A 15-year-old boy is brought to the physician by his parents who are concerned about his development. The boy feels ostracized by classmates at school, who tease him because of his small size. He dreads physical education classes. The other boys have more development of secondary sexual characteristics. He has been an above average student through grade school, but is now performing at just an average level.

Questions:

7.1 Review normal development.

SMR Pubic Hair Stages: Mean chronologic age (CA) and bone age (BA) in males and females (in years)

Stage II-V = 2.7 yrs avg.

SMR Female Breast Stages: Mean chronologic age (CA) and bone age (BA)in females (in years)

Stage II to Stage III = 1.3 yrs avg.

Stage III to Stage V = 2.4 yrs avg.

SMR Male Genital Stages. Mean chronologic age (CA) and bone age (BA) in males (in years)

Females initially show a deposition of adipose tissue and widening of the pelvis and changes in the contour of the hips. The first clinical sign is thelarche (the appearance of breast buds) and adrenarche (the appearance of dark straight pubic hair over the mons veneris, also called the mons pubis). These changes identify a SMR stage (or Tanner stage) II (see tables 1 and 2). Breast development over the next 4 years will proceed from breast stage II (secondary mound of breast tissue to adult breast stage V). Development of pubic hair starts about 1 year after breast budding and may take place over a 1.5 to 3.5 year period. During SMR stage 3, girls experience a very rapid increase in their height. The peak of their height growth (PHV=peak height velocity) should take place before the onset of menarche in most girls. Menarche occurs six months after the PHV and just prior to stage IV of breast development. Most western girls achieve their menarche around 12.4 to 12.8 years of age. African-American girls are maturing earlier.

Puberty in boys also follows a regular sequence of events, but lacks the clear cut landmarks such as breast development and menarche. In the male, the pubertal growth spurt is a late event starting about two years later than in females. The onset of pubertal changes however, are only about 6 months later than in females (see tables 2 and 3). Enlargement of the testes indicates the transition from genital stage I to Stage II, beginning at an average age of 11.5 years. Penile growth occurs about one year later. This is usually preceded by the appearance of pubic hair at the base of the phallus progressing through pubic hair stages II to V. Pubic hair stage III is followed by the appearance of axillary and facial hair growth. Testicular growth is completed anytime between 13.5 and 17 years of age. Growth of the penis reaches a SMR (Tanner) stage V between 12.5 and 16.5 years of age. Nocturnal emissions (wet dreams) may first appear during SMR stage III.

Additional history

Past History: He was the product of a normal term gestation. He weighed 4 kg at birth with normal height (52 cm) and head circumference (35 cm). He met developmental milestones during infancy and childhood. He has had no major medical problems. He takes no medications.

Family History: His mother is 33 years old and in good health. Her height is 175 cm and her weight is 70 kg. She had menarche began at age 13. His father is 36 years old, also in good health. His height is 190 cm and his weight is 90 kg. He remembers having a "growth spurt" at age 12. The boy has a 14-year-old sibling, a sister, who is 165 cm tall and weighs 55 kg. She started menarche at age 12.

Physical examination shows vital signs with T 37 C, P 80/min, RR 19/min, and BP 95/65 mm Hg. His current height is 147 cm and his weight is 41 kg. He appears normally proportioned and there are no apparent congenital anomalies. On auscultation of the chest his heart rate is regular with no murmurs and his lungs are clear. Palpation of his abdomen reveals no masses, and on auscultation bowel sounds are present. Pulses are 2+ and motor strength 5/5 in all extremities. The neurologic examination is unremarkable. The genital exam shows a normal circumcised penis. His Tanner pubic hair stage is 1, with genital stage 2. The scrotum has a normal midline raphe. Both testes are palpable in the scrotum, each with estimated 4 mL in volume by measurement with an orchidometer. His testes are firm, 2.5 cm in length and 4 ml in volume. Laboratory findings include Hgb 13.7 g/dL, Hct 41.3%, MCV 90 fL, platelet count 199,000/microliter, and WBC count 7160/microliter. His serum sodium is 143 mmol/L, potassium 4.1 mmol/L, chloride 105 mmol/L, CO2 26 mmol/L, glucose 74 mg/dL, and creatinine 0.7 mg/dL. A urinalysis shows pH 6.5, sp gr 1.020, and no blood, protein, glucose, or ketones.

7.2 What is suggested by these findings?

There are no specific abnormalities. His sexual development is below that expected for age 15. His sister does not have precocious puberty, but is within the range expected.

A child's potential height can be estimated from the sex-adjusted midparental height, which is the average of the parents' height. For boys, add 5.6 cm and for girls subtract 5.6 cm from this mean value to determine the most probable height for the child as an adult.

7.3 What additional studies can be performed?

The "bone age" can be estimated via radiographs of developing bones, particularly the hand and wrist region, in which there is a progression of appearance of ossification and epiphyseal regions. His bone age is found to be 12.2 years.

Laboratory studies include a screening insulin-like growth factor (IGF-1) test. If a GH stimulation test had been done, it would have shown...low normal.. LH and FSH are low but normal for his Tanner stage.

7.4 What is your diagnosis?

Constitutional short stature and delayed puberty. Since his bone age is delayed, and puberty is late, he has a potentially longer time for prepubertal growth, which predicts a normal adult height. Such children do not exhibit growth failure (a slow growth velocity), but they may have a slow growth velocity in infancy. Their growth velocity is again slow just before puberty. Based on his parents' heights, he does not have familial short stature.

7.5 The parents have seen cases like this on television shows, and those children received treatments that made them "normal". The parents want you to do something.

There is controversy regarding treatment of short children with normal GH secretion and normal IGF-I levels. Some consultants may recommend a trial of GH therapy for 6 to 12 months for these children, continuing GH only if there is a doubling of or an increase of 3 cm/yr over the pretreatment height velocity. Other consultants would argue that this approach is expensive, experimental, and raises ethical and psychosocial concerns. Is height an important parameter for future success and happiness?

You convince the parents that there are drawbacks to drug therapies with growth hormone. You ask them to wait 6 months and determine if any progression in secondary sex characteristics and height occurs during that time. On a return visit, the boy now has growth of pubic hair and his testicular volume has increased. His height is 153 cm and weight 45 kg.

Clinical Course: Over the next 6 months, pubic hair growth is noted. His testes enlarge to 3-4 cm in length and his height increases by 5 cm.

The boy is encouraged to pick an activity at which he can excel and build confidence. He becomes a long distance runner; he eventually gets a full scholarship to a university. He gets an MBA and becomes a successful business executive. Many of the other children who gave him a hard time are now employed at jobs in his company franchises where they repeat phrases such as, "do you want fries with that?"

7.6 What would be your diagnosis if the laboratory value in 7.3 had been lower?

GH deficiency should be suspected. A child with isolated GH deficiency may have delayed pubertal development as well as small stature, though the body habitus is proportional.

Laboratory measurement of IGF-I (also called somatomedin C) screens for GH deficiency. Secretion of GH from the adenohypophysis causes release of IGF-1. Since IGF-I levels increase from infancy to puberty, so that normally low IGF-I levels in infancy and early childhood do not reliably distinguish normal growth and growth deficiency. As children get older, normal IGF-I levels help to exclude GH deficiency. IGF-I levels may also be diminished with hypothyroidism.

The confirmatory test for GH deficiency is the GH stimulation test in which infusion of a stimulatory substancesuch as arginine produces a rise in blood GH. Just a single GH level is not necessarily diagnostic, because GH levels can vary, and are normally low. However, the GH stimulation test is nonphysiologic, subject to laboratory variability, and poorly reproducible. The interpretation of the data relies on arbitrary definitions of "normal" that vary by age and sex.

The diagnosis of GH deficiency thus depends upon both physical measurements and laboratory findings. If GH is deficient, then the levels of other pituitary hormones should be checked. Bone age is typically determined from an x-ray of the left hand. In GH deficiency, skeletal maturation as determined by radiographic bone age is usually delayed to the same extent as height. Radiographic studies of the pituitary gland and sella turcica with CT or MRI help to rule out a neoplasm such as a pituitary adenoma or craniopharyngioma.