Congenital bile acid synthesis defects have been associated with variable phenotypes. In detail, they may cause cholestatic liver disease of neonatal or infantile onset, or may not cause any complaints until adulthood. The hallmark of late-onset forms of the disease is a sensorimotor neuropathy. However, those bile acid synthesis defects resulting in the accumulation of toxic intermediates are usually of the early-onset type and follow a severe progressive form. This is the case with CBAS2, a condition that causes the accumulation of toxic unsaturated oxo-bile acids [1].

Few patients have been described to date, with all of them presenting with severe intrahepatic cholestasis in the neonatal period or infancy [2] [3] [4]. Progressive jaundice with dark urine and acholic stools are commonly reported. Jaundice may be accompanied by pruritus [4], but has been described as atypical elsewhere [5]. During clinical examination, hepatomegaly may be palpated.

The lack of primary bile acids interferes with the digestion and subsequent absorption of lipophilic food components. Thus, CBAS2 patients may additionally present symptoms of fat-soluble vitamin deficiency [3] [6]. The latter comprise nyctalopia and xerophthalmia due to vitamin A deficiency, bone pain and and skeletal deformities because of vitamin D deficiency, and a propensity to bleed due to vitamin K deficiency. Vitamin E deficiency may cause neurological symptoms like areflexia.

• Anemia

  Decreased mean corpuscular volume Abnormal hemoglobin Hypochromic anemia Abnormality of temperature regulation Reduced beta/alpha synthesis ratio Alopecia Retinopathy Anemia of inadequate production Vertigo Ascites Limitation of joint mobility Gynecomastia [mendelian.co]

  A CELLULE FALCIFORMI BLACKFAN-DIAMOND, ANEMIA DI ANEMIA CONGENITA IPOPLASTICA FANCONI, ANEMIA DI PANCITOPENIA DI FANCONI ANEMIE SIDEROBLASTICHE METAEMOGLOBINEMIA DA DEFICIT DI METAEMOGLOBINAREDUTTASI METAEMOGLOBINEMIA CONGENITA EREDITARIA RD0010 SINDROME [retemalattierare.it]

  PANEL DE ANEMIA DE FANCONI (CON MLPA)BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, RAD51C, SLX4, UBE2T, XRCC2 PANEL DE ATAXIA EPISODICA (CON MLPA)CACNA1A, CACNB4, KCNA1, SLC1A3 PANEL CATARATA (CON MLPA [sequence.pe]

  26 Erdheim-Chester病 Erdheim-Chester Disease 27 法布雷病 Fabry Disease 28 家族性地中海热 Familial Mediterranean Fever 29 范可尼贫血 Fanconi Anemia 30 半乳糖血症 Galactosemia 31 戈谢病 Gaucher’s Disease 32 全身型重症肌无力 Generalized Myasthenia Gravis 33 Gitelman综合征 Gitelman Syndrome [xxgk.cnbz.gov.cn]

• Weight Loss

  The complications of Congenital Bile Acid Synthesis Defect, Type 1 may include: Inadequate weight gain in infants Unintended weight loss in older individuals due to intestinal malabsorption Severe jaundice Liver cirrhosis; fibrosis of liver Liver failure [dovemed.com]

  loss, elevated serum aminotransferase levels, increase in skin pigmentation, and/or arthropathy in the metacarpophalangeal joints. [mendelian.co]

• Fatigue

  SYMPTOMATIC FORM OF HEMOCHROMATOSIS TYPE 1 Is also known as symptomatic form of hfe-related hereditary hemochromatosis|symptomatic form of classic hemochromatosis Related symptoms: Peripheral neuropathy Hepatomegaly Fatigue Cardiomyopathy Congestive heart [mendelian.co]

  Signs and symptoms[edit] Watery diarrhea, steatorrhea, and other gastrointestinal symptoms such as bloating, abdominal pain, fatigue, "brain fog", fecal urgency, and fecal incontinence are the common manifestation of BAM.[1][2] Classification[edit] Bile [en.wikipedia.org]

• Surgical Procedure

  Relief of eyelid retraction: a surgical procedure. // Arch Ophthalmol. 1965. - Vol. 74. - p. 205-216. 59. Holds JB, Anderson RL, Thiese SM. [dissercat.com]

• Splenomegaly

  Clinical features include failure to thrive, jaundice, steatorrhea, hepatomegaly, cirrhosis, rickets and splenomegaly. [preventiongenetics.com]

  Other signs and symptoms may include splenomegaly and inability to absorb certain fat - soluble vitamins, vitamin D, in particular, which can lead to rickets in some individuals. [ivami.com]

  Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. In most cases, pruritus is absent. [malacards.org]

  Clinical features include hepatomegaly with or without splenomegaly, jaundice, fat and fat-soluble vitamin malabsorption, and mild steatorrhea. [dovemed.com]

  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 And/or malabsorption syndrome • Steatorrhea • Clinical signs [ctrs.fr]

• Steatorrhea

  The clinical presentation resembles that of congenital BAS defect type 1 (see this term) with hepatosplenomegaly, jaundice, fat-soluble vitamin malabsorption, and steatorrhea. [rarediseases.info.nih.gov]

• Failure to Thrive

  Related symptoms: Growth delay Failure to thrive Muscle weakness Anemia Feeding difficulties SOURCES: OMIM ORPHANET MENDELIAN More info about BETA-THALASSEMIA Medium match SYMPTOMATIC FORM OF HEMOCHROMATOSIS TYPE 1 Symptomatic form of hemochromatosis [mendelian.co]

  Affected infants show failure to thrive and secondary coagulopathy. [malacards.org]

  Clinical features include failure to thrive, jaundice, steatorrhea, hepatomegaly, cirrhosis, rickets and splenomegaly. [preventiongenetics.com]

  Affected infants usually have a failure to gain weight and grow at the expected rate (failure to thrive) and yellowing of the skin and eyes (jaundice) due to impaired bile flow and a buildup of partially formed bile. [ghr.nlm.nih.gov]

  The majority of the cases present intrauterine growth retardation (IUGR), failure to thrive, decreased subcutaneous fat, and low or undetectable C-peptide levels (4). [ncbi.nlm.nih.gov]

• Abdominal Pain

  pain, weakness, lethargy, weight loss, elevated serum aminotransferase levels, increase in skin pigmentation, and/or arthropathy in the metacarpophalangeal joints. [mendelian.co]

  Unfortunately, many patients find them difficult to tolerate; although the diarrhea may improve, other symptoms such as abdominal pain and bloating may worsen. [en.wikipedia.org]

• Pruritus

  Jaundice may be accompanied by pruritus, but has been described as atypical elsewhere. During clinical examination, hepatomegaly may be palpated. [symptoma.com]

  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 3β-HSD deficiency. [ctrs.fr]

  In most cases, pruritus is absent The clinical course of early-onset disease is heterogeneous with some patients resolving jaundice and being identified later in life, or with more fulminant disease that results in death or requires liver transplantation [dovemed.com]

  In most cases, pruritus is absent. Liver function tests present elevated serum transaminases (AST, ALT), conjugated hyperbilirubinemia, and normal gamma-GT. [malacards.org]

  Abnormality of the anterior pituitary Elevated transferrin saturation Abnormality of endocrine pancreas physiology Abnormal macular morphology Histiocytosis Rigidity Acholic stools Prolonged prothrombin time Hypertyrosinemia Chronic hepatic failure Nyctalopia Pruritus [mendelian.co]

• Osteoporosis

  Diseases related with Hepatomegaly and Osteoporosis In the following list you will find some of the most common rare diseases related to Hepatomegaly and Osteoporosis that can help you solving undiagnosed cases. [mendelian.co]

  Jaundice Malabsorption Neonatal cholestatic liver disease Frequently present symptoms in 30-79% of the cases: Abnormality of coagulation Gastrointestinal hemorrhage Splenomegaly Occasionally present symptoms in 5-29% of the cases: Cirrhosis Nyctalopia Osteoporosis [dovemed.com]

• Lethargy

  […] rare, hereditary hemochromatosis characterized by inappropriately regulated intestinal iron absorption which leads to excessive iron storage in various organs and manifests with a wide range of signs and symptoms, including abdominal pain, weakness, lethargy [mendelian.co]

• Vertigo

  […] hypothalamus-pituitary axis Arthralgia Hypochromic microcytic anemia Decreased mean corpuscular volume Abnormal hemoglobin Hypochromic anemia Abnormality of temperature regulation Reduced beta/alpha synthesis ratio Alopecia Retinopathy Anemia of inadequate production Vertigo [mendelian.co]

• Phenylketonuria

  페닐케톤뇨증(Phenylketonuria, PKU) 172 2. 고페닐알라닌혈증과 BH4 대사장애(Hyperphenylalaninemia and defective metabolism of tetrahydrobiopterin : BH4) 182 3. 1 형 타이로신혈증(Hepatorenal tyrosinemia/Fumarylacetoacetate hydrolase deficiency; Tyrosinemia type I) 189 4. [mbikorea.co.kr]

  Ornithine Transcarbamylase Deficiency 86 成骨不全症（脆骨病） Osteogenesis Imperfecta (Brittle Bone Disease) 87 帕金森病（青年型、早发型） Parkinson Disease (Young-onset, Early-onset) 88 阵发性睡眠性血红蛋白尿 Paroxysmal Nocturnal Hemoglobinuria 89 黑斑息肉综合征 Peutz-Jeghers Syndrome 90 苯丙酮尿症 Phenylketonuria [xxgk.cnbz.gov.cn]

The clinical presentation of CBAS2 does not allow for its distinction from other types of congenital bile acid synthesis defects, or even from cholestatic liver disease due to any other pathological condition. In this regard, laboratory results of blood sample analyses often provide valuable first indications as to the underlying disease. In detail, hepatic transaminases and conjugated bilirubin concentrations are usually increased in samples obtained from those suffering from congenital bile acid synthesis defects, while γ-glutamyltransferase levels typically remain within reference ranges or are found to be mildly elevated [4] [7]. Analytical techniques must then be applied to assess the patient's bile acid profiles in plasma and urine. Fast atom bombardment ionization-mass spectrometry, electrospray ionization-tandem mass spectrometry, and gas chromatography-mass spectrometry, and liquid chromatography-tandem mass spectrometry have been used to this end [6] [7]. CBAS2 is associated with an increase of levels of the glycine and taurine conjugates of 7α-hydroxy-3-oxo-4-cholenoic acid and 7α,12α-dihydroxy-3-oxo-4-cholenoic acid, while primary bile acid concentrations are pathologically reduced [3] [6] [7]. Finally, the sequencing of the AKR1D1 gene allows for the identification of the causal mutation and the confirmation of the diagnosis. It is highly recommended to not skip this step, because liver diseases other than CBAS2 may be associated with bile acid profiles very similar to those obtained in case of CBAS2 may be caused by other liver diseases [3] [7] [8]. In fact, distinct hepatopathies may entail a reduced activity of enzymes like delta(4)-3-oxosteroid-5-beta-reductase, thereby provoking symptoms and findings that may be falsely attributed to CBAS2 [6]. Some authors have stated that the ratio of abnormal to normal bile acids in urine samples may serve as an index to distinguish CBAS2 from other liver diseases affecting bile acid synthesis in a similar manner: If the ratio of 3-oxo-delta(4) bile acids is >75 or even 90%, the patient is likely to suffer from CBAS2 [9].

High-throughput sequencing technologies allow for a different approach to diagnosing hereditary liver disease and neuropathies accompanied by non-specific symptoms. Indeed, CBAS2 has been diagnosed based on the results of whole exome sequencing that, in turn, have been confirmed by means of bile acid profiling [10].

Upon histopathological examination, intralobular cholestasis with giant cell transformation, hepatocytes containing few peroxisomes and undergoing necrosis may be observed. Giant cell transformation has been reported to be discernible in all symptomatic infants with congenital bile acid synthesis defects and has been proposed as a marker of such diseases. An extensive list of morphological features in a cholestatic liver that suggest a bile acid synthetic defect has been published elsewhere [1].

• Hypercholesterolemia

  […] dysfunction Ketonuria Galactose intolerance Ataxia Hyperphosphaturia Fasting hypoglycemia Microalbuminuria Ketosis Generalized aminoaciduria Hypouricemia Hypergalactosemia Hyperuricosuria Galactosuria Mild proteinuria Albuminuria Seizures Poor appetite Hypercholesterolemia [mendelian.co]

  가족성 고콜레스테롤혈증(Familial hypercholesterolemia) 434 2. Mevalonic aciduria 438 3. Lipoprotein lipase (LPL) 결핍증/ type I hyperlipoproteinemia 440 4. Lecithin : cholesterol acyltransferase 결핍증 443 5. [mbikorea.co.kr]

  Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy, CADASIL) 43 遗传性痉挛性截瘫 Hereditary Spastic Paraplegia 44 全羧化酶合成酶缺乏症 Holocarboxylase Synthetase Deficiency 45 同型半胱氨酸血症 Homocysteinemia 46 纯合子家族性高胆固醇血症 Homozygous Hypercholesterolemia [xxgk.cnbz.gov.cn]

An early diagnosis and timely initiation of treatment is important to prevent disease progression and liver failure. Therapy relies on the replacement of primary bile acids, namely chenodeoxycholic and cholic acid. Distinct treatment regimens based on the application of either one of those bile acids, or even ursodeoxycholic acid, have been followed in the past [6]. Cholic acid is now recognized as the bile acid of choice because it is not hepatotoxic and has been proven effective in normalizing liver function tests and urine composition, and preventing disease progression to liver failure [5]. If applied, ursodeoxycholic acid needs to be combined with chenodeoxycholic or cholic acid in order to guarantee negative feedback on bile acid synthesis.

In case of persisting fat-soluble vitamin deficiency, the respective vitamins should be supplemented.

If left untreated, CBAS2 inevitably leads to liver failure. The disease is therefore potentially life-threatening. However, patients usually respond well to primary bile acid therapy. In 2009, Gonzalez et al. published their results of long-term follow-ups of patients who had received daily doses of cholic acid for a median of 12 years. They found this therapy to be well tolerated, safe and effective. Some patients did present residual symptoms at the time of their last examination, though [5].

CBAS2 is related to a reduced activity of the enzyme delta(4)-3-oxosteroid-5-beta-reductase, which catalyzes an essential step in bile acid synthesis. This enzyme is encoded by the AKR1D1 gene, located on the long arm of chromosome 7. Distinct types of mutations have been described in CBAS2 patients, e.g., missense and nonsense mutations, deletions, and frame shift mutations [3]. Data is too scarce, though, to derive genotype-phenotype relations.

CBAS2 is inherited in an autosomal recessive manner, i.e., only those with mutations in both alleles of the AKR1D1 gene will develop the disease. Homozygosity and compound heterozygosity have been described in CBAS2 patients [3] [4].

Bile acid synthesis defects are rare disorders. It has been estimated that they account for about 2% of persistent cholestasis in infants [1]. Congenital bile acid synthesis defect type 1 and CBAS2 are supposed to be the most common congenital bile acid synthesis defects [5], but this assumption disregards the fact that milder forms are largely underdiagnosed. In sum, less than two dozen cases of CBAS2 have been reported [5].

The synthesis of bile acids comprises several reactions that take place in distinct cell organelles. An essential step of bile acid synthesis is the reduction of 7α-hydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-4-cholesten-3-one to 7α-hydroxy-5β-cholestan-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one, respectively. This reaction is catalyzed by delta(4)-3-oxosteroid-5-beta-reductase, a cytosolic enzyme [9] [11]. Under physiological conditions, 7α-hydroxy-5β-cholestan-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one undergo further conversions to produce the corresponding C24 bile acids chenodeoxycholic and cholic acid. However, CBAS2 patients are unable to continue bile acid synthesis at this point and thus, the aforementioned intermediates are converted into 3-oxo-delta(4) bile acids by means of side-chain oxidation and are then conjugated to glycine and taurine. The resultant intermediates cannot be secreted into the bile and thus appear in blood and urine [6].

The abnormal intermediates accumulating in CBAS2 patients have been postulated to exert hepatotoxic effects. Furthermore, there is no regulatory feedback inhibition of bile acid production because the necessary threshold of primary bile acids is never reached. This condition enhances those reactions taking place in early bile acid synthesis, leading to the formation of even more potentially toxic compounds. The modified composition of bile in CBAS2 patients interferes with biliary secretion causing cholestasis and malabsorption of lipophilic food components like fat-soluble vitamins [7].

Of note, lack of delta(4)-3-oxosteroid-5-beta-reductase has also been postulated to interfere with steroid hormone synthesis. This hypothesis is based on abnormalities of urinary steroid profiles that have been observed in CBAS2 patients. However, such disturbance of steroid hormone synthesis doesn't seem to cause any clinical symptoms [12].

Affected families may benefit from genetic counseling. The latter does, however, require precise knowledge regarding the underlying mutation. In some cases of CBAS2, familial anamnesis revealed a history of early-onset liver disease and/or fat-soluble vitamin deficiency in living or deceased relatives [2] [9], but the identification of carriers and the prenatal diagnosis of the disease is not feasible without targeted genetic analyses.

Congenital bile acid synthesis defects are rare genetic disorders resulting from mutations in distinct genes that cause enzyme deficiencies. The respective enzymes are required for bile acid synthesis and any reduction of their activity interferes with the production and release of bile from hepatocytes. Accordingly, intrahepatic cholestasis is a clinical hallmark of bile acid synthesis defects.

In detail, the following congenital bile acid synthesis defects are distinguished:

• Congenital bile acid synthesis defect type 1 or 3beta-hydroxy-delta5-C27-steroid oxidoreductase deficiency due to mutations in the HSD3B7 gene
• CBAS2, which will be discussed in this article
• Congenital bile acid synthesis defect type 3, which has been related to CYP7B1 mutations
• Congenital bile acid synthesis defect type 4 or intrahepatic cholestasis with defective conversion of trihydroxycoprostanic acid to cholic acid, resulting from mutations in the AMACR gene
• Congenital bile acid synthesis defect type 5, a disease that is caused by mutations of the ABCD3 gene
• Congenital bile acid synthesis defect type 6, which is triggered by ACOX2 mutations

CBAS2 is also called "cholestasis with delta(4)-3-oxosteroid-5-beta-reductase deficiency" and is caused by mutations in the AKR1D1 gene. In healthy people, delta(4)-3-oxosteroid-5-beta-reductase catalyzes the conversion of certain bile acid intermediates so that the following steps of bile acid synthesis can take place. Any reduction of its activity leads to the formation of abnormal intermediates that can be detected in blood and urine samples. At the same time, primary bile acids chenodeoxycholic and cholic acid are hardly produced at all. As a consequence, bile secretion is largely disturbed and affected individuals develop severe intrahepatic cholestasis at a very early age. They also suffer the consequences of lack of primary bile acids, namely maldigestion and malabsorption of lipophilic food components.

Bile acids are synthesized in the liver and are the secreted into the small intestine. They facilitate the digestion and subsequent absorption of lipids ingested with foods. Bile acid synthesis itself is a complex process involving several reactions, with each of them being catalyzed by a specific enzyme. Due to mutations in the respective genes, some people suffer from congenital enzyme deficiencies and bile acid synthesis defects. In detail, congenital bile acid synthesis defect type 2 (CBAS2) is caused by a mutation in the AKR1D1 gene.

First symptoms become apparent in the neonatal period or in infancy: CBAS2 patients typically develop cholestatic liver disease within their first year of life. It manifests in form of jaundice, dark urine and pale or clay-colored stools. Some patients suffer from pruritus. Because bile acids are required for the absorption of fat-soluble vitamins, namely vitamins A, D, E, and K, affected infants may also present symptoms of vitamin deficiency. For instance, they may develop rickets, neurological symptoms and be prone to bleed. The disease follows a progressive course and if left untreated, leads to life-threatening liver failure.

In order to diagnose the disease, blood and urine samples have to be obtained and analyzed. In CBAS2 patients, plasma and urine contain specific intermediates of bile acid synthesis that cannot be metabolized due to the deficiency of delta(4)-3-oxosteroid-5-beta-reductase, the enzyme encoded by the AKR1D1 gene. The diagnosis must be confirmed by sequencing of the AKR1D1 gene and identifying the causal mutation. Treatment is based on the replacement of those primary bile acids that cannot be produced by the patient due to their enzyme deficiency. Cholic acid is most commonly used to this end and must be applied daily throughout life. Such a therapy is well tolerated and safe. It prevents disease progression to liver failure and is thus life-saving.

1. Bove KE, Heubi JE, Balistreri WF, Setchell KD. Bile acid synthetic defects and liver disease: a comprehensive review. Pediatr Dev Pathol. 2004; 7(4):315-334.
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3. Lemonde HA, Custard EJ, Bouquet J, et al. Mutations in SRD5B1 (AKR1D1), the gene encoding delta(4)-3-oxosteroid 5beta-reductase, in hepatitis and liver failure in infancy. Gut. 2003; 52(10):1494-1499.
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