Medicine:Pachydermoperiostosis

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Short description: Rare genetic disorder that affects bones and skin
Pachydermoperiostosis
Other namesPrimary hypertrophic osteoarthropathy

Pachydermoperiostosis (PDP) is a rare genetic disorder that affects both bones and skin.[1] Other names are primary hypertrophic osteoarthropathy or Touraine-Solente-Golé syndrome.[2] It is mainly characterized by pachyderma (thickening of the skin), periostosis (excessive bone formation) and finger clubbing (swelling of tissue with loss of normal angle between nail and nail bed).[1][3]

This disease affects more men than women.[1][4] After onset, the disease stabilizes after about 5–20 years. Life of PDP patients can be severely impaired.[1][5] Currently, symptomatic treatments are NSAIDs and steroids or surgical procedures.[5][6]

In 1868, PDP was first described by Friedreich as 'excessive growth of bone of the entire skeleton'. Touraine, Solente and Golé described PDP as the primary form of bone disease hypertrophic osteoarthropathy in 1935 and distinguished its three known forms.[1]

Symptoms

PDP has a number of visible signs. Most important clinical features are: pachydermia (thickening and wrinkling of the skin), furrowing of the face and scalp, periostosis (swelling of periarticular tissue and shaggy periosteal new bone formation of long bones) and digital clubbing (enlargement of fingertips).[1] Other features include excessive sweating, arthralgia and gastrointestinal abnormalities.[1] An overview of all symptoms is provided in table 2.

Table 2. Overview of signs [1][5][7][8]

Skin features Pachydermia
Coarse skin
Oily skin
Eczema
Thick hand and foot skin
Leonine facies
Furrowing
Cutis verticis gyrate
Increased secretion of sebum
Sebborheic hyperplasia
Keloid formation
Bone features Periostosis
Acroosteolysis
Mylefibrosis
Thick toe and finger bones
Widening of bone formation
Clubbing Digital clubbing
Sweating Hyperhidrosis
Eye features Drooping eyelids
Thick stratum corneum
Joints Arthralgia
Joint effusion
Muscles Muscle discomfort
Hair Decreased facial and pubic hair
Vascular Peripheral vascular stasis
Gastrointestinal involvement Peptic ulcer
Chronic gastritis
Crohn’s disease

Cause

The locally acting mediator prostaglandin E2 (PGE2) plays a role in the pathogenesis of PDP.[4][9] In PDP patients, high levels of PGE2 and decreased levels of PGE-M (the metabolite of PGE2) were observed.[3]

PGE2 can mimic the activity of osteoblasts and osteoclasts (respectively building and breaking down bone tissue). This is why acroosteolysis and periosteal bone formation can be explained by the action of PGE2.[10] Furthermore, PGE2 has vasodilatory effects, which is consistent with prolonged local vasodilation in digital clubbing.[10]

Elevated levels of PGE2 in PDP patients are associated with mutations of HPGD gene. These patients showed typical PDP symptoms such as digital clubbing and periostosis.[9][10][11][12] The HPGD gene is mapped on chromosome 4q34 and encodes the enzyme HPGD (15-hydroxyprostaglandin dehydrogenase).[5][9] This enzyme catalyzes the first step in the degradation of PGE2 and related eicosanoids.[9][10] So far, eight different mutations are known leading to a dysfunctional HPGD enzyme in PDP patients.[9][10][12] Due to these mutations, the binding of the substrate PGE2 to HPGD is disrupted.[9] As a result of this, PGE2 cannot be transferred into PGE-M down and remain present at high concentrations.[citation needed]

Role of other mediators

Apart from elevated PGE2 levels, studies in patients with hypertrophic osteoarthropathy also showed increased plasma levels of several other mediators, such as Von Willebrand factor and vascular endothelial growth factor (VEGF).[1][13][14][15] These substances could also have a role in PDP progression and proliferation.[1] In contrast to HPGD mutations, suspected mutations for these factors have not been reported yet.[citation needed]

Von Willebrand factor is a marker of platelet and endothelial activation.[14] This suggests that the activation of endothelial cells and platelets play an important role in the pathogenesis of PDP.[16] VEGF promotes angiogenesis (growth of new blood vessels) and differentiation of osteoblasts, which can explain the clubbing and excessive fibroblast formation in PDP patients.[16][17] Other mediators found in increased concentrations in PDP patients, include osteocalcin, endothelin-1, b-thromboglobulin, platelet-derived growth factor (PDGF) and epidermal growth factor (EGF).[1][13][18][19] It has not been described yet what role these mediators have in PDP.

Genetics

Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) in chromosome 4 (4q34.1) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) in chromosome 3 (3q22.1-q22.2).[20] This syndrome occurs if both copies of either gene are mutated (autosomal recessive inheritance)[citation needed]

Diagnosis

The easiest way to diagnose PDP is when pachydermia, finger clubbing and periostosis of the long bones are present.[1][21][22] New bone formation under the periosteum can be detected by radiographs of long bones.[22] In order diagnose PDP, often other diseases must be excluded. For example, to exclude secondary hypertrophic osteoarthropathy, any signs of cardiovascular, pulmonary, hepatic, intestinal and mediastinal diseases must be absent.[21] MRI and ultrasound also have characterictic findings.[23]

Skin biopsy is another way to diagnose PDP. However, it is not a very specific method, because other diseases share the same skin alterations with PDP, such as myxedema and hypothyroidism.[3] In order to exclude these other diseases, hormonal studies are done. For example, thyrotropin and growth hormone levels should be examined to exclude thyroid acropachy and acromegaly.[7] However, skin biopsy helps to diagnose PDP in patients without skin manifestations.[3]

When clubbing is observed, it is helpful to check whether acroosteolysis of distal phalanges of fingers is present. This is useful to diagnose PDP, because the combination of clubbing and acroosteolysis is only found in PDP and Cheney’s syndrome.[24]

Biomarkers and mutation analysis

Since elevated PGE2 levels are correlated with PDP, urinary PGE2 can be a useful biomarker for this disease.[9] Additionally, HPGD mutation analyses are relatively cheap and simple and may prove to be useful in early investigation in patients with unexplained clubbing or children presenting PDP-like features. Early positive results can prevent expensive and longtime tests at identifying the pathology.[9][25]

For the follow-up of PDP disease activity, bone formation markers such as TAP, BAP, BGP, carbodyterminal propeptide of type I procallagen or NTX can play an important role.[3] Other biomarkers that can be considered are IL-6 and receptor activator of NF-κB ligand (RANKL), which are associated with increased bone resorption in some patients. However, further investigation is needed to confirm this use of disease monitoring.[3]

PGE2 may also be raised in patients with lung cancer and finger clubbing.[26] This may be related to raised levels of cyclooxygenase-2, an enzyme involved in the metabolism of prostaglandins.[27] A similar association has been noted in cystic fibrosis.[28]

Classification

PDP is one of the two types of hypertrophic osteoarthropathy. It represents approximately 5% of the total hypertrophic osteoarthropathy cases.[4] The other form is secondary hypertrophic osteoarthropathy (SHO). SHO usually has an underlying disease (such as cardiopulmonary diseases, malignancies or paraneoplastic syndrome). Unlike SHO, PDP does not have an underlying disease or malignancy.[1]

PDP can be divided into three categories:

  • The complete form occurs in 40% of the cases and can involve all the symptoms but mainly pachydermia, periostosis and finger clubbing. This is also referred to as the full-blown phenotype.[1][7]
  • The incomplete form occurs in 54% of the cases and is characterized by having mainly effect on the bones and thereby the skeletal changes. Its effect on the skin (causing for instance pachydermia) is very limited.[1][7]
  • The fruste form occurs in only 6% of the cases and is the opposite of the incomplete form. Minor skeletal changes are found, and mostly cutaneous symptoms are observed with limited periostosis.[1][7]

The cause of these differentiating pathologies is still unknown.[1][7]

Treatment

The effective treatment for PDP is currently unknown due to the lack of controlled data and is largely based on case reports.[29] Although the HPGD enzyme is likely to be involved into the pathogenesis of PDP, no strategies against this mutation have been reported yet, since it is hard to tackle a defective enzyme. Gene therapy could be a solution for this, although this has not been reported yet in literature.[citation needed]

Conventional PDP drug treatment to decrease inflammation and pain includes NSAIDs and corticosteroids.[4] Other drugs used by PDP patients target bone formation or skin manifestations.[4] Surgical care is used to improve cosmetic appearance.[6]

Inflammation and pain drug treatment

Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are most used in PDP treatment.[4] These drugs inhibit cyclo-oxygenase activity and thereby prostaglandin synthesis.[30] Since PGE2 is likely to be involved in periosteal bone formation and acroosteolysis, this is why these drugs can alleviate the polyarthritis associated with PDP.[4] In addition, NSAIDs and corticosteroids decrease formation of inflammatory mediators, reducing inflammation and pain.[30] In case of possible gastropathy, the COX-2 selective NSAID etorixocib is preferred.[4]

Infliximab can reduce pain and arthritis in PDP. It is a monoclonal antibody that blocks the biological action of TNF-α (tumor necrosis factor-alpha). TNF-α is an inflammatory cytokine found in high levels in PDP and it is involved in the production of other inflammatory mediators which increase the expression of RANKL. RANKL is thought to increase bone resorption.[17]

Bone formation and pain drug treatment

Rheumatologic symptoms can be improved by treatment with bisphosphonates, such as pamidronate or risedronate. Bisphosphonates inhibit osteoclastic bone resorption and therefore reduce bone remodeling and alleviate painful polyarthritis.[4]

In isolated cases, tamoxifen was effective in PDP treatment, especially for bone and joint pain. In PDP patients, high levels of nuclear receptors were found for steroids, which was the rationale to use tamoxifen, an estrogen receptor antagonist.[4][21] Tamoxifen and several of its metabolites competitively bind to estrogen receptors on tissue targets, producing a nuclear complex that decreases DNA synthesis. Cells are accumulated in G0 and G1 phases.[31] In vitro studies showed that tamoxifen acts as an estrogen agonist on bone and inhibits the resorbing activity of osteoclasts (disruption of bone tissue).[32]

Skin manifestations drug treatment

Retinoids are used to improve skin manifestations.[4] Retinoids can act on retinoid nuclear receptors and thus regulate transcription.[33] For example, isotretinoin, the most effective drug to treat acne, improves cosmetic features by inducing apoptosis within human sebaceous glands.[34] As a result of this, the increase of connective tissue and hyperplasia of the sebaceous glands is inhibited.[34][35] Retinoids also decrease procollagen mRNA in fibroblasts, improving pachyderma.[24]

Like retinoids, colchicines can also improve skin manifestations.[4] It is able to bind to the ends of microtubules to prevent its elongation. Because microtubules are involved in cell division, signal transduction and regulation of gene expression, colchicine can inhibit cell division and inflammatory processes (e.g. action of neutrophils and leukocytes).[36] It is suggested that colchicine inhibit chemotactic activity of leukocytes, which leads to reduction of pachydermia.[37]

Use of botulinum toxin type A (BTX-A) improved leonine facies of patients. BTX-A inhibits release of acetylcholine acting at the neuromuscular junction. Furthermore, it blocks cholinergic transmission to the sweat glands and therefore inhibits sweat secretion. However, the exact mechanism for improving leonine faces is unknown and needs to be further investigated.[5]

Surgical Care

Aside from drug treatments, there are many surgical methods to improve the facial appearance. One of them is facelift, technically known as facial rhytidectomy. This method is a type of cosmetic surgery procedure used to give a more youthful appearance. It involves the removal of excess facial skin and tightening of the skin on the face and neck.[6] A second option is plastic surgery.[6] This is also used for eye drooping.[4]

Prognosis

The age of onset is often in puberty.[1][4] Of the described cases, as high as 80% of the affected individuals was suffering from the disease prior to the age of 18.[1] However, Latos-Bielenska et al. stated that this percentage should be lower, because also another form of osteoarthropathy – familial idiopathic osteoarthropathy (FIO) - was taken into account in this analysis.[22]

PDP usually progresses for 5 to 20 years, until it becomes stable.[1] Life expectancy may be normal, despite patients getting many functional and cosmetic complications, including restricted motion, neurologic manifestations and leonine facies.[1][5]

Epidemiology

Prevalence

PDP is a rare genetic disease.[1] At least 204 cases of PDP have been reported.[1][7] The precise incidence and prevalence of PDP are still unknown.[1] A prevalence of 0.16% was suggested by Jajic et Jajic.[38]

Distribution

PDP occurs more frequently in men than in women (ratio around 7:1).[1][4] Moreover, men suffer from more severe symptoms (see table 1).[1] African American people are affected to a higher extent.[5]

Table 1. Distribution of different forms of PDP among 201 reported affected men and women (167 men and 34 women).[1]

Form of PDP Sex
Men Women
Complete 45% 18%
Incomplete 50% 71%
Fruste 5% 12%

Heredity

In 25-38% of the cases, patients have a familial history of PDP.[4] It is suggested that the incomplete form and complete form are inherited in different ways: either autosomal dominant inheritance (involving a dominant allele) or autosomal recessive inheritance (involving a recessive allele).[1]

The autosomal dominant model of inheritance with penetrance and variable expression is confirmed in about half of the families, associated with the incomplete form.[1] Of several families, an autosomal recessive model of inheritance is known, associated with the complete form with much more severe symptoms involving joint, bone and skin features. Male-female ratio in PDP is skewed towards males.[1]

Two genes have been associated with this condition: hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) and solute carrier organic anion transporter family, member 2A1/prostaglandin transporter (SLCO2A1).[39][40][41] The underlying pathophysiology appears to be an abnormality of prostglandin E2 but the details have yet to be elucidated.

Society

6 patient organizations facilitate support for PDP patients. 4 of them are situated in Europe (Finland,[42] France,[43] Greece,[44] and Poland).[45] The other two are located in Australia[46] and Morocco (the Association Marocaine des Génodermatoses).

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 "Pachydermoperiostosis: an update". Clin. Genet. 68 (6): 477–486. 2005. doi:10.1111/j.1399-0004.2005.00533.x. PMID 16283874. 
  2. ↑ "Malignancy and rheumatic disorders". MA. 2011. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Prostaglandin E2 and bone turnover markers in the evaluation of primary hypertrophic osteoarthropathy (pachydermoperiostosis): a case report.". Rheumatol. Clin. 28 (10): 1229–1233. 2009. doi:10.1007/s10067-009-1197-9. PMID 19455364. 
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 "Primary hypertrophic osteoarthropathy (pachydermoperiostosis). Report of 2 familial cases and literature review.". Rheumatol Clin. 5 (6): 259–263. 2009. doi:10.1016/s2173-5743(09)70134-0. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Treatment of pachydermoperiostosis pachydermia with botulinum toxin type A.". J. Am. Acad. Dermatol. 63 (6): 1036–1041. 2010. doi:10.1016/j.jaad.2009.08.067. PMID 20933299. 
  6. ↑ 6.0 6.1 6.2 6.3 Leni George (2008). "Frontal rhytidectomy as surgical treatment for pachydermoperiostosis.". J Dermatol Treat 19 (1): 61–63. doi:10.1080/09546630701389955. PMID 18273728. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 "Pachydermoperiostosis". Orphanet Encyclopedia. 2004. http://www.orpha.net/data/patho/GB/uk-pachydermoperiostosis.pdf. 
  8. ↑ Rajul Rastogi (2009). "Pachydermoperiostosis or primary hypertrophic osteoarthropathy: A rare clinicoradiologic case.". Indian J Radiol Imaging 19 (2): 123–126. doi:10.4103/0971-3026.50829. PMID 19881067. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 "Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy". Nat. Genet. 40 (6): 789–793. 2008. doi:10.1038/ng.153. PMID 18500342. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "Homozygous mutations in the 15-hydroxyprostaglandin dehydrogenase gene in patients with primary hypertrophic osteoarthropathy.". Rheumatol Int. 30 (1): 39–43. 2009. doi:10.1007/s00296-009-0895-6. PMID 19306095. 
  11. ↑ "Primary hypertrophic osteoarthropathy with digital clubbing and palmoplantar hyperhidrosis caused by 15-PGHD⁄HPGD loss-of-function mutations.". Exp Dermatol 20 (6): 531–3. 2011. doi:10.1111/j.1600-0625.2011.01248.x. PMID 21426412. 
  12. ↑ 12.0 12.1 "A novel homozygous splice site mutation in the HPGD gene causes mild primary hypertrophic osteoarthropathy.". Clin Exp Rheumatol 28 (2): 153–157. 2010. PMID 20406614. 
  13. ↑ 13.0 13.1 "Hypertrophic osteoarthropathy: endothelium and platelet function.". Clin Rheumatol 15 (5): 435–439. 1996. doi:10.1007/bf02229639. PMID 8894355. 
  14. ↑ 14.0 14.1 Mattuci-Cerinic (1992). "Von Willebrand factor antigen in hypertrophic osteoarthropathy.". J Rheumatol 19 (5): 765–767. PMID 1613707. 
  15. ↑ "Vascular endothelial growth factor and hypertrophic osteoarthropathy.". Clin Exp Rheumatol. 18 (1): 57–62. 2000. PMID 10728444. 
  16. ↑ 16.0 16.1 Jin Hyun Kim (2004). "A Case of Hypertrophic Osteoarthropathy Associated with Epithelioid Hemangioendothelioma.". J Korean Med Sci 19 (3): 484–486. doi:10.3346/jkms.2004.19.3.484. PMID 15201523. 
  17. ↑ 17.0 17.1 "Infliximab treatment in Pachydermoperiostosis.". J Clin Rheumatol 16 (4): 183–184. 2010. doi:10.1097/rhu.0b013e3181df91c6. PMID 20414127. 
  18. ↑ "Circulating plasma levels of platelet-derived growth factor in patients with hypertrophic osteoarthropathy.". Clin Exp Rheumatol 10 (7): 72. 1992. 
  19. ↑ "Pachydermoperiostosis, study of epidermal growth factor and steroid receptors.". Br J Dermatol 133 (1): 128–133. 1995. doi:10.1111/j.1365-2133.1995.tb08638.x. PMID 7756124. 
  20. ↑ Torgutalp M, Durmaz CD, Karabulut HG, Seifert W, Horn D, Akkaya Z, Turgay M (2019) Primary hypertrophic osteoarthropathy mimicking juvenile idiopathic arthritis: A novel SLCO2A1 mutation and imaging findings. Cytogenet Genome Res
  21. ↑ 21.0 21.1 21.2 "Two cases with pachydermoperiostosis and discussion of tamoxifen citrate treatment for arthralgia.". Rheumatol Clin. 26 (1): 8–11. 2007. doi:10.1007/s10067-005-1161-2. PMID 16738844. 
  22. ↑ 22.0 22.1 22.2 "Pachydermoperiostosis–critical analysis with report of five unusual cases.". Eur J Pediatr 166 (12): 1237–1243. 2007. doi:10.1007/s00431-006-0407-6. PMID 17285282. 
  23. ↑ "Primary hypertrophic osteoarthropathy: ultrasound and MRI findings". Pediatr Radiol 46 (5): 727–730. 2017. doi:10.1007/s00247-016-3544-8. PMID 26939972. 
  24. ↑ 24.0 24.1 "Touraine Solente Gole syndrome: the disease and associated tongue fissuring.". Rheumatol Int. 29 (9): 1091–1093. 2009. doi:10.1007/s00296-008-0798-y. PMID 19050893. 
  25. ↑ "Common and recurrent HPGD mutations in Caucasian individuals with primary hypertrophic osteoarthropathy.". Rheumatol. 49 (6): 1056–1062. 2010. doi:10.1093/rheumatology/keq048. PMID 20299379. 
  26. ↑ "Elevation of prostaglandin E2 in lung cancer patients with digital clubbing". J Thorac Oncol 7 (12): 1877–1878. 2012. doi:10.1097/jto.0b013e3181fc76a9. PMID 22024643. 
  27. ↑ "Cyclooxygenase-2 expression in non-small Cell lung cancer correlates With hypertrophic osteoarthropathy". Ann Thorac Surg 101 (2): e51–3. 2016. doi:10.1016/j.athoracsur.2015.09.023. PMID 26777972. 
  28. ↑ "Relationships among digital clubbing, disease severity, and serum prostaglandins F2alpha and E concentrations in cystic fibrosis patients". Am Rev Respir Dis 17 (4): 639–646. 1978. 
  29. ↑ Jaejoon Lee (2008). "Arthroscopic Synovectomy in a Patient with Primary Hypertrophic Osteoarthropathy Korean Rheum Assoc.". Korean Rheum Assoc 15 (3): 261–267. doi:10.4078/jkra.2008.15.3.261. 
  30. ↑ 30.0 30.1 Rang and Dale's Pharmacology. Elsevier. 2007. pp. 230–232, 363. 
  31. ↑ "Improving tolerance of AIs: predicting risk and uncovering mechanisms musculoskeletal toxicity". Oncology (Williston Park) 22 (12): 1416–1424. 2008. PMID 19322949. 
  32. ↑ Molad Y (2002). "Update on colchichine and its mechanism of action". Current Rheumatology Reports 4 (3): 252–256. doi:10.1007/s11926-002-0073-2. PMID 12010611. 
  33. ↑ "Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells". J Clin Invest 118 (4): 1468–1478. 2008. doi:10.1172/JCI33869. PMID 18317594. 
  34. ↑ 34.0 34.1 "Gene expression regulation by retinoic acid.". J Lipid Res 43 (11): 1773–1780. 2002. doi:10.1194/jlr.r100015-jlr200. PMID 12401878. http://www.jlr.org/content/43/11/1773.full.pdf. 
  35. ↑ "Pachydermoperiostosis: trial with isotretinoin.". Yonsei Medical Journal 29 (2): 204–207. 1988. doi:10.3349/ymj.1988.29.2.204. PMID 3064439. 
  36. ↑ Terkeltaub RA (2009). "Colchicine update. Seminars in arthritis and rheumatism.". Seminars in Arthritis and Rheumatism 38 (6): 411–419. doi:10.1016/j.semarthrit.2008.08.006. PMID 18973929. 
  37. ↑ Mattuci-Cerinic (1998). "Colchicine treatment in a case of pachydermoperiostosis with acroosteolysis.". Rheumatol Int. 8 (4): 185–188. doi:10.1007/BF00270458. PMID 3187331. 
  38. ↑ "Prevalence of primary hypertrophic osteoarthropathy in selected population.". Clin Exp Rheumatol. 10 (7): 73. 1992. 
  39. ↑ Khan AK, Muhammad N, Khan SA, Ullah W, Nasir A, Afzal S, Ramzan K, Basit S, Khan S (2017) A novel mutation in the HPGD gene causing primary hypertrophic osteoarthropathy with digital clubbing in a Pakistani family. Ann Hum Genet doi: 10.1111/ahg.12239
  40. ↑ "Exome sequencing identifies SLCO2A1 mutations as a cause of primary hypertrophic osteoarthropathy". American Journal of Human Genetics 90 (1): 125–32. January 2012. doi:10.1016/j.ajhg.2011.11.019. PMID 22197487. 
  41. ↑ "Identification of mutations in the prostaglandin transporter gene SLCO2A1 and phenotypic comparison between two subtypes of primary hypertrophic osteoarthropathy (PHO): A single-center study". Bone 106: 96–102. 2018. doi:10.1016/j.bone.2017.09.015. PMID 28963081. 
  42. ↑ "Home". http://www.iholiitto.fi/. 
  43. ↑ "Accueil". http://asso.orpha.net/FFP/. 
  44. ↑ "Το Μέλλον |". http://www.tomellon.com.gr/. 
  45. ↑ "Wortal Stowarzyszenia na Rzecz Dzieci z Zaburzeniami Genetycznymi GEN". http://www.gen.org.pl/. 
  46. ↑ "Genetic Support – Genetic Resources". http://www.agsa-geneticsupport.org.au/. 

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