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DELAYED GROSS MOTOR
DEVELOPMENT BY :
NurAmalina bt Yahaya 10-5-257
Nur Zakiah bt Zahari 10-5-260
IRON OVERLOAD IN THALASSEMIA
MAJORBY:
Noor Hakimah Hidayah bt Mohd Rahim 10-5-258
Nurul Iman bt Zulkefli 10-5-245
Nur Amalina bt Allaudeen 20-5-256
By Nuramalina Binti Yahaya (10-5-257)
DELAYED GROSS MOTOR DEVELOPMENT
It means
Maturation of organ and system,
Acquisition of function and new skill
Ability of adaptation and assuming responsibilities
• It includes the posture and ability to control large body movement as crawling, sitting, standing
DEFINITION OF DEVELOPMENT
GROSS MOTOR DEVELOPMENT
Neurological
Endocrinal factor as thyroid hormone and growth hormone
Skeletal and muscular for postural and control precise movement
Environmental & socioeconomic; overcrowding
Nutritional factors of mother and children during development
Physical activities as bed ridden and hypoactive may have delay
development
FACTORS AFFECTING NORMAL GROSS MOTOR DEVELOPMENT
AGE GROSS MOTOR MLESTONES
Birth – 2 months Raises head slightly off floor or bed when on
stomach.
Holds head momentarily when supported
3 – 5 months Lifts head & chest when on stomach
Rolls from side to side
Pushes with feet
Sits briefly with arm supported
Makes crawling movement
6 – 8 months Sits alone briefly
Rolls from back to stomach
Stands with support
9 – 11 months Sits alone with trunk rotation
Creeps or crawl
Pulls to stand
Stand alone momentarily
GROSS MOTOR MILESTONES
AGE GROSS MOTOR MILESTONES
12 – 15 months Walks alone
Creeps up stairs
Crawls up on chair
Able to stand without support
16 – 18 months Creeps downstairs
Walk sideway & backway
Stands on one foot with help
Kick large ball forward
19 – 24 months Squats in play & stand back up
Jumps in place
Walks up & down stairs alone
Runs well
• There is normal variation between individual. The ages mentioned in the table are average of the child
but may have early or some delay in acquisition of new motor skills.
•There are also sex differences as girls usually have early development as a whole from boys
1. Familial; Some delay may happen according in variation of every
individual and sex differences.
2. Genetic; Trisomy 21 appears physical phenotype of down syndrome as
mental retardation, hypotonia and other abnormalities of delay the
development.
3. Skeletal disorder; Rickets manifest as hypotonia of muscles and laxity
of ligament. The child may have bow legs and knock knees lead to delay
sitting, standing and walking.
Achondroplasia is a short-limbed dwarfism particularly have short stature
with short upper arms and thighs that limiting the range of movement.
4. Nutritional disorder; Severe protein malnutrition either marasmus or
kwashiorkor usually having muscle wasting which is hypotonic, weak and
unable to stand or walk. The child is hypoactive and lack interest in
surrounding.
ETIOLOGY OF DELAYED GROSS MOTOR MILESTONES
5. Systemic disorder; Congenital heart disease have poor systemic blood flow that lead to retarded growth and easily fatigue infant.
6. Perceptual disorder; blindness may interfere the normal pattern of gross motor development.
7. Environmental factors; emotional deprivation or lack of stimulation due to over protective parents.
8. CNS disorder;
Cerebral palsy is non progressive, permanent impairment of neuromuscular system leading to motor disorder of movement, posture and coordination. CP may manifests as paralysis of the limbs (hemiplegia or quadriplegia) that prevent movement of the limbs and will delay gross motor development of the child.
Mental handicap which have limitation in many adaptive skills and intellectual function.
9. Muscular disorder; any diseases that lead to myopathies and
muscle dystrophy also delay the normal gross motor development
of the child.
10. Metabolism; Phenylketonuria is the most common amino acid
disorders which manifest as severe mental handicap. The child
becomes hyperactive with purposeless movement, rocking and
athetosis.
11. Endocrinal; Cretinism (hypothyroidism) child usually are
sluggish physically and mentally. The child is passive and lies
quietly with little interest in surrounding also with delayed
developmental milestones, stunted height with long trunk and short
legs.
NUR ZAKIAH BINTI ZAHARI
10-5-260
Prenatal history:
~Important especially if there is any complication ( mother, baby )
~TORCH,
Obstetrical history:
~Difficulty during delivery eg: asyphyxia, seizure,
~Evaluate using APGAR scores
Any sign of Infections (eg.GBS)
Past medical history and medications:
~History of taking Ototoxic antibiotics for example Gentamicin, previous surgery and past delivery
Behavior since birth:
~Behavioral disturbances
~Abnormal behavior
Family history:
~Relatives or sibling with
developmental delay, genetic
abnormalities,
~consanguinity
Social History:
~Evidence of neglected or abuse
HISTORY
DIAGNOSTIC APPROACH
1) Physical examination
2) Investigation
DIAGNOSIS PHYSICAL EXAMINATION
Cerebral Palsy HEAD, FACE & NECK: Delayed closure fontanel
EXTREMITIES: Spastic quadriplegia,
NEUROLOGICAL EXAMINATION:
Hypotonia, Hypertonia,Dystonia, Muscle spasms, opisthotonus
Clonus – muscular spasms with regular contractions
o Ankle/foot clonus – spasmodic abnormal movement of the foot
o Wrist clonus – spasmodic movement of the hand
GAIT: Tip toe
Down
Syndrome
HEAD, FACE & NECK: Flat occiput, Brushfield spots, hypertelorism, up slanting eye, epicanthic
folds, Depressed nasal bridge, Abnormal hair whorls, delayed teething, Macroglossia.
EXTREMITIES: Transverse palmar crease , Dry skin, Premature aging, Broad, short hands, feet,
and digits
NEUROLOGICAL EXAMINATION: Neuromuscular hypotonia
RicketHEAD, FACE & NECK: Delayed closure fontanel, Pseudotumor cerebri,
Craniotabes (before 8-10month), delayed teething, frontal bossing.
CHEST EXAMINATIO: Pigeon chest, rachitic rosary, Harrison groove
NEUROLOGICAL EXAMINATION: Neuromuscular hypotonia
Protein
Malnutrition
HEAD, FACE & NECK: Alopecia with dyspigmentation, old man face and sunken eye(marasmus),
edematous cheek and edematous eyelid (kwashiorkor)
EXTREMITIES: epiphyseal enlargement at wrist and ankles, marfan sign, bow leg, knock knee,
severe muscle wasting(marasmus), edema (kwashiorkor), decrease skin elasticity
ABDOMINAL EXAMINATION: Scaphoid abdomen
Genetics:
Karyotyping
FISH analysis
Endocrinology:
TSH, free T4 in case of hypothyroidism
Metabolic:
Metabolic screening – glucose, electrolytes, serum lactate, ammonia, liver function tests, pyruvate, albumin, triglycerides, uric acid, serum quantitative amino acids, urine organic acids, creatine phosphokinase (if suspecting myopathy), and calcium as in case of rickets or Protein energy malnutrition.
Neurology:
It can be EEG in case of affection of brain and mental retardation or head CT scan. While, X-Ray is useful especially in case of rickets that will show positive expanded ends of radius and ulna, rarefied and cup-shaped and the bone is poorly mineralized. While x-ray of the head will shows hair-standing-on-end which is a very characteristic sign. ECG is also of help todetect any congenital heart disease. Neurological test is also important.
INVESTIGATION
REFERENCES
Madkour Essentials of Pediatrics (Paediatrics, Members of the Department of Paediatrics Faculty Of Medicine-University Of Alexandria 12th Edition.
http://www.beststart.org/OnTrack_English/2-factors.html
http://www.brookshealth.org/motor-skills.pdf
http://education-portal.com/academy/lesson/what-are-gross-motor-skills-in-children-development-definition-examples.html#lesson
http://www.abilitypath.org/milestone-concerns/signs-of-possible-delays-gross-motor-and-sensory-development.html
http://www.healthline.com/symptom/developmental-delay
http://www.growingup.ie/fileadmin/user_upload/Conference_2010/Session_D_Factors_Affecting_Gross_Motor_Development_Outcomes.pdf
REFERENCES
REFERENCE:
1-Basic clinical Pediatrics, 2009, second edition
Naseer Gamal
2-Illustrated Textbook of Pediatrics, 2012, fourth international edition
Tom Lissauer, Graham Clayden
3-Madkour’s Essential of pediatric, 2012
Prof. Ahmed A Madkour
Members of Department of Pediatrics Faculty of Medicine-
University of Alexandria Egypt
4-http://www.healthline.com/symptom/developmental-delay
5- http://emedicine.medscape.com/article/943216-clinical#a0256
IRON OVERLOAD IN
THALASSEMIC
PATIENT
PATHOPHYSIOLOGY OF IRON OVERLOAD TRANSFUSION- DEPENDENT THALASSEMIA PATIENTS
Our body has no active mechanism for iron excretion
Complex systems are regulated for iron homeostasis
Several regulatory proteins are involved in iron absorption, transportation and storage
Ferritin – serves for intracellular iron storage
Ferroportin- regulate releasing of stored iron from tissues in the form of Fe2+
Hepcidin- act on ferroportin to release Fe2+
Ceruloplasmin- oxidizes Fe2+ Fe3+ before its transportation
Transferrin- Fe3+ transporter in the circulation
NOOR HAKIMAH HIDAYAH BT MOHD RAHIM 10-5-258
B. Etiology of Iron Overload in Thalassemia patients
1. Increase iron absorption due inappropriate hepcidin suppression
caused by the ineffective erythropoiesis.
2. Excessive iron intake or supplements
3. Hypertransfusions such as those
with thalassemia major, sickle cell diorders
and myelodysplastic syndromes (MDS), hemolytic anemia, etc.
4. Hemolytic process itself
PATHOGENETIC MECHANISMS1. Fully saturated of ferritin, non-transferrin
bound iron (toxic) will present in the circulation
2. Already known that our body is absentnegative feedback mechanism that regulates cellular uptake of transferringbound iron, also previous is said that weare lack of iron excretion
3. Thus, -> uptake of NTBI by the tissue cellsleads to tissue iron accumulation -> deleterious effect
4. The iron deposited & stored in parenchyma tissues (eg : myocytes ) are in 3 forms :-ferritin, hemosiderin, labile cellular ion (free iron) -> most active & mean cause fororgan dysfunction
PATHOGENETIC MECHANISMS
HOW ??
1. Free ion leads to formation of reactive oxygen species (via Fenton reaction) by convertingferrous to ferric with generation of toxic hydroxyl radical.
2. Cellular antioxidant properties are exceeded peroxidation of membrane lipids, cellular proteins & nucleic acids
PATHOGENETIC MECHANISMS1. At the same time, increased ferrous iron
transportation through the L-type calcium channels also results in derangement of cardiomyocytes calcium transportation and impaired excitation-contraction coupling,which may in turn be involved in the development of the diastolic andsystolic ventricular dysfunction
2. Myocardia iron overload develops at a later stage in comparison with hepaticiron overload is due to myocardial intakeis more slower.
WHAT ARE THE IMPACT TO THE ORGANS ?
DIAGNOSIS OF IRON OVERLOAD IN
NURUL IMAN ZULKEFLI
10-5-245
NURUL IMAN BT ZULKEFLI10-5-245
HISTORY
1) Onset of thalassemia
5) Iron chelation therapy
3) jaundice, change colour of urine & stool
2) Manifestation of anemia
4) Blood transfusion
6) Family history
7) Splenectomy & any complication
CLINICAL EXAMINATION
LABORATORY ASSESSMENT
1) Serum Iron level
2) Transferrin saturation & Non Transferrin Bound-
Iron (NTBI) production
3) Serum Ferritin level
1) Liver biopsy
3) Superconducting Quantum Interference
Device (SQUID)
LIVER IRON CONCENTRATION MEASUREMENT
2) Magnetic Resonance Imaging
(MRI)
1) Echocardigraphy (ECHO)
2) MRI
3) Endomyocardial biopsy
CARDIAC IRON CONCENTRATION MEASUREMENT
ONLY FOR SCIENTIFICALLY
APPROACH
1) PANCREAS
ASSESSMENT OF ENDOCRINE FUNCTION
• Iron magnetic susceptibility artifact, spin dephasing (T2*-related signal loss) decreased signal intensity on MRI images.• Pancreas will be markedly hypointense.• When gradient echo sequences are obtained with increasingly longer echo times, iron deposition becomes evident, even in slight iron overload.
2) ORAL GLUCOSE TOLERANCE TEST (OGTT)
1) ECHO
A two-hour oral glucose tolerance test should be performed at 10, 12, 14, and 16 years of age and annually thereafter.
If fasting serum glucose is > 110 mg/dL, an oral glucose tolerance test is indicated.
2) PITUITARY GLAND & GONADS
2) Growth hormone deficiency
1) Growth Assessment Parameters
Endocrine evaluation is required if there is a 5% or more falloff on the growth curve or poor growth velocity for the age.
The evaluation should include the following.1.A dietary assessment by a registered dietitian2.Laboratory tests: serum calcium, PO4, albumin, urinalysis,urine culture T4, TSH, IGF-1, and IGF BP-33.A bone age assessment
Patients are assessed for growth every 6 months to one year.
Child is considered short if :1) Height < 3rd percentile or 2 SD below the mean height for age and sex2) Height is within normal but GV is consistently < 25th percentile over 6-12 months3) The patient is excessively short for his/her mid-parental height, though his absolute height may be within the normal percentiles.
3) Hypogonadism
Tanner staging should be determined every 6 months starting from the age of 12 years.
Girls without evidence of puberty by 13 years and boys by 14 years require screening with measured serum levels of LH, FSH, and estradiol/testosterone:
1) Low FSH and LH for age infer hypogonadotropic hypogonadism (HH) (hypothalamic-pituitary lesion) and MRI of the pituitary (T2*) is recommended.2) Elevated FSH and LH suggests primary hypogonadism (very rare)
4) Hypothyroidism
TSH and free T4 should be measured at five years of age or after three years of transfusion.
1) Elevated TSH and depressed T4 suggest primary hypothyroidism. 2) Depressed TSH and depressed T4 suggest secondary or tertiary hypothyroidism
5) Hypoparathyroidism
Parathyroid status should be evaluated annually with serum calcium, PTH, and 25-hydroxy vitamin D screening.
1) A normal PTH with decreased calcium2) A decreased PTH with normal calcium,is diagnostic of hypoparathyroidism
TREATMENT OF IRON OVERLOAD
NUR AMALINA BT ALLAUDEEN 10-5-256
WHEN TO START?
Treatment should be started when the serum ferritin level is more than 1000 nanogram/litre or after 10-20 serum transfusion.
*however it is advised to delay treatment for children under 3 years as it can cause metaphyseal dysplasia.
GOOD IRON CHELATOR
1) To control body iron- High chelating efficiency - High and specific affinity for Fe3+
2) To minimize iron toxicity - 24-hour coverage- Slow metabolism and elimination rate- Good tissue penetration with stable iron complex
3) Simple and easy monitoring4) Patient acceptance/compliance
- Oral administration- Suitable for monotherapy
5) Cheap
TYPES OF IRON CHELATOR
1) Subcutaneous/intravenous iron chelator: Deferoxamine
2) Oral iron chelator: deferiprone and deferasirox
DEFEROXAMINE
1) Deferoxamine:iron = 1:1
2) Hexadentate molecules form the most stable iron-chelate complex.
3) It chelates iron readily from ferritin and hemosiderin
4) The product is soluble and excreted by kidney.
DOSAGE1) SUBCUTANEOUS deferoxamine, not
exceeding 25 to 35 mg per kilogram body weight/24 hours in young children, infused over 8-24 hours. Rate specified according to patient.
2) 2) IV administration: 40-50mg/kg/day over 8-12 hours for 5-7 days/ week
3) 4) Hydroxyethyl starch deferoxamine(HES-deferoxamine): 80mg/kg IV infusion for 4 hours (half life is 10-30 times longer than deferoxamine)
ADVERSE EFFECT
MAJOR
1) Injection site reaction
2) growth retardation and metaphyseal dysplasia (< 3 years old)
MINOR
1) acute respiratory distress syndrome with dyspnea, cyanosis
2) Nervous System: seizures
3) Special Senses: visual disturbances and high-frequency sensorineural hearing loss
4) Cardiovascular reactions: hypotension with too rapid IV infusion
DEFERIPRONE
1) Deferiprone:iron = 3:1
2) Stable over a wide range of pH values.
3) It readily penetrates myocardial cells
4) rapidly absorbed from upper GI within 5-10 minutes after administration.
5) The complex will be excreted within 24 hours in urine
DOSE: It is administered orally, 50 mg/kg/day.
ADVERSE EFFECT
1) Chromaturia: urine turns reddish or brownish in colour.
2) Neutropenia
3) Gastritis.
DEFERASIROX
1) Deferasirox:iron = 2:1
2) It reduces serum ferritin and the concentration of iron in liver
3) Deferasirox is excreted in faeces (84%) and the rest in urine
DOSE: It is administered orally 20mg/kg/day.
ADVERSE REACTION:
1) Increase serum creatinine level
2) Acute renal failure
3) Hepatic failure
COMBINATION THERAPY
• indicated when monotherapy with any of the iron chelator is not adequate.
• Deferoxamine + Deferiprone = reduce both ferritin iron and liver iron concentration and improve cardiac siderosis.
• Dose: Deferoxamine 40mg/kg/d given at night + deferiprone75 mg/kg/d given during the day