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.

Different mutations at different domains of FGFR3 cause a spectrum of skeletal dysplasias of varying severity: ^[1]

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

• 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]

Lecture slide: posture and seating measures intended to reduce fixed thoracolumbar kyphosis 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
• Avoiding excess weight, assessed on achondroplasia-specific charts

The slide's specific "25th percentile" target is not a universal current recommendation. Current AAP guidance instead advises serial length/height, weight, head circumference, and BMI assessment using achondroplasia-specific charts, alongside practical nutrition and activity support. ^[9]

The lecture shows an older AAP health-supervision table. ^[1] Current practice should be anchored to the 2020 AAP clinical report rather than copying the old schedule verbatim. ^[9]

Selected high-yield screening recommendations:

The slide references advances in treatment: CNP analogue (vosoritide), meclozine, and Peptide P3 as therapeutic strategies. ^[1]

Vosoritide is a CNP analogue. The current US label indicates it to increase linear growth in paediatric patients with achondroplasia who have open epiphyses; approval is based on improved annualized growth velocity, and treatment is stopped when the epiphyses close. It does not replace surveillance or treatment of foramen-magnum, respiratory, hearing, or orthopaedic complications. ^[10]

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]

The slide shows karyotypes: 45,X; 45,X/47,XXX; 46,X,idic(X)(p11.1) ^[1]

Cytogenetics of 196 women attending Adult Turner clinics (Middlesex and Oxford Radcliffe hospitals, UK): ^[1]

Lecture-era estimate: "Only 1% of embryos survive to term" and "7-10% of spontaneous abortions" are historical figures shown on the slide. They should not be used as contemporary individual prognostic estimates. ^[1]

Why is fetal loss high? The mechanism is incompletely understood. Haploinsufficiency of genes that escape X-inactivation, including pseudoautosomal genes, contributes to abnormal lymphatic and cardiovascular development; severe fetal presentations can include cystic hygroma and hydrops.

Affects approximately 1/2,500 live female births. ^[1]

Short stature and ovarian insufficiency - the slide uses the older phrase "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 ovarian insufficiency? X-chromosome abnormalities can accelerate follicular loss. Pubertal development and fertility are variable, particularly with mosaicism; some individuals have spontaneous puberty, menarche, or pregnancy. Assess ovarian function rather than assuming absent puberty from phenotype or karyotype. ^[11]

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.

The percentages above are the lecture's cohort-era estimates and vary substantially by karyotype, age, ascertainment, and imaging method. Use them to remember the systems involved, not as fixed counselling figures; the current guideline reports, for example, a much wider 14-40% range for bicuspid aortic valve. ^[1][11]

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

Historical slide warning: The displayed health-supervision table is from 2003 and is not the current schedule. The 2024 international Turner guideline supersedes it for contemporary care. ^[11]

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. A single arm blood-pressure value or pulse pressure does not diagnose coarctation; assess upper- and lower-limb pressures, femoral pulses, and cardiac imaging. ^[4][11]

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: approximately 5-44
  • Intermediate ("grey zone"): approximately 45-54
  • Premutation: approximately 55-200
  • Full mutation: n > 200
• Full mutation → hypermethylation (M) of the FMR1 promoter → silencing of FMR1 → loss of FMRP protein → Fragile X syndrome

The lecture's older cut-offs (normal 6-50; premutation 60-200) omit the intermediate category. Current interpretation also considers methylation, somatic mosaicism, laboratory measurement uncertainty, family history, and AGG interruptions when estimating expansion risk. ^[12]

From first principles:

• FMRP (fragile X messenger ribonucleoprotein 1; older expansion of the abbreviation used "mental retardation protein") is an RNA-binding protein important in synaptic function and local translation.
• 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 reports a full-mutation-sized result in the boy and a 65-repeat premutation in his mother. Personal identifiers visible in the slide are intentionally not reproduced here. ^[1]

• The mother is a premutation carrier (65 repeats). Premutation carriers often have typical intellect and appearance but have age- and sex-dependent risks including:
  • 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) - impaired ovarian function before age 40 in some carriers
• Expansion risk: Premutations can expand during maternal transmission, but the probability is not determined by repeat count alone; repeat length, AGG interruptions, and family context matter. ^[12]

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: ASD is genetically heterogeneous. The synapse diagram is a map of convergent pathways, not a diagnostic algorithm: a clinical phenotype cannot identify which gene or copy-number variant is involved. FMR1 repeat testing is a targeted assay; a typical exome or genome pipeline does not reliably replace it. Current GeneReviews suggests FMR1 testing for unexplained developmental delay/intellectual disability and for selected unexplained ASD presentations, especially when phenotype or family history raises suspicion. ^[12]

The lecture shows a synapse schematic (Dolen & Bear, 2009) mapping monogenic ASD causes to specific molecular targets: ^[1]

These pathways converge on synaptic protein synthesis and plasticity. The arrows are a mechanistic model from 2009, not proof that every ASD phenotype results from one shared pathway or that a pathway diagram can establish a molecular diagnosis. ^[1]

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)

The lecture references a review (Chung & Tao, J Formosan Med Assoc 2014) summarising CNV loci in ASD: ^[1]

How to read the CNV table: It summarizes small 2014-era cohorts, and some rows were not statistically significant. CNVs can show variable expressivity, incomplete penetrance, and pleiotropy; finding a CNV requires formal laboratory classification and phenotype/family correlation rather than one-to-one syndrome matching. ^[1]

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]

The visual point is allelic heterogeneity: pathogenic variants are distributed across FBN1, rather than being confined to one hotspot, and different variant classes can produce overlapping phenotypes. The pictured 2008 report uses historical variant nomenclature; a contemporary report should identify transcript/build, HGVS description, zygosity, classification, evidence, and phenotype correlation. A pathogenic variant supports diagnosis only within the revised Ghent framework.

From first principles:

• FBN1 (chromosome 15q21.1) encodes fibrillin-1, a glycoprotein that is the main component of microfibrils in the extracellular matrix (ECM).

Marfan syndrome incidence: 2–3 per 10,000 individuals. Approximately 25% of probands have a de novo mutation. Inheritance: autosomal dominant. ^[1]

• Microfibrils serve two functions:
  1. Structural: Provide scaffold for elastic fibers (especially in aortic wall, suspensory ligament of lens, periosteum)
  2. Regulatory: Sequester TGF-β in the ECM, keeping it inactive.

Loss of docking protein FBN1 increases TGF-β1 signalling. ^[1]

This is the mechanistic model emphasized in the lecture:

• When fibrillin-1 is deficient/dysfunctional → microfibrils cannot sequester TGF-β → increased free TGF-β signaling → excess downstream effects including:
  • Aortic wall: Smooth-muscle and extracellular-matrix dysfunction (often termed medial degeneration) → 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]

The mouse histology and early human graphs on slides 45-47 are mechanistic and historical evidence, not a current head-to-head prescribing rule. Current ACC/AHA guidance recommends either a beta-blocker or an angiotensin-receptor blocker at a maximally tolerated dose for Marfan aortopathy; selected patients may receive both under specialist care, but combination therapy is not the universal wording of the recommendation. Aortic imaging and timely prophylactic surgery remain essential. ^[13]

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

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 relative copy number: balanced colour suggests equal dosage; a patient- or control-dominant signal suggests gain or loss
• Detects: Genome-wide copy-number gains and losses, with resolution determined by platform/probe density; SNP-containing arrays can add information about regions of homozygosity and some forms of uniparental disomy
• Usually does not detect: Balanced rearrangements, most single-nucleotide variants or small indels, and repeat expansions; sensitivity for mosaicism depends on tissue, platform, event size, and cell fraction

The preceding normal karyotype and subsequent 22q13 array result in the slides demonstrate the resolution difference: a karyotype can miss a submicroscopic deletion that chromosomal microarray detects. Neither test is globally "better" - karyotype remains useful for aneuploidy and balanced structural rearrangements, while targeted assays remain necessary for repeat expansions such as FMR1.

Whole-Exome Sequencing (WES) is applied in Paediatric Rare Diseases. ^[1] Human exome accounts for about 1-1.5% of the genome. The slide's "85% of pathogenic mutations" is a historical teaching estimate, not the sensitivity of an exome test. One haploid reference genome contains roughly 3 billion bases; a diploid person's two copies contain roughly 6 billion. Please be aware that when a genetic report says "exome", usually it's representing just ~90% of the whole exome. ^[1]

The apple/orange graphics communicate that exome sequencing samples only the protein-coding fraction, not that it captures a fixed percentage of every disease mechanism. NHGRI describes the exome as about 1.5% of the roughly 3-billion-base haploid genome. ^[16]

Limitations and contemporary use of ES/GS:

• Coverage and callable regions vary by laboratory; some exons remain poorly covered
• Exome sequencing is weak for many non-coding variants, repeat expansions, methylation/imprinting abnormalities, some structural variants, and low-level mosaicism unless the assay and pipeline are designed for them
• Genome sequencing broadens accessible sequence and structural-variant detection but still does not replace every targeted biochemical, cytogenetic, repeat, or methylation assay
• Both can return variants of uncertain significance, secondary findings, or no diagnosis; consent and phenotype-informed interpretation are essential
• ACMG recommends considering exome or genome sequencing as a first- or second-tier test for children with congenital anomalies, developmental delay, or intellectual disability - not only after a mandatory karyotype-to-array-to-exome ladder. ^[15]

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]

The photographs show abnormal hand/arm posturing and later wheelchair dependence. They illustrate the evolution from focal lower-limb symptoms to generalized motor disability; they do not identify the gene by appearance.

WES identified a de novo heterozygous nonsense mutation in KMT2B (c.2425C>T, p.Q809) → this led to discovery of a new disease entity: KMT2B-related early-onset generalized dystonia (4 families, 6 patients initially → 27 patients subsequently).* ^[1]

KMT2B (also known as MLL4) encodes a histone lysine methyltransferase critical for gene expression regulation, genomic stability, and normal development. Heterozygous loss-of-function variants cause a complex, progressive childhood-onset dystonia with cervical, cranial, and laryngeal involvement. ^[1]

Early lecture-era cohort: most conventional medicines had no functional benefit, while nine people receiving DBS were reported to improve. ^[1]

Why this case matters: The visual sequence - progressive leg-to-arm dystonia, a long negative investigation list, exome result, then near-simultaneous cohort reports - shows how data sharing and reanalysis can turn an undiagnosed phenotype into a molecular diagnosis. Current evidence is more nuanced than "DBS always works": anticholinergic treatment can help some people, GPi-DBS often gives substantial improvement, but response varies by body region and gait or laryngeal dystonia may persist or worsen. Management belongs with a specialist movement-disorder team. ^[17]