Pfeiffer Syndrome (Acrocephalosyndactyly) With Significant Syndactyly and Brachydactyly: A Case Report

Abstract

We report a case of acrocephalosyndactyly, Pfeiffer syndrome type 1 with a mutation in FGFR2 c.758C>G (p.Ser253Trp) in a newborn with mild midfacial hypoplasia, significant brachydactyly and syndactyly in the hands and feet. One of the hallmark features of Pfeiffer syndrome is webbing or fusion (syndactyly) of the fingers and toes, which can vary in severity affecting both hands and feet. This variable expressivity of Pfeiffer syndrome makes classification of the condition challenging. Diagnosis was confirmed by genetic testing. Imaging investigations, clinical observation and physical examination further highlights the importance of interdisciplinary care involving orthopedic, neurosurgeons, geneticists, and pediatricians. Long-term follow-up is essential to monitor growth and development, while addressing associated complications including hearing loss and tracheal stenosis. This case underscores the complexity of acrocephalosyndactyly and its varying presentation. The baby was born at 35 weeks to non-consanguineous parents, with craniosynostosis, midfacial hypoplasia, broad thumbs, and toes.

Introduction

This introduction aims to provide a brief overview of Pfeiffer syndrome (PS), focusing on its characteristic feature of significant webbing or fusion morphology in the hands and feet as seen in this patient. Pfeiffer syndrome is a rare genetic disorder characterized by craniosynostosis, midfacial hypoplasia and broad thumbs and toes with reports from Europe, Asia, Africa and South America. Generally, pathogenesis revolves around mutations in FGFR1 and FGFR2 genes, premature cranial suture fusion presenting as craniosynostosis, skeletal abnormalities involving hands, feet, and other skeletal structures. ¹ One of the hallmark features of Pfeiffer syndrome is significant webbing or fusion (syndactyly) of the fingers and toes, which can vary in severity and affect both hands and feet. ² This abnormal fusion morphology contributes to the distinctive appearance of the hands and feet in affected individuals. Mutations, predominantly on FGFR2 gene expression, cause aberrant signaling in bone development, cranial sutures and structures with variable expressivity.^3,4 Understanding the unique presentation of webbing or fusion morphology in Pfeiffer syndrome is crucial for early diagnosis and appropriate management, which often involves surgical intervention to improve hand and foot function as well as cranial vault reconstruction. ⁵ The baby is a male newborn delivered at 35 weeks of gestation. He had a rare hereditary craniofacial defect that included substantial brachycephaly and syndactyly in the hands and feet.

Case Presentation

Patient Information and Medical History

A 3-week-old male infant admitted to the neonatal Intensive care unit (NICU) due to craniofacial anomalies and mild respiratory distress noted at birth, delivered at 35 weeks of gestation to a mother of 26 years old and non-consanguineous parents, via uncomplicated vaginal delivery. The mother received prenatal care and had an uneventful pregnancy. Antenatal ultrasound findings were suggestive of craniofacial anomalies, including cloverleaf skull appearance, birth weight was large for gestational age (3.3 kg). No known family history of craniofacial anomalies or genetic syndromes reported.

Physical Examination

Infant with mild tachypnea and increased work of breathing. Craniofacial exam: prominent forehead, the skull is tower-shaped and shortened from front to back, midface hypoplasia, shallow orbits with proptosis, high-arched palate and a beaked nose (Figures 1 and 2). Significant webbing is noted on the hands and feet and a broad great toe (Figures 3 and 4). Alert infant at birth with normal tone and reflexes. APGAR scoring was 7 at 5 minutes. Other systems including cardiovascular, abdominal and genitourinary showed no remarkable findings on examination.

Figure 1.

Showing a prominent forehead, the skull is tower-shaped and shortened from front to back, midface hypoplasia.^1,13

Figure 2.

Frontal view, observe the prominent forehead, beaked nose, and midface hypoplasia. ¹³

Figure 3.

(a) Profound syndactyly, autosomal dominant deformity of the extremities, typified by the fusion of the fourth and fifth metacarpals, including the first and third in this particular case. (b) Thumb is medially deviated.^11,12

Figure 4.

Fusion can vary in severity, ranging from partial to complete, note the partial fusion at the feet sparing the great toes with large size.

Diagnosis

Percutaneous umbilical blood sampling was done using standard techniques for genetic testing, revealing variants in the FGFR2 gene (c.758C>G, p.Ser253Trp), confirming the diagnosis of Pfeiffer syndrome at 12th week of gestation. Arterial blood gas showed slight hypoxemia and respiratory acidosis, chest X-ray revealed normal appearing lungs. Pfeiffer syndrome subtype 1 was found based on physical presentation at birth, imaging findings including prenatal ultrasound. Craniosynostosis was observed and mild respiratory compromise.

Treatment Plan

Respiratory support was initiated with mechanical ventilation using positive end-expiratory pressure (PEEP) to improve oxygenation and ventilation, Genetic counseling arranged with a genetic counselor to discuss the diagnosis, prognosis and potential risk. Surgical evaluation: coordinated with pediatric craniofacial surgery for assessment and consideration of cranial vault reconstruction. Supportive care to monitor vital signs, oxygen saturation and respiratory status closely. We provided appropriate hydration and nutrition via nasogastric tube as needed, while multidisciplinary management involving neonatology, pediatric surgery, genetics and respiratory therapist in the care team to address his complex needs comprehensively.

Outcome

With prompt diagnosis, comprehensive management and ongoing support, the patient remains stable with close monitoring and multidisciplinary care. Postnatal visceral survey using abdominal ultrasound and X-ray for musculoskeletal, gastrointestinal, and cardiovascular anomalies were unremarkable.

Follow-up

Infant was stabilized with airway breathing via nasal cannula and nasogastric tube feeding at the time of reporting. Follow-up showed the patient died within 8 months of admission at the neonatal intensive care unit. The exact cause of death is unknown.

Discussion

This case features a newborn with prominent forehead, midfacial hypoplasia, high-arched palate, a beaked nose, significant brachydactyly, syndactyly in the hands and feet and medially deviated thumb. Normal muscle tone and reflexes with minor signs of developmental delay during initial evaluation. No visceral anomalies were noted on admission. A diagnosis of Pfeiffer syndrome type 1 was made based on genetic testing with a mutation in FGFR2 c.758C>G (p.Ser253Trp; Figures 1 to 4). ⁶ Pfeiffer syndrome is primarily caused by mutations in the FGFR2 genes encoding for fibroblast growth factor receptors. Although there is not enough specific epidemiological and demographic data, It appears to occur in about 1 out of every 100 000 live births, with cases being more prevalent in European nations and less frequent in Asia.^1,7 During the development of the embryo, these receptors are essential for controlling cell migration, differentiation and proliferation. Dysregulated signaling pathways caused by mutations in these genes interfere with proper skeletal and craniofacial development. These sutures normally permit the skull enlargement to allow expansion of the developing brain.^1,8 Pfeiffer syndrome also known as type V acrocephalosyndactyly shares characteristic features with other craniosynostosis syndromes ranging from mild to severe sutural involvement caused by mutations in the FGFR2 gene as seen in Apert syndrome, Crouzon, Saethre-Chotzen syndromes (TWIST).^1,5 However, the main distinguishing feature in Pfeiffer syndrome is seen in limb abnormalities with broad, medially deviated thumbs and toes as seen in this patient (Figure 3b). Unlike Apert syndrome, Pfeiffer syndrome typically shows a cloverleaf skull with mild to severe proptosis, while patients with Crouzon syndrome have proptosis without any limb involvement that is seen in PS. Saethre-Chotzen syndrome is caused by mutations in the TWIST1 gene featuring deep hairline and facial asymmetry, partial syndactyly or short fingers, there is less severe facial and skeletal deformities when compared to Pfeiffer.^1,9,10

In Pfeiffer syndrome, the early fusion limits the growth of the skull in specific directions resulting in distinctive anomalies of the craniofacial structure. Pfeiffer syndrome is characterized by significant webbing or fusion of the fingers and toes, affecting both hands and feet. This presents a unique challenge for newborns with these disorders and the diagnosis of Pfeiffer syndrome.^11,12 In 1993 Cohen described 3 subtypes of Pfeiffer syndrome that had been identified. ¹³ Type 1, this is the classic subtype, accounting for approximately 55% to 75% of all cases of Pfeiffer syndrome, characterized by varying degrees of craniosynostosis, maxillary hypoplasia (midface hypoplasia), hypertelorism, prognathism, and dental abnormalities, and broad thumbs and toes. Type 2, is usually more severe than type 1 and is linked to severe midface hypoplasia, a cloverleaf skull malformation and more extensive craniosynostosis together with ankylosis of the elbows. Such patients do poorly with an early death.^13,14 Type 3 is the rarest subtype, accounting for approximately 15% to 40% of cases. It is characterized by mild craniosynostosis, minimal midface hypoplasia and variable limb abnormalities. The variable expressivity of Pfeiffer subtype 3 makes diagnosis challenging. Identification of type 3 is especially crucial since Pfeiffer syndrome may go undiagnosed in cases of significant ocular proptosis with urogenital tract anomaly “Prune belly” and a variety of visceral abnormalities. ¹⁴ This patient shows evidence of Pfeiffer syndrome type 1. In addition, systematic reviews of existing studies on different types of PS show the plausibility of neurological abnormalities including mental retardation, learning difficulties, and seizures. The variable expression of the limb anomaly as observed in certain cases of this syndrome can complicate diagnosis. Some patients may have fusion of vertebrae, “butterfly” vertebrae, and sacrococcygeal extension not seen in this case. This further emphasizes the importance of limb and nervous system involvement in patients with Pfeiffer syndrome.^2,15

Based on the genetic testing results, the patient harbors a pathogenic variant in the FGFR2 gene (c.758C>G, p.Ser253Trp). This resulted from the substitution of serine with tryptophan at position 253 of the FGFR2 protein, disrupting the normal function of the fibroblast growth factor receptor 2 (FGFR2) confirming the diagnosis of Pfeiffer syndrome. This variant is a known pathogenic mutation associated with Pfeiffer syndrome with similar forms previously reported.^16,17 Variable expression exists with phenotypic overlap with other craniosynostosis, such as Crouzon syndrome, Apert syndrome and Saethre-Chotzen syndromes. Pfeiffer syndrome is caused by mutations predominantly on the FGFR2 gene, whereas other syndromes involve FGFR2, FGFR3, TWIST1 or RAB23 respectively. ¹⁰ A comprehensive physical examination and radiological evaluation can help distinguish features specific to each patient.^3,9,10 Radiological and physical evidence shows a collection of birth defects typified by features of the hands and feet (syndactyly), face and skull (craniosynostosis). The degree of this condition varies. It is essential to comprehend the distinct way that webbing or fusion morphology presents in Pfeiffer syndrome.^18,19 In this infant there is an aberrant fusion morphology that contributes to the distinctive appearance of the hands and feet (Figures 3 and 4). Syndactyly which is the fusion of fingers or toes, is commonly observed in individuals with Pfeiffer syndrome. This fusion can vary in severity, ranging from partial to complete with cutaneous or osseous limits. Fusion of adjacent digits as seen in this case, a complete fusion was observed on the digits of the upper limb including the right and left index, middle, ring, little fingers and a partial fusion at the toes sparing the great toe improving on what was described in a previous report. ²⁰ Another feature of Pfeiffer syndrome is broad and medially deviated thumbs and toes. This abnormality known as brachydactyly, affects the shape, length and positioning of the digits, an anomaly that contributes to this unique phenotype.^21,22 Individuals with Pfeiffer syndrome often exhibit midface hypoplasia, characterized by underdevelopment of the maxillary region. This leads to shallow orbits (eye sockets) and protrusion of the eyes, presenting as proptosis, exophthalmos or other ocular involvement later in course of development of certain mutants. ²³

Although Pfeiffer syndrome’s anatomical characteristics are often reported, some individuals may experience developmental delays or intellectual disabilities, conductive hearing loss due to abnormalities in middle ear structures. Abnormal development of the cartilage rings in the trachea may cause respiratory difficulties as observed in this infant.^14,24,25 A mild form of craniosynostosis was also noted in this infant. Recognizing these distinctive features is crucial for precise diagnosis and suitable management.

Limitations

Due to the nature of this condition at the NICU our focus was on well-being to ensure survival. This patient died within 8 months of admission, as a result we encountered some limitations for research purposes. We were unable to follow up on routine developmental milestones in this patient to verify long term effects on intellectual growth to ascertain the potential for intellectual disability in patients with Pfeiffer subtype 1. Careful evaluation using serial imaging scans was not done in this patient. Serial scans using imaging modalities such as X-rays, CT and MRI should be done to evaluate musculoskeletal and cranial plate for long term brain development where possible. Molecular correlation between mutation type and the severity of expression needs to be investigated specifically on patients with Pfeiffer syndrome due to limited existing research.

Conclusion

The patient is a neonate admitted to the local ward with clinical features consistent with craniofacial anomalies including craniosynostosis, midface hypoplasia, broad medially deviated thumbs and toes. A diagnosis of Pfeiffer syndrome type 1 was made with a mutation in FGFR2 gene variant c.758C>G (p.Ser253Trp). The complexity of acrocephalosyndactyly and the varied morphological presentation of Pfeiffer syndrome are highlighted by this case, recognizing the distinct manifestation of webbing or fusion morphology along with notable syndactyly and brachydactyly is imperative for prompt recognition and diagnosis. Neglecting these features could lead to an incorrect classification of the condition. In clinical practice, management involves early cranial vault reconstruction as well as cosmetic surgical repair to improve hand and foot function.