Prenatal ultrasound and molecular diagnosis elucidate the prognosis of Pfeiffer syndrome¹⁾

Introduction

Pfeiffer syndrome (PS), one of several related craniosynostoses, is an autosomal dominant disorder that occurs in 1 out of every 100,000 live births [9]. The diagnosis is primarily based on the neonatal findings of bilateral coronal craniosynostosis, midface hypoplasia, broad thumbs and great toes. The syndrome has been divided into three subtypes based on skull shape and prognosis due to phenotypic variability, from normal intelligence to death shortly after delivery [3]. There are three types of PS, with type 2 as the most severe and is characterized by a cloverleaf skull, proptosis and significant neurologic involvement. PS type 1, is the classic, mild form, which is inherited in an autosomal dominant fashion. Affected individuals have a normal lifespan and generally normal intelligence. The findings in PS type 3 are similar to those in PS type 2, however those affected have less severe coronal fusion and, therefore, lack the cloverleaf skull.

Until recently, PS had principally been diagnosed postnatally. However, due to advances in prenatal ultrasound and prenatal molecular diagnosis, it is now possible for PS to be diagnosed prenatally [1]. PS has a wide phenotypic spectrum, therefore, sonographic visualization of a cloverleaf skull and broad digits are key markers in prenatal diagnosis for PS type 2.

PS type 2 and 3 are due to mutations in fibroblast growth factor receptor 2 (FGFR2), as are the majority of cases of PS type 1. The remaining PS type 1 cases are caused by a mutation in FGFR1. FGFR1 and 2 are essential in fetal endochondral and membranous ossification and their role in craniosynostosis is likely due to their co-expression in the fetal skull, including the cranial sutures [2]. Testing is available in the clinical setting and because of some known genotypic-phenotypic correlation. The specific FGFR1 or FGFR2 mutation identified may aid in the prenatal prognosis [10]. In this report, we describe a case with the FGFR2 missense mutation p.Y340C in exon 10, which is one of the four FGFR2 mutations (p.W290C, p.Y340C, p.C342R, p.S351C) that are known to be associated with an especially severe phenotype [7].

Case presentation

A 43-year-old primigravida with advanced maternal age and type II diabetes underwent a routine ultrasound at 22+1 weeks gestation, which revealed a fetus with a cloverleaf skull. At 25+2 weeks gestation, a fetal echocardiogram was unremarkable. Further evaluation by a level II ultrasound performed at 27+5 weeks gestation revealed the additional findings of wide-set eyes with proptosis, mild scoliosis, polyhydramnios, a thickened nuchal fold, ventriculomegaly, and long bones less than the 5th percentile by the last menstrual period.

Based on these phenotypic findings, an initial diagnosis of thanatophoric dysplasia (TD) or achondroplasia was suspected and a genetics consultation was performed at 29+3 weeks gestation. Shortly after, a therapeutic amnioreduction was performed concurrently with molecular testing for FGFR3 to evaluate for TD or achondroplasia, both known to be caused by mutations in the FGFR3 gene. A negative result from sequencing known mutational hotspots resulted in reflex genetic testing for mutations in FGFR2. Sequencing of key exons in FGFR2 revealed the presence of a C>T transition at nucleotide 1019 (c.1019C>T) on exon 10 of the FGFR2 gene which is known to result in a p.Y340C missense mutation.

The fetus was diagnosed with PS type 2 based on the specific FGFR2 mutation and the concomitant ultrasound findings. Indeed, the ultrasonographic findings of a cloverleaf skull, proptosis and broad toes were similar to ultrasonographic findings previously reported in cases of PS involving severe FGFR2 mutations [2, 4]. Additional prenatal ultrasound findings also included elbow ankylosis with bilateral humero-radio-ulnar synostosis, broad and deviated big toes and vertebral anomalies including sacrococcygeal eversion [2].

The patient, now 34+3 gestational age, was transferred to our quaternary care institution to undergo further management with a multidisciplinary approach which included perinatology, neonatology, genetics, pediatric surgery, craniofacial surgery and social work. Prenatal genetics consultation revealed that the patient was of Chamorro descent, from the Mariana Islands in the Pacific Ocean. She had short stature measuring 4 feet 8 inches. The father of the fetus had no significant past medical history, but was of advanced paternal age at 56 years. He was of Chamorro and Japanese descent, and there was no consanguinity reported.

A repeat prenatal ultrasound examination confirmed multi-suture synostoses of the cranium resulting in a cloverleaf configuration and associated distortion of the intracranial anatomy with ventriculomegaly, particularly involving the frontal horns. The fetus also had hypertelorism and marked orbital proptosis along with evidence of mid-face hypoplasia. The musculoskeletal abnormalities included short long bones with broad digits as well as a disordered appearing spine, suggestive of segmentation abnormalities, along with an abnormal appearing spinal canal with possible diastematomyelia. Fluid was seen at the distal spinal canal without evidence of open neural tube defect. Significant polyhydramnios was visualized (Figure 1). The patient was counseled extensively regarding the nature of sonographic findings in conjunction with the FGFR2 mutation p.Y340C that is known to result in a severe phenotype. This rare mutation appears to be universally lethal by early childhood due to upper airway obstruction or respiratory complications. The rare neonates who survive are severely affected and experience significant neurocognitive impairment mostly because of improper brain formation in the presence of craniosynostosis [2]. The patient was offered delivery at the time of presentation due to the severity of the condition but desired expectant management. She underwent two additional therapeutic amnioreductions for polyhydramnios prior to delivery.

Figure 1

Ultrasound images at 34+3 weeks gestation. (A) Cloverleaf skull. (B) Ventriculomegaly. (C) Proptosis and hypertelorism. (D) Brachydactyly.

After multiple sessions discussing management options with social work, craniofacial, perinatology, neonatology, fetal treatment and genetics, she desired to continue the pregnancy. A plan was made to administer antenatal corticosteroids and deliver the fetus at 37 weeks’ gestation. As there were concerns for cephalopelvic disproportion given the short maternal height and enlarging fetal cranium, the patient elected to undergo a primary cesarean delivery. A live-born male infant was delivered via primary low transverse cesarean delivery. Physical examination confirmed the anomalies visualized by prenatal ultrasound including cloverleaf skull, extreme proptosis and multiple limb abnormalities (Figure 2). Based on maternal wishes, the infant was first intubated after delivery due to his inability to maintain adequate oxygen saturation, thereafter, comfort care measures were administered and he passed away shortly after extubation.

Figure 2

Neonatal image. Cloverleaf skull with bilateral exophthalmia and brachydactyly.

Discussion

Prenatal detection of PS type 2 has become more common and increasingly recognized with 11 reported cases in the literature since 1994. Reports have described using not only traditional ultrasonography, but also three dimensional ultrasound [8] and fetal MRI. With higher resolution imaging along with the availability of prenatal molecular testing of PS, a diagnosis of PS type 2 can now be confirmed in utero [3, 6].

Although the prenatal ultrasonographic findings of a cloverleaf skull can lead to a broad differential diagnosis, the postnatal prognosis is dependent upon the associated abnormalities and specific diagnosis. Targeted ultrasound findings of broad thumbs and broad great toes in conjunction with a cloverleaf skull have shown to be helpful for a clinical diagnosis of PS type 2. However, results of genetic testing provide the definitive diagnosis and genotype-phenotype correlations. These findings allowed for a conclusive diagnosis and the patient was offered more definitive counseling in regards to outcome. Unfortunately, the diagnosis was not confirmed until the third trimester of the pregnancy. This case highlights the importance of early molecular testing and genetic counseling when findings of prenatal craniosynostosis are visualized on ultrasound.

The specific type of molecular defect detected in the FGFR2 gene may provide additional insights that are critical to medical guidance. In the known mutations in the FGFR2 gene, the p.Y340C missense mutation that was detected in this case is associated with a severe phenotype. This rare mutation appears to be universally lethal by early childhood due to upper airway obstruction or respiratory complications. The rare neonates who survive are severely affected and experience significant neurocognitive impairment mostly due to improper brain formation in the presence of craniosynostosis [2]. This mutation results in the addition of an unpaired cysteine in the III Ig-like loop which is vital for intermediate receptor dimerization. The independent activation of the receptor by dimerization is thought to result in craniosynostosis [4]. The vast majority of, if not all, mutations for severe PS occur de novo. The mutation is generally of paternal origin and associated with advanced paternal age. Interestingly, there is a survival advantage in sperm carrying FGFR2 mutations [5]. In our patient, with a partner of advanced paternal age, the recurrence risk of having another child affected with PS is higher than the general population baseline risk.

In summary, we present a prenatal case whereby key phenotypic findings were initially visualized on ultrasound performed in the second-trimester of pregnancy. Upon sonographic visualization of a cloverleaf skull, several syndromic diagnoses should be considered, including Apert, Crouzon, Jackson-Weiss, Antly-Bixler, Pfeiffer and thanatophoric dysplasia. Additional phenotypic markers provide clues to narrow diagnostic considerations. In this case, the cloverleaf skull in combination with the visualization of broad abducted thumbs and broad great toes lead to a diagnosis of probable PS. Other significant findings of severe proptosis and polyhydramnios suggested a more severe phenotype. As demonstrated in our case, molecular diagnostic testing can confirm the clinical suspicion and is readily available in the clinical setting. With increasing knowledge of outcomes associated with specific genetic mutations, counseling families is becoming more finely tailored, enabling the ability to prenatally predict neonatal prognosis.