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Du Pan syndrome

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Du Pan syndrome
Other namesFibular hypoplasia and complex brachydactyly
Radiograph of the hands of an Egyptian patient with Du Pan syndrome
Radiograph of the feet of an Egyptian patient with Du Pan syndrome
SpecialtyMedical genetics
SymptomsComplicated brachydactyly and dysplastic/aplastic/hypoplastic fibula bones and hands and feet
ComplicationsBalance
Usual onsetBirth
DurationLife-long
CausesGenetic mutation
Risk factorsBeing born to consanguineous parents or having a parent with the disorder
Diagnostic methodThrough symptoms and molecular testing
PreventionNone
PrognosisGood
FrequencyVery rare, around 30 cases have been reported.

Du Pan syndrome, also known as fibular aplasia-complex brachydactyly syndrome, is an extremely rare genetic condition.[1] Unlike other rare genetic conditions, Du Pan syndrome does not affect brain function or the appearance of the head and trunk.[2] This condition is associated with alterations to the GDF5 (also known as CDMP1) gene.[3] The way that this condition is passed on from generation to generation varies, but it is most commonly inherited in an autosomal recessive manner, meaning two copies of the same version of the gene are required to show this condition.[4] Rare cases exist where the mode of inheritance is autosomal dominant, which means having only one version of the gene is enough to cause this condition.[2]

Symptoms

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Du Pan syndrome is a form of Acromesomelic Dysplasia, which is a condition that affects bone growth.[2] It is characterized by the incomplete development of the fibula, resulting in under-developed hands and feet and shorter fingers and toes.[5] However, the development in other aspects of the body and mind is not affected. The impacted extremities will appear disproportionately smaller in comparison to the rest of their body. They often describe the toes and fingers to appear “ball-like”, as they are missing the length between the foot and the ends of the toes, or the hand and the ends of the fingers.[6]

Limb Structure Variations

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One of the primary symptoms of Du Pan syndrome is brachydactyly, the presence of short digits (fingers and toes).[7] The thumbs and big toes are the most severely affected, often featuring shortened and broadened nails.[8] Syndactyly, the fusion of digits, often involves the second, third, and fourth toes.[8]

The condition includes missing or underdeveloped phalanges (bones of the fingers and toes).[3] The hands are the most affected part of the upper limb.[9] Although all metacarpals (bones of the hand) are present, they are relatively short.[9] Some individuals may have an extra finger on both hands, a condition called bilateral postaxial polydactyly.[10] In the lower limb, the middle segments (tibia and fibula) and the feet are significantly affected.[9] Short tarsal bones (bones of the foot) are also present.[9] A defining feature of the syndrome is fibular hypoplasia or aplasia, which refers to the underdevelopment or complete absence of the calf bone.[11]

Joint and Skeletal Variations

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Joint mobility is often restricted in individuals with Du Pan syndrome. Symptoms may include changes in hip and radius (forearm bone) morphology. In some cases, there is synostosis (fusion) of the carpal bones in the wrists.[10] A common feature in the feet is talipes equinovalgus or clubfoot.[7] This causes the feet to point downward and inward which can further affect mobility and posture.[12]

Another hallmark is hypoplastic nails, characterized by underdeveloped or completely absent nails and accompanying soft tissue variations.[9] Deviation of the fingers and toes is also observed.[7]

Additional Skeletal Features

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Short stature is a common trait, although individuals with the syndrome generally maintain a normal growth rate.[8] They may also exhibit unique facial features, like a narrow nose bridge.[1]

Psychomotor and Cognitive Development

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Affected individuals typically exhibit a full range of movement and coordination.[2] There is no significant impact on cognitive functions, and there are no major changes observed in the axial skeleton (spine and torso).[3]

Genetics

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Du Pan syndrome is primarily linked to changes in specific genes that influence bone and joint development.

Diagram showing how GDF-5 interacts with the BMP receptor to send signals that help control bone and cartilage development.

One major gene implicated in the condition is GDF5 (Growth and Differentiation Factor 5), which functions in an autosomal recessive pattern.[9] This means that a person must inherit two copies of the altered gene, one from each parent, to show symptoms.[13] The GDF5 protein binds to a bone morphogenetic protein (BMP) receptor, BMPR1B, which is essential for proper formation of joints and bones during fetal development.[3][6] A known genetic variation in the GDF5 gene involves the substitution of the amino acid Leucine with Proline at position 441 in the protein sequence, leading to the development of Du Pan Syndrome.[9]

The BMPR1B gene itself is also associated with a Du Pan-like syndrome when its function is lost.[10] Like GDF5, BMPR1B follows an autosomal recessive inheritance pattern.[6][8][14] For the BMPR1B protein to fulfill its bone and cartilage-forming role, it requires a functional GDF5 protein to be present and to form that association in the cell.[3]

Another gene involved in bone development, BDA2, has been shown to cause Du Pan syndrome in an autosomal dominant manner.[8] In this case, only one altered copy of the gene is sufficient for an individual to develop the syndrome.[15]

Diagnosis

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Until April 2023, fewer than 30 people worldwide had been diagnosed with Du Pan syndrome.[6] The primary diagnosis of the syndrome largely depends on its clinical symptoms, including short or completely missing leg bones and "ball-like" shaped toes and fingers.[6] Molecular confirmation of the syndrome utilizes genetic testing for alterations in the cartilage-derived morphogenetic protein-1 gene (CDMP1).[16] This method is often used as a complementary tool for diagnosis, and only 5 of all diagnosed Du Pan syndrome patients were molecularly confirmed due to technological limitations before the 2000s.[9]

The first prenatally diagnosed case of Du Pan syndrome was found using a combination of ultrasound imaging and gene sequencing, which identify the DNA sequence of both the fetus and the mother.[6]

Management and Treatments

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Currently, Du Pan syndrome treatments primarily focus on managing the associated symptoms and improving the individual's quality of life. The management of this condition often involves a multidisciplinary approach, with medical professionals, orthopedic specialists, and physical therapists working together.[16]

Orthopedic interventions may include surgical procedures to correct bone position, limb length conditions, or joint issues, which can help improve mobility and reduce pain.[16] Physical therapy and rehabilitation are often recommended to enhance muscle strength, joint flexibility, and overall physical function. Assistive devices such as braces, crutches, or wheelchairs may be used to promote mobility and comfort.[16]

Pain management is an essential aspect of care, and medications or other therapies may be prescribed to alleviate discomfort.[16] Additionally, genetic counselling can provide families with information about the condition's inheritance patterns and guide family planning decisions.[6]

Currently, ongoing studies at Boston Children’s Hospital aim to enhance the diagnosis and treatment of Acromesomelic Dysplasia (which Du Pan syndrome is a subtype of) by investigating its genetic causes, identifying potential associated health issues, and developing methods to assess bone health through blood tests.[17]

Similar Syndromes

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Other Acromesomelic Dysplasias sharing similar symptoms with Du Pan syndrome include Hunter–Thompson dysplasia and Grebe dysplasia.[6][8][14] All of these subtypes are caused by changes in either the GDF5 or BMPR1B genes, which work together in bone and cartilage formation during development.[6][8][14]

Symptoms of Hunter–Thompson dysplasia include increased and more frequent joint differences, like dislocated hips, knees, radial heads, and underdeveloped thigh bone protrusion (femoral condyle) when compared to Du Pan syndrome.[18] Additionally, there are minor differences in the pattern of short supporting bones in the hands and feet.

Individuals with Grebe dysplasia typically have a considerably shorter stature, particularly the femurs (thigh bone) and tibias (shin bone).[6][19] Moreover, there is a marked and consistent reduction in size observed in the smaller tubular bones of the hands and feet.[2]

Commonalities among all these conditions lie in genetic variations affecting GDF5. Carriers with two copies of affected GDF5 alleles usually develop Grebe dysplasia, while carriers with only one copy may exhibit relatively milder symptoms and Hunter–Thompson dysplasia and Du Pan syndrome.[2]

References

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  1. ^ a b "Orphanet: Fibular aplasia-complex brachydactyly syndrome". www.orpha.net. Retrieved 2024-11-23.
  2. ^ a b c d e f Szczaluba, K.; Hilbert, K.; Obersztyn, E.; Zabel, B.; Mazurczak, T.; Kozlowski, K. (2005). "Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene". American Journal of Medical Genetics Part A. 138A (4): 379–383. doi:10.1002/ajmg.a.30969. ISSN 1552-4825. PMID 16222676.
  3. ^ a b c d e Stange, Katja; Désir, Julie; Kakar, Naseebullah; Mueller, Thomas D.; Budde, Birgit S.; Gordon, Christopher T.; Horn, Denise; Seemann, Petra; Borck, Guntram (2015). "A hypomorphic BMPR1B mutation causes du Pan acromesomelic dysplasia". Orphanet Journal of Rare Diseases. 10 (1): 84. doi:10.1186/s13023-015-0299-5. ISSN 1750-1172. PMC 4482310. PMID 26105076.
  4. ^ Ahmad, Mahmud; Abbas, Hasan; Wahab, Abdul; Haque, Sayedul (1990). "Fibular hypoplasia and complex brachydactyly (Du Pan Syndrome) in an inbred Pakistani kindred". American Journal of Medical Genetics. 36 (3): 292–296. doi:10.1002/ajmg.1320360309. ISSN 0148-7299. PMID 2363425.
  5. ^ "Entry - #228900 - ACROMESOMELIC DYSPLASIA 2B; AMD2B - OMIM". omim.org. Retrieved 2024-11-23.
  6. ^ a b c d e f g h i j Turgut, G. Tutku; Kalelioglu, Ibrahim Halil; Karaman, Volkan; Sivrikoz, Tugba Sarac; Karaman, Birsen; Uyguner, Zehra Oya; Kalayci, Tugba (2023). "Fibular Agenesis and Ball-Like Toes Mimicking Preaxial Polydactyly: Prenatal Presentation of Du Pan Syndrome". Molecular Syndromology. 14 (2): 152–157. doi:10.1159/000527955. ISSN 1661-8769. PMC 10091002. PMID 37064338.
  7. ^ a b c "Acromesomelic dysplasia 2B (Concept Id: C1856738) - MedGen - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-11-23.
  8. ^ a b c d e f g Douzgou, Sofia; Lehmann, Katarina; Mingarelli, Rita; Mundlos, Stefan; Dallapiccola, Bruno (2008-08-15). "Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia". American Journal of Medical Genetics Part A. 146A (16): 2116–2121. doi:10.1002/ajmg.a.32435. ISSN 1552-4825. PMID 18629880.
  9. ^ a b c d e f g h Faiyaz-Ul-Haque, M; Ahmad, W; Zaidi, She; Haque, S; Teebi, As; Ahmad, M; Cohn, Dh; Tsui, L-C (2002). "Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome)". Clinical Genetics. 61 (6): 454–458. doi:10.1034/j.1399-0004.2002.610610.x. ISSN 0009-9163. PMID 12121354.
  10. ^ a b c Abdelrazek, Ibrahim; Knaus, Alexej; Javanmardi, Behnam; Krawitz, Peter; Horn, Denise; Abdalla, Ebtesam; Kumar, Sheetal (2024). "Acromesomelic Dysplasia With Homozygosity for a Likely Pathogenic BMPR1B Variant: Postaxial Polydactyly as a Novel Clinical Finding". Molecular Genetics & Genomic Medicine. 12 (10). Wiley Periodicals LLC. doi:10.1002/mgg3.70023. eISSN 2324-9269. ISSN 2324-9269. PMC 11497645. PMID 39441036.
  11. ^ "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2024-11-22.
  12. ^ Karol, Lori A.; Jeans, Kelly A. (2021). "This is a narrative review of the functional evaluation of clubfoot treatment with gait analysis". Annals of Translational Medicine. 9 (13): 1105. doi:10.21037/atm-20-6922. ISSN 2305-5847. PMC 8339835. PMID 34423017.
  13. ^ "Autosomal Recessive Disorder". www.genome.gov. Retrieved 2024-11-23.
  14. ^ a b c Mundlos, Stefan; Horn, Denise (2014), Mundlos, Stefan; Horn, Denise (eds.), "Grebe Dysplasia; Hunter–Thompson Dysplasia; Du Pan Dysplasia; Chondrodysplasia, Acromesomelic, BMPR1B Type", Limb Malformations: An Atlas of Genetic Disorders of Limb Development, Berlin, Heidelberg: Springer, pp. 247–250, doi:10.1007/978-3-540-95928-1_97 (inactive 5 December 2024), ISBN 978-3-540-95928-1, retrieved 2024-11-22{{citation}}: CS1 maint: DOI inactive as of December 2024 (link)
  15. ^ "Autosomal Dominant Disorder". www.genome.gov. Retrieved 2024-11-23.
  16. ^ a b c d e "Acromesomelic Dysplasia - Symptoms, Causes, Treatment | NORD". rarediseases.org (in European Spanish). Retrieved 2024-11-23.
  17. ^ "Acromesomelic Dysplasia | Research Focus Areas | Center for the Study of Genetic Skeletal Disorders Research | Research Centers | Research | Boston Children's Hospital". www.childrenshospital.org. Retrieved 2024-11-23.
  18. ^ "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2024-11-23.
  19. ^ "Orphanet: Clinical signs and symptoms". www.orpha.net. Retrieved 2024-11-23.
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