briefreports

A new syndrome: Heart defects, laryngeal anomahes, preaxial , and colonic agangbonosis m sibs

X~oshengHuarzg, MD, PhD', E11e11R. Elias, MD-', John B. Millliken, Mp,Daniel J. Kirse, M@, and Lewis B. Holmes, MD

We present two siblings, one male and one female, who have cation of the great toes, and postaxial polydactyly of the right heart defects, duplicat~onof toes, airway anomalies, and agan- foot. Radiographs of the feet showed bilateral duplication of the glionosis. The brother also has a bilateral complete cleft lip and hallux and the right fourth toe. (Fig. 1B). An echocardiogram showed an atrial septal defect, coarcta- palate. His airway anomalies lnclude short epiglottis and tion of the aorta, a large patent ductus arteriosus, cleft mitral aryepiglottic folds, which are different from his sister who has valve, and a mildly hypoplastic aortic arch with a gradient of a bifid epiglottis with a central epiglottic mass. Both siblings have 15-20 cm H,O between the upper and lower extremities (nor- had some developmental delay. This constellation of anomalies mally, the pressures are almost equal). Cardiac catheterization appears to be unique and may represent a new autosomal reces- confirmed the presence of these anomalies and also demon- sive disorder. Genetics in Medicine, 1999;1(3):104-108 strated anomalous venous return. JC developed a distended abdomen at one day of age due to spontaneous perforation of the large bowel, and underwent a INTRODUCTION colostomy and appendectomy. Histologic studies showed agan- We describe two siblings, one male and one female, with mul- glionosis of the entire colon and the appendix; cholinesterase stain- tiple congenital anomalies, including Hirschsprung disease, ing was consistent with the diagnosis of Hirschsprung disease. heart defects, preaxial polydactyly and laryngeal anomalies. JC developed respiratory distress at two months of age. Direct This phenotype is distinctive from other multiple congenital laryngoscopy showed a short epiglottis and short aryepiglottic anomaly syndromes previously reported to be associated with folds with redundant mucosa in the arytenoids (Fig. 1C). The colonic aganglionosis, and appears to be a "new" autosomal true vocal cords, subglottics, and distal tracheobronchial tree were recessive disorder. normal. His respiratory distress resolved after epiglottoplasty. JC has shown mild developmental delay, particularly in expres- CLINICAL REPORTS sive language usage. At age of 24 months, he can walk, run, feed Case I: JC was born by spontaneous vaginal delivery to a 33- himself with utensils, knows multiple body parts, and uses mul- year-old G4 P4 mother at 38 weeks of gestational age. There had tiple signs to communicate. He only uses 2 words verbally. He been no known exposure to human teratogens during the preg- has been receiving intensive early intervention service where nancy. The birth weight was 3.7 kg (75-95th percentile); length formal evaluation at the age of 20 months revealed most skills was 49 cm (25th percentile); and head circumference was 35.5 in the 10-month range. cm (50-75th percentile).' The anomalies noted at birth included The karyotype in peripheral blood and skin fibroblast cells bilateral complete cleft lip and palate, telecanthus with an inner showed 46, XY; there was no deletion of chromosome 22q canthal distance of 3.25 cm (95th percentile) (Fig. lA), dupli- detected in a FISH analysis. The head ultrasonogram identified no abnormalities. Case 2: AC (Fig. 2A), the older sister of JC, was born at 38 Froriz the 'Division of Gelzetics aitd Metabolisn~,Chrldrc~zb Hospitol. [ztld Depart- weeks gestational age after an uncomplicated pregnancy. Her tlzcnt of Gcnetrcs, Ho~vclrdHrrghes Medical Instrtutc, Harvrrrd Mcdical School. Bostoiz, MA; 1he2Coordiizated Care Seriticr, Cklldrerr's Hospital. Boston. MA; t/zc birth weight was 4.4 kg (greater than 97th percentile, large for 'Division ofPlnstrcSurgery, Chilrfre~r'sHosp ital, Boston, MA; the 'Departt~rcrrtof the gestation age).' She also had duplication of the great toes Otolarytrgolog}~,Utiiversity of Kaizsos Mrtfic~rlCenter, hbirsus Cit)! KS; aird the (Fig. 2B). An echocardiogram and later cardiac catheterization iGcnetics and Ter(rtology Unit, Pcdiritric Serviir, M(lssczc/rrrsettsGcrzcnrl Hospital, demonstrated an atrial septal defect, cleft mitral valve, and anom- Harvard Medical School, Bostotl, MA. alous venous return from the left superior vena cava to the coro- Address correspotideirce to: Lcivis B. Holnres, MD, Getretics atld Terl~tologyUliit, nary sinus. Warreiz 801, Peditrtric Service. Massaclrusetts Grtlernl Hospital, Harvarii Mcdicnl AC had developmental delay, most obvious in language devel- School, Bostotr, MA 021 14. opment. At 18 months of age, she used no words. Her receptive 01 999 Getzetrcs in A4ctficitze. All rights res~rl~ed. and expressive language was typical for a child of eight to nine New syndrome in sibs

Fig. 1(A) Case 1 at age of 2 112 months, showing bilateral cleft lips and cleft palates. (B)A foot X-ray shows bilateral duplication of the halluces and duplication of the right fourth toe. (C) Direct laryngoscopy shows short epiglottis and short aryepiglottic fold. months with skills scattered to the 12 month level. She also has year of age and did not use her first word until 29 month of age. had fine motor delay, possibly associated with decreased mus- Evaluation at 2 112 years of age showed that her receptive and cle tone in the hands. After intensive early intervention services, expressive languages were at a 9- to 10-month level with skills her motor development has improved significantly,but she con- scattered to the 12-month level on the Verbal Comprehension tinues to show overall delay with more significant weakness in Scale of the Reynell Development Scale. On physical examina- language and speech production. tion, she had and midfacial hypoplasia; her weight AC was evaluated for chronic constipation after her younger was 15.8 kg (50-75th percentile); her height was 98 cm (50th brother, JC, had been diagnosed with Hirschsprung disease. His- percentile); her head circumference was 52 cm (98th percentile); tologic studies from a rectal biopsy also showed aganglionosis but her inner canthal distance was 2 cm (less than 2nd per- of the sigmoid colon. centile) interpupillary distance was 4 cm (less than 2nd per- AC also had history of stridor, particularly when she was sleep- centile), and outer canthal distance was 8 cm (75-97th ing. Direct laryngoscopy showed severe epiglottic abnormality percentile).' Echocardiogram and a brain MRI identified no including bifid epiglottis with a central epiglottic mass (Fig. 2C), structural abnormalities. She has no other known anomalies. but true vocal cords, subglottics, main stem and segmental The ancestors of this family are from Ireland, England, Ger- bronchi, and trachea were normal. many, and Mexico. There is no family history of chronic con- stipation. A maternal cousin had an atrial septal defect and FAMILY HISTORY ventricular septal defect. A paternal cousin had a ventricular The parents are not related and are in a good health. In addi- septal defect. The family history was otherwise unremarkable. tion to JC and AC, they have a 4-year-old son and 3-year-old No other relatives are known to have dysmorphic features or daughter. The 4-year-old son is healthy and has had normal congenital anomalies. development. However, the 3-year-old daughter also has a bifid uvula and developmental delay. The developmental pattern in DISCUSSION the 3 younger siblings is similar, with language delay being most We report two siblings with a similar pattern of multiple mal- prominent. The 3-year-old daughter stood at 13 months, walked formations. Since JC and AC are male and female offspring of at 15 months, and ran at 18 months. She did not babble until 1 healthy patents, autosomal recessive inheritance seems most

March/April I= . VOl. 1 ' No. 3 105 Huang et a/.

Fig. 2 (A)Case ? at age of 2 112 years. (5)A foot X-ray shows bilateral duplication of the great toes, but the fourth right toe is normal. (C) Direct laryngoscopy shows a bifid epiglottis and an unusual central mass of the epiglottis between separated epiglottis.

Table 1 Associations of Hirschsprung disease with other congenital anomalies

JC AC Nowaczvk et al. Lawrence et al. McPheson et al. Santos et al. Pier~ontet al. les~erset al. --- Hirschsprung + + malrotation +

Cleft Palate + - - - + - + -

Cleft Lip + - - - + - + -

Cardiac defects ASD, VSI). ASD, VSD, AVR ASD VSD hypoplastic left - - ASD, PDA cleft MV, heart, DORV, PS aneurysm, hypoplast~c PDA aorta. AVR

Limb anomalies duplication of dupl~cat~onof postaxial postaxial bifid thumb preaxial - - bilateral great b~lateral polydactyly polydactyly polydactyly toes and right great toea of hands of hands 4th toe

Tracheal anomalies short epiglottis, bifid epiglottis - - - - - Laryngeal short and an unusual pharyngeal aryepiglottic epiglottic mass hypoplasia fold

- Hearing loss - - + -

Renal anomalies -

CNS anomalies - - + ASD, atrial septa1 defect; VSD, ventricular beptal defect; MV, mitral valve; A\/R, anomalous venous return; MR, mental retardation; DD, developmental delay; CNS, central nervous system; DORV, double outlet of the right ventricle; PS, pulmonic stenosis; PDA, patent ductus arteriosus.

106 Genetics INltdRdicine New syndrome in sibs likely. The clinical findings in these two patients are distinctive hearing loss, and partial duplication of hallux. Steichen-Gersdorf from those reported to date in association with Hirschsprung et al.22reported a case with type I1 Oral-Facial-Digital syndrome. disease. A comparison of features in our patients and those The features in their case included hypoplastic epiglottis and lar- reported with similar phenotypes is shown in Table 1.3-9 ynx, a stenosis of the trachea, pre-and postaxial polydactyly, growth Hirschsprung disease is genetically heterogeneous. At least three retardation, and hearing loss. The absence of Hirschsprung dis- genes for Hirschsprung disease have been identified: the RET ease and heart defects is distinct from our patients. proto-oncogene,the endothelin receptor-B gene, and the endothe- The developmental pattern in the 3 younger siblings is sim- lin-3 gene.l&l2 The RET protein is a tyrosine kinase receptor. In ilar, with language delay being most prominent. Although the Hirschsprung disease, the RET mutations lead to loss of function. older sibling has no cardiac, limb, or intestinal anomalies, she Ten to forty percent of patients with familial Hirschsprung dis- may represent a very mild manifestations of the same disorder. ease were found in one study to have an RET mutation.13 Another explanation might be that the developmental delay is In analysis of a large kindred, a G-to-T transversion muta- unrelated and represents a separate trait in this family. Molec- tion in exon 4 of the endothelin-B receptor is associated with ular studies in the future may solve this puzzle. Hirschsprung disease.I4 Twenty-one percent of the heterozy- In conclusion, we describe two siblings, one male and one gotes and 74% of homozygotes with the mutation in the endothe- female, with cardiac defects, laryngeal anomalies, preaxial poly- lin-B receptor had aganglionosis of the intestine. A targeted , and aganglionosis. The parents are normal and unre- interruption of the mouse endothelin-3,a ligand of the endothe- lated. This condition may be a new autosomal recessive syndrome. lin-B receptor, caused megacolon.15This and other findings sug- Molecular studies for mutation of RET and endothelin recep- gest that interaction of endothelin-3 and its receptors is crucial tor B are in progress. for neural crest-derived cell lineages.I6 Mice, in which the endothelin-B receptor gene had been deleted, showed a pheno- type similar to that of our patients, i.e., intestinal agangliono- We are grateful to this magnificent family for their coopera- sis, cardiac defects, and cleft liplcleft palate. However, these tion. T.H. is supported by NIHINIGMS grant T32GM07748. genetically engineered mice do not have limb anomalies (Yanag- These studies were also supported in part by the Peabody Foun- isawa, personal comm~nication).~~In addition, mice with the dation, Boston, MA. We are also in debt to Steve Depaloma, PhD deletion have a spotted white color. for his critical reading for this manuscript. Chakravartil7 estimated that the RET mutation accounts for 50% of familial Hirschsprung cases whereas the endothelin-B receptor mutation accounts for about 5%. In his studies, the 1. Jones KL. Smith's recognizable patterns of human malformation, 5th edi- majority of patients with the endothelin-B receptor mutation tion. Philadelphia: WB Saunders Company, 1996. 2. Tan ST, Mulliken JB. Phertelorism. Nosologic analysis of 90 patients. Plast have short segmental aganglionosis, compared with only 25% Reconstr Surg 1997;99:317-327. of RET-associated patients with short segment. In our patients, 3. Passarge E. Whither polygenic inheritance: Mapping Hirschsprung disease. one has short segment and one has entire colon aganglionosis, Nut Genet 1993;4:325-326. supporting the previous finding that the short segment and long 4. Nowaczyk MJM, James AG, Superina R, Siegel-BartletJ. Hirschsprung dis- segment Hirschsprung disease can be caused by the same under- ease, postaxial polydactyly, and atrial septa1 defect. Am J Med Genet lying genetic defect.18 However, these two anatomic variants of 1997;68:74-75. 5. Laurence KM, Prosser R, Rocker I, Pearson JF, Richards C.: Hirschsprung Hirschsprung disease still have different clinical significance disease associated with congenital heart malformation, broad big toe, and because their management is different. ulnar polydactyly in sibs: A case for fetoscopy. J Med Genet 1975;12:334-338. The case presented herein includes a constellation of mal- 6. McPherson E, Clemens M. Cleft lip and cleft palate, characteristic facial formations not previously described in the literature; however, appearance, malrotation of the intestine, and lethal congenital heart dis- Am the association of the bifid epiglottis with polydactyly has been ease in two sibs. I Med Genet 1996;62:58-60. 7. Santos H, Mateus J, Leal MJ. Hirschsprung disease associated polydactyly, rep~rted.'~.~~Although during embryonic development, early unilateral renal agenesis, hypertelorism, and congenital deafness: A new laryngeal development and limb formations occur at the same autosomal recessive syndrome. J Med Genet 1988;25:204-208. time, the mechanism of this association is unknown. In Pallis- 8. Pierpont JW, Jacques D, Seaver HL, Erikson RP. A family with unusual ter-Hall syndrome, malformation can be very extensive. In addi- type I (WSI), cleft palate, and Hirschsprung dis- tion to polydactyly and bifid epiglottis, Hall et al.21described ease is not linked to PAX3. Clin Genet 1995;47:139-143. 9. Iespers A, Buntinx I, Melis K,Vaerenberg M, Janssens G. Two siblings with six patients with this syndrome who also have hypothalamic midline field defects and Hirschsprung disease: Variable expression of hamartoblastoma, imperforate anus, abnormal lung lobulation, Toriello-Carey or new syndrome? Am I Med Genet 1993;47:299-302. renal anomalies, nail hypoplasia, multiple buccal frenula, con- 10. Eng C. The RET proto-oncogene in multiple endocrine neoplasia type 2 genital heart disease, and hypothyroidism. and Hirschsprung's disease. N EnglJ Med 1996;335:943-951. Recently, McClay et al.19 reported a familial bifid epiglottis 11. Attie T, Amiel J, Jan D, Edery P, Pelet A, Salomon R, Munnich A, Lyonnet S, Nihoul-Fekete C. Genetics of Huschsprung disease. Ann Chir 1996;50:538-541. associated with polydactyly in three generations. One member 12. Auricchio A, Casari G, Staiano A, Ballabio A. Endothelin-B receptor muta- of this family also had a congenital heart disease. Bifid epiglot- tion in patients from a non-inbred population. Hum Mol Genet tis and polydactyly are variable. There is no consanguinity in this 1996;5:351-354. family, indicating an autosomal dominant inherited pattern. 13. Pasini B, Borrello MG, Greco A, Bongarzone I, Luo Y, Mondellini P, Among the differential diagnosis is Oro-Facial-Digital syn- Alberti L, Miranda C, Arighi E, Bocciardi R, et al. Loss of function effect of RET mutation causing Hirschsprung disease, Nat Genet 1995;10:3540. drome, type 11, which is characterized by cleft tongue, conductive 14. Puffenberger EG, Kompanek AJ, Kauffman ER, Mascari M, Ladda R.

March/Aprll 1N9 Vol, 1. No. 3 107 A. Huang et a/.

Ch~krav~rtiA. Pedigree ~n.llys~sof a large Mcnnonitc Itindred segregating disease: Variable clinical expression of the RET gene. I Med Genet I-lirschsprung dlseasc (.lhstr~ctl.A171 I A!cd (;L>IIL'I(suppl.1 1992;A4. 1994;3 1:602-606. 15. Hosoda K. H.ln~~i~erR. Rich,i~-dson IA. Il<~yn,lshA(;, Cheung IC, Ciaid A, 19. McClay JE, Wiatrak B, Proud VK. Bifid epiglottis and polydactyly: a new \;dnc~gia.lw3h4.TL1rgeted ,~nd n.~t~~~-~ll (I'ich,~ld-lcth,ll) mutationsoTcndothe- genetic syndrome. Otolarytzgol Head Neck Surg 1987;116:129-133. lin-H receptor gene produce mcplcolon ~ssociatcdwith hpottcd coat color 20. Goldenberg ID, Holinger LD, Bressler FJ, Hutchinson LR. Bifid epiglottis. in mice. (It2//l991;79: 1267-1276. Attn Otol Rllinol Laryngol 1996;105: 155-1 57. Ih. B~yn.lsI1AG, I-1osod.1 ti, Gi,~iciA, Richardson IA, Emotcl N, Hammer RE, 2 1. Hall IG, Pallister PD, Clarren SK, Beckwith JB,Wiglesworth FW, Fraser FC, I:lngis~w~~M. Inter,lction of endothelin-3 with endothclin-H receptor is Cho S, Benke PJ, Reed SD. Congenital hypothalamic hamartablastoma, esscnti'~lfor development of epiderm.11 rncl,lnoiytcs dnd enteric neuron. hypopituitarism, imperforate anus and postaxial polydactyly-a new (Ic// l994;79:1277-12S5, syndrome? Part I: clinical, causal, and pathogenetic considerations. Am ] 17. (Ih.lrkr.lv,lti A. Endothelin reccptor-mediated signaling in t1irschsp1-ung Mcd Gertet 1980;7:47-74. dise,~hc.HI~III Mol Gcrict 1996;5:303-307. 12. Steichen-Gersdorf E, Gassner I, Covi 8, Fischer H. Oral-facial-digital syndrome IS. Edery P, Pclet A, hlulligan Lhl, Ahel L. Attie .C 1)ow E, Ilonneau 11, Ddvid A, 11. Transitional type between Mohr and Majewski syndrome: Report of a new Fl~ntotf\\', J.ln Ll, et JI. Long segment ~ndshort segment familial Hirschsprung case with congenital stenosis of the trachea. Clin Dysrnorphol1994;3:245-250.

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