Apert syndrome: prenatal diagnosis challenge

Abstract

Apert syndrome is a rare genetic disorder that manifests as craniosynostosis, craniofacial and limb dysmorphic features. Mutations in fibroblast growth factor receptor 2 (FGFR2) gene account for almost all cases. Given the impact it can have throughout life, prenatal management becomes a challenge. A healthy 33-year-old woman, gravida 4, para 0, was referred to routine ultrasound at 22 weeks of gestation. Atypical cranial morphology with prominent forehead, ocular proptosis, hypertelorism and mitten hands were detected. Genetic investigation revealed an FGFR2 gene mutation (c.755C>G(p.Ser252Trp)), confirming the diagnosis. Magnetic resonance showed brachycephaly, turricephaly and cortical malformation. Following counselling, parents requested medical termination of pregnancy. Macroscopic features were consistent with ultrasound findings. This case emphasises the importance of early diagnosis to provide the best family counselling and prenatal management. A multidisciplinary team, consisting of an obstetrician with ultrasonography experience, a medical geneticist and a fetal pathologist, should conduct these cases.

Background

Apert syndrome is a rare autosomal dominant disorder that occurs in 6–15 out of 1 million livebirths and accounts for 4.5% of all craniosynostosis. It manifests as craniosynostosis, craniofacial and limb dysmorphic features. Maxillary hypoplasia and bicoronal synostosis are two noticeable craniofacial defects, that cause a flat, recessed forehead and midface. Besides that, hypertelorism and exorbitism, low-set ears, flat nasal structure and palate cleft can also be found. Strabismus and hearing loss are frequent. Syndactyly is a characteristic feature of Apert syndrome, since it allows the differential diagnosis with other craniosynostosis syndromes. Cardiovascular, neurological and genitourinary abnormalities may be present.^{1 2}

Mutations in the gene encoding fibroblast growth factor receptor 2 (FGFR2) located on chromosome 10 account for almost all known cases.²

Given the impact it can have throughout childhood and adult life, the prenatal and perinatal management becomes a challenge. Therefore, it is crucial to proceed to a complete investigation from the moment the first anomaly is detected, in order to make an early diagnosis and offer the parents the appropriate counselling.

Case presentation

A healthy 33-year-old woman, gravida 4, para 0 (3 early pregnant losses), with no risk factors and irrelevant medical and family history, was referred to our prenatal diagnosis unit for routine ultrasound at 22 weeks of gestation. There were no complications during the pregnancy until this evaluation. An atypical cranial morphology with a prominent forehead was detected, associated with ocular proptosis and hypertelorism (figure 1). Mitten hands were also suspected (figure 2). These findings suggested the presence of a craniosynostosis syndrome. Following counselling, the couple opted for the performance of amniocentesis and fetal magnetic resonance, and was referred to genetic counselling.

Figure 1.

The ultrasound showed an atypical cranial morphology of the fetus, with a prominent forehead, and hypertelorism (arrows).

Figure 2.

The fixed position of the fingers in both hands raised the suspicion of mitten hands (arrows).

Investigations

The results showed a normal female karyotype and the molecular study, conducted having the craniosynostosis suspicion in mind, revealed an FGFR2 gene mutation (c.755C>G(p.Ser252Trp)), which confirmed the diagnosis of Apert syndrome.

Further examination of the fetus by MRI showed cranial dysmorphia, with brachycephaly, turricephaly, cortical malformation and hypertelorism (figure 3).

Figure 3.

The magnetic resonance confirmed the presence of cranial dysmorphia, with brachycephaly, turricephaly and hypertelorism (arrows).

Differential diagnosis

Craniosynostosis syndromes, including Crouzon, Pfeiffer, Carpenter and Saethre-Chotzen.

All craniosynostosis syndromes can be caused by mutations in FGFR2 gene, except Carpenter syndrome (which is associated with mutations in RAB23 (Ras-associated protein)), and can have similar clinical manifestations.

In Crouzon syndrome, the facial deformity is usually milder than the one present in Apert syndrome, and defects of hands and feet are not typical.

Pfeiffer syndrome is frequently associated with skeletal (eg, radiohumeral synostosis of the elbow), central nervous system (eg, hydrocephaly) and gastrointestinal abnormalities (eg, imperforated anus), which were not present in this case.

Syndactyly can be present in Pfeiffer and Saethre-Chotzen syndromes, but they are usually partial, unlike Apert syndrome. Indeed, syndactyly is a characteristic feature of Apert syndrome and can be very useful for the distinction from the other craniosynostosis syndromes, since it is usually complex, with the index, middle, ring and fifth fingers sharing fused bone (mitten hands). This can also be present in the feet. In this case, the fetus presented with this feature, which led the authors to suspect of Apert syndrome.^{1 2}

Outcome and follow-up

Following counselling, parents’ requested medical termination of pregnancy.

Macroscopic abnormalities of the fetus included craniosynostosis, hypertelorism and exorbitism, low-set ears and syndactyly of the second through fifth fingers in both hands and all fingers in the feet (figures 4–7). No visceral malformations were observed.

Figure 4.

General macroscopic appearance of the fetus, showing abnormal configuration of the head, hands and feet.

Figure 5.

Macroscopic features of the fetus included craniosynostosis, hypertelorism, exorbitism and low-set ears.

Figure 6.

Syndactyly of the second through fifth fingers in both hands.

Figure 7.

Syndactyly of all fingers in both feet.

Discussion

Apert syndrome is a rare craniosynostosis syndrome that usually manifests as craniosynostosis, craniofacial and limb dysmorphic features.^{1 2}

Prenatal diagnosis of craniosynostosis syndromes is difficult prior to the third trimester. Many cases remain undiagnosed until delivery or are diagnosed in late gestation when craniofacial deformities become more evident.² Moreover, cardiovascular or central nervous system malformations such as atrial or ventricular septum defects or mild ventriculomegaly or agenesis of corpus callosum, respectively, may be visible in some fetuses with Apert syndrome before the pathognomonic skeletal changes are revealed. Even more atypical presentations, such as omphalocele or diaphragmatic hernia, have also been published.³ Therefore, although this syndrome is characterised by a specific set of malformations, the heterogeneity of clinical presentation and the difficulties in its early detection make the diagnosis a challenge.²

In our case, the suspicion of typical malformations of hands and face led to the timely diagnosis of Apert syndrome.

Many studies evaluated the role of ultrasound and MRI in the early prenatal diagnosis of this disorder and they seem to have a complementary role.^{4 5}

This case emphasises the constant need of a thorough fetal ultrasound and a high level of suspicion to detect fetal anomalies, since they can be discrete in some cases. It is important to do this as soon as feasible in order to initiate the necessary investigations to reach a diagnosis and provide adequate family counselling and prenatal management. The use of three-dimensional ultrasound can lead to a more thorough evaluation of structural defects and better patient understanding of genetic conditions.

Family history is usually not significant because most cases of Apert syndrome are sporadic.

Evaluation of the fetal karyotype and molecular study are crucial in many contexts of ultrasound detection of fetal abnormalities, since they can guide or provide the final diagnosis and may give prognosis information. In Apert syndrome, the final diagnosis implies the identification of the FGFR2 mutation, therefore the involvement of a medical geneticist is important.

A fetal pathologist should also integrate the medical team. A detailed fetal autopsy can provide better characterisation of the malformations and reveal further anomalies not previously detected by ultrasound.

Learning points.

• Apert syndrome is a rare genetic disorder caused by an usually sporadic fibroblast growth factor receptor 2 mutation that manifests as craniosynostosis, craniofacial and limb dysmorphic features.

• Prenatal diagnosis of craniosynostosis syndromes is difficult prior to the third trimester, which makes appropriate and timely family counselling a challenge.

• Ultrasonography and magnetic resonance assume complementary roles in the investigation of fetal malformations.

• A multidisciplinary team, consisting of an obstetrician with ultrasound experience, a medical geneticist and a fetal pathologist, should conduct these cases.