Emphasis on Early Prenatal Diagnosis and Perinatal Outcomes Analysis of Apert Syndrome

Apert syndrome is an inherited condition with autosomal dominant transmission. It is also known as acrocephalosyndactyly type I, being characterized by a syndrome of craniosynostosis with abnormal head shape, facial anomalies (median hypoplasia), and limb deformities (syndactyly, rhizomelic shortening). The association can suspect the prenatal diagnosis of these types of anomalies. The methodology consisted of revising the literature, by searching the PubMed/Medline database in which 27 articles were selected and analyzed, comprising 32 cases regarding the prenatal diagnosis of Apert syndrome. A series of ultrasound parameters, the anatomopathological abnormalities found, the obstetric results, and the genetic tests were followed. The distribution of imaging results (US, MRI) identified in the analyzed cases was as follows: skull-shaped abnormalities were evident in 96.8% of cases, facial abnormalities (hypertelorism 43.7%, midface hypoplasia 25%, proptosis 21.8%), syndactyly in 87.5%, and cardiovascular abnormalities in 9.3%. The anomalies detected by the ultrasound examination of the fetus were confirmed postnatally by clinical or gross evaluation or imaging. The management of these cases requires an early diagnosis, an evaluation of the severity of the cases, and appropriate parental counseling.


Introduction
Apert syndrome is a severe autosomal dominant disorder caused by gene mutations that encode fibroblast growth factor receptor 2 (FGFR2) on chromosome 10q [1,2].Most cases appear de novo because of new mutations, so familial recurrence risk is low.However, more than 98% of all cases are infrequent and associated with advanced paternal age [3,4].It is defined by early fusion of the cranial sutures (craniosynostosis) and syndactyly in the hands and feet, other associated anomalies having a low rate of occurrence (skeletal, cerebral, skin, internal organs, and oral/maxillofacial region) [1,5,6].Apert syndrome is a rare condition, accounting for 6 to 15.5 out of 1 million live births, and it represents 4.5% of all cases diagnosed with craniosynostosis syndromes [7,8].The condition's prevalence was 2.9 times higher in Asians compared to Hispanics, and the distribution related to the child's sex (male-female) varied between 0.79 and 0.94 [9].
Establishing an early prenatal diagnosis, especially of severe forms, is very important for counseling parents regarding the poor prognosis of these cases with serious sequelae, and in the case of mild forms of pregnancy monitoring, planning the moment of birth and their neonatal support [7].
The 2D prenatal ultrasound evaluation of the fetus can reveal several anomalies characteristic of this syndrome by highlighting facial morphology anomalies (facial hypoplasia, orbital, pharyngeal bone anomalies) and syndactyly (fusion of fingers and/or toes).The 3D imaging reconstruction of the fetal skull and limbs (ultrasound, MRI) is complementary, being crucial in establishing the diagnosis of Apert syndrome and differentiating it from other craniosynostosis [11,12].Carrying out the 4D ultrasound can reveal the vicious positions that affect fetal mobility.In the absence of the fetal anomalies characteristic of this syndrome, it is necessary to establish the genetic diagnosis by karyotype from the amniotic fluid.Establishing the diagnosis and its severity is important in correct parental counseling.
Often, managing cases with less severe evolution requires a multidisciplinary perspective involving a plastic, oral, maxillofacial, and orthodontic surgical approach, recovery of motor function, and psychological counseling.In cases of Apert syndrome, the medical team requires the involvement of a medical geneticist to establish the FGFR2 mutation; the definitive diagnosis can be confirmed only by molecular testing.In cases of fetal death, the pathologist is necessary to confirm the anomalies detected by imaging and to identify other possible anomalies associated that could not be diagnosed prenatally [10].
This article aims to review the reported cases of severe Apert syndrome detected early prenatally during second-trimester ultrasound screening and to highlight the role of parental counseling, therapeutic management, and prognosis.It has been observed that most cases are diagnosed late in the third trimester when managing these situations becomes much more difficult.

Literature Review
Apert syndrome (acrocephalosyndactyly type I) is a syndrome with a low incidence rate characterized by the following classic triad: craniosynostosis, flat midface, and bilateral syndactyly [7].
Normal brain development will determine the proper development of the fetal skull.Thus, the process of closing the cranial sutures takes place according to the following model: Initially, the metopic suture is closed at the age of two, and then until adulthood, the other sutures are closed after the completion of craniofacial development.When craniosynostosis is an isolated anomaly, it frequently involves the sagittal suture [13], compared to that which is part of a genetic syndrome (Apert, Pfeiffer, Crouzon, Carpenter, and Saethre-Chotzen), when several sutures are affected.In Apert syndrome, a bicoronal synostosis is observed [14].The genetic syndromes that associate craniosynostosis determined by FGFR2 gene mutations are autosomal dominant and show a variable degree of overlap of some clinical signs.The exception is Carpenter syndrome, caused by the RAB23 mutation, which is autosomal recessive [15].
Prenatal identification of the presence of craniosynostosis is important because it induces long-term complications such as impairment of neurodevelopment and cognitive function, increased intracranial pressure (Chiari malformation), impairment of cranial nerve function with vision, hearing and speech deficits, and psychological problems.Ultrasound evidence of hydrocephalus is found in approximately 8% of all cases of craniosynostosis; in the case of Apert syndrome, ventriculomegaly is usually non-progressive [16].The prenatal diagnosis of this syndrome is based on the ultrasonographic examination.There is no specific sign of Apert syndrome in the first trimester due to the insufficient sonographic resolution of the developing fetal structures, such as the fingers.It may be associated with increased nuchal translucency [17].
The severity of cases with Apert syndrome can be evaluated based on the associated craniofacial anomalies that can cause damage to the respiratory tract (reduction in naso/oropharyngeal spaces) and visual impairment.Thus, the prenatal assessment of the severity of craniosynostosis based on the classification of Lu et al. (bicoronal synostosis, pansynostosis, and perpendicular combination of synostosis) can be used as a possible management tool for these patients [18].Any other element of associated anatomical distortion (e.g., mitten hands, proptosis) increases the degree of severity of these cases, negatively influencing the prognosis [11].Delahaye et al. demonstrated that suture closure observed in the third trimester of pregnancy was preceded by anatomical distortions and deformations of the fetal skull shape by 4 to 16 weeks [19].Deformation of the fetal skull shape, abnormal biometry, and ventriculomegaly, identified by 2D/3D ultrasound or MRI, can be imaging markers of fetal craniosynostosis [20,21].
In the second trimester, classic features of Apert syndrome include acrocephaly and brachycephaly, craniofacial dysmorphic elements: flat forehead, maxillary hypoplasia causing a flat midface, hypertelorism, bilateral exophthalmos, low-set ears, small and flat nose, and cleft palate (in one-third of cases).In the conditions of a hypoplastic or malformed pharynx, severe respiratory problems can be associated.During the prenatal examination, possible bone abnormalities can be identified, such as syndactyly present both in the hands and feet, and it is necessary to establish the type of syndactyly (often "mitten-like" hand).Other possible anomalies in the hands and feet that can be identified are the absence of the middle phalanges and absent or supernumerary carpal/tarsal bones [22,23] (Figure 1).
amination, possible bone abnormalities can be identified, such as syndactyly present both in the hands and feet, and it is necessary to establish the type of syndactyly (often "mittenlike" hand).Other possible anomalies in the hands and feet that can be identified are the absence of the middle phalanges and absent or supernumerary carpal/tarsal bones [22,23] (Figure 1).A gross examination of the head and brain revealed craniosynostosis, hypertelorism, exorbitism, hypoplastic nose, pharynx abnormality, gyral anomalies, hypoplastic white matter, and heterotopic gray matter (personal collection) [24].
Other syndromes associated with syndactyly are facial digital syndrome type I, Cornelia de Lange, Russel Silver, Opitz, Adams Oliver, Holt Oram, Roberts, Fraser, Treacher Collins, and Nager syndromes.They are also associated with other anomalies, such as skeletal defects, but they do not involve the presence of craniosynostosis [25].
Fibroblast growth factor (FGF) is a protein that acts through FGF receptor (FGFR) with tyrosine kinase activity and has implications in morphogenesis, migration, proliferation, and differentiation of stem cells involving osteoblasts and chondroblasts.FGF is responsible for the development of the axial and craniofacial skeletal.The study of the molecular basis of Apert syndrome revealed a genetic mutation of the Ser252Trp or Pro253Arg amino acids, which link the immunoglobulin-like domains II and III of FGFR2.The S252W amino acid mutation is the most frequent and associates severe craniofacial anomalies, and the Pro253Arg amino acid mutation associates severe syndactyly and less severe craniofacial defects [4,17].FGF8 and FGF10 trigger limb bud development by proliferation of undifferentiated mesenchymal cells.Limb growth results from regulating various genes, including those of the HOX family, and from the effects of FGFs.Mutations in the genes encoding FGFR1, FGFR2, and FGFR3 can cause skeletal dysplasias and craniosynostosis syndromes [26].The differential diagnosis of Apert syndrome is difficult due to the overlap of clinical signs with other syndromes with craniosynostosis (Table 1).
The early prenatal diagnosis of Apert syndrome and, respectively, of other syndromes involving craniosynostosis is correlated with the prognosis of these cases and the therapeutic management related to the gestational age at which the diagnosis is established; because in many countries, according to the legislation, the termination of pregnancy argued by for medical reasons is allowed up to 24 weeks of gestation.Therefore, we performed an all-time electronic search of the specialized literature.We accessed the PubMed database and selected the articles (case series and case reports) written in English, French, and Spanish.Search terms were "craniosynostosis", "Apert syndrome", "early prenatal diagnosis", "second-trimester screening", "treatment", "prognosis", AND "fetuses" OR "newborns".In the end, 27 articles were eligible, totaling 32 cases included in this article's review (Table 2).
The average maternal age in the presented cases was 31.9 (range 23-39).The average gestational age at which changes suggestive of Apert syndrome were identified in the US was 21.3 weeks (range 17. . Early detection in the second trimester is difficult because the standard anomalies (craniofacial deformities, syndactyly) are often preceded by a non-specific set of anomalies (cardiovascular, central nervous system, renal, digestive) responsible for the heterogeneous nature of the clinical profile.As a result, the severity of Apert forms is assessed based on the early identification of one or more associated anomalies.
Furthermore, 23/32 (71.8%) patients were molecularly tested, of which 82.6% (n = 19) of patients opted for termination of pregnancy (TOP).According to the analysis of the presented cases, it is observed that early prenatal detection is accompanied by an increased rate of TOP (75%) due to the severity of the ultrasound features compared to the cases where the ultrasound markers are detected late.As a result, a careful and systematic ultrasound evaluation during the second trimester is crucial for the prognosis of these cases.
In 31/32 (96.8%) of the cases, there were changes in the shape of the head, of which 26/31 (83.7%) were visualized by ultrasound and 5 by subsequent MRI scanning.In one case, the second-trimester scan showed a normal shape of the skull, and a re-evaluation performed after 3 weeks showed colpocephaly and, after another 3 weeks, craniosynostosis and widely open metopic suture.Thus, two cases of agenesis of the corpus callosum (ACC) were suspected; the MRI analysis confirmed it only in one case.Also, an MRI was used to establish the diagnosis in a case of corpus callosum dysgenesis.Hypertelorism in 14/32 (43.7%) was visualized sonographically in 78.5% (n = 11) cases, and three cases were detected after MRI scanning.The diagnosis of proptosis was established sonographically in 6 out of 11 cases, one was identified after performing an MRI, and 4 cases (36.3%) were diagnosed during fetal examination after TOP.
Anomalies of the fingers (syndactyly) were diagnosed by prenatal imaging in 28 cases (87.5%), of which 18 cases (60%) involved the hands and the feet.The syndactyly involving only the hands was observed antenatally in 10 cases, with mitten type in 9 cases.Additionally, postmortem fetal examination revealed 3 cases of mitten hands.
Antenatal imaging evaluation also identified three cases of cardiovascular anomalies (hypoplastic left ventricle and ascending aorta, coarctation of the aorta, ventricular septal defect, and overriding of the aorta), two cases of renal anomalies (bilateral hydronephrosis), one case with abnormally expanded lungs confirmed both sonographically and MRI, and one case of digestive anomaly (omphalocele) (Table 3).The treatment of patients with Apert syndrome is a real challenge, requiring a multidisciplinary team and scheduled surgical corrections at different stages of development.Thus, craniosynostosis and disorders secondary to brain compression are repaired by craniotomy in the first year of life, palate repair between 6 and 14 months, syndactyly between 1 and 4 years, jaw surgery, and mid-face anomalies between 4 and 6 years, after the completion of growth orthognathic correction.All other associated manifestations, such as strabismus, hearing loss, and sleep apnea, require surgical or drug treatment, depending on severity, to improve the patient's quality of life [57][58][59].
The prognosis, social integration, and quality of life of these patients depend on the severity of the condition.Some patients, although psychologically supported by the family, even after the therapeutic interventions, may present intellectual disabilities or psychosocial disorders.

Conclusions
The presence of suggestive ultrasound changes and/or associated anomalies makes early prenatal diagnosis of Apert syndrome an important tool in the optimal assessment of the degree of severity for each case.The use of 3D ultrasound allowed a better understanding by the parents of the fetal damage, facilitating counseling and providing useful information regarding the decision to terminate the pregnancy in cases with an unfavorable prognosis due to long-term complications such as impaired neurologic and cognitive development or problems caused by facial dysmorphism, craniosynostosis, and skeletal malformations.
Funding: Publication of this paper was supported by the Carol Davila University of Medicine and Pharmacy through the institutional program Publish not Perish.

Table 1 .
Differential diagnosis of Apert syndrome.

Table 2 .
An overview of the early prenatal diagnosis of Apert syndrome in newborns was all-time searched in the PubMed database.

Table 3 .
Distribution of imaging (US, MRI) findings among Apert syndrome cases identified in the review.