A number sign (#) is used with this entry because of evidence that squalene synthase deficiency is caused by homozygous or compound heterozygous mutation in the FDFT1 gene (184420) on chromosome 8p23.

Squalene synthase deficiency (SQSD) is an autosomal recessive disorder characterized by profound developmental delay, brain abnormalities, 2/3 syndactyly of the toes, and facial dysmorphisms, as well as low total and LDL-cholesterol and abnormal urine organic acids (Coman et al., 2018).

Coman et al. (2018) reported 3 patients from 2 families with squalene synthase deficiency. The sibs from family 1 were the products of a nonconsanguineous union of European parents and had very similar features and course. They were both born at term with normal growth parameters and developed seizures in the neonatal period. Brain MRI showed hypoplasia of the corpus callosum and white matter loss. Both had profound global developmental delay at 10 and 7 years, with irritability and poor sleep initiation. Both children developed failure to thrive and required gastrostomy tube feeds. Optic nerve hypoplasia with cortical visual impairment was present, but neither had cataracts. Facial dysmorphisms included depressed nasal bridge, square nasal tip, epicanthal folds, mild micrognathia, and mild retrognathia. The 7-year-old brother had bilateral cryptorchidism, large ears, and dorsal foot fat pads. The 10-year-old sister had low-set, posteriorly rotated ears. Both had thin gracile bones, flexion deformities at the knees, and 2/3 toe syndactyly. Dry skin with photosensitivity was present, and lack of hair pigment was seen on light and electron microscopy. Total and low density lipoprotein (LDL) cholesterol were low in both, while high density lipoprotein cholesterol (HDL-C) was low for the sister, but normal for the brother. Very low density lipoprotein (VLDL) and triglycerides were normal. Plasma farnesol was more than 10 times normal in both. Gas chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy profiles in urine yielded a consistent and complex pattern of elevated methylsuccinic acid, mevalonate lactone, mesaconic acid, and 3-methyladipic acid. Saturated and unsaturated branched-chain dicarboxylic acids and glucuronides derived from farnesol were also observed. The boy from family 2 was also born of nonconsanguineous European parents. Findings were similar except that his brain MRI showed diffuse polymicrogyria as well as central white matter and cortical volume loss. He had hypospadias without cryptorchidism, bicuspid aortic valve, and flexion deformities of elbows rather than knees. Total cholesterol and LDL-C were low, with normal HDL-C and triglycerides. VLDL-C and farnesol were not measured.

The transmission pattern of SQSD in the families reported by Coman et al. (2018) was consistent with autosomal recessive inheritance.

In 3 patients with squalene synthase deficiency, Coman et al. (2018) identified compound heterozygous or homozygous mutations in the FDFT1 gene by whole-exome sequencing. Two sibs were compound heterozygous for a 120-kb deletion (184420.0001) and an intronic mutation resulting in aberrant splicing (184420.0002). An unrelated child was homozygous for a 16-bp intronic deletion (184420.0003).