SNOMEDCT: 720636001; ORPHA: 1415;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq13.1 | Hardikar syndrome | 301068 | X-linked dominant | 3 | MED12 | 300188 |
A number sign (#) is used with this entry because of evidence that Hardikar syndrome (HDKR) is caused by heterozygous mutation in the MED12 gene (300188) on chromosome Xq13.
Hardikar syndrome (HDKR) is an X-linked dominant multiple congenital anomaly disorder reported only in females. Features include foregut malformations, intestinal malrotation, liver and biliary tract disease, genitourinary abnormalities, cleft lip and palate, and pigmentary retinopathy. Some patients may have congenital cardiac defects or vascular abnormalities, including aortic coarctation and carotid/intracranial aneurysms. Neurodevelopment and cognition is normal (summary by Li et al., 2021).
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, pigmentary 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. Poley and Proud (2008) provided follow-up of this girl, noting additional features, including vaginal atresia, hydronephrosis, and a common urogenital sinus requiring neobladder construction, vesicostomy, and nephrostomy. 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. Nydegger et al. (2008) also 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. Ryan et al. (2016) found that the patient reported by Maluf et al. (2002) and Poley and Proud (2008), who was 14 years of age, developed coarctation of the aorta that was successfully treated with aortic angioplasty and stenting, dramatically improving her hypertension. She also had a carotid aneurysm that was treated conservatively.
Li et al. (2021) reported 7 unrelated females, including 2 who were previously reported by Maluf et al. (2002) and Poley and Proud (2008) (patient 4) and Cools and Jaeken (1997) (patient 5), with HDKR. The patients, who ranged from infancy to 21 years of age, had classic features of the disorder, including cleft lip and palate, gastrointestinal abnormalities such as intestinal malrotation, choledochal cyst, biliary tree abnormalities, absent gallbladder, and cholestasis. One patient had a diaphragmatic hernia. Six patients had genitourinary involvement, manifest as hydronephrosis, ectopic ureters, and bladder and cloacal abnormalities. Additional features included poor overall growth, pigmentary retinopathy, usually with preserved vision, strabismus, and preauricular pits. Two patients had hearing loss, 1 mild and the other severe. All patients had cardiac features, including aortic coarctation or dilation in 5, pulmonic stenosis in 1, PDA and partial anomalous pulmonary venous return in 1, and carotid artery aneurysm in 1. Patient 5 died at 21 years of age from an intracranial hemorrhage. CT imaging did not show an aneurysm, but additional studies were not performed. Li et al. (2021) emphasized the cardiac features in these patients, noting that there should be investigation and follow-up to avoid serious events. All patients had normal neurodevelopment and cognition.
The heterozygous mutations in the MED12 gene that were identified in female patients with HDKR by Li et al. (2021) occurred de novo.
In 7 unrelated females with HDKR, including 2 previously reported patients diagnosed clinically with the disorder, Li et al. (2021) identified heterozygous nonsense or frameshift mutations in the MED12 gene (see, e.g., 300188.0007-300188.0009). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, occurred throughout the gene. All were predicted to lead to nonsense-mediated mRNA decay, resulting in haploinsufficiency. All of the mutations either occurred de novo or were presumed de novo. Functional studies of the variants were not performed. Patient cells showed skewed X inactivation. Li et al. (2021) postulated that complete loss of MED12 may be lethal in males. The authors noted that the HDKR phenotype is unique in that neurodevelopment is preserved and that the manifestations include distinct structural abnormalities affecting several organ systems.
Cools, F., Jaeken, J. Hardikar syndrome: a new syndrome with cleft lip/palate, pigmentary retinopathy and cholestasis. Am. J. Med. Genet. 71: 472-474, 1997. [PubMed: 9286458] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19970905)71:4<472::aid-ajmg19>3.0.co;2-d]
Hardikar, W., Smith, A. L., Keith, C. G., Chow, C. W. Multisystem obstruction with cholestasis, pigmentary retinopathy, and cleft palate: a new syndrome? Am. J. Med. Genet. 44: 13-17, 1992. [PubMed: 1519643] [Full Text: https://doi.org/10.1002/ajmg.1320440105]
Li, D., Strong, A., Shen, K. M., Cassiman, D., Van Dyck, M., Linhares, N. D., Valadares, E. R., Wang, T., Pena, S. D. J., Jaeken, J., Vergano, S., Zackai, E., Hing, A., Chow, P., Ganguly, A., Scholz, T., Bierhals, T., Philipp, D., Hakonarson, H., Bhoj, E. De novo loss-of-function variants in X-linked MED12 are associated with Hardikar syndrome in females. Genet. Med. 23: 637-644, 2021. [PubMed: 33244166] [Full Text: https://doi.org/10.1038/s41436-020-01031-7]
Maluf, D. G., Fisher, R. A., Fulcher, A. S., Posner, M. P. Hardikar syndrome: a case requiring liver transplantation. Transplantation 74: 1058-1061, 2002. [PubMed: 12394856] [Full Text: https://doi.org/10.1097/00007890-200210150-00029]
Nydegger, A., Van Dyck, M., Fisher, R. A., Jaeken,J., Hardikar,W. Hardikar syndrome: long term outcome of a rare genetic disorder. Am. J. Med. Genet. 146A: 2468-2472, 2008. [PubMed: 18348269] [Full Text: https://doi.org/10.1002/ajmg.a.32226]
Poley, J. R., Proud, V. K. Hardikar syndrome: new features. Am. J. Med. Genet. 146A: 2473-2479, 2008. [PubMed: 18792981] [Full Text: https://doi.org/10.1002/ajmg.a.32266]
Ryan, K. M., Ellis, A. R., Raafat, R., Bhoj, E. J., Hakonarson, H., Li, D., Schrier Vergano, S. Aortic coarctation and carotid artery aneurysm in a patient with Hardikar syndrome: cardiovascular implications for affected individuals. Am. J. Med. Genet. 170A: 482-486, 2016. [PubMed: 26471230] [Full Text: https://doi.org/10.1002/ajmg.a.37438]