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Fibroblast growth factors, their receptors and receptor disorders
Journalof Cranio-MaxillofacialSurgery (1996)24, Suppl. 1.2-5 © 1996European Association for Cranio-Maxillofacial Surgery
State of the art lectures
Fibroblast Growth Factors, their Receptors and Receptor Disorders Gorlin R.J.
Regents' Professor, Department of Oral Pathology and Genetics, Universityof Minnesota, Minneapolis, USA Nine fibroblast growth factors (FGF) represent a family of polypeptides that, as ligands, play an important role in embryonic development by stimulating cell division (mitogenesis), inducing differentiation of cells of mesenchymal and ectomesenchymal origin, and aiding in development of blood vessels. Some act as oncogenes, others as growth factors. To date, there have been no disorders of F G F reported - - presumably because they are so basic to development and so ubiquitous that a mutation would be lethal. There are four fibroblast growth factor receptors (FGFR 1-4). These cell surface receptors are tyrosine kinase molecules that span the wall of cells and bind and phosphorylate intracellular signal transduction proteins, i.e. a repertoire of the nine FGF described above. Fibroblast growth factor receptors play a role in embryonic development. For example, FGFR1 and specific isoforms of FGFR2 are expressed in precartilage and prebone during craniofacial flat bone formation and in the apical ectodermal ridge of developing limb buds, while FGFR3 is expressed in the cartilage growth plate during enchondral bone formation. In developing limb buds, FGFR1 is expressed throughout the mesenchyme while FGFR1, 2, or 3 is confined to the ectoderm. Homozygosity of FGFR2 or 3 is, in general, lethal. Mutations in these FGFRs cause a variety of disorders that will be discussed in greater detail. Disorders of FGFR3 include achondroplasia, hypochondroplasia, thanatophoric dysplasia and Crouzon syndrome with acanthosis nigricans. Aehondroplasia has autosomal dominant inheritance. It is one of the most common nonlethal skeletal dysplasias (1 per 15 000 live births). Most examples of achondroplasia are sporadic, about 80% representing new mutations. The homozygous state is lethal in infancy, the phenotype being somewhat similar to thanatophoric dysplasia. Clinical findings include large head with prominent forehead and saddle nose, midface hypoplasia, short limbs, trident hands (inability to approximate fingers), short fingers of equal length, thoracolumbar gibbus in infants, lumbar lordosis in children and adults, bowed legs and normal intelligence. Spinal cord compression at various levels, and hydrocephalus are frequent complications. Genetic linkage studies mapped achondroplasia to 4p16.3. The gene was demonstrated to be FGFR3. A specific amino acid mutation (Gly 380 to Arg) in the transmembrane region results in altered cell membrane adhesion and signal transduction. Almost all patients have demonstrated this mutation. Hypoehondroplasia, inherited as. an autosomal dominant disorder, is a relatively common form of underdiagnosed short stature. Hypochondroplasia is characterized by mild, but variable, disproportionate shortness of limbs. The trunk is normal. The face is otherwise unremarkable. The hands and feet tend to be broad and stubby. Lumbar lordosis is
common. Bellus et al (1995) demonstrated a recurrent mutation in FGFR3 in 60% of those with hypochondroplasia, illustrating allelism with achondroplasia and both forms of thanatophoric dysplasia. There seems to be no clinical difference between those with that specific mutation and those without. Possibly the other 40% may be due to a mutation in other than FGFR3. Thanatophorie dysplasia is the most common form of lethal neonatal skeletal dysplasia (1 per 20 000 live births). It is characterized by large head, extreme shortening of limbs, markedly narrow thorax, large abdomen, and redundancy of skin folds of arms and legs. Death occurs soon after birth (0-2 days) due to respiratory distress. Polyhydramnios is common. It has long been recognized that thanatophoric dysplasia, achondroplasia, and hypochondroplasia form a closely related family of disorders of enchondral bone formation affecting the growth of the cartilagenous growth plate of long bones and base of skull. There are two forms, those with curved (French telephone receiver femora) long bones (TDI), which is the more common, and those with straight long hones, (TDII). The latter more often have Kleeblattsch~del (clover-leaf skull). The ribs are short and the scapulae are short. Platyspondyly is severe with wide intervertebral disc spacing. The iliac bones are short with narrow sacrosciatic notches and medial and lateral spines. Features similar to those of homozygous achondroplasia are recognized. It was not long after achondroplasia was mapped to 4p16.3 and the gene identified as FGFR3, that the same gene was found to be involved in thanatophoric dysplasia. All mutations in Type II thanatophoric dysplasia are caused by a Lys 650 Glu change in the intracellular tyrosine kinase part of FGFR3. On the other hand, about 55% of TDI showed an Arg 248 Cys mutation in the extracellular region of the protein between IgII and IgIII suggesting that type I is heterogeneous. Disorders of FGFR2 include Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, some examples of Pfeiffer syndrome, and Beare-Stevenson syndrome. Crouzon syndrome (craniofacial synostosis) has autosoreal dominant inheritance with complete penetrance. There are about 16 per 1 million live births. Anomalies are limited to the skull and face. Premature fusion of coronal sutures results in brachycephaly. There is usually significant ocular hypertelorism with shallow orbits, resulting in exophthalmos. Midfacial hypoplasia is associated with parrot-beaked nose. Normal mandibular growth causes relative mandibular prognathism. Cleft palate, hearing loss due to atresia of auditory canals, airway obstruction and luxation of the eye globes may complicate the clinical picture. Crouzon syndrome was mapped to 10q25-q26, the site for FGFR2. Many mutation sites are involved in Crouzon syndrome. Crouzon syndrome with acanthosis nigricans. In 1995, Meyers and Jabs found that, unlike the usual form of Crouzon syndrome which maps to FGFR2, the acanthosis nigricans variant maps to the transmembrane region of FGFR3, only 11 amino acids away from the achondroplasia gene. Apert syndrome is the most severe of several disorders of intramembranous bone formation that result in craniosynostosis. Most examples of this relatively rare (16 per
State of the art lectures 3 1 million births) are sporadic. Although dominant inheritance had been demonstrated, unattractive appearance and mental retardation cause diminished contribution to the gene pool. The head is tall and brachycephalic. The palpebral fissures are downslanting and ocular hypertelorism is marked. The orbits are shallow with exophthalmos. Often there is exotropia. The midface is hypoplastic, causing relative mandibular prognathism. The mouth is trapezoidshaped and often is held open. The palate is minaret-shaped or, less often, cleft. The hands and feet exhibit marked syndactyly, the thumb and halluces often being separate from the rest of the digits. The hand has mitten-form. Toes are totally fused with a single jointed toenail. Mental retardation and conductive hearing loss are common. Mutations in the FGFR2 at 10q25-q26 have been demonstrated. Pfeiffer syndrome is characterized by acrobrachycephaly, downslanting palpebral fissures, midfacial hypoplasia, relative mandibular prognathism, ocular hypertelorism, exorbitism and small beaked nose. Syndactyly is minimal but thumbs and halluces are very broad. The great toes may deviate medially. Intelligence is usually normal but may be significantly retarded. Conductive hearing loss may be marked. Some patients exhibit Kleeblattsch~idel and joint fixation due to radio-ulnar synostosis or humeroradial synostosis. Others have rocker-bottom feet due to vertical talus. Pfeiffer syndrome has been shown on molecular grounds to be heterogeneous with map positions at 10q25-q26 (FGFR2) and less often at 8pll.2-p12 (FGFR1). Jackson-Weiss syndrome, a rare autosomal dominant craniosynostosis, was found in a huge kindred. Expression is so variable that the entire spectrum of the craniosynostoses was seen save that of Apert syndrome. There is a resemblance to Pfeiffer syndrome but the thumbs are not involved. Some patients have considerable midface hypoplasia. The foot abnormalities are distinguishing: medially deviated hallux, short and broad metatarsals and tarsal bone fusion. Molecular study has demonstrated that Jackson-Weiss syndrome maps to 10q23~t26. A mutation in FGFR2 was found. Beare-Stevenson syndrome is characterized by corrugated skin furrows (cuffs gyratum), acanthosis nigricans, and unusual facies. Additional anomalies have included craniosynostosis with cloverleaf skull, ocular hypertelorism, choanal atresia, bifid scrotum, skin tags, and enlarged umbilical stump. Several cases have been reported. The cutis gyrata principally affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet. All examples have been sporadic. The disorder has been mapped to F G F R 2 at 10q23-q26.
excision of, almost all tumours in this area provided the facial skin is not involved. Very occasionally a Weber-Fergusson incision may be used but this is avoided if possible. It is to the exposure in bony area that the craniomaxillofacial surgeon has contributed very considerably. The Le Fort I osteotomy, originally described for tumour resection, has been repopularized for clival lesions. The mandibular swing allows easy exposure to the infratemporal fossa. The frontal craniotomy limited or extensive, together with a frontonasal ostectomy give excellent exposure to the anterior cranial fossa. The lateral approach with preservation of the facial nerve, zygomatic arch and mandibular osteotomy, together with temporoparietal craniotomy, provides excellent exposure to the middle cranial fossa. In addition to this, the concept of facial disassembly has allowed multiple segments of the craniofacial skeleton to be removed for exposure of deep seated tumours. This enables the neurosurgeon to resect these turnouts more efficiently and more safely under magnification. Reconstruction by side-table assembly speeds up the surgical procedure. Bony defects are reconstructed by the use of free bone grafts, pedicled vascularized bone grafts or microvascular free tissue transfer of bone and/or soft tissue. It is in the area of prevention or treatment of infection that the craniomaxillofacial surgeon has made extremely significant contributions by providing methods to eliminate defects between the oronasopharynx and intracranial contents. Vascularized local tissue, i.e. temporal galea, temporalis muscle, galeofrontalis-periosteal flaps can be used to obtain secure closure of the anterior cranial fossa base. In large defects free tissue transfer using, for example, rectus abdominis, latissimus dorsi or omentum may be chosen. When there is established infection, undoubtedly the most effective method of eliminating this is by free tissue transfer this provides a good blood supply and an environment for antibiotics to reach the area. Finally, free tissue transfer has allowed second chance radiation in those patients having a full dose of radiation previously. The free tissue transfer is the soft tissue through which the second dose of radiation is given. Skull base tumour surgery is a field to which the craniomaxillofacial surgeons have contributed greatly a n d in which they should be actively engaged, in the exposure and reconstruction, and if properly trained also in the resection of tumours in this area.
Fetal Wound Healing and its Application to Craniomaxillofacial Surgery Kaban L.B., Guralnick W.C
Contributions of Craniofacial Surgery to Skull Base Turnout Surgery Jackson L T.
Providence Hospital, Institute for Craniofacial and Reconstructive Surgery, Southfield, USA In 1948, Hayes Martin stated that: the skull base would always remain a barrier to the adequate resection of some head and neck malignancies. We have come a long way since then. The progress has been due in no small way to the advances gained from craniofacial surgery for craniofacial deformities. The craniofacial surgeon and maxillofacial surgeon expanded their teams to cope with tumours in this area. They have brought new approaches, methods of reconstrnction and frequently microsurgical expertise for the treatment of these difficult problems. The coronal approach and intraoral approaches can provide exposure to, and allow
Department of Maxillofacial Surgery, Harvard University, Massachusetts General Hospital, Boston, Massachusetts, USA Fetal wound healing is characterized by tissue regeneration without inflammation and fibrosis. The ability of such wounds to heal without the restrictive forces of scar tissue makes the concept of fetal cleft lip and palate repair potentially attractive. Alternatively, a better understanding of fetal wound healing may make it possible to manipulate postnatal wounds to make them more 'fetal-like'. Our laboratory has been developing fetal models to study in utero cleft lip and palate repair, craniosynostosis, healing of calvarial bone defects and hemifacial microsomia. In this presentation, I will review our experience With wound healing and growth in the fetal rabbit cleft lip model. This procedure has been performed on 174 fetuses in 98 pregnant does. Details of the model and wound healing characteristics will
State of the art lectures
Fibroblast Growth Factors, their Receptors and Receptor Disorders Gorlin R.J.
Regents' Professor, Department of Oral Pathology and Genetics, Universityof Minnesota, Minneapolis, USA Nine fibroblast growth factors (FGF) represent a family of polypeptides that, as ligands, play an important role in embryonic development by stimulating cell division (mitogenesis), inducing differentiation of cells of mesenchymal and ectomesenchymal origin, and aiding in development of blood vessels. Some act as oncogenes, others as growth factors. To date, there have been no disorders of F G F reported - - presumably because they are so basic to development and so ubiquitous that a mutation would be lethal. There are four fibroblast growth factor receptors (FGFR 1-4). These cell surface receptors are tyrosine kinase molecules that span the wall of cells and bind and phosphorylate intracellular signal transduction proteins, i.e. a repertoire of the nine FGF described above. Fibroblast growth factor receptors play a role in embryonic development. For example, FGFR1 and specific isoforms of FGFR2 are expressed in precartilage and prebone during craniofacial flat bone formation and in the apical ectodermal ridge of developing limb buds, while FGFR3 is expressed in the cartilage growth plate during enchondral bone formation. In developing limb buds, FGFR1 is expressed throughout the mesenchyme while FGFR1, 2, or 3 is confined to the ectoderm. Homozygosity of FGFR2 or 3 is, in general, lethal. Mutations in these FGFRs cause a variety of disorders that will be discussed in greater detail. Disorders of FGFR3 include achondroplasia, hypochondroplasia, thanatophoric dysplasia and Crouzon syndrome with acanthosis nigricans. Aehondroplasia has autosomal dominant inheritance. It is one of the most common nonlethal skeletal dysplasias (1 per 15 000 live births). Most examples of achondroplasia are sporadic, about 80% representing new mutations. The homozygous state is lethal in infancy, the phenotype being somewhat similar to thanatophoric dysplasia. Clinical findings include large head with prominent forehead and saddle nose, midface hypoplasia, short limbs, trident hands (inability to approximate fingers), short fingers of equal length, thoracolumbar gibbus in infants, lumbar lordosis in children and adults, bowed legs and normal intelligence. Spinal cord compression at various levels, and hydrocephalus are frequent complications. Genetic linkage studies mapped achondroplasia to 4p16.3. The gene was demonstrated to be FGFR3. A specific amino acid mutation (Gly 380 to Arg) in the transmembrane region results in altered cell membrane adhesion and signal transduction. Almost all patients have demonstrated this mutation. Hypoehondroplasia, inherited as. an autosomal dominant disorder, is a relatively common form of underdiagnosed short stature. Hypochondroplasia is characterized by mild, but variable, disproportionate shortness of limbs. The trunk is normal. The face is otherwise unremarkable. The hands and feet tend to be broad and stubby. Lumbar lordosis is
common. Bellus et al (1995) demonstrated a recurrent mutation in FGFR3 in 60% of those with hypochondroplasia, illustrating allelism with achondroplasia and both forms of thanatophoric dysplasia. There seems to be no clinical difference between those with that specific mutation and those without. Possibly the other 40% may be due to a mutation in other than FGFR3. Thanatophorie dysplasia is the most common form of lethal neonatal skeletal dysplasia (1 per 20 000 live births). It is characterized by large head, extreme shortening of limbs, markedly narrow thorax, large abdomen, and redundancy of skin folds of arms and legs. Death occurs soon after birth (0-2 days) due to respiratory distress. Polyhydramnios is common. It has long been recognized that thanatophoric dysplasia, achondroplasia, and hypochondroplasia form a closely related family of disorders of enchondral bone formation affecting the growth of the cartilagenous growth plate of long bones and base of skull. There are two forms, those with curved (French telephone receiver femora) long bones (TDI), which is the more common, and those with straight long hones, (TDII). The latter more often have Kleeblattsch~del (clover-leaf skull). The ribs are short and the scapulae are short. Platyspondyly is severe with wide intervertebral disc spacing. The iliac bones are short with narrow sacrosciatic notches and medial and lateral spines. Features similar to those of homozygous achondroplasia are recognized. It was not long after achondroplasia was mapped to 4p16.3 and the gene identified as FGFR3, that the same gene was found to be involved in thanatophoric dysplasia. All mutations in Type II thanatophoric dysplasia are caused by a Lys 650 Glu change in the intracellular tyrosine kinase part of FGFR3. On the other hand, about 55% of TDI showed an Arg 248 Cys mutation in the extracellular region of the protein between IgII and IgIII suggesting that type I is heterogeneous. Disorders of FGFR2 include Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome, some examples of Pfeiffer syndrome, and Beare-Stevenson syndrome. Crouzon syndrome (craniofacial synostosis) has autosoreal dominant inheritance with complete penetrance. There are about 16 per 1 million live births. Anomalies are limited to the skull and face. Premature fusion of coronal sutures results in brachycephaly. There is usually significant ocular hypertelorism with shallow orbits, resulting in exophthalmos. Midfacial hypoplasia is associated with parrot-beaked nose. Normal mandibular growth causes relative mandibular prognathism. Cleft palate, hearing loss due to atresia of auditory canals, airway obstruction and luxation of the eye globes may complicate the clinical picture. Crouzon syndrome was mapped to 10q25-q26, the site for FGFR2. Many mutation sites are involved in Crouzon syndrome. Crouzon syndrome with acanthosis nigricans. In 1995, Meyers and Jabs found that, unlike the usual form of Crouzon syndrome which maps to FGFR2, the acanthosis nigricans variant maps to the transmembrane region of FGFR3, only 11 amino acids away from the achondroplasia gene. Apert syndrome is the most severe of several disorders of intramembranous bone formation that result in craniosynostosis. Most examples of this relatively rare (16 per
State of the art lectures 3 1 million births) are sporadic. Although dominant inheritance had been demonstrated, unattractive appearance and mental retardation cause diminished contribution to the gene pool. The head is tall and brachycephalic. The palpebral fissures are downslanting and ocular hypertelorism is marked. The orbits are shallow with exophthalmos. Often there is exotropia. The midface is hypoplastic, causing relative mandibular prognathism. The mouth is trapezoidshaped and often is held open. The palate is minaret-shaped or, less often, cleft. The hands and feet exhibit marked syndactyly, the thumb and halluces often being separate from the rest of the digits. The hand has mitten-form. Toes are totally fused with a single jointed toenail. Mental retardation and conductive hearing loss are common. Mutations in the FGFR2 at 10q25-q26 have been demonstrated. Pfeiffer syndrome is characterized by acrobrachycephaly, downslanting palpebral fissures, midfacial hypoplasia, relative mandibular prognathism, ocular hypertelorism, exorbitism and small beaked nose. Syndactyly is minimal but thumbs and halluces are very broad. The great toes may deviate medially. Intelligence is usually normal but may be significantly retarded. Conductive hearing loss may be marked. Some patients exhibit Kleeblattsch~idel and joint fixation due to radio-ulnar synostosis or humeroradial synostosis. Others have rocker-bottom feet due to vertical talus. Pfeiffer syndrome has been shown on molecular grounds to be heterogeneous with map positions at 10q25-q26 (FGFR2) and less often at 8pll.2-p12 (FGFR1). Jackson-Weiss syndrome, a rare autosomal dominant craniosynostosis, was found in a huge kindred. Expression is so variable that the entire spectrum of the craniosynostoses was seen save that of Apert syndrome. There is a resemblance to Pfeiffer syndrome but the thumbs are not involved. Some patients have considerable midface hypoplasia. The foot abnormalities are distinguishing: medially deviated hallux, short and broad metatarsals and tarsal bone fusion. Molecular study has demonstrated that Jackson-Weiss syndrome maps to 10q23~t26. A mutation in FGFR2 was found. Beare-Stevenson syndrome is characterized by corrugated skin furrows (cuffs gyratum), acanthosis nigricans, and unusual facies. Additional anomalies have included craniosynostosis with cloverleaf skull, ocular hypertelorism, choanal atresia, bifid scrotum, skin tags, and enlarged umbilical stump. Several cases have been reported. The cutis gyrata principally affects the scalp, forehead, face, preauricular area, neck, trunk, hands, and feet. All examples have been sporadic. The disorder has been mapped to F G F R 2 at 10q23-q26.
excision of, almost all tumours in this area provided the facial skin is not involved. Very occasionally a Weber-Fergusson incision may be used but this is avoided if possible. It is to the exposure in bony area that the craniomaxillofacial surgeon has contributed very considerably. The Le Fort I osteotomy, originally described for tumour resection, has been repopularized for clival lesions. The mandibular swing allows easy exposure to the infratemporal fossa. The frontal craniotomy limited or extensive, together with a frontonasal ostectomy give excellent exposure to the anterior cranial fossa. The lateral approach with preservation of the facial nerve, zygomatic arch and mandibular osteotomy, together with temporoparietal craniotomy, provides excellent exposure to the middle cranial fossa. In addition to this, the concept of facial disassembly has allowed multiple segments of the craniofacial skeleton to be removed for exposure of deep seated tumours. This enables the neurosurgeon to resect these turnouts more efficiently and more safely under magnification. Reconstruction by side-table assembly speeds up the surgical procedure. Bony defects are reconstructed by the use of free bone grafts, pedicled vascularized bone grafts or microvascular free tissue transfer of bone and/or soft tissue. It is in the area of prevention or treatment of infection that the craniomaxillofacial surgeon has made extremely significant contributions by providing methods to eliminate defects between the oronasopharynx and intracranial contents. Vascularized local tissue, i.e. temporal galea, temporalis muscle, galeofrontalis-periosteal flaps can be used to obtain secure closure of the anterior cranial fossa base. In large defects free tissue transfer using, for example, rectus abdominis, latissimus dorsi or omentum may be chosen. When there is established infection, undoubtedly the most effective method of eliminating this is by free tissue transfer this provides a good blood supply and an environment for antibiotics to reach the area. Finally, free tissue transfer has allowed second chance radiation in those patients having a full dose of radiation previously. The free tissue transfer is the soft tissue through which the second dose of radiation is given. Skull base tumour surgery is a field to which the craniomaxillofacial surgeons have contributed greatly a n d in which they should be actively engaged, in the exposure and reconstruction, and if properly trained also in the resection of tumours in this area.
Fetal Wound Healing and its Application to Craniomaxillofacial Surgery Kaban L.B., Guralnick W.C
Contributions of Craniofacial Surgery to Skull Base Turnout Surgery Jackson L T.
Providence Hospital, Institute for Craniofacial and Reconstructive Surgery, Southfield, USA In 1948, Hayes Martin stated that: the skull base would always remain a barrier to the adequate resection of some head and neck malignancies. We have come a long way since then. The progress has been due in no small way to the advances gained from craniofacial surgery for craniofacial deformities. The craniofacial surgeon and maxillofacial surgeon expanded their teams to cope with tumours in this area. They have brought new approaches, methods of reconstrnction and frequently microsurgical expertise for the treatment of these difficult problems. The coronal approach and intraoral approaches can provide exposure to, and allow
Department of Maxillofacial Surgery, Harvard University, Massachusetts General Hospital, Boston, Massachusetts, USA Fetal wound healing is characterized by tissue regeneration without inflammation and fibrosis. The ability of such wounds to heal without the restrictive forces of scar tissue makes the concept of fetal cleft lip and palate repair potentially attractive. Alternatively, a better understanding of fetal wound healing may make it possible to manipulate postnatal wounds to make them more 'fetal-like'. Our laboratory has been developing fetal models to study in utero cleft lip and palate repair, craniosynostosis, healing of calvarial bone defects and hemifacial microsomia. In this presentation, I will review our experience With wound healing and growth in the fetal rabbit cleft lip model. This procedure has been performed on 174 fetuses in 98 pregnant does. Details of the model and wound healing characteristics will