Table 9 Growth factor signaling

Abdel-Salam et al., 2011 [310]

Muenke syndrome with pigmentary disorder and probable hemimegalencephaly: An expansion of the phenotype

National Research Centre, Cairo, Egypt

1 Patient, 2 parents

-

Case study

Left HME, inadequate differentiation of white and gray matter, underdeveloped corpus callosum, abnormal hippocampus configuration, right coronal, sagittal, and lambdoid suture synostoses

Frontal bossing, sparse, hypopigmented, curly hair, prominent eyes, low-set ears, hypoplastic maxilla, long philtrum, brachydactyly with fusiform fingers, skin hyperpigmentation

Obstructive

TES

MLPA, DHPLC

AD

4p16.3 (FGFR3 showed a c.749C > G, p.Pro250Arg substitution)

Arnaud-López et al., 2007 [311]

Crouzon with acanthosis nigricans. Further delineation of the syndrome

Instituto Mexicano del Seguro Social, Guadalajara, México

2 Subjects

-

Case series

Craniosynostosis

Laryngomalacia, acanthosis nigricans, choanal stenosis, double collecting system and dysplastic kidney

Communicating

TGS, cytogenetics

Karyotyping

AD

4p16.3 (FGFR3)

Chen et al., 2001 [312]

Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia

Mackay Memorial Hospital, Taipei, Taiwan

4 Subjects, control matched sampling

Chinese

Case series

Cloverleaf skull, macrocephaly, synostosis

Short-limbed dwarfism, multiple skeletal dysplasias

-

TES

Direct sequencing

-

4p16.3 (FGFR3)

Chen et al., 2008 [313]

Craniosynostosis and congenital tracheal anomalies in an infant with Pfeiffer syndrome carrying the W290C FGFR2 mutation

Mackay Memorial Hospital, Taipei, Taiwan

1 Subject

-

Case study

Dandy walker—cerebellar malformations

Turricephalic prominent forehead, hypertelorism, low-set ears, a flat nasal bridge, mid-face hypoplasia, bilateral cleft lip and palate, a thick nuchal fold, and a distended abdomen, and multicystic kidneys

Communicating

-

-

De novo

10q26.13 (c.870 G > T (TGG > TGT) in the FGFR2)

Chen et al., 2017 [314]

Pfeiffer syndrome with FGFR2 C342R mutation presenting extreme proptosis, craniosynostosis, hearing loss, ventriculomegaly, broad great toes and thumbs, maxillary hypoplasia, and laryngomalacia

Mackay Memorial Hospital, Taipei, Taiwan

1 Subject

-

Case study

Multisynostoses of sagittal and coronal sutures

Bilateral hearing loss, brachycephaly, hypertelorism, broad big toes and thumbs, low-set ears, laryngeomalacia and midface hypoplasia

Obstructive

Cytogenetics

Karyotyping

AD

10q26.13 (FGFR2 C342R mutation)

Fonseca et al., 2008 [315]

Second case of Beare-Stevenson syndrome with an FGFR2 Ser372Cys mutation

Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

1 Subject

-

Case study

Craniosynostosis, crouzonoid-like features, and cloverleaf skull

Cutis gyrata, acanthosis nigricans, skin furrows, skin tags, anogenital anomalies, and prominent umbilical stump

Communicating

TES

Direct sequencing

AD

10q26.13 (FGFR2 Ser372Cys mutation.)

González-Del Angel et al., 2016 [316]

Expansion of the variable expression of Muenke syndrome: Hydrocephalus without craniosynostosis

Instituto Nacional de Pediatría, Mexico City, Mexico

56 Subjects

Mexican

Case series

Uni- or bicoronal craniosynostosi

Wide variability

Obstructive

TES

Direct sequencing, restriction enzyme analysis

AD

4p16.3 (FGFR3)

Gripp et al., 1998 [317]

Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III

The Children's Hospital of Philadelphia, Pennsylvania, USA

1 Subject

Caucasian

Case study

Seizures, developmental delay, pansynostosis

Bilateral elbow ankylosis, radial head dislocation,

Extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation

Communicating

TES

SSCP, cycle sequencing

AD

10q26.13 (Ser351Cys in FGFR2)

Gupta et al., 2020 [318]

Crouzon Syndrome in a Ten-week-old Infant: A Case Report

All India Institute of Medical Sciences, Patna, Bihar, India

1 Subject

Japanese

Case study

Neurologic and neuromuscular impairment,

Craniosynostosis

Airway obstruction, craniofacial dysostosis with abnormal shape of the skull, proptosis, hypertelorism, curved nose and frontal bossing

Communicating

-

-

AR

10q26.13 (FGFR2)

Ito et al., 2018 [76]

A ZPR1 mutation is associated with a novel syndrome of growth restriction, distinct craniofacial features, alopecia, and hypoplastic kidneys

University of Ottawa, Ottawa, Canada

4 Subjects, 3 Controls

New Mexican Hispanic heritage

Case series

Microcephaly

Growth restriction, distinctive craniofacial features, congenital alopecia, hypoplastic kidneys with renal insufficiency, global developmental delay, severe congenital sensorineural hearing loss, and genital hypoplasia

-

WES

Sanger sequencing

AR

11q23.3 (ZPR1 Zinc Finger)

Kan et al., 2002 [75]

Genomic screening of fibroblast growth-factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis

The John Radcliffe Hospital, Oxford, United Kingdom

259 Subjects, 128 Controls

-

Case series

Cloverleaf skull, craniosynostosis

Communicating

TES

HA

AD

10q26.13 (FGFR2)

Lajeunie et al., 2006 [319]

Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome

Hôpital Necker-Enfants malades, Paris, France

129 Subjects, 65 Controls

-

Case series

Synostosis of one or several cranial sutures

Ocular proptosis, maxillary hypoplasia and midface retrusion

Communicating

TES

Direct sequencing

AD

8p11.23 (FGFR 1); 10q26.13 (FGFR2); 4p16.3 (FGFR 3 mutation)

Priolo et al., 2000 [320]

Pfeiffer syndrome type 2 associated with a single amino acid deletion in the FGFR2 gene

G. Gaslini Institute, Genova, Italy

1 Subject, 60 Controls

-

Case study

Acrocephalo-trygonocephaly with cloverleaf skull, callosal dysgenesis and Chiari I malformation

Facial dysmorphism, radial clinodactyly of the thumbs and valgus deviation of the halluces

Unclear

TGS

Cycle sequencing

AD

10q26.13 (FGFR2)

Przylepa et al., 1996 [321]

Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome

The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

5 Subjects, 3 Parents, and 50 Controls

-

Case series

Craniosynostosis

Cutis gyrata, acanthosis nigricans, craniofacial dysmorphism, digital anomalies, umbilical and anogenital abnormalities

Communicating

TGS

HA, fluorescent dideoxy terminator method, restriction enzyme analysis

AD

10q26.13 (FGFR2)

Rump et al., 2006 [322]

Severe complications in a child with achondroplasia and two FGFR3 mutations on the same allele

University Medical Center Groningen, University of Groningen, The Netherlands

1 Subject, 2 Parents

Dutch

Case study

Megalencephalic

Midface hypoplasia, lordotic lumbar spine, trident hand configuration, achondroplasia, respiratory failure

Communicating

TGS

Variant analysis

AD

4p16.3 (p.G380R

mutation of FGFR3)

Rutland et al., 1995 [323]

Identical mutations in the FGFR2 gene cause both Pfeiffer and Crouzon syndrome phenotypes

Institute of Child Health, London, UK

12 Subjects

-

Case series

Cloverleaf skull, craniosynostosis

Digital abnormalities

Communicating

TES

SSCP, direct sequencing, restriction endonuclease analysis

De novo

10q26.13 (FGFR2)

Schaefer et al., 1998 [324]

Novel mutation in the FGFR2 gene at the same codon as the Crouzon syndrome mutations in a severe Pfeiffer syndrome type 2 case

H.A. Chapman Research Institute of Medical Genetics, Tulsa, Oklahoma, USA

1 Subject

-

Case study

Cloverleaf skull

Proptosis, radioulnar synostosis and broad thumbs and great toes

Communicating

TES

Cycle sequencing

-

10q26.13 (G to T mutation in codon 290 exon 7 of the FGFR2)

Takenouchi et al., 2013 [325]

Severe congenital lipodystrophy and a progeroid appearance: Mutation in the penultimate exon of FBN1 causing a recognizable phenotype

Keio University School of Medicine, Tokyo, Japan

1 Subject

Japanese

Case study

Craniosynostosis

Progeroid appearance, wide-open anterior fontanelle, low-set ears, long arms and legs, arachnodactyly, and arthrogryposis, hydronephrosis

Communicating

TGS

NGS, sanger sequencing

AD

15q21.1 (exon 64 of the FBN1 gene)