This document discusses Fanconi syndrome and Fanconi anemia. Fanconi syndrome is a generalized proximal tubular defect in the kidneys causing defects in renal tubular reabsorption. It can be hereditary or acquired. Fanconi anemia is a rare inherited bone marrow failure syndrome associated with physical abnormalities and cancer predisposition. It is caused by mutations in genes involved in DNA repair. Supportive care includes transfusions and hematopoietic stem cell transplantation represents the only cure for hematological complications.

1. Fanconi syndrome, Fanconi
Anemia
DR Doha Rasheedy
Assisstant Professor
Geriatrics and Gerontology
Department

2. FANCONI SYNDROME

3. Definition
• Fanconi syndrome consists of multiple defects in
renal proximal tubular reabsorption, causing:
1. Glucosuria
2. Phosphaturia
3. generalized aminoaciduria
4. bicarbonate wasting
5. uric acid
6. Water
7. Potassium
8. sodium.
Fanconi Syndrome is a generalized proximal tubular
defect with a hypokalemic metabolic acidosis
(proximal RTA) associated with vitamin D-resistant
metabolic bone disease

4. Etiology
Hereditary:
• Idiopathic or Accompanies the
following:
1. Cystinosis
2. Wilson disease
3. hereditary fructose intolerance,
4. galactosemia,
5. oculocerebrorenal syndrome
(Lowe syndrome),
6. mitochondrial cytopathies,
7. tyrosinemia.
Acquired
1. vitamin D deficiency.
2. Heavy metal intoxication
3. Renal transplantation
4. various drugs {see later}
5. multiple myeloma
6. amyloidosis
7. Sarcoidosis
8. Acute lymphoblastic
leukemia
Idiopathic: AD , AR, or XLR

5. Drugs causing acquired type
1. chemotherapy drugs (eg, ifosfamide, cisplatinum,
streptozocin)
2. Anti-retrovirals (eg, didanosine, cidofovir)
3. and out- dated tetracycline.
4. Aminoglycosides
5. Rifampin
6. Valproic acid, commonly used as an antiepileptic drug,
may rarely induce severe Fanconi syndrome
7. Deferasirox, a widely used oral iron chelator for the
treatment of patients with iron overload due to chronic
transfusion therapy for diseases such as β-thalassemia
and sickle cell disease, has been reported to cause
reversible Fanconi syndrome..

6. Pathophysiology
Possible mechanisms
1. Alterations in the function of the carriers that transport
substances across the luminal membrane, Because of
the large number of transport abnormalities observed
in Fanconi syndrome, these anomalies are not likely due
to alterations in the carriers, which are specific for each
of the substances reabsorbed in the proximal tubule
2. Disturbances in cellular energy metabolism
3. Changes in permeability characteristics of the tubular
membranes.

7. Symptoms and Signs
• In hereditary Fanconi syndrome:
• the chief clinical features:
1. proximal tubular acidosis
2. hypophosphatemic rickets
3. Hypokalemia
4. polyuria, and polydipsia
• —usually appear in infancy.
• When Fanconi syndrome occurs because of cystinosis,
failure to thrive and growth retardation are common. The
retinas show patchy depigmentation. Interstitial nephritis
develops, leading to progressive renal failure that may be
fatal before adolescence

8. In acquired Fanconi syndrome
adults present with the laboratory abnormalities of
renal tubular acidosis, polyuria, polydipsia
hypophosphatemia, and hypokalemia.
• They may present with symptoms of bone disease
(osteomalacia) and muscle weakness.
• Most patients have proteinuria, although it is often
minimal.
• Acidosis is mainly caused by a defect in the
reabsorption of bicarbonate in the proximal tubule.

9. Diagnosis
• Diagnosis is made by showing the abnormalities of
renal function, particularly glucosuria (in the
presence of normal serum glucose), phosphaturia,
and aminoaciduria.
• In cystinosis, slitlamp examination may show cystine
crystals in the cornea.

10. Lab Findings
• Hypophosphatemia, hypouricemia, hyponatremia,
hypokalemia are common
• Metabolic acidosis from bicarb loss
• Glucosuria with normal plasma glucose levels (rarely leads
to hypoglycemia)
• Aminoaciduria is rarely significant enough to cause wasting
or low total protein
• Hypovolemia from glucose osmotic diuresis and renal
sodium losses

11. Treatment
1. Sometimes sodium bicarbonate or potassium
bicarbonate or sodium citrate or potassium citrate
2. Sometimes potassium supplementation
3. removing the offending nephrotoxin

12. • Liver transplantation has been successfully used in
patients with liver failure due to Wilson disease or
tyrosinemia. Liver transplantation leads to the rapid
disappearance of the renal tubular abnormalities.
• Kidney transplantation has been performed in many
patients with renal failure due to cystinosis. Cystine
accumulates in the monocytes and interstitial cells of
the transplanted kidney but not in proximal tubule
cells. Consequently, the tubular transport
abnormalities do not recur.

13. FANCONI ANEMIA

14. Fanconi Anemia
• A rare inherited bone marrow failure syndrome.
• approximately 2000 cases reported in the medical
literature.
• Initially, cases were recognized only when they had the
combination of aplastic anemia and birth defects, 25%
of known patients with Fanconi anemia do not have
major birth defects. A case reported at age 55 with
neither aplastic anemia nor birth defects.(reference)
• while current diagnostic criteria are more extensive, and
rely on demonstration of chromosomal aberrations in
cells cultured with DNA crosslinking agents .
This genetic disorder may be prevalent in all races
and ethnicities. However, it is most common in
Ashkenazi Jews and Native South Africans

15. • cultured cells from patients with Fanconi anemia had
increased numbers of chromosome breaks; later, the
breakage rate was found to be specifically increased
by the addition of deoxyribonucleic acid (DNA) cross-
linkers, such as diepoxybutane (DEB) or mitomycin C
(MMC).
• This led to the identification of patients with Fanconi
anemia and aplastic anemia without birth defects
and the diagnosis of Fanconi anemia in patients
without aplastic anemia but with abnormal physical
findings.

17. • A 3-year-old patient with
Fanconi anemia.
• short stature,
• microcephaly,
• microphthalmia,
• epicanthal folds
• ,dangling thumbs
• , site of ureteral
reimplantation,
congenital dislocated hips
• rocker bottom feet

18. • Café au lait spot and
hypopigmented area in
a 3-year-old patient
with Fanconi anemia
Dangling thumb
Thumbs attached by
threads

19. Complications
• hemorrhages, infections, leukemia, myelodysplastic
syndrome, liver tumors, and other cancers.
• The first adverse event in patients with FA is usually
aplastic anemia, often sufficiently severe to lead to
death, or to a hematopoietic stem cell transplant
(SCT).
• More than 300 patients were reported to have at
least one cancer; 25 patients had between 2 to 4
malignancies

20. Cancer risk
• Acute myeloid leukemia 9% of patients developed leukemia,
of which 95% were acute myeloid leukemia
• Myelodysplastic syndrome was reported in 7% of patients
• Liver tumors occurred in more than 45 patients, 43 of which
were associated with androgen use,
• There is a marked increase in solid tumors. In order of
frequency, these tumors were tumors of the oropharynx,
esophagus, vulva/vagina, brain, skin (nonmelanoma), cervix,
breast, kidney, lung, lymph nodes (lymphoma), stomach, and
colon, followed by osteogenic sarcoma and retinoblastoma

21. • Due to the high sensitivity to chemotherapeutic
agents, which damage DNA, the outcome for
patients with Fanconi anemia and cancer is quite
poor.
• The risk of liver tumors is increased 400-fold, the risk
of leukemia is about 500-fold, and head and neck
cancers are increased approximately 600-fold. The
risk of esophageal cancer is increased 2000-fold, and
the risk of vulvar/vaginal cancer is increased 3000-
fold.

22. Congenital anomalies
• The vast majority (75%) of individuals with Fanconi
anemia have at least one physical anomaly.
• The most common are short stature and cutaneous,
skeletal, craniofacial, and genitourinary anomalies.
Additionally, approximately 5% of patients with
Fanconi anemia have at least 3 of the defining
features of VATER, or VACTERL, association
(vertebral anomalies, anal atresia, cardiovascular
anomalies, tracheoesophageal fistula, renal and/or
radial anomalies, limb defects).

23. • Other anomalies include developmental delay, hearing loss,
congenital heart disease, and CNS anomalies (arterial
malformation, stenosis of the internal carotid, and small
pituitary gland).
• Individuals with birth defects are diagnosed at younger
ages than are persons without birth defects.
• With regard to the first serious adverse event, patients with
a large number of birth defects are at higher risk of early-
onset severe aplastic anemia, while those with fewer
anomalies are more likely to develop leukemia or a solid
tumor as young adults.

24. Etiology
• Fanconi anemia is an autosomal recessive disease
in more than 99% of patients (FANCB is X-linked
recessive
• each patient with Fanconi anemia is homozygous
or doubly heterozygous for mutations in 1 of the
15 genes known to be responsible for Fanconi
anemia. An inheritance of any mutation in the
BRCA1, RAD51, FANCA, B, C, E, F, G, I, J, L, M or N
gene may result in the disease

27. • Any Physical Abnormality 60%. Male:female 1.2:1
1. Microsomia (40%): Short stature
2. Skin (40%): Generalized hyperpigmentation; cafe au lait
spots, hypopigmented areas
3. Upper Limbs, unilateral or bilateral (35%):
• Thumbs (35%): Absent or hypoplastic, bifid, duplicated,
rudimentary, attached by a thread, triphalangeal, long, low
set
• Radii (7%): Absent or hypoplastic (only with abnormal
thumbs), absent or weak pulse
• Hands (5%): Flat thenar eminence, absent first
metacarpal, clinodactyly, polydactyly
• Ulnae (1%): Dysplastic, short

28. • Skeletal:
– Head (20%): Microcephaly, hydrocephaly,
– Face (2%): Triangular, birdlike, dysmorphic, micrognathia,
mid-face hypoplasia
– Neck (1%): Sprengel, Klippel-Fiel, short, low hairline, web
– Spine (2%): Spina bifida, scoliosis, hemivertebrae, abnormal
ribs, coccygeal aplasia
• Eyes (20%): Small, strabismus, epicanthal folds, hypotelorism,
hypertelorism, cataracts, astigmatism, ptosis
• Renal (20%): Horseshoe, ectopic or pelvic, abnormal, hypoplastic or
dysplastic, absent, hydronephrosis or hydroureter
• Gonads:
– Males (25%): Hypogenitalia, undescended testes,
hypospadias, micropenis, absent testes
– Females (2%): Hypogenitalia, bicornuate uterus, malposition,
small ovaries

29. • Developmental Delay (10%): Mental retardation, developmental delay
• Ears (10%): Deaf (usually conductive), abnormal shape, dysplastic, atretic,
narrow ear canal, abnormal middle ear
• Cardiopulmonary (6%): Congenital heart disease, patent ductus arteriosus,
atrial septal defect, ventricular septal defect, coarctation, situs inversus,
truncus arteriosus
• Low Birth Weight (5%)
• Lower Limbs (5%):
– Feet: Toe syndactyly, abnormal toes, club feet
– Legs: Congenital hip dislocation
• Gastrointestinal (5%): Atresia (esophagus, duodenum, jejunum),
imperforate anus, tracheoesophageal fistula, annular pancreas,
malrotation
• Central Nervous System (3%): Small pituitary, pituitary stalk interruption
syndrome, absent corpus callosum, cerebellar hypoplasia, hydrocephalus,
dilated ventricles

30. Presentation
• macrocytosis usually precedes thrombocytopenia.
• In approximately 35% of patients with Fanconi
anemia who were reported to have cancer, the
diagnosis of leukemia or a tumor preceded the
diagnosis of Fanconi anemia.

31. Approach Considerations
• Chromosome Breakage Test in blood or
fibroblasts
• Siblings who do not apparently have Fanconi anemia
need to be screened for occult Fanconi anemia.

32. Flow Cytometry
• Upon treatment with nitrogen mustard, damaged
DNA shows a characteristic pattern in the cell cycle
compared to normal DNA
• Studies show that DNA damaged from FA are more
likely to be arrested in the G2/M phase

33. adenosine deaminase (ADA
• Red cell adenosine deaminase (ADA) is increased in
approximately 85% of patients with Diamond-
Blackfan anemia (DBA) but appears to be normal in
Fanconi anemia.

34. Serum erythropoietin (Ep)
• Serum erythropoietin (Ep) levels are markedly
increased and higher than expected for the degree
of anemia, similar to that observed in DBA. However,
levels may be low in patients with impaired renal
function.

35. Skeletal survey
• Keep in mind that radiation doses should be limited
in patients with Fanconi anemia. Care should be
taken to avoid unnecessary radiation in patients with
a cancer predisposition.

36. ultrasonography
• Perform initial abdomen ultrasonography to
document the size and location of the kidneys, and
perform follow-up ultrasonography annually to
monitor for liver tumors or peliosis hepatis.
• Perform cardiac ultrasonography to evaluate for
congenital anomalies.

37. Bone marrow aspiration and biopsy
Bone marrow aspiration and biopsy may reveal:
1. hypocellularity,: loss of myeloid and erythroid
precursors and megakaryocytes (with relative
lymphocytosis), or full-blown aplasia with a fatty
marrow.
2. Signs of myelodysplastic syndrome include
dyserythropoiesis (multinuclearity, ringed
sideroblasts), dysmyelopoiesis (hyposegmentation,
hypogranularity, hypergranularity), and
hypolobulated or hyperlobulated megakaryocytes.

38. Supportive care
• Supportive care for patients with symptomatic
Fanconi anemia includes transfusions of packed RBCs
that have been leukodepleted (and are not from
family members, to avoid sensitization in case of a
future transplantation). Symptomatic
thrombocytopenia can be treated with similarly
treated platelets; single-donor platelets are preferred
to reduce the frequency of antibody formation.
Symptomatic neutropenia usually responds to
granulocyte colony-stimulating factor (G-CSF).

39. Treatment
• Currently the only cure for the hematological
complications of FA remains hematopoietic stem cell
transplant.
• Patients with FA are exquisitely sensitive to genotoxic
agents such as cyclophosphamide, busulfan and ionizing
radiation. FA patients are also susceptible to the
damaging inflammatory side effects of graft versus host
disease. The introduction of fludarabine, a highly
immunosuppressive and myelosuppressive nucleotide
analog with minimal toxicity to other organs, has
facilitated the reduction or elimination of other
genotoxic agents without increasing the risk of
engraftment failure.

40. androgens
• The only therapy that can cure the pancytopenia is
stem cell transplantation,
• androgens, to which approximately 50-75% of
patients respond, are used for those in whom
transplantation is not an option.