Clinical and Genetic Studies of the First Monozygotic Twins with Pfeiffer Syndrome

Abstract

Objective: To report the clinical and radiographic findings and molecular etiology of the first monozygotic twins affected with Pfeiffer syndrome. Methods: Clinical and radiographic examination and whole exome sequencing were performed on two monozygotic twins with Pfeiffer syndrome. Results: An acceptor splice site mutation in FGFR2 (c.940-2A>G) was detected in both twins. The father and both twins shared the same haplotype, indicating that the mutant allele was from their father’s chromosome who suffered severe upper airway obstruction and subsequent obstructive sleep apnea. Hypertrophy of nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Increased intracranial pressure in both twins were corrected early by fronto-orbital advancement with skull expansion and open osteotomy, in order to prevent the more severe consequences of increased intracranial pressure, including hydrocephalus, the bulging of the anterior fontanelle, and the diastasis of suture. Conclusions: Both twins carried a FGFR2 mutation and were discordant for lambdoid synostosis. Midface hypoplasia, narrow nasal cavities, and hypertrophic nasal turbinates resulted in severe upper airway obstruction and subsequent obstructive sleep apnea in both twins. Hypertrophy of the nasal turbinates appears to be a newly recognized finding of Pfeiffer syndrome. Fronto-orbital advancement with skull expansion and open osteotomy was performed to treat increased intracranial pressure in both twins. This is the first report of monozygotic twins with Pfeiffer syndrome.

Keywords: Pfeiffer syndrome; discordance; hypertrophy of turbinates; lambdoid synostosis; twins.

Figure 1

Twin A at age 6 months. (A) Brachydactyly, ocular proptosis, and depressed nasal bridge. (B) Brachydactyly and broad thumbs. (C) Broad great toes. (D) Preoperative view of the cranium. Note ridges at metopic and sagittal sutures as a result of synostosis.

Figure 2

Twin B at age 3.5 months. (A) Brachydactyly, ocular proptosis, and depressed nasal bridge. (B) Brachydactyly and broad thumbs. (C) Broad great toes. (D) Preoperative view of the cranium. Note ridge at metopic suture as a result of synostosis.

Figure 3

Radiographs and 3D CT reconstruction of twins A (A,C) and B (B,D). (A) Coronal synostosis (blue arrows) of twin A. (B) Coronal synostosis (red arrows) of twin B. (C) Note the craniolacunia of twin A. Lambdoid synostosis (blue arrow) and ipsilateral mastoid and contralateral parietal bossing with associated downward tilt of the cranial base toward the affected side. (D) Craniolacunia and patent lambdoid suture of twin B.

Figure 4

Axial CT scan and lateral skull radiographs of twins A (A,C,E,G) and B (B,D,F,H). (A) Twin A. Effusion of right middle ear cavity (red arrow) and mastoid air cells (blue arrow). (B) Twin B. Bilateral effusion of middle ear cavities (red arrows) and mastoid air cells (blue arrows). (E,F) CT scan of brain. Shallow orbits leading to exorbitism of (E) twin A and (F) twin B. (G,H) Lateral skull radiographs demonstrating maxillary hypoplasia of (G) twin A. and (H) twin B.

Figure 5

Sagittal view CT. (A) Normal naso-and oropharyngeal airways of twin A. (B) Normal naso-and oropharyngeal airways of twin B. Three-dimensional CT reconstruction. (C) Short anterior cranial bases of twin A and (D) twin B.

Figure 6

Axial and coronal views CT (bone window) oftwins A and B. Obstruction of bilateral nasal cavities (arrows) in (A) twin A and (B) twin B. Bilateral hypertrophy of turbinates (arrows) in (C) twin A (D) twin B.

Figure 7

Electropherograms of aFGFR2mutation. A de novo heterozygous base substitution NM_000141.4:c.940-2A>G in intron 8 at the 3′ splice acceptor site of the FGFR2 gene, leading to abnormal IIIc acceptor splicing in both twins. The parents did not have the mutation.