Welcome to PhenoDis

Cholestasis - pigmentary retinopathy - cleft palate

General Information (adopted from Orphanet):

Synonyms, Signs:	Hardikar syndrome
Number of Symptoms	60
OrphanetNr:	1415
OMIM Id:	612726
ICD-10:
UMLs:
MeSH:
MedDRA:
Snomed:

Prevalence, inheritance and age of onset:

Prevalence:	5 cases [Orphanet]
Inheritance:	Not applicable [Orphanet]
Age of onset:	Neonatal Infancy [Orphanet]

Disease classification (adopted from Orphanet):

Parent Diseases:

Orofacial clefting syndrome
-Rare developmental defect during embryogenesis
-Rare genetic disease
-Rare maxillo-facial surgical disease
-Rare otorhinolaryngologic disease

Symptom Information: Sort by abundance

	Symptom Information	Symptom	Abundance	DB Freq
1	(HPO:0200065)	Chorioretinal degeneration	rare [HPO:skoehler]	7 / 7739
2	(HPO:0000510)	Rod-cone dystrophy	Very frequent [Orphanet]	266 / 7739
3	(HPO:0000580)	Pigmentary retinopathy		49 / 7739
4	(HPO:0004325)	Decreased body weight	Very frequent [Orphanet]	492 / 7739
5	(HPO:0001508)	Failure to thrive		454 / 7739
6	(HPO:0001631)	Atria septal defect		274 / 7739
7	(HPO:0001655)	Patent foramen ovale		31 / 7739
8	(HPO:0001629)	Ventricular septal defect		316 / 7739
9	(HPO:0001671)	Abnormality of the cardiac septa		55 / 7739
10	(HPO:0001680)	Coarctation of aorta		57 / 7739
11	(HPO:0005113)	Dilatation of the aortic arch		12 / 7739
12	(HPO:0001643)	Patent ductus arteriosus		228 / 7739
13	(HPO:0004971)	Pulmonary artery hypoplasia		15 / 7739
14	(HPO:0004415)	Pulmonary artery stenosis		25 / 7739
15	(HPO:0001642)	Pulmonic stenosis		89 / 7739
16	(HPO:0001409)	Portal hypertension		39 / 7739
17	(HPO:0000010)	Recurrent urinary tract infections		56 / 7739
18	(HPO:0002242)	Abnormality of the intestine	Very frequent [Orphanet]	42 / 7739
19	(HPO:0002566)	Intestinal malrotation		89 / 7739
20	(HPO:0005242)	Extrahepatic biliary duct atresia	Very frequent [Orphanet]	9 / 7739
21	(HPO:0001396)	Cholestasis		136 / 7739
22	(HPO:0000952)	Jaundice		105 / 7739
23	(HPO:0002910)	Elevated hepatic transaminases		158 / 7739
24	(HPO:0002240)	Hepatomegaly		467 / 7739
25	(HPO:0001744)	Splenomegaly		337 / 7739
26	(HPO:0001626)	Abnormality of the cardiovascular system	Very frequent [Orphanet]	73 / 7739
27	(HPO:0000148)	Vaginal atresia		16 / 7739
28	(HPO:0000174)	Abnormality of the palate	Very frequent [Orphanet]	298 / 7739
29	(HPO:0000175)	Cleft palate		349 / 7739
30	(HPO:0000204)	Cleft upper lip	Very frequent [Orphanet]	193 / 7739
31	(HPO:0000581)	Blepharophimosis		197 / 7739
32	(HPO:0001070)	Mottled pigmentation		8 / 7739
33	(HPO:0000989)	Pruritus		111 / 7739
34	(HPO:0000076)	Vesicoureteral reflux		94 / 7739
35	(HPO:0000126)	Hydronephrosis		119 / 7739
36	(HPO:0000069)	Abnormality of the ureter	Very frequent [Orphanet]	47 / 7739
37	(HPO:0000072)	Hydroureter		146 / 7739
38	(HPO:0000071)	Ureteral stenosis		9 / 7739
39	(HPO:0001510)	Growth delay		295 / 7739
40	(HPO:0002904)	Hyperbilirubinemia		32 / 7739
41	(HPO:0030151)	Cholangitis		10 / 7739
42	(HPO:0003577)	Congenital onset		133 / 7739
43	(HPO:0003745)	Sporadic		131 / 7739
44	(MedDRA:10008604)	Cholangitis		6 / 7739
45	(MedDRA:10016642)	Fibrosis		9 / 7739
46	(OMIM)	Dilated intrahepatic bile ducts		1 / 7739
47	(OMIM)	Ductal plate malformation		5 / 7739
48	(OMIM)	Hearing impairment, mild (2 patients)		1 / 7739
49	(OMIM)	Hypertrophy of branches of the hepatic artery		1 / 7739
50	(OMIM)	Jejunal web		1 / 7739
51	(OMIM)	Large duct obstruction		1 / 7739
52	(OMIM)	Liver biopsy shows ductal proliferation		1 / 7739
53	(OMIM)	Long narrow palpebral fissures (1 patient)		1 / 7739
54	(OMIM)	Normal cognition		7 / 7739
55	(OMIM)	Obstructive liver disease		1 / 7739
56	(OMIM)	Portal inflammation		3 / 7739
57	(OMIM)	Preauricular dimples		1 / 7739
58	(OMIM)	Pruritus secondary to liver disease		1 / 7739
59	(OMIM)	Small intestinal septum		1 / 7739
60	(OMIM)	Stenosis of common bile duct		1 / 7739

Associated genes:

ClinVar (via SNiPA)

Gene symbol	Variation	Clinical significance	Reference

Additional Information:

Clinical Description OMIM

Hardikar et al. (1992) reported 2 unrelated girls with obstructive hepatic cholestasis and cholangitis associated with cleft lip/palate, hydronephrosis/hydroureter, retinal pigmentation, and intestinal septum. The features were apparent at birth. Both patients had recurrent urinary tract infections, early ... Hardikar et al. (1992) reported 2 unrelated girls with obstructive hepatic cholestasis and cholangitis associated with cleft lip/palate, hydronephrosis/hydroureter, retinal pigmentation, and intestinal septum. The features were apparent at birth. Both patients had recurrent urinary tract infections, early onset of jaundice, and poor weight gain. Both also developed hepatomegaly and pruritus. Nydegger et al. (2008) reported long-term follow-up of the patients reported by Hardikar et al. (1992). The first patient had cleft lip and palate, pigmentary retinopathy, aortic coarctation, vesicoureteric reflux, obstructive liver disease, and malrotation of the gut. Liver biopsy showed ductal proliferation with hepatic artery hypertrophy. She developed recurrent obstructive jaundice that required surgical intervention at age 13 years. The second patient was born by artificial insemination by donor sperm. She had cleft soft palate, pigmentary retinopathy, hydroureters with distal obstruction, jejunal septum, patent foramen ovale, and mild pulmonary artery stenosis. Liver biopsy showed multiple cystic dilations of the intrahepatic ducts and stenosis of the common bile duct. She required liver transplantation at age 15 years. Cognition in both patients was normal. Hardikar et al. (1992) commented on the multiple tubular stenoses apparent in these patients. Nydegger et al. (2008) noted that the syndrome resembled the Kabuki (147920) and Alagille (ALGS1; 118450) syndromes. Cools and Jaeken (1997) reported an infant girl with Hardikar syndrome. She had cleft lip and palate, pigmentary retinopathy, hydroureteronephrosis with severe vesicoureteral reflux, cholestasis, and nonrotation of the gut. Liver ultrasound showed dilated intrahepatic bile ducts, and biopsy showed fibrosis with ductal proliferation and inflammatory cells. She also had patent ductus arteriosus and a small ventricular septal defect. Dysmorphic facial features included long narrow palpebral fissures, depressed nasal tip, and preauricular dimples. She was noted to have moderate psychomotor delay at that time, but follow-up by Nydegger et al. (2008) reported normal development at age 11 years. Cools and Jaeken (1997) had noted that the syndrome resembled the Kabuki syndrome. Maluf et al. (2002) reported a girl with features consistent with Hardikar syndrome. She had cleft lip and palate, retinopathy, intestinal malrotation, and recurrent urinary tract infections associated with stenosis of the ureters. She was jaundiced from birth. Liver biopsy showed cirrhosis with regenerating nodules, portal chronic inflammation with bile duct proliferation, and lobular cholestasis. The liver disease was progressive, requiring transplantation at age 24 months. Nydegger et al. (2008) provided follow-up on the girl and noted that she had an excellent clinical course after transplantation and had normal development at age 8 years. Poley and Proud (2008) reported another girl with Hardikar syndrome who had malrotation of the gut, pigmentary retinopathy, patent ductus arteriosus, hydronephrosis, and persistent cholestasis resulting in liver failure and transplant. Additional features included vaginal atresia and a common urogenital sinus. Mild dysmorphic facial features were also noted: a prominent forehead, hypertelorism, small chin, bulbous nose, and preauricular dimples. Poley and Proud (2008) postulated that the constellation of defects correlated with a critical time of organogenesis between 30 and 70 days' gestation.

Symptoms & Signs

	Field	Query
	Disease
	Symptom