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:
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Craniostenosis with brachycephaly due to synostosis of the coronal sutures [8];
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Hypoplasia of midfacial osseous structures, hypertelorism, and exophthalmos visible on sonography;
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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:
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Various cardiac anomalies have been described;
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Genitourinary: multicystic dysplasias; pelvicaliceal dilatation;
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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.
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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:
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Carpenter syndrome (acrocephalosyndactyly type 1: sagittal, coronal, and lambdoid synostosis);
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Saethre-Chotzen syndrome;
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Pfeiffer syndrome (acrocephalosyndactyly type V: sagittal, coronal, and cranial synostosis;
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Crouzon syndrome (sagittal, coronal, and lambdoid synostosis, differentiated from acrocephalosyndactyly by analysing the digits);
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Antley-Bixler syndrome;
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Rubinstein-Taybi syndrome;
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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.