Delayed growth and sexual development in a 15-year-old: A rose by any other name
By Jane C. Lee, et al
The 15 1/2-year-old seated in your office is obviously uncomfortable. He has been referred for evaluation by his physician because of decreased growth and failure to develop secondary sexual characteristics, or, as he puts it, "not developing like the other boys." A copy of his growth chart has been sent along with the consultation request. Growth had been along the 75th percentile until age 10 years, with a rather dramatic decrease to the 5th percentile occurring in the last five- and-one-half years. The weight curve has been less affected.
According to Mother, the birth history is unremarkable and her son achieved normal developmental milestones. His past medical history is noteworthy only for a right-sided inguinal hernia repair at age 8 years. He is taking no medications and, except for growth and development, his health has been good. There is no history of unexplained fevers, abdominal pain, diarrhea or constipation, rashes, or exercise intolerance.
The family history is reviewed carefully. The young man has three siblings: two older sisters, both of whom had normal pubertal progression and growth with regular menses, and one prepubertal, healthy, 10-year-old sister. Mother is 5 feet 2 inches tall and reports menarche at 13 years. Father is 5 feet 9 inches, but his developmental history is unknown.
On physical examination, the youngster's vital signs are normal. His height, 158 cm, and arm span are the same, although the upper-to-lower body segment ratio (height minus the distance from the symphysis pubis to the floor) is 0.82; a normal ratio is >0.9. He appears healthy but younger than his age. Moderate gynecomastia is present. There are no signs of secondary sexual characteristics, including axillary hair, acne, or body odor. He is Tanner stage 2 for pubic hair and has a bilateral testicular volume estimated to be 2 cm3. His stretched penile length is 4.5 cm by 3 cm, clearly prepubertal. The neurologic examination is unremarkable, including normal visual fields.
The history and physical examination substantiate the delayed growth and sexual development but do not provide an obvious answer to the cause. The onset of puberty in males in the United States is 9 to 14 years, so this young man is clearly beyond the norm. In the general population the incidence of delayed puberty is less than 1%, with less than 2% of 14-year-old males and just 0.4% of 15-year-old males remaining prepubertal.
The first sign of pubertal development in males is scrotal reddening and thinning, followed by testicular enlargement to more than 2.5 cm in the longest axis, clearly not present here. This youngster's early pubic hair development is perhaps related to androgens produced by the adrenals, since the testes appear to be underdeveloped. It is clear that a further assessment needs to be performed.
Sniffing out the likely causes
As you complete the physical examination you consider the diagnostic possibilities and plan for evaluation. The young man's medical history has disclosed no evidence of chronic illness, head trauma, or nutritional disorders or other quirks. The mother's and sisters' pubertal progressions seem normal, and, although the father is unavailable, mother recollects no known unusual history in that sphere. Constitutional delay, the most common cause of pubertal delay, seems unlikely given growth at the 75th percentile until age 10 years. Children with constitutional delay usually demonstrate a slowing of linear growth during the first three years of life, with subsequent growth below but parallel to the 5th percentile. And, there is often a family history of pubertal delay, which does not appear to be the case here. Nevertheless, although the growth pattern is not typical, constitutional delay cannot be excluded entirely.
Could the cause be primary testicular failure? The testes are certainly small enough. Disorders in this group, also known as hypergonadotropic hypogonadism, are characterized by elevated levels of gonadotropin-releasing hormone (GnRH), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in the serum. Failure to produce testosterone results in the overproduction of these gonadotropins because of a lack of feedback to the hypothalamic-pituitary axis. Primary testicular failure may be congenital, as with Klinefelter syndrome (46 XXY), or acquired, as with viral orchitis (mumps or Coxsackie B viruses) or iatrogenic causes (radiotherapy or chemotherapy).The latter seem unlikely, but Klinefelter syndrome may be on the list of possibilities. The young man does have somewhat eunuchoid proportions.
Could the problem be central? Perhaps there is a hypothalamic or pituitary cause, disorders that fall into the category known as hypogonadotropic hypogonadism. The deficiencies in gonadotropins may be absolute or partial, congenital or acquired (sarcoidosis and head trauma, for instance), functional (related to exercise, anorexia, or anabolic steroids) or structural (craniopharyngioma or germinoma). Then there is the ever present idiopathic (we don't know the cause) isolated gonadotropin deficiency and Kallmann syndrome. Hmmm.... Kallmann syndrome. Hypogonadism associated with lack of the sense of smell!
Take time to smell the roses
The history is not complete. You turn to the youngster and ask, "How do you like the smell of roses?" He looks startled and replies, "What do you mean?" Mother suddenly interjects that her son douses himself with cologne. He protests, but then admits that he really cannot smell well.
The simple question and response provides direction for an evaluation. Gonadotropins are ordered and a magnetic resonance imaging study of the brain is scheduled.
The serum gonadotropins are appropriate for Tanner stage 2 of sexual development, but the levels are not appropriate for the young man's chronologic age, which should be in the Tanner 4 or 5 range. The levels reflect hypogonadotropism. The MRI scan report supports your diagnostic suspicion: absent left olfactory sulcus, hypoplastic right olfactory sulcus, and a small pituitary gland, findings consistent with Kallmann syndrome!
Mastre de San Juan, in the mid-19th century, first described the anatomic association between absent olfactory lobes and underdeveloped genitalia in a male with sexual infantilism.Kallmann and Schoenfeld later attributed a genetic basis to this disorder when they observed three families with the condition. DeMorsier is credited with noting the association of hypogonadism and anosmia with agenesis of the olfactory bulb, which he named olfactogenital dysplasia.
Kallmann syndrome is an uncommon disorder with a prevalence of 1 in 10,000 live births and with a male to female ratio of 3.9 to 1.3 Isolated GnRH deficiency may occasionally be detected in the neonatal period when an infant presents with cryptorchidism and microphallus. More typically, GnRH deficiency presents in adolescence when secondary sexual characteristics fail to develop. Unlike patients with constitutional delay, children with Kallmann syndrome may have normal height until adolescence, when they fail to manifest a growth spurt. Eunuchoid proportions are common, with arm spans typically 5 cm greater than height, and upper-to-lower segment ratios less than 0.9.
Impairment of smell may be partial (hyposmia) or complete (anosmia) in this syndrome. Neither patients or families may notice the impairment, especially when the defect is not complete. Testing with graded dilutions of pure scents is necessary to determine a defect in the sense of smell.Affected individuals are still able to smell irritants such as smoke and skunks, however.
Individuals with Kallmann syndrome may have associated physical and neurologic abnormalities, including cleft lip and palate, imperfect facial fusion, sensorineural deafness, cerebellar ataxia, oculomotor abnormalities, and seizure disorders, among other findings.
The most common form of Kallmann syndrome appears to be inherited in an X-linked pattern, although autosomal recessive and dominant forms have been described. Genetic linkage studies have localized the X-linked form to the so-called KAL gene on Xp22.3, which codes for an adhesion molecule that allows olfactory neurons expressing gonadotropin-releasing factor to migrate to the brain from the olfactory placode.Interestingly, there is considerable heterogeneity in families with this disorder. In the same family, some members may have gonadal deficiencies without loss of smell and others may have loss of smell without abnormalities in gonadal function.
How often do we ask about the sense of smell during routine office visits? Not often. But, given an adolescent with pubertal delay and small testes, you have the chance of smelling like a rose if you ask and discover that the youngster lacks function of cranial nerve I!