The document outlines a comprehensive approach to diagnosing children with developmental delays, highlighting the importance of taking detailed medical and family histories, and conducting thorough physical examinations. It lists various associated conditions, physical anomalies, and recommended investigations, including biochemical analyses and genetic testing. Additionally, red flags are identified for inborn errors of metabolism that should prompt further evaluation.

1. APPROACH TO A CHILD WITH
DEVELOPMENTAL DELAY

2. Approach to Development Delay
HISTORY INVESTIGATIONS
EXAMINATION

3. History
 Family History
 Consanguinity
 Family history of GDD/ID
 Parent’s IQ
 Antenatal history
 Maternal drug
intake(Phenytoin,opioids,
isotretinoin)
 Maternal infection (CMV, HSV,
Toxoplasmosis, rubella, syphilis)
 Maternal anemia
 Maternal folic acid intake
 Twin delivery
 Chromosomal abnormalities (Fragile
X, Downs, Angelman, Turner)
 Birth history
 Prematurity
 Birth Asphyxia
 Birth Injury
 IUGR
 Neonatal
 HIE/ Seizures
 Neonatal jaundice
 Inborn errors of metabolism
 Congenital abnormalities
 ICU admissions
 Infections
 Congenital hypothyroidism

4. Anthropometry
• Weight
• Underweight - SAM
• Obesity - Prader-willi syndrome
• Height
• Short stature - Malnutrition, Turner, Noonan syndrome
• Large stature - Sotos syndrome
• Head circumference
• Microcephaly -Cerebral palsy, Angelman syndrome, fetal alcohol effects, Rett
syndrome, Malnutrition
• Macrocephaly - Alexander syndrome, Hydrocephalus, Canavan syndrome, Sotos
syndrome, MPS

5. Physical Examination
Area Anomaly associated
Head Flat occiput: Down syndrome, Zellweger syndrome
Prominent occiput: trisomy 18
Delayed closure of sutures: hypothyroidism, hydrocephalus
Craniosynostosis: Crouzon syndrome, Pfeiffer syndrome
Delayed fontanel closure: hypothyroidism, Down syndrome,
hydrocephalus, skeletal dysplasias
Face Midface hypoplasia: fetal alcohol syndrome, Down syndrome
Triangular facies: Turner syndrome, Russell-Silver syndrome
Coarse facies: Mucopolysaccharidoses, Sotos syndrome
Prominent nose and chin: fragile X syndrome
Flat facies: Apert syndrome, Stickler syndrome
Round facies: Prader-Willi syndrome
Ref:Nelson Textbook of pediatrics, 21st ed

6. Eyes Hypertelorism: fetal hydantoin syndrome, Waardenburg syndrome
Hypotelorism: holoprosencephaly sequence, maternal
phenylketonuria effect
Inner canthal folds/Brushfield spots: Down syndrome
Slanted palpebral fissures: trisomies
Prominent eyes: Apert syndrome, Beckwith-Wiedemann syndrome
Lisch nodules: neurofibromatosis
Blue sclera: osteogenesis imperfecta, Turner syndrome, hereditary
connective tissue disorders
Ears Large pinnae/simple helices: fragile X syndrome
Malformed pinnae/atretic canal: Treacher Collins syndrome,
CHARGE syndrome
Low-set ears: Treacher Collins syndrome, trisomies, multiple
disorders
Ref:Nelson Textbook of pediatrics, 21st ed

7. Ref:Nelson Textbook of pediatrics, 21st ed
Nose Anteverted nares/synophrys: Cornelia de Lange syndrome
Broad nasal bridge: fetal drug effects, fragile X syndrome
Depressed nasal bridge: Down syndrome, Achondroplasia
Mouth Long philtrum/thin vermilion border: fetal alcohol effects
Cleft lip and palate: isolated or part of a syndrome
Micrognathia: Pierre Robin sequence, trisomies, Stickler
syndrome
Macroglossia: Hypothyroidism, Beckwith-Wiedemann
syndrome
Teeth Anodontia: ectodermal dysplasia
Notched incisors: congenital syphilis
Late dental eruption: Hunter syndrome, hypothyroidism
Talon cusps: Rubinstein-Taybi syndrome
Wide-spaced teeth: Angelman syndrome

8. Ref:Nelson Textbook of pediatrics, 21st ed
Hair Hair Hirsutism: Hurler syndrome
Low hairline: Klippel-Feil sequence, Turner syndrome
Sparse hair: Menkes disease, argininosuccinic acidemia
Abnormal hair whorls/posterior whorl: chromosomal aneuploidy
(e.g., Down syndrome)
Abnormal eyebrow patterning: Cornelia de Lange syndrome
Neck Webbed neck/low posterior hairline: Turner syndrome, Noonan
syndrome
Chest Shield-shaped chest: Turner syndrome
Genitalia Macroorchidism: Fragile X syndrome
Hypogonadism: Prader-Willi syndrome

9. Extremities Short limbs: achondroplasia, rhizomelic chondrodysplasia
Small hands: Prader-Willi syndrome
Clinodactyly: trisomies, including Down syndrome
Polydactyly: trisomy 13, ciliopathies
Broad thumb: Rubinstein-Taybi syndrome
Syndactyly: de Lange syndrome
Transverse palmar crease: Down syndrome
Joint laxity: Down syndrome, fragile X syndrome, Ehlers-Danlos
syndrome
Skin Hypopigmented macules/adenoma sebaceum: tuberous sclerosis
Café au lait spots and neurofibromas: neurofibromatosis
Facial port-wine hemangioma: Sturge-Weber syndrome
Nail hypoplasia or dysplasia: fetal alcohol syndrome, trisomies
Ref:Nelson Textbook of pediatrics, 21st ed

10. BASELINE INVESTIGATION:
Biochemistry:
Blood: Calcium ,Phosphate , creatinine kinase , Thyroid function test , lactate,
VLFAs Acylcarnitines, transferrin isoforms.
Urine: Organic acids , amino acids , glycosaminoglycans and oligosachharides ,
sialic acid, sulphite , succinylpurine , creatine and guanidinoacetate
Genetic: Chromosomal microarray , Molecular diagnostic test for fragile X
Radiological: MRI brain ( microcephaly, pigmentary skin anomalies, abnormal
neurological examination)
Ref:Nelson Textbook of pediatrics, 21st ed

11. Additional biochemical investigations in specific
cases :
Urine: Purines and pyrimidines
Blood: Ammonia ,copper and ceruloplasmin, cholesterol and 7-dehydrocholesterol,
biotinidase, white cell lysosomal enzymes , plasmalogens, pipecolic acid and phytanic
acid, cholesterol
Cerebrospinal fluid (CSF) : Glucose (including CSF to plasma glucose ratio), glycine(
including CSF glycine to plasma glycine ratio), lactate , pyruvate, neurotransmitters
Hair: Amino acid analysis
TMS & GC-MS
Ref:Nelson Textbook of pediatrics, 21st ed

12. GENETIC INVESTIGATIONS IN SPECIFIC CASES :
1. Specific genetic test(sanger sequencing and copy number analysis) for suspected
monogenic disorder
2. Next generation sequencing (and copy number analysis) of panel of genes eg
suspected x linked disorder or based on phenotype , eg epilepsy or neuro- imaging
abnormality
3. Chromosomal microarray and /or standard karyotype in cultured skin fibroblasts
 Methylation tests at imprinted chromosomal loci, including methylation – specific
MLPA test for prader Willi and angelman syndromes
4. Whole genome sequencing/Whole Exon Sequencing
Ref:Nelson Textbook of pediatrics, 21st ed

13. Red flags suggestive of inborn errors of metabolism:
• Family history of IEM or GDD or
unexplained neonatal death
• Consanguinity
• Intrauterine growth retardation
• Failure to thrive
• Growth abnormality
• Recurrent episodes of vomiting ,ataxia ,
seizures ,lethargy , coma
• Regression in developmental milestones
• Behavioural or psychiatric problems
• Movement disorder
• Facial dysmorphism
• Organomegaly, Severe hypotonia
• Sensory defects, especially
progressive for eg cataract,
retinopathy
• Non congenital progressive spine
deformities
• Neuroimaging abnormalities
Ref:Nelson Textbook of pediatrics, 21st ed