Indian J Pediat 50: 533-535, 1983

Normal variant short stature

P.S.N. Menon, M.D., R.K. Menon, M.D. and Anil Gupta, M.D.

Human Growth hormone (HGh) deft- ciency is a well recognized cause of short stature and the criteria for its diagnosis is well established. ! From time to time patients not considered to be HGh deficient by the traditional criteria have been said to benefit from treatment with HGh, but have not been systematically studied. 2 Recently a group of children with short stature has been identi- fied who, though not full'riling the usual criteria for HGh deficiency, benefit from HGh therapy. 3 This condition has recently been termed "normal variant short stature" (NVSS), a term first used by David Smith 4 and popularized by Rudman and asso- ciates. 3

The criteria for diagnosing NVSS include (i) current height and predicted adult height below the 3rd percentile, (ii) birth weight greater than 2500 gin, (iii) normal physical examination except for proportionate short stature with or without retarded bone age, (iv) no evidence of economic, psychological or nutritional deprivation, (v) average peak plasma HGh value of more than 12 ng/ml in the provocative tests, (vi) normal thyroid, adrenal and antidiuretic hormone function and (vii) a normal karyotype. 3

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi 110 029.

Reprint requests: Dr. P.S.N. Menon.

Further work on NVSS by the same group of workers led to its subclassification into 4 groups) This subclassification was first based on response to exogenous HGh, but subsequently other parameters were evolved to distinguish the 4 subgroups.

In the pioneering study to subclassify NVSS, 28 children fulfdling the above mentioned criteria (ages 8-10 yr) were given HGh (0.532 U/Kg Bw3A day) for 10 days) Two responses were measured: (1) the anabiolic response of soft tissue in terms of daily retention of sodium, potassium and phosphorus; and (2) the linear growth res- ponse ofthe skeleton in terms of increment in height during the next 12 weeks. Subgroup I consisted of children who showed neither anabolic nor liner growth response to the hormone. Subgroup II were those who showed no linear growth response but had anabolic response comparable to normal control subject. Subgroup III children showed linear growth and anabolic res- ponses which was 25-50 percent of that seen in HGh deficiency children. Subgroup IV were children who had linear growth and anabolic response equal to those of the HGh deficiency control group.

In a attempt to unravel the pathophysio- logic basis of this subclassification, these workers studied the nocturnal release of endogenous HGh by RIA (Radioimmuno-

534 THE INDIAN JOURNAL OF PEDIATRICS Vol. 50, No. 406

assy-immunoactivity) and RRA (Radio- receptor assay-bioactivity), serum somato- medin C level by RIA and urinary excretion of polyamines. 5 Their results supported the hypothesis that in NVSS subgroup III and IV, the pituitary gland releases an endo- genous HGh with normal immunoreactivity but subnormal bioactivity as evidenced by subnormal somatomedin C, normal noctur- nal release of immunoreactive HGh, but subnormal ratio of HGh bioactivity (RRA) to immunoactivity (RIA).

In subgroups I and II, average serum somatomedin C, nocturnal release of HGh immunoreactivity and HGh-RRA/RIA ratios were all normal suggesting that the defect may be in the cellular receptor for HGh or somatomedin, or an impaired pro- duction of polyamines which are said to mediate some of the effects of HGh and somatomedin on cellular growth.

The methods used to subclassify NVSS described above have the following draw- backs: (i) the original method of monitoring anabolic and linear response to HGh is laborious and can only be carried out in metabolic-research units; (ii) an accurate estimation of linear growth response to a 10 day course of HGh requires a base line growth rate of less than 0.2 cms per month, thereby limiting this investigation to a minority of NVSS cases; (iii) classification according to the somatomedin C (basal) level gives some false positive results, while (iv) classification based on HGh-RRA/RIA activity ratio gives some false negative results.

Recently a new method has been evolved. which is classification according to the rela- tion between a basal somatomedin C level (average of 2 days) and the level of somato- medin C on the 10th and l l th day of administering HGh (0.08 u/kg/day• days). 6 This method completely separates

subgroups III and IV (those benefiting from long term HGh therapy) from subgroups I and II (those in whom HGh therapy will have no benefit).

Patients who now can be classified as belonging to subgroups III and IV have been studied by other workers also and a new label of"growth hormone dependent growth failure" has been proposed for these cases pending furthcr clarification regarding their pathophysiology. 7 Laron described 26 children, characterized by abnormally high plasma HGh immunoactivity, dwarfism, retarded bone age and ailure to grow in res- ponse to long term treatment of exogenous HGh. 8 These children differ from NVSS (subgroup I and II) as the levels ofimmuno- reactive basal HGh are increased in Laron syndrome but not in NVSS subgroup I and II.

Children with NVSS constitute 30-50 percent of short stature) This raises the vital question--What is the proportion of type III and IV NVSS children in the population as these are the children who would benefit from long term HGh treatemnt. This has a profound implications for the supply of HGh in that the introduction of biosynthetic HGh derived from recombinant DNA technique will not come a moment too soon as the present state of HGh supply from cadaveric pitutary glands is threatened by a fall in pitutary collection.

Finally a word of caution. A serious objection has been raised by some autho- rities against the subclassification of NVSS.9, 10 This is that scanty attention has been paid to nutritional status in the papers from the Emory group ofRudman et al. This point is of vital importance as suboptimal caloric nutrition is the principal cause of growth retardation and variation in nut- ritional status are critical to the regulation of HGh and somatomedin C levels, hence

MENON ET AL 535

d o u b t r e m a i n s t ha t the s u b c l a s s i f i c a t i o n o f NVSS m a y be i n v a l i d as it d i d no t t ake in to a c c o u n t the n u t r i t i o n a l s ta tus o f the sub jec t s

s tudied. Th i s p o i n t wi l l need c l a r i f i ca t i on be fore the c o n c e p t o f N V S S a n d its sub- g roups g a i n s un ive r sa l accep tance .

R e f e r e n c e s

1. Underwood LE, Van WyL J J: Hormones in normal and aberrant growth. In Testbook of Endocrinology, William RH(Ed); WB Saunders, Philadelphia. 1981, p 1179

2. Trygstad O: Transitory growth hormone deficiency successfully treated with human growth hormone. Acta Endocrinol (Copenh) 84:11. 1977

3. Rudman D, Kutner MH, Blackston RD, Jansen RD, Patterson JH: Normal variant short stature: Subclaasificafion based on responses to exogenous human growth hormone. J Clin Endocrinol

Metab 49: 92, 1979 4. Smith DW: Growth andits disorders. Philadelphia:

WB Saunders, 1977 5. Rudman D, Kutner MH, Goldsmith MA~ Kenny J,

Jennings H, Bain RP: Further observations on four subgroups of normal variant short stature. J Clin Endocrinol Metab 51: 1378, 1980

6. Rudman D, Kutner MH, Blackston DR, Cushman RA, Bain RP, Patterson JH: Children with Normal Variant short stature: Treatment with human growth hormone for six months. N Engl.I Med 305: 123, 1981

7. Frazer T, Gavin JR, Daughaday WH, Hfllman RE, Weldon W : Growth hormone-dependent growth failure. J Pediatr 101: 12, 1982

8. Laron Z: Syndrome of familial dwarfism and high immunoreactive growth hormone. Isr J Med Sci 10: 1247, 1974

9. Preece MA: A new task for human growth hor- mone. Br Med J 283: 1145, 1981

10. Crawford JD: Meal Potatoes. and growth hor- mone. N Engl J Med 305: 163, 1981