This article reports the case of a girl with a remarkable constellation of abnormalities, including bilateral cleft lip and palate, pigmentary retinopathy, bilateral hydronephrosis, vaginal atresia, gut malrotation, and progressive liver disease. The patient had a clinical presentation of progressive cholestasis and hyperbilirubinemia and required a living-donor liver transplantation. This patient appears to be the first case reported in the literature of Hardikar syndrome that has undergone liver transplantation.
The patient is a girl delivered at 33 weeks of gestation by cesarean section to a gravid I, para I, abortive 0, 20-year-old healthy, type O-blood group mother. The baby, at birth, weighed 1,794 g, her length was 43.5 cm, and her head circumference was 31 cm. Her blood type was O Rh+. Amniocentesis had been performed and cytogenetic analysis revealed normal female karyotype 46,XX chromosomes. At delivery, Apgar scores were 9 and 9. Laboratory data and growth rate are shown in Table 1. Because of the presence of jaundice and hyperbilirubinemia, Doppler ultrasonography of the liver was performed showing significant biliary abnormalities and mild dilation in a series of “lakes,” mostly of the left-sided bile ducts. A vascular abnormality was demonstrated in the medial segment of the left hepatic lobe consistent with a group of arteries extending outward in a spider-like fashion from a central branch of the left hepatic artery. No ascites was seen. A hepatoiminodiacetic acid scan using mCi Technetium-99m was performed that demonstrated a nonfunctioning gallbladder with no response to cholecystokinin, and dilated intrahepatic bile ducts. Viral serologies, toxoplasmosis-rubella-cytomegalovirus-and-herpes-simplex-virus (TORCH) titer, and rubella tests were negative. α1-Antitrypsin level was normal. On day 5 after birth, the patient underwent a Ladd’s operation for intestinal malrotation. At 5 months of age, the patient underwent her first operation for the bilateral cleft lip and palate (Fig. 1). At 11 months of age, the patient underwent a gastrostomy and bilateral ureterostomy. The child had treatment of two femur fractures secondary to severe bone demineralization with no child abuse risk. Fluorescent in situ hybridization study for Jagged1 (JAG1) on chromosome 20p12 was normal. Liver biopsy was performed and showed (1) cirrhosis with regenerating nodules, (2) portal chronic inflammation with bile duct proliferation, and (3) lobular cholestasis (Fig. 2). At the age of 12 months, the diagnosis of Hardikar syndrome was made (1). This child had ad libitum breast milk, 12 hr per day continuous feedings of Pregestimil (Mead Johnson Nutritionals, Evansville, IN) 27 kcal with 3% Polycose (Ross, Columbus, OH) (720 mL/day), fat- and water-soluble vitamin supplements, Actigall (Novartis Pharmaceuticals East Hanover, NJ) and phenobarbital therapy, and parenteral vitamin K supplements to correct international normalized ratio before elective plastic surgical care.
The patient was seen first by our transplant group at 14 months of age. Because of failure to thrive despite documented maximal dietary support with excellent close medical follow-up and supportive family care, together with progressive cholestasis and cirrhosis, the child immediately underwent pretransplant evaluation. Liver magnetic resonance imaging (MRI), cardiac examination, and pulmonary evaluation were completed. The MRI scan showed that the right lobe of the liver was small in relation to the left lobe, with a macronodular configuration consistent with cirrhosis. There was tortuosity and a dilated biliary tree centrally and choledochal cyst degeneration of the common hepatic duct not previously identified (Fig. 3). There was asymmetry in the enhanced vascular pattern of the liver. The portal vein was identified and was diminutive in size. The spleen was homogenous and enlarged, measuring 16 cm.
The parents, mother, sister, and estranged father were studied for genetic anomalies, and none were reported. The option of living-donor liver transplantation was offered to the family. The child was listed for liver transplant, and a delay in living-donor evaluation resulted while the family sought second opinions. The 46-year-old healthy grandmother was selected as the donor. Her blood type was O RH+, and she had no significant medical, surgical, or genetic history.
The patient underwent transplantation at 24 months of age and received the left lateral lobe (segments II–III) of her grandmother’s liver, without complications. The donor had an uncomplicated perioperative course and was discharged at day 4 after surgery. The patient remained in the pediatric intensive care unit for 5 days and in the transplant unit for 11 more days before discharge. She developed posttransplant pancreatitis that resolved with conservative supportive care. The immunosuppressive therapy consisted of mycophenolate mofetil, tacrolimus, and steroids. The child had a good clinical outcome after transplant and was discharged 16 days after transplantation.
The child’s appetite has improved, and she has gained weight and improved developmental motor and speech goals with occupational therapy biweekly (Table 1). She is currently followed at the outpatient clinic.
The child discussed in this article has a remarkable combination of abnormalities involving different organ systems. During the first 16 months of her life, she underwent several procedures to correct cleft lip and palate, gut malrotation, and bilateral hydroureter, and gastrostomy tube placement for continuous feeding. The child also had fractures from bone demineralization and multiple urosepsis local hospital admissions.
The patient was studied for a constellation of genetic syndromes. Among others, Hardikar syndrome (1), Alagille syndrome (2), and Kabuki syndrome (3) were evaluated (Table 2). The presence of severe growth failure, histologic and radiologic evidence of cirrhosis, and an undrained choledochal cyst was determined to be best treated by liver replacement.
In 1992, Hardikar et al. reported two unrelated patients with a combination of abnormalities including cleft lip and palate, pigmentary retinopathy, and multiple tubular stenoses (e.g., bile ducts, hydroureter) (1). Hardikar syndrome has variable involvement of other systems. The jejunal web or a rotation anomaly of the gut is frequently present, as are several cardiac endocardial cushion abnormalities. Mental disorders are present in about two thirds of cases. Abnormalities of the extrahepatic bile ducts associated with malrotation anomalies of the gut were described by Korn et al. in 1988 (4). Cholestatic disease leading to cirrhosis of the liver has been described, but we did not find a reported case of Hardikar syndrome requiring liver transplantation or illustrating the liver vascular anomaly seen in our patient. The pathogenesis of this syndrome remains obscure. The anomalies have been ascribed to errors during bile duct and gut embryogenesis (between the fifth and eighth weeks of gestation) (4). The entities most resembling Hardikar syndrome are the Kabuki syndrome, first described in 1981 by Niikawa et al. (3), and the Alagille syndrome, first described by Alagille et al. in 1975 (2).
Kabuki syndrome is a rare multiple malformation disorder characterized by typical face with long palpebral fissures, eversion of the lateral part of the lower eyelid, arched eyebrows, depressed nasal tip, and malformed prominent ears. The features of the face are like the makeup of kabuki actors. There is, in most children with this syndrome, retardation in the acquisition of evolutive psychomotor stages. Speech is not structured, it begins with the first syllables at about 3 years, and remains poor, with close, unclear, and tied words. Other elements that define the syndrome are skeletal anomalies, dermatoglyphic anomalies, rare cardiac anomalies, and renal anomalies. The cause is still unknown; it is thought that it may be X-linked or transmitted in an autosomal dominant fashion. Genetic analysis has shown chromosomal anomalies in only a few cases. All cases present a postnatal deficit of growth, psychomotor and/or mental retardation, autistic traits, dysmorphic facies, skeletal anomalies, rare cardiovascular defects, and rarely growth hormone-responsive correction of height (3).
The persistent fetal fingertip pads, dermatoglyphic anomalies, and congenital heart defects of Kabuki syndrome are not seen in Hardikar syndrome (1,5). Gut malrotation and vesicoureteral reflux, hydronephrosis, and hydroureter have been described only rarely with Kabuki syndrome (Table 2). Liver disease and retinopathy are two characteristics of Hardikar syndrome that are not present in Kabuki syndrome (Table 2) (3,5).
Alagille syndrome is a rare inherited condition, which typically manifests during the first year of life as an episode of prolonged cholestasis. Although the pattern of inheritance is autosomal dominant with almost complete penetrance, highly variable expression may delay the diagnosis, and with passing time the clinical findings may be more difficult to recognize (6). This syndrome presents clinically with features such as chronic cholestasis and cirrhosis, congenital heart disease, “butterfly-like” vertebrae, posterior embryotoxon ocular defects, and a distinctive facial appearance (2).
Mutations in JAG1 can be identified in 70% of Alagille syndrome patients, and they are inherited in 30% to 50%. These mutations include total gene deletions as well as mutations (frameshift, missense, and nonsense) in almost all regions of the 26 exons of the JAG1 gene. Jagged1 is a cell surface protein that functions in an embryologically important signaling pathway, known as the notch signaling pathway. Understanding the role of JAG1 in the cause of Alagille syndrome has improved diagnosis for this variably expressed disorder. Retardation and renal defects have been reported in several cases (7).
More than 50% of patients with Alagille syndrome present with neonatal cholestatic jaundice, about 33% require liver transplantation, and more than 10% of children with Alagille syndrome die because of liver complications. The prognosis of liver disease in Alagille syndrome is worse in children who present with neonatal cholestatic jaundice (7).
Patients with Alagille syndrome have facial features distinctly different from Hardikar syndrome (1,2). The vertebral, retinal, and fingertip abnormalities of Alagille syndrome are not seen in the Hardikar syndrome (2,5). The gut malrotation, genitourinary anomalies, and the bile duct cystic degeneration findings in our patient with Hardikar syndrome are not characteristics of the Alagille patient (Table 2).
We report the case of a girl with a remarkable constellation of abnormalities, including bilateral cleft lip and palate, pigmentary retinopathy, bilateral hydronephrosis, vaginal atresia, gut malrotation, and progressive cholestatic liver disease. These phenotypic features seem to be more closely related to the genetic anomaly described by Hardikar et al. in 1992 (1). The patient had a clinical presentation of progressive cholestasis to cirrhosis requiring a liver transplantation at 2 years of age. The patient has had a good clinical outcome after liver transplant, with stabilization of growth and improving motor and speech development. This patient appears to be the first case of Hardikar syndrome reported in the literature that has undergone liver transplantation.
1. Hardikar W, Smith AL, Keith C, et al. Multisystem obstruction with cholestasis, pigmentary retinopathy, and cleft palate: a new syndrome? Am J Med Genet 1992; 44: 13–17.
2. Alagille D, Odievre M, Gautier M, et al. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr 1975; 86 (1): 63–71.
3. Niikawa N, Matsuura N, Fukushima Y, et al. Kabuki make-up syndrome: a syndrome with mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr 1981; 99: 565–569.
4. Korn O, Csendes A, Bastias J. Anomalies of extrahepatic biliary duct and gallbladder associated with intestinal malrotation: a case report. Surgery 1988; 103: 496–498.
5. Cools F, Jaeken J. Hardikar syndrome: a new syndrome with cleft lip/palate, pigmentary retinopathy and cholestasis. Am J Med Genet 1997; 71: 472–474.
6. Mowat A. Liver disorders in childhood. London, Butterworths, 1987: 219–221.
7. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001; 49: 431–435.