Short Stature & Musculoskeletal

What drives linear bone growth at the growth plate?

Chondrocyte proliferation and differentiation.

What factors influence stature?

Genes, nutrition, GH/endocrine factors, estradiol, leptin, and environment.

When is growth most rapid?

Prenatally and in early childhood.

What does SHOX haploinsufficiency contribute to in Turner syndrome?

Short stature.

Silver-Russell: key growth pattern?

IUGR with persistent postnatal growth delay.

Silver-Russell: genetic regions?

Chromosome 7 or 11p15 epigenetic changes.

Cornelia de Lange: mechanism and common gene?

Cohesinopathy; NIPBL (~80%).

MOPD II: gene?

PCNT.

MOPD II: notable complications?

Vascular disease, chronic kidney disease, and diabetes.

Coffin-Siris: distinctive digit finding?

5th-digit nail hypoplasia.

Aarskog syndrome: classic genital finding?

Shawl scrotum.

Smith-Lemli-Opitz: gene and enzyme?

DHCR7; 7-dehydrocholesterol reductase.

Bloom syndrome: gene?

BLM.

Bloom syndrome: notable risks/features?

Sun sensitivity, immune abnormalities, insulin resistance, early cancer risk.

Ataxia-telangiectasia: gene?

ATM.

Fanconi anemia: key hematologic feature?

Progressive bone marrow failure with pancytopenia.

Fanconi anemia: commonly implicated gene in lecture?

FANCA (~60%).

Cockayne syndrome: genes?

ERCC6 and ERCC8.

Rubinstein-Taybi: characteristic digits?

Broad thumbs and great toes.

Rubinstein-Taybi: genes?

CREBBP and EP300.

Kabuki syndrome: distinctive finding?

Persistent fetal fingertip pads.

Kabuki syndrome: genes?

KMT2D and KDM6A.

Hutchinson-Gilford progeria: gene?

LMNA.

CHARGE: what does the C represent?

Coloboma.

CHARGE: gene?

CHD7.

Costello syndrome: gene?

HRAS.

Cardio-facio-cutaneous syndrome genes?

BRAF, MAP2K1, MAP2K2, or KRAS.

Beckwith-Wiedemann: key findings?

Macroglossia, macrosomia, hemihyperplasia, neonatal hypoglycemia.

Beckwith-Wiedemann: critical region?

11p15.5 imprinted gene region.

Beckwith-Wiedemann: tumor risks?

Embryonal tumors including Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma.

Sotos syndrome: gene?

NSD1.

Weaver syndrome: gene?

EZH2.

Proteus syndrome: gene and pattern?

AKT1; rapidly progressive segmental overgrowth.

PTEN hamartoma tumor syndrome: gene?

PTEN.

PTEN-associated cancer risks listed in lecture?

Breast, thyroid, kidney, endometrial, and colon.

PIK3CA-related overgrowth includes which named syndromes?

MCAP, CLOVES, and Klippel-Trenaunay.

What intake information helps evaluate stature?

Prenatal/delivery history, parental heights, family history, growth charts, development, dentition, skin/hair/nails.

What is a neuromuscular disorder?

A disorder affecting motor/sensory nerves, muscles, or nerve-muscle communication.

What do motor neurons control?

Movement by transmitting signals from CNS to muscles.

What do sensory neurons transmit?

Sensory information from receptors to the CNS.

SMA primarily affects which motor neurons?

Lower motor neurons (anterior horn cells).

SMA inheritance and primary gene?

Autosomal recessive; SMN1.

What is the most common molecular cause of SMA?

Homozygous deletion of SMN1 exon 7 (~95%).

How does SMN2 modify SMA?

More SMN2 copies generally mean a less severe phenotype.

SMN1 vs SMN2 protein production?

SMN1 makes full-length SMN; SMN2 mostly makes unstable protein lacking exon 7.

Which SMN2 copy range is associated with likely SMA type 1 in the lecture?

1–2 copies.

Which SMN2 copy range is associated with likely SMA types 3/4?

4–5 copies.

ALS weakness pattern?

Asymmetric progressive weakness/atrophy, often starting in one region and spreading.

What proportion of ALS is estimated monogenic in the lecture?

10–15%.

Most common genetic cause of ALS in lecture?

C9orf72 G4C2 hexanucleotide repeat expansion.

C9orf72 repeat location?

Intron 1.

SOD1-related ALS: inheritance and penetrance?

Typically AD (can be AR); incomplete penetrance.

DMD/BMD gene and inheritance?

DMD; X-linked.

DMD clinical clues?

Early motor delay, waddling gait, Gowers sign, calf hypertrophy, progressive proximal weakness.

How does BMD generally differ from DMD?

Later onset and slower progression.

DMD/BMD reading-frame rule?

In-frame changes → BMD; out-of-frame changes → DMD (~90% rule).

What proportion of DMD/BMD cases are inherited from the mother?

About two-thirds; about one-third are de novo.

What is myotonia?

Inability to relax muscles.

myotonic dystrophy t1 gene and repeat?

DMPK; CTG expansion in 3' UTR.

myotonic dystrophy type 1 anticipation: which inheritance direction is highlighted?

Maternal inheritance.

myotonic dystrophy type 2 gene and repeat?

CNBP; CCTG expansion in intron 1.

Does myotonic dystrophy T2 show anticipation?

No.

FSHD most affected muscle regions?

Face, shoulder blades, and upper arms.

What is scapular winging associated with?

FSHD.

FSHD1 requires what two features?

D4Z4 repeat contraction (1–10) and permissive 4qA haplotype.

What does D4Z4 contraction do in FSHD1?

Promotes hypomethylation and DUX4 expression.

Why is 4qA permissive in FSHD?

It contains a polyadenylation signal that stabilizes DUX4 transcript.

What is the key genetic combination in FSHD2?

SMCHD1 (or rarely DNMT3B/LRIF1) pathogenic variant plus 4qA.

CMT1A: molecular cause?

PMP22 duplication at 17p11.2.

CMT typical pattern?

Slowly progressive symmetric distal weakness/atrophy with sensory loss.

HNPP: molecular cause?

PMP22 loss of function, usually recurrent 1.5 Mb deletion.

What triggers HNPP episodes?

Pressure on nerves (e.g., leaning on elbows or crossing legs).

CMT1A vs HNPP dosage distinction?

CMT1A = PMP22 duplication; HNPP = PMP22 deletion/loss of function.

Friedreich ataxia: gene and inheritance?

FXN; autosomal recessive.

Friedreich ataxia: repeat expansion?

GAA expansion in intron 1.

Friedreich ataxia: important non-neurologic complications?

Cardiomyopathy (about 2/3) and diabetes (about 3/10).

Does Friedreich ataxia show anticipation?

No.

Nusinersen: route and mechanism?

Intrathecal; modifies SMN2 splicing to increase functional SMN protein.

Zolgensma: mechanism?

Viral vector introduces functional SMN1; one-time IV infusion.

Risdiplam: route and mechanism?

Daily oral SMN2 splicing modifier that increases SMN protein.

Elevidys: what does it deliver?

A gene leading to production of shortened micro-dystrophin.

What do DMD exon-skipping therapies do?

Restore the reading frame for eligible variants.

Tofersen targets what molecule?

SOD1 mRNA; promotes its degradation and reduces SOD1 protein.

What does CK indicate in neuromuscular evaluation?

Muscle damage can release CK into blood; it may be elevated in some disorders.

What does EMG evaluate?

Electrical activity of muscle and function of muscle, nerve, and their communication.

What do nerve conduction studies measure?

Speed and strength of nerve signals.

What does SMA newborn screening detect?

SMN1 exon 7 copy number; not rare variants or SMN2 dosage.

What is a silent SMA carrier [2+0] configuration?

Two SMN1 copies on one chromosome and a deletion on the other.

What variant is linked to silent SMA carrier status in the lecture?

SMN1 c.*3+80T>G.

What does optical mapping assess for FSHD?

D4Z4 repeat number and presence/absence of permissive 4qA alleles.

SBMA is also known as what?

Kennedy disease.

SBMA gene, inheritance, and repeat?

AR gene; X-linked; CAG expansion in exon 1.