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Homocystinuria is characterized by skeletal manifestations (tall stature, dolichostenomelia, scoliosis, and pectus excavatum), ophthalmologic problems (ectopia lentis, severe myopia), vascular thromboembolism, and intellectual disability. Other features sometimes seen include: seizures, psychiatric problems, extrapyramidal signs, hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis.
Homocystinuria is caused by biallelic pathogenic variants in the CBS gene which encodes the cystathionine β-synthase enzyme. Biochemical findings include elevated urine homocystine, elevated plasma total homocysteine, homocystine, and methionine.
Here we present the case of a 14-year-old male of Italian descent who presented to the office of medical genetics after being referred for evaluation of suspected Marfan syndrome. His medical history was significant for life-long hypotonia, inguinal hernia, mild intellectual disability, mitral valve prolapse, proximal muscle wasting, lens dislocation, and joint contractures. On physical examination he was noted to have a Marfanoid habitus with pectus excavatum. Chromosome microarray revealed a 5.9 Mb interstitial deletion of arr [grch37] 21q22.2q22.3(40648264_46505895)x1. This chromosomal deletion is associated with developmental delay and intellectual disability. The deleted region includes the DSCAM gene, noted as a risk factor for autism spectrum disorder when haploinsufficient. This deletion also contains the CBS gene. Additional genetic testing revealed a pathogenic variant in the non-deleted allele of the CBS gene NM_000071.3:c.833T>C, LRG_777p1:p.Ile278Thr which confirmed the diagnosis of autosomal recessive Homocystinuria due to cystathionine beta-synthase deficiency.
Biochemical evaluation revealed a plasma homocysteine level of >250 umol/L (N=<15 umol/L) and serum Methionine 669 umol/L (13.9-36.5).
The patient was treated with a methionine free formula (Homactin AA) and low protein diet (1.2 gm/kg), Betaine, and supplemental B6. Plasma homocysteine level with treatment decreased to 16.6umol/L. The patient reported subjective improvements in sleep and focus. Homocystinuria should be kept in the differential diagnosis of all patients with unexplained Marfanoid habitus and/or ectopia lentis, even when presenting at an older age without thromboembolism.