Metaphyseal Chondrodysplasia, Schmid Type (MCDS): A Comprehensive Overview for Endocrinologists

Created/Updated: #dec2024

Research by : Google Gemini 1.5 Deep Research
Edited by: Dr. Om J Lakhani

Metaphyseal chondrodysplasia, Schmid type (MCDS) is a rare, inherited skeletal dysplasia primarily affecting the long bones1. This condition presents unique challenges for endocrinologists due to its impact on growth and development, and its potential overlap with other endocrine disorders. This comprehensive overview will delve into the clinical presentation, genetic basis, diagnosis, management, and prognosis of MCDS, equipping endocrinologists with the knowledge to effectively diagnose and manage patients with this condition.

Clinical Presentation and Diagnosis

MCDS typically manifests in early childhood, often becoming apparent when a child begins to walk2. It is important to note that MCDS can be misdiagnosed as rickets or achondroplasia3. Historically, MCDS was characterized by irregularities of the long-bone metaphases with normal hand and vertebral development4. Spine involvement was evident in scattered cases, but often resolved as patients aged4. The incidence of MCDS is approximately three to six cases per 1,000,0005.

Clinical Features

Key clinical features include:

Disproportionate short stature: Individuals with MCDS have shortened limbs, particularly in the upper arms and thighs (rhizomelic shortening), leading to a disproportionately short stature1.
Genu varum: Bowed legs are a hallmark of MCDS, resulting from abnormal bone growth in the metaphyses (the wide portions of long bones)6.
Waddling gait: The combination of coxa vara (a deformity of the hip joint) and genu varum often leads to a distinctive waddling gait1. This waddling gait may be caused by insufficient gluteal muscles4.
Lumbar lordosis: An exaggerated inward curve of the lower back is commonly observed6.
Pain: Some children experience pain in the legs and joints, which may worsen with age6. Joint stiffness may also occur6.
Other features: Outward flaring of the lower rib cage and a small chest (thorax) may be present6. Wrist swelling and elbow contractures are also possible7.

Radiographic Findings

While these clinical features can raise suspicion for MCDS, a definitive diagnosis relies on radiographic findings. X-rays typically reveal:

Metaphyseal irregularities: Widened growth plates, metaphyseal flaring, and cupping are characteristic radiographic features, particularly in the long bones of the lower limbs1.
Coxa vara: The angle between the head and neck of the femur is reduced1.
Less common findings: Platyspondyly and vertebral end plate irregularities may be observed in some cases2.

In addition to clinical and radiographic characterization, molecular genetic testing for the COL10A1 gene is useful to confirm a diagnosis8.

Genetic Basis

MCDS is caused by mutations in the COL10A1 gene, which encodes the alpha chain of type X collagen1. This gene is crucial for the proper development and function of growth plate cartilage. COL10A1 encodes the alpha chain of type X collagen, a short chain collagen that is used during endochondral ossification by hypertrophic chondrocytes9. Mutations in this gene disrupt the production or structure of type X collagen, leading to the characteristic bone abnormalities seen in MCDS4. MCDS is inherited in an autosomal dominant manner, meaning that only one copy of the mutated gene is sufficient to cause the condition1.

It's important to note that there can be attenuated phenotypes and intrafamilial phenotypic variations in MCDS1. This means that the severity of the condition can vary significantly between individuals, even within the same family, which can make diagnosis challenging.

Molecular Mechanism

While the exact molecular mechanisms underlying MCDS are still being investigated, research suggests that misfolded collagen X can lead to endoplasmic reticulum (ER) stress and growth plate disruption1. This ER stress contributes to the abnormal bone growth and development seen in MCDS. Further research is needed to fully elucidate the molecular pathways involved and to develop targeted therapies.

Management and Treatment

Currently, there is no cure for MCDS. Management focuses on alleviating symptoms and improving quality of life. Orthopedic correction is the only possible treatment11. This may involve:

Physical therapy: To improve muscle strength, flexibility, and gait. Specific exercises may focus on strengthening the gluteal muscles, improving hip and knee range of motion, and promoting balance and coordination6.
Orthopedic surgery: To correct bone deformities, such as coxa vara and genu varum. Surgical interventions may include osteotomies (cutting and realigning bones) and limb lengthening procedures3. Valgus osteotomy of the proximal femur is to be considered for children with significant coxa vara3. In some patients, varus alignment may improve spontaneously during childhood4.
Pain management: Analgesics and other pain management strategies may be necessary to address joint pain and discomfort. This may include over-the-counter pain relievers, nonsteroidal anti-inflammatory drugs (NSAIDs), or in some cases, stronger pain medications6.
Supportive care: This may include special education services, social support, and vocational training to help individuals with MCDS reach their full potential6.

It's important to note that growth hormone therapy is not effective in increasing final adult height in individuals with MCDS6. However, it might be considered in cases with co-existing growth hormone deficiency, as suggested by a case study where a patient with MCDS was also diagnosed with growth hormone deficiency and hypothyroidism12.

In the initial management of MCDS, it is crucial to evaluate calcium and vitamin D levels to differentiate it from rickets4. Vitamin D deficiency can mimic some of the radiographic features of MCDS, and misdiagnosis can lead to inappropriate treatment. It's important to remember that vitamin D supplementation may precipitate toxicity in patients with MCDS4.

Emerging Therapies

Exciting research is underway to develop targeted therapies for MCDS. One promising avenue is the repurposing of carbamazepine, an anticonvulsant drug, to treat MCDS13. Studies have shown that carbamazepine can reduce endoplasmic reticulum stress, a cellular process that contributes to the pathogenesis of MCDS1.

A phase 1-2 clinical trial is currently evaluating the safety and efficacy of carbamazepine in ambulant children with MCDS up to age 11 years (before growth plates fuse)1. This trial is investigating whether carbamazepine can reduce pain and mobility difficulties in children with MCDS. The results of this trial are eagerly awaited and could potentially lead to a new treatment option for this rare condition.

Prognosis and Long-Term Outcomes

The long-term prognosis for individuals with MCDS is generally good. While short stature and some degree of skeletal deformity are common, intelligence is typically normal, and most individuals can lead fulfilling lives2. Adult height is typically more than 3.5 standard deviations below the mean, although a wide spectrum that overlaps normal height has been reported2. Early motor milestones may be delayed due to orthopedic complications2. Hand and vertebral involvement can resolve with age2.

However, MCDS can be debilitating in the long term because it causes pain, and hip and knee deformity15. At the time of designation, metaphyseal chondrodysplasia, Schmid type affected less than 0.01 in 10,000 people in the European Union (EU)15. This was equivalent to a total of fewer than 500 people15.

To illustrate the challenges and triumphs of living with MCDS, consider the case of Morgan Stalker, a student nurse in Scotland16. Despite undergoing multiple surgeries to correct bone deformities, Morgan has pursued her dream of becoming a nurse and is an advocate for the MCDS community. Her story highlights the resilience and determination of individuals with MCDS.

Key Takeaways

MCDS is a rare skeletal dysplasia caused by mutations in the COL10A1 gene, leading to abnormal bone growth and development.
Early diagnosis and intervention are crucial to minimize long-term complications and improve quality of life3.
Management of MCDS requires a multidisciplinary approach involving endocrinologists, orthopedists, physical therapists, and other healthcare professionals6.
While there is no cure for MCDS, various interventions, including physical therapy, orthopedic surgery, and pain management, can help to alleviate symptoms and improve quality of life.
Emerging therapies, such as carbamazepine, offer hope for new treatment options in the future.
Psychological support and counseling may be beneficial for individuals with MCDS and their families6.

Works cited

Metaphyseal Chondrodysplasia Schmid type - widening the phenotype: Significant variable expression in two familial cases with heterozygous COL10A1 variants, accessed on December 18, 2024, https://www.orthojournal.org/articles/metaphyseal-chondrodysplasia-schmid-type-widening-the-phenotype-significant-variable-expression-in-two-familial-cases-with-heterozygous-col10a1-variants.html
Schmid Metaphyseal Chondrodysplasia - GeneReviews® - NCBI Bookshelf, accessed on December 18, 2024, https://www.ncbi.nlm.nih.gov/books/n/gene/schmid-mcd/
Schmid's Type of Metaphyseal Chondrodysplasia: Diagnosis and Management - PMC, accessed on December 18, 2024, https://pmc.ncbi.nlm.nih.gov/articles/PMC6594483/
Schmid Type Metaphyseal Chondrodysplasia in a Large Single Genetic Lineage, accessed on December 18, 2024, https://www.humangeneticsjournal.com/articles/schmid-type-metaphyseal-chondrodysplasia-in-a-large-single-genetic-lineage.html
A Novel Presentation of Metaphyseal Chondrodysplasia, Schmid Type with Factor VII Deficiency | Cureus, accessed on December 18, 2024, https://www.cureus.com/articles/28631-a-novel-presentation-of-metaphyseal-chondrodysplasia-schmid-type-with-factor-vii-deficiency
Metaphyseal Chondrodysplasia, Schmid Type - Symptoms, Causes, Treatment | NORD, accessed on December 18, 2024, https://rarediseases.org/rare-diseases/metaphyseal-chondrodysplasia-schmid-type/
Metaphyseal Chondrodysplasia - Pediatrics - Orthobullets, accessed on December 18, 2024, https://www.orthobullets.com/pediatrics/4099/metaphyseal-chondrodysplasia
HK J Paediatr (New Series) 2020;25:196-199, accessed on December 18, 2024, https://www.hkjpaed.org/details.asp?id=1299&show=1234
1300 - Gene ResultCOL10A1 collagen type X alpha 1 chain [ (human)], accessed on December 18, 2024, https://www.ncbi.nlm.nih.gov/gene/1300
Basic mechanisms of MCD in animal models - PubMed, accessed on December 18, 2024, https://pubmed.ncbi.nlm.nih.gov/19740719/
Metaphyseal chondrodysplasia, Schmid type - Orphanet, accessed on December 18, 2024, https://www.orpha.net/en/disease/detail/174
A rare case of SCHMID metaphyseal chondrodysplasia associated with hypothyroidism,growth hormone deficiency and celiac disease, accessed on December 18, 2024, https://pmc.ncbi.nlm.nih.gov/articles/PMC10406062/
MCDS-Therapy | EU Horizon 2020 project | Rare bone disease, accessed on December 18, 2024, https://mcds-therapy.eu/
MCDS-Therapy | Drug repurposing project - Beacon for rare diseases, accessed on December 18, 2024, https://www.rarebeacon.org/research/mcds-therapy/
Public summary of opinion on orphan designation Carbamazepine for the treatment of metaphyseal chondrodysplasia, Schmid type - European Medicines Agency, accessed on December 18, 2024, https://www.ema.europa.eu/en/documents/orphan-designation/eu3161746-public-summary-positive-opinion-orphan-designation-carbamazepine-treatment-metaphyseal-chondrodysplasia-schmid-type_en.pdf
Living with MCDS as told by Morgan Stalker, accessed on December 18, 2024, https://mcds-therapy.eu/living-with-mcds-as-told-by-morgan-stalker/