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Craniosynostosis Genetics: the Mystery Unfolds

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Craniosynostosis Genetics: the Mystery Unfolds Review Article Craniosynostosis genetics: The mystery unfolds Inusha Panigrahi Department of Pediatrics, Genetic and Metabolic Unit, Advanced Pediatric Center, PGIMER, Chandigarh, India The syndromes associated with craniosynostosis Craniosynsostosis syndromes exhibit considerable phenotypic and genetic heterogeneity. Sagittal synostosis include Apert syndrome, Crouzon syndrome, Greig is common form of isolated craniosynostosis. The cephalopolysyndactyly, and Saethre-Chotzen syndrome. sutures involved, the shape of the skull and associated malformations give a clue to the specific diagnosis. It is genetically heterogeneous disorder with mutation Crouzon syndrome is one of the most common of the identifi ed in several genes, predominantly the fi broblast craniosynostosis syndromes. Apert syndrome accounts for growth factor receptor genes.[3,4] Saethre-Chotzen 4.5% of all craniosynostoses and is one of the most serious of these syndromes. Most syndromic craniosynostosis syndrome and craniosynostosis (Boston-type) arise require multidisciplinary management. The following review from mutations in the Twist and muscle segment provides a brief appraisal of the various genes involved in craniosynostosis syndromes, and an approach to diagnosis homeobox 2 (MSX2) transcription factors, respectively. and genetic counseling. Rates of neuropsychological defi cits range from 35 to Key words: Apert syndrome, FGFR2 mutations, 50% in school-aged children with isolated single suture hydrocephalus, plagiocephaly, sutural synostosis, craniosynostosis.[5] Secondary effects of craniosynostosis syndromes may include vision problems and increased intracranial pressure, among others. Patients with TWIST gene Introduction mutations may have more ophthalmic abnormalities, including more strabismus, ptosis, and amblyopia.[6] The following discussion gives a comprehensive review Craniosynostosis, premature suture fusion, is one of of different disorders presenting with craniosynostosis, the most common craniofacial anomalies with incidence their diagnosis, and genetic counseling. of 1 in 2,500 live births. Craniosynostosis can be isolated nonsyndromic or it may be part of a larger syndrome with Clinical presentation of craniosynostosis syndromes digital malformations, skeletal defects, cardiac defect, or other organ anomalies.[1,2] The sagittal suture is affected in 40–60% of cases, the coronal suture in 20–30% of cases, 1. Isolated craniosynostosis: In this group, there is and the metopic suture in less than 10% of cases. More premature fusion of one or more of the sutures than 180 syndromes exist that contain craniosynostosis. of the skull. This can be in the form of coronal synostosis. There are no associated skeletal defects, digital, or other anomalies. Access this article online Quick Response Code: Website: 2. Apert syndrome: In classical Apert syndrome, www.ijhg.com there is brachycephaly, flat nasal bridge DOI: [Figure 1], and syndactyly of the fi ngers of hands 10.4103/0971-6866.86171 called mitten hands, and the toes are also similarly affected. However, in nonclassical cases there can be variable syndactyly.[2,4] Address for correspondence: Dr. Inusha Panigrahi, Genetic and Metabolic Unit, Advanced Pediatric Center, PGIMER, Sec-12, Chandigarh, India. E-mail: [email protected] 48 Indian Journal of Human Genetics May-August 2011 Volume 17 Issue 2 Panigrahi: Craniosynostosis genetics 3. Crouzon syndrome: These patients usually have the back of scalp, lumbosacral region, along long face with proptosis, maxillary hypolasia, and with furrowed palms and soles; and acanthosis a prominent jaw (mandibular prognathism). There nigricans.[2,10] There can be cloverleaf skull, is conductive hearing loss. It is associated with hydrocephalus, developmental delay, and bifi d increased paternal age effect. The synostosis scrotum. This is also associated with increased can involve the coronal, sagittal, and lambdoid paternal age. sutures.[1-3] A variant of Crouzon syndrome is 6. Saethre-Chotzen syndrome: These patients Crouzon syndrome with acanthosis nigricans have short stature, brachycephaly, acrocephaly, (CAN) which is genetically different and there is plagiocephaly, facial asymmetry, hypertelorism, progression of acanthosis with increasing age. The beaked nose, deafness, and cardiac defect.[1,4] typical CAN patients present with craniosynostosis There can be ptosis, buphthalmos, brachydactyly, with crouzonoid faces, acanthosis nigricans with syndactyly, clinodactyly, and radioulnar synostosis. wide and atypical distribution, melanocytic nevi, Some patients have mild to moderate mental choanal atresia or stenosis, hydrocephalus, Chiari retardation [Figure 2]. [7,8] malformations, and oral abnormalities. 7. Carpenter syndrome: There is brachycephaly 4. Pfeiffer syndrome: The patients have hypertelorism, with synostosis of coronal, lambdoid, and maxillary hypoplasia, mandibular prognathism, and sagittal sutures; midface hypoplasia; low set turribrachycephaly.[1,9] There is partial syndactyly ears; high arched palate; coxa valga; genu of fi ngers and toes. There can be choanal atresia valgum; and polydactyly/syndactyly/clinodactyly/ or stenosis or radiohumeral synostosis at elbows. camptodactyly.[2,11] Other features include Three types have been described: type 1-milder conductive/sensorineural hearing loss, optic form; type 2-with cloverleaf skull and elbow atrophy, cardiac defect (ASD/VSD/PS/TOF/PDA), ankylosis; and type 3-severe craniosynostosis, and renal defects such as hydronephrosis and without cloverleaf skull, with early death. hydroureter. 5. Cutis gyrata syndrome of Beare and Stevenson: 8. Muenke syndrome: The affected patients have Patients with this syndrome have midfacial macrocephaly, brachycephaly, plagiocephaly, with hypoplasia, hypertelorism, and proptosis. The midfacial hypoplasia, coronal craniosynostosis, characteristic features are cutis gyrata involving developmental delay, and sensorineural hearing a b Figure 1: Photograph of the face (a) in a case of Apert Figure 2: Case clinically diagnosed as Saethre-Chotzen syndrome showing prominent forehead, hypertelorism, syndrome. She had short stature, mental retardation, proptosis, low set ears, and open mouth. The child also triangular faces, prominent eyes, low set ears, short had mitten hands. The feet with extensive syndactyly are neck, brachydactyly, and cyanotic heart disease shown in (b) Indian Journal of Human Genetics May-August 2011 Volume 17 Issue 2 49 Panigrahi: Craniosynostosis genetics loss.[12,13] The acral anomalies include 14. Antley-Bixler syndrome (ABS): ABS is a brachydactyly, clinodactyly, broad thimble like multiple skeletal malformation syndrome with middle phalanges, broad toes, capitate-hamate craniosynostosis, radiohumeral synostosis, fusions, and calcaneocuboidal fusions. Females femoral bowing, choanal atresia or stenosis, joint are more severely affected than males. A majority contractures, urogenital abnormalities, and, often, of the patients (95%) show a mild-to-moderate, low early death.[1,16] frequency sensorineural hearing loss. 15. POR (Cytochrome P450 Oxidoreductase) 9. Shprintzen-Goldberg craniosynostosis syndrome: defi ciency with Antley-Bixler phenotype: POR The patients have dolichocephaly, prominent deficiency is a newly identified condition of forehead, down slanting palpebral fissures, congenital adrenal hyperplasia with or without midfacial hypoplasia, hypertelorism, low skeletal anomalies.[16,17] The presence of set ears, and micrognathia.[14] There can be craniosynostosis, choanal atresia or stenosis, associated joint laxity or contractures, pectus bowed femora, and radioulnar synostosis is excavatum or carinatum, scoliosis, camptodactyly, suggestive of ABS phenotype. arachnodactyly, talipes equinovarus, umbilical, 16. Opitz trigonocephaly syndrome: Partial or and inguinal hernias. The cardiac anomalies seen complete obliteration of the metopic suture is in this syndrome include aortic root dilatation and characteristic of this syndrome. The forehead mitral valve prolapse. is narrow and pointed, often associated with 10. Baller-Gerold syndrome: There is short biparietal widening and triangular shape of the stature, mental retardation, turribrachycephaly, skull. There is facial dysmorphism with upslanting hypertelorism, prominent nasal bridge, of the palpebral fi ssures, small nose with broad micrognathia, and low set ears.[1,2] The synostosis root, abnormally modeled ears, and short neck involves coronal, metopic, and lambdoid sutures. with loose skin. There may be polysyndactyly, There can be associated cardiac defects, omphalocele, or cardiac defect.[2] vertebral, and renal anomalies. 17. Craniofrontonasal dysplasia: Craniofrontonasal 11. Jackson-Weiss syndrome: These patients have dysplasia is a rare, familial X-linked disorder craniosynostosis with midfacial hypoplasia, broad with coronal synostosis (brachycephaly or halluces with medial deviation, and cutaneous plagiocephaly), hypertelorbitism (frequently syndactyly of second and third toes.[1,15] asymmetric), and some extracranial anomalies 12. Craniosynostosis mental retardation syndrome such as scoliosis, congenital diaphragmatic of Lin and Gettig: The patients have fusion hernia, and broad halluces.[18] of sagittal, metopic, or lambdoid sutures 18. Other craniosynostosis syndromes: Around leading to dolichocephaly, trigonocephaly, or 200 syndromes have been associated with turricephaly. There is mental retardation, midfacial craniosynostosis.[2,19] Gomez-Lopez-Hernandez hypoplasia, small
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