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This autosomal dominant association involves primarily
the heart (ventricular septal defect, atrial septal defect), pulmonary
artery stenoses, and hepatic dysfunction. Coagulation disorders can be
important. The presence of a broad forehead and long, thin face are
characteristic.
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Cardiovertebral Syndrome; Alagille-Watson Syndrome;
Watson-Miller Syndrome; Arteriohepatic Dysplasia (AHD);
Cholestasis-Peripheral Pulmonary Stenosis; Hepatic Ductular
Hypoplasia-Multiple Malformations Syndrome; Hepatofacioneuro-Cardiovertebral
Syndrome.
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Autosomal dominant with highly variable
expression. However, 15 to 50% of cases are new mutations. The defect has
been assigned to chromosome 20 band p12.
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Based on the clinical findings, although there is wide
variability in the manifestations of the disease. Diagnostic criteria
require the presence of cholestasis and two of the following findings:
characteristic facies, pulmonary artery stenosis, “butterfly”
hemivertebrae, and posterior embryotoxon (thickening of Descemet membrane
and corneal endothelium).
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Presentation of Alagille syndrome is highly
variable with respect to all the organ systems involved but consists mainly
of prolonged neonatal jaundice or cardiac symptoms/signs. However, patients
may be asymptomatic, or the jaundice may resolve by age 2 years. The
spectrum of hepatic disease is highly variable. Pruritus may be the main
symptom and often is invalidating. Liver biopsy reveals a paucity of
intrahepatic bile ducts. Other features are hepatomegaly, obstructive liver
disease, cirrhosis, splenomegaly, and truncal and facial telangiectasia.
Deficiencies of fat-soluble vitamins are frequent and may result in
coagulopathy (vitamin K), rickets (vitamin D), retinopathy (vitamin A, E),
peripheral neuropathy, and myopathy (vitamin E). Liver function tests show
elevated serum bile acid concentrations, conjugated hyperbilirubinemia, and
elevated serum levels of alkaline phosphatase and γ-glutamyl
transferase. The characteristic features of “cholestasis facies” are a
round face with prominent ears, bulbous nose, and pointed chin. A prominent
forehead, deeply set eyes, hypertelorism, straight nose, short philtrum,
down-slanted palpebral fissures, micrognathia/retrognathia, and
brachycephaly may occur. Cardiovascular anomalies are present in 95% of
patients and may include peripheral pulmonic stenosis, systemic
hypertension, atrial septal defect, ventricular septal defect, coarctation
of the aorta, and tetralogy of Fallot. Musculoskeletal features involve the
vertebrae (“butterfly” hemivertebrae denotes vertebrae, which are split
sagittally into pairs because of failure of fusion of their anterior
arches). Abnormal ribs, spina bifida occulta, delayed bone age, absent or
abnormal ulnae, terminal hypoplasia of the fingers, and clinodactyly of the
fifth finger may be seen. In association with posterior embryotoxon other
ophthalmologic features can occur, such as strabismus secondary to paresis
of ocular muscles, keratoconus (and other structural abnormalities of the
cornea), eccentric or ectopic pupils, enophthalmos, and pigmentary
retinopathy. Cerebrovascular complications may include MoyaMoya
Disease (progressive obliteration of the intracranial carotid arteries and
formation of an extensive vascular network of dilated small branches).
Other signs are regrouped as minor signs and include undescended/ectopic
testes, ureteral anomalies, renal agenesis/hypoplasia/dysplasia, renal
artery stenosis, intrauterine growth retardation, late puberty,
hypogonadism, and mental retardation. Hepatocellular carcinoma and papillary
thyroid carcinoma may occur as a late complication.
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