Big coffee commented on the cutting-edge stripping the cocoon: the diagnosis and treatment of a case of hereditary anemia in a young child

weave

he who

press

Anemia is a common hematologic symptom
in childhood, especially in infancy.
The symptoms of pediatric anemia are related
to the cause, degree of anemia, rate of occurrence, age of onset and other factors.
The symptoms of anemia are mainly caused by tissue hypoxia, the most common clinical manifestation is pale skin and mucous membranes, and in severe cases, it can also affect multiple organ systems, and even affect growth and development
.
The etiology of pediatric anemia is relatively complex ^[1], and detailed medical history, detailed physical examination, and comprehensive analysis of laboratory tests are required in clinical work to clarify the diagnosis and correct treatment
.
"Physician Daily" specially invited Dr.
Chen Jiao, Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, to share the diagnosis and treatment process of a case of pediatric anemia, and invited Professor Wang Jiao of the First Affiliated Hospital of Zhengzhou University to comment and discuss the standardized diagnosis and treatment
of pediatric anemia.

01

Dr.
Chen Jiao: A pediatric anemia case was managed and shared

The child Chen, female, 2 years old, was admitted to our hospital in September 2022 because of "paleness for nearly 2 years, aggravated by 3 days"
。 In the past, he was admitted to the NICU for "jaundice" 2 days after birth, and his blood group O⁺ was checked and blue light was treated10 After a few days, he was discharged from the hospital, and severe anemia was found during hospitalization, and he was discharged after correcting the anemia by blood transfusion (diagnosis unknown).

After that, the family found that the child was pale, and the re-examination of blood routine showed that there was still moderate to severe anemia, only 2 times of symptomatic treatment with intermittent blood transfusion, hemoglobin (Hb) fluctuations between 59~92g/L, mild yellowing of the sclera, Blood bilirubin levels
were not repeated.
At 8 months of age, long-term oral iron treatment according to iron deficiency anemia was not effective, and anemia remained on retest blood routine (specific blood routine results are unknown), and blood
transfusion was not re-transfused.
This time, due to the aggravation of paleness, the outpatient blood routine showed Hb48g/L, so he was admitted to the hospital
as "severe anemia to be investigated".

Physical examination: clear mind, poor mental response, yellow skin and mucous membranes, mild yellow staining of the sclera, superficial lymph nodes not palpated and enlarged, slightly red pharyngeal cavity, no abnormalities
on cardiopulmonary auscultation.
The abdomen is soft, 3 cm below the right rib of the liver and 3 cm under the left rib of the spleen, homogeneous and tough, non-tender and smooth
surface.
Neurological examination shows no abnormalities
.

Diagnosis and treatment ideas:

The causes of anemia are divided into: disorders of red blood cell and hemoglobin production, hemorrhagic anemia, hemolytic anemia; Disorders of red blood cell and hemoglobin production are divided into nutritional anemia, bone marrow failure, and hematopoietic anemia; Hemorrhagic anemia is mainly fetal-maternal blood transfusion, but there is also intrapartum blood loss and postnatal blood loss; Hemolytic anemia is often accompanied by hyperindirect bilirubinemia and is divided into congenital red blood cell defects (red blood cell membrane defects, hemoglobinopathies, red blood cell enzyme defects) and non-red blood cell autodefects (immune, non-immune).

This case of long-term anemia, no clear history of infection, blood loss, breastfeeding after birth, adding complementary foods on time, anemia improvement after long-term iron supplementation is not obvious, no history of lack of hematopoietic materials, combined with the onset of the neonatal period of the child, the focus is on hereditary or congenital hemolytic anemia, and it is necessary to further improve the anemia-related examinations to assist in diagnosis and differential diagnosis
.

Ancillary examinations:

CBC: WBC 10.
2×10⁹/L, RBC 2.
07 ×10¹²/L，Hb53g/L，Plt 392×10⁹/L，N4 .
82×10⁹/L，MCV82 fl，MCH 28pg, MCHC323g/L, reticulocyte percentage 21 %, absolute value of reticulocytes 671×10⁹/L
.

Peripheral blood cell morphology: the total number of white blood cells is normal, the granulocyte ratio is normal, the lymphocyte ratio is normal, the size of mature red blood cells is different, pigment filling can be seen, large cells are visible, and the spherical red blood cell count is 25%.

Bone marrow cell morphological examination: bone marrow hyperplasia is active, granulocytosis ratio is reduced, eosinophils and basophils can be seen, erythroid ratio is increased, large red blood cells and spherical red blood cells are visible, lymphocyte ratio is normal, more than 100 megakaryocytes, piles and scattered in platelets, NAP positive rate 90%.
, score 120, bone marrow iron staining: extracellular iron +, intracellular iron positive rate 51%.

Tip: erythroid hyperplasia bone marrow image
.

Erythrocyte osmotic fragility test: increased
.

Methemoglobin reduction test: negative
.

Hemoglobin electrophoresis: H bA 93.
9%, H bF 3.
6%, HbA2 2.
5%.

。

P NH clonal detection: red blood cell PNH cloning size: III.
+II.
type 0.
23%.
, granulocyte P NH clonal size: FLAER-CD24-0%, monocyte P NH clone size: FLAER-0%.

Blood biochemistry: alanine aminotransferase 10U/L, aspartate aminotransferase 30U/L, total bilirubin 4 4.
9μmol/L, direct bilirubin 1 5.
2 μmol/L, indirect bilirubin 2 9.
7 μmol/L, ceruloplasmin 39.
2 mg/dL, glucose 4.
13 mmol/ L
。

Triathlon: serum iron 3 5.
96 μmol/L, ferritin 260.
4 ng/mL, unsaturated iron binding capacity 5 .
5 μmol/L, total iron binding capacity 41.
46μmol/L
.

Folic acid 21.
2ng/mL, vitamin B12 370pg/mL
.

Coombs test: negative
.

Blood type: O, RH positive
.

Mycoplasma antibody IgM: positive
.

Ultrasound: mild mitral regurgitation; The volume of the liver increased, the oblique diameter of the right lobe was 110mm, the subcostal diameter was 34mm, and the parenchymal echo was densely enhanced; The spleen is 34mm thick and 107mm long, with a large spleen and uniform
parenchymal echo.

Growth and development history: no special.

Family history:

Mother: 28 years old, more than 3 years old due to "anemia, splenomegaly" "splenectomy", blood type: O type, R H Positive
.
The father is 30 years old, and the first sister is 4 years old, both in good health; maternal grandmother: 53 years old, "anemia" at an early age, details unknown, untreated, now alive; maternal grandfather: 55 years old, healthy; Uncle: 25 years old, underwent "splenectomy"
due to "anemia" when he was more than 4 years old.

Initial diagnosis:

1.
Spherocytosis (hereditary?) ）

2.
Mycoplasma infection

Further improve parents' blood routine and peripheral blood cell morphology and anemia genetic examination:

Genetic testing: homozygous mutation of TFR2 gene, heterozygous mutation of
ANK1 gene.

Mother: Blood Routine: WBC10 91×10⁹/L，RBC4.
47×10¹² /L，Hb141g/L，Plt926 ×10⁹/L，N6.
63×10⁹/L
。 Peripheral blood cell morphology: mature red blood cells vary in size, mainly small cells, pigment can be filled, spherical red blood cell count 19%, and the number of platelets increases
.
Increased
osmotic fragility of erythrocytes.
Genetic testing: TFR2 gene heterozygous mutation, ANK1 gene heterozygous mutation
.

His father: blood CB: WBC7.
16×10⁹/L, RBC 4.
53×10¹²/L，Hb151g/L ，Plt245×10⁹/L，N 4.
23×10⁹/L
。 Peripheral blood cell morphology: mature red blood cells vary in size mildly, and pigmentation can be
sufficient.
Erythrocyte osmotic fragility test: negative
.
Genetic testing: TFR2 gene heterozygous mutation, ANK1 gene is wild-type
.

Genetic test results:

Final diagnosis:

1.
Hereditary spherocytosis

2.
Hemochromatosis (type 3).

3.
Mycoplasma infection

Treat:

There is no specific treatment, if necessary, the spleen is cut and temporarily symptomatic treatment
.

After admission, a small dose of red blood cells (5 ml/kg) was given to correct anemia, and azithromycin was given antimycoplasma to remove the aggravating factors
that predisposed hemolysis.
Give 0.
5-1mg/kg methylprednisolone intravenous drip to stabilize the red blood cell membrane, reduce hemolysis, monitor hemoglobin stable at 100g/L level, and then change to oral prednisone tablets 0.
5 mg/kg.
d, gradually reduced according
to Hb level.
Indirect bilirubin is maintained at about 35μmol/L, ursodeoxycholic acid tablets 1/3 tablet, oral once a day to prevent cholelithiasis
.

Follow-up after 1 month:

Review CBC: WBC19.
83×10⁹/L, RBC3.
52 ×10¹²/L，Hb109g/L，Plt 404×10⁹/L，N10.
05×10⁹ /L，MCV90.
9fl，MCH31pg， MCHC341g/L，Ret%16.
97%
。 Blood bilirubin: total bilirubin 57.
61 μmol/L, direct bilirubin 8.
09 μmol/L, indirect bilirubin 39.
52 μmol/L
。

02

Professor Wang Nao's comments: The cause of anemia mainly depends on laboratory tests, and genetic factors need to be tested genetically

The diagnosis of the cause of anemia mainly relies on laboratory tests, and when hereditary or congenital anemia is considered, genetic testing is required to confirm the diagnosis, but it still needs to be closely combined with the clinic
.

This case had anemia and jaundice after birth, no clear history of infection and blood loss at birth, excluding hemorrhagic and infectious anemia, the blood type of mother and child is the same, excluding neonatal homoimmune hemolysis caused by maternal and child blood group incompatibility, diagnosed as hyperbilirubinemia, severe anemia (cause unknown), jaundice improves after treatment, but anemia persists, hereditary or congenital anemia is considered; The child was given complementary food in order, and was treated with oral iron for 2 months according to iron deficiency anemia at the age of 8 months, with poor efficacy, and the blood concentrations of ferritin, folic acid and vitamin B12 were normal when admitted to the hospital, and nutritional anemia caused by the lack of hematopoietic raw materials was excluded; Anemia gradually worsens at the age of 2, severe anemia, combined with jaundice (indirect bilirubin elevation), splenomegaly, in line with the typical chronic hemolytic anemia "triad", negative Coombs test, excluding autoimmune hemolytic anemia, reticulocytes significantly increased, peripheral blood globular erythrocytes, increased erythrocyte osmotic fragility, positive family history, Consider hereditary spherocytosis (HS), which is autosomal dominant, and further genetic testing for heterozygous mutations in the ANK1 gene (father is wild-type, does not occur, mother is heterozygous mutations, onset), so hereditary spherocytosis occurs ^[2] The diagnosis is valid
.

There is currently no specific treatment for HS, and splenectomy is the mainstay of treatment
.
In recent years, European and American HS diagnosis and treatment guidelines have repeatedly emphasized that HS patients are stable at 50 due to the adaptability of chronic hemolysis process to low hemoglobin concentration and low oxygen Patients over 1 year of age of ~60g/L can no longer receive blood transfusion to avoid secondary hemochromatosis and reduce feedback inhibition
of bone marrow hematopoietic stress function.
Folic acid supplementation to prevent haemolytic and aplastic crises, and EPO may be given to children under 9 months of age to reduce or eliminate
transfusions.
Splenectomy surgery has a definite effect and significantly improves clinical symptoms
.
In the past, the minimum age of surgery was 6 years old to prevent fatal infections
in young children due to weak immune systems.
The latest HS guidelines suggest that children with hemoglobin in 60~80g/L can cut the spleen after 5 years old; Children with hemoglobin <</b324> pneumococcal vaccine should be given 1~2 weeks before splenectomy.

The current 2-year-old child has a hemoglobin level of 100g/L and indirect bilirubin maintained at about 35μmol/L after oral hormones and ursodeoxycholic acid, and can continue to be followed up for the time being, and elective surgical splenectomy treatment
after his age increases.

Genetic testing also detected homozygous mutations in the TFR2 gene (both parents are heterozygous mutations and do not develop the disease), and the associated disease is hemochromatosis type 3 ^[3].
, chronic iron overload disease, is an autosomal recessive genetic disease; Due to an inappropriate increase in intestinal iron absorption, excessive iron is stored in parenchymal cells such as the liver, heart, and pancreas, leading to tissue and organ degeneration and diffuse fibrosis, metabolism, and dysfunction
.
The main clinical features are skin pigmentation, liver cirrhosis, secondary diabetes, hepatomegaly, arthritis, hypogonadism, heart disease and other manifestations
.
Men are significantly more susceptible to the disease than women, and the incidence of the disease increases
with age.
The genetic detection of TFR2 gene homozygous mutation in this case is in line with the recessive inheritance mode of the disease, ferritin is slightly higher, but blood glucose, cardiac enzymes, liver enzymes are normal, the skin is not pigmented, there is no obvious iron deposition leading to organ damage, and the clinical diagnosis criteria for hemochromatosis have not yet been reached.

：1，HFE；2，HJV(2A)HAMP(2B)；3TFR2；4SLC40A1
。1，2、34，，
。
。，200，2，
。

，，，HS，，
。3，，，，，
。，
。

03

The etiology of anaemia in children is complex, and diagnosis relies on sound laboratory screening, family history, and genetic testing to help confirm the diagnosis
of hereditary or congenital anaemia.
For anemia caused by different causes, it is necessary to pay attention to detailed differential diagnosis and standardized treatment
after diagnosis.
Hemochromatosis is a rare multi-organ damage disease secondary to excessive iron deposition, and repeated blood transfusions should be avoided, iron metabolism indicators should be closely monitored, and excess iron should be actively removed from the body, which can improve the prognosis
of children.
Clinicians should combine theoretical knowledge with clinical practice, standardize diagnosis and treatment, and make children obtain beneficial outcomes
.

Expert profiles

Professor
Wang Yi

Department of Hematology and Oncology, Children's Hospital, The First Affiliated Hospital of Zhengzhou University

Associate Chief Physician, Associate Professor, Master Supervisor, Ph.
D.
Scholar of the United States

Youth Committee Member of Pediatric Branch of Chinese Medical Association

Deputy Head of the Youth Committee of Hematology Group, Pediatric Branch of Chinese Medical Association

Chairman of the Youth Committee of Pediatrician Branch of Henan Medical Association

Vice Chairman of the Youth Committee of Pediatric Branch of Henan Medical Association

Member of the Translational Medicine Committee of the Pediatric Branch of the Chinese Medical Association

Youth member of the Disaster Medicine Committee of the Pediatric Branch of the Chinese Medical Association

Member of Pediatrician Branch of Henan Medical Association;

Member of Hematologist Branch of Henan Medical Association

Member of the Chinese Alliance for Hemophagocytic Syndrome

Member of the Lymphoma Professional Committee of China Cancer Prevention and Control Alliance;

Member of the medical malpractice appraisal expert database of Henan Province and Zhengzhou City

He has won the honorary titles of "The Most Beautiful Young Pediatrician" and "Excellent Teacher for Standardized Training of Resident Doctors" in China

Expert profiles

Professor Jiao Chen

Department of Hematology and Oncology, Children's Hospital, The First Affiliated Hospital of Zhengzhou University

Attending physician, master student

Graduated from Children's Hospital of Soochow University

Professional direction: diagnosis and treatment of common pediatric hematological neoplastic diseases

The First Affiliated Hospital of Zhengzhou University is the first pediatric department in Henan Province to carry out hematopoietic stem cell transplantation, and the "Henan Pediatric Hematology and Oncology Disease Diagnosis and Treatment Center, Zhengzhou University Pediatric Hematology and Oncology Institute" are all located in the Department of Pediatric Hematology and Oncology of
our hospital.
Our hospital is also the designated point for the rescue of major diseases and chronic diseases such as acute lymphoblastic leukemia, acute promyelocytic leukemia, hemophilia, aplastic anemia and other serious diseases in Henan Province, and the leader of
Henan Province Pediatric Hematology and Neoplastic Disease Specialist Alliance.
In 2019, it became the first batch of designated hospitals for pediatric hematology diseases and the collaborative group for the diagnosis and treatment of pediatric malignant tumors (solid tumors), and undertook the National Natural Science Foundation of China youth project and a number of provincial and departmental scientific research projects
.
At the beginning of each year, more than 300 cases of leukemia are treated, and the disease-free survival rate of standardized chemotherapy for 5 years is more than 86%, and the standardized diagnosis and treatment of pediatric solid tumors and coagulation diseases has also reached the domestic advanced level, greatly benefiting children
inside and outside the province.

References: (swipe to view)

[1] Huang Shaoliang, Chen Chun, Zhou Dunhua, eds.
; Xu Honggui, Associate Editor of Huang Ke; Sun Xiaofei, Zhou Dunhua, Huang Ke, et al.
eds.
Practical pediatric hematology[M].
Beijing:People's Medical Publishing House, 2014.
03.

[2] Bacon B R, Adams P C, Kowdley K V, et al.
Diagnosis and management of hemochromatosis:2011 Practice Guideline by the American Association for the Study of Liver Diseases [J] .
Hepatology, 2011, 54(1): 328-343.

[3] European Association for the Study of the Liver.
Electronic address: easloffice@easloffice.
eu; European Association for the Study of the Liver.
EASL Clinical Practice Guidelines on haemochromatosis.
J Hepatol.
2022 Aug; 77(2):479-502.

Typesetting: Hu Haiyan

Editor: Wang Lina

Reviewed: Lina Wang