ISSN International Journal of Innovative and Applied Research (2017) RESEARCH ARTICLE

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1 Journal home page: RESEARCH ARTICLE A CASE SERIES WITH EMPHASIS ON INHERITANCE PATTERN OF APERT SYNDROME. Dr. Vindhiya K.Sundaram, Dr. Vidhya shankari Nanjappan *, Dr. S Sundari. *Corresponding Author:- Vindhiya K.Sundaram. Abstract: Apert syndrome (acrocephalosyndactylia) is a developmental malformation characterized by craniosynostosis, a cone-shaped calvarium (acrocephaly), hypertelorism, midface hypoplasia, pseudo cleft-palate, a parrot beak-shaped nose, pharyngeal attenuation, and syndactyly of the hands and feet. According to Cohen, the incidence of Apert syndrome is about 15 per 1,000,000 live births. It is rarely reported from India. Apert syndrome was first reported by Wheaton in 1894 and French pediatrician Eugene Apert published a series of nine cases in The inheritance of Apert syndrome is autosomal dominant with the locus of mutation of FGFR2 on chromosome 10q (10q25-26) or may develop as a spontaneous mutation often associated with increased paternal age. We report 3 children with clinical features of Apert syndrome highlighting the inheritance pattern. Key Words:-Apert syndrome, syndactyly, craniosynostosis, inheritance pattern. Introduction:- Apert syndrome (acrocephalosyndactylia) is a developmental malformation characterized by craniosynostosis, a cone-shaped calvarium (acrocephaly), hypertelorism, midface hypoplasia, pseudo cleft-palate, a parrot beak-shaped nose, pharyngeal attenuation, and syndactyly of the hands and feet(1,6). Apert syndrome was first reported by Wheaton in 1894 and French pediatrician Eugene Apert published a series of nine cases in The inheritance of Apert syndrome is autosomal dominant with the locus of mutation of FGFR2 on chromosome 10q (10q25-26) or may develop as a spontaneous mutation often associated with increased paternal age (2,3). We report a case series involving 3 children who presented with clinical features of Apert Syndrome. The purpose of this study is to highlight the etiological basis of Apert Syndrome. Case report:- 3 years old male child presented to our department with complaints of difficulty in breathing since one week. Child was initially stabilised and on examination found to have cone shaped calvarium, craniosynostosis, midfacial hypoplasia, hypertelorism, antimongoloid slant, depressed nasal bridge, syndactyly of the fingers and toes, maloccluded teeth and low set ears. His head circumference was 48 cm(50 th centile) and weight 13 kg (50 th centile). He had ronchi on auscultation of the chest wall bilaterally. His vitals were stable. His speech was incoherent. On observation, his mother had similar facial features and syndactyly, but her speech was found to be normal. He is second born to consanguineous parents. His father and elder sister were normal phenotypically. His mother was 30 years and his father was 33years of age at the time of conception. There was no history of previous abortion. USG- Abdomen, Chest X ray and Echocardiography was normal. CECT- Brain showed cavum septum pellucidum and mild brain volume loss. Karyotyping was normal. Counselling was done regarding the need for genetic testing and prenatal diagnosis. After symptomatic treatment of his lower respiratory tract infection, he was referred to plastic surgery department and dentistry for further rehabilitative measures. The second case was a newborn full term female baby delivered through normal vaginal delivery in our hospital. The baby cried after 5 minutes of neonatal resuscitative measures with Apgar score less than 3 at 10 minutes. Birth weight of the baby is kg (3 rd centile),hc- 38 cm (> 97 th centile).on examination, the baby had acrocephaly, depressed nasal bridge, midfacial hypoplasia, exophthalmos, craniosynostosis, low set ears, short neck, 68

2 ecchymosis of both conjunctiva, syndactyly involving second and third digit in both hands and feet. The baby was first born to non consanguineous parents with maternal age being 22 years and paternal age 25 years at conception. There is no history of previous abortion, no positive family history. The baby died at 6 hours of age, inspite of the resuscitative and supportive measures. The parents were counselled regarding the inheritance pattern of the syndrome and need for genetic testing and prenatal diagnosis. Third case is a 6 month old infant first born to non-consanguineous parents who was brought for acute febrile illness. On examination, dysmorphism in the form of large head, down slanting eyes with hypertelorism, depressed nasal bridge and low set ear was noted. There was symmetric syndactyly of both hands and feet with mitten hand appearance. Mother s age was 33years and father was 35 years at conception. Both parents were normal phenotypically. There was no history of abortion. Anthropometry showed HC= 42cm( 15 th centile) with weight of 7.5kg(15 th centile). Vitals were stable. Systemic examination was normal except for pan systolic murmur in left lower sternal border. Investigations revealed normal blood counts with mild cardiomegaly in the chest x-ray. X-ray skull revealed craniosynostosis. USG abdomen was normal. Echocardiogram showed small muscular VSD of size 2mm with left to right shunt. Patient was treated with supportive measures. Cardiologist opinion was obtained and advised follow up. Karyotyping was normal. Genetic analysis could not be done due to financial constraint. Child is doing well and parents have been counselled regarding the future pregnancy. Discussion:- The two of the most common syndromic craniosynostoses, collectively known as acrocephalosyndactyly, are Crouzon and Apert, which together make up 70% of such cases. As described by Dr Eugene Apert in 1906 (8), Apert syndrome is characterized by the clinical triad of craniosynostosis, midface hypoplasia, and symmetric syndactyly of the hands and feet (4,5), which were present in all the 3 cases reported. According to Cohen, the incidence of Apert syndrome is about 15 per 1,000,000 live births. It is rarely reported from India. Major Features of Apert Syndromeinclude prematurely fused cranial sutures, retruded midface i.e. abnormal shaped head and face, cleft palate, abnormalities of eyes, including down slanting palpebral fissures, hypertelorism, exophthalmos, low-set ears, hearing loss, hydrocephalus, learning disability and syndactyly(7, 10). Other related features are congenital heart defects (dextrorotation, pulmonary atresia, patent ductus arteriosus), tracheoesophageal fistula, pyloric stenosis, polycystic kidneys, bicornuate uterus, excessive sweating and severe acne. The 6 month male child that we reported presented with small muscular ventricular septal defect and the newborn female child had a large head ( HC > 97 th centile) with high probability of hydrocephalus(7). The inheritance of Apert syndrome is autosomal dominant but most cases arise as spontaneous mutations that appear to originate almost exclusively in the paternal germ line. Two mutations found in adjacent codons leading to altered structure in the Fibroblast Growth Factor Receptor 2(FGFR) have been identified as being responsible for the defects seen in Apert syndrome. Mutations in the FGFR2 gene, which is active at the metaphysis, diaphysis and also in the interdigital mesenchyme, alters the protein and causes prolonged signaling, which can promote the premature fusion of bones in the skull, hands, and feet. The FGFR2 also is responsible for early fusion of several sutures of the skull (9). All acrocephalosyndactyly syndromes show limb abnormalities. The typical hand anomalies of Apert syndrome distinguish it from other craniosynostosis. The hands of Apert are of three types i.e. type I (spade), type II (mitten) and type III (rose bud) (7).The offspring of a parent with Apert syndrome has a 50% chance of inheriting the condition. Males and females are affected equally. It can be inherited from a parent who has Apert, or may be a fresh mutation. This mutation usually occurs in a sperm and Apert syndrome is one of the few genetic conditions linked to older fathers, particularly men over the age of 50. One of our cases, the 3 year old male child has a strong family history, with mother being affected, most probably autosomal dominant inheritance. The newborn female baby might be sporadic mutation, because both the parents had normal phenotype, but parents age was below 30 years. The 6 months male child was born to older father ( 35 yrs) with probable inheritance of mutation in paternal germ line. 69

3 Figure 1:-Picture depicts a 3 year old male child with cone shaped calvarium, craniosynostosis, midfacial hypoplasia, hypertelorism, antimongoloid slant, depressed nasal bridge, syndactyly of the fingers and toes, maloccluded teeth and low set ears. 70

4 Figure 2:-Mother and child with similar features of Apert syndrome showing syndactyly of both hand and feet 71

5 Figure 3:-Hand and foot of a newborn female baby showing syndactyly involving second and third digit. 72

6 Figure 4:-Hand and foot of a newborn female baby showing syndactyly involving second and third digit. Figure 5:-Picture depicts a newborn girl child with acrocephaly, depressed nasal bridge, midfacial hypoplasia, exophthalmos, craniosynostosis, low set ears, short neck, ecchymosis of both conjunctiva, syndactyly involving second and third digit in both hands and feet. Conclusion:- There is no cure for Apert syndrome, but much can be done to prevent or treat complications and help the child grow as normally as possible. 73

7 The current modality is ultrasound, genetic analysis and counseling. Surgical treatment requires a team approach consisting of neuroradiologist, craniofacial surgeon, pediatric surgeon, pediatric anesthetist, plastic surgeons for hand surgery and orthodontist. This case series thus provides information regarding different patterns of inheritance, which will be helpful in counseling the families who have a child with Apert Syndrome. References:- 1. Alp E, Alp H, Koc H, Ucar C, Cimen D. Apert syndrome. Türkiye Klinikleri J Pediatr 2007;16: Canpolat M, Buyukayhan D, Gunes T, Akcakus M, Ozturk A, Kurtoglu S. Apert syndrome: A case report. Erciyes MedicalJournal 2009;31: Rynearson RD. Case Report: Orthodontic and dentofacial orthopedic considerations in Apert s syndrome. Angle Orthod 2000;70: Chonka ZD, Beall DP, Jennings BT, Wu DH, Ly JQ, Wolff JD. Apert s syndrome. Applied Radiology Online 2004 Sep 9:33(9). 5. Shweta Dixit, Asha Singh, Mamatha GS, Rajiv S Desai, Prashant Jaju Apert s Syndrome: Report of a New Case and itsmanagementjaypee s International Journal of Clinical Pediatric Dentistry, September-December 2008;1(1): Zehra Ileri,Yasar Bedii Goyenc. Apert syndrome: A case report. European Journal of Dentistry, January 2012; Vol-6: S. Saritha, Sumangala, G. Supriya, M. Praveen Kumar. Apert syndrome (Acrocephalosyndactyly): a case report. International Journal of Research in Medical Sciences, 2013 Feb;1(1): Mukhopadhyay AK, Mukherjee D. Apert's syndrome. Indian J Dermatol Venereol Leprol 2004;70: Felipe Paes Varoli, Karina Cecília Panelli Santos, Claudio Costa, Jefferson Xavier Oliveira. Apert syndrome: clinical and radiographic features and case report.rev Odonto Cienc 2011;26(1): Surman TL, Logan RM, Townsend GC, Anderson PJ. Oral features in Apert syndrome: a histological investigation. Orthod Craniofac Res 2010; 13: