This document discusses an approach to evaluating children with dysmorphic features or congenital anomalies. It begins by outlining common birth defects, their estimated incidences, and potential causes. It then describes the goals and purposes of a dysmorphology evaluation, including establishing diagnoses, determining recurrence risks, and providing management and counseling. The rest of the document discusses specific aspects of evaluating congenital anomalies, such as recognizing normal and abnormal phenotypic variation, determining whether features are isolated or represent a genetic syndrome, and managing patient care.

1. An Approach to Dysmorphic
Child
Dr.Sid Kaithakkoden MD
MBBS,DCH,DNB,MD,MRCPCH,FCPS
alavisaid@aol.com

2. 02/25/15 Sid 2
Congenital Anomalies
• 20 - 25% of perinatal deaths are due to
lethal birth defects
– 10% of deaths in infants weighing 500 - 1500
gm
– 50% of deaths in infants > 1500 gm

3. 02/25/15 Sid 3
Birth Defects Estimated Incidence
Structural/Metabolic
Heart and circulation 1 in 115 births
Muscles and skeleton 1 in 130 births
Club foot 1 in 735 births
Cleft lip/palate 1 in 930 births
Genital and urinary tract 1 in 135 births
Nervous system and eye 1 in 235 births
Anencephaly 1 in 8,000 births
Spina bifida 1 in 2,000 births
Chromosomal syndromes 1 in 600 births
Down syndrome (Trisomy 21) 1 in 900 births
Respiratory tract 1 in 900 births
Metabolic disorders 1 in 3,500 births
PKU 1 in 12,000 births
Congenital Infections
Congenital syphilis 1 in 2,000 births
Congenital HIV infection 1 in 2,700 births
Congenital rubella syndrome 1 in 100,000 births
Other
Rh disease 1 in 1,400 births
Fetal alcohol syndrome 1 in 1,000 births
March of Dimes, 2000.

4. 02/25/15 Sid 4
Causes of Birth Defects
• Multifactorial: 20-30%
• Single gene disorders: 10-20%
• Chromosomal: 15%
• Infection: 2.5%
• Maternal diabetes: 1.5%
• Maternal medications: 1-2%
• Rest unknown

5. 02/25/15 Sid 5
Empiric Recurrence Risks for for Birth Defects
Condition Affected Relatives(s)
None 1 sib/parent 2 sibs / sib & parent
Cleft lip/palate 0.1 4 10-11
Cleft palate only 0.04 2-7 15
NTD 0.1 3 8
CHD (any) 0.3 4-5 10-11
VSD 3-4 10
Hypoplastic left heart 2 6

6. 02/25/15 Sid 6
• Dysmorpholgy: study of abnormal forms
• Dysmorphic: abnormal appearing
• Congenital: at birth
• Anomaly: abnormality
• Just because it’s congenital it doesn’t mean it’s
genetic
• One goal of the dysmorphologist is help determine
the etiology of congenital anomalies

7. 02/25/15 Sid 7
Who needs a dysmorphology evaluation?
•A history of intrauterine growth retardation or failure to thrive
•Abnormal growth (short, excessive)
•Abnormal or unusual facial features
•Abnormal body and limb proportions or asymmetry
•Major and/or minor congenital anomalies
•Microcephaly, macrocephaly or craniosynostosis
•Ambiguous or abnormal genitalia, early or late onset of puberty
•Psychomotor delay or mental retardation
•Hypotonia, hypertonia
•A relative with problems similar to those of patient
•Metabolic problems
•Bleeding tendency
•Blindness or deafness
•A significant regression in developmental progress
•An unusual body odor
•Excessive unexplained vomiting
•Unusual behaviors, especially when associated with minor malformations

8. 02/25/15 Sid 8
Purposes of a Medical Genetics Evaluation:
New Patients:
• Establish or confirm a specific diagnosis
• Enable accurate, individualized counseling
• Determine precise recurrence risks
• Obtain necessary diagnostic tests
• Provide specific education and support
• Initiate appropriate referrals
• Plan for focused medical management and follow-up
Established Patients (follow-up care):
• Assess new medical problems and related concerns
• Determine compliance with recommended management
• Keep patients informed about new diagnostic and
management strategies
• Provide ongoing age-appropriate education/support
• Help coordinate necessary referrals and evaluations
• Evaluate other at risk family members

9. 02/25/15 Sid 9
Approach to Birth Defects &
Congenital Anomalies
• Recognize associated abnormalities and medical problems
• Make an accurate diagnosis
• Give an accurate, realistic prognosis and natural history of
the disorder to the family
• Discuss options and alternatives for management
• Deliver appropriate medical care and/or treatment
• Prevent subsequent related complications
• Optimize quality of life
• Determine and provide recurrence risks
• Offer genetic and psychosocial counseling
• Provide anticipatory guidance and education

10. 02/25/15 Sid 10
1.Where are the problems?
2.What are the problems?
3.What is the diagnosis?
4.What are associated problems?
5.When could they have happened?
6.How did they arise?
7.Why did they occur?
8.Who is at risk?

11. 02/25/15 Sid 11
Observable Differences
of Human Phenotypes
• Normal variations
• Minor anomalies
• Major anomalies
Anomalies and normal variants can serve as
indicators of altered morphogenesis and
clues to patterns of malformation

12. 02/25/15 Sid 12
A Range of Phenotypic
Variation is Normal
• “Normal” spectrum of human variation
of morphological features with
absolutely no medical significance (eg.
Epicanthal folds, ‘attached’ vs.
‘unattached ear lobes’,
• Observed in > 4% of the population

13. 02/25/15 Sid 13
Minor Anomaly
• Minor variations of normal morphological
features of little of no known medical,
surgical, or cosmetic significance
• Observed in < 4% of the population

14. 02/25/15 Sid 14
Copyright ©2002 Canadian Medical Association or its licensors
Hunter, A. G.W. CMAJ 2002;167:367-372

15. 02/25/15 Sid 15

16. 02/25/15 Sid 16
Major Anomaly
• Abnormality that has
– Medical
– Surgical or
– Cosmetic significance

17. 02/25/15 Sid 17
Suspect a genetic condition or
syndrome when...
• Multiple anomalies
• More than 3 minor anomalies
• More than one major anomaly
• One major anomaly and a few minor
anomalies

18. 02/25/15 Sid 18
Variable Expression
• Morphological features may be expressed at different
degrees of severity in individuals resulting in different
levels of dysfunction and problems for individuals having
the “same” abnormality, even when due to the same
etiology
• Each individual with a particular syndrome, sequence, or
association will not have every known feature of that
disorder, or all the same features as one another, even if in
the same family
• The degree of variable expression may correlate with the
degree of pleiotropy in single gene disorders

19. 02/25/15 Sid 19
Incomplete Penetrance
• An “all or none” phenomena referring to the
presence or absence of observable
phenotypic expression of features of a
dominant disease in an individual known to
have a mutant allele
• Some individuals with Tuberous Sclerosis
appear to have incomplete penetrance

20. 02/25/15 Sid 20
Sex-Influenced or Limited
Expression
• Some congenital anomalies and/or genetic
syndromes due to autosomal defects are
more easily recognized, or only recognized,
in individuals of a particular gender
– Sex influenced: Genital hypoplasia, hypospadias,
virulization with hypertrophy of the clitoris
– Sex limited: Hereditary prostate cancer

21. 02/25/15 Sid 21
Types of Morphologic
Abnormalities
• Malformation
• Deformation
• Disruption
• Dysplasia

22. 02/25/15 Sid 22

23. 02/25/15 Sid 23
Malformation
• Defect of morphogenesis in an organ or structure
due to an intrinsically abnormal problem with
formation, growth, or differentiation of an organ
or structure
– hypoplasia of an organ or structure (microtia),
incomplete closure (NTDs, cleft palate), incomplete
separation (syndactaly)

24. 02/25/15 Sid 24

25. 02/25/15 Sid 25
Timing
is
everything!

26. 02/25/15 Sid 26
Malformations are not specific
• The same morphological defect, or even a
similar pattern of abnormalities, may occur
as:
– An isolated anomaly in an otherwise normal individual
– A feature in a syndrome, sequence, or association
– A feature of a chromosome disorder, a single gene
defect, multifactorial disorder, or secondary to a
teratogenic effect

27. 02/25/15 Sid 27
Deformation
• Abnormal form or position of a body or region of
the body caused by extrinsic non-disruptive
mechanical forces on a normally developing
structure (fetal constraint)
– clubfoot, congenital hip dislocation, craniofacial
asymmetry, over folded ear…..

28. 02/25/15 Sid 28
Disruption
• Defect of morphogenesis resulting from a
destructive breakdown of, or interference with, a
normally developing structure resulting in death of
cells or tissue destruction. May be secondary to
mechanical forces, infections, or even vascular
events.
– Loss of digit due to amniotic bands, lack of normal
limb development due to intrauterine vascular accident

29. 02/25/15 Sid 29
Dysplasia
• Error of morphogenesis due to the abnormal
cellular organization of function in a
specific type of tissue most often due to
single gene defects
– Achrondroplasia, ectodermal dysplasia,
osteogenesis imperfecta,

30. 02/25/15 Sid 30

31. 02/25/15 Sid 31
Recognizable Patterns of
Anomalies
• Syndromes
• Associations
• Sequences or field defects

32. 02/25/15 Sid 32
Syndrome
• Multiple anomalies in one or more tissues or
structures thought to be pathologically related due
to a specific etiologic mechanism (chromosome
disorder, single gene defect, environmental agent,
or unknown factor), not due to a related sequence
of defects or field defect.
– Down syndrome, Williams syndrome, FAS, Turner
syndrome, Gorlin syndrome….
• From Greek meaning “running together”

33. 02/25/15 Sid 33
Genetic heterogeneity
• Even when phenotypically similar disorders have
clear genetic etiologies, locus heterogeneity, and
sometimes even allelic heterogeneity, may
complicate laboratory testing and influence
diagnosis, counseling, management, and prognosis
– Locus heterogeneity: Tuberous Sclerosis, PKD
– Allelic heterogeneity: Craniosynostosis, CF

34. 02/25/15 Sid 34
Sequence/Field Defect
• Constellation of defects derived from a cascade of
effects related to a single known, or presumed,
localized abnormality (malformation, deformation,
disruption)
– Potter sequence
• Renal dysplasia, pulmonary hypoplasia, facial dysmorphisms
– Mandibular hypoplasia (Robin sequence)
• Cleft palate
– Meningomyelocele
• Club foot, hip dislocation, hydrocephalus

35. 02/25/15 Sid 35
Association
• Non-random occurrence of a combination
of several anomalies not yet identified as a
specific sequence or syndrome that occur
more often together than by chance alone.
– VATER and CHARGE associations

36. 02/25/15 Sid 36
General Caveats of Dysmorphology
• Having a diagnosis, even if bad, is more useful for
families than having no diagnosis
• A wrong diagnosis is worse than no diagnosis
• A diagnosis depends on the clinical recognition of
patterns of abnormalities as supported by
appropriate laboratory and imaging tests
• Etiological heterogeneity and variable expression of
abnormalities often makes the diagnostic
evaluation challenging
• Time and library/database searches can provide
clues to diagnosis

37. 02/25/15 Sid 37
Reasons why difficulty in diagnosing
Syndromes may be encountered
• Some are very rare disorders - not well described
• Problems with lumping and splitting
• Variable expression
• Incomplete penetrance
• Sex influenced or limited expression
• Pleiotropy
• Etiologic heterogeneity

38. 02/25/15 Sid 38

39. 02/25/15 Sid 39
Management of Congenital Anomalies
in the Fetus or Newborn
• Conduct careful clinical evaluation
• Review family, prenatal history, and perinatal history
• Obtain diagnostic studies
– Imaging studies: Photographs, X-rays
– Laboratory studies: Chromosome, DNA, biochemical assays
• If deceased, request autopsy and specific pathological analyses
• Provide parents an opportunity to see child
– Name, photograph,obtain hair, memorialize, bury...
• Provide referrals to social work/psychological services and
support groups as appropriate
• Arrange follow-up genetic counseling

40. 02/25/15 Sid 40
Talking with Families about Birth Defects
• Avoid delivery room diagnosis and counseling
• Explain medical concerns openly and honestly
• Humanize abnormal findings and note normal findings
• Use diagnostic/medical terms only as appropriate
• Avoid extensive differential diagnoses
• Be careful about premature prognostication
• Watch your facial expressions and body language
• Listen to concerns and adhere to their agenda
• Be supportive but not unrealistic or enmeshed
• Provide frequent, honest updates of accurate information
• Provide psychosocial support services

41. Ambiguous genitalia of a baby girl - the simple virilising form of
congenital adrenal hyperplasia

42. 02/25/15 Sid 42
Ogilvy-Stuart, A L et al. Arch Dis Child 2004;89:401-407
Differential virilisation of the external genitalia using the staging system of Prader, from normal female
(left) to normal male (right). Sagittal (upper panel) and perineal (lower panel) views shown.
Ambiguous Genitalia

43. 02/25/15 Sid 43
Ogilvy-Stuart, A L et al. Arch Dis Child 2004;89:401-407
Investigation flow plan for assessment of ambiguous genitalia

44. 02/25/15 Sid 44

45. Down syndrome

46. 02/25/15 Sid 46
Trisomy 21
• Brachycephaly
• Flat facial profile
• Small ears
• Folded helix
• Conductive hearing loss
• Upslanting palpebral fissures
• Epicanthal folds
• Iris Brushfield spots
• Protruding tongue
• Congenital heart defect
• Atrioventricular canal
• Duodenal stenosis/atresia
• Imperforate anus
• Hirschsprung disease
• Atlanto-axial instability
• Hypoplastic iliac wings
• Shallow acetabulum
• Joint laxity
• Short, broad hands
• Fifth finger mid-phalanx hypoplasia
• Single transverse palmar crease
• Excess nuchal skin
• Single transverse palmar crease
• Mental retardation
• Alzheimer disease
• Hypotonia, poor Moro reflex
• Hypothyroidism
• Acute megakaryocytic leukemia
• Increased recurrence risk with
parental translocation
• Incidence, 1 in 650-1000 live births
• Full trisomy 21, 94%
• Mosaic trisomy 21, 2.4%
• Translocation 21, 3.3%

47. 02/25/15 Sid 47
Trisomy 18

48. 02/25/15 Sid 48
Trisomy 18
• Incidence: 1 in 3000
• Girls : Boys 3:1
• Low birth weight infant
• Mental deficiency
• Low-set ears
• Small jaw (micrognathia)
• Clenched hands
• Hypoplastic (underdeveloped)
fingernails
• Umbilical hernia or inguinal hernia
• Diastasis recti
• Cryptorchidism
• Crossed legs (preferred position)
• Congenital heart disease
o VSD)
o ASD
o PDA Congenital kidney
abnormalities
o Horseshoe kidney
o Hydronephrosis
o Polycystic kidney
• Coloboma of iris
• Microcephaly
• Pectus carinatum

49. 02/25/15 Sid 49
Trisomy 13

50. 02/25/15 Sid 50
Trisomy 13
• Incidence 1 in 5000 live births
• Mental retardation, severe
• Seizures
• Small head (microcephaly)
• Scalp defects (absent skin)
• Small eyes (microphthalmia)
• Cleft lip and/or palate
• Eyes close set (hypotelorism) --
eyes may actually fuse together
into one
• Iris defects (coloboma)
• low set ears
• Simian crease
• Ventricular septal defect (VSD)
• Atrial septal defect (ASD)
• Patent ductus arteriosus (PDA)
• Hernias: umbilical hernia,
inguinal hernia
• Undescended testicle
(cryptorchidism)
• Hypotonia
• Micrognathia
o Skeletal (limb) abnormalities
• Extra digits (polydactyly)

51. 02/25/15 Sid 51
Marfan syndrome

52. 02/25/15 Sid 52
Marfan syndrome
• Autosomal dominant
• Disproportionate tall stature, upper to
lower segment ratio less than 0.85
• Arm span to height > 1.05
• Dolichocephaly
• Long, narrow face
• Malar hypoplasia
• Micrognathia
• Retrognathia
• Enophthalmos
• Ectopia lentis
• Myopia
• Retinal detachment
• Early glaucoma
• Early cataracts
• Down-slanting palpebral fissures
• High-arched palate
• Aortic regurgitation
• Mitral regurgitation
• Mitral valve prolapse
• Aortic root dilatation
• APectus excavatum
• Pectus carinatum ortic dissection
• Scoliosis
• Kyphoscoliosis
• Thoracic lordosis
• Spondylolisthesis
• Arachnodactyly
• Caused by mutations in the fibrillin-1
gene
• About 25% of cases due to new
mutations

53. 02/25/15 Sid 53

54. 02/25/15 Sid 54
Cornelia De Lange Syndrome
• The incidence is 1 case per 10,000-
50,000 live births
• Short stature
• Microcephaly (98%)
• Short neck (66%)
• Hirsutism (78%)
• Cutis marmorata and perioral cyanosis
(56%)
• Hypoplastic nipples and umbilicus
(50%)
• Micromelia (93%)
• Undescended testes (73%)
• Confluent eyebrows (synophrys) (99%)
• Long curly eyelashes (99%)
• Low anterior &posterior hairline (92%)
• Underdeveloped orbital arches (100%)
• Neat, well-defined, and arched
eyebrows (as though they had been
penciled)
• Long philtrum
• Anteverted nares (88%)
• Down-turned angles of the mouth
(94%)
• Thin lip (especially upper vermillion
border)
• Low-set ears
• Depressed nasal bridge (83%)
• High arched palate (86%) and reports of
cleft palate
• Late eruption of widely spaced teeth
(86%)
• Micrognathia (84%)

55. 02/25/15 Sid 55

56. 02/25/15 Sid 56
Apert Syndrome
• Craniostenosis
• Large late-closing
fontanels
• Gaping midline defect
• Flattened, often
asymmetric face
• Maxillary hypoplasia with
retruded midface
• Cardiovascular (10%)
– Atrial septal defect
– Patent ductus arteriosus
– Ventricular septal defect
• Syndactyly
• Brachydactyly
• Congenital cervical spinal
fusion (68%), especially
C5-C6
• Aplasia or ankylosis of
shoulder, elbow and hip
joints
• Tracheal cartilage
anomalies
• Rhizomelia

57. 02/25/15 Sid 57

58. Turner syndrome
(a) Puffy feet, (b) redundant skin at back of neck. (c) Histology of gonads:
ovarian cortical stroma devoid of germ cell elements.

59. 02/25/15 Sid 59
Turner Syndrome
• Short stature:
• Ovarian failure:
• Nails: Many patients have
hypoplastic or hyperconvex nails.
• Nevi: Excessive numbers of nevi
• Webbed neck:
• Lymphedema
• Cubitus valgus (increased carrying
angle): Short fourth metacarpal or
metatarsal: Although this finding is
of minimal clinical significance, it
can be a clue to the presence of
Turner syndrome.
• Shield chest:
• Eye: Ptosis, strabismus, amblyopia,
and cataracts
• Gastrointestinal bleeding:
• Hip dislocation:
• Scoliosis: This occurs in 10%
• Hypertension:
• Murmurs: Cardiovascular
malformations include coarctation
of the aorta, bicuspid aortic valve,
and aortic dissection in adulthood
• Thyroid: 10-30% develop
hypothyroidism.
• Cutis laxa:

60. 02/25/15 Sid 60

61. 02/25/15 Sid 61

62. 02/25/15 Sid 62
Noonan syndrome
• Autosomal dominant
• Short stature
• Failure to thrive in infancy
• Triangular face with age
• Low-set ears
• Nerve deafness
• Ptosis
• Hypertelorism
• Down-slanting palpebral
fissures
• Epicanthal folds
• Myopia
• Mental retardation (25%)
• Malignant schwannoma
• High arched palate
• Micrognathia
• Dental malocclusion
• Low posterior hairline
• Webbed neck
• Cystic hygroma
• Atrial septal defects
• Ventricular septal defects
• Pulmonic stenosis
• Shield chest, Pectus carinatum
superiorly,
• Pectus excavatum inferiorly
• Caused by mutations in the
protein tyrosine phosphatase,
nonreceptor-type, 11 gene

63. 02/25/15 Sid 63

64. 02/25/15 Sid 64
Crouzon Syndrome
• Craniosynostosis: resulting in
acrocephaly, brachycephaly,
turricephaly, oxycephaly, flat
occiput
• Shallow orbits
• Face - Midface (maxillary)
hypoplasia
• Eyes
– Exophthalmos (proptosis)
secondary to shallow orbits
resulting in frequent exposure
conjunctivitis or keratitis
– Ocular hypertelorism
– Divergent strabismus
• Choanal atresia or stenosis
• Mandibular prognathism
• Cervical fusion (18%), C2-C3
and C5-C6
• acanthosis nigricans
• Central nervous system
– Approximately 73% of
patients have chronic tonsillar
herniation. Of these, 47% have
progressive hydrocephalus.
– Syringomyelia may be present
– Hydrocephalus (progressive in
30%)

65. 02/25/15 Sid 65
Aarskog syndrome

66. 02/25/15 Sid 66

67. 02/25/15 Sid 67
Foetal Valproate syndrome

68. 02/25/15 Sid 68

69. Prader-Willi syndrome
(marked hypotonia)

70. 02/25/15 Sid 70

71. 02/25/15 Sid 71
Prader-Willi syndrome
• Failure to thrive
• Central obesity
• Dolichocephaly
• Narrow bitemporal diameter
• Almond-shaped eyes
• Strabismus
• Upslanting palpebral fissures,
Myopia
• Thin upper lip
• Small-appearing mouth
• Down-turned corners of mouth
• Thick, viscous saliva
• Early dental caries
• Hypoventilation
• Hypogonadotropic hypogonadism
• Cryptorchidism
• Osteoporosis
• Scoliosis, Kyphosis
• Small hands
• Syndactyly
• Small feet :
• Frontal hair upsweep
• mental retardation Learning
disabilities
• Seizures
• Global developmental delay
• Childhood polyphagia
• Microdeletion of 15q11 in 70%

72. 02/25/15 Sid 72
(A); A) both chromosomes 15 are inherited from the mother and the PWS region from the
father is missing (present in about 25 percent of patients) (B); and a defect in methylation
inherited from the father (present in less than 5 percent of patients) (C). In this case, the
genes in the PWS critical region on the chromosome 15 inherited from the father are
inactivated, similar to those of the mother

73. Angelman syndrome

74. The 15q11q13 deletion in Prader-Willi or Angelman syndrome patients
is sometimes just visible under the microscope in a standard cytogenetic
preparation. In most cases a molecular test (FISH or PCR) is needed to
make the diagnosis

75. Rubinstein-Taybi syndrome
a) The typical face, (b) broad thumb, and (c) characteristic appearance of
large toes

76. Rett syndrome
characteristic hand-wringing.

77. 02/25/15 Sid 77
45,X

78. 02/25/15 Sid 78
47,XXY

79. 02/25/15 Sid 79
47,XX,+13

80. 02/25/15 Sid 80
47,XX,+18

81. 02/25/15 Sid 81
47,XX,+21

82. 02/25/15 Sid 82
46,Y,fra(X)(q27.3)

83. Thank you