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Cholestasis-pigmentary retinopathy-cleft palate syndrome(HDKR)

MedGen UID:
208652
Concept ID:
C0795969
Disease or Syndrome
Synonyms: Hardikar syndrome; HDKR
SNOMED CT: Cholestasis with pigmentary retinopathy and cleft palate syndrome (720636001); Hardikar syndrome (720636001)
Modes of inheritance:
Not genetically inherited
MedGen UID:
988794
Concept ID:
CN307044
Finding
Source: Orphanet
clinical entity without genetic inheritance.
 
Gene (location): MED12 (Xq13.1)
 
Monarch Initiative: MONDO:0012997
OMIM®: 301068
Orphanet: ORPHA1415

Disease characteristics

Excerpted from the GeneReview: MED12-Related Disorders
MED12-related disorders include the phenotypes of FG syndrome type 1 (FGS1), Lujan syndrome (LS), X-linked Ohdo syndrome (XLOS), Hardikar syndrome (HS), and nonspecific intellectual disability (NSID). FGS1 and LS share the clinical findings of cognitive impairment, hypotonia, and abnormalities of the corpus callosum. FGS1 is further characterized by absolute or relative macrocephaly, tall forehead, downslanted palpebral fissures, small and simple ears, constipation and/or anal anomalies, broad thumbs and halluces, and characteristic behavior. LS is further characterized by large head, tall thin body habitus, long thin face, prominent nasal bridge, high narrow palate, and short philtrum. Carrier females in families with FGS1 and LS are typically unaffected. XLOS is characterized by intellectual disability, blepharophimosis, and facial coarsening. HS has been described in females with cleft lip and/or cleft palate, biliary and liver anomalies, intestinal malrotation, pigmentary retinopathy, and coarctation of the aorta. Developmental and cognitive concerns have not been reported in females with HS. Pathogenic variants in MED12 have been reported in an increasing number of males and females with NSID, with affected individuals often having clinical features identified in other MED12-related disorders. [from GeneReviews]
Authors:
Michael J Lyons   view full author information

Additional description

From OMIM
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).  http://www.omim.org/entry/301068

Clinical features

From HPO
Abdominal pain
MedGen UID:
7803
Concept ID:
C0000737
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) and perceived to originate in the abdomen.
Hydronephrosis
MedGen UID:
42531
Concept ID:
C0020295
Disease or Syndrome
Severe distention of the kidney with dilation of the renal pelvis and calices.
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Recurrent urinary tract infections
MedGen UID:
120466
Concept ID:
C0262655
Disease or Syndrome
Repeated infections of the urinary tract.
Hydroureter
MedGen UID:
101073
Concept ID:
C0521620
Anatomical Abnormality
The distention of the ureter with urine.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Hypoplasia of the bladder
MedGen UID:
340845
Concept ID:
C1855335
Finding
Underdevelopment of the urinary bladder.
Coarctation of aorta
MedGen UID:
1617
Concept ID:
C0003492
Congenital Abnormality
Coarctation of the aorta is a narrowing or constriction of a segment of the aorta.
Patent ductus arteriosus
MedGen UID:
4415
Concept ID:
C0013274
Congenital Abnormality
In utero, the ductus arteriosus (DA) serves to divert ventricular output away from the lungs and toward the placenta by connecting the main pulmonary artery to the descending aorta. A patent ductus arteriosus (PDA) in the first 3 days of life is a physiologic shunt in healthy term and preterm newborn infants, and normally is substantially closed within about 24 hours after bith and completely closed after about three weeks. Failure of physiologcal closure is referred to a persistent or patent ductus arteriosus (PDA). Depending on the degree of left-to-right shunting, PDA can have clinical consequences.
Patent foramen ovale
MedGen UID:
8891
Concept ID:
C0016522
Congenital Abnormality
Failure of the foramen ovale to seal postnatally, leaving a potential conduit between the left and right cardiac atria.
Atrial septal defect
MedGen UID:
6753
Concept ID:
C0018817
Congenital Abnormality
Atrial septal defect (ASD) is a congenital abnormality of the interatrial septum that enables blood flow between the left and right atria via the interatrial septum.
Ventricular septal defect
MedGen UID:
42366
Concept ID:
C0018818
Congenital Abnormality
A hole between the two bottom chambers (ventricles) of the heart. The defect is centered around the most superior aspect of the ventricular septum.
Hypertensive disorder
MedGen UID:
6969
Concept ID:
C0020538
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
Portal hypertension
MedGen UID:
9375
Concept ID:
C0020541
Disease or Syndrome
Increased pressure in the portal vein.
Partial anomalous pulmonary venous return
MedGen UID:
450995
Concept ID:
C0158634
Congenital Abnormality
A form of anomalous pulmonary venous return in which not all pulmonary veins drain abnormally. Partial anomalous pulmonary venous return frequently involves one or both of the veins from one lung.
Pulmonary artery stenosis
MedGen UID:
65965
Concept ID:
C0238397
Anatomical Abnormality
An abnormal narrowing or constriction of the pulmonary artery, in the main pulmonary artery and/or in the left or right pulmonary artery branches.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Bladder exstrophy
MedGen UID:
2661
Concept ID:
C0005689
Disease or Syndrome
Eversion of the posterior bladder wall through the congenitally absent lower anterior abdominal wall and anterior bladder wall.
Cholestasis
MedGen UID:
925
Concept ID:
C0008370
Disease or Syndrome
Impairment of bile flow due to obstruction in bile ducts.
Esophageal varix
MedGen UID:
5027
Concept ID:
C0014867
Disease or Syndrome
Extreme dilation of the submucusoal veins in the lower portion of the esophagus.
Gastric varix
MedGen UID:
8965
Concept ID:
C0017145
Disease or Syndrome
Extreme dilation of the submucusoal veins in the stomach.
Hematemesis
MedGen UID:
6770
Concept ID:
C0018926
Sign or Symptom
The vomiting of blood.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Hepatosplenomegaly
MedGen UID:
9225
Concept ID:
C0019214
Sign or Symptom
Simultaneous enlargement of the liver and spleen.
Jaundice
MedGen UID:
43987
Concept ID:
C0022346
Sign or Symptom
Yellow pigmentation of the skin due to bilirubin, which in turn is the result of increased bilirubin concentration in the bloodstream.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Vomiting
MedGen UID:
12124
Concept ID:
C0042963
Sign or Symptom
Forceful ejection of the contents of the stomach through the mouth by means of a series of involuntary spasmic contractions.
Hepatic failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Intestinal malrotation
MedGen UID:
113153
Concept ID:
C0221210
Congenital Abnormality
An abnormality of the intestinal rotation and fixation that normally occurs during the development of the gut. This can lead to volvulus, or twisting of the intestine that causes obstruction and necrosis.
Feeding difficulties
MedGen UID:
65429
Concept ID:
C0232466
Finding
Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it.
Decreased liver function
MedGen UID:
65430
Concept ID:
C0232744
Finding
Reduced ability of the liver to perform its functions.
Hepatic fibrosis
MedGen UID:
116093
Concept ID:
C0239946
Disease or Syndrome
The presence of excessive fibrous connective tissue in the liver. Fibrosis is a reparative or reactive process.
Bile duct proliferation
MedGen UID:
120603
Concept ID:
C0267818
Disease or Syndrome
Proliferative changes of the bile ducts.
Intrahepatic bile duct cysts
MedGen UID:
586535
Concept ID:
C0400991
Finding
The presence of cyst of the intrahepatic bile duct.
Prolonged neonatal jaundice
MedGen UID:
347108
Concept ID:
C1859236
Finding
Neonatal jaundice refers to a yellowing of the skin and other tissues of a newborn infant as a result of increased concentrations of bilirubin in the blood. Neonatal jaundice affects over half of all newborns to some extent in the first week of life. Prolonged neonatal jaundice is said to be present if the jaundice persists for longer than 14 days in term infants and 21 days in preterm infants.
Portal inflammation
MedGen UID:
412612
Concept ID:
C2748698
Pathologic Function
Infiltration of portal fields by inflammatory cells.
Intrahepatic bile duct dilatation
MedGen UID:
903901
Concept ID:
C4229071
Anatomical Abnormality
Increased diameter (caliber) of intrahepatic bile ducts (bile ducts that transport bile between the Canals of Hering and the interlobar bile ducts).
Vertigo
MedGen UID:
53006
Concept ID:
C0042571
Sign or Symptom
An abnormal sensation of spinning while the body is actually stationary.
Mild hearing impairment
MedGen UID:
868364
Concept ID:
C4022758
Finding
The presence of a mild form of hearing impairment.
Irritability
MedGen UID:
397841
Concept ID:
C2700617
Mental Process
A proneness to anger, i.e., a condition of being easily bothered or annoyed.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
Umbilical hernia
MedGen UID:
9232
Concept ID:
C0019322
Anatomical Abnormality
Protrusion of abdominal contents through a defect in the abdominal wall musculature around the umbilicus. Skin and subcutaneous tissue overlie the defect.
Osteoporosis
MedGen UID:
14535
Concept ID:
C0029456
Disease or Syndrome
Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).
Thoracolumbar scoliosis
MedGen UID:
196671
Concept ID:
C0749379
Anatomical Abnormality
Celiac disease
MedGen UID:
3291
Concept ID:
C0007570
Disease or Syndrome
Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms.
Cholangitis
MedGen UID:
40258
Concept ID:
C0008311
Disease or Syndrome
Inflammation of the biliary ductal system, affecting the intrahepatic or extrahepatic portions, or both.
Hypersplenism
MedGen UID:
9372
Concept ID:
C0020532
Disease or Syndrome
A malfunctioning of the spleen in which it prematurely destroys red blood cells.
Pyelonephritis
MedGen UID:
19590
Concept ID:
C0034186
Disease or Syndrome
An inflammation of the kidney involving the parenchyma of kidney, the renal pelvis and the kidney calices.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Hyperbilirubinemia
MedGen UID:
86321
Concept ID:
C0311468
Finding
An increased amount of bilirubin in the blood.
Elevated hepatic transaminase
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Lacrimal duct stenosis
MedGen UID:
116054
Concept ID:
C0238300
Finding
Narrowing of a tear duct (lacrimal duct).
Unilateral cleft lip
MedGen UID:
451047
Concept ID:
C0392006
Congenital Abnormality
A non-midline cleft of the upper lip on one side only.
Cleft soft palate
MedGen UID:
98471
Concept ID:
C0432098
Congenital Abnormality
Cleft of the soft palate (also known as the velum, or muscular palate) as a result of a developmental defect occurring between the 7th and 12th week of pregnancy. Cleft soft palate can cause functional abnormalities of the Eustachian tube with resulting middle ear anomalies and hearing difficulties, as well as speech problems associated with hypernasal speech due to velopharyngeal insufficiency.
Bilateral cleft lip and palate
MedGen UID:
853256
Concept ID:
C1398522
Congenital Abnormality
Cleft lip and cleft palate affecting both sides of the face.
Unilateral cleft palate
MedGen UID:
867754
Concept ID:
C4022143
Congenital Abnormality
Pruritus
MedGen UID:
19534
Concept ID:
C0033774
Sign or Symptom
Pruritus is an itch or a sensation that makes a person want to scratch. This term refers to an abnormally increased disposition to experience pruritus.
Preauricular pit
MedGen UID:
120587
Concept ID:
C0266610
Congenital Abnormality
Small indentation anterior to the insertion of the ear.
Premature rupture of membranes
MedGen UID:
8826
Concept ID:
C0015944
Pathologic Function
Premature rupture of membranes (PROM) is a condition which occurs in pregnancy when the amniotic sac ruptures more than an hour before the onset of labor.
Decreased serum insulin-like growth factor 1
MedGen UID:
892792
Concept ID:
C4072897
Finding
A reduced level of insulin-like growth factor 1 (IGF1) in the blood circulation.
Impaired growth-hormone response to glucagon stimulation test
MedGen UID:
1384725
Concept ID:
C4476961
Finding
Failure of growth hormone levels to respond adequately (by increasing) to the glucagon stimulation test.
Convergence excess esotropia
MedGen UID:
743581
Concept ID:
C1960822
Disease or Syndrome
An intermittent esotropia with binocular single vision present at distance fixation but esotropia on accommodation for near fixation. Usually associated with hypermetropia but patients can be emmetropic and rarely myopic. Associated with a high accommodative convergence/accommodation (AC/A) ratio.
Pigmentary retinopathy
MedGen UID:
1643295
Concept ID:
C4551715
Disease or Syndrome
An abnormality of the retina characterized by pigment deposition. It is typically associated with migration and proliferation of macrophages or retinal pigment epithelial cells into the retina; melanin from these cells causes the pigmentary changes. Pigmentary retinopathy is a common final pathway of many retinal conditions and is often associated with visual loss.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCholestasis-pigmentary retinopathy-cleft palate syndrome
Follow this link to review classifications for Cholestasis-pigmentary retinopathy-cleft palate syndrome in Orphanet.

Recent clinical studies

Etiology

Poley JR, Proud VK
Am J Med Genet A 2008 Oct 1;146A(19):2473-9. doi: 10.1002/ajmg.a.32266. PMID: 18792981
Nydegger A, Van Dyck M, Fisher RA, Jaeken J, Hardikar W
Am J Med Genet A 2008 Oct 1;146A(19):2468-72. doi: 10.1002/ajmg.a.32226. PMID: 18348269

Diagnosis

Pillai NR, Miller D, Bronken G, Salunke AK, Aggarwal A
Am J Med Genet A 2022 Jul;188(7):2231-2236. Epub 2022 Apr 6 doi: 10.1002/ajmg.a.62756. PMID: 35385210Free PMC Article
Li D, Strong A, Shen KM, Cassiman D, Van Dyck M, Linhares ND, Valadares ER, Wang T, Pena SDJ, Jaeken J, Vergano S, Zackai E, Hing A, Chow P, Ganguly A, Scholz T, Bierhals T, Philipp D, Hakonarson H, Bhoj E
Genet Med 2021 Apr;23(4):637-644. Epub 2020 Nov 27 doi: 10.1038/s41436-020-01031-7. PMID: 33244166
Poley JR, Proud VK
Am J Med Genet A 2008 Oct 1;146A(19):2473-9. doi: 10.1002/ajmg.a.32266. PMID: 18792981
Maluf DG, Fisher RA, Fulcher AS, Posner MP
Transplantation 2002 Oct 15;74(7):1058-61. doi: 10.1097/00007890-200210150-00029. PMID: 12394856
Cools F, Jaeken J
Am J Med Genet 1997 Sep 5;71(4):472-4. doi: 10.1002/(sici)1096-8628(19970905)71:4<472::aid-ajmg19>3.0.co;2-d. PMID: 9286458

Prognosis

Ryan KM, Ellis AR, Raafat R, Bhoj EJ, Hakonarson H, Li D, Schrier Vergano S
Am J Med Genet A 2016 Feb;170A(2):482-486. Epub 2015 Oct 15 doi: 10.1002/ajmg.a.37438. PMID: 26471230
Poley JR, Proud VK
Am J Med Genet A 2008 Oct 1;146A(19):2473-9. doi: 10.1002/ajmg.a.32266. PMID: 18792981
Nydegger A, Van Dyck M, Fisher RA, Jaeken J, Hardikar W
Am J Med Genet A 2008 Oct 1;146A(19):2468-72. doi: 10.1002/ajmg.a.32226. PMID: 18348269

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