Turner Syndrome2

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MYH, 9/F

CC: SHORT STATURE


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History of Present Illness

5 yrs PTC Noted to be the shortest in class

10 monthsPTC

Consult with another endocrinologistFBS, BUN, SGPT, Crea, CBC, UA, Stool,FT4 and TSH: NormalGrowth Hormone: 1.43 ng/mL (NV 0.01-10)Referred to Dietician

1 yr PTC Referred by a family friend toEndocrinologist

CA: 8 1/12 yrs; BA: 5 yrsLevothyroxine 25 mcg/tab, tab OD x 3months

CONSULT


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BIRTH/MATERNAL HISTORY:

Born Term to a 34 year old G3P2 via NSD. No illnesses orcomplications during pregnancy and at birth.

BW: 5 lbs

FEEDING HISTORY: Purely breastfed for six months; started on solids at six

months of age. On mixed diet with good appetite.

DEVELOPMENTAL HISTORY:

At par with age. Currently in Grade 3 with good academicperformance.


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FAMILY HISTORY:

(+) Short stature: Mother; uncle, aunts andgrandparents on maternal side


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Review of Systems

No weight loss

no headache

no seizuresno cough

no difficulty of breathing

no chest pain

no cyanosis

no dysuria/oliguria/polyuria

no edema


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Physical Examination

Conscious, coherent, ambulatory, not incardiorespiratory distress

HR 135 bpm RR 21 cpm BP 100/80 Wt 19 kg (42 lbs) (


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No tragal tenderness, nonhyperemic externalauditory canal, intact tympanic membraneboth ears

Midline septum, turbinates not congested, nonasoaural discharge; high arched palate

Moist buccal mucosa, nonhyperemicposterior pharyngeal wall, tonsils notenlarged

No neck webbing, no CLADS


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Symmetrical chest expansion, clear breath sounds

Adynamic precordium, normal rate, regular rhythm,Apex Beath 5th LICS MCL, no murmurs; (-) shield

chest appearance Flabby abdomen, normoactive bowel sounds, no

tenderness, no palpable masses/organomegaly

No cubitus valgus, no nail dysplasia, No cyanosis, no

edema, full and equal pulses Tanner Stage I

Cranial nerves intact, cerebellar intact, gait normal,DTRS: +2-+3 , no tremors


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F: 165.1cm

M: 147 cmMPH: 149.5cm

(144.5-154.5cm


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Work Up

FT4, TSH

Glucose

Prolactin

BUN/Crea

SGOT/SGPT

Ca, P)4

Growth Hormone Stimulation Test using oral

clonidine MRI Brain w/ contrast

Bone age: 6 yrs old

Karyotyping


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TURNER SYNDROME


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Definition

Loss or abnormality of thesecond X chromosome in atleast one cell line in aphenotypic female

Donaldson 2006

Combination of:

1) Characteristic physical features

2) Complete or partial absence of

second sex chromosome, withor without cell line mosaicism

Saenger et al. 2001

Saenger et al, Recommendations for the Diagnosis and Management of Turner Syndrome, 2001

Donaldson MDC. Optimising management in Turner syndrome: from infancy. Arch Dis Child 2006;91:513520


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Incidence and prevalence

Prenatal studies (chorionic villus sampling)

Week 11: 392/100,000 female fetuses

Week 16: 176/100,000

Peak intrauterine mortality: week 13

Postnatal studies

25-210/100,000 females

Gravholt. Epidemiological, endocrine and metabolic features of Turner Syndrome. 2004.


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MorbidityDisease Relative Risk

Endocrine

Hypothyroidism 5.8

Thyroiditis 16.6

Type 1 DM 11.6

Type 2 DM 4.4

Cardiovascular disease Ischemic heart disease

and arteriosclerosis 2.1

Hypertension 2.9

Vascular disease of the brain 2.7

Others

Liver cirrhosis 5.7

Osteoporosis 10.1

Fractures 2.16

Cancer (colonic and rectal) 4.94



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Mortality

Increased in Turner Syndrome

Relative risk of death: 4.2

Due to diseases in the nervous, digestive,cardiovascular, respiratory and genito-urinarysystems

Increased 3-fold especially in females with

congenital malformations Aortic dissection: 3 cases



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Table 2 Distribution of all prenatal and postnatal Turner

syndrome karyotypes



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Clinical Features

Davenport. Approach to the patient with Turner Syndrome. 2010.


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Redundant Nuchal Skin and Puffiness of the Hands and Feet in Turners Syndrome


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Feature Frequency (%)

1. Retarded growth and reduced adult

Height 951002. Gonadal dysgenesis No pubertal development 85 Infertility 98 Chronic estrogen deficiency 9598 Androgen insufficiency ?

3. Endocrine disturbances Glucose intolerance 1550 Type 2 diabetes 10

Type 1 diabetes ? Thyreoiditis 15 Elevated hepatic enzymes 5080 Hypertension 50 Android body composition ?



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4. Physical abnormalities Frequency %

Eyes

Epicanthus (mongol-fold) 20

Nearsightedness 20

Strabismus 15

Ptosis 10

Ears

Infection of middle ear 60

Hearing defects 30

Deformity of external ear 15Mouth

Micrognatia (small mandibular bone) 60

High arched palate 35

Abnormal dental development ?

Neck

Low posterior hairline 40

Broad short appearing neck 40

Pterygium colli (webbed neck) 25

Excess loose skin in the back of the neck of newborns 25



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Thorax Frequency %

Broad chest (shield chest) with widely spaced nipples 30

Inverted nipples 5

Skin, nails, and hair

Increased skin ridge count 30Lymphoedema of hands and feet at birth (or later) 25

Multiple pigmented naevi 25

Nail hypoplasia 10

Vitiligo 5

Alopecia 5

Skeleton

Bone age retardation 85

Decreased bone mineral content 5080

Cubitus valgus 50

Short 4th metacarpal 35

Genu valgum 35Congential hip luxation 20

Scoliosis 10

Madelungs deformity 5



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Heart Frequency %

Bicuspid aortic valves 1434

Coarctatio aortae 714Aortic dilation/aneurysm 342

Kidneys

Horseshoe kidney 10

Abnormal positioning or duplication of renal

pelvis, ureters or vessels 15Renal aplasia 3

5. Psychosocial problems*

Emotional immaturation 40

Specific learning problems 40

Mental problems 25

Neurocognitive deficits ?

6. Others

Poor thriving during 1st year of life 50



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Pathophysiology X chromosome: >1000 genes

Y chromosome: ~200 genes

One of the X chromosomes

is silenced in the somatic cells

of females Pseudoautosomal genes

15-20% of the silent X chromosome that continues to beexpressed

Have homologous genes in the Y chromosome

Clustered in the tip of the X short arm HAPLOINSUFFICIENCY: loss of an entire sex

chromosome/ a portion of the X chromosome thatincludes the tip of the short arm



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Pathophysiology

Short Stature Haploinsufficiency of the short-stature homeobox

containing gene on the X-chromosome (SHOX)

SHOX: family of homeobox genes, transcriptional

regulators and key controllers of developmentalprocesses

Involved in longitudinal growth and bonedevelopment

Suggested that it represses growth plate fusionand skeletal maturation, but cannot explain allgrowth reduction in Turner syndrome

Davenport. Approach to the patient with Turner Syndrome. 2010.Gravholt. Epidemiological, endocrine and metabolic features of Turner Syndrome. 2004.


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Pathophysiology

Short Stature Embryogenesis: specific skeletal abnormalities

such as cubitus valgus, genu valgum, short 4thmetacarpals

Localized in 1st and 2nd pharyngeal arches from 6wks AOG onwards

High palate, prominent ears, chronic otitis media,obstructive sleep apnea, increased sensitivity to

noise, problems in sucking, blowing, eating andarticulating



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Short Stature

Growth hormone: bioactivity is reduced, 24H GH excretion

is low, normal increase in puberty is absent, fewerpulses at night

IGF-1:

effector hormone of some of the actions of GH

Uniformly reduced during childhood; pubertal rise

absent; diminished bioactive fraction ofcirculating IGF-1



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Pathophysiology

Gonadal dysgenesis

Haploinsufficiency of multiple genes on both armsof the X chromosome, in addition to pairing failure

during meiosis

Germ cell development is normal, but withaccelerated loss of oocytes by 15 wks AOG



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Gonadal failure

Occur in most individuals with TS

Accelerated loss of oocytes in the 45, X ovary,leaving few follicles in a fibrous streak by

birth 1/3 have spontaneous puberty but only half of

these complete puberty with menarche

Exagerrated biphasic pattern ofgonadotropin secretion: very high in infancyand at 9-11 yrs of age (menopausal levels)



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Estrogen Deficiency

Causes several problems associated with Turnersyndrome

Aromatase and estrogen receptors are

expressed in reproductive and nonreproductivetissues

Estradiol deficiency: Cancellous bone loss

Endothelial dysfunction Decreased insulin production Abnormal lipid pattern Increased central adiposity Early atherosclerosis


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DiagnosisAlways consider Turner syndrome in any female patient with an

unexplained growth failure or pubertal delay

Karyotyping1. All girls with short stature (


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Indications for karyotyping

Newborn infant

Any age:

cubitus valgus, nail hypoplasia, hyperconvex uplifted nails, multiplepigmented nevi, characteristic facies, short fourth metacarpal, and higharched palate extensive and chronic problems with otitis media

edema of the hands or feet

nuchal folds

left-sided cardiac

anomalies low hairline, low set ears,

and small mandible

short stature with declininggrowth velocity (growth velocity10th percentile for age)

markedly elevated levels of FSH

absence of breast developmentby 13 yr of age

pubertal arrest

primary or secondaryamenorrhea with elevated levelsof FSH


Childhood

Adolescence


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Work Up Cardiac evaluation: complete PE and 2D Echo; repeat 2D Echo at

adolescence Hypertension: Blood pressure at each PE

Renal evaluation: renal ultrasound

Thyroid function: TSH and FT4 at diagnosis and every 1-2 yrs

Glucose intolerance

Weight: obesity

ENT small and retrognathic mandible Outer ear: mild malformation, low set ears Middle ear: otitis media

Inner ear: sensorineural hearing loss Speech problems

Opthalmologic evaluation: strabismus, amblyopia and ptosis

Orthopedic: congenital hip dislocation

Lymphedema



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Bondy. Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group. J Clin Endocrinol 2007.


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SYSTEM TIMING CLINICAL ISSUE INTERVENTION


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AUDITORY At diagnosis and every one tofive years thereafter

Childhood

Sensorineural Hearing Loss

Recurrent Otitis Media

Hearing evaluation; audiology; hearing aids

Pressure-equalizing tubes for middle ear effusion inpatients older thanthree months

BONES From 10 years of age toadulthood

First adult office visit

Mid- to late adulthood

Osteopenia; osteoporosis

Bone mineral density

Osteoporosis

Elemental calcium (1,200 to 1,500 mg perday); vitamin D supplementation;

Appropriate estrogen therapy; exerciseBaseline dual energy x-ray absorptiometry

scanBisphosphonate therapy (if high risk)

CARDIO

VASCULAR

At diagnosis

Every five to 10 years

All ages

Older girls/adulthood

Congenital heart defects

Aortic root dilatation

Hypertension

Hyperlipidemia

Cardiovascular evaluation;2Dechoor MRI; ECG

Echocardiography or MRI

Blood pressure in all four extremities

Annual fasting lipid screening

DENTAL Seven years and older Malocclusion and other toothanomalies

Orthodontic Evaluation

GENETICAll ages Presence of Y chromosomematerial Laparoscopic gonadectomy to preventgonadoblastoma

IMMUNE At diagnosis and annuallythereafter

Every two to four years afterfour years of age

Thyroiditis (hypo- orhyperthyroid)

Celiac disease

Thyroid function tests (i.e., thyroxine and thyroid-stimulating hormone levels)

Tissue transglutaminase immunoglobulin Ameasurement

HEPATIC Every one to two years after six

years of age

Liver enzymes persistently

elevated for more than six

Ultrasonography to evaluate for hepatic steatosis;

hepatology consult


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LYMPHATIC Usually younger than twoyears of age

Lymphedema Support stockings; decongestive physiotherapy

METABOLIC Older girls/adulthood

All ages

Diabetes

Obesity

Annual fasting plasma glucose screening

Target body mass index less than 25 kg per m2

SKELETAL/GROWTH

Nine to 24 months of age toadulthood (bone age of 14years)

Infancy to four years of age

Teenagers

Short stature (i.e., more thantwo standard deviations belowthe mean)

Hip dislocation

Scoliosis; kyphosis

Human growth hormone with or without oxandrolone(Oxandrin)

Physical examination with Barlow/Ortolani maneuvers

Physical examination with a scoliometer

PSYCHOLOGIC-AL

All ages Self esteem; learning issues Psychoeducational evaluation (school based); support

OPHTHALMO-LOGIC

At diagnosis if older than oneyear

Strabismus; hyperopia Ophtalmologic evaluation

RENAL At diagnosis Renal malformations Renal ultrasound

REPRODUCTIVE Preteen

Adulthood

Puberty

Planned pregnancy

Infertility

Estrogen deficiency

Estrogen therapy

Echocardiography or cardiac MRI; high-risk consult

Assisted reproduction or infertility consult

Female sex hormone replacement


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Management of Growth Failure

Growth Failure Plot height in TS-specific growth curves, specific to

ethnicity if possible

Provocative GH testing: only if growth is clearlyabnormal

Appraise familial risks associated with GH therapy DM Scoliosis Series cardiovascular events

Intracranial HPN Slipped capital femoral epiphysis Pancreatitis New malignancies




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GROWTH HORMONE

with or without anabolic steroids, can accelerategrowth in girls with TS

Increase in FINAL HEIGHT (up to 150 cm)

Critical factors: GH dosage; years of treatment before

estrogenization

should be started as soon as patient has dropped

below p5; as early as 2 years Directed by a pediatric endocrinologist

Dose:0.375-0.4 mg/kg/wk divided daily, given atbedtime




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Management of Growth Failure

9-12 yrs or in girls >8yrs far below p5 : considernonaromatizable steroid such as

OXANDROLONE (0.05 mg/kg/day) Monitor for clitoral enlargement, virilization,

glucose intolerance

Continue until satisfactory height has beenattained or until bone age is above 14 yrs andpatients height has increased by


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Benefits of early GH therapy

Decreased GH costs

Rapid normalization of height

Elimination of stature-related physical limitations

Improved likelihood of being treated age-appropriately

Increased likelihood of pubertal induction at anormal age



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Takano et al. Clinical trials of GH treatment in patients with Turnerssyndrome in Japan a consideration of final height Eur J Endo. 1997.


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Management of Gonadal Failure

Goal of estrogen replacement therapy: normalizedevelopmental changes in secondary sex characteristics

Early GH therapy and careful choice of estrogens and doseallow initiation at a normal age but still allow a normal adult

height to be attained Low dose systemic estradiol combined with GH may

actually enhance final adult stature

Adverse effects: increase resistance to activated Protein C and decrease

antithrombin III : increased risk of thrombosis Cause GH resistance Decrease IGF-I and IGF binding protein-3 levels Increase HDL and LDL atherogenicity



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Bondy. Care of Girls and Women with Turner Syndrome: A Guideline of the Turner Syndrome Study Group. J Clin Endocrinol2007.


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Thank You!

Documents

Turner Syndrome2