CLINICAL REPORT
Simplified Gyral Pattern With Cerebellar Hypoplasia in Sedaghatian Type Spondylometaphyseal Dysplasia: A Clinical Report and Review of the Literature Canan Aygun,1† Fatma Cakmak Celik,1‡* Mehmet Selim Nural,2§ Emine Azak,3# S¸ukru Kucukoduk,1{ Gonul Ogur,4§§ and Lutfi Incesu2## 1
Faculty of Medicine, Department of Pediatrics, Neonatalogy Division, Ondokuz Mayis University, Samsun, Turkey
2
Faculty of Medicine, Radiology Department, Ondokuz Mayis University, Samsun, Turkey
3
Faculty of Medicine, Department of Pediatrics, Pediatric Cardiology Division, Ondokuz Mayis University, Samsun, Turkey Faculty of Medicine, Department of Pediatrics, Pediatric Genetic Division, Ondokuz Mayis University, Samsun, Turkey
4
Manuscript Received 2 March 2011; Manuscript Accepted 22 January 2012
We report on a patient with Sedaghatian type spondylometaphyseal dysplasia (SSMD) who presented with metaphyseal dysplasia, congenital atrioventricular block, simplified gyral pattern, hypogenesis of corpus callosum, and severe cerebellar hypoplasia. We want to emphasize that in this rare congenital lethal skeletal dysplasia with unknown etiology, central nervous system malformations might be a major component of the disorder and should be evaluated in detail to possibly uncover the underlying pathophysiology. Ó 2012 Wiley Periodicals, Inc.
How to Cite this Article: Aygun C, Celik FC, Nural MS, Azak E, Kucukoduk S¸, Ogur G, Incesu L. 2012. Simplified gyral pattern with cerebellar hypoplasia in Sedaghatian type spondylometaphyseal dysplasia: A clinical report and review of the literature. Am J Med Genet Part A 158A:1400–1405.
Key words: Sedaghatian type spondylometaphyseal dysplasia; simplified gyral pattern; cerebellar hypoplasia; congenital atrioventricular block; newborn
atrioventricular block and CNS anomalies; which were colpocephaly, hypogenesis of corpus callosum, simplified gyral pattern (SGP) and severe cerebellar hypoplasia.
INTRODUCTION Sedaghatian type spondylometaphyseal dysplasia (SSMD; OMIM number %250202) is a rare type of lethal congenital severe spondylometaphyseal dysplasia that was first described by Sedaghatian in 1980 in three sibs of Iranian nonconsanguineous parents [Sedaghatian, 1980]. Autosomal recessive inheritance was further supported by consanguinity observed in three additional families and by the presence of affected siblings in nonconsanguineous families [Opitz et al., 1987; Kerr et al., 2000; Mahendran et al., 2007]. The condition is characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, normal intrauterine growth, cardiac conductive defects, and central nervous system (CNS) abnormalities. Seventeen cases from 12 families have been reported in the literature till now. Many of the patients had been reported to have a short life span, and died in the first days of life due to respiratory failure [Sedaghatian, 1980; Opitz et al., 1987; Campbell et al., 1992; Peeden et al., 1992; Kerr et al., 2000; Mahendran et al., 2007]. The longest life span reported has been 161 days [Koutouby et al., 2000]. We present a male infant diagnosed as SSMD with radiological findings who had accompanying features such as 3rd degree
Ó 2012 Wiley Periodicals, Inc.
CLINICAL REPORT The baby was the first born child to first degree cousins of Turkish origin at 37 weeks of gestation. The mother aged 35 had experienced four molar pregnancies and two first trimester abortions. She was given low molecular weight heparin and acetyl salicylic acid through the pregnancy due to high risk of microthrombi. †
Associate Professor in Neonatalogy. Fellow in Neonatalogy. x Associate Professor in Radiology. # Fellow in Pediatric Cardiology. { Professor in Neonatalogy. xx Professor in Pediatric Genetics. ## Professor in Radiology. *Correspondence to: Fatma Cakmak Celik, MD, Faculty of Medicine, Neonatal Intensive Care Unit, Ondokuz Mayis University, Kurupelit, Samsun, Turkey. E-mail:
[email protected] Article first published online in Wiley Online Library (wileyonlinelibrary.com): 23 April 2012 DOI 10.1002/ajmg.a.35306 ‡
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AYGUN ET AL. Antenatally mild ventriculomegaly was detected at 30 weeks of gestation, but the parents were informed that it had regressed on follow-up. The baby was born via cesarean due to maternal anxiety that developed after the initiation of labor. Birth weight was 3,300 g (75th–90th centile), length 48 cm (50th–75th centile), and head circumference 35 cm (50th–90th centile). Since the first minute Apgar score was 5, the baby was intubated in the delivery room. He was referred to a tertiary health center, university hospital due to respiratory failure. Physical examination showed generalized severe hypotonia, insufficient respiratory effort, bradycardia, dysrhythmia, hypertelorism, mild retromicrognathia, brachydactyly, bilateral rocker bottom feet, and left femur being 1 cm shorter than the right one. He had been on mechanical ventilation soon after birth. Heart rate was dysrhythmic and 90/min on admission but it decreased to 50/min within 2 hr. Third degree atrioventricular block was detected on electrocardiography. Echocardiographic evaluation revealed patent ductus arteriosus and patent foramen ovale. A transvenous pacemaker was introduced via left femoral vein at 22 hr of life. Heart rhythm returned to normal with heart rate of 140/min. Pacemaker was removed after 3 days and control echocardiography was normal. Maternal AntiRo and AntiLa antibodies were negative. Skeletal survey revealed increased intervertebral disc spaces, irregularities of end plates and platyspondyly (Fig. 1a), widening and cupping of metaphyses of long tubular bones in upper and lower extremities (Figs. 1b and 2a), flat acetabular roof, decreased sacrosciatic notch, small hypoplastic iliac bones, lacy iliac crest (Fig. 2b), shortening and cupping of short tubular bones
1401 of the hand (Fig. 3a), irregular ossifications in calcaneus (Fig. 3b). Myoclonic jerky convulsions started on the 5th day of life and they were hardly controlled with midazolam, phenobarbital, phenytoin, and pyridoxine. Cranial magnetic resonance imaging revealed colpocephaly, mildly enlarged ventricles, severe gyral simplification with normal cortical thickness, and abnormal signal intensities suggestive for white matter disease (Fig. 4a), severe cerebellar hypoplasia (vermis and hemispheres) and severe hypogenesis of corpus callosum (Fig. 4b). The gyral index calculated as 1.24, according to Vermeulen et al. [2010], was supportive for severe gyral simplification. The gyral index measurements are shown on transverse T2 weighted images (Fig. 5). TORCH, screening for syphilis, chromosome analysis, blood gas analysis, and lactate levels were normal. The baby was mechanically ventilated throughout NICU stay, rarely had convulsions initiated with tactile stimuli. He was hypotonic with no sucking, gag reflexes, was fed by a feeding tube and died at the 120th day of life.
DISCUSSION SSMD is characterized by normal intrauterine growth, neonatal respiratory distress/insufficiency, rhizomelic shortening of the long bones, brachydactyly, redundant skin folds, somewhat narrow but otherwise normal rib cage, cardiac conduction defects, metaphyseal cupping and irregularity, platyspondyly, delayed epiphyseal ossification, and irregular iliac crests. CNS abnormalities have also been described in some reported cases. The radiologic and clinical features in the present case are suggestive for the diagnosis of
FIG. 1. a: Increased intervertebral disc spaces, irregularities of end plates and platyspondyly are observed on lateral thoracolumbar vertebral X-ray. b: Supine chest X-ray demonstrates temporary pacing electrode overlying the heart inserted transvenously via left femoral vein for atrioventricular block. Widening and cupping of metaphyses of upper extremity tubular bones is observed with distal ends of radius and ulna being more severely affected.
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FIG. 2. a: Widening and cupping of metaphyses of long tubular bones on lower extremity X-ray. b: Flat acetabular roof, decreased sacrosciatic notch, small hypoplastic iliac bones, and lacy iliac crest on pelvic X-ray.
SSMD [Sedaghatian, 1980]. Clinical characteristics of the reported SSMD cases including the present patient are summarized in Table I. Generally, shortness of the extremities is not apparent on physical examination due to mild rhizomelic shortness but the radiographic findings are characteristic and more severe; including severe metaphyseal changes, platyspondyly, irregular ossifications in iliac wings and calcaneus, short metacarpals and phalanges [Elc¸ioglu and Hall, 1998]. The patient’s birth length and weight were normal except left femur being 1 cm shorter than the right one. He showed typical radiological findings that were suggestive for SSMD. It is important to note that five reported patients had cardiac conduction defects [Sedaghatian, 1980; Peeden et al., 1992; Kerr et al., 2000; Mahendran et al., 2007] and three of them had complete heart block [Peeden et al., 1992; Kerr et al., 2000; Mahendran et al.,
2007]. Four cases had structural cardiac anomalies, which included atrial septal defect in two [Peeden et al., 1992; Koutouby et al., 2000], preductal coarctation of the aorta was revealed at postmortem examination in one [Campbell et al., 1992] and small muscular ventricular septal defect in another patient [English et al., 2006]. Although our case did not show any structural cardiac anomalies he had third degree AV block which necessitated pacemaker implantation. We speculate that some affected babies with complete heart block may have died well before pacemakers could be placed and were undiagnosed due to very early neonatal death. CNS malformations have been reported frequently in the literature for SSMD. Albeit, they might be more common than expected, and even a sine qua non of SSMD. In eight of the cases including the one reported herein CNS abnormalies have been
FIG. 3. a: Shortening and cupping of metacarpals and phalanges. b: Irregular ossification of calcaneus on lateral X-ray of foot.
AYGUN ET AL.
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FIG. 4. a: Axial T2-weighted image reveals colpocephaly, mildly enlarged ventricles, severe gyral simplification with normal cortical thickness, and abnormal signal intensities suggestive for white matter disease. b: Sagittal T2-weighted image shows severe cerebellar hypoplasia (Vermis and hemispheres) and severe hypogenesis of corpus callosum.
FIG. 5. Simplified gyral pattern observed on T2 weighted images with the related measurements shown. The gyral index is calculated by dividing the length of the inner (border of gray and white matter, with following the sulci) contour to the length of outer (border of gray matter and CSF, without following the sulci) contour of the brain; indicated by green lines.
reported. In some of the reported cases cerebral ultrasonography was the neuroimaging method for evaluation which would not reveal migration disorders. Although cranial MRI is the best method to evaluate the neuronal migration disorders had been used only in a few reported cases since some date back to 1980s and 1990s when cranial MRI was not in use. Six cases had been reported as displaying neuronal migration disorders, SGP, two evaluated by cranial computerized tomography [Peeden et al., 1992; Koutouby et al., 2000] and one by cranial MRI [English et al., 2006]. Two other cases were reported as having immature sulcal development which can well be suggestive for SGP [Foulds et al., 2003; Witters et al., 2009]. One patient had a partial lissencephaly, which is a neuronal migration disorder or could also well be SGP [Peeden et al., 1992]. The observation in our case of SGP supports the high prevalence of SGP in SSMD cases. Although the case reported is unique since it is the first reported case of SSMD with severe cerebellar hypoplasia. Fould reported a patient with immature sulcal development suggestive for SGP [Foulds et al., 2003]. English et al. [2006] reported corpus callosum agenesis and SGP revealed by cranial MRI. One fetus diagnosed as SSMD at 18th gestational week had SGP, corpus callosum agenesis and dilated lateral ventricules at postmortem examination [Witters et al., 2009], but that was a very early stage of CNS development and only a few sulci may have developed at that time [Clouchoux et al., 2012]. In addition to SGP and severe hypogenesis of corpus callosum, the patient presented here also had hypoplasia of cerebellum; which has not been reported previously in the literature. In another case partial lissencephaly was reported as an autopsy finding [Peeden et al., 1992]. One case presented by Elc¸ioglu was reported to have porencephaly, which was detected by cranial ultrasonography [Elc¸ioglu and Hall, 1998].
M
M M M M F F M F
M
Middle East
Pacistanian
Turkish (present case)
þ
þ Birth
Still born Birth 12 hr Birth 2 hr Birth Birth Terminated at 18 thgestational week
Birth
þ
Birth Birth Stillborn
Onset of respiratory failure Birth NM Birth Birth In utero death
3rd degree AV block
NM CHB A-V dissociation ASD — Small muscular VSD Complete heart block Structurally normal heart on autopsy
NM
Dilated heart ASD, CHB NM
Cardiac Problem Wide QRS, bundle branch block NM NM — Preductal coarctation
30
Death (day) 3 3 1 4 Still born (30 gwks) 1 2 Still born
NM Still born NM 1 NM 1 Cerebral atrophy, SGP 161 SGP 30 SGP, CC agenesis 17 Not mentioned 3 SGP ?, CC agenesis, Terminated at 18th absent septum pellucidum, gestational week dilated lateral ventricles SGP, colpocephaly, 120 cerebellar hypoplasia, hypogenesis of CC
Porencephaly
— Partial lissencephaly NM
Brain Abnormality NM NM NM — Aqueduct stenosis
ASD, atrial septal defect; VSD, ventricular septal defect; A-V, atrio ventricular; CHB, congenital heart block; M, male; F, female; NM, not mentioned; SGP, simplified gyral pattern; CC, corpus callosum.
Yemenian Caucasian Caucasian Caucasian NM
M M M
Sex Consanguinity M M F M þ M
Black American Pacistanian
Iranian Caucasian
Ethnicity Iranian
TABLE I. Clinical Characteristics of the Reported SSMD Cases Including Present Case
This study
Koutouby et al. [2000] Foulds et al. [2003] English et al. [2006] Mahendran et al. [2007] Witters et al. [2009]
Peeden et al. [1992] Elc¸ioglu and Hall [1998], Family 1 Elc¸ioglu and Hall [1998], Family 2 Kerr et al. [2000]
Opitz et al. [1987] Campbell et al. [1992]
Refs. Sedaghatian [1980]
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AYGUN ET AL. In one SSMD case with hydrops fetalis, aqueductal stenosis was reported as an autopsy finding [Campbell et al., 1992]. The reported abnormalities of CNS until now imply that there might be a defect leading to abnormal neuronal and glial proliferation and/or abnormal neuronal migration in SSMD, according to a developmental and genetic classification for malformations of cortical development, suggested by Barkovich et al. [2005]. These CNS findings may underlie the etiopathogenesis of hypotonicity, convulsions and respiratory failure observed in the patients. Consanguinity has been reported in 3 of 12 families; which suggests autosomal recessive inheritance [Opitz et al., 1987; Kerr et al., 2000; Mahendran et al., 2007]. The case herein born to first cousin marriage further supports autosomal recessive inheritance as the mode of inheritance. All reported cases have severe hypotonia with cardio-respiratory problems and die due to respiratory failure. Some patients had showed cardiac conduction anomalies similar to the reported case. The molecular etiopathogenesis of SSMD is not clear yet, and we suggest that the gene responsible could be cloned with a single family by whole exome sequencing or homozygosity mapping. The cloning of the gene would probably unveil the developmental link between the skeletal system, neuronal migration disorders, and cardiac conduction defects that are observed in SSMD.
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