Introduction: Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome associated with neurodevelopmental disorders and craniofacial dysmorphisms caused by variations in the TCF4 transition factor. The aim of this article was to report the case of two twin infants diagnosed with PTHS, confirmed by the identification of a heterozygous pathogenic variant in the TCF4 gene through DNA extracted from a buccal swab. Case Presentation: Both infants presented with craniofacial asymmetry with a metopic crest and cranial deformity. During the diagnostic investigation, computed tomography with three-dimensional reconstruction of the skull showed premature fusion of the left coronal and metopic sutures in both twins. They underwent craniofacial reconstruction at the 9th month of age using a combination of techniques. The postoperative outcomes were satisfactory in both cases. Conclusion: To the best of our knowledge, this is the first case report to describe the occurrence of complex craniosynostosis (CCS) in children with PTHS. Further studies are needed to determine whether the co-occurrence of PTHS and CCS described here indicates an association or is explained by chance.

Established Facts

  • Craniofacial dysmorphisms are observed in certain cases of complex craniosynostosis, especially associated with Apert, Crouzon, Saethre-Chotzen, Pfeiffer, Muenke, Beare-Stevenson, and even rarer syndromes.

  • Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome associated to a neurodevelopmental disorder characterized by intellectual impairment, breathing anomalies, disturbances of intestinal motility, and craniofacial dysmorphisms.

  • Association or occurrence between PTHS and craniosynostoses is not described in the literature.

Novel Insights

  • The possible co-occurrence or association between PTHS and craniosynostoses is being first described here.

  • Further studies are needed to define whether the co-occurrence described here indicates an association or is explained by chance.

  • Multidisciplinary discussion for planning the most appropriate surgical choice is essential.

Pitt-Hopkins syndrome (PTHS) is a rare genetic syndrome first described in 1978 [1]. It is associated with a neurodevelopmental disorder caused by variations in the TCF4 transition factor and is mainly characterized by intellectual impairment, breathing anomalies, disturbances of intestinal motility, and craniofacial dysmorphisms [1‒3]. Craniofacial dysmorphisms are also observed in certain cases of complex craniosynostosis (CCS), especially those associated with Apert, Crouzon, Saethre-Chotzen, Pfeiffer, Muenke, Beare-Stevenson, and even rarer syndromes [3‒7]. Using the keywords craniosynostosis, neurosurgery, and PTHS in the databases and search tools of Google Scholar, PubMed (National Library of Medicine National Institutes of Health), Lilacs (Latin American and Caribbean Health Science Literature), and Scielo (Scientific Electronic Library Online), we did not identify any report of the co-occurrence or association between PTHS and CCS in the reviewed literature. The scope of this article is to report two such cases, describing the surgical technique used for craniofacial reconstruction and the outcomes obtained.

Authorization to report the cases was obtained and signed by the parents. This study protocol was reviewed and approved by the research Ethics Committee of the São Rafael Hospital, D’Or Institute for Research and Education (IDOR) [Salvador da Bahia, Brazil], approval number CAAE: 68845223.7.0000.0048 nº 6.021.070. The diagnosis was suspected based on clinical scoring criteria described in the literature [2] and confirmed through DNA extracted from buccal swabs and identification of a heterozygous pathogenic variant of the TCF4 gene in two twin infants. CCS classification was based on a preoperative three-dimensional computed tomography (3DCT) scan, according to previous publications [4, 7]. Both infants underwent craniofacial reconstruction, and the postoperative outcomes were based on previously established classification [8, 9].

Male preterm infants (monozygotic twins) were born at the 32nd gestational week, both with a low weight (1,400 g) and nonspecific cranial asymmetry. In view of the cognitive-motor developmental delay and progressive craniofacial asymmetry (right posterior parietal bossa, metopic bone crest, hypertelorism, and frontal facial asymmetry) (shown in Fig. 1), they were referred for neurosurgical evaluation at the 9th month of age (chronological age: 9 months; corrected age: 7 months). Neurological examination of the two infants showed cognitive motor developmental delay (score 2), impairment of motor coordination with age (score 1), and typical PTHS facial features (score 4), resulting in a PTHS score of 7 (Table 1).

Cranial measurements showed head circumference within the appropriate standard deviation for the age (43.3 cm and 43.5 cm; considering the corrected age, the curves were in the 15th percentile, standard deviation −1) and cranial index of 70% and 69%, respectively (Table 2). The 3DCT of the skull identified premature fusion of the left coronal and metopic sutures with digitiform impressions (copper-beaten-type images) of the cranial bone in both twins (shown in Fig. 2a, b). No papilledema or radiological findings such as hydrocephalus or Chiari 1, associated with the copper-beaten sign identified on 3DCT, were identified. Both siblings had corpus callosum dysgenesis identified on magnetic resonance imaging of the brain. Due to the rarity of PTHS and the team’s doubts regarding the best management of CCS in these children, the surgical indication was discussed in a multidisciplinary manner, considering the parental report of progressive craniofacial deformity and 3DCT findings.

Both twins underwent surgery at around the 9th month of life (7th month corrected age). In the twin A, bilateral frontal craniotomy was performed with the removal of the left coronal suture in conjunction with the frontal flap. The lower edge of the craniotomy site was marked 15 mm above the orbital ridge. A combination of shell-type techniques and a 10-mm left fronto-orbital advancement was used in this infant (twin A), whose metopic crest was more prominent (shown in Fig. 3a, b). In the twin B, craniofacial reconstruction with frontal remodeling and left fronto-orbital advancement of 20 mm was chosen since his greater asymmetry was related to left anterior plagiocephaly (shown in Fig. 4a, b). In both infants, the fronto-orbital block was fixed to the skull using resorbable plates and screws. There were no intraoperative anesthetic or surgical complications, such as laceration of the dura mater or bleeding greater than expected for the proposed surgery. Both patients required blood transfusions during surgery. The two siblings remained in the pediatric intensive care unit for the first 48 h after surgery, without postoperative complications. The infants were discharged on the 4th day after surgery. In the follow-up period, clinical and radiological examinations (3DCT) performed 1 year after hospital discharge did not identify craniofacial deformities or secondary craniosynostoses that indicated the need of surgical re-approach in the first year after surgery, neither deformities clinically visible or identified in control imaging examinations. The medical and parental evaluations regarding the surgical outcomes performed in the first 12 months after surgery were satisfactory (Sloan score 1).

PTHS is a rare genetic syndrome with an incidence of 1:225,000 to 1:400,000. It is a neurodevelopmental disorder characterized by cognitive and motor impairment caused by deletions or mutations in the TCF4 gene and may involve intellectual cognitive impairment, seizures, respiratory disorders, and craniofacial dysmorphisms [1, 2, 10‒12]. A narrow forehead, wide nasal bridge, flared nasal alae, full cheeks with a prominent midface, wide mouth, and full lips are some of the main craniofacial dysmorphisms [1, 2, 10‒12]. Scores between 6 and 8 for clinical suspicion of PTHS warrant TCF4 molecular analysis [2], which was performed in both cases described here.

The presence of congenital microcephaly, characterized by a cranial perimeter of less than two standard deviations below the mean for age [13], is described in 18% of PTHS cases and is one of the main findings related to craniometry [2, 12]. A brachycephalic skull shape has also been described by some authors but without a detailed definition that can corroborate the diagnosis of craniosynostosis [14]. Craniometry in both cases described herein ruled out microcephaly or brachycephaly, considering the vector patterns of Virchow’s law [4, 7].

Craniosynostoses resulting from premature fusion of the coronal and metopic sutures are considered rare, corresponding to only 0.4% of all craniosynostoses. This type of craniosynostosis does not follow the vector patterns of Virchow’s law observed in the most common craniosynostoses, making clinical diagnosis difficult and 3DCT indispensable for a conclusive diagnosis [4, 7]. In the 2 cases analyzed in this study, 3DCT showed, in addition to the closure of unilateral coronal and metopic sutures, digitiform impressions on the cranial bone that may be associated with increased intracranial pressure and consequently increased risk of neurological deficits [15, 16]. The latter method (3DCT) also allows the identification of radiological images associated with possible signs of increased intracranial pressure, which is one of the factors considered in surgical decision-making.

Multidisciplinary discussions for planning the most appropriate surgical choice are essential, especially in cases of CCS [16, 17]. The surgical techniques used for the correction of craniosynostoses include suturectomy, Lauritzen’s spring-assisted expansion, and various craniofacial reconstruction techniques [8, 9, 15‒22]. A consensus decision (pediatric neurosurgery and craniofacial plastic surgery) was made to combine and adapt previously established techniques. The postoperative hospitalization time was similar to that previously published by one of the authors, considering other craniosynostoses [9]. Both children were classified with a Sloan score of 1 (satisfactory outcome), according to clinical and radiological examinations carried out 1 year after hospital discharge, considering previously described scales of assessment after cranial reconstruction [8, 9, 17]. These findings reinforce the importance of multidisciplinary surgical planning and knowledge of the various available techniques for adequate adaptation and combination. We emphasize that the decision for surgical intervention was a consensus between the multidisciplinary team and the parents, after discussions about possible management options for a rare and poorly known congenital disease, especially concomitant with early closure of cranial sutures.

To the best of our knowledge, the possible association or co-occurrence of PTHS and craniosynostoses is being first described here. Further studies are needed to determine whether the co-occurrence of PTHS and craniosynostoses indicates an association or whether it is explained by chance. Therapeutic management and decision-making must be multidisciplinary.

The study was approved by the research Ethics Committee (São Rafael Hospital, D’Or Institute for Research and Education [IDOR] [Salvador da Bahia, Brazil], approval number CAAE: 68845223.7.0000.0048 no 6.021.070) after obtaining consent and authorization from parents and guardians for the disclosure and reporting of the case and photos/images without identification of the child and was conducted ethically in accordance with the Declaration of Helsinki. Informed consent for the publication and report of the case was signed by the parents, who also authorized the disclosure of the images published here.

The authors declare that they have no conflicts of interest.

There were no funding sources. This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

All the authors contributed to the conception and design of the study. Material preparation, data collection, and analysis were performed by José Roberto Tude Melo, Ana Rita de Luna Freire Peixoto, and Danilo Marden de Lima Souza. The first draft of the manuscript was written by José Roberto Tude Melo, and all the authors commented on the previous version of the manuscript. All authors have read and approved the final manuscript.

Data supporting the findings of this study are available for this article. No supplementary materials are available for this case report. Further inquiries can be directed to the corresponding authors.

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