Skeletal Radiology

, Volume 41, Issue 11, pp 1479–1487

Metaphyseal chondromatosis combined with D-2-hydroxyglutaric aciduria in four patients

Authors

  • Hye Jung Choo
    • Department of RadiologyInje University Pusan Paik Hospital
  • Tae-Joon Cho
    • Division of Pediatric OrthopaedicsSeoul National University Children’s Hospital
  • Junghan Song
    • Department of Laboratory MedicineSeoul National University Bundang Hospital
  • George E. Tiller
    • Department of GeneticsSouthern California Permanente Medical Group
  • Sun Hee Lee
    • Department of PediatricsInje University Pusan Paik Hospital
  • Gunbo Park
    • Department of Orthopaedic SurgeryInje University Haeundae Paik Hospital
  • In Sook Lee
    • Department of RadiologyPusan National University Hospital
  • Ralph Lachman
    • Medical Genetics InstituteCedars-Sinai Medical Center
  • Andrea Superti-Furga
    • Department of PediatricsUniversity of Lausanne
    • Department of RadiologyAjou University Hospital
Case Report

DOI: 10.1007/s00256-012-1442-1

Cite this article as:
Choo, H.J., Cho, T., Song, J. et al. Skeletal Radiol (2012) 41: 1479. doi:10.1007/s00256-012-1442-1

Abstract

We report four patients who presented with a severe form of metaphyseal chondromatosis in association with D-2-hydroxyglutaric aciduria (D-2-HGA). All patients showed splaying columns of irregular ossification defects with bulbous metaphyses of the long tubular bones, as well as remarkable involvement of the short tubular and flat bones. The vertebral bodies revealed platyspondyly with irregular, stippled endplates. D-2-HGA has been described as a neurometabolic disorder manifesting a broad range of impairment in mental and motor development. Although hydroxyglutaric acid was excreted in high amounts in the urine of all four patients described herein, no significant neurologic abnormalities were evident. This unusual combination of characteristic skeletal and metabolic abnormalities has rarely been reported. Thus, our report will facilitate the recognition of this distinctive entity, and we suggest that a urine organic acid screening be obtained in patients who present with generalized enchondromatosis.

Introduction

In 2000, Talkhani et al. [1] first reported spondyloenchondromatosis in association with D-2-hydroxyglutaric aciduria (D-2-HGA). Subsequently, two more cases were reported with similar findings [2, 3]. In spite of the extremely rare reports in the literature, a unique combination of skeletal and metabolic abnormalities led to the recognition of this disorder as a specific entity which was included as “metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria” in the most recent nosology and classification of genetic skeletal disorders [4]. In addition, whole-exome sequencing recently detected somatic mutations in the isocitrate dehydrogenase 1 gene (IDH1) in two patients with metaphyseal chondromatosis with D-2-HGA [5]. In the present report, we describe four unrelated patients with severe metaphyseal enchondromatosis with or without spinal involvement in combination with D-2-HGA, and discuss an unusual link between enchondromatosis and organic aciduria.

Case presentation

Patient 1

Patient 1 is a 4-year-old Korean boy who presented with short stature (93 cm, <10th percentile) and bowed legs. Prenatal and familial histories were unremarkable, and his motor and mental development was normal. Since 8 months of age, the child manifested deformity of the legs and swelling of the fingers. Radiographs of the lower extremities and hands at age 8 months showed columnar lucencies and streaks through the metaphyses of both lower extremities and iliac crests (Fig. 1). Metacarpals and phalanges showed uneven distribution of eccentric and irregular lucencies. MR imaging of the lower extremity at age 22 months showed extensive proliferation of the cartilage engulfing the adjacent osseous tissue along the iliac crest, acetabuli, and metaphyses of the lower extremities. Follow-up radiographs at age of 4 years revealed progression of the expansive and spiculated metaphyseal lucencies in the short and long tubular bones. Radiographs of the spine demonstrated mild platyspondyly with irregular endplates and punctate calcifications, thus supporting the diagnosis of spondyloenchondromatosis. Analysis of urinary organic acids revealed a highly elevated concentration of 2-hydroxy-glutaric acid, performed independently in the Seoul laboratory (240 μmol/mmol creatinine; normal <54) and in the Lausanne laboratory (481 μmol/mmol creatinine; normal <15). A DNA sample was submitted for whole-exome sequencing [5], however, no mutations were identified.
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Fig. 1

Patient 1. a Radiograph of the pelvis and lower extremities at age of 8 months shows symmetrically oval and striated radiolucent defects extended from the metaphyses into diaphyses of the femora, tibiae, and fibulae. Note irregular radiolucent defects at the rims of the iliac bones. b Hands at age 13 months show short and broad metacarpals and phalanges with metaphyseal cupping and multiple nodular or irregular metaphyseal lucent defects. c Coronal fat-suppressed contrast-enhanced T1-weighted image of the lower extremities at age of 22 months shows extensive nodular proliferations of the cartilaginous tissue, engulfing the adjacent osseous tissue at the rims of the pelvic bones and all the metaphyses of long bones. Follow-up radiographs at 4 years (df) reveal pronounced radiolucent defects with punctuated calcifications along the iliac wings, ischiopubic bones, sacral bones, long bone metaphyses, and tarsal bones. Note concurrent angular deformity at the right distal tibia and fibula. Lateral spine radiograph shows mild platyspondyly with irregular punctuate calcifications at the vertebral endplates and sacrococcygeal bones. Costochondral junctions of the ribs are expanded and containing irregular foci of calcification

Patient 2

Patient 2 is a 3-year-old Korean boy, followed in the Pediatric Orthopedic Clinic for leg length discrepancy. He was not short (height 94.5 cm, 50th percentile), and his physical and mental development was normal. On physical examination, the left lower extremity was shorter than the right without accompanying shape abnormality. His fingers were stout and curved. At the age of 5 months, radiographs disclosed irregularity of the iliac crest and metaphyses of the left proximal femur, which raising suspicion of a marrow infiltrative disease; however, hematologic and biochemical analysis showed no abnormality. At age of 8 months, radiographs of the lower extremities revealed shortening of the left leg with irregular streaks and metaphyseal lucencies. By 20 months of age, the leg length discrepancy had progressed and an out-toeing gait was observed. Skeletal survey revealed progression of the extent and degree of bulbous metaphyses with streaks and oval lucencies toward the diaphyses in the left lower extremity, irregularity of the left iliac crest, with a similar but milder metaphyseal changes in the right lower extremity (Fig. 2). The metacarpals and phalanges of the hands showed punched-out metaphyseal defects, more extensive in the left hand. The spine showed mild hypoplasia of the thoracolumbar vertebral bodies with irregularities of the endplates. Urine organic acid analysis confirmed an increased excretion of 2-hydroxyglutaric acid (236 μmol/mmol creatinine; normal <54). His cognitive development at age 3 years was normal and brain MRI disclosed no abnormality.
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Fig. 2

Patient 2 at age of 22 months. a The pelvis and lower extremities show splaying of the metaphyses of the left femur, tibia, and fibula, with expansile lucent defects, and the right side shows changes similar but subtle in extent, resulting in leg length discrepancy. The rims of the left pelvic bones are irregular with punched out defect along the iliac crest. The epiphyses of the left femur and tibia are irregular, containing radiolucent areas. b The left hand shows short and broad metacarpals and phalanges with eccentric radiolucent defects. The distal radius and ulna show changes similar to those in the hand. The lesser extent and degree of metaphyseal defects are seen in the right hand. c Lateral spine radiograph shows mild platyspondyly with irregularities of the anterior borders and endplates of the vertebral bodies. Note flaring of the costochondral junctions of ribs

Patient 3

Patient 3 is a 17-year-old Korean boy referred to the orthopedic clinic for limb-lengthening surgery due to marked short stature (132 cm, <3 percentile). He was the first child of normal parents and extended family history was unremarkable. He was consistently short through childhood, but psychomotor development was normal. Radiographs of the knees and hands at age of 6 years showed a marked degree of bulbous expansion of the distal femora, proximal tibia, and fibula with lucencies and speckled calcifications. The hands showed disproportionate finger length, with shortening of metacarpals and phalanges, and expansion of its metaphyses with irregular lucencies (Fig. 3). At age 17, hands were stout with digital disproportion, and several bluish nodules were observed. Pectus excavatum and calcaneovalgus were also noted. Follow-up radiographs revealed persistence of bulbous enlargement and streaky lucencies at the metaphyses. The pelvis showed small iliac wings containing columns of lucencies and dense streaks. Disproportional lengths of the fingers were exaggerated and obvious enchondromatosis persisted. In addition to enchondromatous lesions, multiple calcified phleboliths within the swollen soft tissues suggested associated hemangiomas, and the possibility of Maffucci syndrome was raised. Radiographs of the spine showed no distinct platyspondyly or irregularity of the end plates. Urinary screening for 2-HGA revealed a markedly increased excretion (943 μmol/mmol creatinine; normal <20).
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Fig. 3

a, b Patient 3 at age of 6 years. Radiographs of the knees and hands show symmetrically expanded metaphyses of the long bones, with irregular radiolucencies and stippled calcifications at the metaphyses of the distal femora, proximal tibiae, fibulae, ulnae, and radii. The pins due to previous surgery are seen at the left tibia. The metacarpals and phalanges of the hands are short and stout with metaphyseal cupping and irregular radiolucencies. c At age 17, he shows short limbed short stature (height 132 cm). Pectus excavatum and calcaneovalgus are noted. Hand shows nodular enlargement with digital disproportion. d, e Radiograph of the pelvis demonstrates small and narrow iliac wings, containing dense vertical streaks intermixed with irregular lucencies. Note narrow sciatic notches. The femoral necks are short and wide with coxa valga deformity. The metaphyses of the distal femur, proximal tibia and fibula are symmetrically expanded and show the same pattern of irregularly lucent and dense lesions as compared to the earlier radiograph. f The hands show persistent radiolucencies and metaphyseal cupping of the shortened metacarpals and phalanges. Note multiple exophytic soft tissue masses containing calcified phleboliths. The disproportional growth of the fingers is accentuated. g Lateral spine radiograph shows pectus excavatum. The costochondral junctions of the ribs are expanded. The vertebral bodies are essentially normal. Spinal stenosis is noted at the lower lumbar spinal canal

Patient 4

Patient 4 is of Hispanic origin who presented to the genetics clinic at 7 years of age with short stature. He was short since birth, and had a history of mild delays in motor and speech development. However, by age 7 years, he was performing at grade level. At that time, his height was 92 cm (<5 percentile; 50 percentile for 3 years). He had a mildly increased lumbar lordosis. Extremities were short in all segments, with bowing of the long bones, ulnar deviation of the left forearm, and multiple nontender bony protuberances. Skin exhibited three small café au lait spots as well as reticular hypopigmentation over the left chest. Radiographic survey revealed shortening of all segments of the tubular bones, with extensive widening and distortion of the metaphyses (Fig. 4). Stippling was evident in the metaphyses of all of the long bones. There was a mild increase of the intervertebral spaces, with irregularities of the vertebral endplates and some stippling throughout the spine. The iliac wings had a sunburst appearance with multiple lytic lesions superimposed. Urine mucopolysaccharide screen was normal, but urine organic acid analysis revealed high levels of 2-HGA; the presence of the D-isomer was confirmed in the laboratory of Cornelius Jakobs.
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Fig. 4

Patient 4 at age of 7 years. a Humerus exhibits severe enchondromatous changes containing punctuate/popcorn calcifications extending down from the proximal metaphysis into the diaphysis. There is less involvement at the elbow and glenoid region. b Hand and wrist reveal typical enchondromas with expanded lesion of the proximal and middle phalanges, metaphyses of the 2nd, 3rd, and 4th metacarpals as well as wrist involvement. c. Pelvis and hips show symmetrical involvement of iliac wing and ischia with sunburst appearance of ovoid and streaks of lucent lesions. The same pattern of disorganized growth is seen in the femoral neck portions. The capital femoral epiphyses are spared. d Mid femurs to ankles again revealing typical enchondromata involving the dia-metaphyseal areas with club-shaped long bone ends; the severe involvement has resulted in significant long bone shortening. Ossification in the metaphyses is distorted and intermingled with spotty and dense nodules. e Lateral view of the thoraco-lumbar spine shows mild platyspondyly with endplate irregularity of vertebral bodies suggesting enchondromatous involvement

The clinical and radiographic features of the present patients are summarized in Table 1 as compared to five previous reports documenting generalized enchondromatosis associated with 2-HGA.
Table 1

Clinical and radiological summary of five reported and four present patients with metaphyseal chondromatosis associated with 2-hydroxyglutaric aciduria

 

Case 1

Case 2

Case 3*

Case 4

Case 5

Case 6*

Case 7

Case 8

Case 9

Patients in previous reports and present cases

Talkhani et al. 2000

Honey et al. 2003

Bayar et al. 2005

Vissers et al. 2011

Vissers et al. 2011

Present case (patient 1)

Present case (patient 2)

Present case (patient 3)

Present case (patient 4)

Clinical

 Consanguinity

+

 Age at exam

2 years

11 months

30 months

14 months

14 months

4 years

3 years

17 years

7 years

 Short stature

+

+

+

+

+

+

+

 Developmental delay

+

+

+

+

+

 Mental retardation

nd

+

 Visceral abnormalities

Gall stone chylothorax

Tongue lymphangioma laryngomalacia

ASD, VSD, Lt renal agenesis

 CNS abnormalities

Large head

Brain MRI: ventriculomegaly

Brain MRI: delayed myelination, brain atrophy, ventriculomegaly

 Walking difficulty

+

+

+

+

+

+

+

+

+

 Limb shortening

+

+

+

+

+

+

+

+

+

 Genu valgum/varum

+

+

+

+

+

+

+

 Hand abnormalities

+

+

+

+

+

+

+

+

+

 Other abnormalities

Skin pigmentation

Muscular hypotonia, anal fistula

Hand hemangioma

Skin pigmentation

Radiological

 Scoliosis

+

+

+

+

 Platyspondyly/Irregular endplates

+

+

+

+

+

 Hip subluxation

+

 Narrow sciatic notch

+

+

+

+

+

+

 Bulbous metaphyses

+

+

+

+

+

+

+

+

+

 Short metacarpal/metatarsal

+

+

+

+

+

+

+

+

+

 Short phalanges

+

+

+

+

+

+

+

+

+

Urinalysis

D-2-hydroxy glutaric acid (normal range: <50 μmol/mmol creatinine)

High level

High level

High (>400)

High (>400)

High (>1,834)

High (>240)

High (>236)

High (>943)

High level

*Cases 3 and 6 included for mutation study in 2011 by Vissers et al. (ASD atrial septal defect, VSD ventricular septal defect, nd non-described)

Discussion

In the literature, there is nosologic confusion in the group of generalized enchondromatoses with vertebral involvement, and within that category, spondyloenchondrodysplasia and spondyloenchondromatosis seem to be used interchangeably. In 1976, Schorr et al. [6] reported enchondromatosis with severe platyspondyly in two brothers, and they proposed the term “spondyloenchondrodysplasia.” In 1978, Spranger et al. [7] reviewed the generalized enchondromatoses and outlined six subtypes. Of these, a particular form of enchondromatosis or spondylometaphyseal dysplasia, where multiple metaphyseal enchondromas were associated with irregular dysplasia of the vertebral bodies or mild platyspondyly, was described as “spondyloenchondromatosis.” Subsequently, several unrelated patients or siblings were reported under the term of spondyloenchondrodysplasia [810]. Most patients had normal intellect, except one patient reported by Tuysuz et al. [10] who manifested mental retardation and exhibited calcifications of the basal ganglia on brain CT. Renella et al. [11] reported spondyloenchondrodysplasia with spasticity, cerebral calcifications, and immune dysregulation. Recently, Lausch et al. [12] reported mutations in the gene for tartrate-resistant acid phosphatase (ACP5) in spondyloenchondrodysplasia associated with cerebral calcifications and autoimmunity. Although spondyloenchondrodysplasia and spondyloenchondromatosis have been used without distinction, there seem to be clinical distinctions that may reflect their different molecular basis.

In addition to the above conditions, another type of spondyloenchondromatosis, which is associated with D-2-HGA, was first reported by Talkhani et al. [1]. Bayar et al. [3] reported a similar patient with severe metaphyseal lesions and presence of 2-HGA, and proposed the name of metaphyseal enchondrodysplasia with 2-HGA. Recently, Vissers et al. [5] undertook whole-exome sequencing in four patients with severe metaphyseal chondromatosis associated with D-2-HGA; of these, one patient was reported previously by Bayar et al. [3] and another is patient 1 in the present report. The authors identified mutations in the IDH1 gene in somatic mosaic pattern in two of these patients. However, the remaining two patients (including our patient 1) did not harbor IDH1 mutations. Whether this represents genetic heterogeneity or significant genetic mosaicism may be resolved upon further study.

We have documented four patients who have the severe form of enchondromatoses, where lesions are present in almost all metaphyses of long tubular bones, as well as remarkable involvement of the short tubular and flat bones. Three patients in the present study had vertebral changes (either endplate irregularity, associated speckling calcifications or platyspondyly), hence, it seems reasonable to conclude that the patients described here have the diagnostic radiological features of spondyloenchondromatosis.

Short stature with asymmetrical or symmetric shortening of the tubular bones, as well as stout and/or bumpy appearance of hands were often the first clinical abnormalities noted. Walking was delayed, but other psychomotor developmental milestones were not significantly retarded in our patients. The extent and stage of development of the enchondromatous lesions differed in each patient according to the age at the time of skeletal survey. However, it should be noted that the lesions became more dramatic with age. Radiologically, there was usually bilaterally symmetric distribution of enchondromatoses with remarkable progression of the lesions in patients 1 and 4, whereas, despite the initial unilateral involvement, concurrent bilateral involvement developed on follow-up radiographs in patient 2. Follow-up radiographs were obtained in patient 3 at the age of 17 years. Though enchondromatous lesions stabilized after complete fusion of the growth plates, bulbous widening of the metaphyses as a residue of enchondromatoses persisted, which resulted in earlier failure of longitudinal growth and modifications of shape in the long bones. In addition, patient 3 had another interesting finding: palpable bluish nodules on both hands. The presence of multiple phlebolith-like calcifications in the exophytic swollen soft tissues on radiographs was consistent with cutaneous hemangiomas. Enchondromatoses with hemangiomas is well known as Maffucci syndrome.

The combination of two distinct abnormalities, enchondromatosis and 2-HGA, has been reported previously in five patients [13, 5]; clinical and radiologic features are summarized in Table 1. They had mild developmental delay but only one patient had mental retardation. Brain MRI in two patients showed hydrocephalus, delayed myelination, brain atrophy, and cerebellar dysplasia [5]. These imaging features of the brain are similar to those of D-2-HGA, of which the most consistent brain MR imaging findings are regarded as ventricular enlargement, delayed cerebral maturation, and subependymal cysts, but the milder phenotype had less consistent MRI findings [13]. D-2-HGA is an early onset neurometabolic disorder with a variable degree of mental and motor developmental abnormalities. The clinical problems vary from a neonatal-onset encephalopathy with seizures, mild-to-severe developmental delay, or no neurologic deficit [9, 1316]. There appears to be no correlation between the levels of D-2-hydroxyglutaric acid and clinical symptoms, making it impossible to predict the long-term outcome of the D-2-HGA itself [17]. All of our four patients had an exceedingly high level of urinary excretion of D-2-HGA with no significant CNS abnormalities or symptoms to date. However, ascertainment of additional cases and long-term surveillance are necessary to monitor for the possibility of late-onset CNS dysfunction.

To date, the pathophysiology of metaphyseal enchondromatosis in the presence of D-2-HGA remains elusive. It has been suggested that enchondromatosis associated with D-2-hydroxyglutaric aciduria may be related to the pleiotropic effects of a single gene defect or be due to a contiguous gene deletion [3]. Recent genetic investigations revealed mutations in IDH1 in patients with severe metaphyseal enchondromatosis associated with D-2-hydroxyglutaric aciduria [5]. In addition, somatic mosaic mutations of IDH1 and IDH2 were confirmed in patients with Ollier disease and Maffucci syndrome [18, 19]. However, analysis of IDH1 in one of our patients did not reveal a mutation. Another possibility is the mosaic pattern of IDH1 mutation effects only skeletal tissue and mutation analysis of the tumor tissue may reveal IDH1 mutations. Vissers et al. [5] speculated that a phenotype that recapitulated several of the neurologic, skeletal and metabolic aspects seemed to be acting independently of IDH1 mutations. Further genetic investigations may reveal other responsible genetic loci, which may uncover a common metabolic pathway.

In conclusion, we report four patients who had metaphyseal chondromatosis associated with D-2-hydroxyglutaric aciduria, as well as Maffucci syndrome. The clinical manifestations among patients need to be studied since there is no apparent correlation between the levels of D-2-HGA and the severity of the enchondromatous bone changes. We therefore recommend all patients with generalized enchondromatosis (with or without vertebral involvement) be evaluated for D-2-hydroxyglutaric aciduria and with brain MRI as well.

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