Familial hypercholesterolaemia

Gene: CYP27A1

Comment on list classification: This gene is rated as green as Tendon xanthomas are a feature of Cerebrotendinous xanthomatosis, 213700, which could lead to patients being investigated for FH.

Created: 9 Jul 2019, 9:21 a.m. | Last Modified: 9 Jul 2019, 9:21 a.m.

Panel Version: 1.25

Green List (high evidence)

Mutations in CYP27A1 lead to elevated serum cholestanol concentration & elevated urinary bile alcohols levels and a variety of neurological & non-neurological symptoms including tendon xanthomas which could lead to patients being investigated for FH. CTX is a rare and highly heterogeneous condition which regularly suffers from large delays in diagnosis. Including CYP27A1 on this panel has the potential to improve timely diagnosis.
1. Mignarri et al developed a ‘Suspicion Index’ with the aim of reducing the time to diagnosis of CTX and they commented;
‘We assigned a higher score to tendon xanthomas than to juvenile cataract, despite the higher frequency of the latter. Indeed, tendon xanthomas point strongly to CTX, although they may also be observed in sitosterolemia, which is very rare and does not share other phenotypical manifestations with CTX, and occasionally in familial hypercholesterolemia.
2. Wong et al published the results of a literature review which identified 91 publications and 194 cases which was presented along with their own case series of 5 patient. These selective quotes from the paper show that tendon xanthomas are a common manifestation of CTX.
‘Non-neurological symptoms were also documented: 147 (75.8%) had cataracts, 138 (71.1%) had xanthomas, and 42 (21.6%) had diarrhoea.’
‘As for non-neurological abnormalities, cataracts tended to develop earlier and throughout life; xanthomas developed throughout life’
They also calculated Cumulative Incidence Function (CIF) for each CTX symptom which gives an indication of the likelihood of a particular symptom having developed at any given age (best- & worst-case scenario) based on a subset of cases where age of symptom onset was available. The CIF graphs show that xanthomas may develop from childhood through into adulthood.
References
1. Mignarri et al, A Suspicion Index for early diagnosis and treatment of cerebrotendinous xanthomatosis. J Inherit Metab Dis (2104) 37:421-429
2. Wong et al, Natural history of neurological abnormalities in cerebrotendinous xanthomatosis. J Inherit Metab Dis. 2018 Jul;41(4):647-656

Created: 18 Jun 2019, 11:07 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebrotendinous xanthomatosis, 213700; Tendon Xanthomas, suspected FH

Publications

• 24442603: 29484516

Red List (low evidence)

Biallelic mutations cause cerebrotendinous xanthomatosis, a condition with many more features than FH; very unlikely to present like FH so shouldn't be on the panel.

Created: 13 Dec 2015, 9:49 p.m.