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Seckel Syndrome Accompanied by Semilobar Holoprosencephaly and Arthrogryposis
Pediatric Neurology 46 (2012) 189e191
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Seckel Syndrome Accompanied by Semilobar Holoprosencephaly and Arthrogryposis Dilek Sarici MD a, *, Mustafa Ali Akin MD a, Ahu Kara MD b, Selim Doganay MD c, Selim Kurtoglu MD a a b c
Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey Department of Radiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
article information
abstract
Article history: Received 8 September 2011 Accepted 3 January 2012
Seckel syndrome is a rare autosomal recessive disorder, and its characteristic features include prenatal and postnatal growth retardation, microcephaly, and “bird-like” face with prominent, beak-like nose and micrognathia. Additional abnormalities were described in the cardiovascular, hematopoietic, endocrine, and central nervous systems. We present the magnetic resonance imaging findings of a neonate with Seckel syndrome accompanied by semilobar holoprosencephaly and arthrogryposis. Major brain malformations may be associated with Seckel syndrome. Imaging studies should be performed to determine any central nervous system abnormalities. Considering the basic defect of neuroblast proliferation in Seckel syndrome, neuronal migration disorders should be sought in these patients. Ó 2012 Elsevier Inc. All rights reserved.
Introduction Seckel syndrome is a rare autosomal recessive disorder of primordial dwarfism. Its characteristic features include severe prenatal and postnatal proportionate dwarfism, severe microcephaly, a “bird-headed” profile with receding forehead and chin, a large, beaked nose, and severe mental retardation [1]. Additional abnormalities were described in the cardiovascular, hematopoietic, endocrine, and central nervous systems [2-4]. Various abnormalities of the central nervous system are described in the literature. We present a case of Seckel syndrome (in a female newborn) accompanied by semilobar holoprosencephaly and arthrogryposis. This association, to the best of our knowledge, was not previously reported in the literature. Case Report A 1-day-old female newborn was admitted because of dysmorphic features and feeding difficulties. The patient was born at 37 gestational weeks to a 37-year-old gravida 4, para 3 mother by vaginal delivery after a pregnancy complicated by intrauterine growth retardation. She presented with no history of polyhydramnios or oligohydramnios, and the parents and other two siblings of the patient were healthy. The parents were consanguineous, and the father was 48 years old. On physical examination, the patient’s length was 31 cm, her weight was 940 g, and her head circumference was 23 cm (all below the 3rd centile). The phenotypic features
* Communications should be addressed to: Dr. Sarici; Division of Neonatology; Department of Pediatrics; Faculty of Medicine; Erciyes University; 38039 Kayseri, Turkey. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.01.002
of the baby included microcephaly, closed anterior-posterior fontanelles with sutural ridges, a sloping forehead, micrognathia, a prominent beaked nose, a higharched palate, hypotelorism, fifth finger clinodactyly, a bilateral simian crease, and arthrogryposis (bilateral ulnar deviation of the hands, difficulty with extension of the elbows and knees, bilateral cubitus valgus, bilateral pes equinovarus, and bilateral partial syndactyly of the second and third toes; Fig 1). No external midline defects, such as a pilonidal dimple or a hairy tuft in the sacral midline, were observed. A blood count, biochemistry parameters, and an X-ray and ultrasound of the abdomen produced normal results. Echocardiography revealed a patent foramen ovale. Transfontanel ultrasonography indicated holoprosencephaly. Cranial magnetic resonance imaging was thus performed, and axial and coronal images revealed semilobar holoprosencephaly, lissencephaly/pachygyria, dilatation of the occipital horn of the lateral ventricle, hypoplasia of the frontal horn of the lateral ventricle, and anterior noncleavage of the basal ganglion and frontal lobe (Figs 2 and 3). A sagittal view revealed dysgenesis of the corpus callosum and microcephaly. Because of the patient’s central nervous system anomalies, hormones of the hypophyseal and thyroidal glands were assessed on day 10 of age, and findings included growth hormone at 7.05 ng/mL, insulin-like growth factor-1 at <25 ng/mL, insulin-like growth factor binding protein-3 at 748 ng/mL, free T3 at 2.53 pg/mL, free T4 at 1.91 ng/dL, thyroid-stimulating hormone at 8.07 mU/L, thyroglobulin at >300 ng/mL, folliclestimulating hormone at 1.30 mIU/mL, and luteinizing hormone at <0.100 mIU/mL. The hormone levels were borderline normal, and were reevaluated on day 16 of age, and findings included growth hormone at 10.4 ng/mL, insulin-like growth factor binding protein-3 at 925 ng/mL, free T4 at 1.45 ng/dL, free T3 at 2.67 pg/mL, thyroidstimulating hormone at 14.01 mU/L, thyroglobulin at >300 ng/mL, urine iodine at 46 mg/dL, follicle-stimulating hormone at 2.25 mIU/mL, and luteinizing hormone at 0.257 mIU/mL. These findings were within normal limits. A mutation analysis could not be performed because of the absence of an appropriate genetic center. The patient, with a weight of 5000 g, a length of 57 cm, and a head circumference of 43 cm at 18 months of age, is being followed at the Department of Pediatrics. During her most recent neurologic examination, deep tendon reflexes were absent, whereas her muscle tone and olfactory function were normal. However, limitation was evident in the bilateral abduction of the hips, with limited extension in her right elbow. She can sit without support with good head control, but cannot crawl and
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D. Sarici et al. / Pediatric Neurology 46 (2012) 189e191
Figure 1. Seckel syndrome with microcephaly, sloping forehead, micrognathia, prominent beaked nose, high-arched palate, hypotelorism, fifth finger clinodactyly, bilateral simian crease, and arthrogryposis.
walk. No dentition has yet appeared. She demonstrates no problem with hearing, but can only voice meaningless sounds. An electroencephalogram performed at age 17 months indicated irregularity on the background rhythm and spike-wave activity with high amplitude originating from both the hemispheric centro-occipital and central regions, more prominent in the right hemisphere. Despite the absence of seizures, vigabatrin was initiated to suppress potentially epileptic foci observed on electroencephalogram.
Discussion The central nervous system is affected in various degrees by Seckel syndrome. Our patient manifested holoprosencephaly. Holoprosencephaly is caused by the failure of the telencephalic vesicle to cleave, and results in a fusion of the two hemispheres and
Figure 2. Axial T1-weighted magnetic resonance image indicates pachygyria and noncleavage of the forebrain.
Figure 3. Coronal T2-weighted magnetic resonance image indicates lissencephaly and a clear division of the cerebral hemispheres.
deep brain structures [5]. Microlissencephaly, a classic finding of holoprosencephaly, is characterized by a smooth cortical surface with a thickened cortex, and is usually associated with hypoplastic frontal lobes and a thin and hypoplastic corpus callosum [6,7]. It is presumably caused by a defect in ongoing neuronal migration, and results from a paucity of neurons [7]. The malformation of the cerebral cortex in the present patient involves lissencephaly/ pachygyria, occurring secondary to an arrest in neuroblast proliferation and holoprosencephaly. In one fetal patient, telencephalic micrencephaly with reduced neuroblast production, retarded functional differentiation of the pituitary gland, and generalized hypotrophy with craniofacial stigmata were determined during 29th week of gestation [8]. Shanske et al. suggested that neuronal migration abnormalities may constitute the cause of these abnormalities in the central nervous system [1]. The basic pathogenetic mechanism in Seckel syndrome may involve a deficit in neuroblast proliferation [8], and this defect may be responsible for the central nervous system findings of holoprosencephaly and lissencephaly/ pachygyria. Arthrogryposis, defined as multiple contractures involving more than one area of the body, is not a specific diagnosis but rather a description of clinical findings. Normal findings of a neurologic examination suggest that arthrogryposis is attributable to amyoplasia, distal arthrogryposis, a generalized connective tissue disorder, or fetal crowding, whereas abnormal findings of a neurologic examination indicate that movement in utero was diminished as the result of an abnormality of the central or peripheral nervous system, the motor endplate, or muscles of any extremity[9]. A reduction in the severity of arthrogryposis (a limitation only in bilateral abduction of the hips) at 18 months of age when compared to the extent of arthrogryposis at birth, and not worsening upon neurologic examination suggest that our patient’s arthrogryposis was of a distal arthrogrypotic origin. The traditional morphologic classification of holoprosencephaly into alobar, semilobar, and lobar forms is based on grades of severity, and each form occurs in all of the known genetic mutations. Of the four most important defective genes identified as primary in human holoprosencephaly, three exhibit a ventrodorsal gradient of expression (SHH, SIX3, and TGIF), and one exhibits a dorsoventral gradient (ZIC2). However, in addition to the vertical axis, genes expressed in the neural tube also may demonstrate rostrocaudal and mediolateral gradients in the other axes. These other gradients may be as important as the vertical axis. If the
D. Sarici et al. / Pediatric Neurology 46 (2012) 189e191
rostrocaudal gradient extends as far as the mesencephalic neuromere, it may interfere with the formation, migration, or apoptosis of the mesencephalic neural crest, which forms the membranous bones of the face, orbits, nose, and parts of the eyes, and may explain the midfacial hypoplasia observed in many, but not all, children with holoprosencephaly [10]. The mechanism of facial dysmorphism in our patient may thus be attributable to defective mesencephalic neural crest tissue formation, as described in detail by Sarnat and Flores-Sarnat [10]. Most of the time, alterations in ZIC2 correlate with a normal face, and in some cases are associated with neural tube defects or syntelencephaly (middle interhemispheric variant). Spina bifida and anencephaly were also described in association with holoprosencephaly in the same patient or in the same family. SIX3 is a homeobox-containing gene that is homologous to the Drosophila sine oculis gene; it is involved in head midline and eye formation. Mice with reduced levels of SIX3 expression present a failure of forebrain and eye development. Heterozygous and homozygous deletions of the third exon of TGIF in mice can result in a defined spectrum of brain developmental defects, including exencephaly, microcephaly, and holoprosencephaly. Abnormalities in embryonic brain ventricle formation and cleavage GLI2 include defective anterior pituitary formation and pan-hypopituitarism [11]. The evaluation of the present patient was foremost limited by our inability to perform a detailed genetic/mutational analysis. In the literature, few case reports include the imaging of the various anomalies of the central nervous system in Seckel syndrome. Shanske et al. reported agenesis of the corpus callosum, hypoplasia of the cerebellar vermis, a dysgenetic cerebrum with pachygyria, and a medially located dorsal cyst in a newborn on cranial computed tomography [1]. Thapa et al. described an open and closed lip schizencephaly detected on a computed tomography scan of a boy aged 2 years and 8 months [12]. A 14-year-old boy presented with hypoplasia of the corpus callosum and the frontal brain horn, and pachygyria with hydrocephaly [13]. Magnetic resonance imaging of a 3-month-old boy demonstrated severe tonsillar herniation, with compression of the brainstem [14]. Magnetic resonance imaging in an 8-year-old boy with congenital mirror movements of the upper extremities revealed agenesis of the corpus callosum and cerebellar tonsillar herniation [15]. Kumar et al. reported semilobar holoprosencephaly and an extra-axial cyst communicating with the body of the right lateral ventricle in the temporoparietal region on magnetic resonance imaging in a 24-day-old boy [4]. The magnetic resonance imaging of our patient indicated semilobar holoprosencephaly, lissencephaly/pachygyria, dilatation of the occipital horn of the lateral ventricle, hypoplasia of the frontal horn of the lateral ventricle, and anterior noncleavage of the basal ganglion and frontal lobe. To our knowledge, the association of arthrogryposis and semilobar holoprosencephaly with Seckel syndrome was not previously reported in the literature. Some case reports described hypophyseal abnormalities. Magnetic resonance imaging in a newborn demonstrated thinning of the corpus callosum, a very small anterior lobe of the pituitary gland, and dilated posterior horns of the lateral ventricles [16].
191
Another patient demonstrated slight hypophyseal hypoplasia with a slight reduction of human chorionic gonadotrophin serum levels [17]. However, no report was found on the hormonal functions of the hypophysis. Our patient’s human chorionic gonadotrophin levels were normal. Major brain malformations may be associated with Seckel syndrome. Imaging studies should be performed to determine any abnormalities in the central nervous system. Here, we present the magnetic resonance imaging of an infant with Seckel syndrome accompanied by semilobar holoprosencephaly and arthrogryposis. To the best of our knowledge, this association was not previously reported. Considering the basic defect in neuroblast proliferation in Seckel syndrome, neuronal migration disorders should be sought in these patients. The authors thank Aslı Uzak, MD and Munis Dundar, MD from the Department of Genetics (Faculty of Medicine, Erciyes University, Kayseri, Turkey) for their contributions in establishing the diagnosis, and S. Umit Sarici, MD for his valuable efforts in preparing, typing, and reviewing the manuscript.
References [1] 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;70:155e8. [2] Can E, Bulbul A, Uslu S, et al. A case of Seckel syndrome with tetralogy of Fallot. Genet Couns 2010;21:49e51. [3] Hayani A, Suarez CR, Molnar Z, LeBeau M, Godwin J. Acute myeloid leukaemia in a patient with Seckel syndrome. J Med Genet 1994;31:148e9. lu M, Aycan Z, Evliyaog lu O, Ocal G. Seckel-like [4] Adiyaman P, Berberog syndrome: A patient with precocious puberty associated with nonclassical congenital adrenal hyperplasia. J Pediatr Endocrinol Metab 2004;17:105e10. [5] Tanaka T, Gleeson JG. Genetics of brain development and malformation syndromes. Curr Opin Pediatr 2000;12:523e8. [6] Abdel Razek AA, Kandell AY, Elsorogy LG, Elmongy A, Basett AA. Disorders of cortical formation: MR imaging features. AJNR 2009;30:4e11. [7] Gleeson JG. Inherited neurodevelopmental brain diseases: Applications of homozygosity mapping to identify new genetic causes of disease. Iran J Child Neurol 2008;2:7e13. [8] Hori A, Tamagawa K, Eber SW, Westmeier M, Hansmann I. Neuropathology of Seckel syndrome in fetal stage with evidence of intrauterine developmental retardation. Acta Neuropathol (Berl) 1987;74:397e401. [9] Bamshad M, Van Heest AE, Pleasure D. Arthrogryposis: A review and update. J Bone Joint Surg [Am] 2009;91:40e6. [10] Sarnat HB, Flores-Sarnat L. Neuropathologic research strategies in holoprosencephaly. J Child Neurol 2001;16:918e31. [11] Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V. Holoprosencephaly. Orphanet J Rare Dis 2007;2:8. [12] Thapa R, Mallick D, Biswas B, Ghosh A. Open and closed lip schizencephaly in Seckel syndrome: A case report. J Child Neurol 2010;25:494e6. [13] De Coster PJ, Verbeeck RM, Holthaus V, Martens LC, Vral A. Seckel syndrome associated with oligodontia, microdontia, enamel hypoplasia, delayed eruption, and dentin dysmineralization: A new variant? J Oral Pathol Med 2006;35:639e41. [14] Hopkins TE, Haines SJ. Rapid development of Chiari I malformation in an infant with Seckel syndrome and craniosynostosis: Case report and review of the literature. J Neurosurg 2003;98:1113e5. [15] Thapa R, Mukherjee K. Seckel syndrome with asymptomatic tonsillar herniation and congenital mirror movements. J Child Neurol 2010;25:231e3. [16] Carfagnini F, Tani G, Ambrosetto P. MR findings in Seckel’s syndrome: Report of a case. Pediatr Radiol 1999;29:849e50. [17] Di Blasi S, Belvedere M, Pintacuda S, et al. Seckel’s syndrome: A case report. J Med 1993;24:75e96.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Case Report
Seckel Syndrome Accompanied by Semilobar Holoprosencephaly and Arthrogryposis Dilek Sarici MD a, *, Mustafa Ali Akin MD a, Ahu Kara MD b, Selim Doganay MD c, Selim Kurtoglu MD a a b c
Division of Neonatology, Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey Department of Radiology, Faculty of Medicine, Erciyes University, Kayseri, Turkey
article information
abstract
Article history: Received 8 September 2011 Accepted 3 January 2012
Seckel syndrome is a rare autosomal recessive disorder, and its characteristic features include prenatal and postnatal growth retardation, microcephaly, and “bird-like” face with prominent, beak-like nose and micrognathia. Additional abnormalities were described in the cardiovascular, hematopoietic, endocrine, and central nervous systems. We present the magnetic resonance imaging findings of a neonate with Seckel syndrome accompanied by semilobar holoprosencephaly and arthrogryposis. Major brain malformations may be associated with Seckel syndrome. Imaging studies should be performed to determine any central nervous system abnormalities. Considering the basic defect of neuroblast proliferation in Seckel syndrome, neuronal migration disorders should be sought in these patients. Ó 2012 Elsevier Inc. All rights reserved.
Introduction Seckel syndrome is a rare autosomal recessive disorder of primordial dwarfism. Its characteristic features include severe prenatal and postnatal proportionate dwarfism, severe microcephaly, a “bird-headed” profile with receding forehead and chin, a large, beaked nose, and severe mental retardation [1]. Additional abnormalities were described in the cardiovascular, hematopoietic, endocrine, and central nervous systems [2-4]. Various abnormalities of the central nervous system are described in the literature. We present a case of Seckel syndrome (in a female newborn) accompanied by semilobar holoprosencephaly and arthrogryposis. This association, to the best of our knowledge, was not previously reported in the literature. Case Report A 1-day-old female newborn was admitted because of dysmorphic features and feeding difficulties. The patient was born at 37 gestational weeks to a 37-year-old gravida 4, para 3 mother by vaginal delivery after a pregnancy complicated by intrauterine growth retardation. She presented with no history of polyhydramnios or oligohydramnios, and the parents and other two siblings of the patient were healthy. The parents were consanguineous, and the father was 48 years old. On physical examination, the patient’s length was 31 cm, her weight was 940 g, and her head circumference was 23 cm (all below the 3rd centile). The phenotypic features
* Communications should be addressed to: Dr. Sarici; Division of Neonatology; Department of Pediatrics; Faculty of Medicine; Erciyes University; 38039 Kayseri, Turkey. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2012.01.002
of the baby included microcephaly, closed anterior-posterior fontanelles with sutural ridges, a sloping forehead, micrognathia, a prominent beaked nose, a higharched palate, hypotelorism, fifth finger clinodactyly, a bilateral simian crease, and arthrogryposis (bilateral ulnar deviation of the hands, difficulty with extension of the elbows and knees, bilateral cubitus valgus, bilateral pes equinovarus, and bilateral partial syndactyly of the second and third toes; Fig 1). No external midline defects, such as a pilonidal dimple or a hairy tuft in the sacral midline, were observed. A blood count, biochemistry parameters, and an X-ray and ultrasound of the abdomen produced normal results. Echocardiography revealed a patent foramen ovale. Transfontanel ultrasonography indicated holoprosencephaly. Cranial magnetic resonance imaging was thus performed, and axial and coronal images revealed semilobar holoprosencephaly, lissencephaly/pachygyria, dilatation of the occipital horn of the lateral ventricle, hypoplasia of the frontal horn of the lateral ventricle, and anterior noncleavage of the basal ganglion and frontal lobe (Figs 2 and 3). A sagittal view revealed dysgenesis of the corpus callosum and microcephaly. Because of the patient’s central nervous system anomalies, hormones of the hypophyseal and thyroidal glands were assessed on day 10 of age, and findings included growth hormone at 7.05 ng/mL, insulin-like growth factor-1 at <25 ng/mL, insulin-like growth factor binding protein-3 at 748 ng/mL, free T3 at 2.53 pg/mL, free T4 at 1.91 ng/dL, thyroid-stimulating hormone at 8.07 mU/L, thyroglobulin at >300 ng/mL, folliclestimulating hormone at 1.30 mIU/mL, and luteinizing hormone at <0.100 mIU/mL. The hormone levels were borderline normal, and were reevaluated on day 16 of age, and findings included growth hormone at 10.4 ng/mL, insulin-like growth factor binding protein-3 at 925 ng/mL, free T4 at 1.45 ng/dL, free T3 at 2.67 pg/mL, thyroidstimulating hormone at 14.01 mU/L, thyroglobulin at >300 ng/mL, urine iodine at 46 mg/dL, follicle-stimulating hormone at 2.25 mIU/mL, and luteinizing hormone at 0.257 mIU/mL. These findings were within normal limits. A mutation analysis could not be performed because of the absence of an appropriate genetic center. The patient, with a weight of 5000 g, a length of 57 cm, and a head circumference of 43 cm at 18 months of age, is being followed at the Department of Pediatrics. During her most recent neurologic examination, deep tendon reflexes were absent, whereas her muscle tone and olfactory function were normal. However, limitation was evident in the bilateral abduction of the hips, with limited extension in her right elbow. She can sit without support with good head control, but cannot crawl and
190
D. Sarici et al. / Pediatric Neurology 46 (2012) 189e191
Figure 1. Seckel syndrome with microcephaly, sloping forehead, micrognathia, prominent beaked nose, high-arched palate, hypotelorism, fifth finger clinodactyly, bilateral simian crease, and arthrogryposis.
walk. No dentition has yet appeared. She demonstrates no problem with hearing, but can only voice meaningless sounds. An electroencephalogram performed at age 17 months indicated irregularity on the background rhythm and spike-wave activity with high amplitude originating from both the hemispheric centro-occipital and central regions, more prominent in the right hemisphere. Despite the absence of seizures, vigabatrin was initiated to suppress potentially epileptic foci observed on electroencephalogram.
Discussion The central nervous system is affected in various degrees by Seckel syndrome. Our patient manifested holoprosencephaly. Holoprosencephaly is caused by the failure of the telencephalic vesicle to cleave, and results in a fusion of the two hemispheres and
Figure 2. Axial T1-weighted magnetic resonance image indicates pachygyria and noncleavage of the forebrain.
Figure 3. Coronal T2-weighted magnetic resonance image indicates lissencephaly and a clear division of the cerebral hemispheres.
deep brain structures [5]. Microlissencephaly, a classic finding of holoprosencephaly, is characterized by a smooth cortical surface with a thickened cortex, and is usually associated with hypoplastic frontal lobes and a thin and hypoplastic corpus callosum [6,7]. It is presumably caused by a defect in ongoing neuronal migration, and results from a paucity of neurons [7]. The malformation of the cerebral cortex in the present patient involves lissencephaly/ pachygyria, occurring secondary to an arrest in neuroblast proliferation and holoprosencephaly. In one fetal patient, telencephalic micrencephaly with reduced neuroblast production, retarded functional differentiation of the pituitary gland, and generalized hypotrophy with craniofacial stigmata were determined during 29th week of gestation [8]. Shanske et al. suggested that neuronal migration abnormalities may constitute the cause of these abnormalities in the central nervous system [1]. The basic pathogenetic mechanism in Seckel syndrome may involve a deficit in neuroblast proliferation [8], and this defect may be responsible for the central nervous system findings of holoprosencephaly and lissencephaly/ pachygyria. Arthrogryposis, defined as multiple contractures involving more than one area of the body, is not a specific diagnosis but rather a description of clinical findings. Normal findings of a neurologic examination suggest that arthrogryposis is attributable to amyoplasia, distal arthrogryposis, a generalized connective tissue disorder, or fetal crowding, whereas abnormal findings of a neurologic examination indicate that movement in utero was diminished as the result of an abnormality of the central or peripheral nervous system, the motor endplate, or muscles of any extremity[9]. A reduction in the severity of arthrogryposis (a limitation only in bilateral abduction of the hips) at 18 months of age when compared to the extent of arthrogryposis at birth, and not worsening upon neurologic examination suggest that our patient’s arthrogryposis was of a distal arthrogrypotic origin. The traditional morphologic classification of holoprosencephaly into alobar, semilobar, and lobar forms is based on grades of severity, and each form occurs in all of the known genetic mutations. Of the four most important defective genes identified as primary in human holoprosencephaly, three exhibit a ventrodorsal gradient of expression (SHH, SIX3, and TGIF), and one exhibits a dorsoventral gradient (ZIC2). However, in addition to the vertical axis, genes expressed in the neural tube also may demonstrate rostrocaudal and mediolateral gradients in the other axes. These other gradients may be as important as the vertical axis. If the
D. Sarici et al. / Pediatric Neurology 46 (2012) 189e191
rostrocaudal gradient extends as far as the mesencephalic neuromere, it may interfere with the formation, migration, or apoptosis of the mesencephalic neural crest, which forms the membranous bones of the face, orbits, nose, and parts of the eyes, and may explain the midfacial hypoplasia observed in many, but not all, children with holoprosencephaly [10]. The mechanism of facial dysmorphism in our patient may thus be attributable to defective mesencephalic neural crest tissue formation, as described in detail by Sarnat and Flores-Sarnat [10]. Most of the time, alterations in ZIC2 correlate with a normal face, and in some cases are associated with neural tube defects or syntelencephaly (middle interhemispheric variant). Spina bifida and anencephaly were also described in association with holoprosencephaly in the same patient or in the same family. SIX3 is a homeobox-containing gene that is homologous to the Drosophila sine oculis gene; it is involved in head midline and eye formation. Mice with reduced levels of SIX3 expression present a failure of forebrain and eye development. Heterozygous and homozygous deletions of the third exon of TGIF in mice can result in a defined spectrum of brain developmental defects, including exencephaly, microcephaly, and holoprosencephaly. Abnormalities in embryonic brain ventricle formation and cleavage GLI2 include defective anterior pituitary formation and pan-hypopituitarism [11]. The evaluation of the present patient was foremost limited by our inability to perform a detailed genetic/mutational analysis. In the literature, few case reports include the imaging of the various anomalies of the central nervous system in Seckel syndrome. Shanske et al. reported agenesis of the corpus callosum, hypoplasia of the cerebellar vermis, a dysgenetic cerebrum with pachygyria, and a medially located dorsal cyst in a newborn on cranial computed tomography [1]. Thapa et al. described an open and closed lip schizencephaly detected on a computed tomography scan of a boy aged 2 years and 8 months [12]. A 14-year-old boy presented with hypoplasia of the corpus callosum and the frontal brain horn, and pachygyria with hydrocephaly [13]. Magnetic resonance imaging of a 3-month-old boy demonstrated severe tonsillar herniation, with compression of the brainstem [14]. Magnetic resonance imaging in an 8-year-old boy with congenital mirror movements of the upper extremities revealed agenesis of the corpus callosum and cerebellar tonsillar herniation [15]. Kumar et al. reported semilobar holoprosencephaly and an extra-axial cyst communicating with the body of the right lateral ventricle in the temporoparietal region on magnetic resonance imaging in a 24-day-old boy [4]. The magnetic resonance imaging of our patient indicated semilobar holoprosencephaly, lissencephaly/pachygyria, dilatation of the occipital horn of the lateral ventricle, hypoplasia of the frontal horn of the lateral ventricle, and anterior noncleavage of the basal ganglion and frontal lobe. To our knowledge, the association of arthrogryposis and semilobar holoprosencephaly with Seckel syndrome was not previously reported in the literature. Some case reports described hypophyseal abnormalities. Magnetic resonance imaging in a newborn demonstrated thinning of the corpus callosum, a very small anterior lobe of the pituitary gland, and dilated posterior horns of the lateral ventricles [16].
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Another patient demonstrated slight hypophyseal hypoplasia with a slight reduction of human chorionic gonadotrophin serum levels [17]. However, no report was found on the hormonal functions of the hypophysis. Our patient’s human chorionic gonadotrophin levels were normal. Major brain malformations may be associated with Seckel syndrome. Imaging studies should be performed to determine any abnormalities in the central nervous system. Here, we present the magnetic resonance imaging of an infant with Seckel syndrome accompanied by semilobar holoprosencephaly and arthrogryposis. To the best of our knowledge, this association was not previously reported. Considering the basic defect in neuroblast proliferation in Seckel syndrome, neuronal migration disorders should be sought in these patients. The authors thank Aslı Uzak, MD and Munis Dundar, MD from the Department of Genetics (Faculty of Medicine, Erciyes University, Kayseri, Turkey) for their contributions in establishing the diagnosis, and S. Umit Sarici, MD for his valuable efforts in preparing, typing, and reviewing the manuscript.
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