DIAGNOSTICO AMBIENTAL PLANO
4.4. FUNCIONES FISICO-ESTRUCTURALES
Perturbations in any of the factors discussed in section 1.2.1 above could potentially affect the development of the ENS, but only a few have known clinical correlations with HSCR. It is likely that the polygenic nature of HSCR is responsible for the lack of simple genetic correlations.
At the grossest level, the sex distribution of short segment HSCR provides evidence of an underlying genetic cause. In slightly more detail, chromosomal abnormalities are also linked to HSCR. Trisomy 21 (Down syndrome) is by far the most frequent, involving 2-‐10% of HSCR cases(Bodian and Carter, 1963, Spouge and Baird, 1985, Garver et al., 1985). However, apart from one sequence that seems to be specific to a particular kindred, to date a specific genetic locus on chromosome 21 conferring susceptibility to HSCR has not been identified(Puffenberger et al., 1994b). There are other chromosomal abnormalities associated with HSCR; they are summarised in Table 1.3.
Table 1.3 Association of chromosomal abnormalities with HSCR.
Adapted from (Chakravarti and Lyonnet, 2001) and (Amiel and Lyonnet, 2001)
Chromosome Key features Number
of reports
Gene
Trisomy21 Down syndrome, S-‐HSCR, 5 to 10 male:female sex ratio
2 to 10% of HSCR cases 21q22 implicated in 1 study
Del 10q11 Mental retardation, L-‐HSCR 2 cases RET
Del 13q22 Mental retardation, growth retardation, dysmorphic features, S-‐ HSCR
7 cases EDNRB
Del 2q22-‐q23 Postnatal growth retardation and microcephaly, mental retardation, epilepsy, dysmorphic features, HSCR*
3 cases SIP1
Del 17q21 4 cases ?
Dup 17q21-‐q23 Multiple anomalies 4 cases ?
Trisomy 22pter-‐ q11
Cat eye syndrome ?
The association of HSCR with various syndromes also provides insight into the genetic causes of HSCR. These are summarised in Table 1.4 and commented upon in more detail where relevant to specific gene/protein abnormalities.
Table 1.4: Syndromes associated with HSCR.
Adapted from (Chakravarti and Lyonnet, 2001, Amiel and Lyonnet, 2001) and OMIM
Syndrome Associated genetic
anomalies
Features and comments
Neurocristopathy syndromes
Waardenberg-‐syndrome and related syndromes
PAX3 and MITF mutations in WS1, endothelin and SOX10 mutation in WS4s
Pigmentary anomalies (white forelock, iris hypoplasia, patchy hypopigmentation), deafness. Shah-‐Waardenberg syndrome is associated with HSCR (WS4).
Congenital central
hypoventilation syndrome
PHOX2B mutation in most; other mutations in RET, GDNF and EDN3 reported
Haddad syndrome when associated with HSCR. Failure of autonomic control of ventilation during sleep) and other autonomic disturbances also.
Yemenite deaf-‐blind-‐
hypopigmentation
SOX 10 mutations identified in some cases
Hearing loss, eye anomalies (microcornea, coloboma, nystagmus), pigmentary anomalies.
BADS (Black locks-‐albinism-‐
deafness syndrome)
Hearing loss, hypopigmentation of the skin and retina. One patient described with HSCR.
Piebaldism KIT mutations Patchy hypopigmentation of the skin
MEN2A RET mutations Medullary thyroid carcinoma, phaeochromocytoma, parathyroid
adenomas
HSCR always present Goldberg-‐Shprintzen KIAA1279 mutations Cleft palate, hypotonia, learning difficulties, facial dysmorphism
Mowat-‐Wilson syndrome ZFHX1B mutation Clinically very similar to Goldberg-‐Shprintzen. Microcephaly, learning difficulties, epilepsy, facial dysmorphism
HSCR with limb
abnormalities
Various rare syndromes exist with other associated anomalies (cardiac, facial and spinal).
BRESHEK syndrome
X-‐linked Brain anomalies, retardation, ectodermal dysplasia, skeletal malformations, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia
HSCR occasionally present
Bardet-‐Biedl Syndrome 9 genetic subtypes identified.
Pigmentary retinopathy, obesity, hypogonadism, mild mental retardation, postaxial polydactyly. Related to Kauffman-‐McKusick syndrome and shares a similar aetiology in some cases.
Kauffman-‐McKusick Gene on c20p12 encoding a protein similar to the chaperonins
Hydrometrocolpos, postaxial polydactyly, congenital heart defect
Cartilage-‐hair hypoplasia RMRP gene mutations
(codes an
endoribonuclease)
Short limb dwarfism, metaphyseal dysplasia, immunodeficiency
Mesomelic dysplasia,Werner
type
Absence of tibiae and preaxial polysyndactyly of hands and feet.
Smith-‐Lemli-‐Opitz syndrome Sterol delta-‐7-‐reductase gene mutations – related to cholesterol synthesis; may disrupt SHH signalling.
Growth retardation, microcephaly, learning difficulties, hypospadias, 2–3 toes syndactyly, dysmorphic features
Rare associations Fukuyama congenital muscular dystrophy
Muscular dystrophy, polymicrogyria, hydrocephalus, MR, seizures
Clayton-‐Smith syndrome Dysmorphic features, hypoplastic toes and nails, ichthyosis.
Kaplan syndrome Agenesis of corpus callosum, adducted thumbs, ptosis, muscle
In terms of specific genetic abnormalities associated with HSCR, 8 genes have been identified with clinical manifestations of HSCR. These are the RET (RET), glial cell line derived neurotrophic factor (GDNF), neurturin (NTN), endothelin B receptor (EDNRB), endothelin 3 (EDN3), endothelin converting enzyme 1 (ECE1), SOX10, and SIP1 genes.
Mutations in the RET gene are responsible for approximately 50% of familial HSCR cases(Chakravarti and Lyonnet, 2001), and they can produce a variety of phenotypes in the same family (Edery et al., 1994, Romeo et al., 1994). Linkage studies in affected populations have also identified a non-‐coding mutation in intron 1 of the gene to be associated with HSCR (Emison et al., 2005), and could explain several features of the complex inheritance pattern of HSCR. This study concluded that RET mutations in coding and/or non-‐coding sequences are probably a necessary feature of all cases of HSCR. However, the non-‐coding mutations in isolation are not sufficient for HSCR to occur, and need to be coupled with another mutation of some kind (Emison et al., 2005). GDNF mutations have been identified in only a handful of HSCR patients to date, and can be regarded as a rare cause of HSCR (<5%)(Salomon et al., 1996, Angrist et al., 1996, Ivanchuk et al., 1996). Moreover, GDNF mutations may not be sufficient to lead to HSCR since four out of six patients have additional contributory factors, such as RET mutations or trisomy 21.(Salomon et al., 1996, Angrist et al., 1996). Similarly, a NTN mutation has been identified in one family, in conjunction with a RET mutation(Doray et al., 1998).
EDN3 and EDNRB polymorphisms have been described in syndromic and isolated HSCR, although the genetic background is important and penetrance variable(Puffenberger et al., 1994a, Kusafuka and Puri, 1998). Individuals lacking EDN3 mutations but having decreased levels of EDN3 mRNA expression have also been described(Kenny et al., 2000). In non-‐syndromic HSCR, less than 5% of cases appear to be a direct consequence of EDN3/EDNRB mutations(Brooks et al., 2005). More recent research however looking at 196 cases of HSCR has shown that a specific EDN3 haplotype is overexpressed in sporadic cases, leading to the conclusion that EDN3 alleles act as low penetrance susceptibility
modifiers(Sánchez-‐MejÃ-‐as et al.). This may be reflected in the amount of EDN3 mRNA expressed as noted above, and indeed in mice a reduced expression of ECE-‐1 and EDN3 mRNA has been observed in males at a time point critical for ENSC migration(Vohra et al., 2007). This observation may partly explain the male preponderance observed in HSCR. In addition, a heterozygous ECE1 mutation has been identified in a patient with HSCR and craniofacial and cardiac defects(Hofstra et al., 1999).
The WS4 variant of Waardenburg-‐Shah syndrome (HSCR plus partial albinism) has been shown to be related to mutations in SOX10(Pingault et al., 2000) with patients showing defects in NC cells necessary for both melanocyte and ENS development. WS4 can also be caused by homozygous mutations in EDN3 and ENDRB(Southard-‐Smith et al., 1999, Southard-‐Smith et al., 1998, Hofstra et al., 1996). Another syndrome with a direct genetic link between HSCR and NC stem cell development is Haddad syndrome (central hypoventilation with HSCR), where mutations in Phox2b have been reported as the underlying cause(Verloes et al., 1993, Amiel and Lyonnet, 2001).
Overall, although studies with animal models and human genetic studies have improved our understanding of HSCR, it is clear that this is a complex polygenic disease with interacting genetic elements, as discussed in section 1.2.8.7 about SOX10, RET and EDN3. The clinical implications of this are that HSCR can be associated with other congenital anomalies and there is a risk of other family members also being affected with HSCR. Overall, the risk of inheriting HSCR in an affected family has been put at 3% for short segment HSCR and 17% for long segment HSCR, although this is subject to considerable variations (see table 1.5)(Chakravarti and Lyonnet, 2001).
Table 1.5: Percentage of risk of familial recurrence in HSCR