An early prenatal diagnosis of type III Pfeiffer syndrome: a case description

Introduction

Pfeiffer syndrome, an infrequent autosomal dominant disorder linked to mutations in the fibroblast growth factor receptor (FGFR), represents a form of premature cranial suture closure syndrome, with an estimated prevalence of approximately 1 per 100,000 (1-3). It is characterized by varying degrees of cranial suture closure, midfacial hypoplasia, skeletal dysplasia, and additional abnormalities. Although most literature reports focus on type II Pfeiffer syndrome, distinguished by a distinctive trefoil cranium, the less common type III Pfeiffer syndrome deviates from the typical trefoil structure and is associated with a poorer prognosis. Koga et al. (4) reported that at out of 23 examined cases with type II or III Pfeiffer syndrome, 5 died before the age of 1 year, representing a mortality rate of 22% over a 22-month observation period. In our particular case, we observed cranial microconcavity, facial anomalies, skeletal dysplasia, and other abnormalities (hypospadias, single umbilical artery). The confirmation of our prenatal ultrasound diagnosis was substantiated by the postnatal presentation of the fetus and the results of genetic testing.

Case presentation

At 23 weeks of gestation, a thorough prenatal ultrasonography examination was conducted on a 29-year-old pregnant woman (G4P1). Her medical history revealed no instances of gestational hypertension, diabetes, other medical conditions, or consanguineous marriage. The early pregnancy nuchal translucency test showed no significant abnormalities. Targeted ultrasound screening unveiled distinctive observations, including cranial microconcavity, mild bilateral lateral ventricle broadening (11 mm) (Figure 1A), increased intraocular distance (22 mm) in the >95th percentile, protruding eyeballs and flat and short nasal bone (the length of the left and right nasal bones of 3.3 and 3.0 mm respectively) (Figure 1B), flattening of the bridge of the nose and upper pressure groove (Figure 1C), smaller and shorter vertebrae above the C10 vertebra, a narrowed C9–C11 intervertebral arch space and spinal canal, and fusion of the S2–S5 vertebrae (Figure 1D). The thumbs of both hands and the first phalanges of both feet exhibited marked enlargement (Figure 1E). Additionally, the external genitalia of the fetus exhibited hypospadias, presenting with a “tulip sign” because of the short and curved penis and the split scrotum on both sides, which formed a tulip-like pattern as if being embedded in petal-shaped betel nuts (Figure 1F). Only one umbilical artery was visible on the left side of the bladder; the other was not visualized.

Figure 1 Prenatal ultrasound imaging. (A) Two-dimensional ultrasound revealed a cranial microconcavity (indicated by blue arrows) and mild broadening of the bilateral lateral ventricles (11 mm) (indicated by *). (B) Two-dimensional ultrasound demonstrated widening of the eye distance (22 mm intraocular distance), protruding eyeballs (indicated by blue arrows), and a flat and short nasal bone (indicated by white arrows). (C) Median sagittal view in two-dimensional ultrasound displayed flattening of the bridge of the nose and upper pressure groove. (D) Two-dimensional ultrasound captured smaller and shorter vertebrae above the C10 vertebra, narrowing of the C9–C11 intervertebral arch space and the spinal canal, and fusion of the S2–S5 vertebrae. (E) Three-dimensional ultrasound indicated markedly enlarged first phalanges of both feet, combined with an overlapping toe deformity. (F) Ultrasound image revealed abnormalities in the external genitalia, referred to as the “tulip sign” (indicated by blue arrow).

Overall, the prenatal ultrasound suggested a diagnosis of type III Pfeiffer syndrome. The diagnosis was thoroughly discussed with the pregnant woman and her family, who, upon consideration, requested induction labor to terminate the pregnancy. Subsequently, a male infant, weighing 620 g, was born at 23+3 weeks of gestation. The newborn’s appearance displayed cranial microconcavity, protruding eyeballs (Figure 2A), contractures of the hands with large fingers (Figure 2B), pronation of the feet, overlapping fingers of the feet, and large toes (Figure 2C). Parental consent was obtained for whole-exome sequencing of fetal DNA to establish an accurate diagnosis. The analysis revealed a missense mutation in the FGFR2 gene [c.870G>C(p.Trp290Cys)] with the infant, whereas both parents did not carry the mutation, having the wild-type FGFR2 gene (Figure 3). The combined evaluation of ultrasound features, genetic sequencing results, and postpartum fetal appearance led to the conclusive diagnosis of type III Pfeiffer syndrome.

Figure 2 Postpartum images. (A) Newborn appearance included a cranial microconcavity and protruding eyeball. (B) The infant had contractures of the left hand with large fingers. (C) Postpartum image of the newborn showing pronation of the feet, overlapping fingers of the feet, and a large toe. L, left; R, right.

Figure 3 Sequencing of FGFR2 of the infant and parents. Sequencing of FGFR2 for the infant and parents showed a missense mutation [c.870G>C (p.Trp290Cys)] (indicated by the red arrow) in the FGFR2 gene with the infant, while neither of parents carried the mutation. FGFR2, fibroblast growth factor receptor 2.

All procedures performed in this study were in accordance with the ethical standards of the Medical Ethics Committee of Gansu Provincial Maternity and Child-Care Hospital [No. (2023) GSFY Lunshen 54] and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient’s next of kin for publication of this article and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Pfeiffer syndrome, an infrequent autosomal dominant disorder linked to mutations in the FGFR gene, manifests with varying degrees of cranial suture closure, midface hypoplasia, skeletal dysplasia, and additional abnormalities. Cohen (5) classified the syndrome into three types based on clinical manifestations. Type I is characterized by premature closure of cranial sutures, midface hypoplasia, and distinctive thumb and toe deformities. Typically, individuals with type I exhibit normal-to-near-normal intelligence and have a favorable prognosis. Type II is characterized by a cloverleaf-shaped cranium; markedly protruding eyes; conjunctival congestion; collapsed nose; low ear position; bilateral atresia of external auditory canals; high palatal arches; short, thick thumbs and big toes; osseous fusion of radial ulnar humerus; and severe neurologic injuries, caudal spondylolysis, ventricular dilatation with hydrocephalus, and other polymorphic deformities. Type III shares similarities with type II but has no obvious cranial cloverleaf deformity, making it easily overlooked in the early stages. Types II and III are often associated with severe neurologic and respiratory malformations, resulting in a poor prognosis and a high risk of early death (6).

In our case, the fetus exhibited prominent eyeball protrusion, mild bilateral lateral ventricle broadening, and additional structural malformations. The final diagnosis of Pfeiffer syndrome type III was established due to the absence of the characteristic cranial cloverleaf structure and was supported by genetic testing results. This underscores the importance of a comprehensive diagnostic approach involving clinical presentation and genetic confirmation in accurately categorizing and prognosticating Pfeiffer syndrome cases.

The fibroblast growth factor (FGF) family comprises at least 22 recognized FGF ligands that interact with 5 closely related receptor tyrosine kinases, initiating receptor monomer dimerization, activation of kinase structural domains, and subsequent receptor phosphorylation (7-9). FGF-FGFR signaling plays a crucial role in regulating the differentiation of mesenchymal and neural ectodermal cells, particularly in bone development and homeostasis (10). Mutations in three members of the FGFR family (FGFR1, FGFR2, and FGFR3) lead to dysregulated FGF signaling and premature closure of cranial sutures. While mutations in the FGFR2 gene predominantly contribute to craniopharyngeal dysfunction, most patients exhibiting craniofacial anomalies associated with FGFR2 gene mutations develop cranial suture fusion (11).

Heterozygous mutations in the FGFR2 gene typically manifest in various syndromes characterized by premature closure of cranial sutures, including Apert, Crouzon, Pfeiffer, Antley-Bixler, Beare-Stevenson cutis gyrata, Jackson-Weiss, bent bone dysplasia, and Seathre-Chotzen-like syndromes. Specific missense mutations, such as Ser252Trp or Pro253Arg, localized in the highly conserved linkage region between the IgII and IgIII structural domains of FGFR2, often cause Apert syndrome (12). Overlapping FGFR2 mutations associated with Crouzon and Pfeiffer syndromes are frequently identified in the extracellular IgIII structural domain encoded by exons 8 (IIIa) or 10 (IIIc) (13). Cys278Phe and Cys342Tyr missense mutations can contribute to both syndromes, while severe cases of Pfeiffer syndrome may result from mutations such as Trp290Cys, Tyr340Cys, Cys342Arg, or Ser351Cys (14). Various other related syndromes have also been attributed to mutations occurring in genes associated with different structural domains.

The early morphological diagnosis of Pfeiffer syndrome poses challenges due to its extensive clinical variability and overlapping features. Although the trilobal cranium is a common ultrasound sign, it is not exclusive to Pfeiffer syndrome, and it can also appear in Crouzon syndrome, Apert syndrome, thanatophoric dysplasia, and Carpenter syndrome, among others (15-18). The atypical presentation of a trilobal cranium in type III Pfeiffer syndrome, particularly when accompanied by hand and foot deformities, necessitates careful differentiation from other cranial suture prematurity syndromes.

For Apert syndrome, the primary ultrasound manifestations include midface hypoplasia, wide eye spacing, proptosis, and complex syndactyly involving the fusion of the second, third, and fourth fingers with bony joint fusion—a characteristic feature distinguishing it from similar syndromes. Additionally, vertebral body fusion is common in Apert syndrome (19). Crouzon syndrome, closely resembling Apert syndrome in clinical phenotype, typically exhibits normal hand and foot structures (20).

Carpenter syndrome manifests with premature closure of the cranial sutures, particularly the herringbone and sagittal sutures. Associated features include proptosis, orbital shallowness, medial canthus folding, underdeveloped ears, low nasal dorsum, elevated dorsally maxillary arches, and unique finger characteristics involving the webbing of soft tissues without bony fusion which often affects the third and fourth fingers and is accompanied by polydactyly (21); cardiovascular malformations are common and often associated with mutations in the RAB23 gene (22,23).

Saethre-Chotzen syndrome presents with diverse clinical manifestations and potential premature closure of cranial sutures. Ear deformities in Saethre-Chotzen syndrome include small, rounded auricles, cleft palate or cleft uvula, flattened nose back, linear frontonasal angle, short limbs, huge thumbs, bunions, ectropion deformities, and syndactyly, often between the second, third, or second and third fingers. Some patients may exhibit a penetrating palm and cryptorchidism (24,25).

The clinical phenotype of syndromic premature closure of cranial sutures is intricate and variable, often being associated with midface and mandibular malformations, limb anomalies, internal organ malformations, growth retardation, mental impairment, and in severe cases, premature death. Achieving a definitive diagnosis remains challenging. Hence, when confronted with complex cases involving premature closure of cranial sutures and craniofacial anomalies, clinicians should adopt a meticulous diagnostic approach is essential. Prenatal genetic diagnosis is preferred, playing a pivotal role in prognosis determination.

In our particular case, the fetal trichobezoar cranial atypia presented as an atypical manifestation. A thorough ultrasound examination, coupled with postnatal genetic analysis, ultimately validated our initial ultrasound diagnosis. Research indicates that the average gestational week for the initial diagnosis of Pfeiffer syndrome is around 27 weeks (1), with instances of detection as early as 20 weeks reported (26). Given the unfavorable prognosis associated with Pfeiffer syndrome, achieving an early prenatal diagnosis is crucial. The absence of a distinct trichobezoar cranium and the relatively small gestational age observed in this case underscore the capability of ultrasound to provide an early morphologic prenatal diagnosis. This, in turn, facilitates prompt and comprehensive management of the prognosis for patients with Pfeiffer syndrome.

Acknowledgments

Funding: This work was supported by the Natural Science Foundation of Gansu Province (No. 23JRRA1391) and the Gansu Health Industry Scientific Research Program (No. GSWSQN2021-006).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-440/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the Medical Ethics Committee of Gansu Provincial Maternity and Child-Care Hospital [(No. (2023) GSFY Lunshen 54] and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient’s next of kin for publication of this article and any accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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