We report on a female infant born at 33/40 weeks gestation by caesarean section for suboptimal CTG trace. Birthweight was 1.8kg (less than 50th centile). Head circumference was 31.7cm (greater than 50th centile). The infant required transfusion at birth, developed abdominal distension on day two and underwent a laparotomy, revealing a dilated colon, indicative of Hirschsprung disease (HD). A blood sample was sent to this department for chromosome analysis. The infant was bruised at birth and was noted to be thrombocytopaenic with decreased megakaryocytes and a platelet count of 7, with no evidence of any immunological cause for this. A bone marrow sample was sent for chromosome analysis. She has since required repeat transfusions to treat her continued thrombocytopaenia. The infant had several dysmorphic features, hypertelorism with down slanting palpebral fissures, upturned nose, low set posteriorly rotated ears, a single palmar crease, oedema of the neck, hands and feet at birth, an atrial septal defect, pulmonary stenosis and asymmetry of the frontal horns. A repeat bowel biopsy at full term (corrected for gestation) no longer showed evidence of HD.

This is a multigenic neurocristopathy or neural crest disorder described by Hirschsprung in 1888 and also known as Aganglionic Megacolon. It is a congenital disorder with an incident of 1 in 5000 livebirths. The disorder is characterised by absence of enteric ganglia, due to abnormal neuronal migration, along a variable length of the intestines (short or long) and is probably multifactorial in its causation with a male predominance of 3:1 to 5:1. The dominant gene of HD was mapped to 10q11.2 by Lyonet et al in 1993, a region to which the RET oncogene was also mapped. In 1994 Edery et al deduced that both the short segment (accounting for about 80%of cases) and long segment (accounting for about 20%of cases) forms of HD are the same disorder differing only in the length of intestine involved and the missense or nonsense mutations present in the RET oncogene resulting in a loss of function.

The RET Proto-Oncogene is one of the receptor tyrosine kinases which are cell-surface molecules that transduce signals for all growth and differentiation. Grieco et al 1990, showed that RET can undergo oncogenic activation in vivo and in vitro by Cytogenetic rearrangement. The RET gene has been assigned to 10q11.2 and the 250Kb interval that it has been mapped to, also houses the autosomal dominant gene that causes HD. Abnormalities of expression and function of RET protein have been found in the intestines of HD patients. Mutations at the RET locus are scattered along the length of the gene and account for at least one third of sporadic HD cases. A significant fraction of papillary thyroid carcinomas, pheochromocytomas and multiple endocrine neoplasias, have been shown to have RET oncogene mutations. In fact, RET gene mutations are said to be 100% predictive for the ultimate development of these tumours.

Karyotype

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Results

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At birth this female infant presented with D2 abdominal distension, which resulted in malrotation of the Jejunum. A laparotomy revealed a dilated Colon and possible Hirschprung.s disease (HD) from a biopsy taken at that time. Cytogenetic analysis of the Blood revealed a microdeletion of chromosome 10q11.22. The dominant gene of HD and the RET oncogene have both been mapped to this region. Although chromosome analysis of the bone marrow did not reveal a Cytogenetically abnormal clone, nevertheless, this infant presented with and still remains persistently thrombocytopaenic, with decreased Megakaryocytes and a Platelet count of 7, which have not been attributed to a non-oncogenic cause. All this evidence would strongly indicate a clinical diagnosis of HD. A repeat bowel biopsy was taken when this infant would have been full term when corrected for gestation. This showed no evidence of HD. Lobo et al 1992, reviewed 9 cases of patients with deletions of 10q including the proximal region. As in this case, low set malformed ears, hypertelorism and heart defects were consistent findings. Therefore, the dysmorphisms seen in this infant, could be attributed to the deletion of chromosomal material in the proximal region of chromosome 10q. The reviewed cases though did not have abnormal abdominal features.

This case raises several questions:

• Could this patient still have Hirschsprungs disease, despite the correction of the abdominal distension and dilated colon, or is this a variant form ?
  
  
• Has the Cytogenetically visible microdeletion of 10q11.2 caused an as yet undocumented disruption of the RET oncogene, with a juxtaposition effect on the dominant HD gene ?
  
  
• Is this a completely different disorder altogether ?

Hirschsprung, H. Jahrb. Kinderheilk, 27 , 1-7, 1888.

Grieco et al. Cell, 60, 557-563, 1990.

Lyonet et al. Nature Genet, 4, 346-350, 1993.

Lobo et al. Am J Med Gen, 43, 701-703, 1992.

Edery et al. Nature, 367, 378-380, 1994.