Knowledge on rare diseases and orphan drugs

Only 4 cases have been reported in the literature to date.

Microcephaly is present at birth along with hypotonia, failure to thrive and facial dysmorphic features such as bitemporal narrowing, ptosis, puffy cheeks, and micrognathia. Limb anomalies that have been reported include postaxial polydactyly of upper or lower limbs (mainly feet), bilateral syndactyly between the 2nd and 3rd or 2nd and 4th toes and bilateral club feet. Developmental delay and learning disability starting in early childhood have been noted in all patients. Additional anomalies have also been reported such as corneal clouding, cataract, conductive hearing loss, gingival hypertrophy, ambiguous genitalia, horseshoe kidney (see this term) and neurological manifestations (i.e. myoclonus). Liver disease seen in patients ranges from hypertransaminasemia to progressive cholestasis and can lead to end stage hepatic disease, occurring in childhood.

Lathosterolosis is due to mutations in the SC5D gene (11q23.3). A mutation in this gene leads to a deficiency in 3-beta-hydroxysteroid-delta-5-desaturase, which is necessary in the conversion of lathosterol into 7-dehydrocholesterol. This prevents the synthesis of cholesterol, which among other functions acts as a structural lipid, a precursor for bile acids and steroid hormones, and is necessary for the maturation of hedgehog morphogens during embryonic development.

Diagnosis is based on clinical and biochemical findings. An elevation of lathosterol by gas chromatography/mass spectroscopy (GC/MS) is noted in both skin fibroblasts and plasma. The levels of 7-dehydrocholesterol and cholesterol are normal or low. Molecular genetic testing revealing mutations in the SC5D gene confirms the diagnosis.

The main differential diagnosis is Smith-Lemli-Opitz syndrome (see this term) that shares many clinical features with lathosterolosis but that can be excluded with biochemical and genetic testing.

Prenatal diagnosis is feasible if the mutations are known but it has never been performed given the rarity of the disease.

Lathosterolosis is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and they therefore have a 25% risk of having an affected child at each pregnancy.

Treatment involves cholesterol supplementation and reduction of 7-hydrocholesterol. Simvastin, a 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitor, has been proven to be beneficial in normalizing the lathosterol level in one patient. Liver transplantation was successful in normalizing liver function and cholesterol levels in a patient who had developed end stage liver disease. Moreover, it appeared to improve neurocognitive functions. Regular opthalmological evalutations and ultrasound monitoring of the liver are recommended.

The prognosis is poor but treatment appears to prolong life and arrest progression of neurological damage.

Last update: November 2014 - Expert reviewer(s): Dr Nicola BRUNETTI PIERRI - Pr Giancarlo PARENTI