Discussion in 'Spot Diagnosis' started by neo_star, Jan 15, 2013.
Laron Syndrome (Growth hormone receptor deficiency)
welcome to our new members, lili_medstudent and cemhiper.
@ lili_medstudent - look at the hint ( last slide ), it says ' upper and lower seg are in proportion ' which is not the case with achondroplasia
@ cemhiper - Individuals with 'Nanism' have a triangular face.
Nanism. So achondroplasia.
[FONT=&]Answer: Pituitary Dwarfism aka Pituitary nanism due to Growth hormone deficiency
[/FONT][FONT=&]This case happens to be form my own state and is a confirmed case of GH def.
[FONT=&]Laron syndrome, is also possible…but since Idipathic Isolated def of GH is far more common presentation, I will put the diff in the following order[/FONT]
[FONT=&]1) Pituitary Dwarfism aka Pituitary nanism due to - Idipathic Isolated def of GH [/FONT]
[FONT=&]2) Laron’s syndrome[/FONT]
[FONT=&]3) other cases of proportionate dwarfism ( and most will have mental retardation and a relatively smaller head as well )[/FONT]
[FONT=&]Note: Most cases of idiopathic pituitary dwarfism ( due to isolated GH def ) have normal intelligence, like in the case of the girl in the spot siagnosis ( atleast to start with..later repeated seizures due to hypoglycemia and the anti-seizure meds can cause brain damage ).[/FONT]
[FONT=&]Some genetic variations of laron’s syndrome have mental retardation to varying degrees.[/FONT]
I will cover the topic of dwarfism, in as few words as possible with special focus on GH and related cases
First, let me clear up some terms / definitions[/FONT]
a) Nanism – According to Taber’s 18[SUP]th[/SUP] ed. Nanism = Dwarfism …… and why not, becos nano has always got to do with something that is small ex – nanosecond, nanomedicine, nanogram etc. ( end of thinking capacity )[/FONT]
[FONT=&]Goes without saying, that – Achondroplasia is an ex. Of nanism and so is dwarfism / stunted growth from any endocrine cause or any of the mucopolysacchyroides or intrauterine insults ( ex. Placental insufficiency, intrauterine infection etc. )[/FONT]
[FONT=&]But when Nanism is used without a qualifier (ex - Pituitary Nanism ), then most people including me, assume it to be MuLiBrEy Nanism ( short form for – Muscle Liver Brain Eye nanism ) and the triangular face that i have demonstrated above is charecteristic for MuLiBrEy Nanism.[/FONT]
When cemhiper posted the ans as Nanismo Hipofisario.... I think our friend was referring to Pituitary Nanism and so is the winner of the thread.
[FONT=&]b) Primordial dwarf – this term is used to describe a large and diverse group of children with normal endocrine functions but inherent limitations in skeletal growth. The cause of short stature in these children is usually easily identified on the basis of abnormal body proportions ( skeletal dysplasias ), dysmorphic features ( chromosome abnormalities ) and other chareteristics of the history and physical ( ex. – Prader – willi, Noonan, IUGR etc. )[/FONT]
[/FONT][FONT=&]To keep the topic simple, I will not draw inspiration from the homonguous list of classifications ( in all the reputed textbooks )…but rather draw an anolgy with what goes into making a fire.[/FONT]
[FONT=&]So to have a fire we need[/FONT][FONT=&]
[/FONT]1) a spark…let’s equate GH and it’s mediator IGF 1 to the spark ( I am keeping Thyroid, ACTH/cortisol and the andogens out of the discussion, to keep things somple )
2) Then we need Oxygen….let’s equate that with the nutrients ( both micro and macro and O2 as well ) and the guys who transport or modify them…ex liver, heart kidney etc.
3) Last but certainly not the least, we need – firewood / fuel…let’s equate that with the mesenchyme which will convert into - bone, cartilage, muscle & Xtra cellular matrix )
4) And let’s call the fire that we see from the marriage of the above three ( for a change let’s get three people married into a wedlock ) as Growth.
[FONT=&]Let’s start with the discussion about the spark – [/FONT]
But let me preface the discussion by saying 2 things
[FONT=&]1[SUP]st[/SUP] thing – in utero growth does not depend on Growth Hormone from fetus but rather on hPL ( human placental lactogen ), hGH ( human placental growth hormone ) and IGF – 2 ( which is not GH dependent ). It’s IGF – 1 which is GH dependent.
[FONT=&]2[SUP]nd[/SUP] thing – There is a common misconception that all axns of GH are mediated by IGF – 1, well that’s not true. GH has direct axn on adipose tissue, muscle and liver wheras GH acts on bone, cartilage, heart and lungs through IGF – 1 or Somatomedin.[/FONT]
[FONT=&]From the above discussion, it should be clear that when growth hormone or it’s mediator is the problem, then intrauterine growth should be reasonably normal but post natal growth will suffer…but his absence is not absolute and the lower segment will catch up and the final height will result in a proportionate dwarf i.e a small fire[/FONT]
[FONT=&]Classical examples -
a) ‘Pituitary Dwarfism’ aka ‘Pituitary Nanism’ due to - Idiopathic Isolated def of GH
b) Laron’s syndrome[/FONT] ( due to deficient or mutated GH receptors )
[FONT=&]Now let’s discuss the O2 in our anology i.e nutrients and their transporters[/FONT]
[FONT=&]Nutrition problem in utero i.e either due to infection, placental insufficiecy, or toxic exposure (tobacco, cocaine use etc) or problems in major organ systems – will result in a small for gestational age baby and the final height will be stunted. Again since this will hit the entire body equally, u will have a proprtinate dwarf + / - dysmorphic features.[/FONT]
[FONT=&]Lastly the firewood i.e mesenchyme [/FONT]
[FONT=&]Most that fall under this category are part of the ‘chondroskeletal dysplasias’ and form part of major syndromes ( with underlying mutaion or chromosomal anomalies ). In this case the new born in addition to being small is also grossly dysmorphic and that gives us the classical – ‘Disproportionate Dwarfs’. [/FONT]
I will discuss some classic cases / self assessment questions on Pituitary dwarfism and Laron syndrome in the next post...stay tuned
The most commonly tested case scenario first
An otherwise healthy 7-year-old child is brought to you to be evaluated because he is the shortest child in his class. Careful measurements of his upper and lower body segments demonstrate normal body proportions for his age. Which of the following disorders of growth should remain in your differential? [FONT=&]
[FONT=&]B. Morquio disease[/FONT]
[FONT=&]D. Growth hormone deficiency[/FONT]
[FONT=&]E. Marfan syndrome[/FONT]
Alteration of body proportion results from selective regional rates of growth at different stages during the developmental period. At birth, the head is large for the body size, the limbs are short, and the upper to lower segment ratio (crown to pubis/pubis to heel) of 1.7 is high. As the growth of the limbs exceeds that of the trunk from infancy to adolescence, there is a change in body proportions reflected in the upper to lower segment ratios: 1.3 at 3 years, 1.1 at 6 years, and 1.0 at 10 years of age. [/FONT]
[FONT=&]In achondroplasia, there is a disproportion between the limbs and the trunk; that is, the limbs are relatively short. The head in this condition is also disproportionately large. Achondroplasia is the most common genetic skeletal dysplasia. This disorder has an autosomal dominant mode of inheritance. [/FONT]
[FONT=&]Marfan syndrome[/FONT][FONT=&] is a serious disease of connective tissue that is inherited in the autosomal dominant mode. The predominant findings in this condition are bilateral subluxation of the lens, dilatation of the aortic root, and disproportionately long limbs in comparison with the trunk. The decreased upper to lower segment ratio in Marfan syndrome reflects this relative increase in the length of the legs compared with the trunk. [/FONT]
[FONT=&]Morquio syndrome[/FONT][FONT=&] is one of the mucopolysaccharidoses (MPS IV). Abnormal amounts of keratan sulfate accumulate as a result of an enzyme deficiency, and widespread storage of this material in the body results in problems in morphogenesis and function. Skeletal malformations are similar to those seen in osteochondrodysplasias, namely, short trunk with short stature, marked slowing of growth, severe scoliosis, pectus carinatum, and short neck. [/FONT]
[FONT=&]Thyroid hormone[/FONT][FONT=&] is necessary for physical growth and development and, along with sex hormones, has an essential role in development of bone and linear growth. Thyroid deficiency results in delayed puberty in most cases and in stunting of growth with persistence of immature body proportions; signs and symptoms of hypothyroidism are also frequently seen. [/FONT]
[FONT=&]In growth hormone deficiency, the upper to lower segment ratio is normal, often without other signs or symptoms.[/FONT]
[FONT=&]The answer is D.[/FONT]
Now the 2nd scenario, wherein we have to choose between GH deficiency and Laron's syndrome. This is one of the discriminatory questions ( separates the creamy layer from the rest ) on competitive exams.
Mr. Jones ( 7 ft tall and plays for NBA ) and his wife( 6 ft 5 in tall and plays for WNBA ), comes in with their son 'little Timmy', who is below the 5th percentile for height. Jones is wondering whether the family tree is intact...U do a fingerprinting ( DNA ) and tell him that - Timmy is his son...much to the relief of his wife P:
U have narrowed the cause of Timmy's dwarfism to GH or it's mediator / GH receptor....So you wish to know whether he is releasing GH or not. How will you investigate ?
Step 1) send blood for baseline GH level and IGF -1
Step 2) then small dose of insulin ( to render him hypoglycemic )
Step 3) again check for GH levels in blood
low gh levels at baseline and after stimulation - GH def problem...pituitary nanism / dwarfism
gh level rises from baseline levels but there is no rise in IGF -1 ( note the rise in IGF - 1 has to be synthesised by the liver in response to rising GH levels and hence will take longer to show a rise i.e GH would always be ahead in the race) - likely problem is Gh receptor or it's downstream signalling ex. - Laron's syndrome
Q) now suppose you are told b4 hand that the problem is GH related i.e either GH or it's receptor....and if u r asked, which is the one test that will distinguish between GH & IGF -1 problem.
A) Blood sugar level
low blood sugar - Gh is the problem
blood sugar is Normal - IGF-1 is the problem
remember, i said b4 that GH axn on liver is direct and not mediated by IGF-1...so gluconeogenesis is not hampered when Gh levels are normal ( pecisely the reason why hypoglycemia induced seizures are more common in pituitary nanism than Laron's syndrome )
One more case to consolidate this concept
A child is at the 5th percentile of the growth curve
Lab - Serum Na[SUP]+[/SUP], K[SUP]+ [/SUP]and Cl[SUP]-[/SUP] are Normal vitals - Normal. Blood sugar - normal
what is the possibility?
a) Gh deficiency
b) thyroxine def
c) IGF-1 def
d) lack of mother's love
Ans C IGF-1 def ( see explanation above )
Laron Syndrome is right...
Laron syndrome is equally right as Pituitary Nanism. But pituitary nanism is far more common than laron syndrome..the reason that i put it ahead of Laron in the differentials.
Additionally this child is not mentally retarded, which makes pituitary nanism more likely.
Another commonly asked question ( Step 2 )
[FONT=&]The parents of a 14-year-old boy are concerned about his short stature and lack of sexual development. By history, you learn that his birth weight and length were 3 kg and 50 cm, respectively, and that he had a normal growth pattern, although he was always shorter than children his age. The physical examination is normal and his growth curve is shown on the next page. His upper-to-lower segment ratio is 0.98. A small amount of fine axillary and pubic hair is present. There is no scrotal pigmentation; his testes measure 4.0 cm[SUP]3[/SUP] and his penis is 6 cm in length. In this situation, which of the following is the most appropriate course of action?
A. Measure pituitary gonadotropin
B. Obtain a computed tomographic (CT) scan of the pituitary area
C. Biopsy his testes
D. Measure serum testosterone levels
E. Reassure the parents that the boy is normal
A record of the sequential pattern of growth in height is very helpful in the differential diagnosis of a child with short stature. A child with constitutionally short stature and delayed puberty will have a consistent rate of growth below, but parallel to, the average for his or her age, whereas patients with organic disease do not follow a given percentile but progressively deviate from their prior growth percentile. Knowledge of the patterns of growth and sexual maturation of family members is helpful, because such patterns are often familial. Reassurance that normal sexual development will occur and that a normal adult height (usually a midparental height) will be attained is frequently the only therapy indicated.
Puberty is said to be delayed in males if physical changes are not apparent by 14 years of age. Identification of the earliest signs of sexual maturation by means of careful physical examination avoids unnecessary workup. In this case, measurement of pituitary gonadotropins is unnecessary because the child already shows evidence of pubertal development (a penile length of more than 2.5 cm and a testicular volume more than 3.0 cm3). The single most useful laboratory test is the radiographic determination of bone age.
In those of constitutionally short stature with delayed pubertal maturation, the bone age is equal to the height age, both of which are behind chronologic age.
In familial short stature, bone age is greater than height age and equal to chronologic age.
In a child at any age, the administration of human chorionic gonadotropin (hCG) will stimulate interstitial cells of testes to produce testosterone, thereby serving as a method of assessing testicular function. The finding of testicular enlargement is evidence of pituitary secretion of gonadotropins and of testicular responsiveness and obviates the need for administration of hCG.
Elevated serum gonadotropins are found in children 12 years of age or older who have primary hypogonadism (Klinefelter syndrome, bilateral gonadal failure from trauma or infection). Because the secretion of gonadotropins is not constant but occurs in spurts, children with constitutional delay of puberty may have normal or low levels of gonadotropins.
The answer is E.
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