Academic journal article Genetic Counseling

Craniosynostosis and Congenital Tracheal Anomalies in an Infant with Pfeiffer Syndrome Carrying the W290c Fgfr2 Mutation

Academic journal article Genetic Counseling

Craniosynostosis and Congenital Tracheal Anomalies in an Infant with Pfeiffer Syndrome Carrying the W290c Fgfr2 Mutation

Article excerpt

Summary: Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation: Pfeiffer syndrome (OMIM 101600) is an autosomal dominant disorder characterized by craniosynostosis, midface hypoplasia, ocular proptosis and digital malformations. We report on a type II Pfeiffer female infant with craniosynostosis, hydrocephalus, and characteristic craniofacial and digital abnormalities. The patient had a history of airway difficulty. Bronchoscopy at age four months revealed low tracheal stenosis and fibrous cartilaginous rings. She underwent tracheostomy for the treatment of cyanotic episodes. Molecular analysis revealed a de novo missense mutation c.870 G>T (TGG>TGT) in the FGFR2 gene that predicts a substitution of cysteine for tryptophan at the codon 290, (W290C). There is phenotypic heterogeneity of tracheal anomalies due to FGFR2 mutations. A review of the literature shows that Pfeiffer patients with the similar tracheal abnormalities can be caused by different FGFR2 mutations and, likewise, the patients with the same FGFR2 mutation may manifest different kinds of tracheal anomalies. Tracheal anomalies may occur in Pfeiffer patients and cause morbidity and mortality because of airway obstruction. Recognition and detailed evaluation of tracheal anomalies should be included in the early diagnostic workup for severe Pfeiffer patients.

Key-words: Craniosynostosis - FGFR2 mutation - Pfeiffer syndrome - Tracheal anomalies

INTRODUCTION

Pfeiffer syndrome (OMIM 101600) is an autosomal dominant disorder manifesting craniosynostosis, midface hypoplasia, ocular proptosis and digital malformations, and affects about 1 in 100,000 individuals (26). Three subtypes of Pfeiffer syndrome have been identified (3). Type I is associated with mild manifestations, normal neurological and intellectual development, and a good outcome. Type II and type III are associated with severe features, a cloverleaf skull, severe neurological and respiratory problems, and a poor prognosis. Here, we present an infant with type II Pfeiffer syndrome, craniosynostosis, and congenital tracheal anomalies, and a review of the literature.

CASE REPORT

The propositus was the first child of a healthy unrelated Taiwanese couple. Father aged 40 and mother 32 at her birth. There was no family history of congenital malformations. The pregnancy was uncomplicated. She was born at term by vaginal delivery. Birth weight was 2984 g (25 centile) and height 48 cm (25 centile). She was diagnosed with Pfeiffer syndrome after birth. She manifested craniosynostosis, a cloverleaf skull, hydrocephalus, ocular proptosis, midface hypoplasia, a depressed nasal bridge, low-set ears, elbow synostosis, and broad thumbs and great toes. The patient subsequently had a long history of airway difficulty. She underwent ventriculoperitoneal shunting for the treatment of hydrocephalus at age 4 months. She underwent tracheostomy at age 4 months for the treatment of cyanotic episodes. Bronchoscopy performed prior to surgery revealed low tracheal stenosis and fibrous cartilaginous rings. On examination at age 10 months, she displayed characteristic features of type II Pfeiffer syndrome (Figs 1 and 2). Molecular analysis of the patient revealed a de novo missense mutation c.870 G>T (TGOTGT) in the FGFR2 gene that predicts a substitution of cysteine for tryptophan at the codon 290 (Trp290Cys or W290C). No mutations were found in the parents.

DISCUSSION

Craniosynostosis is the major feature in several genetic disorders such as Pfeiffer, Crouzon, Jackson-Weiss and Apert syndromes. Mutations in three FGFRs, including FGFRl on 8pll, FGFR2 on 10q26 and FGFRS on 4p16.3 have been responsible for these craniosynostosis syndromes (8-9, 11, 19-20, 22, 27). Mutations in the FGFR1 and FGFR2 genes can result in Pfeiffer syndrome. To date, at least 11 cases of Pfeiffer syndrome with the W290C FGFR2 mutation have been reported (1, 7, 10, 16, 21, 23, 25, 28) (Table I). …

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