A Hirschsprung Disease Locus at 22Q11? J Med Genet: First Published As 10.1136/Jmg.36.3.221 on 1 March 1999
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J Med Genet 1999;36:221–224 221 A Hirschsprung disease locus at 22q11? J Med Genet: first published as 10.1136/jmg.36.3.221 on 1 March 1999. Downloaded from W S Kerstjens-Frederikse, R M W Hofstra, A J van Essen, J H C Meijers, CHCMBuys Abstract 10q11 and 13q33 have been reported in HSCR We report a boy with truncus arteriosus, cases, consistent with the finding of mutations dysmorphic features, developmental in the RET910and EDNRB11 genes, which map delay, passing hypotonia, short segment within these deletions. In addition, mutations Hirschsprung disease (HSCR), and par- of two other genes have been found associated oxysmal hypoventilation. FISH analysis with the development of HSCR in humans: showed an interstitial deletion in chromo- GDNF, coding for the ligand of the RET some band 22q11.2 coinciding with the protein,12 13 and EDN3, the gene coding for deletions found in DiGeorge syndrome endothelin 3, one of the ligands of the and velocardiofacial syndrome. Mutation endothelin B receptor encoded by EDNRB.14 15 scanning of RET, GDNF, EDNRB, and It is estimated that mutations in these four EDN3, genes associated with Hirsch- genes are responsible for approximately 20% of sprung disease, showed no aberrations. all HSCR patients (R M W Hofstra, unpub- Since we know of two more patients with lished data). This implies that there must be velocardiofacial syndrome and HSCR, we other genes with mutations predisposing to hypothesise that a gene responsible for HSCR. proper development of the enteric nerv- We report a boy with a deletion of 22q11.2, ous system may be included in the 22q11.2 whose clinical features fit into the CATCH 22 region. spectrum associated with 22q11.2 deletions, (J Med Genet 1999;36:221–224) but who also has short segment Hirschsprung disease and paroxysmal hypoventilation. We Keywords: CATCH 22; Hirschsprung disease; hypo- suggest that the DiGeorge chromosomal re- ventilation gion at 22q11.2 may contain a gene that is required for proper development of the enteric nervous system. Deletions of the chromosomal region 22q11.2 are associated with a wide spectrum of congenital malformations, aVecting the face, Case report palate, parathyroid glands, thymus, heart, The patient is the second child of a non- limbs, and kidneys. Several distinct clinical consanguineous, healthy 24 year old mother http://jmg.bmj.com/ syndromes have been recognised to be associ- and 27 year old father, both white. At the age of ated with 22q11.2 deletions, including Di- 3 days a rectal suction biopsy was performed in George syndrome (DGS),1 velocardiofacial or the referring hospital, because of constipation Shprintzen syndrome (VCFS),2 conotruncal and bile vomiting, but no abnormalities were anomaly face syndrome (CTAFS),3 Cayler car- found. One day later he was referred to the diofacial syndrome,4 and Opitz G/BBB University Hospital. He weighed 2995 g (25th- syndrome.5 Deletions of the 22q11.2 region 50th centile), measured 49 cm (25th-50th cen- have also been reported in familial and tile), and had a head circumference of 34.5 cm on September 27, 2021 by guest. Protected copyright. sporadic heart disease, isolated hypo- (10th centile). A cardiac defect was assumed parathyroidism,6 psychiatric diseases,7 and because of tachypnoea and a systolic murmur. palatoschisis.8 It is unclear at present whether A truncus arteriosus type II was diagnosed by the CATCH 22 phenotype, an acronym for ultrasound. Because of this he was screened for Department of Cardiac defect, Abnormal facies, Thymic deletion of 22q11.2 (see below). Serum Medical Genetics, hypoplasia, Cleft palate, and Hypoparathy- calcium was normal and lymphocyte subpopu- University of Groningen, Antonius roidism, is the result of a single gene defect or lations had a normal distribution. An antigen Deusinglaan 4, 9713 represents a contiguous gene syndrome. It is stimulation test gave normal results. AW Groningen, The even possible that variations in the CATCH 22 Re-evaluation of the rectal biopsy showed an Netherlands phenotype are the result of epigenetic factors, increase of cholinergic fibres. Staining did not W S Kerstjens-Frederikse diVerences in genetic background, polymor- allow the presence or absence of ganglionic R M W Hofstra phisms in the opposing allele, or position cells to be judged. A repeated rectal suction A J van Essen CHCMBuys eVects influencing gene expression over long biopsy at the age of 7 months, however, showed distances. absence of ganglionic cells and an increase of Department of Cell Hirschsprung disease (HSCR) or agangli- cholinergic fibres, indicating HSCR. The Biology, Erasmus onic megacolon is a congenital disorder patient underwent a partial sigmoid resection University, Rotterdam, characterised by the absence of intrinsic (a short segment HSCR was found) and a The Netherlands ganglion cells in both the myenteric and the colostomy was performed. J H C Meijers submucosal plexuses of the digestive tract. This The parents were referred to the Depart- Correspondence to: aganglionosis results in motility disorders of ment of Medical Genetics for genetic counsel- Dr Hofstra. the colon leading to severe constipation. The ling when the patient was 1 year old. His length prevalence of HSCR is 1 in 5000 live births. was 70 cm (<3rd centile), weight 7.52 kg (10th Received 4 June 1997 Revised version accepted for The chance of males being aVected is four centile in relation to length), head circumfer- publication 17 July 1998 times higher than of females. Microdeletions of ence 47 cm (50th centile), inner canthal 222 Kerstjens-Frederikse, Hofstra, van Essen, et al distance 3.0 cm (97th centile), and outer can- D22S239, Sc11.1a, TUPLE, M51, M56, thal distance 7.0 cm (25th-50th centile). The Sc4.1, Sc11.1B, COS39, and D22S111-S112. J Med Genet: first published as 10.1136/jmg.36.3.221 on 1 March 1999. Downloaded from skull was brachycephalic and the tip of the nose All but D22S239 and D22S111-S112 were was broad. The mouth was small with a tented found to be heterozygously deleted in the upper lip. The palate was high arched, but patient.The interstitial deletion spanned from without a cleft. The ears showed overfolding of sc11.1A to ZNF74 (COS39), coinciding with the helices but were otherwise normal (fig 1). the most common type of 22q11.2 deletion. Neurological evaluation showed marked hypo- In view of the presence of HSCR, we decided tonia, especially of the legs. An MRI scan of the to screen for mutations in the genes that have brain showed no abnormalities. been implicated in the aetiology of HSCR so At the age of 2 years, he was admitted to far. High molecular weight DNA was prepared hospital because of recurrent periods of one to according to standard methods. DGGE analy- three minutes of hypoventilation and cyanosis. sis of all exons of RET, GDNF, EDNRB, and His pulse was 150/minute and oxygen satura- EDN3 was performed. Mutation analysis of tion was 50% on the pulse oximeter during RET,16 EDNRB,14 EDN3,14 and GDNF (Hof- these episodes. He showed mild psychomotor stra et al, in preparation) was performed as pre- delay. The hypotonia of his legs had decreased. viously described. Apart from already known Re-evaluation of the boy at the age of 4 years neutral variants,14 16 no mutations were de- showed that his phenotype had evolved towards tected in these four genes. velocardiofacial syndrome with relatively small eye fissures, a broad nasal tip, open mouth with Discussion a tented upper lip, small, round ears with a In this report we describe a patient with broad helix, hypernasal speech, regurgitation of truncus arteriosus, dysmorphic features, and food and liquids through the nose, long taper- hypotonia in combination with HSCR and ing fingers, and growth retardation. His paroxysmal hypoventilation and an interstitial psychomotor development appeared to be two deletion of chromosome 22q11.2. The number years behind and he showed some autistic of symptoms found in patients with the behaviour. Depakine treatment was started for CATCH 22 spectrum is still increasing and, as a seizure-like disorder but no epileptic manifes- illustrated by our patient, HSCR might be tations were seen on EEG. added to the list of features. Whether these represent true phenotypic associations or LABORATORY INVESTIGATIONS merely reflect random events remains to be The patient appeared to have a normal 46,XY elucidated. The combination of a 22q11.2 karyotype. Initial FISH analysis with routine deletion, a CATCH 22 phenotype, HSCR, and probes for 22q11.2 deletions (M51 and sc4.1) paroxysmal hypoventilation has not been re- showed a deletion. Additional FISH probes ported previously. In a large European collabo- were used to estimate the position of the dele- rative study the combination of a 22q11.2 tion boundaries. FISH analysis was performed deletion and HSCR has been found in two http://jmg.bmj.com/ on metaphase spreads using the following patients, one of whom was our patient.17 We probes (in order from proximal to distal): know of one more patient with HSCR who is clinically diagnosed as a VCF patient but whose parents refuse testing for microdeletion 22q11.2 (N Elzenga, Department of Paediatric Cardiology, Groningen, personal communica- tion). HSCR is not only a heterogeneous, but pos- on September 27, 2021 by guest. Protected copyright. sibly also a polygenic disease,11–13 18 sometimes occurring in association with a wide range of additional anomalies. Interpretation of the par- oxysmal hypoventilation as an atypical form of hypoventilation might be in accordance with a number of reports on the combined occurrence of hypoventilation problems (congenital cen- tral hypoventilation syndrome (CCSH) or Ondine’s curse) with HSCR, a combination referred to as Haddad syndrome.19 20 In the four genes known to be involved in HSCR, we could not detect any mutations in our patient (RET, GDNF, EDNRB, and EDN3).