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2006-12-04-12 Larsen - Bourbon syndrome © Cuillier

Larsen - Bourbon syndrome  

Fabrice Cuillier, MD*, J. L.  Alessandri, MD**, J. M. Laville, MD***, D. Durandeu, MD****, J. P. Bourdil, MD*****K. Comalli Dillon, BA, RDMS******


Gynecologist, Hôpital Félix Guyon, 97400  Saint-Denis, Ile de la Réunion, France. Telephone: 0262 90 55 22; fax: 0262 90 77 30;


Neonatologist, Hôpital Félix Guyon, 97400 Saint-Denis, Ile de la Réunion, France;


Pediatric surgeon, Hôpital Felix Guyon, 97400 Saint-Denis, Ile de la Réunion, France;


143 Republic Avenue, Saint André, Ile de la Réunion, France;


Obstetrician, Quartier du Chaudron, Saint-Denis, Ile de la Réunion, France;


Diagnostic Medical Sonographer, Editor, Translator, Novato, California.



Larsen syndrome is a skeletal dysplasia occasionally characterized by short stature, but essentially featuring (1) multiple joint luxations and (2) characteristic facies [4]. There are two forms of Larsen syndrome: a nonlethal and a lethal form, the latter being almost always fatal due to pulmonary hypoplasia.

We describe a case of osteochondrodysplasia, referred at 19 weeks’ GA for bilateral clubfoot.  Several additional anomalies had been detected at the 18–week ultrasound examination; at that time, these anomalies were felt to represent an abnormal karyotype.
The authors describe anatomy, pathogenesis, and sonographic imagery of a particular form of Larsen syndrome and reiterate the newly prominent importance of ultrasonography in prenatal evaluation of its diagnosis and prognosis.  This rare skeletal dysplasia is specific to Réunion Island, a French territory located off of the East African coast.
Examination of all extremities is a crucial part of ultrasonographic assessment of the fetus. Criteria which must be established to rule out anomalies of the limbs include:

• Presence of all three segments of the extremities;
• Normality of size, axis, and mobility; and
• Relation of the limb to the spine.

A critical anatomic feature correlated with Larsen syndrome in our case is congenital genu recurvatum, an extremely rare condition observed at birth [1-2].  It is defined as pathologic hyperextension of the knee greater than 30° associated with limited flexion [3]. The degree of recurvatum (dislocation) is not correlated with prognosis; the prognosis depends directly on association with other malformations, for example, genetic entities such as Larsen Syndrome. 

Case report

Our patient is a 30-year-old G3P2. There is no known family or personal history of skeletal dysplasia. The patient has not been exposed to any teratogenic agents nor received any chemotherapy.

The initial prenatal clinical examination was normal.  At 13 weeks GA, the nuchal translucency was normal, as was the triple-marker screen.  At 18 weeks GA, bilateral clubfoot was discovered, presenting with left genu recurvatum (images 1A-B). The patient was referred to our prenatal diagnosis center in Saint-Denis (Réunion Island).

On scans performed at 19, 22, 23, and 26 weeks GA, ultrasound image quality was not good despite a normal amount of amniotic fluid.  At the 19-week scan, we confirmed the bilateral clubfoot (images 2A-C), and the left knee recurvatum (image 3), with few movements at the knee joint. During this scan, we found additional anatomic anomalies: we suspected unilateral elbow luxation (images 4A-B); additionally, all the long bones measured below the 5th percentile. The fetus remained in a lateral recumbent position during the entire examination. Three-dimensional (3D) ultrasound was then performed, which confirmed hyperextension of both knees with genua recurvata (images 4C--F). The 3D scan further confirmed the presence of a unilateral elbow luxation. At 22 weeks GA, amniocentesis was performed, revealing a normal karyotype (46XX). At 23 weeks GA, the anomalies seen previously were reconfirmed (images 5A--F).
Further 2D and 3D examination at 26 and 27 weeks GA (images 7A--D) confirmed the anomalies of the extremities. The facial anomalies were present as well, with characteristic facies including prominent forehead (frontal bossing), short and broad nasal bridge, micrognathia, and low-set ears, all of which led us to the diagnosis of a special form of Larsen syndrome specific to Réunion Island (images 6, 8). Muscle wasting was not observed on realtime ultrasound. The amniotic fluid and the placenta were normal. A detailed brain survey was completed which proved normal as well.

The patient was informed about the fetal prognosis. The couple decided to terminate the pregnancy at 27 weeks GA. Placenta previa prevented vaginal delivery, so caesarean section was performed after fetal lysis. The baby was born dead (images 10A-D). A skeletal x-ray was performed, confirming left knee dislocation with bilateral clubfeet (image 11). A necropsy did not reveal any internal anomalies.

Images 1A, 1B: 
At 19 weeks GA, endovaginal 3D sonography of the feet with a "sandal gap", clubfeet and genu recurvatum.


Images 2A, 2B: 
At 22 weeks GA, abdominal 2D and 3D sonography of the feet showing clubfeet.


Images 2C, 3: 
2C - At 22 weeks GA, abdominal 2D sonography of the feet showing clubfoot.
3 - 2D abdominal sonography at 23 weeks GA showing right genu recurvatum.


Images 4A, 4B:
Sonographic comparison at 19 and 23 weeks GA with suspected elbow luxation. 


Images 4C, 4D: 
4C - 2D abdominal sonography at 23 weeks GA showing right genu recurvatum.
4D - At 22 weeks GA, abdominal 2D sonography of the feet showing clubfoot.


Images 4E, 4F: 
4E - At 22 weeks GA, abdominal 3D sonography of the feet showing clubfoot.
4F - 2D abdominal sonography at 23 weeks GA showing genu recurvatum.


Image 5A, 5B:
3D profile visualisation of the hand, which seems small at 19 weeks GA.


Images 5C, 5D:
5C - At 23 weeks GA, abdominal 3D sonography of the foot showing clubfoot and genu recurvatum.
5D - At 23 weeks GA, vaginal 2D sonography of the feet showing clubfeet and genu recurvatum.


Images 5E, 5F:
5E - At 23 weeks GA, vaginal 3D sonography of the feet showing clubfoot.
5F - At 23 weeks GA, vaginal 2D sonography of the feet showing clubfoot and genu recurvatum.


Images 6, 7A:
6 - sagittal view of the head of the fetus at 26 weeks GA.
7A - 2D view with the genu recurvatum of the fetus at 26 weeks GA.


Images 7B, 7C:
- 3D view of the leg with genu recurvatum at 26 weeks GA.
7C - 3D view of the clubfoot at 26 weeks GA.


Images 7D, 8:
- 3D view of the upper extremity with elbow luxation at 26 weeks GA .
8 - 2D sagittal view of the head of the fetus showing frontal bossing at 26 weeks GA.


Images 9A, 9B:
At 27 weeks GA, spiral CT scan showing articular anomalies.


Images 10A, 10B, 10C, 10D:
Postnatal appearance of the neonate.



Image 11:
Postnatal radiography showing the genua recurvata.


The history of Larsen syndrome is quite recent. The first official document about Larsen syndrome was found in the 18th  century [5].

  • Larsen (1950) first described Larsen syndrome, six cases [6]. The children presented with essentially a flat face, a prominent forehead, hypertelorism, and multiple joint luxations. Another two hundred cases have been described since. 
  • Latta (1971) spoke about Larsen syndrome [6] as well.
  • Desbuquois (1966) described one child with facial dysmorphia, articular laxity, luxations, and intrauterine growth restriction (IUGR).
  • Silvermann (1972) compiled a review of the literature and described 46 other cases. He emphasized the difficulty in differentiating a “strict syndrome” because of polymorphism. Nevertheless, in classic Larsen syndrome, cognitive deficits and dwarfism are not described [7].
  • In 1975, Payet (from Réunion Island), described five Larsen syndrome children born on the island [8-9]. Their morphology resembled Larsen syndrome, but there were clinical and radiological differences, in particular the presence of significant dwarfism and facial dysmorphia distinct from that observed before [10]. Other cases were discovered on Réunion Island (images 11-16). Some authors have used the eponyms Larsen-Bourbon syndrome or Payet syndrome . 
  • Maroteaux (1975) said, “Larsen-Bourbon syndrome seems different from Larsen syndrome; this syndrome (Larsen-Bourbon syndrome) is possibly autosomal-recessive in nature.” 
  • Payet (1979) described the first adult case of Larsen-Bourbon syndrome [9].
  • In 1982, Tollenaere described nine other cases and made a comparison between Larsen-Bourbon syndrome and Larsen syndrome in his Ph.D thesis [12].


 As there are no definite synonyms for Larsen-Bourbon syndrome; it might be considered:

  • A subgroup of Larsen syndrome; or
  • A component of Larsen syndrome.


Larsen syndrome is an extremely rare congenital anomaly with an estimated incidence of 1/100,000 births. In the literature, more than 200 cases of Larsen syndrome  have been described [18]. Congenital genu recurvatum, one of its signal features, is a rare condition, affecting 7/10,000 live births worldwide [2].
Réunion Island (population 850,000) is situated in the Indian Ocean, near Madagascar. Larsen syndrome prevalence worldwide is 4/100,000 [19-20]; by contrast, Larsen-Bourbon syndrome incidence on Réunion Island is estimated to be 1/1500. More than 42 cases of Larsen-Bourbon syndrome have been reported on Réunion Island during the past twenty-five years [10].  Residents of the island often display autosomal-recessive conditions (such the rare condition R.A.V.I.N.E syndrome), which is specific to Réunion Island). Larsen-Bourbon syndrome transmission seems to be essentially autosomal-recessive. The widespread consanguinity on the island seems an explanation. Larsen-Bourbon syndrome affects essentially “white Créoles,” who certainly share a common ancestor. The first colonists of Réunion Island arrived in the 17th century.  Lavier [8, 9] demonstrated that 10/12 of the affected families have white Créole origins and reside near the town of Saint Louis [14] (the region of the island where there is the greatest concentration of consanguinity).

Regarding other cases of Larsen-Bourbon syndrome, the authors have concluded that reporting of Larsen-Bourbon syndrome might be falsely low due to noninclusion of illegitimate children.


The underlying pathology of Larsen syndrome is a defect of collagen formation that results in skeletal deformities.  These include (1) congenital dislocation of multiple large joints (knees, hips and elbows); and (2) characteristic limb abnormalities [21-23]. 
Larsen-Bourbon syndrome is caused specifically by a collagen anomaly due to a decreased 1- and 2- chain ratio in type I collagen [23].  Its transmission is autosomal-dominant with incomplete penetrance, and its clinical expression is variable [25]. The Larsen syndrome gene 1 is situated between locus 3p14 and locus 3p21, with mutation of filament B [24].

Larsen-Bourbon syndrome, on the other hand, is most likely autosomal-recessive, but might instead be autosomal-dominant with incomplete penetrance [17]. Collagen types I, III, and V are not responsible.

Larsen syndrome is basically a generalized mesenchymal disorder involving connective tissues. It is a heterogeneous disorder, polymorphic in presentation, and can be either dominant or recessive. Larsen syndrome may be inherited as an autosomal-recessive disorder; or it may be caused by mutation in the LAR1 gene at locus 3p21.1-p14.1.25
Autosomal-dominant Larsen syndrome is caused by mutations in the gene encoding filament B (FLNB). This cytoplasmic protein regulates the structure and organization of F-actin.
The three different forms of Larsen syndrome described in the literature are as follows:

1. Classic form of Larsen syndrome:  initially described by Larsen [6] in 1950;
2. Larsen syndrome with familial dwarfism: this was reported once. Fryns [26-27] described a family dwarfism with an appearance of “aged facies;”
3. Lethal form of Larsen syndrome:  described initially by Chen in 1982 [28-29]. Chen mentions that pulmonary hypoplasia and tracheal stenosis were seen as well.

There are doubtless other forms of Larsen syndrome, Larsen-Bourbon syndrome certainly being one of them. Réunion Island is an island with a great deal of consanguinity. On Réunion, there are  seven genopathies seen with high frequency:   

 1.  Type I spinal amyotrophy;
 2.  Mucoviscidosis;
 3.  Alport syndrome;
 4.  Congenital adrenal hyperplasia;
 5.   Myopathy;  
 6.  Friedreich ataxia; and
 7.  Albinism.

Larsen-Bourbon syndrome would seem to be the eighth genopathy seen on the island [12]. 

Sonographic findings

Prenatal recognition of Larsen syndrome is very difficult; in a review of the literature by Shih et al (2004),21 only six cases of prenatal diagnosis have been realized. They are as follows:

Three cases were diagnosed following targeted US examination in women who themselves were affected by the syndrome or who had previous affected children :

  • Mostello (1991) made the first ultrasonographic discovery of a recurrent familial case of Larsen syndrome at 20 weeks GA (genu recurvatum). The baby died of pulmonary hypoplasia after birth [30];
  • Rocheteau (1993) also described a recurrent case at 21 weeks GA. The mother was also affected by Larsen syndrome [31]; 

Rodriguez (1994) described a fetus of a Larsen syndrome mother [32].
Three other cases presented as incidental findings during routine fetal ultrasonography: 

  • Lewit (1995) described the earlier case, analyzed at 15 weeks GA [18]. 
  • Lumbroso (1982) described another case [28].
  • Rodriguez (1993) described one case [32].

The cardinal feature of our case was the anterior knee dislocation.  Also detected with 3D ultrasound were unilateral luxation of the left elbow and dwarfism.
Distinctions between Larsen syndrome and Larsen-Bourbon syndrome:
Criteria for Larsen-Bourbon syndrome diagnosis are the association of (1) dwarfism; (2) facial dysmorphism; and (3) articular laxity and/or luxation.

  1. Dwarfism: Dwarfism in Larsen-Bourbon syndrome is extremely important (quite the opposite to Larsen syndrome), with mature height expected to be < 125 cm.  Dwarfism has been very rarely reported in classic Larsen syndrome: only one citation each from Silvermann, Latta, Fauré, and Harris, and a few observations from Maroteaux. Topley described two Larsen syndrome cases in Saudi Arabia [33] which seem to share characteristics with our Réunion Island cases.
  2. Facial dysmorphia (facies) is quite similar between Larsen-Bourbon syndrome and Larsen syndrome. There is no hypertelorism, but the eyes are globular. The mouth and ears appear small; the forehead is prominent. The general aspect of an adult or adolescent affected with Larsen-Bourbon syndrome is  that of an old, grotesque gnome [34-35-36].
  3. Articular laxity is  more significant in Larsen-Bourbon syndrome than in Larsen syndrome; it presents with the aspect of a disarticulated jumping-jack. Hyperlaxity of the fingers is most often observed as well. Luxations, usually bilateral, are most crucial in the elbow and the knee. In the upper extremities, the shoulders are normal, but the wrists can display hyperlaxity with metacarpophalangeal luxations (“rubber hand“). Luxation of the hip is more rare in Larsen-Bourbon syndrome than in Larsen syndrome [36]. There is a “clinical homogeneity” of Larsen-Bourbon syndrome. The eponym Larsen-Bourbon syndrome was proposed in 1982 by Tolleanere [12].

Psychomotor deficits present more frequently in Larsen-Bourbon syndrome than in Larsen syndrome.  According to Payet [9], debility is significant in Larsen-Bourbon syndrome patients, but Laville does not agree with this idea [36]. Indeed, here on Réunion Island, after birth, children are hospitalized during the month, isolated from family, who visit only at weekends. These children have no education or socialization, and sadly, the characteristic course is that of a solitary adult who spends his or her life in a specialized institute.

Spinal anomalies: Luxations are possible, particularly cervical compressions [37-38]. Lack of fusion of the posterior vertebral segments and kyphoscoliosis may be seen. There is a significant risk of cervical medullar compression resulting in sudden death. 

 Chronic respiratory infections are possible, due to costal cartilage luxations, sometimes with severe thoracic deformation. 

The global physical impression of Larsen-Bourbon syndrome is that of a sad puppet [34].

Implications for targeted ultrasound examinations

On Isle de la Réunion, it is essential that we clarify the differential diagnosis between Larsen syndrome and Larsen-Bourbon syndrome. Larsen syndrome is characterized by the triple association of facial dysmorphia, luxations, and anomalies of the extremities.
Facial dysmorphia in Larsen syndrome is typically constituted of hypertelorism, prominent forehead, micrognathia, and a flat face.
Multiple joint luxations (dislocations): clubfoot; luxations of the hips and elbows; knees demonstrating congenital genu recurvatum; radial luxation [34]; short metacarpals with cylindrical fingers lacking the usual tapering; as well as characteristic facies, are typical of Larsen syndrome.
Orthopedic malformations are the principal anomalies of the extremities, with malformed congenital genu recurvatum, usually bilateral; rocker-bottom feet; supernumerary carpal bones; and short terminal phalanges creating pseudoclubbing.
Additional possible associated anomalies in both Larsen syndrome and Larsen-Bourbon syndrome are cleft palate, hydrocephalus, cerebellar agenesis, vertebral anomalies, cardiac defects, laryngo-tracheomalacia, hearing loss and pulmonary hypoplasia [39-42].

Fetal position during the examination may obscure the genua recurvata, especially after the second trimester. Indeed, Lewit et al suggested that Larsen syndrome may be more easily detected in early gestation using two- and sometimes three- dimensional US (by endovaginal ultrasonography as well) when the fetus has its legs fully extended [18].

Nevertheless, even though three major signs are consistently part of Larsen syndrome, this syndrome fails in specificity.  After birth, radiologic analysis can differentiate Larsen syndrome from Larsen-Bourbon syndrome (in Larsen-Bourbon syndrome, long bones are all short with tibial and cubital bowing; radiocubital synostosis is frequently described).

Differential diagnosis

Chromosomal anomalies: Amniocentesis must be performed to exclude partial trisomy 1q, monosomy 6p, Down syndrome and Turner syndrome, all of which can be associated with congenital genu recurvatum. Nevertheless, oligohydramnios or footling breech presentation can be responsible for postural congenital genu recurvatum. Early amniocentesis (< 14 weeks GA) may also be associated with congenital genu recurvatum. Congenital genu recurvatum can be an isolated finding or can be associated with other anomalies or genetic syndromes. When one finds joint dislocations, Larsen-Bourbon syndrome must be suspected and differentiated from other syndromes.

Desbuquois syndrome is another genetic entity which must be ruled out. Intrauterine growth restriction, abnormal facies (with exophthalmos) and abnormalities of the hands (bifid thumbs; luxation of the fingers). The femoral heads are described as having a “Swedish key” or “monkey-wrench” appearance;  and there can be some supernumerary bones near the second phalanx, which can feature radial deviation. Cardiopathy, constant cognitive deficits, respiratory deficits and orthopedic complications (of which kyphoscoliosis is the most important) are common. The neonatal death rate is 30 %. The transmission seems to be autosomal-recessive. The morbid locus is on the 17q25 gene.43

Other genetic syndromes characterized by joint hypermobility include the following: 

Arthrogryposis multiplex congenita is a heterogeneous group of pathologies with limitations of movement and severe joint ankyloses. There are deformities of the extremities which usually symmetric with increasing severity distally, and which feature significant limitation of movement flexion and extension. The face is normal [5].

Ehlers-Danlos syndrome (type II) is a connective-tissue disorder caused by a defect of collagen production, characterized by skin extensibility and fragility, and joint hypermobility. In utero, Ehlers-Danlos type II can be suspected if one sees an association of clubfoot, spondylolisthesis, spondylolysis, kyphoscoliosis, arachnodactyly, radial dislocation, and micrognathia. The rest of the face is normal. 

Marfan syndrome is a connective-tissue disorder as well; it is caused by an anomaly of protein fibrillin 1. Typical prenatal signs are cardiovascular and skeletal anomalies. The latter include pectus carinatum or excavatum; reduced upper-lower limb segment ratio; anomalies of length in the wrist and thumb; reduced extension of the elbows; medial displacement of the medial malleolus causing pes planus (flat feet); and ocular signs (blue sclera are discovered postnatally) [44].

Osteogenesis imperfecta is easily excluded in Larsen syndrome, because in osteogenesis imperfecta, all the long bones will display unmistakable sonographic characteristics (fractures, abnormal ossification, deformations) [45].

Diastrophic dwarfism is easily excluded in Larsen syndrome as well. It features micromelia with rocker-bottom feet; however, in the hands, there are no congenital luxations (disginguishing it from Larsen syndrome).

Greig-cephalo-polysyndactyly syndrome;

Pena-Shokeir phenotype;

Cerebro-occulo-facio-skeletal syndrome

Congenital tibiofemoral subluxation, spastic cerebral palsy, and cervical myopathy are among other conditions to be considered in the differential diagnosis between Larsen syndrome and Larsen-Bourbon syndrome [3]. In these cases, the congenital genu recurvatum is usually bilateral.

Isolated congenital genu recurvatum: Isolated congenital genu recurvatum is a rare condition with a low incidence (6.8/10,000). Its cause can be oligohydramnios as well as breech presentation. According to Monteagudo, the typical transient oligohydramnios present after selective interruption of pregnancy can be responsible for isolated congenital genu recurvatum as well. Gorincour et al described a case identical case to that of Monteagudo [3].

Associated anomalies

In Larsen-Bourbon syndrome, in addition to multiple joint dislocations, additional anomalies may be observed [34-36]:  

  • Talipes equinovarus or equinovalgus; 
  • Spatulate thumbs; 
  • Short metacarpals; 
  • Characteristic facies, inluding prominent forehead, hypertelorism, depressed nasal bridge, and micrognathia; 
  • Cleft palate ;
  • Cervical spine instability : atlanto-axial spine instability may lead to permanent neurological sequelae; 
  • Cardiac defects; 
  • Tracheomalacia; and
  • Pulmonary hypoplasia.

In Larsen-Bourbon syndrome, the fetal karyotype is normal. The muscular and skin biopsy are strictly normal.  However, laboratory findings (LFTs, Hb/Hct, etc.) will rarely be normal.


When Larsen syndrome is suspected in utero, the birth of the baby must be scheduled via caesarian section so as to prevent risk of high spinal injury and motor handicaps due to undue fetal neck traction.
The following symptoms must also be managed carefully to improve the prognosis: tracheomalatia; pulmonary insufficiency; and vertebral instability, in particular atlantoido-axial.  

Regarding the prognosis of Larsen-Bourbon syndrome, the course is very serious, with significant complications and deterioration of the joints. Concerning the 42 cases of Larsen-Bourbon syndrome which we have followed on Ile de la Réunion, six babies died during the first six months of life due to C-spine medullary compression,  tracheomalacia, and/or pulmonary infection [16].

In Larsen syndrome, the cognitive prognosis is normal; but in Larsen-Bourbon syndrome cases, the cognitive prognosis is gloomy, because the levels of education and of socialization are very unfavorable.


Prenatal diagnosis of Larsen-Bourbon syndrome is possible. Therefore, when Larsen syndrome or Larsen-Bourbon syndrome are suspected, a careful prenatal investigation must be performed to rule out other anomalies (cardiovascular and neurological anomalies in particular). The presence of any other lesions has a bad impact on prognosis and must lead us to propose an interruption of pregnancy.  According to French law, the option of pregnancy termination must be discussed if the diagnosis of Larsen syndrome or Larsen-Bourbon syndrome is made.

Amniocentesis and karyotyping must be offered to eliminate the possibility of chromosomal abnormalities. A careful analysis of family history should be made to rule out genetic inheritance. Molecular studies for mutations in the LAR1 gene must be studied as well.

Prenatal recognition of congenital dislocation of the knee is rarely described, and the diagnosis is usually made after the birth of the baby. Nevertheless, since it can be associated with Larsen-Bourbon syndrome, every attempt should be made to evaluate the knees prenatally.


We can speak about Larsen-Bourbon syndrome as an Larsen syndrome with some particularities: facial dysmorphia (giving the baby “family resemblance”), different articular luxations (knees, elbows, wrist, and fingers), rocker-bottom feet, and often having  intrauterine growth restriction (IUGR). Larsen-Bourbon syndrome is well known to Réunion Island’s pediatric orthopedic teams [34-36]. Indeed, Dr Laville, on our team, has the greatest experience with this osteochondrodysplasia in Europe, perhaps in the world.

Nevertheless, now, with advances in sonography, this syndrome can be discovered prenatally. Our case represents only the second prenatal discovery of Larsen syndrome [10]. After prenatal diagnosis, care of the baby will be scrupulous, with treatment of the orthopedic problems and the use of growth hormones.

In the future, it will be essential to identify the responsible gene and its locus.  In this way, for the ensuing pregnancy/pregnancies of the Larsen-Bourbon syndrome patient, one will be able to suggest complete genetic prognosis/diagnosis and counseling after amniocentesis.  This, however, is not yet possible without the gene locus. 

Two salient last points of concern must be raised about the obstetric course of the woman affected by Larsen-Bourbon syndrome: (1) she must receive no intubation during surgery (due to risk of cervical luxation); (2) and risk of possible cervical incompetence during pregnancy (due to collagen anomalies affecting successive pregnancies).



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