Severe Congenital Anomalies RequiringTransplantation in Children With Kabuki Syndrome

Amanda Ewart-Toland,1 Gregory M. Enns,1 Victoria A. Cox,1 G. Chandra Mohan,3 Philip Rosenthal,2and Mahin Golabi1*1Division of Medical Genetics, University of California, San Francisco, California2Pediatric Liver Transplant Program, Department of Pediatrics and Surgery, University of California,San Francisco, California

3Pediatric Nephrology, Department of Pediatrics, King Drew Medical Center, Los Angeles, California

Kabuki syndrome (KS) is a rare multiplemalformation disorder characterized by de-velopmental delay, distinct facial anoma-lies, congenital heart defects, limb and skel-etal anomalies, and short stature. Renalanomalies have been reported in a few casesof KS, but to our knowledge, hepatic anoma-lies have not. Here, we document two casesof KS requiring liver or kidney transplanta-tion: one with severe hepatic and renalanomalies and one with severe renal anoma-lies. Both cases had the characteristic facialappearance of children with KS, postnatalgrowth deficiency, and developmental de-lay. At birth, case 1 presented with hypogly-cemia, ileal perforation, right hydroureter,and hydronephrosis. The patient subse-quently developed hyperbilirubinemia, he-patic abscess, and cholangitis. At age 8months, he underwent a liver transplant.Hepatic pathology diagnosed neonatal scle-rosing cholangitis. Case 2 presented with re-nal failure at age 6 years. Renal ultrasoundstudy showed markedly dysplastic kidneysrequiring transplantation. In addition tocharacteristic findings of KS, she had coro-nal synostosis and was shown to have im-mune deficiency and an autoimmune disor-der manifesting as Hashimoto thyroiditisand vitiligo. We conclude: 1) severe hepaticand renal anomalies leading to organ fail-ure can occur in KS; 2) patients with neona-tal sclerosing cholangitis should be exam-ined closely for features of KS; 3) coronalsynostosis may occur in KS; and 4) immunedeficiency and autoimmune disorder can be

associated with KS. Am. J. Med. Genet. 80:362–367, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: Kabuki syndrome; neonatalsclerosing cholangitis; kid-ney anomalies; coronal syn-ostosis; immune deficiency;autoimmune disease; Hashi-moto thyroiditis; vitiligo; hy-poglycemia

INTRODUCTION

Kabuki syndrome (KS) is a rare multiple congenitalanomaly disorder characterized by a unique combina-tion of craniofacial anomalies, congenital heart defects,skeletal anomalies, persistent fetal fingertip pads, der-matoglyphic abnormalities, mild-to-moderate mentalretardation, and short stature [Niikawa et al., 1981;Kuroki et al., 1981]. Some infants have neonatal hypo-glycemia [Niikawa et al., 1988]. The diagnosis of KS isoften made based on laterally sparse arched eyebrows,long palpebral fissures, eversion of the lower eyelid, adepressed nasal tip, down-turned corners of the mouth,and prominent ears with preauricular pits. In addition,congenital heart defects, especially coarctation of theaorta, can be seen [Schrander-Stumpel et al., 1994].

Hydronephrosis has been reported in a few cases ofKS [Niikawa et al., 1988; Philip et al., 1992], but renaldysplasia has only been reported once in the past andwas not severe enough to require surgery [Ilyina et al.,1995]. To our knowledge no biliary or hepatic anoma-lies were reported previously. Here, we document twocases of KS: one with severe hepatic anomalies requir-ing liver transplantation and additional renal anoma-lies and one with severe renal anomalies requiring re-nal transplantation. In addition, the patient describedhere with severe renal disease also had bilateral coro-nal synostosis, an anomaly not previously recognized inKS, and immune deficiency and autoimmune disease,reported previously only once in a KS patient [Hostof-fer et al., 1996].

Contract grant sponsor: The National Institutes of Health;Contract grant number: GM07085.

*Correspondence to: Mahin Golabi, Division of Medical Genet-ics, Box 0706, 3rd and Parnassus, University of California, SanFrancisco, CA 94143.

Received 24 March 1998; Accepted 12 August 1998

American Journal of Medical Genetics 80:362–367 (1998)

© 1998 Wiley-Liss, Inc.

CLINICAL REPORTS

The anomalies common to both patients are summa-rized in Table I, and their facial appearances are pre-sented in Figures 1 and 2. Findings that are rare or notpreviously reported in KS are summarized in Table II.

Case 1

Case 1 was born at 35 weeks of gestation to a 28-year-old G3 P3 woman. He was the product of a non-consangunious mating. Prenatal ultrasonographyshowed right hydronephrosis, echogenic bowel, andpolyhydramnios. Amniocentesis showed a normalkaryotype, 46,XY. At birth, he was hydropic with aweight of 3110 g (90th centile) and head circumference(OFC) of 32 cm (50th centile). He had an ileal perfora-tion requiring ileostomy. Ultrasound study showedright hydronephrosis. At age 7 weeks, an ileal reanas-tomosis and repair of right hydronephrosis and hydro-ureter were performed. After surgery, the patient de-veloped disseminated coagulopathy and thrombocyto-penia. Subsequently, he was noted to have progressiveconjugated hyperbilirubinemia for which he underwenta modified Kasai procedure with liver biopsy, a Roux-en-Y porto-jejunostomy, and a resection of a chole-dochal cyst. Findings on liver biopsy suggested obstruc-

tive disease. At 3 1/2 months, he was noted to have ahepatic abscess and cholangitis. A percutaneous tran-shepatic cholangiogram revealed numerous dilated bil-iary ducts. The diagnosis of Kabuki syndrome wasmade at age 6 months based on long palpebral fissures,large ears, preauricular pits, flat nasal tip, down-turned corners of the mouth, webbed neck, and promi-nent fetal fingertip pads. He was also noted to havepostnatal growth retardation, developmental delay,and frequent infections. A repeat karyotype was nor-mal. At age 8 months, he underwent a living-relatedliver transplant. Pathological examination of his liverdetected findings consistent with neonatal sclerosingcholangitis. When last evaluated at age 11 months, hewas short of stature and had a history of continuedinfections including urinary tract infections, however acomplete immunological evaluation was not performed.

Case 2

Case 2 was born at term to a 20-year-old G2 P2 His-panic woman following an uncomplicated pregnancy.Parents were first cousins once removed. Birth weightwas 3650 g (50 to 75th centile), birth length 52 cm (75thcentile), and OFC 32.5 cm (5th centile). At age 9months, she was evaluated and noted to have bilateral

TABLE I. Common Clinical Findings in Two Individuals with Kabuki Syndrome

Finding Case 1 Case 2

Nikawa et al., 1988

n %

Growth/developmentPre/postnatal microcephaly + + 3/51 (6)Mental/psychomotor retardation + + 57/62 (92)Postnatal growth deficiency + + 50/60 (83)

Facial featuresHigh, prominent forehead + + 6/10a (60)High-arched eyebrows + + 51/58 (88)Sparse lateral eyebrows + + 9/9a (100)Long palpebral fissures + + 10/10a (100)Hypertelorism + − 3/5b (60)Blue sclerae + + 14/52 (27)Lower eyelid eversion − + 61/62 (98)Broad, depressed nasal tip − + 45/57 (79)Down-turned corners of mouth + +High-arched palate + − 24/38 (63)Micrognathia + − 20/55 (36)Prominent ears + + 51/60 (85)Preauricular pits + + 20/52 (39)

Congenital heart defect − ASD, PS 19/59 (32)Skeletal

Vertebral anomalies/scoliosis − − 29/41 (71)Other − Clubfoot 7/31 (21)

ExtremitiesClinodactlyly of 5th digits + − 7/10a (70)Brachydactyly − − 47/53 (89)Persistent fetal digital pads + + 35/45 (78)

Other anomaliesHearing loss − + 9/11c (82)Neonatal hypoglycemia + − 4/58 (60)Susceptibility to infection + + 31/52 (60)Immune deficiency − + d (2)

Abnormal karyotype − (46,XY) − (46,XX) 3/60 (5)

+ present; − absent.aIlyina et al., 1995.bGalan-Gomez et al., 1995.cPeterson-Falzone et al., 1997.dHostoffer et al., 1996. One case personal observation.

Renal and Liver Anomalies in Kabuki Syndrome 363

coronal synostosis, esotropia, club feet, postnatalgrowth deficiency, hypotonia, and developmental de-lay. At 1 1/2 years, she underwent operative repair ofher birth defects. The diagnosis of Kabuki syndromewas based on characteristic facial appearance, includ-ing long palpebral fissures with eversion of the lower

eye lids, blue sclerae, midline indentation of nasal tip,down turned corners of mouth, large ears with preau-ricular pits, hearing loss, congenital heart defects(atrial septal defect and pulmonic stenosis), prominentpersistent fetal fingertip pads, and bilateral verticaltalus. She also had an ataxic gait and developmental

Fig. 1. Facial characteristics of KS in case 1. (A) Note long palpebralfissures, laterally sparse high arched eyebrows, long eyelashes, and de-pressed nasal tip. (B) Note large ears, preauricular pits, and (C) persis-tent fetal fingertip pads.

364 Ewart-Toland et al.

delay. At age 6 years, she presented with renal failure.Ultrasound study showed markedly dysplastic kidneysfor which she required a kidney transplant. In addi-tion, she was shown to have an IgA deficiency resultingin autoimmune disease that manifested as Hashimotothyroiditis and vitiligo. Case 2 did not have other signsof ataxia telangectasia.

DISCUSSION

Based on the characteristic clinical features (TableI), we diagnosed KS in our two patients. There are nolaboratory tests to confirm the diagnosis of KS indi-viduals, thus the diagnosis of KS remains based solelyon clinical findings. The clinical features are often dif-

Fig. 2. Findings in case 2. (A) Note broad forehead, laterally sparsehigh arched eyebrows, long palpebral fissures, depressed nasal tip, andvitiligo. (B) Case 2 also had characteristic prominent ears, preauricularpits, and (C) persistent fetal fingertip pads.

Renal and Liver Anomalies in Kabuki Syndrome 365

ficult to recognize during the newborn period, espe-cially if the individual is presenting with rare featuresof KS. Long-term followup should reveal the diagnosisof KS in these individuals. This was true in our case 1.

Table I summarizes characteristic features of KSseen in our patients, and Table II summarizes rarefindings, most of which were not previously reported inKS. Case 1 had neonatal sclerosing cholangitis severeenough to require liver transplantation, hydronephro-sis, and neonatal hypoglycemia (seen in 7% of individu-als with KS) [Niikawa et al., 1988]. Case 2 had dys-plastic kidneys leading to renal failure requiring a re-nal transplant, bilateral coronal synostosis, andimmune deficiency associated with autoimmune dis-ease, consisting of Hashimoto thyroiditis and vitiligo.

To our knowledge, this is the first report of hepaticanomalies seen in KS. Neonatal sclerosing cholangitisis a chronic cholestatic disease affecting the intrahe-patic and extrahepatic biliary systems. It is character-ized by chronic inflammation of the medium-sized bileducts, leading to obliteration of the bile duct lumen andbiliary cirrhosis [Wilschanski et al., 1995; Debray etal., 1994]. The clinical course of neonatal sclerosingcholangitis is characterized by jaundice, pruritus, fatmalabsorption, and growth retardation [Baker et al.,1993]. It can be associated with other diseases includ-ing immune deficiency, human immunodeficiency virusinfection, cryptosporidum infection, histiocytosis X,sickle cell anemia, Hodgkin disease, cystic fibrosis, al-pha-1-antitrypsin deficiency, and defects in bile saltmetabolism [Baker et al., 1993; Wilschanski et al.,1995]. Sclerosing cholangitis-like biliary abnormalitieshave also been reported in syndromes including Downsyndrome, Bardet-Biedl syndrome, and Wiedemann-Beckwith syndrome [Roussel et al., 1985].

Case 1 also presented with cholestasis. No individu-als with KS have been reported with cholestasis; how-ever two recent papers described patients with someKS manifestations and hepatic disease. Cools andJaeken [1997] reported a patient with cholestasis andanomalies similar to those found in KS including longpalpebral fissures and a depressed nasal tip. This childalso had cleft lip and palate, pigmentary retinopathy,hydronephrosis, and malrotation of the gut. They pro-posed that this individual did not have Kabuki syn-drome, but a new syndrome that was similar to that ofthe two cases reported by Hardikar et al. [1992], whodescribed two unrelated patients with cholestasis, cleft

lip and palate, hydronephrosis and hydroureter, pig-mentary retinopathy, and normal intellect. Minor fa-cial anomalies were not reported. Our patient repre-sents the first definite case of KS with liver disease.

Here, we also describe bilateral coronal synostosis asa new association with KS. Craniosynostosis has notbeen described previously in patients with KS, al-though other types of cranial anomalies, including in-complete development of the frontal bones and a digitalimpression of the skull have been reported [Niikawa etal., 1988].

Renal and urinary tract malformations were re-ported in a few cases of KS. Previously reported find-ings include horseshoe kidneys (3 in 70), double renalpelvis (3 in 58), duplication of the collecting system (3in 16), hydronephrosis (3 in 70), renal hypoplasia (1 in10), and megaloureter (2 in 58) [Niikawa et al., 1988;Philip et al., 1992; Ilyina et al., 1995]. Both of the pa-tients described here had renal findings including case1 with hydronephrosis and hydroureter and case 2 witha dysplastic kidney requiring transplantation.

Recurrent infections are a common finding in indi-viduals with KS with approximately 60% of individualsshowing increased susceptibility to infection. Most ofthese cases have recurrent otitis media [Niikawa et al.,1988]. This might reflect an underlying immune disor-der. In addition to case 2, described here with an IgAimmune deficiency, two additional patients with KShave been observed with IgA immune deficiency [Hos-toffer et al., 1996; M. Golabi, unpublished observa-tions].

In conclusion, patients with KS should be evaluatedfor hepatic defects, renal anomalies, IgA deficiency, au-toimmune disorder, and craniosynostosis in addition toother more commonly associated features of KS.

ACKNOWLEDGMENTS

Gregory Enns was supported, in part, by NIH Train-ing Grant GM07085.

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TABLE II. Rare Findings in Individuals With KabukiSyndrome

Feature Case 1 Case 2 Literature reports

Coronal synostosis − +Immune system

Hashimoto thyroiditis − +Vitiligo − +

HepaticSclerosing cholangitis + −Cholestasis + − Cools and Jaekan, 1997; 1/1

Renal/urinary tract Niikawa et al., 1988; 7/58Philip et al., 1992; 7/16

Hydronephrosis + − Niikawa et al., 1988; 2/58Hydroureter + −Dysplastic kidneys − + Ilyina et al., 1995; 1/10

366 Ewart-Toland et al.

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