Renee Kinman, MD PhD
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1 Renee Kinman, MD PhD
2 9 y/o girl Referred by PMD for short stature Fell off growth chart
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5 Idiopathic Familial Genetic causes/ Turner syndrome Chronic Disease Constitutional Delay Growth Hormone Deficiency
6 Calculating the Genetic Potential: Midparental Height Boy: MPH (inches) = Mom s ht + Dad s ht Girl: MPH (inches) = Mom s ht + Dad s ht
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8 Hypothyroidism T4, TSH Growth Hormone Deficiency IGF 1 IGF binding protein 3 Genetic Causes: Karyotype Chronic Disease CBC ESR CMP UA TTG IgA IgA levels Bone age X-ray
9 Labs: 46XX, all screening labs normal Bone age x-ray: Bone age 7 chronologic age of 9 y/o MPH
10 Familial short stature: Constitutional Delay Endocrine Causes Chronic disease Genetic Causes Decreased spinal growth Idiopathic No Yes Unlikely given normal labs Unlikely given normal labs Unlikely given 46XX & not funny looking Unlikely given no spina bifida features or history spinal XRT Likely some component
11 Growth Hormone Deficiency Turner Syndrome Renal disease Prader-Willi syndrome SGA with no catch-up growth by 2 y/o Idiopathic short stature
12 Growth Hormone Deficiency - NO Turner Syndrome - NO Renal disease - NO Prader-Willi syndrome - NO SGA with no catch-up growth by 2 y/o - NO Idiopathic short stature - YES
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15 English neurosurgeon Reported in 1886 that removed pituitary twice in dogs Dogs then lived for 5 & 6 months w/o any nervous or other symptoms Obviously, he didn t remove the whole pituitary
16 Pierre Marie ( ) 1886 paper on acromegaly Described a non-congenital hypertrophy of upper and lower limbs & head Paper brought to clinical attention this rare disorder But was described as abnormal example of Paget s disease
17 Oskar Minkowski German internist & physiologist Reported 30 y/o musician with acromegaly & enlarged pituitary fossa Interestingly, musician was originally a violinist: had to change to flute when fingers became too big then abandoned flute because of lip thickening then sight deteriorated & couldn t read the music But was assumed that acromegaly was a deficiency disorder
18 Independently suggested relationship between pituitary & dwarfism Postulated that in pituitary is a sort of growth regulating center for entire body
19 Overactivity could lead to gigantism or acromegaly Underactivity could lead to dwarfism
20 21 y/o: 3 ft 10.5 inches 32 y/o: 7 ft 2 inches Lost ability to stand on his own 51 y/o: 7 ft 8 death Only man in history to be classified as both dwarf & giant
21 1 st demonstration of growthpromoting factor from pituitary gland Injected whole anterior lobe extracts of beef pituitary Produced gigantic rats Evans awarded Gold Medal of AMA in 1923 for this discovery Local history: Evans born in Modesto in 1882 Later became Professor of Surgery & Dean of University of California, School of Medicine
22 1930 s: Several attempts made to treat human dwarfism with purified growth hormone from bovine pituitaries 1944: Li & Evans prepared homogenous protein with growth-promoting activity from ox anterior pituitaries Caused rats to gain weight But when injected with monkey or human GH, rats initially showed good response, but stopped growing after 10 days treatment Suggested this was due to production of antibodies & thus structure of primate GH must differ significantly from rat GH
23 1950 s: Reasonable amounts of GH prepared from ox & pig pituitaries by Armour Research Labs But generally agreed these substances inactive in humans Knobil & Greep showed that primates could only respond to primate GH, not to GH from other species Findings quickly confirmed in humans
24 Treatment of pituitary dwarfism in early 1950 s consisted of testosterone & chorionic gonadotrophin Did stimulate growth But caused premature epiphyseal closure & virilization Li & Papkoff 1 st purified preparation of human GH Method was laborious & had low yield
25 Maurice Raben introduced simpler procedure to purify human GH in 1957 Used glacial acetic acid Thought this method was sufficiently violent to destroy bacteria or viruses that might be lurking in pituitaries collected indiscriminantly at autopsy Tried it on 17 y/o patient whose growth rate increased 5-fold during 10-month trial
26 After hearing of Raben s success, many endocrinologists made arrangements with local morgues to obtain pituitary glands of autopsied cadavers This form of GH became known as cadaver-gh In 1960, the NIH formed a branch called National Pituitary Agency Did this to better control procurement & distribution of cadaver-gh Arranged for large scale procurement & purification of cadaver-gh Distributed it to select endocrinologists for treatment of GH-deficiency in children Several other countries followed by developing their own cadaver-gh controlling agencies
27 Treatment was reserved for only most severe cases of GH-deficiency Only children with GH-deficiency were allowed treatment Treatment ceased when child reached a minimal height For these reasons, few children were treated during the 20 years of cadaver-gh treatment
28 In 1985, four cases of Creutzfeldt- Jakob Disease (CJD) diagnosed in patients treated with cadaver- GH in 1960 s By 2003, number had risen to 26 Use of cadaver-gh quickly ceased upon discovery of cadaver-gh treatments that each CJD-diagnosed individual received in their youth Hazardous to Health
29 Weekly June 21, 1985 / 34(24);359-60,365-6 Fatal Degenerative Neurologic Disease in Patients Who Received Pituitary-Derived Human Growth Hormone Reports of rapidly progressive & fatal degenerative neurologic disorders in 3 recipients of hgh have been received by the U.S. FDA & NIH In 2 cases, diagnoses of Creutzfeldt-Jakob disease (CJD) were made at autopsy All 3 patients had growth failure 2 to GH deficiency & were treated during childhood & adolescence with hgh extracted from pooled human cadaver pituitary glands The hormone used to treat these patients was produced & distributed by National Hormone & Pituitary Program (formerly National Pituitary Agency) under investigational exemption for use of new drug
30 Had grown poorly during 1st year of life Hypothyroidism diagnosed at 15 m/o Diagnosed with GH deficiency in 9/66. Treated with daily injections of hgh from 9/66 to 7/80 Developed dysarthria & gait disturbance in May 1984 By September, neurologic status had deteriorated, could no longer walk, could not care for himself, & required bladder catheterization Mental status had deteriorated, & could not carry on meaningful conversation Died in November Examination of brain revealed spongiform encephalopathy consistent with CJD
31 Evaluated for growth failure at 7 y/o & found to be GH deficient. Treated with hgh from 6/69 10/77 Developed weakness & gait disturbance in fall 1983 During next 6 months, developed severe ataxia involving extremities, trunk, & head Also had speech impairment, difficulty swallowing, & dementia Died in April Histologic exam of brain revealed extensive changes of spongiform encephalopathy, compatible with CJD
32 Received hgh from 1963 to 1969 Developed gait disturbance in 12/83 In 6/84, had nystagmus, mild intention tremor, & widebased gait Symptoms worsened over next several months, with increasing somnolence, memory loss, & urinary incontinence Symptoms progressed to include swallowing difficulties, diplopia, & dementia Died in February No autopsy done
33 Genentech (American pharmaceutical company), collaborated with Kabi (Swedish pharmaceutical company), to develop 1st synthetic human GH Called recombinant human growth hormone (rhgh) Initially produced using biosynthetic process called Inclusion Body technology Later, improved process called Protein Secretion technology used to produce rhgh This method is most common form of current hgh synthesis GH produced this way is known as Somatropin
34 Can increase final adult height in variety of conditions Caveat is that need to start early enough, especially in non-gh deficient patients Can increase lean body mass Can decrease fat mass Can improve bone mineral density Can increase feelings of self-esteem by increasing height
35 Left slipped capital femoral epiphysis (SCFE)
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38 Cost can range from $20,000 to $60,000 per year depending on body weight & clinical indication for GH therapy
39 The Risk of the Unknown
40 Growth Hormone is NOT for Everyone
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