Because patients suffering from rare or neglected diseases are looking for solutions, we are committed to finding the best ones by building effective partnerships and developing new therapies. Our goal is to bring life to hope for patients all around the world.
Because patients suffering from rare or neglected diseases are looking for solutions, we are committed to finding the best ones by building effective partnerships and developing new therapies. Our goal is to bring life to hope for patients all around the world.
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What is sickle cell disease?
Sickle cell disease (SCD) or sickle cell anemia (SCA) is the most common inherited blood disorder consisting of the production of a variant of hemoglobin-A (HbA), known as hemoglobin-S (HbS), responsible for the sickling of red blood cells.
Red blood cells with HbA are smooth, round and flexible therefore they glide through blood vessels even in tight capillary beds, whereas red blood cells with HbS can form long, rod-like structures and clump together. This causes red blood cells to become stiff, assuming a sickle shape. These sickled red blood cells tend to pile together, creating clots, and blocking the flow of blood through vessels.
Worldwide, the incidence is estimated to be between 300,000 and 400,000 neonates each year, with the majority in sub-Saharan Africa where most children born with the disease die before 5 years of age without screening and simple treatments.
In the US, SCD affects nearly 100,000 Americans, decreases life expectancy by 25 to 30 years and induces great morbidity.
In Europe, we estimate that around 60,000 people are affected by the disease according to the different publications.
Most of the affected people are of African ancestry; a minority are of Hispanic or southern European, Middle Eastern, or Asian Indian descent 1,5.

What is the impact on patients?

SCD can cause a number of acute complications, including vaso-occlusive crises, acute chest syndromes, strokes and anemic events, with damage to several organs and disabling pain episodes. In well-resourced countries, acute complications are rarely fatal, but can be life-threatening and require prompt and well-structured organisation to deliver emergency and specialised care.
These complications can begin at a very young age and their improved management is now associated with a longer survival for the patients. This is why in the long term, repeated sickling and ongoing anemia lead to chronic complications (including chronic pain, avascular necrosis of the hip or chronic kidney disease, for instance) and can damage all organs6.
Therefore, an early and adapted management of the disease in children is crucial to minimize the impact of these complications. As well as chronic and acute complications, sickle cell patients face social and psychological difficulties. It is a disabling condition.

Management of sickle cell anemia

To date, the management of sickle cell anemia includes: a preventive component (prevention of infections, prevention of VOC, etc.), a symptomatic component (management of complications) and a curative component (bone marrow transplant).


  1. Platt, OS et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9;330(23):1639-44.
  2. Patrick T McGann & Russell E Ware. Hydroxyurea therapy for sickle cell anemia, Expert Opinion on Drug Safety. 2015. 14:11, 1749-1758.
  3. Siklos® Prescribing Information,
  4. Strousse, J. Hydroxyurea for the Treatment of Sickle Cell Disease: Efficacy, Barriers, Toxicity, and Management in Children. Pediatr Blood Cancer 2012;59:365–371.
  5. Kato G. J. et al. Sickle cell disease. Nature reviews 2018; 18010.
  6. Russell E Ware et al. Sickle cell disease. Lancet 2017; 390: 311–23.

Bile acid synthesis disorders (BASD) are rare genetic conditions that can present as cholestasis, neurologic disease, or fat-soluble-vitamin deficiencies. They are responsible for 1-2% of cases of neonatal cholestasis.1 There are nine subtypes of BASDs, classified either as primary or secondary:2

  • Primary BASDs arise from congenital deficiencies in the enzymes required for synthesizing the two main bile acids: cholic acid and chenodeoxycholic acid.
  • Secondary metabolic defects impacting primary bile acid synthesis include peroxisomal disorders, such as Zellweger spectrum disorder (ZSD), and Smith-Lemli-Opitz syndrome caused by a deficiency of Δ7-desaturase.
What are primary bile acid synthesis disorders?

Primary bile acid synthesis disorders (BASD) are genetic autosomal recessive diseases. They are associated with mutations in the coding genes for enzymes involved in the biosynthesis of primary bile acids (cholic acid and chenodeoxycholic acid). They are rare causes of liver disease in children that can occur at any age (from birth to adolescence). They usually present as cholestatic jaundice and/or liver failure. 3 Early diagnosis of these disorders is essential.

The two most frequent ones responsible for chronic liver disease are:3

  • 3ß-hydroxy-Δ5-C27-steroid oxidoreductase (or dehydrogenase/isomerase) deficiency; may also be called 3ß-HSD deficiency, or BAS defect type 1.
  • Δ4-3-oxosteroid-5ß reductase deficiency; may also be called Δ4-3-oxoR, or 5ß-reductase deficiency, or BAS defect type 2.

They correspond to a lack of one of the two enzymes, 3ß-HSD or Δ4-3-oxoR, which are involved in the transformation of cholesterol into primary bile acids in liver cells. When they are missing, cholesterol transformation is incomplete which leads to the absence of production of primary bile acids and accumulation of toxic intermediates in the liver causing its deterioration.3

These enzyme deficiencies are very rare liver diseases, diagnosed in most cases in infants and children. However, the possibility of diagnosing these diseases in older children or in adults should not be ruled out. The scientific literature describes a few cases of patients diagnosed with 3ß-HSD deficiency in adulthood following unexplained cirrhosis.

Did you know?

For a long time, bile acid synthesis disorders were confused with other liver diseases grouped under the name “progressive familial intrahepatic cholestasis” in the French literature, or under the names “progressive familial cholestatic cirrhosis”, “fatal familial intrahepatic cholestasis”, “Byler syndrome”, “Byler’s disease”, and “progressive familial intrahepatic cholestasis” in the Anglo-Saxon literature.

Thanks to the development of new medical analysis techniques allowing analysis of urinary bile acids, it is now possible to identify and diagnose these diseases since the 1980s. Deficiencies in 3ß-HSD and Δ4-3-oxoR were identified respectively in 1987 and 1988. Their genetic origins were only confirmed in the 2000s.3

What are the figures?

Bile acid synthesis disorders are responsible for approximately 1 to 2% of cholestasis in neonates.4

In Europe, the prevalence of 3ß-HSD and Δ4-3-oxoR deficiencies is at least 1.13 cases per 10 million people: 5

  • 0.99 per 10 million people for 3ß-HSD deficiency,
  • 0.14 per 10 million people for Δ4-3-oxoR deficiency.

However, it is possible that these prevalences may be underestimated because of the rarity of the diseases and because: 5

  • The potential inexperience of physicians in these diseases can make diagnosis complicated: some patients may go undiagnosed or may be misdiagnosed.
  • The number of specialized medical laboratories that can confirm the diagnosis is limited.

How are these diseases transmitted?

Deficiencies in 3ß-HSD and Δ4-3-oxoR are genetic diseases with autosomal recessive inheritance. They are due to abnormal genes, referred to as “mutated”.
The genes are carried by the DNA present in the chromosomes. Each chromosome exists in pairs, and during embryonic development, people inherit half of their mothers’ chromosomes and half of their fathers’ chromosomes. Therefore, 50% of every person’s DNA, and therefore their genes, come from their mother and 50% come from their father.
Because of the autosomal recessive nature of these diseases, for them to develop, a person has to inherit two mutated genes (a mutated gene from the mother and a mutated gene from the father), that is, to say two identical alleles.
For every pregnancy*, a child has the following risks:

ITALY 1.98 per 10 million people
FRANCE 4.98 per 10 million people
UK 1.69 per 10 million people


  • Inheriting both mutated alleles
  • Developing the disease
  • Transmitting a mutated allele to offspring


  • Inheriting one mutated allele (healthy carrier)
  • No development of the disease
  • Possibly transmitting a mutated allele to offspring


  • Absence of mutated allele
  • No development of the disease
  • No transmission of a mutated allele to offspring
*If both parents are carriers of a mutated allele

As for any disease with autosomal recessive inheritance, parent consanguinity increases the risk of carrying the disease and developing it. With 3ß-HSD and Δ4-3-oxoR deficiencies, the mutated gene is carried by a non-sexual chromosome (neither the X nor the Y chromosome). The diseases are not linked to sex, they can affect both women and men. The following genes have been identified as being responsible for the development of these diseases when they are mutated: 3 HSD3B7 gene for 3ß-HSD deficiency, AKR1D1 gene (formerly SRD5B1) for Δ4-3-oxoR deficiency

What are bile acids?

Bile acids play a role in regulating their own production. They exert negative feedback on their synthesis pathway: when the amount produced is sufficient, synthesis is stopped.

Bile 6
  • Greenish-yellow biological fluid produced by the liver
  • Facilitates digestion, especially that of lipids and fat-soluble elements
  • 97% water
  • 3% of different non-aqueous elements of which bile acids are the major part

Primary bile acids 6

  • Main constituents of bile: cholic acid and chenodeoxycholic acid
  • Synthesized in liver cells from cholesterol: involving about twenty different enzymes
  • Main functions:
  • – Major route of cholesterol elimination
  • – Provides the main driving force for the circulation and secretion of bile
  • Essential role in the elimination of toxic substances including bilirubin, and medicinal product metabolites
  • – Facilitates the absorption of fat-soluble vitamins and lipids in the intestines
Enterohepatic circulation of bile acids7
  1. Synthesis of the main constituent of bile, primary bile acids, from cholesterol in hepatocytes
  2. Transportation of bile in the gallbladder through the biliary tract
  3. Storage of bile in the gallbladder
  4. Release of bile in the duodenum following bolus-related stimulation
  5. Reabsorption of 95% of bile acids through the ileum and colon, transported through the portal vein to the liver and 5% loss of bile acids in stools.

How do these diseases work?

3ß-HSD and Δ4-3-oxoR are enzymes that play an important role in the primary bile acid synthesis pathway. If they are deficient, synthesis of primary bile acids, which is essential for promoting biliary secretion, is prevented leading to accumulation of toxic bile acid precursors in the liver. This results in cholestasis, then liver cirrhosis or progressive and irreversible liver failure.

The pathophysiological consequences are as follows: 5

  1. Absence of primary bile acids
  2. Accumulation of intermediate hepatotoxic and cholestatic bile acids
  3. Intestinal malabsorption of fats and fat-soluble vitamins
  4. – Rickets due to lack of vitamin D,
  5. – Haemorrhage due to lack of vitamin K,
  6. – Neurological disorders due to lack of vitamin E,
  7. – Eye problems due to lack of vitamin A.
  8. Defect in the negative feedback of primary bile acids:
  9. – Intermediate bile acids which are toxic for the liver continue to be produced and accumulate in the liver, aggravating the diseases.

How to recognize 3ß-HSD and Δ4-3-oxoR deficiencies?

These diseases may be suspected based on a combination of clinical and laboratory signs, and histological findings of the liver. Observed together, they should lead to a specific urine test and then a genetic test being conducted. Furthermore, since these diseases are inherited, it is important to investigate the patient’s family history: cases of unexplained liver problems (or even deaths) in young children in the family can help with the diagnosis of BASD.

Clinical signs

  1. Cholestasis and/or hepatocellular insufficiency during the first months of life or in childhood(1)
    • Progressive and prolonged jaundice
    • Hepatomegaly, splenomegaly
    • Sings of liver failure
  2. And/or malabsorption syndrome
    • Steatorrhea
    • Clinical signs associated with fat-soluble vitamin deficiency: A, D, E, K (eye disorders, rickets, neurological disorders, haemorrhage)
  3. Or cirrhosis
  4. And no pruritus
(1) Exceptionally, the disease may be discovered late, in teenagers or adults; the possibility the patient may have the disease should be considered in case of unexplained liver cirrhosis.


  1. Elevation in serum transaminase levels (ALAT, ASAT)
  2. Conjugated hyperbilirubinemia
  4. Normal or low serum total bile acids

(2) Primary bile acids contribute to the release of GGT from the canalicular membrane to the blood. Except in special cases, given their absence, they do not lead to an increase in GGT levels in the blood.


  1. Cases of unexplained liver problems
  2. Deaths in young children
  3. . Consanguineous parents


  1. Canalicular cholestasis
    • Without bile duct proliferation
    • metimes with signs of giant cell hepatitis
  2. Portal and lobular fibrosis with features of septal fibrosis or cirrhosis, depending on the stage


A specific urine diagnostic tests

Analysis of bile acids in urine by mass spectrometry(3)

A genetic test

Sequencing of the genes
involved in the diseases

(3) If you are a healthcare professional and have difficulties getting the specific diagnostic tests performed, do not hesitate to contact us for more information.

Diagnosis can be difficult because many diseases manifest as neonatal cholestasis or chronic liver disease, and there are no specific clinical features or biomarkers allowing the specific identification of BASDs. However, most patients with BASDs present with: 1;8

  • Normal or low total serum bile acid concentrations
  • Normal γ-glutamyl transpeptidase concentrations
  • No pruritus

Patients with Δ4-3-oxoR deficiency are similar to patients with 3ß-HSD deficiency. However, the average diagnosis is 3 months in patients with Δ4-3-oxoR versus 3 months to 14 years in patients with 3ß-HSD deficiency. 1-2 They also tend to have more severe liver disease than patients with 3ß-HSD deficiency and more rapid progression to cirrhosis and death without intervention.2
Early diagnosis of these diseases is therefore essential.

What about treatment of these diseases?

Early diagnosis is important because these disorders can be treated. Without treatment, there is a 50% mortality rate of Δ4-3-oxoR deficiency in infants for whom diagnosis is delayed. 1-4
Treatment should be initiated in a specialised environment, where the patient should also be monitored. In between visits to the reference centre specialist, the paediatrician or GP may treat intercurrent diseases in consultation with the specialist at the reference centre.3

Follow-up includes regular visits and regular blood and urine tests. The frequency of the visits varies according to the state of each patient and at the physician’s discretion. It is important to take medical treatments continuously because stopping them may lead to the reappearance of symptoms and further deterioration of the liver.

Useful associations and groups for primary BASD

  • Association Maladie Foie Enfant – Child Liver Disease Association. Created in 2009, the aim of this French association is to raise funds for paediatric liver disease research, including biliary atresia. Funds can also be used for social actions to help families cope with their child’s illness.
  • Filfoie – French network for rare liver diseases. The French rare diseases network’s objective is dual: to help guide patients and healthcare professionals through a multidisciplinary patient care pathway and thus reduce delays in diagnosis and treatment, to encourage exchanges, implement synergy and create a link between the actions of partners in healthcare, medico-social sectors, research and patients’ organizations.


  1. Sundaram SS, Bove KE, Lovell MA, Sokol RJ. Mechanisms of disease: Inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 2008;5:456-68.
  2. Heubi JE, Setchell KDR, Bove KE. Inborn errors of bile acid metabolism. Clin Liver Dis 2018;22:671-87
  3. Protocole national de diagnostic et de soins : Déficits de synthèse des acides biliaires primaires. Centre de Référence Coordonnateur de l’Atrésie des Voies Biliaires et des Cholestases Génétiques; 2019
  4. K E Bove, J E Heubi, W F Balistreri , K D R Setchell. Bile acid synthetisis defects and liver disease : a comprehensive review. Pediatric and Developmental Pathology; 2004 (7), 315-334.
  5. J Jahnel, E Zohrer, B Fischler, L D’Antiga, D Debray, A Dezsofi, et al. Attempt to determine the prevalence of two inborn errors of primary bile acid synthesis: results of a european survey. JPGN, 2017 (64), 864–868.
  6. Monte MJ, et al. Bile acids: Chemistry, physiology, and pathophysiology. World J Gastroenterol 2009; 15(7): 804-816
  7. Van Mil SW, Houwen RH, Klomp LW. Genetics of familial intrahepatic cholestasis syndromes. J Med Genet 2005;42:449-63.
  8. Bile acid synthesis disorders. NORD: National Organization for Rare Disorders, 2017. (Accessed April, 2020, at https://rarediseases org/rare-diseases/bile-acid-synthesis-disorders/.)

The term myeloma refers to a disease of cells located in the bone marrow, the plasma cells. It is called “multiple” because many bones are affected by the disease. Multiple myeloma was also called Kahler’s disease.

What is multiple lymphoma?

Multiple myeloma is a lymphoid malignant blood disease. It is characterized by the multiplication of abnormal plasma cells in the bone marrow.
In most cases, multiple myeloma tends to become chronic: patients go through a succession of remissions and relapses. The durations of these phases are variable. Suitable treatment needs to be instituted by medical teams.

What are the figures?

Myeloma is a relatively rare cancer:
– 2nd most common malignant blood disease representing 1% of cancers 1,

– 6-8 people out of 100 000 affected in Europe1 but this figure is increasing partly due to the ageing of the population,

– The 5-year survival rate with treatment is close to 50% 2,
– The median age at diagnosis is 70 years for men and 74 years for women 3.
– Younger people are occasionally also affected: 3% of cases are diagnosed before age of 40 4.

What is the mechanism of the disease?

Plasma cells are the most mature cells of the B-cell line. Their role is the production and excretion of antibodies, or immunoglobulins, into the blood plasma.
Plasma cells normally produce and secrete different types of antibodies to meet the needs of the immune system. In the context of multiple myeloma, an abnormal plasma cell multiplies identically and uncontrollably in the bone marrow causing its invasion, it is a clone.

Reminder on bone marrow

Bone marrow, which should not be confused with the spinal cord, is located in the bones. It produces, in particular, hematopoietic stem cells which in turn give rise to:

  • red blood cells (oxygen transport in the body),
  • white blood cells (immune defences),
  • platelets (coagulation).

What are the symptoms?

The four most common clinical and laboratory signs of multiple myeloma can be recalled using the mnemonic C.R.A.B.:

  • Calcium (abnormal increase in calcium blood levels)
  • Renal failure (deterioration of kidney function),
  • Anemia (decreased red blood cells),
  • Bone damage, lesions in the tissue constituting the bones (often bone pain and/or spontaneous fractures).

The onset of symptoms is usually related to disease progression. Multiple myeloma can however also be discovered in asymptomatic patients, particularly during a health check.

It is important to note that these clinical and laboratory signs are not specific to multiple myeloma and are not sufficient for a diagnosis to be made.

Symptoms at diagnosis 5

Bone pain


Weight loss



How is the disease diagnosed?

Various in-depth examinations are required to confirm the disease, its nature and its extent in order to best adapt the choice of treatments to each patient’s needs:

  • A clinical examination, to assess the general state of health of the person and the presence of possible symptoms,
  • Blood and urine tests, to check for abnormal results and assess kidney function,
  • A myelogram, to confirm diagnosis,
  • An imaging assessment, to locate any bone lesions.

Useful associations and groups:

  • INCa – Institut National du Cancer – the French National Cancer Institute. It is the health and science agency in charge of cancer control in France and is responsible for coordinating actions to fight against cancer.
  • IFM – Intergroupe Francophone du Myélome (IFM)–French Language Myeloma Intergroup. Created in 1994, the IFM is a non-profit organisation that brings together clinicians and biologists in France and Belgium. The aim of the association is to optimize basic and clinical research efforts in myeloma.
  • AF3M – Association Française des Malades du Myélome Multiple – French Association of Multiple Myeloma Patients. AF3M is a patient organisation that was created in 2007 by people with myeloma and their relatives. The association was recognized by the Ministry of Health in 2012. It’s main tasks are to :
  • – Help, support, represent and inform patients with multiple myeloma,
  • – Support and encourage research,
  • – Improve the care and the quality of life of patients.
  • IMF – International Myeloma Foundation. Founded in 1990, the IMF has more than 525 000 members in 140 countries worldwide. It is the largest organisation focused specifically on myeloma in the world. The foundation acts through its research, education and support programmes for patient and relatives and is dedicated to helping patients gain access to treatment.


  1. Dimopoulos MA, Terpos E. Multiple myeloma. Annals of Oncoloy 2010 ;21 (Suppl 7) : 143-150.
  2. David Robinson et al. Impact of Novel Treatments on Multiple Myeloma Survival. Blood 2014 Volume 124 (Issue 21) : 5676.
  3. Haute Autorité de Santé. Guide – Affection de longue de durée : Tumeur maligne, affection maligne du tissu lymphatique ou hématopoïétique Myélome Multiple., consulted on March 27th, 2018.
  4. INCa, AF3M. Comprendre le myélome multiple., consulted on March 16th, 2018.
  5. Kyle RA. et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Procceedings 2003 Volume 78 (Issue 1): 21-33

What are the skin particularities?

The skin is the body’s largest organ (up to 15% of its weight approximatively) forming a flexible membrane which covers its entire surface. It is a stable but flexible outer covering that acts as a barrier, protecting the body from harmful things in the outside world such as moisture, the cold and sun rays, as well as germs and toxic substances.
The skin is made of three different layers: the outer layer (epidermis), the middle layer (dermis) and the deepest layer (subcutis) 1.
Regarding the depth, the origin, and the site, a wound can range from simple to life threatening. Wounds can be opened or closed, deep or superficial, clean or contaminated, acute or chronic, and each type of wound will need a specific management in order to heal correctly 2.
What is the wound healing process?

Regeneration and tissue repair processes are based on a sequence of molecular and cellular events occurring right after the beginning of a tissue lesion.

This sequence of events, called wound healing, can be divided into 4 stages 3:
  • Hemostasis phase: process of the wound being closed by clotting.
  • Inflammatory phase: controls bleeding and prevents infection.
  • Proliferative phase: the wound is rebuilt with new tissue made up of collagen and extracellular matrix.
  • Maturation phase: also called the remodeling stage, consisting of fully closing the wound. It begins about 21 days after an injury and can continue for a year or more.

What are the challenge for wound healing?

For injuries that require further management it is imperative to assess the wound and determine how best to treat it.
Multiple techniques can be used for wound closure. The three main techniques are sutures, staples and adhesive tapes/skin glues. In percutaneous wounds or simple pediatric cases, skin glues are particularly useful as they are quick, relatively painless and can be combined with deeper sutures too. They cause minimal wound inflammation, have a lower infection rate than sutures, and are removed easily 4-5.