Titel: Fourth Patient With Metaphyseal Chondromatosis With D-2-Hydroxyglutaric Aciduria Caused By A Recurrent IDH1 Mosaic Mutation
ID: P-ClinG-057
Art: Postertalk
Redezeit: 2 min
Session: Poster Session

Referent: Bianca Greiten (Lübeck/DE)

Abstract - Text


Mutations in the isocitrate dehydrogenase (IDH) enzyme IDH1, found in various tumors, lead to elevated levels of D-2-hydroxyglutarate (D-2HG) by changing the enzymatic activity of the IDH enzyme: α-ketoglutarate is converted to D-2HG instead of isocitrate to α-ketoglutarate. Mutations of the IDH1 gene as somatic mosaics cause metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid (MC-HGA). MC-HGA is a rare disorder characterized by metaphyseal disorganization, chondrodysplasia, urinary excretion of D-2HG and cerebral involvement. So far only 3 patients with an IDH1 mosaic variant have been described in the literature. Two of them had the pathogenic variant c.395G>A, p.(Arg132His) and one the pathogenic variant c.394C>A, p.(Arg132Ser) in the IDH1 gene. We report on one new patient with MC-HGA and review the literature.

We report on a 7-months-old girl with MC-HGA. Prenatal ultrasound revealed shortened long bones of the upper and lower extremities (from -2,4 SD to -4,0 SD), intrauterine growth retardation and an enlargement of the subarachnoid space. A prenatal karyogram from amnion cells showed a normal female karyotype (46,XX). Echocardiography showed a patent foramen ovale and tricuspid insufficiency. The patient had generalized hypotonia, motor delay, shortened long bones and flexion contractures of the right 3rd and 4th fingers. She presented with short stature (-2,2 SD) and head circumference was relatively large (+1,7 SD). Dysmorphic features included low-set ears, epicanthus, short nose with slightly anteverted nostrils, long philtrum, small upper lip, retrognathia and a prominent forehead. The girl suffered from hearing loss. Cerebral MRI showed enlarged subarachnoid space, immature and altered gyration, subdural hygroma, small pons, poorly developed tentorium cerebelli and falx cerebri as well as cerebral atrophy with a loss of white matter. Urine analysis showed an excessive excretion of hydroxy-glutaric-acid.

A 200 kb gain in 5p13.1p12(42493787_42695214) (GRCh37/hg19) encompassing exons 2 to 4 of the GHR gene was detected via Array-GCH in the patient and her mother (body height: 158 cm). The mother had pubertas praecox and was treated with decapeptyl to prolong the growth period (predicted body height without treatment 145 cm). It is unclear whether this gain plays a role in the familial short stature.

Whole exome sequencing showed the pathogenic variant c.395G>A, p.(Arg132His) in the IDH1 gene in somatic mosaicism. The variant was found in 59 of 152 reads (38,8%). This missense mutation has been described in various cancers and is predicted to be likely pathogenic. The mutation was not found in the parents. The phenotype of our patient overlaps with the phenotype of the three patients in the literature. Thus, this is the fourth reported patient with metaphyseal chondromatosis with urinary excretion of D-2-hydroxy-glutaric acid and a mosaic IDH1 variant.