International Journal of Pharma and Bio Sciences. Meckel-Gruber Syndrome Associated with CNS Malformations A Case Report

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International Journal of Pharma and Bio Sciences RESEARCH ARTICLE PATHOLOGY Meckel-Gruber Syndrome Associated with CNS Malformations A Case Report Corresponding Author DR. N.

1 International Journal of Pharma and Bio Sciences RESEARCH ARTICLE PATHOLOGY Meckel-Gruber Syndrome Associated with CNS Malformations A Case Report Corresponding Author DR. N. HIMA BINDU Assistant Professor, Bhaskar Medical College, Moinabad, RR Dist. AP, India Co Authors DR. SUSEELA VAVILALA and DR. GEETA Fetal Medicine Consultants, Fernandez Hospital, Hyderabad, AP, India ABSTRACT Meckel-Gruber syndrome is a rare autosomal recessive lethal malformation characterised by typical manifestations of occipital encephalocele, bilateral polycystic kidneys and post axial polydactyly. But clinically unsuspected or atypical features may be discovered at autopsy or pathological study. One such rare case, diagnosed by ultrasound scan at 21weeks of gestation was terminated and presented here for discussion, with its phenotypic manifestations detailed by autopsy and histo-pathological examination. B - 484

KEY WORDS Meckel-Gruber syndrome, occipital encephalocele, polycystic kidneys, post axial polydactyly, agenesis of corpus callosum, schizencephaly INTRODUCTION Meckel-Gruber syndrome is an autosomal

2 KEY WORDS Meckel-Gruber syndrome, occipital encephalocele, polycystic kidneys, post axial polydactyly, agenesis of corpus callosum, schizencephaly INTRODUCTION Meckel-Gruber syndrome is an autosomal recessive disorder characterised by multiple congenital malformations such as occipital encephalocele, post axial polydactyly, multicystic renal dysplasia and hepatic duct proliferation, fibrosis and cysts. These manifestations of the disorder can be recognised by ultrasound as early as 14weeks of gestation. The phenotypic manifestations include occipital encephalocele, post axial polydactyly and polycystic kidneys. There may be association of other system anomalies. We report a rare case of Meckel-Gruber syndrome identified by prenatal ultrasound at 21weeks of gestation. Case report: A 19 year old primi gravida, non consanguineous marriage, presented at 21weeks of gestation for anomaly scan. Ultrasound examination revealed single gestation corresponding to gestational age of 21weeks, severe oligohydromnios, BPD on -4SD, HC on 5 th centile and AC above 95 th centile, a large occipital encephalocele, and bilateral polycystic kidneys (Figure 1) and non visualisation of bladder. Polydactyly could not be appreciated due to extreme oligohydromnios. Considering the syndromic association of the above features a possible diagnosis of Meckel-Gruber syndrome was made and a detailed counselling of the parents was done. After counselling, the couple decided to undergo termination of pregnancy. The fetus was sent for autopsy with the consent of the parents. Gross examination of the fetus detailed, phenotypic features of microcephaly, low set frontal hairline, potter facies, lowest ears, B - 485

External genitalia were of female type with labia and clitoris.

3 (Figure 2) high arched palate, short neck, small and constricted thorax and distended abdomen. External genitalia were of female type with labia and clitoris. Upper limbs showed bilateral post axial polydactyly and lower limbs showed bilateral talipes and rocker bottom feet. (Figure 3) (Figure 4) B - 486

On examination of the cranial mass in occipital region measuring

oblongata through the defect in the squamous part of occipital

extending from the surface to the ventricles (Schizencephaly) and

4 On examination of the cranial mass in occipital region measuring cm, showed herniation of meninges, cerebellum and medulla oblongata through the defect in the squamous part of occipital bone. (Figure 5) The cerebral hemispheres showed deep clefts extending from the surface to the ventricles (Schizencephaly) and agenesis of corpus callosum. All ventricles were dilated. (Figure 6) B - 487

(Figure 8) Histopathology of kidneys revealed dilated cysts of varying sizes lined by simple cuboidal epithelium (dilated collecting ducts)

5 A detailed internal examination revealed bilateral enlargement of kidneys with multiple cysts of varying sizes. Ureters were hypoplastic and urinary bladder was rudimentary. (Figure 7) On cut section the kidneys showed multiple cysts with dilated calyces. (Figure 8) Histopathology of kidneys revealed dilated cysts of varying sizes lined by simple cuboidal epithelium (dilated collecting ducts) extending from cortex to medulla. Cortex was thinned out with immature glomeruli. No islands of cartilaginous tissue or mesenchymal proliferation were observed. (Figure 9) B - 488

Grossly, the liver appeared normal. But, histopathology of the liver revealed distorted parenchyma due to extensive fibrosis. Bile ducts showed marked proliferation.

(Figure 10) DISCUSSION 1,2 Meckel-Gruber syndrome (MKS) was first described by Johann Friedrich Meckel in 1822 in two siblings who died of identical malformations of occipital encephalocele,

6 Grossly, the liver appeared normal. But, histopathology of the liver revealed distorted parenchyma due to extensive fibrosis. Bile ducts showed marked proliferation. A few areas of dilated bile ducts forming micro cysts were observed. (Figure 10) DISCUSSION 1,2 Meckel-Gruber syndrome (MKS) was first described by Johann Friedrich Meckel in 1822 in two siblings who died of identical malformations of occipital encephalocele, polycystic kidneys and polydactyly. 3 George B Gruber in 1934 reported many familial cases with similar features and coined the term dysencephalia splanchnocystica. In 1969, 4 Opitz and Howe proposed the name Meckel syndrome. In 2006, 5 Opitz et al gave detailed review of developmental pathology of Meckel syndrome. 6 The worldwide incidence of MKS varies from 1 in 13,250 to 1 in 140,000 live births. Highest incidence was reported in Gujarathi Indians, with 1 per 1300 live births (carrier rate of 1 in 18). The incidence was high among Belgians and Bedouins in Kuwait (1 in 3,500 with a carrier rate of 1in 30), Finnish population (1 in 9000 with a carrier rate of 1 in 50). Meckel Gruber syndrome affects all races and ethnic groups with equal incidence in males and females. B - 489

7 There is high mortality and morbidity rate (almost 100%) due to polycystic kidneys and pulmonary hypoplasia. 7 Although Meckel-Gruber syndrome is associated with many anomalies, the major diagnostic criteria include at least 2 of 3 classic manifestations (cystic renal dysplasia, occipital encephalocele or other anomalies of central nervous system and polydactyly were found in 100%, 90% and 83.3% respectively). Other anomalies consistent with MKS form minimal diagnostic criteria and include facial abnormalities, ambiguous genitalia, cardiac septal defects, gastro intestinal anomalies like omphalocele and CNS abnormalities like agenesis of corpus callosum, Dandy-Walker and Arnold-Chiari malformations. In most of the cases, hepatic fibrosis, ductal proliferation and cystic dilatation of bile ductules was a consistent feature. Meckel-Gruber syndrome inherits in families as autosomal recessive disease with 25% of chance of recurrence in each pregnancy. 8,9 There are three types of MKS Type 1 to 3. The type 1 MKS gene was located on Chromosome 17q21- q24, telomeric to the homeobox B region. Type 2 MKS gene was mapped on 10,11 chromosome 11q13. Type 3 MKS gene was localised on 8q8q24. Polydactyly appears to be less common in MKS3 when compared to MKS1 and 2 types. Perinatal diagnosis of MKS can be made by routine ultrasonic screening for fetal anomalies. MKS can be diagnosed as early as 14weeks of gestation by ultrasound by characteristic findings of occipital encephalocele, polycystic kidneys and post axial polydactyly. These findings depend on gestational age of the fetus. These manifestations can be made out in early gestation than in the later gestational age as it is difficult to visualise in later due to severe oligohydramnios. In these cases, a meticulous autopsy on the newborn/abortus is necessary to establish the diagnosis. Measurement of alpha fetoprotein levels in maternal serum or amniotic fluid after 12weeks of gestation may help to detect encephalocele or any neural tube defects. MKS has to be differentiated from other disorders like Smith-Opitz syndrome, trisomy 13, hydrolethalis syndrome, Senior-Loken syndrome, Joubert syndrome and Bardet-Biedl syndrome. Unfortunately, there is no effective treatment or cure for Meckel-Gruber syndrome. The high mortality and morbidity is due to non functional kidneys, liver and pulmonary hypoplasia. This anomaly can be detected as early as 14weeks of gestation and the parents can be counselled about the outcome and prognosis of the fetus and recurrence risk for the next pregnancy. If the couple decides to terminate the pregnancy, fetal autopsy is advised to establish the correct diagnosis. CONCLUSION Meckel-Gruber syndrome is a lethal malformation characterised by Occipital encephalocele, polycystic kidneys and post axial polydactyly. This is a case of MKS associated with other CNS malformations such as agenesis of corpus callosum and schizencephaly in addition to the classic triad of manifestations. As there is no treatment available for this syndrome, pre pregnancy counselling should be offered to the couple about the recurrence risk of subsequent pregnancies. B - 490

8 REFERENCES 1. Editorial. Johann Friedrich Meckel, the younger ( ). JAMA 1970; 214: Seidler E. Johann Friedrich Meckel, the younger ( ). Am J Med Genet 1984; 18: Gruber BG. Beiträge zur frage gekoppelter missbildungen. (Acrocephalo-Syndactylie und Dysencephalia spanchnocystica). Beitr Path Anat 1934; 93: Opitz JM, Howe JJ. The Meckel syndrome (dysencephalia spanchnocystica, the Grüber syndrome). Birth Defects Orig Art Ser 1969; 2: Opitz JM, Schultka R, Gobbel L. Meckel on developmental pathology. Am J Med Genet 2006; 140A: Salonen R, Norio R. The Meckel syndrome in Finland: epidemiologic and genetic aspects. Am J Med Genet 1984; 18: Meckel JF. Beschreibung zweier, durch sehr ähnliche bildungsabweichungen entstelter geschwister. Dtsch Arch Physiol 1822; 7: Paavola P, Salonen R, Weissenbach J, Peltonen L. The locus for Meckel syndrome with multiple congenital anomalies maps to chromosome 17q21-q24. Nat Genet 1995;11: Paavola P, Avela K, Horelli-Kuitunen N, et al. High-resolution physical and genetic mapping of the critical region for Meckel syndrome and mulibrey nanism on chromosome 17q22-q23. Genome Res 1999;9: Kyttala M, Tallila J, Salonen R, et al. MKS1, encoding a component of the flagellar apparatus basal body proteome, is mutated in Meckel syndrome. Nat Genet 2006;38: Roume J, Genin E, Cormier-Daire V, et al. A gene for Meckel syndrome maps to chromosome 11q13. Am J Hum Genet 1998;63: B - 491

MECKEL SYNDROME: GENETICS, PERINATAL FINDINGS, AND DIFFERENTIAL DIAGNOSIS

REVIEW ARTICLE MECKEL SYNDROME: GENETICS, PERINATAL FINDINGS, AND DIFFERENTIAL DIAGNOSIS Chih-Ping Chen 1,2,3,4 * Departments of 1 Obstetrics and Gynecology, and 2 Medical Research, Mackay Memorial Hospital,