Hirschsprung disease

Hirschsprung disease is the most common cause of intestinal obstruction in neonates and infants. It may occur in isolation (about 70% of cases) or as part of a syndrome (20%–30% of cases). It is therefore important to thoroughly assess the patient for additional features.

Characteristic features of Hirschsprung disease include:

• the delayed passage of meconium in the newborn (beyond the first 48 hours of life);
• abdominal distension;
• bilious vomiting; and
• chronic (usually severe) constipation.

The majority of patients receive a diagnosis early in life. Mucosal biopsy is diagnostic, and histology determines how much of the colon is affected and classifies the disease as being either short or long segment. Short-segment disease (affecting only the distal segment of the large intestine) is most common (about 80% of cases) and occurs more often in boys, with a male-to-female gender bias of 4:1. Long-segment disease (affecting most of the large intestine) occurs in about 20% of cases and affects both sexes equally.

Sporadic, short-segment Hirschsprung disease is believed to have an oligogenic mechanism of inheritance and can be associated with single-gene variants, variants in non-coding regions, copy number variants (CNVs) and chromosomal anomalies. Incomplete penetrance and the presence of genetic modifiers are both recognised.

Around 40%–50% of familial cases and 10%–20% of sporadic cases will be found to have a loss-of-function variant in the RET pathway. Variants have most commonly been described in the RET gene, but also in SOX10, PHOX2B, L1CAM, KIF1BP, EDNRB, EDN3, ZEB2.

A list of specific genetic conditions in which Hirschsprung disease is recognised as an associated feature is presented below.

• Down syndrome (additional copy of trisomy 21): A multisystem condition characterised by intellectual disability, a higher chance of congenital anomalies and other health problems, and recognisable physical features. Around 2%–15% of affected infants are born with Hirschsprung disease.
• Shah-Waardenburg syndrome (causative genetic variants are found in EDN3, EDNRB and SOX10): An auditory-pigmentary syndrome characterised by pigmentary anomalies of the hair (white forelock), skin (steaky hypopigmentation) and eyes (iris heterochromia), congenital sensorineural hearing loss, and Hirschsprung disease.
• Mowat-Wilson syndrome (causative genetic variants are found in ZEB2): A variable condition comprising distinctive facial features (up-turned earlobes, deep-set eyes), intellectual disability (often severe), microcephaly, seizures and congenital anomalies (heart, genitalia).
• Multiple endocrine neoplasia (causative genetic variants are found in MEN2B) and familial medullary thyroid cancer (causative genetic variants are found in RET – particularly within exons 10 and 11).
  • Both conditions have been associated with Hirschsprung disease in some families. Look for features of thyroid cancer, hyperparathyroidism and phaeochromocytoma in the patient history.
• A rare neurological condition characterised by inadequate breathing (apnoea) during sleep. It is typically caused by a polyalanine expansion within the PHOX2B Around 20% of those affected experience Hirschsprung disease, and some also experience neuroblastoma. When congenital central hypoventilation syndrome and Hirschsprung disease occur together, it is termed Haddad syndrome.
• X-linked hydrocepahlus (causative genetic variants are found in L1CAM): An X-linked disorder presenting with hydrocephalus, adducted thumbs, spasticity and seizures in boys. Hirschsprung disease has been associated with this condition in several studies.
• Goldberg-Shprintzen megacolon syndrome (causative genetic variants are found in KIFBP): A disorder associated with microcephaly, distinctive facial features, intellectual disability, neuronal migration defect (pachygyria or polymicrogyria) and Hirschsprung disease.

For information about testing, see Neonate with failure to pass meconium.

The inheritance pattern of syndromic Hirschsprung disease will depend on the condition. Many syndromic conditions arise de novo in the child (examples include those conditions caused by genetic variants in SOX10, PHOX2B, EDNRB, EDN3 and ZEB2), and if parents are found not to carry the gene change, the risk of recurrence will be low (though there remains the possibility of germline mosaicism). The risk of an affected individual passing on the gene change to their offspring would be 50%, though some genes demonstrate incomplete penetrance. Inheritance of causative variants in L1CAM (X-linked hydrocephalus) is X-linked recessive, and in KIFBP (Goldberg-Shprintzen megacolon syndrome) is autosomal recessive.

In non-syndromic Hirschsprung disease where a RET pathogenic variant is identified, inheritance is autosomal dominant with incomplete penetrance (50%–70%).

Where the proband has sporadic Hirschsprung disease, the empiric (pre-genomic test) sibling risk is around 4%. This will be higher where there is long-segment involvement and/or a family history. There is a variable sibling recurrence risk (see table 1).

Table 1: Hirschsprung disease sibling risk based on sex

Definitive management of Hirschsprung disease involves surgical resection of the affected colon. Treatment of constipation with medical therapies is often also required.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• U.S. National Library of Medicine: ClinicalTrials.gov database

References:

• Tilghman JM, Ling AY, Turner TN and others. ‘Molecular genetic anatomy and risk profile of Hirschsprung’s disease’. The New England Journal of Medicine 2019: volume 380, issue 15, pages 1,421–1,432. DOI: 10.1056/NEJMoa1706594

For patients

• NHS Health A to Z: Hirschsprung’s disease