Page 922 - Williams Hematology ( PDFDrive )

896 Part VI: The Erythrocyte Chapter 58: The Porphyrias 897

Pathogenesis of the Clinical Findings also increased. Fecal porphyrins are increased, and are predominantly
Porphyrins in their oxidized state are reddish, fluorescent, and photo- coproporphyrin I. Plasma total porphyrins are markedly increased as
sensitizing, whereas porphyrin precursors and the reduced porphyrin- well, with a pattern of individual porphyrins similar to that in urine.
ogens are colorless and nonfluorescent. Most marrow normoblasts in Markedly increased erythrocyte porphyrins are predominantly uropor-
CEP display marked fluorescence as a result of porphyrin accumula- phyrin I and coproporphyrin I, although protoporphyrin IX may pre-
tion (located principally in the nuclei, probably because of fixation arti- dominate especially in milder cases.
fact). Anemia and the excess production and excretion of porphyrins CEP must be distinguished by biochemical testing from other
92
is largely accounted for by ineffective erythropoiesis in the marrow. causes of blistering skin lesions. HEP can present with photosensitivity
Porphyrin concentrations are also increased in circulating erythrocytes, in early childhood. Mild cases of CEP may be misdiagnosed as PCT.
and intravascular hemolysis may result from exposure to light in the The diagnosis should be confirmed in all cases by DNA studies,
dermal capillaries, causing erythrocyte damage and lysis or uptake by which can identify causative mutations in almost all cases. This is espe-
the spleen. Splenomegaly is very common in CEP and is presumed to cially important for genetic counseling and for prenatal diagnosis in
be secondary to the hemolytic process. The excess porphyrins that are subsequent pregnancies. Demonstration of a GATA-1 mutation in one
produced by the marrow or released by hemolysis are transported in case, illustrates that on occasion a genetic defect outside the heme bio-
plasma to the skin, leading to photosensitivity. synthetic pathway can cause CEP. 93
Clinical Features Therapy
Severe cutaneous photosensitivity is noted soon after birth in most cases. Patients should be advised that to avoid severe scarring and loss of facial
The disease may be recognized even earlier as a cause of hydrops fetalis. features and digits it is essential to avoid sunlight, trauma to the skin,
Phototherapy for hyperbilirubinemia may cause severe cutaneous burns and infections. Topical sunscreens that block long-wave ultraviolet
and scarring in newborns with unrecognized CEP. Brown staining of light (ultraviolet A light) and oral treatment with β-carotene are some-
the teeth by porphyrins (erythrodontia) is evident when the teeth erupt. what helpful, but are marginally beneficial in most cases. Erythrocyte
94
Blistering and scarring resemble those found in PCT, but are usually transfusions are essential in patients with severe anemia. Transfusions
95
much more severe, reflecting the much higher plasma porphyrin levels to maintain the hematocrit above 35 percent, with an iron chelator to
observed in CEP. Some cases are relatively mild, and can closely mimic avoid iron overload, has been beneficial in some cases. Hydroxyurea
96
PCT. Late-onset cases are often associated with myeloproliferative dis- to reduce erythropoiesis and porphyrin production may also be con-
orders, with expansion of a clone of erythroid cells bearing a somatic sidered. Splenectomy has provided short-term benefit. Oral charcoal
97
mutation and displaying UROS deficiency. 88 reportedly was quite effective in one patient, and ascorbic acid and
98
Subepidermal bullous lesions are characteristic, and progress to α-tocopherol improved anemia in another. Unaffected infants born to
89
crusted erosions that heal with scarring and areas of hyper- and hypop- mothers with CEP may have erythrodontia as a result of exposure to
igmentation. Also common is hypertrichosis, which is sometimes maternal porphyrins before birth. 99
severe, and alopecia. Loss of facial features and digits are common and Hematopoietic stem cell transplantation is the treatment of choice
result from recurrent blisters, infection, and scarring. Fingers may be when a suitable donor is available, especially for young patients.
100
shortened and tapered as a consequence of scarring and contraction of When transplantation is successful, there is marked clinical improve-
the skin during childhood growth. Erythrodontia, with brown staining ment and reduction in porphyrin levels, even if these are not completely
and red fluorescence of the teeth under long-wave ultraviolet light is normalized. Gene therapy is being explored using retroviral and lenti-
characteristic, and results from deposition of porphyrins in the develop- viral vectors and hematopoietic stem cells from patients with CEP. 101,102
ing deciduous and permanent teeth in utero. Porphyrins are also depos-
ited in bone. The skeleton is also affected by expansion of the marrow, ERYTHROPOIETIC PROTOPORPHYRIA
leading to pathologic fractures, vertebral compression, short stature,
and osteolytic and sclerotic lesions. Vitamin D deficiency resulting from Definition and History
avoiding sunlight might also contribute. EPP is caused by a partial deficiency of FECH (see Fig. 58–4, step 8)
Anemia may be severe and lead to transfusion dependence in the activity, which results in the accumulation of the substrate protopor-
more severe cases. Uncorrected anemia can increase erythropoiesis, phyrin in the marrow. XLP has the same phenotype but is much less
which, in turn, is a stimulus to porphyrin production by the abnormal common, and is a result of ALAS2 gain-of-function mutations (ALAS;
37
erythropoietic cells in the marrow. Erythrocytes exhibit polychromasia, see Fig. 58–1). EPP and XLP are characterized by onset of nonblis-
poikilocytosis, anisocytosis, and basophilic stippling, and reticulocytes tering cutaneous photosensitivity in early childhood. EPP is the most
and nucleated red blood cells are increased. 93 common porphyria in children and the third most common in adults.
Reported prevalence varies between 5 and 15 cases per 1 million indi-
Diagnosis viduals. 103–105 Protoporphyric hepatopathy is a potentially fatal compli-
CEP may be suspected even before birth if a sibling is known to have cation estimated to occur in less than 5 percent of patients.
CEP. However, the family history is often negative. CEP should be sus-
pected as a cause of hydrops fetalis, as the disease can be diagnosed and Pathophysiology
treated in utero. Aspirated amniotic fluid is dark brown in color and In most families, EPP is best described as an autosomal recessive dis-
contains large amounts of porphyrins. The diagnosis of CEP is often ease, in which a severe FECH mutation is inherited from one parent and
made after birth when pink to dark-brown staining of the diapers, with a low-expression (hypomorphic) FECH allele from the other. More than
red fluorescence under long-wave ultraviolet light, is noted. Cutaneous 75 different severe mutations, including nonsense, missense, and splice-
vesicles and bullae on sun-exposed areas may be severe, with scarring. site mutations, and deletions, insertions, and rearrangements have been
Urinary porphyrin excretion is markedly increased, and often in described. Splicing mutations are most common. Recombinant human
the range of 50 to 100 mg/day (normal: up to ~0.3 mg/day). Uroporphy- FECH, when engineered to have individual exon skipping for exons 3
rin I and coproporphyrin I account for most of the increase, although through 11, lacks significant enzyme activity when expressed in E. coli
the III isomers and hepta-, hexa-, pentacarboxylate porphyrins are and almost all such variants lacked the [ Fe- S] cluster. 106
2
2

Kaushansky_chapter 58_p0889-0914.indd 897 9/18/15 5:58 PM