11-year old boy with facial hair, acne and deepened voice

Abstract

11-year old twin boy found to have idiopathic precocious puberty after routine well-child examination revealed discordant pubertal growth between the two brothers.

Background   

Our case represents a unique scenario of discordant puberty among dizygotic twins, which is a rare occurrence. Several studies have demonstrated the high heritability of pubertal timing. Therefore, especially for twins, one would expect concordant pubertal development. The finding of discordant puberty among twins should raise concern for an underlying pathological process.

Case presentation

11-year old dizygotic twin males present for routine well-child care. They were born at 38 weeks gestation via Caesarean section and had an uncomplicated course in the newborn nursery. Their medical history is significant for mild persistent asthma and attention deficity hyperactivity disorder (ADHD), both well controlled with no recent medication adjustments. Neither twin has required daily inhaled corticosteroids for control of asthma.

Their mother discloses that she is concerned that twin A seems to have grown taller, developed facial hair, acne, and a deeper voice; while twin B has not had any of these changes. She is concerned that her son who is not having these changes, twin B, has delayed puberty.

On physical exam, twin A has sexual  maturity  rating (SMR) IV pubic hair and testicular development. His testicular volume is approximately 20 mL bilaterally. There is no evidence of asymmetry, varicocele or hydrocele, hernia or testicular mass. Examination of his face reveals mild comedonal acne, prominent around the forehead and presence of facial hair. The remainder of his exam, including vitals, is unremarkable. His growth chart (figure 1) reveals a current height of 155.60 cm, correlating with the 94th percentile for age on the Centers for Disease Control and Prevention (CDC) curve.

Figure 1.

Twin A growth chart for height. This growth chart demonstrates twin A’s height was following a linear pattern, corresponding to the ~75th percentile and then increased to correspond to the ~90th percentile, representing a growth spurt (indicated by the arrows).

Twin A’s last well-child check 14 months ago revealed SMR I pubic hair and no other signs of pubertal development. Testicular volume was not recorded. His height at that visit was recorded at 144.10 cm, correlating with 78th percentile for age on the CDC curve. His growth velocity in the last year is approximately 11 cm/year.

Twin B’s physical exam and vital signs are also unremarkable. His genitourinary exam is notable for SMR II pubic hair and testicular size (measured to be 5 mL bilaterally) and no signs of asymmetry, varicocele or hydrocele, hernia or testicular mass. His current height is 147.60 cm, correlating with the 66th percentile for age on the CDC curve. A review of last year’s data reveals a height of 142.40 cm (70th percentile) and growth velocity of approximately 5 cm/year in the last year (figure 2).

Figure 2.

Twin B growth chart for height. This growth chart demonstrates twin B’s height is following a linear pattern, corresponding to the ~75th percentile. There is no evidence of increased height velocity or growth spurt on twin B’s growth chart.

Additional history reveals that the mother is Filipino and father is Latin American. Mother’s height is 160.02 cm and father’s height is 165.10 cm, yielding a mid-parental height of 169.06 cm. Mother reports her age at menarche was 14 years and father was approximately 16 years old when his voice deepened.

A thorough review of systems is performed on twin A which is negative, including no recent headaches, vision changes, difficulty concentrating, changes in behaviour or mood, fatigue, fevers, change in appetite or activity, chest pain, palpitations, cough or breathing difficulty, abdominal pain, vomiting, diarrhoea, skin rashes, muscle aches or weakness, numbness/tingling or bowel/bladder incontinence. He also denies ingestion of exogenous steroids or use of products containing oestrogen or testosterone.

Given that twin A had evidence of advanced puberty on exam, height acceleration as evidenced on his growth chart and signs of androgen exposure (deepened voice, facial hair), a bone age was ordered. The family was discharged from clinic with the plan to follow up in 6 months to monitor progression, or sooner if concerns arose from the bone age.

Investigations

Using the standards in Greulich and Pyle’s atlas of skeletal development, twin A’s bone age obtained at a chronological age of 11 years 2 months was consistent with an age between 13 years 6 months and 14 years. One standard deviation (SD) for the patient’s chronological age is 10.1 months.¹ Given the advanced bone age and physical exam findings of advanced puberty, endocrinology was consulted for concern of precocious puberty. They recommended a laboratory evaluation including follicle  stimulating hormone (FSH), luteinising hormone (LH), testosterone, dehydroepiandrosterone  sulfate (DHEA-S), alpha   fetoprotein  (AFP) and beta  human   chorionic gonadotropin (B-HCG), as well as a brain MRI.

Twin A’s labs, summarised in table 1, revealed an LH level in the pubertal range, a pubertal testosterone level, a DHEA-S that was elevated for age but normal for pubertal status, and negative AFP and B-HCG levels. A brain MRI was performed to evaluate for structural causes of precocious puberty (such as hypothalamic or pituitary abnormalities) and was found to be normal.

Table 1.

Twin A lab results

Lab	Result	Reference range
Alpha fetoprotein	1.0 ng/mL	0–15 ng/mL
B-human chorionic gonadotropin	<0.1 mIU/mL	0–3 mIU/mL
Dehydroandostenedione-sulfate	234.6 µg/dL	15–115 µg/dL
Testosterone	90 ng/dL	Prepubertal male: <10 ng/dL Adult male: 700±300 ng/dL
Luteinising hormone	1.64 IU/L	Prepubertal male: <0.7 IU/L Adult male: 1.4–11.1 IU/L
Follicle stimulating hormone	1.55 IU/L	Prepubertal male: <3.1 IU/L Adult male: 1.3–12.7 IU/L

Outcome and follow-up

The patient was seen in Endocrinology Clinic and, based on his physical exam, accelerated growth velocity, pubertal range LH and testosterone, and lack of other findings, was diagnosed with idiopathic precocious puberty.

Given that the patient had already achieved his peak height velocity and was 87.5% of his predicted adult height,¹ treatment was not initiated. He will follow up in Endocrinology Clinic in 6 months to monitor development.

Discussion

This case represents a unique scenario of an 11-year-old boy who was ultimately found to have idiopathic precocious puberty after noting a more rapid progression through puberty than one would typically expect. This case was particularly striking because we could compare the sexual maturity of twins A and B directly and see the discordance.

Interestingly, several studies have looked at the correlation of genetics and pubertal timing. Studies among monozygotic female twins reveal similar age of menarche. Additionally, twin studies have looked at the correlation between monozygotic twins and dizygotic twins and the timing of puberty and found a greater correlation among monozygotic twins, suggesting that genetics play a significant role in pubertal development.^{2 3} Two studies, in 1977 and 1983, demonstrated a higher concordance among monozygotic twins compared with dizygotic twins when they looked at intrapair height and weight differences throughout puberty.^{4 5} Overall, several studies suggest that similarity in timing of pubertal development in boys and girls is influenced both by genetics and the environment.^{6 7} Estimates of genetic influence range from 50–100% based on previous twin studies.^{8 9}

From our literature search, only two reports of discordant puberty among twins were identified, suggesting the rarity of this finding. The first report described a case of precocious puberty in a male monozygotic twin at 6 months of age and believed to be secondary to a hypothalamic astrocytoma.¹⁰ The second report described discordant puberty in female monozygotic twins, one of whom was ultimately diagnosed with neurofibromatosis 1.² Although twins A and B are dizygotic twins, given that dizygotic twins share roughly 50% of their genes, one would still expect similar pubertal development.¹¹ Furthermore, studies have also shown a significant correlation between the timing of puberty in parents and children.¹² Both maternal and paternal pubertal timing has been found to be a strong predictor of age of pubertal onset in boys and girls.¹³ In our case, the parents reported puberty around the ages of 14 and 16, therefore twin A’s pubertal development at age 11 is striking. There are several other features to note about twin A’s development that should raise concern for precocious development.

Puberty typically begins after the age of 9 years in boys with testicular enlargement being the first sign; and in girls puberty occurs after the age of 8 years with the first sign being breast bud development. Progression from beginning to end of puberty typically takes 3–4 years, with peak height velocity (growth spurt) in males achieved about 2 years after the start of puberty and in females, about 1 year after the start of puberty. In males, peak height velocity is manifest by a growth of 9.5 cm/year on average, and in females, growth of 8.3 cm/year on average.^{14 15}

In our patient, the fact that he was a SMR IV for pubic hair and testicular volume at age 11 should raise concern that his pubertal development may have started prior to the age of 9. The second piece of information suggesting precocious development is his growth spurt. As mentioned above, males typically achieve their peak height velocity about 2 years after entering puberty, which again would put his initial development prior to the age of 9 years. On review of his medical record, he was noted to be SMR I pubic hair 1 year prior. This raises the concern that our patient is progressing through puberty too quickly, which could be due to a pathological cause. It is important to mention that a key physical exam finding, testicular volume, was not documented at the visit 1 year prior. Examination of testicular volume is paramount when assessing for pubertal development in males, given that it is the first indicator of puberty. Therefore, examination of testicular volume must be included in routine bedside examination of males, especially those who are nearing puberty or demonstrating other signs of pubertal development.

Precocious puberty is defined as testicular enlargement in boys prior to the age of 9 years and in girls as the development of breast buds prior to the age of 8 years.¹⁶ In the USA, the incidence of precocious puberty is 0.01%–0.05% and is more common in females than males. It is seen more frequently in the African–American population compared with the Caucasian population.¹⁷

Both the causes and effects of precocious puberty can be deleterious for patients, which is why identification and referral are of utmost importance.^{18 19} Pathological causes of precocious puberty include central  nervous   system (CNS) tumours (astrocytoma, optic gliomas, hypothalamic hamartomas, craniopharyngiomas, ependymomas and pineal tumours), adrenal tumours, congenital adrenal hyperplasia, human chorionic gonadotropin producing tumours, and ovarian or testicular tumours. CNS insults such as cerebral palsy, hydrocephalus, radiation, infection or trauma can also result in precocious puberty.

Other diseases and syndromes associated with precocious puberty include tuberous-sclerosis, Sturge-Weber, McCune-Albright syndrome, familial testotoxicosis and Peutz-Jeghers syndrome.^{18 20}

Exposure to exogenous sex hormones is also a potential cause and therefore it is important to ask about the use of oestrogen or testosterone containing pills or creams when taking a history. Given the rise in obesity in children, it should be noted that this can also be related to precocious development.¹⁸

Although pathological causes can be responsible for precocious development, 90% of cases in females are idiopathic. For males, the incidence of a central cause is higher, although still rare overall.¹⁸

Precocious development can lead to short adult stature and have a significant psychosocial impact. Precocious puberty initially causes a rapid growth spurt but then leads to premature closure of the growth plates. Several studies have assessed adult final height in those with a history of precocious puberty and have shown that in untreated patients there is a loss of 20 cm in males and 12 cm in females as compared with average adult height.²¹

There can also be a significant psychosocial impact on individuals with precocious puberty. It is necessary to have a discussion with the patient and family about the psychosocial stressors that may arise and provide counseling as needed. In females in particular, unwanted attention from the development of breasts may arise, as well as the inability to maturely understand and process menarche at a young age. There is also an increased rate of high risk and delinquent behaviours, earlier sexual debut and more sexual partners.²² Development of depression and anxiety has also been reported.²³

When precocious puberty is suspected, workup should begin with a thorough history and physical exam focused on signs and symptoms of pathological causes.¹⁷ Family history of pubertal development in parents and siblings, such as age of menarche in women or voice change in men, or the presence of family members with diseases or syndromes related to precocious puberty should be obtained. History should include the age of development of sexual characteristics and any signs of headache or visual impairment that may suggest a central cause. The height velocity should be noted as well as the SMR stage. A bone age is helpful to evaluate the growth plates as well as predict adult height. Skeletal maturation is reflective of the influence of sex hormones and typically with precocious puberty, a bone age will be advanced greater than two SD. However, bone age may also be advanced in benign variants of pubertal development, such as premature thelarche and adrenarche; therefore, it is always important to review the complete clinical picture and have close follow-up with patients who are undergoing workup. An advanced bone age itself may not indicate true pathology.^{19 24}

Our patient’s history did not indicate any overt pathological cause. He denied symptoms of headache or vision changes, which would suggest increased intracranial pressure from a brain mass; he had no evidence of a testicular mass to suggest a testicular tumour and his normal blood pressure and lack of significant weight changes made adrenal pathology less likely as well. However, his height velocity of 11 cm/year over the past year and advanced bone age did raise concern of precocious development.

Laboratory testing should focus on evaluating for activation of hypothalamic–pituitary gonadotropin (HPG) axis, tumours and adrenal pathology. Generally, LH and FSH should be obtained in all patients in whom there is suspicion for precocious puberty. In males, testosterone is obtained and in females, estradiol is obtained. Tumour markers, such as B-HCG and AFP, are useful when evaluating for potential testicular tumours. If adrenal pathology is suspected, DHEA-S and 17-hydroxyprogesterone measurements should be obtained.^{19 25}

Based on results of laboratory evaluation, pelvic or testicular ultrasonography may be warranted. In males particularly, given the higher incidence of central causes, a brain MRI should be obtained.

Our patient’s LH and FSH were in the pubertal range as shown in table 1, demonstrating that there had been central activation of the HPG axis. His tumour markers (B-HCG and AFP) were also negative, making a testicular tumour less likely. His DHEA-S was elevated, however appropriate for his stage of puberty, and not elevated to the degree that would be seen with adrenal pathology. Given the evidence of central activation of the HPG axis, a brain MRI was obtained, which ruled out a central pathological process.

Referral to an endocrinologist is warranted if there are laboratory abnormalities and treatment is being considered.

Before initiating treatment for patients with idiopathic precocious puberty, it is important to keep in mind the patient’s age, height velocity and potential for negative psychosocial outcomes. Goals of treatment therefore are mainly to preserve adult height and minimise psychosocial difficulties.²⁵ Our patient had already reached his peak height velocity and based on his bone age, his predicted adult height surpassed his MPH.¹ Therefore, treatment was not pursued.

Gonadotropin-releasing hormone (GnRH) analogues are generally used for treatment of precocious puberty. Pulsatile GnRH leads to stimulation of LH and FSH secretion, however when given in doses that maintain a constant serum concentration, GnRH causes a paradoxical inhibition of LH and FSH, thereby stopping further precocious development. GnRH analogues are available in an intramuscular injection form and may be given monthly or every 3 months.^{16 18 19} An implantable form is also available that can last for up to 2 years.²² Continued follow-up with Endocrinology is necessary to ensure proper response to treatment.

Learning points.

• Our case presents an uncommon finding of precocious puberty in a twin boy.

• It highlights the importance of understanding the normal progression of puberty and recognising the signs of precocious puberty.

• Given that both the causes and effects of precocious puberty can be deleterious for patients, identification and referral to a specialist for potential treatment is crucial.