Metaphyseal Enchondromatosis With D-2-Hydroxyglutaric Aciduria

Clinical Features

Talkhani et al. (2000) described an English girl with D-2-hydroxyglutaric aciduria (see 600721) in association with spondyloenchondromatosis. The patient had macrocephaly, short stature, and weight below the 3rd percentile. She also had global developmental delay, dysmorphic features, alopecia, abnormal dental eruption, divergent squint with large corneas and thoracolumbar structural scoliosis. Upper and lower limbs showed features of rhizomelic shortening. Hip abduction was restricted by 50% bilaterally and associated with bilateral genu valgum. Radiographs of her spine revealed a double curve left thoracolumbar and right thoracic scoliosis; the vertebral bodies exhibited vertebral body hypoplasia with irregular end plates. The T11-L3 vertebrae showed modified central beaking. Radiographs of the pelvis revealed lateral subluxation of the capital femoral epiphyses with shallow, irregular acetabula of both hips. Narrowed sacrosciatic notches were also noted. The metaphyses of the distal femur and the knees showed gross abnormality with splaying columns of ossification centrally containing islands of unossified cartilage and deficient ossification peripherally with bulbous metaphyses resembling enchondromata. Metacarpals, metatarsals, and phalanges were short and stout, with flaring and irregular ossification of metaphyses.

Honey et al. (2003) described a male infant in South Africa with spondyloenchondromatosis and persistent D-2-hydroxyglutaric aciduria. The patient had shortening of the femurs, tibias, and fibulas bilaterally as well as bony irregularities with flaring of the metaphyses and bowing of the limbs. His motor and general milestones were slightly delayed, his speech development was severely delayed, and he was hypotonic. He also had a hyperpigmented skin discoloration with whorls and streaks covering the entire body. He had short stature, head circumference just below the 97th centile, low nasal bridge, epicanthic folds, simple ears with reduced cartilage, a left thoracolumbar scoliosis, short hands, stubby and tapering fingers, and joint laxity. Radiologic skeletal survey at the age of 17 months revealed extensive patchy irregularities or circumscribed radiolucencies in the metaphyses of the tubular bones. The metaphyses themselves were expanded and the diaphyses were shortened but otherwise normal. To a lesser extent the flat bones showed similar lucencies. The vertebral bodies were ovoid and dysplastic with end-plate sclerosis. These changes were maximal in the lumbar region. MRI of the skull and brain demonstrated a number of abnormalities. Moderate dilatation of the lateral ventricles and especially of the occipital horns was noted, with the anterior aspect of the right temporal horn also being grossly dilated. A large cavum septum pellucidum et vergae was present. The posterior fossa was small, with a low-lying tentorium and resultant relative crowding of the cerebellum. A septum in the body of the left lateral ventricle gave rise to a lateral loculation. The falx cerebri was deficient in its central portion with mild interdigitation of the medial gyri.

Bayar et al. (2005) reported a 17-month-old boy with waddling gait, swollen joints, generalized and severe ossification defects in the metaphyses of the long bones, normal motor (except for delay in walking) and mental development, and a simple posterior fusion defect of L5. Calcium, phosphate, and alkaline phosphatase levels were normal, but targeted analysis of urinary organic acids repeatedly revealed excretion of 2-hydroxyglutaric acid. Bayar et al. (2005) noted that this patient and those reported by Honey et al. (2003) and Talkhani et al. (2000) were similar in terms of severe metaphyseal lesions, mild vertebral involvement, and presence of 2-hydroxyglutaric acid in the urine. They suggested that the 3 patients had a radiographically and biochemically distinct entity, which they called 'metaphyseal enchondrodysplasia with 2-hydroxyglutaric aciduria.'

Vissers et al. (2011) described 4 patients with what they called 'metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria (MCHGA)', one of whom (patient 1) was the patient described by Bayar et al. (2005).

Molecular Genetics

Vissers et al. (2011) performed exome sequencing of blood DNA in 4 unrelated patients, one of whom (patient 1) was previously described by Bayar et al. (2005), with metaphyseal enchondromatosis with urinary excretion of D-2-hydroxyglutaric acid. No evidence for recessive mutations was found; instead, 2 patients showed mutations in the IDH1 gene (147700), predicting R132H and R132S as apparent somatic mosaicism. Sanger sequencing confirmed the presence of the mutation in blood DNA in one patient (patient 2), and in blood and saliva (but not in fibroblast) DNA in the other patient (patient 3). In enchondromas and hemangiomas from patients with other forms of enchondromatosis, i.e., Ollier disease (166000) and Maffucci syndrome (614569), somatic heterozygous mutations were found by Pansuriya et al. (2011) and Amary et al. (2011) in the IDH1 gene as well as in the IDH2 gene, including R132H in IDH1. Patient 2 described by Vissers et al. (2011), with the R132H mutation in IDH1, had retarded growth, macrocephaly, a wide forehead, slightly downslanting palpebral fissures, telecanthus, long philtrum, thin lips, retrognathia, short neck, shield thorax, widely spaced nipples, discrete widening of wrist, knee, and ankle joints, genua vara, and lumbar scoliosis. Radiographic study confirmed the scoliosis and showed metaphyseal dysplasia and enchondromatosis. Also, an MRI done at age 6 months showed a lymphangioma within the base of the tongue. Patient 3 described by Vissers et al. (2011), with the R132S mutation in IDH1, had some additional, previously undescribed features such as an ostium secundum-type interatrial defect with a subaortic interventricular septum defect, dry skin, visible veins, multiple joint contractures, an anal fistula, generalized muscular hypotonia, severe psychomotor delay, horizontal nystagmus, agenesis of the left kidney, microcephaly, delayed myelination and gyration, mildly enlarged frontal subarachnoid spaces, enlarged ventricles, white matter atrophy, a cystic structure in the left temporal lobe, symmetrical hyperintensity of globus pallidus and central pontine tracts, cerebellar dysplasia, ectasia, and marked tortuosity of intracerebral vessels.