: EVCS. 
 
The features of these subtypes of SRPDS overlap considerably which makes it difficult to distinguish among them. The last one, EVCS, is a rare, non systematically lethal, chondral and ectodermal dysplasia characterized by post-axial polydactyly, ectodermal dysplasia and heart defects, with acromelic and mesomelic shortness of limbs associated with antenatal and postnatal growth retardation3. The other characteristics of EVCS are disproportionate short trunk (not always associated with narrow thorax) with short ribs or predominantly short limbs. Congenital heart defects (CHD) are also common2. Ectodermal dysplasia appears as hypoplastic nails, thin hair and abnormal teeth3
  
 
Synonyms:
 
Ellis-Van Creveld syndrome (EVCS); Chondro-ectodermal dysplasia.  
 
 
Genetics: 
 
EVCS is an autosomal recessive condition with variable expression, with pleiotrophic effects5. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as cause5. Five different mutations have been described including one mutation in the Older Order Amish4. Each of the five mutations is possibly responsible for the variation of phenotypic expression6
 
Sequencing of EVC1 and EVC2 identified mutations in two thirds of patients with EVCS. Gene testing for mutational analysis of EVC1 and EVC2 is not currently available clinically for up-to-date information on gene testing.  
 
A chromosome aberration such as a karyotype 47 XXY (in Guschmann‘s case) has been reported in EVCS and probably coincidental5
 
Galdzicka described a novel gene that is mutated in an Ashkenazi individual with EVCS19
 
Prenatal diagnosis using DNA analysis on cells obtained at chorionic villus sampling and at fetoscopy has been reporte5.
 
 
History: 
 
EVCS was first described by Ellis and Van Creveld in 19404. Theses authors published three cases. They defined this syndrome comprising a certain bilateral postaxial polydactyly of the hands, shortness of the long bones, congenital heart defects 5 and ectodermal dysplasia (small and dysplastic nails, multiple frenula, dysplastic and hypoplastic nails). The authors coined the term chondro-ectodermal dysplasia for this condition. Now, it is usually referred to as EVCS. 
 
In 1964, McKusick et al published a study « Dwarfism in the Amish », where it was established that ethnic individuals with disproportionate short stature, polydactyly, ectodermal anomalies and disabling congenital heart defects suffered from chondroectodermal dysplasia, better known as the EVCS6
 
However, only a few cases have been prenatally documented. More than 200 cases have been described since then7-8
 

Prevalence: 
 
EVCS is a very rare disease. EVCS occurred approximately 1/60 000 births in general population5-7. EVCS was reported to occur in all ethnic groups. Nevertheless, EVCS is more common in the Amish population of Lancaster (Pennsylvania, USA), occurring in 2:10,000 births, as in the Arabs of the Gaza strip or some Australian arborigene groups.
  
 
Pathogenesis: 
 
EVCS is mainly a generalized disorder of the maturation of the endochondral ossification: 
 
Retardation of short columnar arrangement of the chondrocytes of the physis is a common finding, whereas physeal growth plate disorganization, defined as disorganization of the chondrocytes of the physis, may be present.  
 
A thin epiphyseal line with irregularly shaped lacunae, abnormal chondrocytes and island soft hyaline cartilage in metaphyseal trabeculae was the first description of the physeal growth plate of a patient with EVCS8
 
In the Zoubaa’s article, histopathology showed diffuse retardation of the growth plate with unremarkable testing cartilage in all endochondral ossification sites. Pronounced disorganization was only observed in the upper mesomelic bone segments. 
 
Abnormal membranous ossification of the cranial sutures may occur. Advanced, but not disorganized membranous ossification was found at the coronal, sagittal and lambdoid sutures with shortening of the inter-osseous space.   

 
Sonographic findings: 
 
In EVCS, increased first-trimester fetal nuchal translucency thickness has been rarely described at 13 weeks once7. Our observation shows the possible antenatal diagnosis of EVCS during the first trimester.  
 
During the second and third trimester, ECVS has been described prenatally by both fetoscopy initially and by ultrasound. The major diagnosis features of EVCS are disproportionate short stature, polydactyly, congenital heart defects  and anomalies of tissue of ectodermal origin (ectodermal dysplasia). The prenatal diagnosis of EVCS is made by the ultrasonography triade detection of postaxial polydactyly, shortness of the long bones and a heart defect 10,11,12. Skeletal abnormalities are confined either to the extremities, the pelvis and the ribs. The full pictures, however, are evident only after birth. 
 
Postaxial polydactyly of the hands is a constant feature of EVCS, and polydactyly of the hands associated with onychodystrophy is characteristic. According to different authors, all affected individuals have polydactyly of the hands. Heptadactyly of the hands are possible. Polydactyly of feet is seen only in about 10 % of the cases13,14The hamate and capitate bones of the wrist are fused 7 . Shortening of the extremities is more stricking distally (radius/ulna, tibia/fibula), in contrast to classical achondroplasia, where proximal shortening is more commonly found. The dwarfism primarily affects the middle and the distal segments of the limbs so that the tibia, fibula, radius and ulna are disproportionately short7.  
 
The pelvis is also abnormal on X-ray. The iliac wings appear broad and short. There is a trident configuration over the acetabulum (as with achondroplasia or Jeune syndrome)5. But it is a difficult prenatal diagnosis. 
 
The thorax is narrow because of short ribs, in more than 50 % of the patients. Approximately 60% of the infants with EVCS have congenital heart defects , classically a single atrium, ASD or VSD and ASD. Transposition of the great vessels and atrio-ventricular canal may also occur11. According with Chen, prenatal sonographic identification of endocardial cushion defects in association with shortening of the long bones should alert sonographers to the possibility of EVCS and prompt a careful search of hexadactyly of the hands. 
 
The other ectodermal signs are not prenatal diagnosis. They are constant features of EVCS, as sparse hair, underdevelopped and dysplastic nails and abnormal, missing or even natal teeth5. Ectodermal defects include oral and dental anomalies, dysplastic finger nails or epispadia in male infants. Fusion of the gums of the maxilla and the upper lips and obliteration of the sulcus gingivo-labialis are also frequently seen. Other possible anomalies can be iris colobomas, strabismus or hepatomegaly, but presumably rare in EVCS5
 
 
Implication for targeted examinations: 
 
There are few reports in medical literature describing affected newborns and even, older children. Initially, EVCS has been diagnosed using fetoscopy and ultrasound in the second trimester of pregnancy. 
 
Mahoney and Hobbins used a combination of ultrasound and fetosocopy to diagnose the first reported case of EVCS at 17 weeks 10.  
 
Bui et al reported on an additional case diagnosed by fetosocopy at 21 weeks 12
 
Muller and Cremin reported a case in a primigravida in which bilateral postaxial polydactyly of the hands, a constricting thorax, bilaterally bowed and short femurs and shortening of the other long bones were noted at 36 weeks. The diagnosis of EVCS was made after an autopsy and postnatal radiography.   
 
Dugoff presented the first published report of prenatal diagnosis of EVCS using ultrasound in the first trimester7
 
Guschmann and al (1999) described the clinical findings in a 15-week-old affected fetus5. The diagnosis of EVCS was based on a positive family history (an affected sib) and shortness of the long bone as well as hexadactyly diagnosed by prenatal sonography. 
 
 
Differential diagnosis: 
 
The sonographic findings suggesting ECVS in our case included the shortened ribs, shortened limbs with polydactyly and a congenital heart defects . The size of the thorax was particularly not striking in comparison to the size of the abdomen and head at 13 weeks and latter. The differential diagnosis of the different SRPDS can be difficult, because there is a considerable overlap of the phenotypes. The sonographic differential diagnosis in our case presented different forms, because each sign of EVCS is non specific and is also seen in other syndromes, as13 :
SRP I : or Saldino Noonan syndrome, is usually associated with extremely short ribs, markedly shortened limbs (micromelia) and abnormal vertebrae3. There are frequently intestinal and genital malformations5
 
SRP II : or Majewski syndrome is similar to SRP I, but involves normal vertebrae and median cleft lip. There is usually a pre-axial polydactyly. Furthermore orofacial clefts are common. The radiographic appearance of the pelvis is normal14.   
 
SRP III : or Verma-Naumoff syndrome is similar to type I, but here malformations of the inner organs occur less frequently17. Especially, SRP III is discussed in the prenatal differential diagnosis16.  
 
SRP IV : or Beemer-Langer syndrome. There is usually an omphalocele and polydactyly is rare in this type15
 
 
Jeune syndrome (JS): The most likely alternative diagnosis in our case was JS or asphyxiating thoracic dysplasia16, which is usually difficult to distinguish from EVCS. However, JS is frequently associated with cystic renal dysplasia and multiple renal cysts5, whereas EVCS is frequently associated with congenital heart defects . However, the presence of congenital heart defects  and the absence of cystic renal changes eliminated the possibility of JS16
 
In fact, diagnostic differentiation between two syndromes may not be critical. Both are recessively inherited and both have similar prognosis. Furthermore, these two syndromes have so many overlapping features that some authors have suggested that they form part of a disease spectrum rather than being distinct conditions3
 
McKusik-Kaufmann syndrome18 : is eliminated too, because there is no micromelia. 
 
Laurence-Moon-Bardet-Biedl syndromeThere is polydactyly with endochondral sign, but without chondrodysplasia. 

 

Associated anomalies: 
 
The ectodermal defects including hypoplastic nails, dysplastic fingernails, neonate teeth, partial anondotia, short upper lip bound by frenula to the alveolar ridge and epispadias7 could not be demonstrated in associated with EVCS by prenatal ultrasound.
 
 
Prognosis: 
 
The management of an EVCS fetus diagnosed in the pregnancy is complicated and the parents must be counselled3. After birth, cardinal features are short stature, short ribs, polydactyly and dysplastic fingernails and teeth. But prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. EVCS usually has severe consequences, but is not always lethal19-20
 
One third of all patients die before two weeks as a result of either congenital heart defects  or respiratory distress, caused by bronchomalacia of lung hypoplasia, secondary to a narrow rib cage6. The infant can die of pulmonary insufficiency shortly after birth.
 
About half of the patients die in early infancy as a consequence of cardio-respiratory problems7. Congenital heart defects, especially abnormalities of atrial septation which occur in 50-60 % of the afflicted patients, are the main determinants of longevity. The presence of congenital heart defects is strongly related to the mortality rate3. Thus, prenatal diagnosis of this condition is important. If the diagnosis is established before fetal viability, termination of pregnancy may be justified . 
 
Usually, some limitation of hand function is observed, such as in inability to form a clenched fist. The infants who survive may suffer handicaps due to short stature, finger abnormalities which diminish manual dexterity, hip joint degeneration, causing impaired gait and various dental problems3. Often, surgical intervention must be considered for repairing of congenital heart defects , extra-digits, genu valgum and correction of dental conditions6
 
Prognosis of the final body height is difficult to predict. Birth length is always below the 5th percentile. So short stature, with adult height ranging from 110 to 150 cm, is usual, and all afflicted patients have small chests, but the degree of respiratory distress varies from negligible to rapidly lethal. Cognitive and motor development is normal. Most survivors have intelligence in the normal range.  
 
End-organ involvement may include the following: 
 
Renal involvement including nephrotic syndrome, nephronophthisis, and renal failure 
 
Hepatic involvement, including a congenital paucity of bile ducts that leads to progressive fibrosis and hepatic failure 
 
Hematologic involvement ranges from myelodysplastic changes with dyserythropoiesis to acute leukemia 
 
 
But cognitive and motor development is normal. Most survivors have intelligence in the normal range.
 
 
Reccurence risk: 
 
Because EVCS is inherited with an autosomal recessive pattern, the chance of recurrence in subsequent pregnancies is 25%. Prenatal assessment for EVCS should be considered in this patient’s future pregnancies2
 
 
Conclusion: 
 
Our case was diagnosed early in the pregnancy. Our case supports to our belief that EVCS can be readily diagnosed prenatally during the first trimester, essentially by demonstration of short limbs with polydactyly and cardiac anomalies. The stage of fetal development at which the skeletal abnormalities becomes distinct sonographically is now well established, after 12 weeks. 
 

 

 
 
References: 
 
1- Romero R., Pilu G. , Jeanty P., Ghidinis A., Hobbins J.C.– Prenatal diagnosis of congenital anomalies. 1988. Appletonand Lange. Norwalk, Connecticut/san Mateo, California. USA. 
 
2- Parilla B.V., Leeth E.A., Kambich M.P., Chilis P., Mac Gregor S.N.- Antenatal detection of skeletal dysplasias. J Ultrasound Med 2003 ; 22 : 255-8; quiz 259-61. 
 
3- Sergi C., Voigtlander T., Zoubaa S., Hentze S., Meyberg-Solomeyer G., Troeger J., Tariverdian G., Otto H.F., Schiesser M.- Ellis-van Creveld syndrome : A generalized dysplasia of endochondral ossification. Pediatr Radiol. 2001 ; 31 : 289-93. 
 
4- Horigome H., Hamada H., Sohda S., Oyake Y., Kurosaki Y.- Prenatal ultrasonic diagnosis of a case of Ellis-van Creveld syndrome with a single atrium. Pediatr Radiol 1997 ; 27 : 942-4. 
 
5- Dugoff L., Thieme G., Hobbins J.C.- First trimester prenatal diagnosis of chondroectodermal dysplasia (Ellis-Van Creveld syndrome) with ultrasound. Ultrasound Obstet Gynecol 2001 ; 17 : 86-8. 
 
6 George E., DeSilva S., Lieber E., Raziuddin K., Gudavalli M.- Ellis Van Creveld syndrome (chondroectodermal dysplasia, MIM 22550) in three siblings from a non-consanguineous mating. J Perinat Med 2000 ; 28 : 425-7.  
 
7 Tongsong T., Chanprapaph P.- Prenatal sonographic diagnosis of Ellis-van creveld syndrome. J Clin Ultrasound 2000 ; 28 : 38-41. 
 
8- Mahoney M.J., hobbins J.C.- Prenatal diagnosis of chondroectodermal dysplasia (Ellis Van Creveld syndrome) with foetoscopy and ultrasound. N Eng J med 1977 ; 297 : 259-60.  
 
9- Guschmann M., Horn D., Gasiorek-Wiens A., Urban M., Kunze J., Vogel M.- Ellis-Van Creveld syndrome : examination at 15 weeks .Prenatal Diagn 1999 ; 19 : 879-83. 
 
10- Kajantie E., Andersson S., Kaitali I. Familial sphyxiating thoracic dysplasia : Clinical variability and impact of improved neonatal intensive care. J Pediatr  2001 ; 139 : 130-3. 
 
11- Bui T.H., Marsk L., Eklof O., Theorell K.- Prenatal diagnosis of chondroectodermal dysplasia with fetoscopy. Prenat Diagn 1984 ; 4 : 155-9. 
 
12- Torrente I., Mangino M., De Luca A., Mingarelli R., Gennarelli M., Giannotti A., Novelli G., Dallapiccola B.- First-trimester prenatal diagnosis of Ellis-van Creveld syndrome using linked microsatellite markers. Prenat Diagn 1998 ; 18 : 504-6. 
 
13- Frikiche A, Verloes A, Stassen M, Schaaps JP, Soyeur D, Senterre J.- Ellis-Van Creveld syndrome. A propos of a case diagnosed in utero. Rev Med Liege 1989 44 : 68-72. 
 
14- Qureshi F, Jacques SM, Evans MI, Johnson MP, Isada NB, Yang S.S.- Skeletal histopathology in fetuses with chondroectodermal dysplasia (Ellis-van Creveld syndrome). Am J Med Genet 1993 15 ; 45 : 471-6. 
 
15- Berardi J.C., Moulis M., Laloux V., Godard J., Wipff P., Botto C.- Ellis-van Creveld syndrome. Contribution of echography to prenatal diagnosis. A propos of a case. J Gynecol Obstet Biol Reprod 1985 ; 14 : 43-7. 
 
16- Hill L.M., Leary J.- Transvaginal sonographic diagnosis of short-rib polydactyly dysplasia at 13 WEEKS. Prenat Diagn 1998 ; 18 : 1198-1201. 
 
17- Meizner I., Barnhard Y.- Short-rib polydactyly syndrome (SRPS) type III diagnosed during routine prentala ultrasonographic screening. A case report. Prenat diagn 1995 ; 15 : 665-8. 
 
18- Den Hollander N.S., Van Den Harten H.J., Laudy J.A.M., Van de Weg P., Wladimiroff J.W.- Early  transvaginal ultrasonographic diagnosis of Beemer-langer dysplasia : a report of two cases. Ultrasound Obstet Gynecol 1998 ; 11 : 298-302.    
 
19- Galdzicka M., Patnala S., Hirshman M.G., Cai J.F., Nitowsky H., Egeland J.A., Ginns E.I.- A new gene, EVC2, is mutated in Ellis–van Creveld syndrome. MolGenet Metab 2002 ; 77 : 291-5. 
20- Chen CP, Su YN, Hsu CY, Chern SR, Tsai FJ, Wu PC, Chen PT, Wang W. Ellis-van Creveld syndrome: prenatal diagnosis, molecular analysis and genetic counseling. Taiwan J Obstet Gynecol. 2010 ; 49 : 481-6. 
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