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Madelin Cotton, Janice John, Maria C Caldas – Vasquez .

Department of Pediatrics, High Risk Children’s Clinic

Introduction

Learning Objectives:

- Describe clinical presentation of Hereditary Multiple Osteochondromas (HMO)

- Report a case of HMO with a premature patient with rickets

Hereditary Multiple Osteochondromas (HMO) is a rare genetic disorder characterized by the formation of multiple benign bone tumors called osteochondromas. It is a complex skeletal disorder caused by an autosomal dominant loss-of- function mutation on the EXT1 or EXT2 genes. These growths primarily develop in the long bones, such as the femur, tibia and humerus and are often associated with cartilage capped exostoses. While most osteochondromas remain asymptomatic, some can lead to complications such as pain, deformities, nerve compression or malignant transformation into chondrosarcoma. The conditions severity can range from mild with few symptoms to more severe forms where functional limitation and cosmetic concerns become prominent. Early diagnosis of HMO is important as there is a low risk (2-5%) of malignant transformation to osteochondrosarcoma within a patient’s lifetime. Therefore, effective management involves monitoring the growth of osteochondromas, symptomatic treatment and in some cases surgical intervention.

Case Report

A 4-month-old female presented for an endocrine evaluation of rickets. During a hospital admission shortly after birth, the patient was noted to have elevated alkaline phosphatase and low calcium, and phosphate. A long bone x-ray obtained demonstrated evidence of healing rickets. Patient was treated with supplemental Vitamin D.

After first year of life patient had failure to thrive , reason why a genetic evaluation was done in the setting of rickets and poor growth. Hereditary Multiple Osteochondromas was diagnosed via whole exon sequencing (WES) at 2 years-old.

Imagining

Discussion

HMO is a complex skeletal disorder due to an autosomal dominant loss-of-function mutation on the EXT1 or EXT2 genes. Early diagnosis of HMO is important as there is a low risk, 2-5%, of malignant transformation to osteochondrosarcoma within a patient’s lifetime and therefore patients will need routine surveillance of their osteochondromas to monitor for malignant transformation. Diagnosis can often be delayed as HMO can often be misdiagnosed as solitary osteochondroma, especially if there are only a few lesions present in a particular extremity. To help prevent misdiagnosis, X-rays should be done in all extremities at the time of diagnosis to assess for the presence of other lesions. Additionally, due to the autosomal dominant inheritance pattern of this disorder, genetic counseling to the family and patient is crucial

Conclusion

Hereditary multiple osteochondromas (HMO is characterized by growths of multiple osteochondromas. The median age of diagnosis is three years; the case presented was diagnosis at 3 years old. Nearly all affected individuals are diagnosed by age 12 years.

Osteochondromas can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, short stature, premature osteoarthrosis, and compression of peripheral nerves, however the case was asymptomatic at time of diagnosis.

At time of diagnosis no lesions were concerning for malignancy. The risk for malignant degeneration to osteochondrosarcoma increases with age, although the lifetime risk for malignant degeneration is low (~2%-5%).

HMO is inherited in an autosomal dominant manner. Penetrance is approximately 96% in females and 100% in males. In 10% of affected individuals HMO is the result of a de novo pathogenic variant. At the time of this case presentation, there were results available for family members.

References

Rueda-de-Eusebio, A., Gomez-Pena, S., Moreno-Casado, M.J. et al. Hereditary multiple exostoses: an educational review. Insights Imaging 16, 46 (2025).

Clement ND, Porter DE. Hereditary multiple exostoses: anatomical distribution and burden of exostoses is dependent upon genotype and gender. Scott Med J. 2014b;59:35–44. PubMed PMID: 24413927.

Hennekam RC. Hereditary multiple exostoses. J Med Genet. 1991;28:262–6. PubMed PMID: 1856833.

Li Y, Wang J, Wang Z, Tang J, Yu T. A genotype-phenotype study of hereditary multiple exostoses in forty-six Chinese patients. BMC Med Genet. 2017;18:126. PubMed PMID: 29126381.

Case Report

WES Results:

-WES reported a heterozygous pathological variant c.600 G>A p.(W200) of EXT1.

Lab results at the time of initial evaluation:

Calcium: 10.5 mg/dL (8.5-10.6 mg/dL)

Phosphorus: 5.0 mg/dL (4.0-8.0 mg/dL)

Vit D, 25-hydroxylase: 27 ng/dL (30-100 ng/dL)

Alkaline Phosphatase: 453 U/L (100-334 U/L)

Lab results at the time of last visit:

Calcium: 10.3 mg/dL (8.5-10.6 mg/dL)

Phosphorus: 5.2 mg/dL (4.0-8.0 mg/dL)

Vit D, 25-hydroxylase: 44 ng/dL (30-100 ng/dL)

Alkaline Phosphatase: 210 U/L (100-334 U/L)

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Imaging

An Infant with Suspected Rickets: Unveiling Hereditary Multiple Osteochondroma

A. Increased metaphyseal cupping and fraying of the distal femur and proximal tibia. Periosteal reaction of the femur and tibia

B. Exostoses present on the proximal femurs bilaterally

C. Bony changes present on the left tibia laterally

D. Exostoses present on the left proximal humerus and distal radius laterally