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2007-02-12-11 Apert syndrome: acrocephalosyndactyly © Cuillier www.thefetus.net/

Apert syndrome: acrocephalosyndactyly

Fabrice Cuillier, MD*, K. Comalli Dillon, BA, RDMS**, P. Lamaire, MD***, M. Deshayes, MD***.

*

Department of Gynecology, Felix Guyon Hospital, 97400 Saint- Denis, Ile de la Reunion, France; tel: 0262 90 55 22; fax : 0262 90 77 30;

**

***

 

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

Sonographers, Mouffia Street, 97400 Saint- Denis, Ile de la Réunion, France.

Definition

Craniosynostoses are the consequence of premature fusion of one or several cranial sutures. They are often associated with facial structural anomalies. The frequency of craniosynostosis is estimated at 0.2:10,000 births [1]. When craniosynostoses are isolated, they are considered nonsyndromic; this occurs in 85% of cases. They are classified by the type of suture affected [2]. When craniosynostoses are associated with facial or limb anomalies, they are considered syndromic (15% of cases). 

We report the case of a fetus with acrocephalosyndactyly discovered in the second trimester. We used a spiral scanner to confirm our initial diagnosis. The patient chose to interrupt pregnancy.

Case report

The patient, 30 years old, G2P1, had an unremarkable family history and was exposed to no teratogens. Her triple screen was normal as was nuchal translucency on her 12-week ultrasound exam. At 24 weeks, the patient had her second ultrasound exam where an abnormal profile and abnormal fingers were seen. The patient was then referred to our prenatal center. On sonography we discovered:

  • Frontal bossing (Image 1, 2) and a very marked frontonasal angle (Image 2). Prognathia and low-set ears were also seen (Image 4);

  • Exophthalmos (Image 5) and eyelid edema (Image 6);

  • Bilateral dilatation of the atria of the lateral ventricles to 12 mm, dilatation  of their lateral horns, and hypoplasia of the corpus callosum;

  • At the neurocranial level, the coronal suture appeared to have fused prematurely. The anterior cranium was unusually convex with a “strawberry” shape (Images 15, 16);

  • Abnormal upper extremities with digital fusion (“mitten hands”) (Images 7, 8, 9, 10, 11). 3D sonography confirmed these anomalies (Images 13, 14);

  • Possible syndactyly of the lower extremities (Image 12).

The remainder of fetal morphology seemed unremarkable. The presumed diagnosis was acrocephalosyndactyly, specifically Apert syndrome, confirmed on spiral CT scan at 25 weeks. Craniosynostosis with closed coronal sutures was seen. (Images 15, 16).

Interruption of pregnancy was carried out with amniocentesis and cord puncture. Pathophysiologic analysis confirmed diagnosis (Images 17, 18, 19). Postmortem radiography was done (Image 20).

Images 1, 2: 2D sagittal scans of the fetal head showing frontal bossing.

 

Images 3, 4: 3D images showing frontal bossing (left); and low set ear (right).

 

Images 5, 6: Transverse planes through the skull showing protuberant eyes and eyelid edema.

 

Images 7, 8: 2D scans showing "mitten hands".

 

Images 9, 10: 2D scans showing "mitten hands".

 

Images 11, 12: 2D scans showing "mitten hands" (left); and possible syndactyly of the lower extremities (right). 

 

Images 13, 14: 3D scans showing "mitten hands".

 

Images 15, 16: Transverse planes through fetal cranium showing impresions at the level of coronal suture due to its premature fusion.

 

Images 17, 18: Postmortem images of the baby.

  

Image 19: Postmortem image of baby"s hand showing syndactyly.

 

Images 20, 21: Postnatal radiogram (left) and spiral CT image (right).

 

Synonyms

Apert syndrome; acrocephalosyndactyly; acrocephalopolysyndactyly; dyscraniodysphalangeal syndrome [11].

History

The first description of Apert syndrome was made by Wharton in 1894. In 1906, Apert studied nine afflicted children, delineating the syndrome much further [5]. The first prenatal diagnosis of acrocephalosyndactyly was done on fetoscopy by Leonard in 1982 [6]. Ferreira et al described the first sonographic discovery of acrocephalosyndactyly, later confirmed on DNA analysis. Prenatal diagnosis of acrocephalosyndactyly is nonetheless rare. Third-trimester diagnosis of acrocephalosyndactyly  has been common for twenty years (Kim et al in 1986, then Hill et al in 1987) [7]. The first second-trimester diagnosis was made at 17 weeks by Narayan and Scott in 1991; this family had several afflicted members. In 1997, Chi-Chen Chang et al reported a case of acrocephalosyndactyly in a fetus of 20 weeks whose mother had the syndrome. In her subsequent pregnancy, acrocephalosyndactyly was excluded after amniocentesis and genetic analysis [8]. In 2003, Skidmore reported discovery of acrocephalosyndactyly at 19 weeks. In 1998, Chang et al made the first successful genetic analysis of the mutation responsible for acrocephalosyndactyly.

Prevalence

Acrocephalosyndactyly is the most severe craniosynstosis, but only represents 4.5 % of all craniosynostoses. Prevalence is approximately 0.16:10,000 cases. Incidence is estimated at 1:100,000 pregnancies; however, this figure may not be accurate due to additional, undocumented  causes of intrauterine death, and spontaneous abortions. The gender ratio of acrocephalosyndactyly is 1:1. Acrocephalosyndactyly is associated with advanced paternal age [10].

Etiology

Three skeletal dysplasias and seven craniosynostoses result from mutation of two FGFR (fibroblast growth factor receptor) genes. A mutation on one of these genes leads to developmental mesenchymal anomalies, which results in defects in cartilaginous growth as well as premature fusion of cranial sutures. 12 In 1995, Ferreira established established that two mutations of FGFR2 (Fibroblast growth factor receptor 2) are responsible for 98% of all acrocephalosyndactyly [5]. The anomaly is situated on the 10q25-10q26 chromosome; the mutation involves substitution of an amino acid. Substitution involves either amino acid Ser252Trp or Pro253Arg, either of which can act as a link between the second and third extracellular immunoglobulins of FGFR2 [12]. Certain authors [6] find that the form of acrocephalosyndactyly  manifests as more or less severe depending on the function of the mutation. For example, acrocephalosyndactyly  with the mutation on amino acid Pro253Agr features less severe craniofacial anomalies, but syndacytlies of a more complex nature which are more difficult to correct surgically. Over 98% of cases of acrocephalosyndactyly are sporadic, resulting from spontaneous mutation of FGFR2 [5]. Rare recurrent cases have been described in cases with unafflicted parents, probably explained by germinal mosaicism [8]. The vast majority of acrocephalosyndactyly cases have a normal karyotype. Nonetheless, autosomal dominant transmission is possible; if a parent is a carrier of the mutation, transmission risk is 50%. Autosomal recessive transmission has not been described. Prenatal diagnosis is possible on chorionic villi sampling or after amniocentesis [13].

Sonographic findings

There is no specific sign of acrocephalosyndactyly in the first trimester, primarily due to insufficient sonographic spatial resolution of tiny developing structures such as the digits. Even endovaginal ultrasound is not sufficient in most cases. However, Chenoweth-Mitchel and Cohen (1984) described a case of acrocephalosyndactyly with normal nuchal translucency discovered in the first trimester [13]. Recently, Aleem et al [14] also described another first-trimester case of acrocephalosyndactyly with normal nuchal translucency. A striking first-trimester observation of acrocephalosyndactyly was made in 1997 by Filkins, who documented “mitten hands,” confirmed in the third trimester [13]. In the second trimester, classic signs of acrocephalosyndactyly are:

  • Craniostenosis with brachycephaly due to synostosis of the coronal sutures [8];

  • Hypoplasia of midfacial osseous structures,  hypertelorism, and exophthalmos visible on sonography;

  • Cutaneous and/or osseous syndactyly of all four distal extremities “mitten hands”. The thumbs sometimes have independent mobility, but are unusally large and thick.

Other anomalies may present in the second trimester:

  • Various cardiac anomalies have been described;

  • Genitourinary: multicystic dysplasias; pelvicaliceal dilatation;

  • Cerebral: partial or total agenesis of the corpus callosum is the most classic anomaly, but ventriculomegaly, hydrocephalus, and abnormal gyri are also described [10].

In the third trimester, polyhydramnios is classically seen, a result of impaired fetal deglutition. Craniofacial and distal upper extremity malformations are better visualized at this term of pregnancy.

Implications for targeted examinations

Membranous syndactyly is a normal part of fetal development, and apoptosis causes the disappearance of the membranes at approximately 8-9 weeks GA. However, in craniosynostosis, membranous syndactylies continue and osseous syndactylies are present in all embryos. The first sign (in the first trimester) of craniosynostosis is syndactyly; premature closure of cranial sutures only appear later, in the second trimester, as Kuan-Jiin et all showed in 2000 [11].

For this reason, diagnosis of acrocephalosyndactyly is often made only in the third trimester [7], and often in pregnancies with no other perceived risk. Recently, Lam et al described acrocephalosyndactyly discovered at 19 weeks with the aid of 3D ultrasound analysis of cranial sutures [7]. 3D permits early visualization of premature ossification of the coronal sutures, sometimes seen with widening of the metopic suture as well. Pathognomonic “mitten hands” are the cardinal feature of acrocephalosyndactyly and constitute a red flag when seen in utero. Cranial turricephaly is the second prominent feature of note; if these two malformations are seen, concern arises for premature closure of the coronal sutures. When these features along with deformation of calvarial contours and abnormal facial profile are seen between 24 and 28 weeks, most authors consider the diagnosis of acrocephalosyndactyly to be confirmed.

Differential diagnosis

Distinction is made between the different syndromes.
  • Crouzon syndrome, or craniofacial dysostosis: acrocephalosyndactyly type II, associated with craniosynostosis of the coronal sutures and facial bone hypoplasia.

  • Pfeiffer syndrome: acrocephalosyndactyly type V, associated with brachycephaly (with cloverleaf skull) and membranous syndactyly of hands and feet. Also noted is an enlargement of the thumbs and big toes with lateral deviation of the toes.

  • Saethre-Chotzen syndrome: acrocephalosyndactly type III. The craniosynostosis is variable. Ptosis of the eyelids and ears with prominent antihelical crura (crux cymbae) are seen; syndactyly of the second and third fingers may present.

  • Apert syndrome: accrocephalosyndactyly type I. This is the most severe craniosynostosis, associated with bicoronal facial craniosynostosis, osseous and/or membranous syndactyly of all four extremities, giving the appearance of “mitten” hands and feet [3-4].

Although acrocephalosyndactyly  can be differentiated from other craniosynostoses, certain are close within the differential:

  • Carpenter syndrome (acrocephalosyndactyly type 1: sagittal, coronal, and lambdoid synostosis);

  • Saethre-Chotzen syndrome;

  • Pfeiffer syndrome (acrocephalosyndactyly type V: sagittal, coronal, and cranial synostosis;

  • Crouzon syndrome (sagittal, coronal, and lambdoid synostosis, differentiated from acrocephalosyndactyly by analysing the digits);

  • Antley-Bixler syndrome;

  • Rubinstein-Taybi syndrome;

  • Skeletal dysplasias such as achondroplasia or thanatophoric dysplasia.

Prognosis

Although decompression cranial surgery is frequently performed in cases of acrocephalosyndactyly unfortunately the surgery does not forestall psychomotor damage. Craniosynostosis almost always creates intracranial hypertension. Other defects such as corneal lesions and problems of dental articulation present as well. The prognosis of acrocephalosyndactyly is grave. Profound functional and mental disability is frequently present, and intellectual impairment, in a coefficient proposed by Regnier et Lajeunie [12], is always below 80% of normal. Very rare cases of adults of normal intellect have been described; nevertheless they must undergo serial surgeries of the extremities with limited functional and esthetic success.

Conclusion

Spiral CT scans may be useful, as in our case, to reach early diagnosis of craniosynostosis. However, 3D ultrasound, as shown by Lam et al [7], can yield even earlier diagnosis at the end of the first trimester, and provides a means of studying cranial shape and the state of cranial sutures. Upon prenatal discovery of acrocephalosyndactyly in France, parents are offered interruption of pregnancy, given the negative intellectual and surgical prognosis of the condition. In the United States, predilection to interruption of pregnancy seems more controversial. If parents wish to continue pregnancy, prenatal care, labor, and delivery will be closely followed. In cases of macrocrania, cesarian section may be necessary depending on the cephalopelvic relationship.

References

1.    

Lépinard C.-Craniosténoses: diagnostic antenatal échographique. Med Foet Echo Gynecol 1994; N°17: 31-6

2.    

Rénier D., Lajeunie E.- Craniosténoses. Med Foet Echo Gynecol 2000; N°44: 65-74.

3.    

Chi-Chen Chang, Fuu-Jen Tsai, Horng-Der Tsai, Chaung-Hai Tsai, Yao-Yuan Hsieh, Chien-Chung Lee, Tung-Chuan Yang, Jer-Yuarn Wu- Prenatal diagnosis of Apert syndrome. Prenatal Diagnosis 1998; 18: 621-5.

4.    

Delinière F., Lepinard C., Kerjean F., Wartanian R., Rabourdin-Bleytou S., Grosieux P.- Syndrome d’Apert. Diagnostic échographique, prise en charge obstétricale. J Gynecol Obstet Biol Reprod 1995; 24: 613-7.

5.    

Ferreira J.C., Carter S.M., Bernstein P.S., Jabbs E.W., Glickstein J.S., Marion R.W., Baergen R.N.- Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol 1999; 14: 426-30.

6.    

Hansen W.F., Rijhsinghani A., Grant S., Yankowitz J.- Prenatal diagnosis of Apert syndrome. Fetal Diagn Therapy 2004; 19: 127-30.

7.    

Lam H., Tsk-Kin Lo, Lau E., Chin R., Tang L. - The use of 2- and 3-Dimensional sonographic scans in the evaluation of cranial sutures. Prenatal diagnosis of Apert syndrome. J Ultrasound Obstet 2006; 25: 1481-4.

8.    

Hill L.M., Thomal L.M., Peterson C.S. - The ultrasonic detection of Apert syndrom. J Ultrasound Med 1987; 6: 601-4.

9.    

Skidmore D.L., Pai A.P., Toi A., Steele L; Chitayat D.- Prenatal diagnosis of Apert syndrome: report of two cases. Prenatal diagnosis 2003; 23: 1009-13.

10. 

Izquierdo L.A., Puente Y.- Apert syndrome. Thefetus.net 2001-03-16-10.

11. 

Kuan Jiin Lyu, Tsang-Ming Ko- Prenatal diagnosis of apert syndrome with widely separated cranial sutures. Prenatal Diagn 2000; 20; 254-6.

12. 

Pooh R.K., Nakagawa Y., Pooh K.H., Nakagawa Y., Nagamashi N.- Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome. Ultrasound Obstet Gynecol 1999; 13: 274-80.

13. 

Filkins K., Russo J.F., Boehmer S., Camous M., Przylepa K.A., Jiang W., Wang Jabs E.- Prenatal ultrasonographic and molecular diagnosis of Apert syndrome. Prenatal Diagn 1997; 17: 1081-4.

14. 

Aleem S, Howarth ES. Apert syndrome associated with increased fetal nuchal translucency Prenat Diagn. 2005 Nov; 25(11):1066-7.

 

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