Search for a rare disease
Other search option(s)
A rare multisystemic disease characterized by small-vessel brain disease, cerebral aneurysm, and extracerebral findings involving the kidney, muscle, and small vessels of the eye.
ORPHA:73229Classification level: Disorder
- Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome
- Hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome
- Prevalence: <1 / 1 000 000
- Inheritance: Autosomal dominant
- Age of onset: Childhood
- ICD-10: I99
- OMIM: 611773
- UMLS: C2673195
- MeSH: -
- GARD: 10889
- MedDRA: -
The prevalence of HANAC syndrome (hereditary angiopathy-nephropathy-aneurysms-muscle cramps syndrome) is not available, but at least six affected families have been reported worldwide to date.
Typical clinical manifestations of HANAC syndrome are the presence of bilateral retinal arteriolar tortuosity (systematically observed), small-vessel brain disease (including porencephaly, leukoencephalopathy, dilated perivascular spaces, lacunar infarcts, and microbleeds, with variable clinical expression), single or multiple intracranial aneurysms (mainly located on the carotid siphon), bilateral cortical and medullary renal cysts, muscle cramps, hematuria, and persistent elevation of serum creatine kinase (CK) concentration. Other eye defects (non-syndromic autosomal dominant congenital cataract, eye anterior segment anomaly of Axenfeld-Rieger type) and glomerular filtration rate decrease have also been reported. More occasional clinical signs include Raynaud phenomenon and supraventricular arrhythmia.
The causative gene of HANAC is COL4A1 (13q34) encoding the alpha1 chain of collagen IV, a major component of basement membranes also involved in embryogenesis and cell migration/differentiation. To date, six pathogenic variants have been identified; all localized in exons 24 and 25 within the CB3 [IV] domain of COL4A1. They affect glycine residues localized in a 30-amino acid region of the protein.
The diagnosis is based on the characteristic clinical findings. Testing to establish the diagnosis includes fundoscopic examination (retinal arterial tortuosity), renal ultrasound examination (cysts), and brain MRI (white matter lesion, chronic hemorrhagic foci, cerebral arterial aneurysm). Diagnosis is established in an individual with suggestive features of HANAC and the identification of a heterozygous pathogenic variant in COL4A1 by molecular genetic testing.
The differential diagnosis includes anophthalmia/microphthalmia (A/M), autosomal dominant retinal vasculopathy with cerebral leukodystrophy (RVCL), brain small-vessel with hemorrhage, cerebral autosomal dominant/recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL/CARASIL), COL4A2-related porencephaly and intracerebral hemorrhages, and porencephaly type I.
Prenatal diagnosis is possible for pregnancies at increased risk for a COL4A1-related disorder if the COL4A1 pathogenic variant has been identified in an affected family member.
The pattern of inheritance of HANAC syndrome is autosomal dominant. Genetic counseling can inform parents that the risk of transmitting the mutation responsible for the disease to their children is 50%. The proportion of HANAC syndrome cases caused by a de novo pathogenic variant has been estimated to be at least 27%.
Management and treatment
There is no effective treatment to date for individuals with COL4A1-related disorders. Possible symptomatic therapies include supportive care (based on individual needs, e.g. cataract surgery for severe lens opacities), treatment of hypertension to reduce risk of stroke and avoiding (unless if absolutely necessary) anticoagulant and platelet anti-aggregant use.
Very rarely, end stage renal disease or hemorrhagic stroke may occur.
- Clinical genetics review
- English (2016)