I haven’t posted a medical whodunnit for a while and I’ve got a good one (at least I think it’s a good case). The patient is a 7 year old male whose mother told a friend that her son, Jimmy had been growing very fast over the past 6-12 months. Jimmy’s mother wasn’t sure if she should be concerned or if it was just one of those childhood “growth spurts.” She took Jimmy to see his pediatrician and the physical examination showed that Jimmy had, in fact picked up his rate of growth and was now well above the 95% for height. Since Jimmy’s mother and father are both tall (mother 68 inches tall and father 74 inches tall), the pediatrician reassured the parents that Jimmy’s growth spurt was of no concern.
Jimmy’s mother was not completely reassured by the pediatrician particularly since she had also noted some personality changes along with the increased growth, most notably much more aggressive behaviors. The friend listened to Jimmy’s mother and suggested that, perhaps, a second opinion was in order, if only to allay the mother’s anxiety over the situation.
Is Jimmy’s mother’s anxiety justified?
The question is whether so-called “growth spurts” really do occur during childhood as part of the normal growth process. The answer is that sustained major changes in growth velocity during childhood are not normal. If one studies growth in children with careful height measurements every month for many years, there are definite month-to-month differences in rates, but they tend to average out over time. One very important principle of growth is that children tend to follow whatever growth channel they are at all through childhood. This means that a child who is at the 10% for height at age 2 years, is very likely to remain at that percentile throughout childhood, assuming the child is generally healthy; serious illnesses or other medical conditions can affect the growth rate. There are 2 exceptions to the rule; the first is growth from birth until about age 18 months, and the other is growth during puberty.
A child who starts out in a higher height channel than the one he is genetically programmed to follow, typically follows the higher channel for about 6 months and then gradually falls and falls until about age 18 months when he reaches the channel he will follow faithfully thereafter (by thereafter, I mean until the onset of puberty). This growth pattern is called deceleration. It can give doctors gray hair since the deceleration could be a normal physiologic growth pattern or one that indicates some medical disorder.
In a newborn who is programmed to follow a higher growth channel than the one at birth, the growth pattern is called acceleration; the infant picks up his linear growth rate almost immediately after birth and attains the channel he will follow thereafter, by about one year of age.
Puberty is the second exception to the general rule that children stick to growth channels almost no matter what . All bets are off as to the growth rate during puberty. Typically, girls show pubertal growth acceleration about the time they start breast development (on average age 10.5-11 years) and are slowing down by the time they have their first menstrual period, about 2 years after starting breast development. Boys typically show pubertal changes at about age 11.5-12 years but do not show much in the way of growth acceleration until 12.5-13 years and don’t slow down until about age 15-16 years.
Back to Jimmy
So, when Jimmy’s mother took him to see a pediatric endocrinologist (I am partial to pediatric endocrinologists but I might have recommended that Jimmy’s mother first make another appointment with the pediatrician to address her continuing concerns). After the pediatric endocrinologist obtained the medical history, which included old medical records with serial height measurements, he formulated a preliminary differential diagnosis. Review of the old records showed clearly a rather impressive acceleration in linear growth as well as weight beginning about 18 months earlier.
So, how would the pediatric endocrinologist think about things so far? Even before the physical examination, it is likely the “wheels are turning” and the physician is formulating a preliminary differential diagnosis that will help guide the physical examination. Assuming the medical history is accurate (rapid growth, personality change), the differential diagnosis is not very difficult; very few conditions are associated with the historical information. Rapid growth in children could be cause by improvement in a medical condition that was inhibiting growth such as celiac disease. The history does not suggest such a possibility. Another cause of rapid growth could be excess growth hormone. Since there was no history of growth hormone injections or administration of any other drugs, the likely causes of growth hormone excess would be central nervous system tumors, particularly pituitary adenomas. This is a rare cause of accelerated growth in children, but I have seen a few cases so it does occur. Much more likely would be an excess of either male or female sex hormones. The history of aggressive behavior would certainly fit with an excess of make sex hormones. What disorders might cause excessive male or female sex hormones? The possibilities include central (hypothalamic-pituitary origin) precocious puberty for whatever reason (e.g, a variety of central nervous system diseases, idiopathic central precocious puberty), or pubertal changes that are the result of non-central system conditions. Examples would include a human chorionic gonadotropin-secreting tumor, possibly of the testis, autonomous overfunction of the testes (so-called “testitoxicosis) leading to precocious puberty, or the most likely possibility, a condition affecting the adrenal glands, either congenital adrenal hyperplasia or an adrenal tumor (adenoma or carcinoma). That’s about it in terms of the possibilities. The physical examination would help a great deal in “narrowing the field.”
The physical examination
The patient was quite cooperative. Vital signs were normal. His height and weight were greater than the 95% for age. The general examination was normal for age except for the presence of mild facial acne and genital abnormalities. The penis was clearly pubertal in size and the patient had pubic hair. The testes were normally descended and were pre-pubertal in size. Underarm sweating was present.
What do the physical examination findings mean?
The physical examination was clearly abnormal for a 7 year old boy; in a male, the earliest pubertal change is normally testicular enlargement at about age 11.5-12 years along with some underarm sweating and perhaps a bit of pubic hair. By definition, pubertal changes in males are considered precocious if they begin before age 9-9.5 years of age. So, Jimmy has precocious puberty and this is clearly the reason for the rapid growth. Now the question is what has caused the precocious puberty? There are many different ways of classifying precocious puberty. I like to separate precocious puberty into 2 broad categories, true puberty and pseudo-puberty. I use the term “true puberty” to mean pubertal changes that are the result of pituitary hormones, FSH and LH stimulating the gonads to produce male sex hormones, principally testosterone in males, and estrogen in females. If the puberty is caused byFSH and LH-like hormones (principally human chorionic gonadotropin or HCG) that may or may not be coming from the pituitaryI would still call it true puberty. The other category, “pseudo-puberty”, refers to pubertal changes that are not caused by pituitary or pituitary-like hormone messengers to the gonads. The pseudo-puberty could be either isosexual or heterosexual; in isosexual puberty the sexual changes are what one would expect given the person’s chromosomal make-up (i.e., breast development in a female) while in heterosexual puberty the sexual changes would be just the opposite (i.e.,breast enlargement in a male). So, in Jimmy we havearly puberty which is clearly isosexual but pseudo-puberty. We know that because the testes are pre-pubertal in size; if it had been true puberty, the testres would have been enlarged from pituitary or pituitary-like hormones with production of male sex hormones in the testes.
Where do we go from here?
So, Jimmy has precious puberty which is not the result of male sex hormones being produced by the testes. In this situation the most likely possibility is that the male sex hormones are coming from one or both adrenal glands (it is pretty unlikely that Jimmy is taking anabolic steroids to improve his athletic performance). The differential diagnosis is either an adrenal tumor, adenoma or carcinoma, both quite rare in children, or a disorder called congenital adrenal hyperplasia or CAH. CAH is a group of genetic disorders that are the result of various blocks in the pathway to synthesis of the adrenal gland hormone cortisol, and in some instances, also a block in the salt-retaining hormone, aldosterone. There are 5 known different types of CAH, each caused by a deficiency in a specific enzyme necessary for cortisol synthesis. The blocks can be complete or partial. Each of the 5 types of CAH are quite distinct in the way they present. The most common form of CAH is deficiency of an enzyme called 21-hydroxylase. Patients with 21-hydroxlase deficiciency CAH produce large quantities of male sex hormones. At any rate it is quite easy to diagnose the various forms of CAH and pin down the specific enzyme deficiency. In fact, most states in the U.S., screen newborns for the 21-hydroxlase deficiency form of CAH.
So, armed with some knowledge about the various forms of precocious puberty, a medical history and a physical examination, the pediatric endocrinologist is ready to order a few laboratory studies. I would be inclined to order the following tests: an X-ray of the left hand to determine Jimmy’s “bone age,” to get some idea of how advanced his bone growth centers were; both male and female sex hormones cause maturation of the bone growth centers which can greatly affect linear growth potential. If for example, Jimmy’s bone age has already advanced to 12 or 13 years of age, his growth potential is much more limited than if his bone age were appropriate for age. Thus, even though Jimmy might be tall for his age now, he might end up quite short. I would order some hormone levels- testosterone, 17-hydroxyprogesterone, dehydroepiandrosterone (DHEA), and renin. The results of these 3 tests would go a long way in helping the pediatric endocrinologist determine the exact cause of the precocious puberty. One could order many more tests including MRIs and CAT scans (to look for tumors), but I would start simple and do a stage evaluation.
What did the laboratory studies show and what do the results mean?
The bone age was read by the radiologist as being 12 years. This means that the radiologist looked at Jimmy’s left hand X-ray (by convention bone ages are always of the left hand) and compared the appearance of the bone growth centers to those in an atlas and found that Jimmy’s hand bone growth centers looked most like the 12 year old male standard photo in the atlas ,hich is just a series of hand X-rays taken at different ages (obviously, there are separate male and female atlas sections). So, Jimmy has quite an advanced bone age and it has to be the result of excessive male sex hormones. The blood studies showed elevated levels for the testosterone and the 17-hydroxprogesterone but not the other analytes. This was actually all the pediatric endocrinologist needed to make a more-or-less definitive diagnosis.
The pre-hormone 17-hydroxprogesterone, is the product in the synthetic pathway for cortisol just before the step catalyzed by the enzyme 21-hydroxylase. If the level of 21-hydroxylase is low, cortisol synthesis will slow up (or be completely blocked if there is no 21-hydroxlase present) and the pre-hormones before the block will pile up- just like water backing up where a dam is built. As it turns out, the pre-hormones before the 17-hydroxprogesterone can follow an alterntive pathway and it shouldn’t surprise you that they march down the pathway to make male sex hormones, testosterone and androstendione. The DHEA was ordered because another form of CAH that can cause precocious puberty is the result of a “back-up” at the step just after formation of DHEA. One other form of CAH causes precocious puberty, but in that disorder, patients usually have very high blood pressures, something Jimmy did not have. Finally, the renin was ordered to see if along with a deficiency in cortisol synthesis, there was also a deficiency in the salt-retaining hormone, aldosterone which is found in about 70% of children with 21-hydroxylase deficiency.
So, Jimmy likely has CAH due to a deficiency in the enzyme, 21-hydroxylase which results in an excess of 17-hydroxprogesterone which in turn results in excess synthesis of male sex hormones.
Next step: treatment and confirmation of the diagnosis
The next step is to treat the patient with a glucocorticoid hormone such as cortisol which basically turns off the oversynthesis of male sex hormones. If we obtain a blood specimen for 17-hydroxyprogesterone and testosterone several weeks after starting the treatment with cortisol, we can definitively confirm the diagnois of 21-hydroxlase deficiency CAH if the 17-hydroxprogesterone and testosterone levels have decreased. This also means that the reason for the elevated testosterone cannot be an adrenal tumor since the tumor production of male sex hormones is not affected by treatment with cortisol- just think of how much money we saved by holding off on the MRI and CAT scan tests!
So, now we know what made Jimmy grow so fast and we know how to treat it. Our goal is to treat him with enough cortisol to completely block the excessive adrenal hormone production but not so much as to lead to side effects from overtreatment (this would be called Cushing’s syndrome). With some luck, we have caught the problem early enough that it will not markedly decrease Jimmy’s growth potential. One potential problem is that when the bone age gets to a pubertal level, that may trigger onset of true puberty. But, we now have drugs that can slow that process if necessary. The main lesson to be learned from this case is that physicians should not be so quick to assume that a particular physical finding or symptom in a patient is ok just because it may “run in the family.” Tall stature in a child would not be surprising if the parents were tall but tall stature that does not “follow the rules” should raise red flags. Similarly, just because a parent has a history of migraine heaaches does not mean that the child’s severe headaches are also migraines.
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