Paula and Bobby
Parents of Lillie
What is Pfeiffer syndrome?
It is a rare genetic syndrome. It includes the premature fusion of specific skull bones, as well as thumb anomalies and anomalies affecting the large toes. Other main features include protruding eyes and hearing loss. There are currently 3 main types of the syndrome that have been identified. They vary in their causes, and the exact specific symptoms associated with them.
This syndrome is also known as:
Acrocephalosyndactyly - type V Acrocephalosyndactyly type V Acrocephalosyndactyly, Type V; Acs5 Acs V ACSV Noack Syndrome
What gene changes cause Pfeiffer syndrome?
Type 1 is caused by changes in the FGFR1 and FGFR2 gene.
Types 2 and 3 are caused by changes in the FGFR2 gene.
The syndrome is inherited in an autosomal dominant pattern. In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
What are the main symptoms of Pfeiffer syndrome?
The main symptoms may vary according to the type of the syndrome individuals are affected by.
Type 1: the main symptoms a prominent forehead, widely spaced eyes, underdeveloped upper jaw, prominent lower jaw and dental abnormalities. The syndrome usually does not impact on intellectual ability and development.
Type 2: the symptoms with this type of the syndrome are considered more severe. Individuals have what is known as a cloverleaf skull which can also lead to an increase of fluid in the skull and a subsequent increase of pressure on the brain. This type of the syndrome also affects neurodevelopment and usually presents with intellectual disability and developmental delay. Health issues associated with this type of the syndrome can be serious if not treated properly and promptly during infancy.
Type 3: this presents with similar symptoms as Type 2, but without the cloverleaf skull. Other features of this form of the syndrome include a shorter skull base, babies born with teeth, protrusion of the eyes and anomalies of internal abdominal organs. Intellectual disability is a defining feature of this form of the syndrome as well.
Possible clinical traits/features:
Short middle phalanx of toe, Ptosis, Strabismus, Short philtrum, Synostosis of carpal bones, Symphalangism affecting the phalanges of the hand, Shortening of all middle phalanges of the fingers, Brachydactyly, Coronal craniosynostosis, Elbow ankylosis, Cloverleaf skull, Clinodactyly of the 5th finger, Facial asymmetry, Finger syndactyly, Dental crowding, Malar flattening, Downslanted palpebral fissures, Intellectual disability, Short nose, Mandibular prognathia, Hypoplasia of the maxilla, Hypoplasia of the zygomatic bone, High forehead, High palate, Hydrocephalus, Humeroradial synostosis, Hypertelorism, Hyperlordosis, Depressed nasal bridge, Short stature, Autosomal dominant inheritance, Open mouth, Shallow orbits, Short neck, Abnormality of the hip bone, Bronchomalacia, Broad hallux, Broad thumb, Cartilaginous trachea, Brachyturricephaly, Wide nasal bridge, Arnold-Chiari malformation, Abnormality of thumb phalanx, Abnormal palate morphology, Choanal stenosis, Choanal atresia
How does someone get tested for Pfeiffer syndrome?
The initial testing for Pfeiffer syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
Medical information on Pfeiffer syndrome
The main features of this condition are craniostenosis, broad thumbs and great toes, and variable soft tissue syndactyly. In the feet the halluces are characteristically in the varus position. Craniostenosis usually affects the coronal sutures, but a clover-leaf skull can also be seen. The facies resemble Crouzon syndrome. Radiographs of the hands and feet reveal brachymesophalangy, broad distal phalanges, deformed proximal phalanges of the thumbs and great toes, symphalangism and a broad or duplicated first metatarsal. Ohashi et al., (1993) reported a case with anal atresia. It is difficult to evaluate the case with coronal craniosynostosis, anal atresia and syndactyly of toes 2 and 3 reported by Pfeiffer et al., (1996) because no photos were published. Kodaka et al., (2004) published another case (could be Pfeiffer or Saethre-Chotzen), with an imperforate anus. As with other craniosynostosis syndromes (See Apert syndrome and Crouzon syndrome) some cases can have fusion of the tracheal cartilage rings (Stone et al., 1990; Lin et al., 1995; Okajima et al., 2003; Zackai et al., 2003) or a cartilaginous tracheal sleeve (Gonzales et al., 2005). Some patients with the FGFR1 mutation (see below) have the hand anomalies without craniosynostosis (Hackett and Rowe, 2006). Deafness, especially conductive, is frequent (Desai et al., 2010) and anterior segment ocular findings have been reported (Barry et al., 2010).
Cohen (1993) recognises three subtypes. Type 1 is the classic form as reported by Pfeiffer. Type 2 has a cloverleaf skull together with ankylosis of the elbows (Plomp et al., 1998; Robin et al., 1998; Stevens et al., 2006). Type 3 is similar to type 2, but without a cloverleaf skull and with severe proptosis. Types 2 and 3 have a poor prognosis for survival but mental development may not be severely affected (Robin et al., 1998). Cases with cloverleaf skull are usually sporadic. Martinelli et al., (1997) reported a case with subtype 2 diagnosed prenatally by ultrasound because of the cloverleaf skull. The case reported by Soekarman et al., (1992) of a boy with apparent cloverleaf skull whose mother was affected with classic Pfeiffer syndrome may not be an exception, as the cranial abnormalities were not as severe as usually seen in classic cloverleaf skull abnormality. A limited number of recurrent amino-acid changes (W290C, Y340C, C342R and S351C) are responsible for the most severe Pfeiffer phenotypes (Lajeunie et al., 2006). A fetus with facial and skeletal features of Pfeiffer syndrome and lethal multiple pterygium syndrome was reported by Baynam et al., (2008). Twenty-three Japanese patients were reviewed by Koga et al., (2012), Elbow ankylosis and sacrococcygeal defects strongly suggest the pesence of Pfeiffer syndrome in newborns with craniosynostosis. Severe cases (fetuses) reported by Khonsari et al., (2012) had megalencephaly, dilated ventricles and distinctive changes in the hippocampus and amygdala.
Muenke et al., (1994) showed that mutations in the fibroblast growth factor receptor-1 (FGFR1) gene caused Pfeiffer syndrome in a proportion of families. This gene maps to 8p11.2-p12 (Robin et al., 1994). Mutations in five unrelated families were found - all the same. There was a C to G transversion in exon 5 causing a proline to arginine substitution in the link between the second and third immunoglobulin-like domains of the extracellular portion of the molecule. Rossi et al., (2003) noted that the appearance of the feet is characteristic in this condition with a broad big toe in varus position and degrees of 2-3 toe syndactyly. They reported a father and daughter with this foot appearance without evidence of craniosynostosis.
Rutland et al., (1995) and Lajeunie et al., (1995) reported mutations in the B exon of FGFR2 in cases of Pfeiffer syndrome with relatively severe skull abnormalities. All the cases were isolated. Five cases were shown to have a T to C transition at nucleotide 1036 resulting in the replacement of a cysteine by an arginine. This mutation has previously been observed in a single case of Crouzon syndrome. Park et al., (1995) reported a sporadic case with an identical mutation. They interpreted the phenotype as being that of Jackson-Weiss syndrome, but it was the same as the Rutland and Lajeunie cases (see Jackson-Weiss syndrome for comment on ""sporadic"" Jackson-Weiss syndrome). A further replacement of the same cysteine by tyrosine in another case has been reported in three cases of Crouzon syndrome. Schafer et al., (1998) reported a case of Pfeiffer syndrome type 2 with a TRP290 cys mutation in FGFR2 that had previously been reported a patient with a Crouzon phenotype. Schell et al., (1995) found similar mutations in the FGFR2 gene. Meyers et al., (1996) showed further mutations in the FGFR2 gene in cases with Crouzon, Pfeiffer and 'Jackson-Weiss' phenotypes. In one family with a novel exon IIIc mutation (valine 359 phenyalanine) the proband and his father exhibited classical features of Crouzon syndrome whereas the paternal aunt resembled Pfeiffer syndrome with broad thumbs and great toes. Passos-Bueno et al., (1997) reported a case with severe syndactyly and duplication of the hallux - interpreted as an 'Apert-like phenotype' who had an A to G transition at the 3' acceptor splice site of the intron adjacent to exon B of FGFR2. Gripp et al., (1998) reported a case with type 3 who had a Ser351Cys mutation of FGFR2. Cornejo-Roldan et al., (1999) reported further mutations in the FGFR2 gene in Pfeiffer syndrome. Lajeunie et al., (2000) reported monozygotic twins with a Cys342Tyr mutation in the FGFR2 gene. One twin had a unilateral bifid thumb but in the other the hands were normal. A further comprehensive mutation series in the FGFR2 gene was reported by Kan et al., (2002). Six mutations in this series were in the tyrosine kinase domain (most are in exon 3a or 3c). Another tyrosine kinase domain mutation, in a severely affected child (with clover-leaf skull) was reported by Zankl et al., (2004). This was the same mutation as found in one of the Kan et al., (2002) series. In that family there was considerable phenotypic variability.
The infant reported by Sagehashi (1992) with craniosynostosis, ""deformation of thumbs"", choanal stenosis, a cartilaginous trachea and a caudal appendage most likely has Pfeiffer syndrome. Lai et al., (2008) also reported a case with a sacral appendage. The case reported by Cantrell et al., (1994) most likely has Pfeiffer syndrome.
The patient reported by Roscioli et al., (2000) with an FGFR1 P252R mutation, as an example of Jackson-Weiss syndrome has classical features of FGFR1 Pfeiffer syndrome.
Sweeney et al., (2002) reported a male infant who died at seven weeks with features of Pfeiffer syndrome and a sacral appendage. A Ser351Cys mutation was detected. Gonzales et al., (2005) reported three fetuses with vertebral anomalies including sacrococcygeal eversion with the same mutation.
Shotelersuk et al., (2002) reported a 15-year-old boy with a severe form of Pfeiffer syndrome associated with acanthosis nigricans. A W290C mutation in the FGFR2 gene was demonstrated. The patient also had multiple joint and vertebral ankyloses. Cohen (2002) reviews syndromes with acanthosis associated with other FGFR mutations.
Machado et a. (2017) described a mother and a daughter with Pfeiffer syndrome due to a novel heterozygous missense mutation. Clinical characteristics included coronal craniosynostosis, brachycephaly, asymmetry (more prominent in the mother), short forehead, midface hypoplasia, hypertelorism, exophthalmos, strabismus, high arched palate, slight enlarged first metacarpal, distal deviation of phalanges, and broad-deviated hallux.
* This information is courtesy of the L M D.
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