6_Vascone_Prenatal 3/4-2014 03/07/15 12:58 Pagina 70
Case report
Antenatal diagnosis of Seckel Syndrome: a rare case report
Carmine Vascone1 Filippo Di Meglio2 Letizia Di Meglio3 Luigi Carlo Lo Turco4 Salvatore Giovanni Vitale5 Pietro Cignini6 Ilaria Marilli5 Agnese Maria Chiara Rapisarda5 Gaetano Valenti5 Stefano Cianci5
1
2
3
4
5
6
Department of Woman, Child and General and Specialistics Surgery, II University of Naples, Naples, Italy Department of Ginecological-Obstetrical Sciences and Urological Sciences, “Sapienza” University of Rome, Rome, Italy Clinical Department of Ginecology and Ostetricics of Physiopathology Reproduction, “Federico II” University of Naples, Naples, Italy Clinical Department for the Woman’s Health and Protection, Newborning life, Child and Adolescent. Catholic University of “ Sacro Cuore”, “Agostino Gemelli” Polyclinic of Rome, Italy Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy Department of Gynecologic Ultrasound Imaging, Altamedica Fetal Maternal Medical Centre, Rome, Italy
Corresponding author: Salvatore Giovanni Vitale Department of General Surgery and Medical Surgical Specialties, University of Catania Via Santa Sofia 78 95123 Catania, Italy E-mail: [email protected]
Abstract Introduction: Seckel Syndrome is a rare autosomal recessive disorder characterized by dwarfism, microcephaly and the absence of visceral malformations. Case report: we observed sonographic features of a Seckel Syndrome, in a patient during the 24th week of pregnancy. Her family history was negative for malformation and chromosomal disorders. The diagnosis was later confirmed by molecular tests.
70
Conclusion: diagnosis should be made only by expert operators. Karyotype analysis is essential to confirm the diagnosis. Key word: bird-headed appearance, dwarfism, microcephaly, Seckel Syndrome, ultrasound, prenatal diagnosis.
Introduction Seckel Syndrome is an autosomal recessive disorder and the most common microcephalic osteodysplastic dwarfism. Recent evidences suggest that Seckel syndrome and Primary autosomal recessive microcephalies constitute a same spectrum rather than distinct entities of the same disease and are both characterized by microcephaly and the absence of visceral malformations where stature is no longer a discriminating feature. Microcephaly Onset during the second trimester of gestation showing an occipito-frontal head circumference (OFC) at birth equal to or less than -2 SD below the mean for sex, age, and ethnicity. Moreover this Circumference (OFC) increases slower after birth. Other alterations occur in Seckel syndrome and Primary autosomal recessive microcephalies such as: brain abnormality, degree of cognitive impairment (usually mild to moderate without significant motor delay but more severe when brain malformations occurs), small brain with small gyri, short stature (previously these diseases were distinguished by height: typically in Primary autosomal recessive microcephalies stature was between -1 SD and -2 SD and in Seckel syndrome between -4 and 12 SD) and Craniosynostosis (1). Particularly, Seckel Syndrome is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation. Hematological abnormalities with chromosome breakage have only been found in 15 to 25% of patients. The differential diagnosis with microcephalic osteodysplastic dwarfism type II can only be made with a complete radiographic survey in the first years of life. Besides a wide phenotypic heterogeneity among affected patients, genetic heterogeneity has also been proven, with three loci identified to date by homozygosity mapping: SCKL1 [3q22.1-q24, ataxiatelangiectasia and Rad3-related protein (ATR) gene], SCKL2 (18p11.31-q11.2, unknown gene) and SCKL3 (14q23, unknown gene). SCKL3 seems to be the predominant locus for Seckel Syndrome. Approaching the function of the ATR gene, the genes with a role in DNA repair are good candidates for SCKL2 and SCKL3 (2). Mental retardation is usually severe and Journal of Prenatal Medicine 2014; 8(3/4):70-72
6_Vascone_Prenatal 3/4-2014 03/07/15 12:58 Pagina 71
Antenatal diagnosis of Seckel Syndrome: a rare case report
families often go through substantial lifestyle changes that might need social support. In case of associated hematological abnormalities (anemia, pancytopenia, acute myeloid leukaemia), medical treatment should be provided (3).
Case Report We observed by ultrasound a 25-year-old woman, at the second pregnancy, during the 24th wk of pregnancy. Family history was negative for malformation and chromosomal disorders. Through transabdominal ultrasound we observed: brachycephaly (Fig. 1), with a head circumference in the 19th percentile and this is strongly suggestive of a future microcephaly; micrognathia (Fig. 2); low-set ears (Fig. 3); long bones were small, in particular rhizo – mesomelic segments; clinodactyly of the 5° finger; gallbladder couldn’t be visualized during ultrasound study (this sign is not important for the diagnosis, but suggests an higher risk of biliary atresia after birth); ptosic right kidney (Fig. 4); single umbilical artery. The sonographic features suggested a Seckel Syndrome diagnosis, which was later confirmed by molecular tests.
Figure 3. Low-set ears.
Figure 4. Ptosic right kidney.
Discussion
Figure 1. Brachycephaly.
Sonographic features of Seckel Syndrome, especially the full-blown form, are represented by major intracranial abnormalities such as the typical birdlike head, microcephaly and severe growth restriction. These conditions should be diagnosable by prenatal sonography. This diagnosis is extremely rare and can only be made by an expert operator. Nonetheless, it should be underlined that the clinical variability of the condition is relatively high (4). Moreover, other types of osteodysplastic dwarfism characterized by severe growth restriction and micrognathia have also been described. This extreme variability in the Seckel Syndrome phenotype may explain why this Syndrome tends to be overdiagnosed and should be differentiated from closely similar syndrome such as Cockayne syndrome, progeria, Hallermann-Streiff syndrome, and Dyggve-Melchior-Clausen syndrome. Misdiagnosis is most often, but not exclusively, made during the neonatal period (5).
Conclusions
Figure 2. Micrognathia. Journal of Prenatal Medicine 2014; 8(3/4):70-72
The take home message is that the diagnosis of Seckel Syndrome is a rare and very difficult diagnosis that should be made only by expert operators. Karyotype analysis (SCKL1 - SCKL2 - SCKL3) and genet-
71
6_Vascone_Prenatal 3/4-2014 03/07/15 12:58 Pagina 72
C. Vascone et al.
ic counseling are essential for the definitive diagnosis. In these circumstances a NMR is the exam of choice for the evaluation of any central nervous system abnormalities. Finally, despite Seckel Syndrome, by defined, combines microcephaly with the absence of visceral malformations we reported, rhizo-mesomelic segments, clinodactyly of the 5° finger, gallbladder absence and single umbilical artery.
2.
3.
Conflict of interest The Authors report no conflict of interest. The Authors attest that they have obtained written consent from the patient.
4.
References
5.
1.
72
Alain Verloes, MD, PhD, Severine Drunat, MD, PhD,
Pierre Gressens, MD, PhD, and Sandrine Passemard, MD, PhD. Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders. GeneReviews Initial Posting: September 1, 2009; Last Update: October 31, 2013. Kilinç MO, Ninis VN, Ugur SA, Tüysüz B, Seven M, Balci S, Goodship J, Tolun A. Is the novel SCKL3 at 14q23 the predominant Seckel locus? Eur J Hum Genet. 2003 Nov; 11(11):851-857. Shanske A, Caride DG, Menasse-Palmer L, Bogdanow A, Marion RW. Central nervous system anomalies in Seckel Syndrome: report of a new family and review of the literature. Am J Med Genet. 1997 May 16; 70(2):155-158. Gupta A, Fazal TS, Arora R. Antenatal diagnosis of Seckel Syndrome. J Obstet Gynaecol India. 2014 Dec; 64(Suppl 1):6-8. Sisodia R, Raj RK, Goel V. Seckel syndrome: a rare case report. J Indian Soc Pedod Prev Dent. 2014 AprJun; 32(2):160-163. doi: 10.4103/0970-4388.130983.
Journal of Prenatal Medicine 2014; 8(3/4):70-72
Case report
Antenatal diagnosis of Seckel Syndrome: a rare case report
Carmine Vascone1 Filippo Di Meglio2 Letizia Di Meglio3 Luigi Carlo Lo Turco4 Salvatore Giovanni Vitale5 Pietro Cignini6 Ilaria Marilli5 Agnese Maria Chiara Rapisarda5 Gaetano Valenti5 Stefano Cianci5
1
2
3
4
5
6
Department of Woman, Child and General and Specialistics Surgery, II University of Naples, Naples, Italy Department of Ginecological-Obstetrical Sciences and Urological Sciences, “Sapienza” University of Rome, Rome, Italy Clinical Department of Ginecology and Ostetricics of Physiopathology Reproduction, “Federico II” University of Naples, Naples, Italy Clinical Department for the Woman’s Health and Protection, Newborning life, Child and Adolescent. Catholic University of “ Sacro Cuore”, “Agostino Gemelli” Polyclinic of Rome, Italy Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy Department of Gynecologic Ultrasound Imaging, Altamedica Fetal Maternal Medical Centre, Rome, Italy
Corresponding author: Salvatore Giovanni Vitale Department of General Surgery and Medical Surgical Specialties, University of Catania Via Santa Sofia 78 95123 Catania, Italy E-mail: [email protected]
Abstract Introduction: Seckel Syndrome is a rare autosomal recessive disorder characterized by dwarfism, microcephaly and the absence of visceral malformations. Case report: we observed sonographic features of a Seckel Syndrome, in a patient during the 24th week of pregnancy. Her family history was negative for malformation and chromosomal disorders. The diagnosis was later confirmed by molecular tests.
70
Conclusion: diagnosis should be made only by expert operators. Karyotype analysis is essential to confirm the diagnosis. Key word: bird-headed appearance, dwarfism, microcephaly, Seckel Syndrome, ultrasound, prenatal diagnosis.
Introduction Seckel Syndrome is an autosomal recessive disorder and the most common microcephalic osteodysplastic dwarfism. Recent evidences suggest that Seckel syndrome and Primary autosomal recessive microcephalies constitute a same spectrum rather than distinct entities of the same disease and are both characterized by microcephaly and the absence of visceral malformations where stature is no longer a discriminating feature. Microcephaly Onset during the second trimester of gestation showing an occipito-frontal head circumference (OFC) at birth equal to or less than -2 SD below the mean for sex, age, and ethnicity. Moreover this Circumference (OFC) increases slower after birth. Other alterations occur in Seckel syndrome and Primary autosomal recessive microcephalies such as: brain abnormality, degree of cognitive impairment (usually mild to moderate without significant motor delay but more severe when brain malformations occurs), small brain with small gyri, short stature (previously these diseases were distinguished by height: typically in Primary autosomal recessive microcephalies stature was between -1 SD and -2 SD and in Seckel syndrome between -4 and 12 SD) and Craniosynostosis (1). Particularly, Seckel Syndrome is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation. Hematological abnormalities with chromosome breakage have only been found in 15 to 25% of patients. The differential diagnosis with microcephalic osteodysplastic dwarfism type II can only be made with a complete radiographic survey in the first years of life. Besides a wide phenotypic heterogeneity among affected patients, genetic heterogeneity has also been proven, with three loci identified to date by homozygosity mapping: SCKL1 [3q22.1-q24, ataxiatelangiectasia and Rad3-related protein (ATR) gene], SCKL2 (18p11.31-q11.2, unknown gene) and SCKL3 (14q23, unknown gene). SCKL3 seems to be the predominant locus for Seckel Syndrome. Approaching the function of the ATR gene, the genes with a role in DNA repair are good candidates for SCKL2 and SCKL3 (2). Mental retardation is usually severe and Journal of Prenatal Medicine 2014; 8(3/4):70-72
6_Vascone_Prenatal 3/4-2014 03/07/15 12:58 Pagina 71
Antenatal diagnosis of Seckel Syndrome: a rare case report
families often go through substantial lifestyle changes that might need social support. In case of associated hematological abnormalities (anemia, pancytopenia, acute myeloid leukaemia), medical treatment should be provided (3).
Case Report We observed by ultrasound a 25-year-old woman, at the second pregnancy, during the 24th wk of pregnancy. Family history was negative for malformation and chromosomal disorders. Through transabdominal ultrasound we observed: brachycephaly (Fig. 1), with a head circumference in the 19th percentile and this is strongly suggestive of a future microcephaly; micrognathia (Fig. 2); low-set ears (Fig. 3); long bones were small, in particular rhizo – mesomelic segments; clinodactyly of the 5° finger; gallbladder couldn’t be visualized during ultrasound study (this sign is not important for the diagnosis, but suggests an higher risk of biliary atresia after birth); ptosic right kidney (Fig. 4); single umbilical artery. The sonographic features suggested a Seckel Syndrome diagnosis, which was later confirmed by molecular tests.
Figure 3. Low-set ears.
Figure 4. Ptosic right kidney.
Discussion
Figure 1. Brachycephaly.
Sonographic features of Seckel Syndrome, especially the full-blown form, are represented by major intracranial abnormalities such as the typical birdlike head, microcephaly and severe growth restriction. These conditions should be diagnosable by prenatal sonography. This diagnosis is extremely rare and can only be made by an expert operator. Nonetheless, it should be underlined that the clinical variability of the condition is relatively high (4). Moreover, other types of osteodysplastic dwarfism characterized by severe growth restriction and micrognathia have also been described. This extreme variability in the Seckel Syndrome phenotype may explain why this Syndrome tends to be overdiagnosed and should be differentiated from closely similar syndrome such as Cockayne syndrome, progeria, Hallermann-Streiff syndrome, and Dyggve-Melchior-Clausen syndrome. Misdiagnosis is most often, but not exclusively, made during the neonatal period (5).
Conclusions
Figure 2. Micrognathia. Journal of Prenatal Medicine 2014; 8(3/4):70-72
The take home message is that the diagnosis of Seckel Syndrome is a rare and very difficult diagnosis that should be made only by expert operators. Karyotype analysis (SCKL1 - SCKL2 - SCKL3) and genet-
71
6_Vascone_Prenatal 3/4-2014 03/07/15 12:58 Pagina 72
C. Vascone et al.
ic counseling are essential for the definitive diagnosis. In these circumstances a NMR is the exam of choice for the evaluation of any central nervous system abnormalities. Finally, despite Seckel Syndrome, by defined, combines microcephaly with the absence of visceral malformations we reported, rhizo-mesomelic segments, clinodactyly of the 5° finger, gallbladder absence and single umbilical artery.
2.
3.
Conflict of interest The Authors report no conflict of interest. The Authors attest that they have obtained written consent from the patient.
4.
References
5.
1.
72
Alain Verloes, MD, PhD, Severine Drunat, MD, PhD,
Pierre Gressens, MD, PhD, and Sandrine Passemard, MD, PhD. Primary Autosomal Recessive Microcephalies and Seckel Syndrome Spectrum Disorders. GeneReviews Initial Posting: September 1, 2009; Last Update: October 31, 2013. Kilinç MO, Ninis VN, Ugur SA, Tüysüz B, Seven M, Balci S, Goodship J, Tolun A. Is the novel SCKL3 at 14q23 the predominant Seckel locus? Eur J Hum Genet. 2003 Nov; 11(11):851-857. Shanske A, Caride DG, Menasse-Palmer L, Bogdanow A, Marion RW. Central nervous system anomalies in Seckel Syndrome: report of a new family and review of the literature. Am J Med Genet. 1997 May 16; 70(2):155-158. Gupta A, Fazal TS, Arora R. Antenatal diagnosis of Seckel Syndrome. J Obstet Gynaecol India. 2014 Dec; 64(Suppl 1):6-8. Sisodia R, Raj RK, Goel V. Seckel syndrome: a rare case report. J Indian Soc Pedod Prev Dent. 2014 AprJun; 32(2):160-163. doi: 10.4103/0970-4388.130983.
Journal of Prenatal Medicine 2014; 8(3/4):70-72
