The document discusses congenital malformations, including: - Types of congenital anomalies like major anomalies that interfere with normal functioning and minor anomalies that have only cosmetic significance. - Causes of congenital anomalies which can be genetic like chromosomal or single gene defects, or non-genetic like drugs, infections, or maternal illness. - Stages of normal morphogenesis and how abnormalities can occur if stages are incomplete, take an aberrant form, or functional defects develop. Timing of different malformations is outlined. - Specific genetic syndromes are mentioned as causes for different malformation patterns. Deletion 22q11 syndrome is discussed in detail as a common microdeletion syndrome.

1. CONGENITAL
MALFORMATIONS
Dr. Chakshu Chaudhry
Senior Resident
GENETIC METABOLIC UNIT
PGIMER

2. Congenital Malformations
• Incidence
• Types of Congenital anomalies/ Classification
• Terminologies
Basic Concepts
• Normal Morphogenesis
• Normal Stages in Morphogenesis
• Abnormal Morphogenesis
• Developmental Pathology - various systems
Causes
 GENETIC
 Chromosomal
 Single gene
 Multifactorial
 NON GENETIC
 Drugs
 Infections
 Maternal Illness

3. Introduction
More than 5000 dysmorphic and multiple congenital anomaly
syndromes are described in the London Dysmorphology Database-
 single gene disorders
 sporadic and non-genetic condition
 teratogenic conditions

4. Incidence of Congenital Anomalies

5. Incidence
Spontaneous First-Trimester Pregnancy Loss
Chromosome abnormalities (trisomy, monosomy, or triploidy) - 50% of all
spontaneous abortions.
60% - gross structural abnormality is present
Perinatal deaths: 25% to 30% - serious structural abnormality
80% of these cases genetic factors can be implicated.
Newborns: 2% to 3% - one major abnormality.
The true incidence - 5%.
Minor abnormalities - 10% of all newborns.
If two or more minor abnormalities - 10% to 20% risk that the baby will also
have a major malformation.

6. Incidence at Birth

7. Definition and Classification
A malformation is a morphological abnormality that arises due to a
primary, intrinsic developmental defect.
Caused by genetic/ environmental causes or both; many have a
multifactorial etiology; risk of recurrence accordingly varies
Abnormal processes during organogenesis

8. Types of congenital anomalies
• Congenital anomalies:
A. Major: interfere with the normal functioning of an
individual; pose a significant health/ social burden
B. Minor: do not interfere with the normal functioning
of an individual; usually have only cosmetic
significance and no other significant health problem.

9. Congenital Anomalies
• Major anomalies: Eg. Spina bifida, anencephaly,
congenital heart disease, cleft palate, omphalocele etc.

10. • Minor anomalies: polydactyly, 5th finger clinodactyly, accessory
nipples, epicanthal folds, pre-auricular tags or pits, sacral pits and
dimples, transverse palmar crease, 2/3 syndactyly of toes.
Congenital Anomalies

11. Common Single primary defects in development
• Malformation-
• Cleft lip +/- Palate
• Cleft palate
• Cardiac Septal defects
• Defect in Neural tube closure
• Deformation
• CDH
• CTEV
• Dysplasia
• Achondroplasia
• Tuberous sclerosis
Congenital Anomalies

12. Abnormal Morphogenesis
1. Malformation – poor formation of tissue
2. Deformation – extrinsic forces on normal tissue
3. Disruption – breakdown of previously normal tissue
4. Dysplasia – lack of normal organization of cells into tissue

13. Deformation
• Examples:
• Club feet
• Torticollis
• Plagiocephaly
• Risk of recurrence is minimal unless the same mechanical
forces are operative in the next pregnancy (eg. maternal uterine
malformation)

14. Disruption
• Examples:
• Amniotic band sequence
• Tissue ischaemia
• Risk of recurrence is minimal unless genetic causes are
involved

15. Dysplasia
• Dysplasia is an abnormal cellular organization within
a tissue resulting in structural changes, e.g. within
cartilage and bone in
skeletal dysplasias.
• Almost always genetic in etiology.

16. Syndrome
• A dysmorphic syndrome is a recognized composite pattern of 2
or more anomalies with a common specific etiology.
• Most syndromes are made up of 1 or more major anomalies
together with a variable number of minor anomalies.
• Rarely, any one of these features is diagnostic.
• More often the entire constellation of defects must be taken into
consideration to define the diagnosis.
• Etiology: genetic/ a specific environmental agent eg. teratogen

17. Association
• Association is the non-random occurrence of 2 or more
anomalies that occur more frequently than expected by chance
alone, but for which no specific etiology has been
demonstrated.
• Core anomalies usually consist of 5 or more features but any
individual patient rarely has all the core features.
• When 1 component of an association is noted it prompts the
search for others.
• Example: VACTERL association (vertebral, anal, cardiac,
tracheo-esophageal, renal and limb anomalies)

18. Sequence
• A sequence is a pattern of anomalies that results from a single
primary anomaly or a single mechanical factor.
• The factor or event that initiates the sequence may produce
multiple secondary anomalies or may produce a secondary
anomaly that leads to a tertiary anomaly and so on in a
cascading manner.
• The etiology is often heterogeneous.

19. Sequence

20. Field Defects
• Field defects are pattern of multiple anomalies that arise from
disturbance of a single developmental field during embryonic
development.
• Etiology could be defect in a single gene, vascular disturbance
etc.
• Two types:
• polytopic field defects (resultant anomalies are in different
body areas) Eg. Goldenhar syndrome
• Monotopic field defects (resultant anomalies are limited to a
single body area) eg. Holoprosencephaly with midline cleft
palate, sacral agenesis and Poland anomaly

21. Complex & Spectrum
• Complex is a general term used to define a composite of
manifestations. It is sometimes used to describe developmental
field defects eg. sacral agenesis complex.
• Spectrum is sometimes used to describe entities with multiple
features particularly those in which prominent features can be
expressed with considerable variation eg. neurofibromatosis
spectrum

22. Morphogenesis
Knowledge of Morphogenesis
Interpretation of Structural Defects

23. Phenomena of Morphogenesis
• Zygote – genetic information that guides morphogenesis and
function.
• After first few divisions - differentiation – by activation and
inactivation of certain genes – diverse roles of cells.
• Programmed timely – sequential order – early morphogenesis – no
scope for error.

24. Normal Morphogenesis
1. Cell Migration – germ cells move from yolk sac ectoderm to
urogenital ridge to form Gonads.
2. Control over Mitotic rate – size and shape
3. Interaction between Adjacent Tissues –
• Optic disc – lens from overlying ectoderm
• Ureteric bud – kidney from metanephric tissue
• Notochord – overlying neural tissue
• Prechordal mesoderm – overlying forebrain

25. Normal Morphogenesis
4. Adhesive Associations of Like Cells – like long bones
5. Controlled Cell Death – finger separation, recanalization of
duodenum
6. Hormonal Influence over Morphogenesis – 8 weeks –Y
chromosome – testosterone - phallus enlargement
7. Mechanical forces – size, form – brain, calvarium, upper face

26. Normal Stages in Morphogenesis
1st week – cell division without much enlargement. Metabolic needs –
ova
Day 8 – outlying trophoblast cells invade the endometrium. Early
placenta – nourishment.
Inner cell mass is bilaminar – ectoderm – amniotic cavity
Endoderm – yolk sac
Day 14 – primitive node develops into ectoderm – embryo has axis.
Mesoderm starts developing

27. Normal Stages in Morphogenesis
3rd week – mesoderm -heart begins to develop. Blood cells produced
in yolk sac.
Paraxial mesoderm segmented into somites - Foregut and hindgut
pouches

28. Types of Malformation
Incomplete Morphogenesis – incomplete stages in the development
of a structure examples:
Lack of development – Renal agenesis secondary to failure of ureter
formation.
Hypoplasia – micrognathia
Incomplete separation - syndactyly
Incomplete closure – cleft palate
Incomplete septation - VSD
Incomplete migration of mesoderm – exostrophy of bladder
Incomplete rotation – malrotation of gut
Incomplete resolution of early form – Meckel diverticulum
Persistence of earlier location - cryptorhidism

29. Types of Malformation
Aberrant form – that never exists in normal morphogenesis
Example pelvic spur in nail patella syndrome
Accessory tissue – presumed to have been initiated at about the same
time as the normal tissue.
Example polydactyly, pre auricular tags, accessory spleens.
Functional defects – clubfoot

30. Relative Timing of Malformations
CNS
Face
Gut
GU system
Heart
Limb
Complex

31. CNS
Anencephaly – prior to 26 days
Defect in Closure of anterior neural tube
Degeneration of forebrain
MMC – prior to 28 days
Defect in Closure of posterior neural tube
80% lumbosacral

32. Face
Cleft Lip - prior to 36 days
Defect in closure of lip
42% associated with cleft palate
Cleft maxillary palate - prior to 10 weeks
Defect in closure of maxillary palatal shelves
Branchial sinus or cyst - prior to 8 weeks
Defect in resolution of branchial cleft
Preauricular and along the line anterior to SCM

33. Cleft Lip/ Palate
22q del (CP)
Kabuki syndrome (CP)
van der Woude syndrome (VWS—CL/P and CP)
Stickler syndrome (CP)
Treacher–Collins syndrome (CP)

34. Cleft Lip/ Palate
Smith–Lemli–Opitz (SLO) syndrome (CP)
XL CP and ankyloglossia
Ectrodactyly, ectodermal dysplasia, and clefting syndrome (EEC; CL/P)
Non-syndromic CL/P due to MSX1

35. Gut
Esophageal atresia - < 30 days
Defect in Lateral septation of foregut into trachea and foregut
Rectal atresia - < 6 weeks
Defect in Lateral septation of cloaca into rectum and urogenital sinus
Duodenal atresia - < 7-8 weeks
Defect in Recanalisation of duodenum
Malrotation of gut - < 10 weeks
Defect in Rotation of intestinal loop so that cecum lies to the right

36. Gut
Omphalocele - < 10 weeks
Defect in return of midgut from yolk sac to abdomen
Meckel diverticulum - < 10 weeks
Defect in Obliteration of vitelline duct
Diaphragmatic hernia - < 6 weeks
Defect in Closure of pleuroperitoneal canal

37. Tracheo-oesophageal fistula or oesophageal atresia
VATER/VACTERL
Goldenhar(facio-auriculo-
vertebral)syndrome.
OEIS
Teratogens
Feingold syndrome.
CHARGE syndrome
Opitz syndrome
Mandibulo-facial dysostosis with
microceph- aly (MFDM).
AEG syndrome.
Martinez–Frias syndrome.
Hydrocephalus with features of VATER.
Disorders of laterality due to mutations in
ZIC3.

38. Gut
Duodenal atresia (DA)
Maternal diabetes and caudal regression.
OEIS
Vascular disruption.
Feingold syndrome.
Mitchell–Riley syndrome.
Fryns syndrome.
Jejuno-ileal atresia
CF
Stromme syndrome
Colonic atresia
Martinez–Frias syndrome
MGIA (Multiple gastrointestinal atresias )

39. Genitourinary
Exstrophy of bladder - < 30 days
Defect in Migration of infraumblical mesenchyme
Associated with Mullerian and Wolfian duct defects
Bicornuate uterus - <10 weeks
Defect in Fusion of lower portion of mullrian ducts
Hypospadias - < 12 weeks
Defect in Fusion of urethral folds
Cryptorchidism – 7-9 months
Defect in descent

40. Genitourinary
Smith–Lemli–Opitz syndrome (SLO)
WAGR (Wilms tumour–aniridia–genitourinary anomalies– mental retardation)
Drash syndrome or Wilms tumour and pseudohermaphroditism and Frasier syndrome
Opitz syndrome
Mowat–Wilson syndrome
Hand–foot–genital syndrome

41. Heart
TGV - < 34 days
Directional development of bulbus cordis septum
del 22q11
VSD - < 6 weeks
Perimembranous VSD is the most common cardiac defect seen in trisomy 21;
trisomy 18 and trisomy 13, del 22q11, FAS, maternal diabetes
PDA – 9-10 months

42. Heart
Trisomies
22q11 deletion
Noonan syndrome (NS)
Smith–Lemli–Opitz (SLO)
Turner syndrome
Williams syndrome
Alagille syndrome
Holt–Oram syndrome
Kabuki syndrome
VACTERL (vertebral defects–anal atresia–cardiac anomalies–
tracheo-oesophageal fistula–(o)esophageal atresia–renal anomalies–
limb defects) association
CHARGE (coloboma–heart defects–atresia choanae– retardation of
growth and/or development–genital defect–ear anomalies and/or
deafness)

43. Limb
Aplasia of radius – prior to 38 days
Defect in genesis of radial bone
Syndactyly, severe – prior to 6 weeks
Defect in separation of digital rays

44. Polydactyly
Ciliopathies - usually lethal
Meckel–Gruber syndrome
Hydrolethalus syndrome.
Short-rib–polydactyly syndromes.
Non-lethal ciliopathies
Bardet–Biedl syndrome (BBS)
Ellis–van Creveld syndrome (EVC)
Mohr–Majewski syndrome
Kaufman–McKusick syndrome
Joubert syndrome (JS)
Oro-facial-digital (OFD) syndromes
Greig cephalopolysyndactyly.
Pallister–Hall syndrome (anocerebrodigital syndrome)

45. Polydactyly
Simpson–Golabi–Behmel (SGB)
Smith–Lemli–Opitz (SLO) syndrome
Central or mesoaxial polydactyly

46. Syndactyly
Moebius Syndrome
Synpolydactyly
Apert Syndrome (FGFR2)
Cenani–lenz Syndrome
Oro-Facial-digital (OFD) Syndromes, especially OFD1.
Filippi Syndrome.

47. Limb
Amniotic bands
Adams–Oliver Syndrome.
Moebius Syndrome.
Poland anomaly.
Oromandibular –limb–Hypogenesis (OMLH) Syndrome.

48. Limb
Thumb anomalies
Thrombocytopenia–absent radius (tar) syndrome.
Holt–oram syndrome
Okihiro syndrome (duane radial ray syndrome).
Acrofacial dysostosis with limb defects (miller syndrome, post-axial acrofacial
dysostosis syndrome (POADS).
Ulnar–mammary syndrome.

49. Limb
Split hand/foot malformation (SHFM)
Ectrodactyly–ectodermal dysplasia–clefting (EEC) syndrome.
10q duplication
Mesoaxial synostoticc syndactyly (MSSD).
Multiple types of reduction defect
Cornelia de lange syndrome (cdls)
Femur–fibula–ulna complex
Roberts syndrome

50. Complex
Cyclopia, holoprosencephaly – prior to 23 days
Defect in prechordal mesoderm development
Secondary defects of mid and forebrain
Chromosomal imbalance
AD HPE
Environmental causes
Pallister–Hall syndrome
Smith–Lemli–Opitz (SLO) syndrome
Pseudotrisomy 13 or HPE polydactyly syndrome
Fetal akinesia sequence

51. Causes of Congenital Anomalies

52. Deletion 22q11 syndrome
• DiGeorge/ Sedláčková syndrome/ Velocardiofacial Syndrome
• Most common of the micro- deletion syndrome- approximately 1:4000 births,
• Usually sporadic - autosomal dominant inheritance in some families.
• The molecular defect is a 3-Mb microdeletion on chromosome 22 (22q11.2).
deleted DNA segment is still called the DiGeorge Critical Region - phenotypic
features may be due largely to haploinsufficiency for the TBX1 gene
• Characterized by heart malformations (particularly those involving the cardiac
outflow tract), thymic and parathyroid hypoplasia, cleft palate and typical
facies.
• Approximately 25% have schizophrenia-like episodes in adult life

53. Multifactorial

54. Neural Tube Defects
PREVALENCE - Southeast Asia (15.8 per 10,000 births)
Differences in genetic predisposition, environmental factors and
application of interventions.
Factors causing decrease in the prevalence of open NTDs-
1. Periconceptional folic acid supplementation, food fortification
with folic acid.
2. prenatal screening for open NTDs combined with access to
pregnancy termination (83 percent of anencephaly and 63 percent
of spina bifida affected pregnancies are terminated)

55. Types of Neural Tube Defects
• Open NTDs (80 percent) - defect is only covered by a membrane or,
rarely, nothing at all
Myelomeningocele (spina bifida)
Meningocele
Encephalocele
Anencephaly
• can be associated with cerebral ventriculomegaly.

56. • Closed NTDs (20%) - defect is covered by skin
Lipomyelomeningocele
Lipomeningocele
• associated with a tuft of hair, dimple, birthmark, lump, or other skin
abnormality at the site of the defect, as well as cerebral
ventriculomegaly.

57. Etiology
• Most isolated open NTDs appear to be caused by folate deficiency,
likely in combination with genetic or other environmental risk factors.
• Open NTDs have also been associated with some fetal syndromes,
amniotic band sequence, hyperthermia in early pregnancy,
pregestational diabetes, and obesity.

58. Screening
• We perform ultrasound screening for NTDs (ideally at 18 to 20 weeks)
because it appears to detect more open NTDs than maternal serum
alpha-fetoprotein (MSAFP) screening.
• If optimal images of the fetal spine or intracranial anatomy are not
obtained (eg, fetal position or maternal obesity) or high quality
ultrasound examination is unavailable, MSAFP screening should be
offered.

59. • For maternal serum alpha-fetoprotein (MSAFP) screening, the
American College of Medical Genetics and Genomics reports –
• the detection rate for anencephaly is ≥95 percent at 2.0 or 2.5
multiples of the median (MoMs).
• open spina bifida, the detection rate at 2.0 MoMs is 75 to 90 percent
versus 65 to 80 percent at 2.5 MoMs, with false-positive rates of 2 to 5
percent and 1 to 3 percent, respectively.

60. Recurrence risk
• Recurrence is likely related to a multifactorial inheritance pattern,
including genetic and environmental risk factors.
• The risk of recurrence for isolated NTDs is approximately 2 to 4
percent with one affected sibling
• With two affected siblings, the risk is approximately 10 percent
• The risk of recurrence appears to be higher in countries such as Ireland
where the occurrence (prevalence) of NTDs is high

62. • The recurrence risk for anencephaly is estimated at 2 to 5 percent.
• may be part of specific genetic syndromes if there are associated
anomalies –the risk of recurrence for an encephalocele with Meckel-
Gruber syndrome (posterior encephalocele, cleft palate, and
polydactyly) is 25 percent secondary to known autosomal recessive
inheritance.
• Testing for MTHFR polymorphisms is not recommended as
routine folic acid supplementation at 0.4 mg/day will adequately
increase red cell and serum folate concentrations whether or not the
woman has a polymorphism.

64. Empiric Recurrence Risk for Common
Multifactorial Disorders
new

65. Noonan syndrome
• Prevalence 1 in 1000 to 1 in 2500 live births
• Characteristic features :
• Facial features
• Short stature
• Congenital heart defects
• Autosomal dominant
• Complete penetrance but variable expressivity
• Mutations in PTPN11 on chromosome 12
- Missense (50%), gain of function (48%),

66. • Facial features
•Most characteristic in infancy and early
childhood
•Broad high forehead
•Eyes: hypertelorism, epicanthal folds,
down slanting palpebral fissures, light
colored iris
•Ears: low set, posteriorly rotated, thick
helix
•Lips: thick upper lip, deeply grooved
philtrum

67. • Webbing of neck
• Low posterior hairline
• Chest: (70-95%)
• pectus carinatum superiorly
• Pectus excavatum inferiorly
• Wide spaced nipples
• Cubitus valgus in 50 %
• Joint hyperextensibility in 50%

68. Systemic manifestations
• CVS: seen in 60 to 80 % cases
- ECG – wide QRS, left axis deviation, giant Q
waves, negative pattern in left precordial leads
• Oral- high arched palate, dental malocclusion
• Genitourinary:
• Males: many are infertile
• Cryptorchidism (77%)
• Sertoli cell dysfunction
• Females : mostly fertile

69. Systemic manifestations
• Growth
• Short stature: proportionate (60%)
• Normal birth weight and length
• Respond to an extent to growth hormone
therapy
• Hematological / oncological
• Bleeding disorders(55%):
• Coagulation factor defeciencies
• Thrombocytopenia
• Myeloproliferative disorders

70. Systemic manifestations
• Neurological:
• Low normal intelligence
• Mild developmental delay(mainly motor)
• Ocular problems – strabismus (48-60%), refractive errors
(61%), amblyopia (33%)
• Behavioral problems
• Feeding difficulties
• Orthopedic: joint hypermobility, cubitus valgus, CTEV
• Anesthesia risk
• Malignant hyperthermia

72. Noonan and Other RASopathies
Half cases - protein tyrosine phosphatase, non-receptor-type, 11 (PTPN11) gene.
phenotype-genotype correlation - mutation- positive cases - higher frequency of pulmonary stenosis
facial features are similar.
PTPN11-negative cases:
SOS1, SHOC2, KRAS, RIT1, and MAPZK1 genes
Pathway, known as RAS-MAPK
Protein product of PTPN11 is SHP-2 and this, together with SOS1, positively transduces signals to Ras-
GTP, a downstream effector.
The KRAS mutations in NS appear to lead to K-ras proteins with impaired responsiveness to GTPase
activating proteins
Neurofibromatosis, the most common disorder of this group

74. Genes of the RAS-MAPK Pathway and Associated
Syndromes

75. Noonan and Other RASopathies
spectrum of disorders - overlapping features – NS, cardio- facio-
cutaneous, Costello syndromes
RAS-MAPK pathway - for RAS to bind GTP, which results in
activation of the pathway (gain-of-function)- increase in solid tumors
in Costello syndrome,
cellular proliferation in some tissues in cardio-facio-cutaneous
syndrome (e.g., hyperkeratosis).
tumor suppressor - Neurofibromin is a GTPase activating protein

76. Environmental Agents (Teratogens)

77. Maternal Infections Maternal Illnesses –
DM
PKU
Epilepsy

78. Take home messages
• Understanding the type of Congenital Malformation and classifying it,
helps in identifying the etiology.
• Further management of index patient and genetic counselling
regarding risk of recurrence depends on the underlying cause.

79. References:
1. Smith’s recognizable patterns of malformation (7th edition)
2. Emery and Rimoin’s Principles and Practice of Medical Genetics
(6th edition)
3. Oxford Desk Reference Clinical Genetics & Genomics (2nd
edition)

80. Thank You!