The Malformed Child: Hereditary Syndromes and Anomalies
Hereditary syndromes and anomalies in the malformed child encompass genetically determined patterns of congenital structural defects arising from chromosomal abnormalities, single-gene mutations, or multifactorial inheritance that result in recognizable dysmorphic features and developmental malformations.
The Malformed Child: Hereditary Syndromes and Anomalies — Introduction to Clinical Genetics
This GC 151 lecture by Dr. Brian Chung (Department of Paediatrics & Adolescent Medicine, HKU) introduces clinical genetics through the lens of the malformed child. It is a foundational lecture that bridges basic genetic mechanisms with clinical recognition of dysmorphic syndromes, rare diseases, and congenital anomalies. The lecture is structured around three clinical scenarios — short stature, developmental delay/autism, and congenital heart disease — to illustrate how clinical geneticists approach diagnosis. It covers the genetic-environmental spectrum of disease, the work of a clinical geneticist, specific syndromes (achondroplasia, Turner syndrome, Fragile X syndrome, Marfan syndrome, and others), modern genetic testing (array CGH, whole-exome sequencing), and the concept of precision medicine for rare diseases.
How this fits into exams: This lecture is commonly tested in MCQs asking you to match clinical features to a syndrome, understand inheritance patterns, or identify the appropriate genetic test. Past papers (2024, 2025) have tested Turner syndrome, achondroplasia, and the approach to short stature directly. [1][2]
Learning Objectives (from the lecture)
Learning Outcomes in Genetics for Medical Students (NHS UK, as cited in GC 151):
- Understand and describe the mechanisms that underpin human inheritance
- Have an understanding of the role of genetic factors in health and disease
- Be able to identify patients with, or at risk of, a genetic condition
- Be able to communicate genetic information in an understandable, non-directive manner, being aware of the impact genetic information may have on an individual, family and society
- Be familiar with the uses and limitations of genetic testing and the differences between testing and screening
- Know how to obtain current information about scientific and clinical applications of genetics, particularly from specialised genetics services [1]
The contributions of genetic and environmental factors to human diseases exist on a continuous spectrum. [1]
This is the most important conceptual slide in the lecture. Diseases are not simply "genetic" or "environmental" — they lie on a spectrum:
| Predominantly Genetic | Multifactorial (Both) | Predominantly Environmental |
|---|---|---|
| Duchenne muscular dystrophy | Club foot | Scurvy |
| Haemophilia | Pyloric stenosis | Tuberculosis |
| Osteogenesis imperfecta | Dislocation of hip | |
| Phenylketonuria | Spina bifida | |
| Galactosaemia | Ischaemic heart disease | |
| Peptic ulcer | ||
| Diabetes | ||
| Ankylosing spondylitis |
Also Chromosomal, mitochondrial disorders — the slide reminds you that these are additional categories beyond simple Mendelian inheritance. [1]
Key Principles from this Spectrum
| Feature | Unifactorial (Genetic end) | Multifactorial (Middle/Environmental end) |
|---|---|---|
| Frequency | Rare | Common |
| Genetics | Simple | Complex |
| Inheritance pattern | Unifactorial | Multifactorial |
| Recurrence risk | High | Low |
Why this matters: When you see a rare disease with a clear Mendelian pattern, the recurrence risk is high and predictable (e.g., 25% for AR, 50% for AD). When you see a common disease like diabetes, genetics is just one of many contributing factors, and recurrence risk is low and harder to predict. This distinction is critical for genetic counselling.
Two Genomes in Every Cell
Remember that each cell contains two sets of genome: the nuclear genome (chromosomes — linear DNA) and the mitochondrial genome (circular DNA in the cytoplasm). Mitochondrial inheritance is strictly maternal because mitochondria are inherited from the egg. This matters for conditions like Leber hereditary optic neuropathy (LHON). [3]
The clinical geneticist's workflow involves: [1]
- In the Clinic: Patient assessment, taking family history (pedigree), dysmorphic examination
- Back-Stage Work: Literature review, searching rare disease databases, overseas consultation, organizing clinical/research genetic testing
- Endpoint: Reaching a genetic diagnosis → genetic counselling
- Research & Development: Developing new testing platforms for undiagnosed genetic diseases
Why this matters for exams: You should understand that clinical genetics is not just "send a test." The process involves careful clinical phenotyping (what the patient looks like and what features they have), constructing a pedigree, searching databases (OMIM, Orphanet), and then selecting the right test. The diagnosis drives counselling — which includes recurrence risk, prognosis, management, and family implications.
In total, there are at least 400,000 people in HK who will be affected by a rare disease. [1]
A "rare disease" is defined as affecting < 1 in 2,000 people. But collectively, rare diseases are common — this is a critical public health point.
Evaluation Algorithm
The lecture presents a systematic evaluation framework for FTT/Short stature: [1]
Proportionate or disproportionate? BW 10%, BH 3%, HC 75% — This slide shows a clinical photograph prompting you to assess whether the child's body segments are proportional. [1]
Why this matters: The single most important clinical question when you see a short child is: are the body proportions normal?
- Proportionate short stature → think chromosomal (Turner), endocrine (GH deficiency, hypothyroidism), nutritional, chronic disease
- Disproportionate short stature → think skeletal dysplasia (achondroplasia, hypochondroplasia, etc.)
The example on the slide (BW 10th centile, BH 3rd centile, HC 75th centile) is classic for achondroplasia: the head is relatively large, height is very short, and the limbs are disproportionately short compared to the trunk.
Syndrome 1: Achondroplasia
Fibroblast Growth Factor Receptor 3 (FGFR3) and Classes of Mutation — The lecture shows the FGFR3 protein structure with its extracellular domain, transmembrane domain, and intracellular tyrosine kinase domains. [1]
From first principles:
- FGFR3 is a receptor tyrosine kinase that normally acts as a negative regulator of bone growth. When FGF binds FGFR3, it sends signals (via STAT and MAP kinase cascades) that slow down chondrocyte proliferation in the growth plate.
- In achondroplasia, a gain-of-function mutation (usually G380R in the transmembrane domain) causes FGFR3 to be constitutively active → excessive negative signaling → severely impaired endochondral ossification → short limbs.
- This is autosomal dominant. ~80% of cases are de novo mutations (advanced paternal age is a risk factor).
- The mutation is highly specific: >97% of patients have the same G380R point mutation.
FGFR3 signal transduction and therapeutic strategies: [1]
- FGF + heparin binding → FGFR3 kinase activation → downstream STAT and MAP kinase cascades → inhibition of bone growth
- CNP (C-type natriuretic peptide) binding to NPR-B → cGMP → PKG → attenuation of MEK pathway via RAF → partially counteracts FGFR3 signaling
- Therapeutic targets: Peptide P3 blocks ligand binding; meclozine antagonizes MEK activation of ERK
High Yield: Achondroplasia Mechanism
Achondroplasia = gain-of-function mutation in FGFR3 → constitutive activation of a negative regulator of bone growth → impaired endochondral ossification → disproportionate short stature with rhizomelic (proximal) limb shortening. [1]
- Disproportionate short stature with rhizomelic (proximal) limb shortening
- Macrocephaly with frontal bossing
- Midface hypoplasia with depressed nasal bridge
- Trident hand (short fingers with a gap between 3rd and 4th digits)
- Lumbar lordosis (exaggerated)
- Genu varum (bowed legs)
- Normal intelligence in most cases
Spinal canal stenosis — This is a major concern in achondroplasia. The foramen magnum and spinal canal are narrowed due to abnormal endochondral ossification of the vertebral column. [1]
Prevention of Symptomatic Spinal Canal Stenosis in Achondroplasia/Hypochondroplasia: [1]
- Firm back support from birth
- Reclined seating (delayed upright sitting) & Reclined handling
- Prone play in older infants
- Trunk strengthening exercises
- Shock absorbing footwear
- Good sitting posture
- Providing a foot rest
- Maintaining weight on the 25th percentile for achondroplasia
Why "25th percentile for achondroplasia"? Achondroplasia has its own growth charts. Obesity worsens spinal stenosis symptoms, so weight control relative to achondroplasia-specific curves is critical.
The slide references advances in treatment: CNP analogue (vosoritide), meclozine, and Peptide P3 as therapeutic strategies. [1]
Vosoritide is a CNP analogue that has been approved for treating achondroplasia in children. It works by counteracting the overactive FGFR3 pathway through the NPR-B/cGMP/PKG axis, attenuating MEK signaling, thereby partially restoring normal growth plate function.
Syndrome 2: Turner Syndrome (45,X)
This is one of the most heavily tested syndromes in HKUMed exams. Both the 2024 and 2025 Fourth Summative MCQs tested Turner syndrome recognition. [2][4]
Turner syndrome: Phenotypic females who have lost an entire sex chromosome or a portion of the X chromosome that includes the tip of its short arm. [1]
| Cytogenetic Finding | Frequency |
|---|---|
| 45,X (monosomy X) | ~50% |
| Mosaicism (e.g., 45,X/46,XX or 45,X/47,XXX) | ~30% |
| Structural X abnormalities (e.g., 46,X,i(Xq), 46,X,del(Xp), 46,X,idic(X)(p11.1)) | ~20% |
The slide shows karyotypes: 45,X; 45,X/47,XXX; 46,X,idic(X)(p11.1) [1]
Only 1% of embryos survive to term. Responsible for 7-10% of all spontaneous abortions. [1]
Why so lethal in utero? Most 45,X conceptuses die because X-linked gene dosage is critical during embryonic development. The genes on the X chromosome that escape X-inactivation (pseudoautosomal regions and others) need two copies for normal development. With only one X, haploinsufficiency of these genes causes severe lymphatic and cardiovascular developmental defects leading to hydrops fetalis and death.
Affects approximately 1/2,500 live female births. [1]
Short stature and premature ovarian failure [1]
Why short stature? The SHOX (Short stature HOmeoboX) gene is located in the pseudoautosomal region of the X chromosome (PAR1). It escapes X-inactivation, so normally both copies are active. In Turner syndrome, there is haploinsufficiency of SHOX → impaired growth plate development → short stature. This is the same gene implicated in SHOX-related short stature and Léri-Weill dyschondrosteosis (Madelung deformity).
Why premature ovarian failure? Two functional X chromosomes are needed for normal ovarian maintenance. With monosomy X, oocytes undergo accelerated atresia, leading to streak gonads by puberty. Most girls with Turner syndrome will not undergo spontaneous puberty and are infertile.
Clinical features of Turner syndrome arise from haploinsufficiency of genes on the X chromosome. [1]
Variability of phenotypes in TS: Early surveys emphasized physical traits (e.g., webbed neck, low-set or malrotated ears, ptosis, skeletal abnormalities). Now reported in far fewer than half of affected girls. [1]
This is an important exam point: not all girls with Turner syndrome have the "classic" webbed neck and lymphedema. Many are diagnosed late because of short stature and delayed puberty alone.
| System | Features |
|---|---|
| Growth | Short stature (nearly universal) |
| Reproductive | Premature ovarian failure, streak gonads, delayed/absent puberty, infertility |
| Cardiovascular | Bicuspid aortic valve (10-15%); Coarctation of aorta (10%); Aortic dilation (8-28%) and dissection (2.5%); Hypertension (20%) |
| Renal | Renal anomalies (7-8%) — horseshoe kidney, duplex collecting system |
| Endocrine | Autoimmune hypothyroidism (25-30%); Diabetes mellitus (2-4x risk) |
| GI | Inflammatory bowel disease (2.5%) |
| ENT | Hearing loss (60%) |
| MSK | Osteoporosis; cubitus valgus; short 4th metacarpal; Madelung deformity |
| Lymphatic | Webbed neck (from cystic hygroma in utero), lymphedema of hands/feet at birth |
| Dermal | Multiple pigmented naevi |
Medical conditions in TS and their management: [1]
- Short stature → GH treatment
- Gonadal insufficiency → Monitor pubertal development ± estrogen replacement
- Cardiovascular → Refer cardiac: Bicuspid aortic valve (10-15%), Coarctation of aorta (10%), Aortic dilation (8-28%) and dissection (2.5%), Hypertension (20%)
- Renal anomalies (7-8%) → Renal ultrasound
- Autoimmune hypothyroidism (25-30%) → Screen TFT
- IBD (2.5%)
- Hearing loss (60%) → ± refer ENT
- DM (2-4x risk)
- Osteoporosis
Health supervision in Turner syndrome follows AAP guidelines 2003. [1]
High Yield: Turner Syndrome Screening Protocol
At diagnosis: Karyotype, echocardiogram (bicuspid aortic valve, coarctation), renal ultrasound, TFT, audiometry. Ongoing: annual TFT, BP monitoring, periodic cardiac imaging (for aortic dilation), monitor growth with GH therapy, assess pubertal development, DEXA for osteoporosis, screen for DM. [1]
2024 Fourth Summative MCQ Q92: A 5-year-old girl with recurrent infections, short stature (height < 3rd centile), head circumference 25th centile, webbed neck, low-set ears → Most likely diagnosis: Turner syndrome. [2]
2025 Fourth Summative MCQ Q77: A 15-year-old girl with height below 0.4th centile, webbed neck, low-set ears, shield chest, cubitus valgus, Madelung deformities, BP 135/65 mmHg → Most likely diagnosis: Turner syndrome. (Note: BP 135/65 with wide pulse pressure suggests coarctation of aorta.) [4]
Exam Trap: Turner vs Noonan
Turner syndrome = 45,X = female only, left-sided cardiac lesions (coarctation, bicuspid aortic valve), streak gonads. Noonan syndrome = autosomal dominant (PTPN11 most common), affects both sexes, right-sided cardiac lesions (pulmonary valve stenosis with dysplastic cusps, HCM), cryptorchidism in males. Both can have webbed neck, short stature, low-set ears. The discriminators are: sex + cardiac lesion side + karyotype. [1][5]
Syndrome 3: Fragile X Syndrome
Case 1: A 5-year-old boy referred for developmental delay and autistic features. The pedigree shows the boy's maternal uncle also has intellectual disability (MR), consistent with X-linked inheritance. [1]
Molecular mechanism for Fragile X syndrome: [1]
- FMR1 gene on Xq27.3
- (CGG)n repeats in the 5' UTR:
- Normal: n = 6-50
- Pre-mutation: n = 60-200
- Full mutation: n > 200
- Full mutation → hypermethylation (M) of the FMR1 promoter → silencing of FMR1 → loss of FMRP protein → Fragile X syndrome
From first principles:
- FMRP (Fragile X Mental Retardation Protein) is an RNA-binding protein essential for synaptic plasticity and neuronal development. It regulates translation of hundreds of mRNAs at the synapse.
- When CGG repeats expand beyond 200, the CpG island in the FMR1 promoter becomes hypermethylated → gene is silenced → no FMRP → abnormal synaptic function → intellectual disability and autistic features.
The case letter states: "300 CGG repeats were found in the FMR1 gene of Lee Yan, whereas 65 CGG repeats was found in his mother." [1]
- The mother is a pre-mutation carrier (65 repeats). Pre-mutation carriers are usually clinically unaffected regarding intellectual function but may develop:
- Fragile X-associated tremor/ataxia syndrome (FXTAS) — late-onset progressive cerebellar ataxia and intention tremor (mainly in males)
- Fragile X-associated primary ovarian insufficiency (FXPOI) — premature menopause (in females)
- Anticipation: The pre-mutation is unstable during maternal meiosis and tends to expand. A mother with 65 repeats can pass on a full mutation (>200) to her son. This is why the mother has 65 and the son has 300.
High Yield: Trinucleotide Repeat Expansion Diseases
The lecture includes a slide on "Triplet expansions" — a table of diseases caused by trinucleotide repeat expansions. [1] Key examples:
- Fragile X: CGG in 5' UTR of FMR1, X-linked
- Huntington disease: CAG in coding region of HTT, AD, anticipation with paternal transmission
- Myotonic dystrophy type 1: CTG in 3' UTR of DMPK, AD, anticipation with maternal transmission
- Friedreich ataxia: GAA in intron of FXN, AR
- Spinocerebellar ataxias (SCAs): CAG in various genes, AD
The lecture shows a Venn diagram of overlap between ASD and monogenic causes: [1]
- Fragile X syndrome
- Tuberous sclerosis
- Rett syndrome
- PTEN mutation
- Angelman syndrome
Why this matters: ~5-10% of ASD cases have an identifiable genetic cause. Fragile X is the most common single-gene cause of ASD. Any child with ASD should be considered for genetic testing, especially if there are additional features (intellectual disability, family history, dysmorphic features).
Rare diseases among common disease(s) — listed with ASD: [1]
- Fragile X syndrome
- Isodicentric chromosome 15
- Distal chromosome 16p11.2 deletion
- PTEN mutation
- Phelan-McDermid syndrome (SHANK3/22q13 deletion)
Syndrome 4: Marfan Syndrome
FBN-1 gene and Mutation spectrum in HK Chinese patients — The lecture shows the mutation spectrum across the fibrillin-1 protein, with missense, nonsense, and frameshift mutations. [1]
From first principles:
- FBN1 (chromosome 15q21.1) encodes fibrillin-1, a glycoprotein that is the main component of microfibrils in the extracellular matrix (ECM).
- Microfibrils serve two functions:
- Structural: Provide scaffold for elastic fibers (especially in aortic wall, suspensory ligament of lens, periosteum)
- Regulatory: Sequester TGF-β in the ECM, keeping it inactive.
Loss of docking protein FBN1 increases TGF-β1 signalling. [1]
This is a critical pathophysiology point:
- When fibrillin-1 is deficient/dysfunctional → microfibrils cannot sequester TGF-β → increased free TGF-β signaling → excess downstream effects including:
- Aortic wall: Smooth muscle apoptosis, matrix metalloproteinase activation → cystic medial necrosis → aortic root dilation and dissection
- Skeleton: Excessive long bone growth (via periosteal effects)
- Lungs: Increased compliance → spontaneous pneumothorax
Beta blocker to reduce aortic wall stress. [1] Postnatal treatment with TGF-β neutralizing antibody; Pre- and postnatal treatment with Losartan and Propranolol. [1]
Why losartan specifically? Losartan is an ARB (angiotensin II receptor blocker) that also has TGF-β antagonist properties independent of its antihypertensive effect. In animal models of Marfan syndrome, losartan reduced aortic root dilation more effectively than propranolol alone. Clinical trials have shown benefit, and losartan + β-blocker is now standard therapy for aortic protection in Marfan syndrome.
Marfan syndrome (Revised Ghent criteria) – Systemic features: [1]
- Pes planus
- Protrusio acetabulae
- Pectus carinatum
- Pectus excavatum
The full Revised Ghent Criteria (2010) for Marfan syndrome diagnosis center on two cardinal features:
- Aortic root dilation/dissection (Z-score ≥ 2)
- Ectopia lentis (upward subluxation of the lens)
With a positive FBN1 mutation: Either aortic root dilation OR ectopia lentis is sufficient for diagnosis. Without a known mutation: Both aortic root dilation AND a systemic score ≥ 7 are needed (or ectopia lentis + aortic root dilation).
Systemic features scored include: wrist and thumb signs, pectus carinatum/excavatum, hindfoot valgus, pes planus, pneumothorax, dural ectasia, protrusio acetabulae, reduced US/LS ratio, scoliosis, skin striae, myopia, MVP.
Rare diseases among common disease(s) — with congenital heart disease: [1]
- 22q11.2 deletion (DiGeorge/velocardiofacial syndrome)
- Loeys-Dietz syndrome (LDS)
- Marfan syndrome
- Long QT syndrome
- Noonan syndrome
- Williams syndrome
Understanding the precise terminology is essential for both clinical communication and exam answers. [6]
| Term | Definition | Pathophysiology | Examples | Recurrence Risk |
|---|---|---|---|---|
| Malformation | Morphologic defect of organ/larger region from intrinsically abnormal developmental process | Abnormal organogenesis | Neural tube defect, cleft lip/palate, Down syndrome, VSD | Up to 100% in malformation syndromes |
| Deformation | Abnormal form/shape/position caused by mechanical forces acting over prolonged period | Extrinsic compression after organogenesis complete | Club foot from oligohydramnios, plagiocephaly, breech hip dislocation | < 1% to 100% (depends on cause) |
| Disruption | Morphologic defect from breakdown of previously normal tissue | Vascular accident, teratogen exposure | Amniotic band syndrome, thalidomide embryopathy | Low (unless teratogen persists) |
| Dysplasia | Abnormal organization of cells into tissue | Abnormal histogenesis | Skeletal dysplasias (achondroplasia), ectodermal dysplasia | Depends on underlying genetic cause |
Patterns of Multiple Anomalies
| Pattern | Definition | Example |
|---|---|---|
| Syndrome | Multiple anomalies thought to be pathogenetically related and not a sequence | Down syndrome, Turner syndrome |
| Sequence | Multiple anomalies derived from a single known or presumed primary anomaly or mechanical factor | Potter sequence (renal agenesis → oligohydramnios → lung hypoplasia + limb deformities + flat facies) |
| Association | Non-random occurrence of multiple anomalies not explained by a syndrome or sequence | VACTERL association (Vertebral, Anal, Cardiac, Tracheo-Esophageal, Renal, Limb) |
High Yield: VACTERL Association
VACTERL is a commonly tested association: Vertebral anomalies, Anal atresia (imperforate anus), Cardiac defects, Tracheo-Esophageal fistula, Renal anomalies, Limb defects (radial ray). It is NOT a syndrome because it does not have a single unifying genetic cause. If you see ≥3 of these features, think VACTERL. [7]
3% of liveborn infants have major congenital abnormalities (MCAs), and another 3% have minor congenital abnormalities. Among MCAs, 15-20% involve the CNS, and another 15-20% involve the heart. [6]
| Developmental Period | Timing | Normal Events | Effect of Error |
|---|---|---|---|
| Preimplantation | < 3 weeks | Ovulation → fertilization → blastocyst | Miscarriage (all-or-none phenomenon) |
| Embryonic | 3-8 weeks | Gastrulation → neurulation → organogenesis | Major malformations (earlier = more complex) |
| Fetal | 3 months - birth | Tissue maturation + rapid body growth | Minor malformations or deformations |
Genetic Testing Modalities
Genomic arrays: Probe production → Printing onto glass slides → Hybridization of Control DNA + Patient DNA [1]
How it works:
- Patient and control DNA are differentially labeled with fluorescent dyes
- Both are hybridized to a microarray containing DNA probes representing the entire genome
- The ratio of fluorescence at each probe indicates copy number: equal ratio = normal; skewed = gain or loss
- Detects: Microdeletions and microduplications (copy number variants, CNVs) as small as ~50-100 kb
- Does NOT detect: Balanced translocations, point mutations, trinucleotide repeats, low-level mosaicism
Array CGH is now the first-tier genetic test for children with intellectual disability, developmental delay, autism, or multiple congenital anomalies (when karyotype and specific syndrome testing are not indicated).
Whole-Exome Sequencing (WES) is applied in Paediatric Rare Diseases. [1] Human exome accounts for 1% of human genome. About 85% of pathogenic mutations can be found in human exome. Size of the human genome = 6 billion bp. Size of the human exome = 30 million bp. Please be aware that when a genetic report says "exome", usually it's representing just ~90% of the whole exome. [1]
Why WES and not whole-genome sequencing (WGS)?
- The exome is only 1% of the genome but contains ~85% of disease-causing mutations
- WES is cheaper, faster, and generates less data to analyze
- WES is ideal for identifying the cause of undiagnosed rare diseases, especially Mendelian disorders
Limitations of WES:
- Misses non-coding mutations (introns, regulatory regions, deep intronic variants)
- Misses large structural variants (deletions, duplications, inversions)
- Misses trinucleotide repeat expansions
- Coverage gaps (~10% of exome may not be adequately captured)
- Variant interpretation can be challenging (variants of uncertain significance, VUS)
A 10-year-old with gross motor clumsiness, progressive dystonia from LL to UL, worsening gait, wheelchair bound. Seen in HK, Shenzhen, Boston. Extensive workup including MRI brain, echocardiogram, USG abdomen, aCGH, various metabolic tests — all unrevealing. [1]
WES identified a novel gene mutation → this led to discovery of a new disease entity (4 families, 6 patients initially → 27 patients subsequently). [1]
Most received medical treatment including L-dopa, baclofen, clobazam — no functional benefits. 9 received deep brain stimulation (DBS) — all had considerable improvements. [1]
Why this case matters: This is the "poster child" for precision medicine. WES discovered a new disease, identified a cohort worldwide, and led to a specific treatment (DBS) that worked when conventional medications failed. This illustrates the Undiagnosed Disease Program/Network concept — a global initiative to diagnose and treat rare diseases. [1]
This integrates GC 151 content with supporting material from multiple sources. [1][5]
| Syndrome | Genetics | Key Dysmorphic Features | Cardiac Defects |
|---|---|---|---|
| Down syndrome (Trisomy 21) | 47,+21 (95% free trisomy, 4% Robertsonian translocation, 1% mosaic) | Hypotonia, epicanthic folds, upslanting palpebral fissures, flat nasal bridge, protruding tongue, single palmar crease, sandal gap | AVSD (most characteristic), VSD, ASD, PDA, TOF |
| Turner syndrome (45,X) | Monosomy X | Short stature, webbed neck, shield chest, cubitus valgus, lymphedema | Left-sided lesions: Coarctation, bicuspid aortic valve, aortic dilation/dissection |
| Noonan syndrome | AD (PTPN11 most common) | Turner-like but affects both sexes, ptosis, hypertelorism, low-set ears, cryptorchidism | Right-sided lesions: Dysplastic pulmonary valve stenosis, ASD, HCM |
| Williams syndrome | 7q11.23 microdeletion (includes ELN gene) | Elfin facies, full cheeks, flat nasal bridge, prominent lips, hypercalcemia, friendly personality | Supravalvular aortic stenosis, peripheral PA stenosis |
| DiGeorge/22q11.2 deletion | 22q11.2 microdeletion | Abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia (CATCH-22) | Conotruncal defects: Interrupted aortic arch, truncus arteriosus, TOF |
| Marfan syndrome | AD, FBN1 mutation | Tall, long limbs, arachnodactyly, pectus deformity, ectopia lentis | Aortic root dilation/dissection, MVP |
| Loeys-Dietz syndrome | AD, TGFBR1/2 mutation | Bifid uvula, hypertelorism, arterial tortuosity | Aggressive aortic aneurysms/dissection |
The clinical geneticist performs a systematic "head-to-toe" dysmorphic examination. Key areas: [6]
| Area | What to Look For | Associated Syndromes |
|---|---|---|
| Head | Microcephaly, macrocephaly, brachycephaly, frontal bossing, prominent occiput | Down (brachycephaly), Edward (prominent occiput), achondroplasia (macrocephaly + frontal bossing) |
| Face | Flat midface, long philtrum, hypertelorism, hypotelorism | FAS (long smooth philtrum), Williams (elfin facies), DiGeorge (long face) |
| Eyes | Epicanthic folds, upslanting/downslanting palpebral fissures, coloboma, lens subluxation | Down (upslanting), Noonan (downslanting), Marfan (ectopia lentis upward), homocystinuria (ectopia lentis downward) |
| Ears | Low-set, posteriorly rotated, preauricular pits/tags | Many syndromes; ear anomalies often co-occur with renal anomalies |
| Mouth | Cleft lip/palate, micrognathia, macroglossia, high-arched palate | Pierre Robin sequence (micrognathia), Down (macroglossia), BWS (macroglossia) |
| Neck | Webbed neck, short neck, redundant skin | Turner, Noonan, Edward, Patau |
| Chest | Shield chest, pectus carinatum/excavatum, widely spaced nipples | Turner (shield chest), Marfan (pectus), Noonan (shield chest) |
| Hands | Single palmar crease, clinodactyly, polydactyly, arachnodactyly, brachydactyly | Down (single crease, clinodactyly), Patau (polydactyly), Marfan (arachnodactyly) |
| Feet | Sandal gap, rocker-bottom feet | Down (sandal gap), Edward (rocker-bottom) |
| Skin | Café-au-lait spots, hypopigmented macules, striae | NF1 (café-au-lait), tuberous sclerosis (ash-leaf macules), Marfan (striae) |
| Genitalia | Cryptorchidism, hypospadias, ambiguous genitalia | Noonan (cryptorchidism), Fanconi (hypospadias), DSD syndromes |
Ear-Kidney Connection
Kidney anomalies commonly co-occur with ear anomalies. Renal US should be offered if there are other malformations/dysmorphic features, or with family history of deafness / ear or renal malformation / maternal gestational diabetes. [6] This is because both the ear and kidney develop from similar embryological structures and share developmental gene expression programs (e.g., PAX2, EYA1, SIX1).
BWS is an imprinting disorder (11p15.5) characterized by: [8]
- Macrosomia (large birth weight)
- Macroglossia (large tongue — most consistent feature)
- Omphalocele (abdominal wall defect)
- Visceromegaly (liver, spleen, kidneys, adrenals, pancreas)
- Neonatal hypoglycemia (due to pancreatic beta-cell hyperplasia → hyperinsulinism)
- Ear anomalies (anterior ear lobe creases, posterior helical ear pits)
- Hemihypertrophy → increased risk of embryonal tumors
- Embryonal tumors: Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma
Hemihypertrophy → increased risk of embryonal tumors. Isolated hemihypertrophy has 5.9% risk. Screening: Renal US every 3 months (until 8 years), serum AFP every 3 months (until 5 years). [6]
| Feature | Edward Syndrome (T18) | Patau Syndrome (T13) |
|---|---|---|
| Incidence | 1/3000, F:M = 4:1 | 1/8000 |
| Head | Microcephaly + prominent occiput | Microcephaly + sloping forehead |
| Hands | Clenched hands with overlapping fingers (95%) | Polydactyly (postaxial) |
| Feet | Rocker-bottom feet (90%) | — |
| Heart | VSD (94%), 100% have cardiac defects | Complex CHD |
| Classic triad (T13) | — | Microphthalmos + cleft lip/palate + polydactyly |
| Other | Short sternum, widely spaced nipples, low BW | Scalp defects, holoprosencephaly |
| Prognosis | Median survival 14 days, 5% reach 1 year | Most die in infancy |
Genetic counselling is a non-directive process that involves: [1]
- Explaining the diagnosis and its natural history
- Recurrence risk for the family (based on inheritance pattern)
- Available testing for at-risk family members (cascade screening)
- Reproductive options (prenatal diagnosis, preimplantation genetic testing, donor gametes)
- Psychosocial support and referral to support groups
- Management plan and multidisciplinary care coordination
Non-Directive Counselling
A common exam mistake is suggesting that the doctor should "recommend" or "advise" the couple what to do regarding reproduction. Genetic counselling should be non-directive — you present the facts, risks, and options, and the family makes their own informed decision. This is a professional and ethical standard. [1]
Likely Exam Questions
Based on past papers and lecture content, the following question types are most likely:
- Syndrome recognition: Given clinical features (webbed neck, short stature, low-set ears, coarctation) → identify Turner syndrome
- Short stature approach: Proportionate vs disproportionate → differential diagnosis
- Fragile X mechanism: CGG repeat expansion → methylation → FMR1 silencing
- Marfan pathophysiology: FBN1 mutation → increased TGF-β signaling → aortic root dilation
- Achondroplasia mechanism: FGFR3 gain-of-function → impaired endochondral ossification
- Genetic test selection: When to use karyotype vs array CGH vs WES vs targeted gene testing
- "A 5-year-old girl is referred for short stature. Describe your approach to evaluation."
- "A couple's first child has Down syndrome due to Robertsonian translocation. Explain the recurrence risk and counselling."
- "Describe the clinical features and health surveillance plan for Turner syndrome."
- "Explain the molecular basis of Fragile X syndrome and the concept of anticipation."
- Clinical vignette of a child with multiple anomalies → identify the syndrome → state the genetic test → outline management
| Trap | How to Avoid |
|---|---|
| Confusing Turner (45,X) with Noonan | Turner = females only, left-sided cardiac; Noonan = both sexes, right-sided cardiac |
| Confusing Marfan lens subluxation with homocystinuria | Marfan = upward; Homocystinuria = downward (and inferonasal). Both are tall and have lens issues. |
| Saying achondroplasia is AR | It is autosomal dominant. Most cases are de novo (new mutations). |
| Forgetting that Fragile X pre-mutation carriers have their own clinical risks | FXTAS (tremor/ataxia in older males), FXPOI (premature ovarian insufficiency in females) |
| Using "unifactorial" when meaning "monogenic" | They mean the same thing. "Unifactorial" = single gene. GC slides use this term. |
| Calling VACTERL a "syndrome" | It is an association, not a syndrome. |
| Thinking all Turner patients have webbed neck | Now fewer than half have classic features. Many diagnosed on short stature + delayed puberty alone. |
High Yield Summary
- Diseases exist on a genetic-environmental spectrum. Unifactorial (rare, simple genetics, high recurrence) ↔ Multifactorial (common, complex, low recurrence).
- Short stature evaluation: First determine proportionate vs disproportionate. Disproportionate → skeletal dysplasia. Proportionate → chromosomal, endocrine, nutritional, chronic disease.
- Achondroplasia: FGFR3 gain-of-function, AD, disproportionate short stature with rhizomelic shortening, macrocephaly. Complication: spinal canal stenosis. Treatment: CNP analogues (vosoritide).
- Turner syndrome (45,X): 1/2,500 female births. Two cardinal features: short stature (SHOX haploinsufficiency) + premature ovarian failure. Screen for: cardiac (bicuspid AV, CoA), renal, thyroid, hearing, DM, osteoporosis. Treatment: GH + estrogen replacement.
- Fragile X syndrome: CGG expansion in FMR1 > 200 → methylation → silencing. Most common single-gene cause of intellectual disability and ASD. X-linked. Pre-mutation carriers at risk for FXTAS/FXPOI. Anticipation through maternal transmission.
- Marfan syndrome: FBN1 mutation → loss of TGF-β sequestration → increased TGF-β signaling → aortic root dilation, ectopia lentis, skeletal overgrowth. Treatment: β-blocker + losartan. Revised Ghent criteria for diagnosis.
- Genetic testing ladder: Karyotype → Array CGH (first-line for unexplained DD/ID/MCA) → WES (for undiagnosed rare diseases). WES covers ~1% of genome but ~85% of pathogenic mutations.
- Genetic counselling is non-directive. Present facts, risks, and options. Let the family decide.
Active Recall - The Malformed Child: Hereditary Syndromes and Anomalies
[1] Lecture slides: GC 151. The malformed child hereditary syndromes and anomalies.pdf (all pages) [2] Past papers: 2024 Fourth Summative MCQ.pdf (Q92) [3] Lecture slides: Block C - The malformed child_ hereditary syndromes and anomalies.pdf [4] Past papers: 2025 Fourth Summative MCQ.pdf (Q77) [5] Senior notes: Ryan Ho Cardiology.pdf (p185 — Syndromes associated with CHD) [6] Senior notes: Adrian Lui Pediatrics Notes.pdf (p37-42 — Major Congenital Abnormalities, Dysmorphic Examination) [7] Lecture slides: Neonatal Surgery.pdf (p20 — VACTERL association) [8] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p865 — BWS features)