Tutor : Dr Bothaina El Domiaty

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