Endo: Genetics Abnormal Growth

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Social status and tallness

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Tallness positively correlated with social status, perceived competence, financial and other success

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Genetics of heigh

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Multifactorial trait, 90% genetics, 10% environmental

Environmental factors: Timing of puberty, nutrition, prenatal environment. Maternal GRANDMOTHER nutrition (b/c mother as fetus making eggs and methylation status determined).

Genetics: Height is determined by >180 Quantitative trait loci (QTLs) - each locus either gives or takes away from baseline height of 150 cm (eg IL11 and SMAD3 with 6-8mm reduction)

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Short stature definition

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<2SD, for some it is <1.3 SD though

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Head circumference role in children, length and weight tables

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Measured at max circumference and a surrogate marker for brain growth. Estimates volume and works ONLY IF head is normal shape.

Compare to population, ethnic variances not taken into account

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Evaluation of Short Stature

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Age of onset - prenatal, post-natal, older (when falling behind)

Proportionate vs disproportionate - tells systemic (endocrine/metabolic) or local (skeletal). See if one of main three growth parameters is affected more than others (head circumference, weight and length). Seen in achondroplasia vs marfans

Symmetric vs asymmetric - is everything affected same or something more than others. Ex nutritional FTT is asymmetric and affects weight>height>OFC. Height and nutrition is rare and would have to be VERY longstanding. Whereas, genetic is symmetric and weight-height-OFC are all about same

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Short stature pt, weight and length both same degree away from norm, can they have nutritional FTT

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NO, not the main pathology b/c nutrition primarily asymmetrically affects weight

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Of the three measurements an asymmetric deficiency in which one is worst

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Head circumference, lowest long term survival

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Def
a) Rhizomelic
b) Mesomelic
c) Acromelic

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a) Rhizomelic - shortness affecting femur and humerus portions more
b) Mesomelic - shortness affecting forearms and lower legs more
c) Acromelic - shortness affecting fingers and toes/hands and feet most

Use body proportions to evaluate

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Primary vs Secondary short stature, causes, Presentation, Types, Idiopathic

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Secondary - due to EXTRINSIC factors
Causes: nutritional, GI, endocrinologic, metabolic, iatrogenic, psycogenic; but can be genetic ex CF causing GI malabsorption
Presentation: DELAYED bone age, PROPORTIONATE small size. Normal birth length/weight, medical eval norm.

Idiopathic - "constitutional growth delay" - don't hit puberty till late teens and grow in college, strongly genetic but normal varient. Bone age will be below but consistent with size


Primary - due to INTRINSIC abnormalities
Can be generalized (all cells) or localized (bone and CT)
Presentation: Often prenatal in onset, and often with a genetic abnormality, may have dysmorphia
Types:
a) Proportionate - Chromosomal aneuplodies (eg Trisomy 21, 18), single gene (Seckles syndrome)
b) Disproportionate - Skeletal dysplasias (achondroplasia), abnormal bone metabolism

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Wolf-Hirschhorn Syndrome

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4p-

Less cells in the body

Primary short stature cause, proportionate

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Single gene mutation cause for short stature

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Njimegen breakage syndrome - underlying gene defect affects the way DNA is made or repaired

Will have a child verys mall compared to siblings

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Imprinting Defects cause for short stature

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Russell silver Syndrome -

Spared head size with proportionately. small b3odies due to an imprinting defect that is mirror image to Beckwith Wiedmann defect (which has "bigness")

50% by mat UPD10, 5% by mat UPD 7

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Primordial dwarfism

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Individuals dramatically small, but PROPORTIONATE

Diminished life span and intellectual capacity, no known gene cause may have something with DNA repair or replication

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Pituitary dwarfism

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Any issue with GH axis from hypothalamus-pituitary-liver

GH resistance, insufficiency, etc

Subtly different but consistent phenotypes of small size

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Skeletal Disorders Short Stature Keys, Dx, 2 main types

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Rare but present, clinically distinct but many gene causes (CT, extracellular matrix, transcription factors)

Key: DISPROPORTIONATE, X-rays are key for skeletal dysmorphia

Achondroplasia - most common, relative MACROCEPHALY and body well below height curve, UPPER LIMBS more affected, forearms and lower legs, hands and feet also small. TRIDENT FINGERS, bowing of legs, Squared iliac crest, increased sciatic notch. X-ray gives ID and can get confirmatory gene test

Thanatophoric dysplasia - much more dramatic, prenatal skeletal dysplasia detected (rare to detect one of these so usually this), lethal

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Prenatal detection of skeletal dysplasia

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via ultrasound

Before week 24 see femur and or other long bone, if detect dysplasia send to specialist

Evaluate:
Malformed bones, ratio of long bones (femur to foot)
Chest circumference: abdominal circumference and/or abdominal circumference/femur length and predict lethality

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Clinical Disorders Associated with Type II collagen mutations

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Range in severity from mild to severe: from familial osteoarthritis to Stickler syndrome to SED to Kneist syndrome to hypochondrogenesis to achondrogenesis

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Spondyloepiphyseal Dysplasia Congenita Genetics, Presentation, Detection role

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Genetics: AD short trunk dwarfism, SED tarda due to mutations in sedlin (Xp22)

Presentation: Long fingers, cleft palate, MYOPIA/retinal detachment, SUBLUXATION C1/C2 with odontoid hypoplasia, early osteoarthritis, waddling gate. NORMAL intelligence

Children have extremely short thorax due to spinal vertebral compression

Detection role: early detection impt to prevent skull from slipping off vertebral column and killing them

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Kniest dysplasia Genetics, Presentation

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Presentation: Normal intelligence w/ DELAYED MOTOR & SPEECH, Craniofacial - LARGE HEAD, midface HYPOPLASIA, myopia/retinal detachment, SNHL, cleft palate

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Hypo/Achondrogenesis II Clinical, Presentation

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Most lethal form of Type II collagenopathy

Clinical: neonatal lethal, SHORT BARREL CHEST, short limbs, HYDROPS, cleft palate

Rx: Unossified cervical and lumbar vertebrae, pubic bones, short broad bones with metaphyseal cupping.

Found around 24 weeks gestation and one of most common reasons for medical abortions b/c lethal to baby

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Overgrowth overview
a) too big
b) too chubby
c) segmental overgrowth
d) too tall

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a) too big - Beckwith Wiedemann
b) too chubby - Prader Willi syndrome; leptin
c) segmental overgrowth - Proteus syndrome
d) too tall - Marfan's syndrome

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Beckwith Wiedeman Syndrome Genetics, Triad, Other findings, metabolic findings, Associations, Growth Pattern

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Genetics: imprinting syndrome (mirrors russell silver) , PATERNAL UPD problem

aka EMG

Triad - Exomphalos (omphalocele), Macroglossia, Gigantism

Other - organomegaly, HEMIHYPERTROPHY, helical pits/creases, glabellar nevus flamus

Metabolic findings: neonatal hypoglycemia due to islet cell hyperplasia; can lead to intellectual disability if not corrected

Associations: Wilm's tumor or hepatoblasoma or adrenal tumor (esp if hemihypertrophy), associated with assisted reproductive technology, preterm delivery

Growth pattern - normal IQ, above height and weight curves, usually slows down

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Single gene obesity

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Obesity is hard to treat and usually multifactorial

20% of morbid obesity is due to SINGLE gene. One of 20 known genes/loci (ex LEPTIN or leptin receptors) that run along neuro-endocrine axis from brain to adipocyte

Can sometimes treat with leptin replacement

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Segmental Overgrowth Disorders, Categories

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Conditions in which one segment of the body is much larger than the rest. 2 explanations

a) Vascular anomaly
Kippel-Trenaunay Weber - one part of body has vascular defects, enlarges, dysfunctional and atrophies
b) Genetic mosaicism - hallmark is PIGMENT differences on one side of body
1) hypomelanosis of Ito
2) Hemihypertrophy (BWS variants)
3) Proteus syndrome - activating mutation of AKT1 gene which is ONLY present in overgrown tissue (and all tissues in area - bone, muscle, dermis, lymphatic), Moccasin foot malformation is the classic finding, can also see macrodactyly, very variable and disfiguring

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Marfan's Syndrome Dx Criteria, Genetics, Presentation, Pathology

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Very tall with arms and legs longer than expected for height.

Arm span ratio >1.05 be suspicious (1.07 for sub-saharan africans)

Genetics: 1:5k, 75% inherit, 25% de novo,
Fibrillin 1 (FBN-1) gene or TGFBR1/2 (Leoys Dietz syndrome)

Dx: Req 2 + some involvement of third of: Cardiovascular, skeletal, ocular, family history (+ diagnosis in FDR)

Presentation: Dolichostenomelia (arm span/height >1.05), Arachnodactyly (thumb sign, wrist sign),

Pathology: Fibrillin acts as a buffer for TGF-B, molecule which breaks down ECM, overactivity of TGF-B (due to fibrillin defect) is root of CT findings, TGFB is downstream of effects of fibroblast growth factors so FGFs supposed to be ddoing something slowing down skeletal development

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Drug used in Marfan's role

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Losartan

Inhibits AT1 activation. This blocks TGF-beta activation by inhibiting Tsp-1 production

Get muscle regeneration, slows down and may even reverse aortic dilation (can lead to aneurysm in pts)

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FGFR3 KO in mice

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TGFB is in the FGFR3 pathway

Hypermorphic FGFR3 changes lead to skeletal dysplasias like achondroplasia

KO in mice leads to Marfan like phenotype, heterozygote loss is normal phenotype

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Did Lincoln have Marfan's?

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No need 2 categories and some of a third

Family history - neg
Skeletal - pos
Ocular - FAR sighted (not nearsighted)
Cardiac - no evidence on autopsy

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Gynecomastia causes

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Excess estrogen - pituitary dysfunction, thyroid disease can cause

Kleinfelter Sydnrome

Normal aging

17-ketosteroid reductase deficiency - can cause male pseudohermaphroditism (blocks weak to strong androgen converstion); Late onset form (testicular) causes hypogonadism and gynecomastia in adult men due to decreased testosterone and increased estrogen. May have been Napoleon