|Year : 2016 | Volume
| Issue : 1 | Page : 53-56
Meckel-Gruber Syndrome: Autopsy Based Approach to Diagnosis
Asaranti Kar1, Ipsita Dhal1, Neha Madurwar2, Shyama Kanungo2
1 Department of Pathology, Medical College, Cuttack, Odisha, India
2 Department of O and G, S.C.B. Medical College, Cuttack, Odisha, India
|Date of Web Publication||3-Feb-2016|
Department of Pathology, S.C.B. Medical College, Qrs. No. JO 1, S.C.B. Medical College Campus, Cuttack - 753 007, Odisha
Source of Support: None, Conflict of Interest: None
Meckel-Gruber syndrome (MGS) is a rare lethal congenital malformation affecting 1 in 13,250-140,000 live births. The classical diagnostic triad comprises multicystic dysplastic kidneys, occipital encephalocele, and postaxial polydactyly. It can variably be associated with other malformations such as cleft lip and palate, pulmonary hypoplasia, hepatic fibrosis, and anomalies of central nervous system. A 20 weeks fetus was diagnosed as MGS with classical features along with many other congenital abnormalities such as microcephaly, microphthalmia, hypertelorism, cleft lip and palate, neonatal teeth, and the right side club foot which were detected only after doing autopsy. This case is reported because of its rarity emphasizing the importance of neonatal autopsy in every case of fetal death, especially where the antenatal diagnosis has not been made previously. A systematic approach to accurate diagnosis of MGS based on autopsy will be described here which can allow recurrence risk counseling and proper management in future pregnancies.
Keywords: Autopsy, congenital anomaly, encephalocele, hypertelorism, Meckel-Gruber syndrome
|How to cite this article:|
Kar A, Dhal I, Madurwar N, Kanungo S. Meckel-Gruber Syndrome: Autopsy Based Approach to Diagnosis. J Forensic Sci Med 2016;2:53-6
| Introduction|| |
Meckel-Gruber syndrome (MGS) is a rare genetic disorder not compatible with life. This is autosomal recessive in inheritance, characterized by the classical triad of multicystic dysplasia of kidney, occipital encephalocele, and polydactyly, which are observed in 100%, 90%, and 83.3% cases, respectively. , Besides the clinically recognized classic malformations, it can be variably associated with oral clefting, central nervous system (CNS) malformations such as anencephaly, holoprosencephaly, polymicrogyria, cerebellar hypoplasia, pulmonary hypoplasia, and hepatic fibrosis. The worldwide incidence of MGS ranges from 1 in 13,250 to 140,000 live births.  Although antenatal ultrasonographic examination (USG) can detect many of the features, it can be difficult to diagnose defects after 14 weeks of gestation, in presence of oligohydramnios and may fail to detect all the defects and thereby may not provide an accurate diagnosis.  Therefore, a neonatal autopsy is necessary for syndrome diagnosis and to document all the associated anomalies along with counseling of parents regarding future pregnancies. We present a rare case of MGS with classical triad along with other associated congenital malformations such as microcephaly, microphthalmia, hypertelorism, cleft lip and palate, neonatal teeth, bifid apex, hepatic fibrosis with bile duct proliferation, adrenal agenesis, and right side club foot in a 20 weeks fetus, diagnosed by neonatal autopsy. To the best of our knowledge, association of so many characteristic abnormalities with the typical MGS has not been documented in the literature.
| Case Report|| |
A 23-year-old primigravida presented with 20 weeks of gestation for routine antenatal examination. There was no significant antenatal history of any infection, teratogenic drug intake, hypertension, diabetes mellitus, or radiation exposure to the mother. The marriage was nonconsanguineous. Routine USG showed features of anencephaly with bilateral multicystic kidneys and amniotic fluid index of 4.0 ml. With the consent of parents, the pregnancy was terminated, and the fetus was sent to our department for neonatal autopsy and detailed histopathological evaluation. On examination, the placenta and umbilical cord were found to be normal.
The weight of the fetus was 350 g; the crown-rump length was 18 cm, crown-heel length 33.5cm, head circumference 16 cm, chest circumference 18 cm, and foot length was 3cm.
Ear cartilage, hair, and nails were well-developed, palmar, and plantar creases were absent. Examination of head and neck revealed encephalocele through posterior fontanelle [Figure 1]a], low-set, deformed right ear [Figure 1]a], microcephaly microphthalmia, orbital hypertelorism [Figure 1]b], micrognathia, cleft lip, and palate [Figure 1]b]. Flat nose with broad nasal bridge [Figure 1]b]. Lobulated tongue and neonatal teeth (upper and lower lateral incisors) [Figure 1]c]. Both upper limbs and right foot showed postaxial polydactyly with right side club foot [Figure 1]b and d].
|Figure 1: (a) Fetus with occipital encephalocele, low set deformed right ear, (b) cleft lip and palate, micrognathia, flat nose, polydactyly, (c) lobulated tongue and neonatal teeth, (d) polydactyly with right side club foot|
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The internal examination was done following Virchow's technique and by giving a modified "Y" shaped incision starting from below the ears to symphysis pubis encircling umbilicus on the left side. Both thorax and abdomen were opened. The heart was dissected out of the thorax and after opening revealed bifid apex with left atrial thrombus [Figure 2]a and b]. The liver was enlarged showing surface congestion [Figure 2]c]. Microscopic examination of the liver showed features of hepatic fibrosis, lymphocytic infiltration, and reactive bile ductular proliferation [Figure 2]d]. Both kidneys were found to be enlarged each measuring 5.5 cm × 3.5 cm × 3 cm. On cut section, multiple minute cysts of various sizes were detected, with bilateral adrenal agenesis [Figure 3]a and b]. Histopathological examination revealed multiple cystically dilated spaces lined by flattened epithelium with severely deficient nephrons [Figure 3]c and d]. Other viscera were normal both in the gross and microscopic examination. Based on the presence of above classical features, a diagnosis of MGS was suggested. The parents of the baby did not give consent for genetic analysis.
|Figure 2: (a and b) Bifid apex with left atrial thrombus, (c) enlarged liver with surface congestion, (d) photomicrograph showing hepatic fibrosis, lymphocytic infiltration, and reactive bile ductular proliferation. (H and E, ×200)|
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|Figure 3: (a and b) Enlarged kidneys with multiple minute cysts of various sizes, (c and d) photomicrograph showing multiple cystically dilated spaces lined by flattened epithelium with parenchymal destruction|
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| Discussion|| |
Congenital anomalies (also referred as birth defects) account for 7% of all neonatal mortality and 3.3 million of deaths under 5 years according to joint World Health Organization and March of Dimes meeting report.  MGS is a fatal major congenital malformation characterized by the involvement of multiple systems such as CNS, kidney, and skeletal system. Although improved prenatal testing has increased the detection of fetal abnormalities, an autopsy remains valuable, as it provides morphological confirmation. There needs to be a methodical approach for detection of all birth defects so that an accurate diagnosis can be done which will provide scope for recurrent risk counseling of parents and proper management decisions can be taken for both the ongoing and future pregnancies. In these cases, a meticulous autopsy is necessary to document complete anomalies and syndrome diagnosis.
In the present case, due to oligohydramnios, USG could detect multicystic dysplastic kidneys clearly, but failed to reveal other malformations (it detected anencephaly rather than encephalocele) which were documented during the thorough neonatal autopsy. Therefore, we are describing an autopsy based approach to congenital malformations particularly in context with the present case.
The patient presented with encephalocele through posterior fontanelle. An encephalocele may occur as an isolated lesion or may be part of a syndrome.  There are more than 30 different syndromes, including Meckel syndrome, Fraser syndrome, Roberts syndrome, Trisomy 13, Amniotic band syndrome, and Walker-Warburg syndrome which can be associated with encephalocele. MGS accounts for 5% of all neural tube defects.  In general, recurrence of a neural tube, defect is 1-3% in a given family, whereas recurrence of MGS is 25% due to autosomal inheritance pattern.  Hence, the presence of occipital encephalocele indicates the need to search for other abnormalities to assess the recurrence risk in future pregnancy.
The internal examination was carried out in the present case to assess the gross and histopathological findings of the viscera. There were abnormalities in kidneys, liver, and heart. Kidneys were grossly enlarged, on microscopic examination, revealed multiple small cystic spaces lined by flattened cells with destruction of the renal parenchyma. In 1981, Fraser and Lytwyin suggested that the cystic dysplastic kidneys are a constant anomaly in Meckel syndrome and, therefore, must be present in addition to at least two minor defects to make the diagnosis. 
If the presence of renal abnormalities and encephalocele are considered, the possible congenital anomalies will be Roberts syndrome, Joubert syndrome, Fraser syndrome, and Trisomy 13. ,, Roberts syndrome is characterized by multiple craniofacial anomalies, but they usually have tetraphocomelia or hypomelia and bilateral renal agenesis instead of cystically enlarged kidneys. Joubert syndrome can be variably associated with occipital encephalocele, polymicrogyria, polydactyly, ocular coloboma, retinal dystrophy, cystic kidney disease, nephronophthisis, and hepatic fibrosis. However, the key finding is cerebellar vermis hypoplasia with a complex brainstem malformation. Patients with Trisomy 13 present with holoprosencephaly, polydactyly, cardiac, and renal abnormalities usually of hydronephrosis and hydroureter type. The proposed diagnostic criteria for Fraser syndrome include major criteria consisting of cryptophthalmos, syndactyly, abnormal genitalia, and positive family history. Minor criteria are a congenital malformation of the nose, ears, larynx, cleft lip and/or palate, skeletal defects, umbilical hernia, renal agenesis, and mental retardation. Diagnosis is based on the presence of at least 2 major and 1 minor criteria or 1 major and 4 minor criteria. However, the clue is cerebellar vermis hypoplasia with a complex brainstem malformation. 
MGS may demonstrate variations in phenotypic expression in addition to classical findings. The association of minor and infrequent features in MGS should be kept in mind while doing an autopsy so that it will not lead to misdiagnosis. The reported incidence of renal disorder in this syndrome varies from 95% to 100%. Cystic dysplasia is the most constant characteristic feature of MGS. Occipital encephalocele is present in 60-80%. Postaxial polydactyly is present in 55-75%. Finding of at least two out of the three features of the classical triad, in the presence of multicystic dysplastic kidneys can clinch the diagnosis.
Besides occipital encephalocele, we observed microcephaly along with microphthalmia, cleft lip and palate, micrognathia, and ear abnormality. Lobulated tongue and neonatal teeth are exceptionally rare associations of MGS, which are seen in the present case.  The absence of bilateral adrenal glands was noted in our case. Hepatic lesions can be considered one of the hidden abnormalities of MGS because they are visible only during postmortem examination. There is arrested development of the intrahepatic biliary system with varying degrees of reactive bile duct proliferation, bile duct dilatation, portal fibrosis, and portal fibrous obliteration all of which were present in the above case. There was the bifid apex of heart with right atrial thrombus. The features such as bifid apex with atrial thrombus in heat, hepatic lesions, multicystic kidneys, adrenal agenesis, and pulmonary hypoplasia could be detected in the present case only after doing a detail autopsy examination along with histopathological evaluation of internal organs. This condition has 100% mortality with death in utero or soon after birth. The fetus seldom survives more than a few days. The implicated cause is dysplastic kidneys that result in oligohydramnios, which ultimately leads to fetal pulmonary hypoplasia and death.  The longest known survivor lived only until 4 months.  Since, there is no treatment, it is preferable to diagnose the condition prenatally and abort the affected fetus.
The authors conclude that the prenatal diagnosis based on ultrasound scan findings may not be adequate for the final and correct syndrome diagnosis. Furthermore, there remains the issue of recurrence of anomalies in future pregnancies. Therefore, the performance of a neonatal autopsy is quite significant in these cases for giving complete information and correct management. We, therefore, strongly recommend that an autopsy should always be performed in almost all fetal deaths.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]