craniosynostosis , premature suture fusion , is one of the most common craniofacial anomalies with incidence of 1 in 2,500 live births . craniosynostosis can be isolated nonsyndromic or it may be part of a larger syndrome with digital malformations , skeletal defects , cardiac defect , or other organ anomalies . the sagittal suture is affected in 4060% of cases , the coronal suture in 2030% of cases , and the metopic suture in less than 10% of cases . the syndromes associated with craniosynostosis include apert syndrome , crouzon syndrome , greig cephalopolysyndactyly , and saethre - chotzen syndrome . it is genetically heterogeneous disorder with mutation identified in several genes , predominantly the fibroblast growth factor receptor genes . saethre - chotzen syndrome and craniosynostosis ( boston - type ) arise from mutations in the twist and muscle segment homeobox 2 ( msx2 ) transcription factors , respectively . rates of neuropsychological deficits range from 35 to 50% in school - aged children with isolated single suture craniosynostosis . secondary effects of craniosynostosis may include vision problems and increased intracranial pressure , among others . patients with twist gene mutations may have more ophthalmic abnormalities , including more strabismus , ptosis , and amblyopia . the following discussion gives a comprehensive review of different disorders presenting with craniosynostosis , their diagnosis , and genetic counseling . isolated craniosynostosis : in this group , there is premature fusion of one or more of the sutures of the skull there are no associated skeletal defects , digital , or other anomalies.apert syndrome : in classical apert syndrome , there is brachycephaly , flat nasal bridge [ figure 1 ] , and syndactyly of the fingers of hands called mitten hands , and the toes are also similarly affected . however , in nonclassical cases there can be variable syndactyly.crouzon syndrome : these patients usually have long face with proptosis , maxillary hypolasia , and a prominent jaw ( mandibular prognathism ) . the synostosis can involve the coronal , sagittal , and lambdoid sutures.[13 ] a variant of crouzon syndrome is crouzon syndrome with acanthosis nigricans ( can ) which is genetically different and there is progression of acanthosis with increasing age . the typical can patients present with craniosynostosis with crouzonoid faces , acanthosis nigricans with wide and atypical distribution , melanocytic nevi , choanal atresia or stenosis , hydrocephalus , chiari malformations , and oral abnormalities.pfeiffer syndrome : the patients have hypertelorism , maxillary hypoplasia , mandibular prognathism , and turribrachycephaly . three types have been described : type 1-milder form ; type 2-with cloverleaf skull and elbow ankylosis ; and type 3-severe craniosynostosis , without cloverleaf skull , with early death.cutis gyrata syndrome of beare and stevenson : patients with this syndrome have midfacial hypoplasia , hypertelorism , and proptosis . the characteristic features are cutis gyrata involving the back of scalp , lumbosacral region , along with furrowed palms and soles ; and acanthosis nigricans . there can be cloverleaf skull , hydrocephalus , developmental delay , and bifid scrotum . this is also associated with increased paternal age.saethre-chotzen syndrome : these patients have short stature , brachycephaly , acrocephaly , plagiocephaly , facial asymmetry , hypertelorism , beaked nose , deafness , and cardiac defect . there can be ptosis , buphthalmos , brachydactyly , syndactyly , clinodactyly , and radioulnar synostosis . some patients have mild to moderate mental retardation [ figure 2].carpenter syndrome : there is brachycephaly with synostosis of coronal , lambdoid , and sagittal sutures ; midface hypoplasia ; low set ears ; high arched palate ; coxa valga ; genu valgum ; and polydactyly / syndactyly / clinodactyly / camptodactyly . other features include conductive / sensorineural hearing loss , optic atrophy , cardiac defect ( asd / vsd / ps / tof / pda ) , and renal defects such as hydronephrosis and hydroureter.muenke syndrome : the affected patients have macrocephaly , brachycephaly , plagiocephaly , with midfacial hypoplasia , coronal craniosynostosis , developmental delay , and sensorineural hearing loss . the acral anomalies include brachydactyly , clinodactyly , broad thimble like middle phalanges , broad toes , capitate - hamate fusions , and calcaneocuboidal fusions . a majority of the patients ( 95% ) show a mild - to - moderate , low frequency sensorineural hearing loss.shprintzen-goldberg craniosynostosis syndrome : the patients have dolichocephaly , prominent forehead , down slanting palpebral fissures , midfacial hypoplasia , hypertelorism , low set ears , and micrognathia . there can be associated joint laxity or contractures , pectus excavatum or carinatum , scoliosis , camptodactyly , arachnodactyly , talipes equinovarus , umbilical , and inguinal hernias . the cardiac anomalies seen in this syndrome include aortic root dilatation and mitral valve prolapse.baller-gerold syndrome : there is short stature , mental retardation , turribrachycephaly , hypertelorism , prominent nasal bridge , micrognathia , and low set ears . there can be associated cardiac defects , vertebral , and renal anomalies.jackson-weiss syndrome : these patients have craniosynostosis with midfacial hypoplasia , broad halluces with medial deviation , and cutaneous syndactyly of second and third toes.craniosynostosis mental retardation syndrome of lin and gettig : the patients have fusion of sagittal , metopic , or lambdoid sutures leading to dolichocephaly , trigonocephaly , or turricephaly . there is mental retardation , midfacial hypoplasia , small nose , hypertelorism , ptosis , and blepharophimosis . other abnormalities described are umbilical hernia , cryptorchidism , hydronephrosis , cardiac defects , and intestinal malrotation.hunter-mcalpine craniosynostosis syndrome : there is short stature , mental retardation , facial dysmorphism with almond - shaped palpebral fissures and downturned corners of mouth , and subtle skeletal anomalies.antley-bixler syndrome ( abs ) : abs is a multiple skeletal malformation syndrome with craniosynostosis , radiohumeral synostosis , femoral bowing , choanal atresia or stenosis , joint contractures , urogenital abnormalities , and , often , early death.por ( cytochrome p450 oxidoreductase ) deficiency with antley - bixler phenotype : por deficiency is a newly identified condition of congenital adrenal hyperplasia with or without skeletal anomalies . the presence of craniosynostosis , choanal atresia or stenosis , bowed femora , and radioulnar synostosis is suggestive of abs phenotype.opitz trigonocephaly syndrome : partial or complete obliteration of the metopic suture is characteristic of this syndrome . the forehead is narrow and pointed , often associated with biparietal widening and triangular shape of the skull . there is facial dysmorphism with upslanting of the palpebral fissures , small nose with broad root , abnormally modeled ears , and short neck with loose skin . there may be polysyndactyly , omphalocele , or cardiac defect.craniofrontonasal dysplasia : craniofrontonasal dysplasia is a rare , familial x - linked disorder with coronal synostosis ( brachycephaly or plagiocephaly ) , hypertelorbitism ( frequently asymmetric ) , and some extracranial anomalies such as scoliosis , congenital diaphragmatic hernia , and broad halluces.other craniosynostosis syndromes : around 200 syndromes have been associated with craniosynostosis . gomez - lopez - hernandez syndrome or cerebello - trigeminal - dermal dysplasia is a rare syndrome comprising short stature , cerebellar abnormalities , parieto - occipital alopecia , trigeminal nerve anesthesia , intellectual impairment , craniosynostosis , and craniofacial anomalies . the characteristic features include forehead retrusion , frontal bossing , turribrachycephaly , and cloverleaf skull , with no hand / foot abnormalities . individuals with adelaide - type craniosynostosis have various degrees of craniosynostosis leading to facial asymmetry , a broad forehead , brachyturricephaly , and facial abnormalities such as hypertelorism , maxillary hypoplasia , mandibular prognathism , a low anterior hairline , and hearing loss . craniometaphyseal dysplasia manifests with macrocephaly , proptosis , hypocalcemia , hyperparathyroidism , wide metaphyses , and sensorineural deafness . other conditions with craniosynostosis include di - george syndrome , smith - magenis syndrome , triploid - diploid mosaicism , submicroscopic deletions of 11q25 and 9q22.3 , camptomelic dysplasia , and jansen metaphyseal dysplasia . isolated craniosynostosis : in this group , there is premature fusion of one or more of the sutures of the skull apert syndrome : in classical apert syndrome , there is brachycephaly , flat nasal bridge [ figure 1 ] , and syndactyly of the fingers of hands called mitten hands , and the toes are also similarly affected . however , in nonclassical cases there can be variable syndactyly . crouzon syndrome : these patients usually have long face with proptosis , maxillary hypolasia , and a prominent jaw ( mandibular prognathism ) . the synostosis can involve the coronal , sagittal , and lambdoid sutures.[13 ] a variant of crouzon syndrome is crouzon syndrome with acanthosis nigricans ( can ) which is genetically different and there is progression of acanthosis with increasing age . the typical can patients present with craniosynostosis with crouzonoid faces , acanthosis nigricans with wide and atypical distribution , melanocytic nevi , choanal atresia or stenosis , hydrocephalus , chiari malformations , and oral abnormalities . pfeiffer syndrome : the patients have hypertelorism , maxillary hypoplasia , mandibular prognathism , and turribrachycephaly . there is partial syndactyly of fingers and toes . three types have been described : type 1-milder form ; type 2-with cloverleaf skull and elbow ankylosis ; and type 3-severe craniosynostosis , without cloverleaf skull , with early death . cutis gyrata syndrome of beare and stevenson : patients with this syndrome have midfacial hypoplasia , hypertelorism , and proptosis . the characteristic features are cutis gyrata involving the back of scalp , lumbosacral region , along with furrowed palms and soles ; and acanthosis nigricans . there can be cloverleaf skull , hydrocephalus , developmental delay , and bifid scrotum . saethre - chotzen syndrome : these patients have short stature , brachycephaly , acrocephaly , plagiocephaly , facial asymmetry , hypertelorism , beaked nose , deafness , and cardiac defect . there can be ptosis , buphthalmos , brachydactyly , syndactyly , clinodactyly , and radioulnar synostosis . carpenter syndrome : there is brachycephaly with synostosis of coronal , lambdoid , and sagittal sutures ; midface hypoplasia ; low set ears ; high arched palate ; coxa valga ; genu valgum ; and polydactyly / syndactyly / clinodactyly / camptodactyly . other features include conductive / sensorineural hearing loss , optic atrophy , cardiac defect ( asd / vsd / ps / tof / pda ) , and renal defects such as hydronephrosis and hydroureter . muenke syndrome : the affected patients have macrocephaly , brachycephaly , plagiocephaly , with midfacial hypoplasia , coronal craniosynostosis , developmental delay , and sensorineural hearing loss . the acral anomalies include brachydactyly , clinodactyly , broad thimble like middle phalanges , broad toes , capitate - hamate fusions , and calcaneocuboidal fusions . a majority of the patients ( 95% ) show a mild - to - moderate , low frequency sensorineural hearing loss . shprintzen - goldberg craniosynostosis syndrome : the patients have dolichocephaly , prominent forehead , down slanting palpebral fissures , midfacial hypoplasia , hypertelorism , low set ears , and micrognathia . there can be associated joint laxity or contractures , pectus excavatum or carinatum , scoliosis , camptodactyly , arachnodactyly , talipes equinovarus , umbilical , and inguinal hernias . the cardiac anomalies seen in this syndrome include aortic root dilatation and mitral valve prolapse . baller - gerold syndrome : there is short stature , mental retardation , turribrachycephaly , hypertelorism , prominent nasal bridge , micrognathia , and low set ears . jackson - weiss syndrome : these patients have craniosynostosis with midfacial hypoplasia , broad halluces with medial deviation , and cutaneous syndactyly of second and third toes . craniosynostosis mental retardation syndrome of lin and gettig : the patients have fusion of sagittal , metopic , or lambdoid sutures leading to dolichocephaly , trigonocephaly , or turricephaly . there is mental retardation , midfacial hypoplasia , small nose , hypertelorism , ptosis , and blepharophimosis . other abnormalities described are umbilical hernia , cryptorchidism , hydronephrosis , cardiac defects , and intestinal malrotation . hunter - mcalpine craniosynostosis syndrome : there is short stature , mental retardation , facial dysmorphism with almond - shaped palpebral fissures and downturned corners of mouth , and subtle skeletal anomalies . antley - bixler syndrome ( abs ) : abs is a multiple skeletal malformation syndrome with craniosynostosis , radiohumeral synostosis , femoral bowing , choanal atresia or stenosis , joint contractures , urogenital abnormalities , and , often , early death . por ( cytochrome p450 oxidoreductase ) deficiency with antley - bixler phenotype : por deficiency is a newly identified condition of congenital adrenal hyperplasia with or without skeletal anomalies . the presence of craniosynostosis , choanal atresia or stenosis , bowed femora , and radioulnar synostosis is suggestive of abs phenotype . opitz trigonocephaly syndrome : partial or complete obliteration of the metopic suture is characteristic of this syndrome . the forehead is narrow and pointed , often associated with biparietal widening and triangular shape of the skull . there is facial dysmorphism with upslanting of the palpebral fissures , small nose with broad root , abnormally modeled ears , and short neck with loose skin . craniofrontonasal dysplasia : craniofrontonasal dysplasia is a rare , familial x - linked disorder with coronal synostosis ( brachycephaly or plagiocephaly ) , hypertelorbitism ( frequently asymmetric ) , and some extracranial anomalies such as scoliosis , congenital diaphragmatic hernia , and broad halluces . gomez - lopez - hernandez syndrome or cerebello - trigeminal - dermal dysplasia is a rare syndrome comprising short stature , cerebellar abnormalities , parieto - occipital alopecia , trigeminal nerve anesthesia , intellectual impairment , craniosynostosis , and craniofacial anomalies . the characteristic features include forehead retrusion , frontal bossing , turribrachycephaly , and cloverleaf skull , with no hand / foot abnormalities . individuals with adelaide - type craniosynostosis have various degrees of craniosynostosis leading to facial asymmetry , a broad forehead , brachyturricephaly , and facial abnormalities such as hypertelorism , maxillary hypoplasia , mandibular prognathism , a low anterior hairline , and hearing loss . craniometaphyseal dysplasia manifests with macrocephaly , proptosis , hypocalcemia , hyperparathyroidism , wide metaphyses , and sensorineural deafness . other conditions with craniosynostosis include di - george syndrome , smith - magenis syndrome , triploid - diploid mosaicism , submicroscopic deletions of 11q25 and 9q22.3 , camptomelic dysplasia , and jansen metaphyseal dysplasia . photograph of the face ( a ) in a case of apert syndrome showing prominent forehead , hypertelorism , proptosis , low set ears , and open mouth . the feet with extensive syndactyly are shown in ( b ) case clinically diagnosed as saethre - chotzen syndrome . she had short stature , mental retardation , triangular faces , prominent eyes , low set ears , short neck , brachydactyly , and cyanotic heart disease these include crouzon syndrome , apert syndrome , pfeiffer syndrome , saethre - chotzen syndrome , and jackson - weiss syndrome.[13 ] the autosomal recessive disorders include baller - gerold syndrome , por deficiency with abs phenotype , opitz c syndrome , and craniosynostosis - mental retardation syndrome of lin and gettig . recent advances in molecular genetics have led to a better understanding of the role of specific genes implicated in different craniosynostosis syndromes.[2024 ] most of these disorders or syndromes have mutations in the fibroblast growth factor receptor genes . mutations in the fgfr2 , fgfr3 , twist1 , and efnb1 genes have been shown to account for around 25% of craniosynostosis . chromosomal alterations are important causative mechanisms of the syndromic forms of craniosynostosis accounting for at least 10% of the cases.[2527 ] table 1 lists the different conditions along with underlying genetic defect . in craniosynostosis - type mcgillivray , mutations in different genes in craniosynostosis syndromes l1 cell adhesion molecule ( l1cam ) gene plays a major role in the development of the white matter and its mutation in humans ( callosal agenesis , retardation , adducted thumbs , spasticity , and hydrocephalus syndrome ) . a defect in interaction of fgfr with l1cam may be the cause of the brain malformations and mental retardation in children with craniosynostosis . nonsyndromic craniosynostosis is a clinically and genetically heterogeneous condition that has the characteristics of a multifactorial trait . the most common craniosynostosis syndromes being autosomal dominant in inheritance , the risk of recurrence is 50% for each pregnancy if there is one affected child or one parent affected . for autosomal recessive craniosynostosis syndromes such as baller - gerold syndrome if only child is affected and there are no clinical features in parents or other family members , then the disease may be sporadic with negligible risk of recurrence . the pediatricians can identify the causes of the majority of abnormal head shapes by combining their understanding of normal calvarial growth with a careful physical examination [ figure 3 ] . the treatment of craniosynostosis syndromes - medical and surgical - is multidisciplinary and involves neurosurgeons , plastic surgeons , ent specialist , pediatrician , and clinical genetics specialist . the high definition of three - dimensional computed tomography and magnetic imaging resonance allows precise surgery planning of reconstruction and management of associated malformations . an early surgery and team effort is necessary to optimize the long - term outcomes .
craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity . 
 sagittal synostosis is common form of isolated craniosynostosis . 
 the sutures involved , the shape of the skull and associated malformations give a clue to the specific diagnosis . 
 crouzon syndrome is one of the most common of the craniosynostosis syndromes . 
 apert syndrome accounts for 4.5% of all craniosynostoses and is one of the most serious of these syndromes . 
 most syndromic craniosynostosis require multidisciplinary management . 
 the following review provides a brief appraisal of the various genes involved in craniosynostosis syndromes , and an approach to diagnosis and genetic counseling .