REVIEW ARTICLE
Year : 2011  |  Volume : 17  |  Issue : 2  |  Page : 48-53

Craniosynostosis genetics: The mystery unfolds

Inusha Panigrahi
Department of Pediatrics, Genetic and Metabolic Unit, Advanced Pediatric Center, PGIMER, Chandigarh, India

Correspondence Address:
Inusha Panigrahi
Genetic and Metabolic Unit, Advanced Pediatric Center, PGIMER, Sec-12, Chandigarh
India

Source of Support: None, Conflict of Interest: None

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Abstract

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.

Keywords: Apert syndrome, FGFR2 mutations, hydrocephalus, plagiocephaly, sutural synostosis, syndromes

Introduction

Clinical presentation of craniosynostosis syndromes

1. Isolated craniosynostosis: In this group, there is premature fusion of one or more of the sutures of the skull. This can be in the form of coronal synostosis. There are no associated skeletal defects, digital, or other anomalies.
2. 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. ^[2],[4]

Figure 1: Photograph of the face (a) in a case of Apert syndrome showing prominent forehead, hypertelorism, proptosis, low set ears, and open mouth. The child also had mitten hands. The feet with extensive syndactyly are shown in (b) Click here to view

3. Crouzon syndrome: These patients usually have long face with proptosis, maxillary hypolasia, and a prominent jaw (mandibular prognathism). There is conductive hearing loss. It is associated with increased paternal age effect. The synostosis can involve the coronal, sagittal, and lambdoid sutures. ^[1],[2],[3] 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 malformation ^{More Details}s, and oral abnormalities. ^[7],[8]
4. Pfeiffer syndrome: The patients have hypertelorism, maxillary hypoplasia, mandibular prognathism, and turribrachycephaly. ^[1],[9] There is partial syndactyly of fingers and toes. There can be choanal atresia or stenosis or radiohumeral synostosis at elbows. 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.
5. 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. ^[2],[10] There can be cloverleaf skull, hydrocephalus, developmental delay, and bifid scrotum. This is also associated with increased paternal age.
6. Saethre-Chotzen syndrome: These patients have short stature, brachycephaly, acrocephaly, plagiocephaly, facial asymmetry, hypertelorism, beaked nose, deafness, and cardiac defect. ^[1],[4] There can be ptosis, buphthalmos, brachydactyly, syndactyly, clinodactyly, and radioulnar synostosis. Some patients have mild to moderate mental retardation [Figure 2].

Figure 2: 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 Click here to view

7. 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. ^[2],[11] Other features include conductive/sensorineural hearing loss, optic atrophy, cardiac defect (ASD/VSD/PS/TOF/PDA), and renal defects such as hydronephrosis and hydroureter.
8. Muenke syndrome: The affected patients have macrocephaly, brachycephaly, plagiocephaly, with midfacial hypoplasia, coronal craniosynostosis, developmental delay, and sensorineural hearing loss. ^[12],[13] The acral anomalies include brachydactyly, clinodactyly, broad thimble like middle phalanges, broad toes, capitate-hamate fusions, and calcaneocuboidal fusions. Females are more severely affected than males. A majority of the patients (95%) show a mild-to-moderate, low frequency sensorineural hearing loss.
9. Shprintzen-Goldberg craniosynostosis syndrome: The patients have dolichocephaly, prominent forehead, down slanting palpebral fissures, midfacial hypoplasia, hypertelorism, low set ears, and micrognathia. ^[14] 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.
10.  Baller-Gerold syndrome ^{More Details}: There is short stature, mental retardation, turribrachycephaly, hypertelorism, prominent nasal bridge, micrognathia, and low set ears. ^[1,2] The synostosis involves coronal, metopic, and lambdoid sutures. There can be associated cardiac defects, vertebral, and renal anomalies.
11. Jackson-Weiss syndrome: These patients have craniosynostosis with midfacial hypoplasia, broad halluces with medial deviation, and cutaneous syndactyly of second and third toes. ^[1],[15]
12. 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. ^[2]
13. 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. ^[2]
14.  Antley-Bixler syndrome ^{More Details} (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. ^[1],[16]
15. 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. ^[16],[17] The presence of craniosynostosis, choanal atresia or stenosis, bowed femora, and radioulnar synostosis is suggestive of ABS phenotype.
16. 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. ^[2]
17. 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. ^[18]
18. Other craniosynostosis syndromes: Around 200 syndromes have been associated with craniosynostosis. ^[2],[19] 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. Craniosynostosis-Boston type was described by Warman et al., in 1993. The characteristic features include forehead retrusion, frontal bossing, turribrachycephaly, and cloverleaf skull, with no hand/foot abnormalities. ^[4] Most affected individuals were myopic or hyperopic. Intelligence was normal. Other features described include seizures, short first metatarsal, and triphalangeal thumb. Craniosynostosis-Adelaide and Philadelphia types have also been described. 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.

Inheritance of craniosynostosis syndromes

Genetic basis of craniosynostosis syndromes

Table 1: Mutations in different genes in craniosynostosis syndromes Click here to view

Genetic counseling

Management

Figure 3: Flow chart depicting approach to clinical diagnosis of craniosynostosis syndromes Click here to view

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