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Constitutional Growth Delay

Clinical topic.

• Impaired Growth

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June 17, 2020

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Constitutional growth delay and familial short stature: a guide for families, what is short stature.

Doctors usually define short stature based on standard growth charts, rather than how a child compares in height with his or her classmates. Growth charts show that for each age, there is a range of heights that are normal for boys and girls. Most charts show the lowest line as the third percentile, which means that if a child is at the third percentile, he or she is shorter than all but 3% of children the same age. If a child is at or above the 10th percentile, he or she is somewhat short but in the lower end of the normal range and usually not short enough to see a growth specialist. The exception is when such a child was previously at, for example, the 25th or 50th percentile and crosses lines to the 10th percentile or below; for these children, a growth evaluation may be needed. This “crossing the growth line” suggests that your child’s rate of growth may have decreased.

What Are the 2 Most Common Causes of Short Stature?

Most short children seen by specialists are healthy, and their growth charts usually show that they have been growing close to or slightly below the third or fifth percentile curves but not falling further below over time. In such children, the chances of finding an endocrine problem, such as growth hormone deficiency, or a chronic medical condition serious enough to affect growth that has not already been diagnosed is low. In most cases, the diagnosis will be familial short stature or constitutional growth delay . What are the differences between these 2 diagnoses?

What is Familial Short Stature?

Familial short stature is the most likely diagnosis when a child is growing at a normal rate (following his or her curve) and one or both parents are short—that is, the mother is 5’1” or shorter and/or the father is 5’5” or shorter. Screening laboratory tests almost always produce a normal result. Some specialists order laboratory studies and some do not. A hand radiograph for bone age is sometimes helpful because in children aged 7 years and older, it can help make a prediction of how tall the child will be as an adult. In most cases, the bone age will be within a year of the child’s age and the adult height prediction will be within 2 to 3 inches of that estimated by the following formula: (mom’s height + dad’s height + 5”)/2 for boys; (mom’s height + dad’s height – 5”)/2 for girls. Growth hormone is sometimes used to treat familial short stature but mainly when it is very severe. Insurance will not always cover the costs of growth hormone treatment.

What is Constitutional Growth Delay?

Constitutional growth delay is similar to familial short stature in that the child is usually healthy and growing normally but slightly below the curve. The difference is that, in most cases, neither parent is short, and in most cases, one parent was a late maturer. This means the mother may have started her periods at age 14 years or later, or the father had his growth spurt late (starting after age 15 years) and may have continued to grow in height until age 18 or 19 years. Aunts, uncles, and older brothers or sisters often have the same growth pattern. Screening laboratory test results are generally normal with the exception of the x-ray of the hand (bone age x-ray) . The bone age is a useful test because bone maturation is generally delayed by longer than 1 year and often by 2 years or more. This means that the child will likely start puberty later than many of his or her peers, will continue to grow when other children are finished, and will reach an adult height in the normal range for his or her family. Growth hormone treatment is rarely needed, but some boys with this diagnosis may benefit from a brief course of testosterone if they have not started puberty by age 14 years.

Can Your Child Have Both of These Conditions?

Yes; sometimes, children have short parents with a history of delayed puberty in the family, and they may be diagnosed with both conditions. Again, a bone age x-ray is often helpful in giving an idea as to how tall the child is likely to be when fully grown.

Pediatric Endocrine Society/American Academy of Pediatrics Section on Endocrinology Patient Education Committee

Copyright © 2018 American Academy of Pediatrics and Pediatric Endocrine Society. All rights reserved. The information contained in this publication should not be used as a substitute for the medical care and advice of your pediatrician. There may be variations in treatment that your pediatrician may recommend based on individual facts and circumstances.

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Constitutional Delay of Growth and Puberty

• First Online: 14 April 2016

Cite this chapter

• M. Tracy Bekx M.D. 2 &
• Ellen Lancon Connor M.D. 2  

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Girls with constitutional growth delay typically present in childhood with short stature and/or early adolescence with delayed puberty. Candidate genes producing the picture of short stature and delayed puberty with normal final height are being elucidated but are generally not sought in evaluation outside of research studies. If a family history of delayed puberty is known, review of growth history is reassuring, and bone age radiograph is delayed, diagnosis may be predicted and appropriate counseling given. In other cases in which family history is unknown or negative, evaluation for hypergonadotropic hypogonadism and hypogonadotropic hypogonadism must be undertaken. Although therapeutic options exist, most girls with constitutional delay will not require intervention. This chapter will examine the genetics and presentation of constitutional delay of puberty and growth, the differential diagnosis, therapeutic options, and prognosis for girls with this diagnosis.

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Constitutional Delayed Puberty

Constitutional Delay of Puberty

Genetic causes of delayed puberty, abbreviations.

Acid labile subunit

Constitutional delay of growth and puberty

Follicle-stimulating hormone

Gonadotropin-releasing hormone

Hypogonadotropic hypogonadism

Insulin-like growth factor

Binding protein 3

Luteinizing hormone

Mid-parental prediction of height

Predicted adult height

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Heather L. Appelbaum

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Bekx, M.T., Connor, E.L. (2016). Constitutional Delay of Growth and Puberty. In: Appelbaum, H. (eds) Abnormal Female Puberty. Springer, Cham. https://doi.org/10.1007/978-3-319-27225-2_3

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Patient Education Dec | 13 | 2019

Constitutional Delay in Growth and Puberty

What is constitutional delay in growth and puberty.

Constitutional delay in growth and puberty is a condition in which children experience delayed puberty compared to their peers of similar age associated with a delay in the pubertal growth spurt (‘late bloomers’). These children have short stature relative to their parents’ heights, and a delayed bone age. The bone age is typically determined by examining the maturity of the individual’s bones relative to what is expected for their age in years since birth. These children typically have a family history of ‘late bloomers’. Once puberty begins, it progresses as expected, followed by the pubertal growth spurt. These children will typically have an adult height that is within range of what is expected for their genetic potential. 

The following conditions need to be considered and ruled out in making a diagnosis of constitutional delay in growth and puberty:

• Familial short stature: This is a condition in which the child is short because the parents are short. There is no pathological cause of short stature in the parents or the child
• Achondroplasia and other skeletal dysplasias: These are genetic conditions in which there are abnormalities in how bones develop and grow. These children usually have abnormal body proportions.
• Growth hormone deficiency (GHD): These children are short because their pituitary gland makes insufficient amounts of growth hormone (GH)
• Hypothyroidism: These children are deficient in thyroid hormone, another hormone that is very important for growth
• Cushing syndrome: In this condition, the adrenal glands make excessive amounts of cortisol (the hormone involved in the body’s response to stress), resulting in marked weight gain and a decrease in growth rate (in height), resulting in short stature
• Early onset of puberty: Going through puberty too early may result in short stature because the children have an early growth spurt and also stop growing early
• Nutritional disorders: In certain nutritional disorders, children are short because of associated inflammation and an inability to absorb nutrients appropriately
• Small for Gestational Age (SGA): Some infants who are smaller than average for gestational age at birth fail to demonstrate sufficient “catch-up” growth after birth, and remain short relative to their genetic potential
• Idiopathic short stature (ISS): This refers to children who are short relative to their genetic potential with no identifiable cause

What are the symptoms of constitutional delay in growth and puberty?

Here are the most common symptoms and signs of constitutional delay in growth and puberty:

• Normal growth rate but short stature
• Delayed puberty and the pubertal growth spurt with a delayed bone age (bones mature at a slower rate than expected)

How is constitutional delay in growth and puberty diagnosed?

Your healthcare provider will review your child’s health history, family history and physical exam, and may perform certain tests, including an x-ray of your child’s hand and wrist (bone age), to establish a diagnosis of constitutional delay in growth and puberty.

How is constitutional delay in growth and puberty treated?

Treatment of constitutional delay in growth and puberty depends on the child, and may include:

• Observation with careful monitoring of growth
• Attempting to “jumpstart” puberty by giving monthly testosterone injections for 4-6 months in boys

When should I call my healthcare provider?

Inform your healthcare provider if your child’s height is lower than expected based on the parents’ heights

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Constitutional Growth Delay

• A 1-year-old girl is brought to the pediatrician by her parents for a routine check-up. Her height and weight at the current visit are found to be in the 10th percentile for her age, despite having a birth height and weight in the 50th percentile. A karyotype is obtained at the request of her concerned parents, and is found to be 46,XX. Thyroid function tests reveal TSH and T4 levels within normal ranges.
• constitutional growth delay, in which there is slowed linear growth within the first 3 years of life , is the most common cause of short stature and delay of puberty in children
• ~15% of children with short stature who are referred for endocrinologic evaluation
• may reflect greater proportion of males who are referred for delayed growth
• delays in growth and sexual development
• adolescents will have a normal growth spurt and normal adult height
• may be autosomal dominant, autosomal recessive, or X-linked
• usually normal birth weight and height
• drop in percentiles on growth curve within first 3-6 months of life and up to 3 years of age
• normal growth velocity resumes by 2-3 years of age
• lagging growth in early childhood
• may be reflected in body proportions (i.e., upper-to-lower body ratio may be ↑ compared to normal)
• bone age begins to lag behind child's chronologic age during early childhood and may be delayed in adolescence
• within reference range in constitutional growth delay
• used to rule out hypothyroidism as causative factor
• reflect production of growth hormone
• used to rule out growth hormone insufficiency as a causative factor
• used to rule out Turner syndrome in girls
• chronic respiratory infections, pancreatic enzyme insufficiency, and other complications
• ↓ levels of growth hormone-dependent IGF-1 and IGFBP-3
• karyotype reveals partially or completely missing X chromosome (45,XO)
• reassurance
• growth measurements at frequent intervals (i.e., every 6 months) to establish a trajectory on a growth curve

• - Constitutional Growth Delay

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• Open access
• Published: 24 March 2022

Current clinical management of constitutional delay of growth and puberty

• Rossella Gaudino 1   na1 ,
• Gianpaolo De Filippo 2 , 3   na1 ,
• Elena Bozzola   ORCID: orcid.org/0000-0003-2586-019X 4 ,
• Manuela Gasparri 5 ,
• Mauro Bozzola 6 ,
• Alberto Villani 4 &
• Giorgio Radetti 7  

Italian Journal of Pediatrics volume  48 , Article number:  45 ( 2022 ) Cite this article

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6 Citations

Metrics details

Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences.

A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended.

Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

The most common cause of both short stature and pubertal delay is constitutional delay of growth and puberty (CDGP), which affects over 2% of adolescents, mainly boys. These subjects experience a slowdown in the linear growth within the first 3 years of life, followed by a regular growth even if lower than their peers in the subsequent years. At the average age of puberty, the height begins to move further from the growth curve because of delay in the pubertal growth spurt onset. The CDGP subjects present a spontaneous catch-up growth, an onset of puberty, and a pubertal growth spurt later than average but often fail to achieve the genetic target height [ 1 , 2 ]. Although CDGP is a variant of normal growth rather than a disease, short stature and retarded sexual development may contribute to psychological difficulties, sometimes associated to with poor academic performance. Patients with CDGP have a family history of delayed puberty in 50-75% of cases. The aetiology is not clear. The key genetic regulators in self-limited delayed of puberty (DP) are largely unknown. Via next generation sequencing, mutations in the following genes including HS6ST1 , GNRHR , IL17RD , SEMA3A , TACR3 and TAC3, have been found in patients with DP and spontaneous onset of puberty [ 3 ]. You may speculate that a single deleterious mutation lead to a phenotype of DP, whilst two or more mutations may be required to cause absent puberty, for example in congenital hypogonadotropic hypogonadism (HH) [ 4 ].

The clinician who consults a subject with both short stature and inadequate virilisation may suspect a condition of a delay of growth and puberty. He must keep in mind some main points. First of all, DP is considered the very end of the distribution of the normal timing of puberty, not a pathology. In Caucasians, DP may be defined as the absence of breast bud at 13 years of age in the female or a time gap of more than 5 years from the breast buds to menarche, or no menstruation by age 16 years [ 5 ]. As for the male gender, DP may be defined as lack of increase in testicular volume > 4 ml at 14 years of age or a time gap of more than 5 years from the start to the end of genital growth [ 6 ].

Diagnostic approach

To make a correct diagnosis the clinician should follow a simple iter [ 7 ]. After a detailed medical history and a correct auxological evaluation including height, weight, growth rate and evaluation of pubertal development and its progression, a clinical examination aimed at identifying particular signs should be done. CDGP occurs in healthy adolescents with an height reduced considering chronological age but appropriate considering bone age and pubertal development, which are delayed as well. In particular, CDGP adolescents may show a peripubertal deceleration of growth velocity (slowing down) associated with both delayed pubertal development and bone maturation [ 8 ]. The diagnosis requires the exclusion other causes of pubertal delay mainly organic, genetic and nutritional diseases, such as intestinal malabsorption, subclinical hypothyroidism or cystic fibrosis. A close relation between the stages of pubertal development and the start of pubertal spurt has been suggested. The pubertal growth spurt is usually observed in girls at the first stages of breast, approximately at Tanner II and III stage, while in boys when testicular volume reaches 10-12 ml. Loss of the normal harmony of growth and puberty could suggest an endocrinopathy. However, the normal consonance of growth and pubertal development is characteristic of the subjects with CDGP who do not require specific investigation. Distinguishing between CDGP and HH is especially difficult during initial evaluation because adolescents with these aetiologies are often prepubertal. Neither baseline nor GnRH stimulated gonadotropin levels are capable to differentiate CDGP from permanent hypogonadotropic hypogonadism [ 7 ]. Recently, new developments raise the availability of differentiate CDGP from CHH in the clinical setting [ 9 ]. The FSH-stimulated inhibin B has been shown to correctly differentiate pubertal delay from a hypogonadoptrophic hypogonadism; however further studies are need to confirm this interesting point [ 10 ]. A family history of DP strongly suggests a condition of CDGP (observed in 50–75%). The main characteristics of the three groups are summarized in Table  1 . (Table 1 ) Generally, delayed puberty is a transient condition and has a good prognosis both in terms of final height and of reproductive ability. As growth potential is related to the degree of epiphyseal maturation, bone age delay allows a final stature within the normal range. Actually, there is no consensus whether boys with DP may reach a final height related to the target height [ 11 ]. Either the precise and timely diagnosis of CDGP and the elimination of possible pathological growth patterns are useful to an adequate management of CDGP. The classification of pubertal delay is based on a precise anamnestic investigation and a careful examination with the exclusion of either dysmorphic syndromes and systemic diseases. In some cases a physical examination alone may be sufficient.

Therapeutic approach

The indication of treating CDGP is limited to prepubertal subjects who are older than 14 years of age and have serious psychological distress, mainly correlating to bullying. In girls with CDGP, treatment with a limited dose of estradiol (5-10 mcg daily) for up to 12 months is rare and should led to breast development. Hormonal treatments should be carefully prescribed not to stimulate acceleration in skeletal maturation and not to increase the consequent risk of reduced stature. In fact, in cases of constitutional DP, the best course of action is patience and reassurance. In males a cycle of 50 mg/month of testosterone, increased to 100 mg after 6 months may be offered if psychological problems are exacerbated by the delay [ 12 ]. Another possibility is transdermal testosterone administration, beginning with one puff every second day for 3 months, increasing the dosage progressively [ 13 ]. During treatment a progressive increase of the testicular volume confirms the diagnosis of CDGP. The treatment should continue until a volume of 12 ml is reached, since at that point the boy can produce a substantial amount of testosterone allowing a normal growth. Therefore, the start of treatment should be individualized depending mainly on the psychological repercussions including low self-esteem, poor school performance, depression and bullying [ 12 ]. On the other hand, in hypo- or hyper-gonadotropic hypogonadism long-term hormone substitutive therapy is advised. Girls usually start on a low dose of estrogen administered orally with tablets (5-10 μg/Kg per day) or through transdermal patches every 3-4 days per week, for cycles of 6 months until breast development reaches Tanner III stage. Because of individual variability in the absorption of estradiol, serum estradiol values must be monitored. In 1 year, progesterone is added to facilitate the menstrual cycle and to increase bone density in puberty. Boys usually start with intramuscular injections of 50 mg/month of testosterone for 6 months, rising progressively the dose until an adult dosage (250 mg/month) is reached. However, as for stature, data are not consistent with the indication of growth hormone therapy in increasing adult height in subjects with reduced height and delayed puberty, particularly in the female sex [ 14 ]. While, in cases of significant pubertal delay, if no sex steroid hormones treatment is started, acquisition of bone mass can be reduced leading in adulthood to a major risk of future fractures mainly in men [ 15 ]. Current studies do not demonstrate that initial testosterone therapy impairs future fertility in boys with PHH; however, if new studies were to demonstrate superiority of early gonadotropin treatment, identifying youth with CHH may guide therapy. Thus, the identification of a generalizable, economic and easily administered diagnostic test for delayed puberty still remains an important endpoint for researchers [ 9 ]..

In conclusions, the ability to make a correct and prompt diagnosis has clinical implications. CDGP subjects have a late but normal puberty, which starts spontaneously. On the contrary, hypogonadic patients do not initiate spontaneous pubertal development. The spontaneous start of puberty by 18 years of age is the gold standard for distinguish CDGP from HH. Paediatricians often cannot differentiate CDGP from isolated HH, until the absence of spontaneous puberty by age 18. The lack of pubertal progression for more than 2 years after spontaneous onset at the appropriate age is indicated in girls by a failure to achieve menarche from the onset of puberty. As for boys it is the failure of testes adult size from 4 mL for more than 5 years. Paediatric Endocrinologists should routinely propose GnRH or GnRH agonist tests as early discriminators to obtain a correct diagnosis quickly and thus avoid anxiety in patients and their families. A detailed personal medical history, including auxological parameters and bone maturation, as well as a precise physical examination are useful in diagnostic approach to an adolescent with DP. Familial history may be used to support the diagnosis of CDGP. Finally, biochemical and haematological parameters may be prescribed to spot some chronic systemic conditions that can present only by delayed growth and puberty.

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Abbreviations

• Constitutional delay of growth and puberty
• Delayed puberty

hypogonadotropic hypogonadism

growth hormone

Permanent hypogonadotropic hypogonadism

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Rossella Gaudino and Gianpaolo De Filippo contributed equally to this work.

Authors and Affiliations

Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Pediatric Division, University of Verona, Verona, Italy

Rossella Gaudino

Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Service d’Endocrinologie et Diabétologie Pédiatrique, Paris, France

Gianpaolo De Filippo

French Clinical Research Group in Adolescent Medicine and Health, Paris, France

Pediatric Unit, IRCCS Bambino Gesù Children Hospital, Rome, Italy

Elena Bozzola & Alberto Villani

Department of Pediatrics, San Paolo Hospital, Milan, Italy

Manuela Gasparri

University of Pavia, Pavia, Italy

Mauro Bozzola

Provincia Autonoma di Bolzano, Bolzano, Italy

Giorgio Radetti

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BE planned the study, RG coordinated the study, DFG and BM analyzed the literature, GR and GM analyzed hormonal and psychological aspects, VA was a major contributor in writing the manuscript study. All authors read and approved the final manuscript.

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Correspondence to Elena Bozzola .

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Gaudino, R., De Filippo, G., Bozzola, E. et al. Current clinical management of constitutional delay of growth and puberty. Ital J Pediatr 48 , 45 (2022). https://doi.org/10.1186/s13052-022-01242-5

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DOI : https://doi.org/10.1186/s13052-022-01242-5

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• Hypogonadotropic hypogonadism

Italian Journal of Pediatrics

ISSN: 1824-7288

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A girl aged 15 is referred to an Endocrine Clinic for short stature and delayed puberty

• February 24, 2019
• Pituitary disorders
• By Wendy Schwarz

Case history

A girl aged 15 years and 2 months is referred to the Endocrine Clinic for short stature and delayed puberty.

Read the patient information below and answer Question 1 .

Early history

• Born in Malaysia
• Full term, unknown birth weight, reported as “average”
• Diagnosed with asthma at age 2 months
• Immigrated to Canada at age 2 years

Health and medication history

• Previous health issues: recurrent right ear infections
• No known allergies
• Immunizations are up to date
• No history of head trauma
• No regular medications, but occasional salbutamol for cold-induced asthma
• Operations: right ear cholesteatoma requiring tympanomastoidectomy
• Computed tomography after surgery to look at the mastoid bone found possible Chiari malformation, but no follow-up MRI to confirm

School history

• Average grades, but feels she has to work harder than peers
• Has a few friends, reports bullying from other students about her height
• Extracurricular activities: dance

Family history

• Mom 150.9 cm, delayed menarche at age 14–15 years
• Dad 168.5 cm, average age for puberty history
• Mid-parental height centile: just below 10th
• Two older sisters, age 18 and 20 years, both had menarche at age 12 year

Question 1.

What would your differential diagnoses be?

• Constitutional delay of growth and puberty
• Turner syndrome
• Chronic condition, with malnutrition i.e. Celiac disease
• Hypopituitarism

The role of the nurse

The nurse is pivotal in providing quality healthcare for adolescent patients while communicating in an appropriate intellectual level. They must also appreciate the adolescent’s vulnerability and inexperience with the healthcare structure, their need for respect, privacy and confidentiality, and their developing need for independence.

Vulnerability

A medical diagnosis may make the adolescent feel vulnerable. Nurses should make the patient and family aware of any services that may be available for them. These services may include: support groups, measures to help them attend appointments, and access to treatments.

The attitude of the healthcare staff should be respectful, supportive, and honest. Adolescents are particularly sensitive to the behaviour of others.

During adolescent development, privacy is a very important aspect of their interactions with the healthcare system. A routine examination may be a source of embarrassment and may be very stressful for the adolescent. Offer privacy for undressing (such as behind a curtain, or alone in the examination room) and a gown to cover themselves.

Communication

The nurse should speak to the adolescent with respect, as well as clarity and honesty. They should make sure that the discussion is age appropriate, and give the adolescent the opportunity to ask questions. The nurse should also offer adolescents the opportunity to be involved in the decision-making about investigations and their treatment options.

Testing/diagnosis

Question 2..

Which laboratory tests do you think are needed to refine the diagnosis?

• Complete blood count, C-reactive protein
• Puberty hormones; LH, FSH, Estradiol
• Androgen panel; cortisol, androstendione, 17OH-P (hydroxiprogesterone), DHEA-S (dehydroepiandrosterone)
• Electrolytes, creatinine, TSH and FT4 (Free T4)
• Chromosone analysis (Karyotype)

Question 3.

What other tests would you carry out?

• Laboratory tests
• Genetic testing
• Pelvic ultrasound
• MRI of pituitary

On examination of the patient

• Height 132.5 cm (<1% for age, –4.35  SD )
• Weight 29.5 kg (<1%,–-3 SD)
• BMI 16.9 m 2  (7%)
• Puberty Tanner stage: Axillary hair 1, Breast 1, Pubic hair 1
• Blood pressure: 84/58 mmHg (<90% for age and height)

Treatment plan

Laboratory investigations ordered, as well as bone age X-ray and pelvic ultrasound.

Bone age : Chronologic age of 15 years 2 months with bone age of 10 years

Pelvic ultrasound : Small uterus with no visible endometrium, right ovary small (0.33 mL), left ovary not visualized

Question 4.

Which diagnoses are confirmed/refuted?

• Constitutional delay

Panhypopituitarism

• Other diagnosis
• Turner syndrome – Refuted
• Constitutional delay – Refuted
• Panhypopituitarism – Confirmed
• Other diagnosis – Refuted

Question 5.

What tests are needed to further refine the diagnosis?

GnRH stimulation/provocative testing (Gonadotropin Releasing Hormone)

• Growth Hormone stimulation/provocative testing
• Cortrosyn stimulation/provocative testing

Follow-up plan : Endocrine stimulation/provocative tests

MRI : Absent pituitary infundibulum and hypoplastic anterior pituitary gland in the pituitary fossa

Question 6.

What is your final diagnosis?

• Chronic condition, with malnutrition i.e. Celiac disease, anorexia nervosa

Question 7.

What is your management plan and in what order would you do this?

• Start glucocorticoid replacement
• Start growth hormone replacement
• Start thyroid replacement
• Start puberty induction

Management plan

Started on hydrocortisone 10mg three times daily for 1 week, then started on levothyroxine 50 μg/day.

Started on recombinant human growth hormone 0.18 mg/kg per week (0.026 mg/kg per day) at 1 month after the Free T4 level had increased into the normal range.

Three-month update

Continued on hydrocortisone, levothyroxine, and growth hormone with excellent compliance.

Latest bone age at chronological age 17 years and 5 months is 12 years.

There was discussion with the parents and patient about maximising growth potential before introducing oestrogen, but patient was started on oestrogen replacement (oestradiol transdermal patch 0.375 mg/day) for psychosocial reasons.

Meet the author

Wendy schwarz.

Clinical Resource Nurse, Alberta Children’s Hospital, Calgary, Canada

• Adrenal disorders
• Bone disorders
• Obesity/Type 2 diabetes
• Pituitary/growth disorders
• Puberty disorders
• Thyroid disorders
• Type 1 diabetes

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Article Contents

Who is a typical patient with delayed puberty, what are the differential diagnoses for this patient, what first line assessments should be considered, what second-line investigations should be considered during evaluation of delayed puberty, what is a typical approach to the management of delayed puberty, what are some alternative clinical scenarios, how does the approach to the girl with pubertal delay differ, what if the youth presents at an older age, what about youth who present at younger ages, conclusions, financial support, disclosures, data availability.

• < Previous

An Approach to the Patient With Delayed Puberty

• Article contents
• Figures & tables
• Supplementary Data

Jennifer Harrington, Mark R Palmert, An Approach to the Patient With Delayed Puberty, The Journal of Clinical Endocrinology & Metabolism , Volume 107, Issue 6, June 2022, Pages 1739–1750, https://doi.org/10.1210/clinem/dgac054

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Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population.

The onset of puberty is typified by the re-emergence of pulsatile gonadotropin releasing hormone (GnRH) signaling from the hypothalamus, leading to increased pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH), which in turn stimulates gonadal sex hormone production. Delayed puberty is defined as the absence of clinical signs hypothalamic-pituitary-gonadal (HPG) axis activation (breast development in girls and testicular development ≥ 4 mL in boys), at an age at least 2 SDs later than the population mean ( 1-5 ). Traditional age cutoffs for this diagnosis are 13 years for girls and 14 years for boys ( 6 , 7 ). Pubic hair development is not included in the definition as its onset can be due to adrenarche, a process that is separate from HPG axis activation ( 2 , 8 , 9 ).

The underlying mechanisms that lead to delayed puberty are often unknown. For example, we do not understand fully what causes one young man to enter puberty at age 11 years and another, who has constitutional delay of growth and puberty (CDGP), to initiate puberty at age 14.5 years. Nor do we understand fully the mechanisms underlying how illnesses cause co-morbid pubertal delay, or all the genetic bases of congenital hypogonadotropic hypogonadism (CHH).

On the other hand, research related to genetic causes of delayed puberty has taught us much. In research settings, a genetic cause is found in approximately 50% of cases of CHH (reader is referred to several recent comprehensive reviews ( 10-13 )). More than 50 genes are known to cause CHH, and the identified genes have informed understanding of the function of the HPG axis. For example, key aspects of the embryology of GnRH neurons and their migration along the olfactory placode to the hypothalamus include products of ANOS1 (a cause of Kallmann syndrome) , PROK2 , PROK2R, FGFR1, and CHD7 (a cause of CHARGE syndrome). Genes that regulate gonadotroph function and GnRH secretion (such as TAC3, TAC3R, KISS1, KISS1R ) and GnRH action ( GnRHR ) have also been identified. Genes for transcription factors that play key roles in pituitary development (such as HESX1 and PROP1 ) are now known too. The link between energy balance and HPG axis function/GnRH secretion is better understood due to identification of the genes for the adipocyte hormone leptin and its receptor. Among these discoveries the identification of KISS1 and TAC3 are particularly noteworthy as they played important roles in the identification of the KNDy neurons in the hypothalamus, which co-express kisspeptin (the product of KISS1 and a vital upstream regulator of GnRH secretion), neurokinin B (product of TAC3 ), and dynorphin ( 14 ). Data from animal models indicate that the coordinated release of these 3 peptides is an important regulator of GnRH pulses and may play a key role in sex differences in HPG function, including differences in sex steroid feedback that contribute to the preovulatory GnRH/LH surge ( 15-17 ).

Genetic analyses have also increased understanding of the regulation of the timing of puberty within the general population, as well as the basis of CDGP. Genome-wide association studies (GWAS) have identified nearly 400 loci that affect the timing of puberty ( 18-20 ). The locus with the most robust statistical signal is near the gene for LIN28B, a suppressor of micro-RNA biogenesis, particularly of the let-7 micro-RNA family. The discovery of this locus helped to focus attention on micro-RNAs and their potential role in the regulation of pubertal timing and of related sex differences, although mechanistic understanding of how LIN28B and let-7 micro-RNAs regulate the timing of puberty remains unclear ( 21-23 ). GWAS also identified loci near a small number of known CHH genes (eg, LEPR, TAC3R ) and genes known to cause central precocious puberty (eg, MKRN3 ( 24 )), underscoring the role that these genes play in regulating the timing of puberty in disease (due to loss of function mutations) and in the general population (due to variants with more modest effects). The identified loci provide additional insights into mechanisms that may regulate maturation of the HPG axis; for example, many of the loci exert effects on body mass index (BMI), highlighting the important co-regulation of body mass and pubertal timing, but BMI independent mechanisms are also implicated. Most findings stem from assessment of age of menarche, but pubertal timing in males has also been studied, commonly using age at voice breaking as the marker of pubertal timing. Results indicate that most loci contribute to the timing of puberty in both sexes, but some male/female differences have been identified ( 25 , 26 ). All told, the identified loci explain about 7% of the population variance in the timing of puberty and about 25% of its heritable variance ( 18-20 ).

Although not as numerous as for CHH, sequencing studies have identified several genes that underlie CDGP ( 27-31 ). These genes include IGSF10 , which impacts GnRH neural migration ( 28 ), EAP1, which modulates the GnRH promoter and affects GnRH gene transcription ( 29 ), and FTO , which once again draws attention to the impact of body mass regulation on the regulation of the timing of puberty ( 32 ). Importantly, these sequencing studies have also revealed that although there is some overlap in the genetic bases of CHH and CDGP, most causes seem to be distinct ( 11-13 , 31 , 33 ).

Other forms of genetic investigation have also provided important insights. For example, the GWAS identification of CBX7 as an important regulatory locus ( 18 ) combined with comprehensive rodent studies ( 34 ), has demonstrated that polycomb group proteins (PcG, which include Cbx7) are important regulators of Kiss1 expression. This regulatory mechanism, mediated by complex changes in DNA methylation and histone modifications, ultimately leads to decreased suppression of Kiss1 expression by PcGs and increased GnRH secretion with the onset of puberty. These combined human and rodent data further highlight the importance of epigenetics in the regulation of the HPG axis ( 35 , 36 ) and are consistent with the earlier identification of LIN28B and micro-RNAs (another epigenetic control mechanism) by initial age of menarche–related GWAS. More recent work has detailed additional PcG-related control mechanisms that modulate pubertal timing in rodents via a gene network that includes Lin28 ( 37 ).

The relationship between nutritional status and reproductive endocrine function has long been recognized ( 38 ), and it is well-accepted that undernutrition is a functional cause of delayed puberty. In another example of the importance of epigenetic mechanisms, changes to chromatin structure have recently been identified as key components of this interconnection ( 36 , 39 ). The deacetylase sirtuin 1 (SIRT1) has been identified as a molecule involved in the restraint of female puberty in rodents via repression of Kiss1 expression. At puberty SIRT1 mediated repression of Kiss1 expression is reduced—a mechanism that acts in coordination with the polycomb complex and which can be accelerated by early overnutrition and delayed by undernutrition. These findings solidify SIRT1 as an important energy sensor that mediates the impact of nutritional status on HPG axis activation and puberty.

As will be discussed below through a series of clinical questions, these mechanistic insights inform the evaluation and management of youth with delayed puberty; however, many questions remain, and direct applicability of mechanistic knowledge to day-to-day clinical management remains somewhat limited.

Consider the case of a 14-year-old young man with height of 147 cm (58 inches, < 3%) and weight of 35.5 kg (78 lbs, ~3%) whose testes are 3 mL bilaterally and whose pubic hair is Tanner stage 1. His father was a “late bloomer” who attained his adult height after his eighteenth birthday; his mother had her first menstrual period at age 13.5 years. His mid-parental height is 171 cm (67.5 inches, 25%). His past medical, surgical, and social histories are negative except for being cut from a competitive hockey team due to his relative short stature and lack of muscle mass.

The etiologies of delayed puberty can be grouped into 4 categories ( Table 1 ) and include hypergonadotropic hypogonadism as well as permanent and transient forms of hypogonadotropic hypogonadism. Hypergonadotropic hypogonadism, typified by elevated concentrations of gonadotropins, is most commonly due to primary gonadal insufficiency. Hypogonadotropic hypogonadism, characterized by low gonadotropins, can either be due to a permanent gonadotropin deficiency (isolated or in combination with other pituitary hormone deficiencies) or a transient deficiency due to either a primary delay in the maturation of the HPG axis (known as constitutional delay of growth and puberty, CDGP) or a secondary delay in HPG maturation (known as functional hypogonadotropic hypogonadism) that stems from an underlying condition. CDGP, the most common cause of delayed puberty in both sexes, is self-limited and has classically been described as representing late variants of the normal spectrum of pubertal timing. The frequency of the different etiologies of delayed puberty have been reported from academic centers ( 2-5 , 40 ) ( Table 1 ). However, the incidence of transient forms of hypogonadotropic hypogonadism, in particular CDGP, may be underrepresented in these reports, as many youth may only present to their primary doctor or not at all.

Differential diagnostic categories for delayed puberty

Abbreviations: CDGP, constitutional delay of growth and puberty; CHH congenital hypogonadotropic hypogonadism; CNS, central nervous system; FHH, functional hypogonadotropic hypogonadism; HH hypogonadotropic hypogonadism; HPG, hypothalamic-pituitary-gonadal; MPHD, multiple pituitary hormone deficiency; MRI, magnetic resonance imaging.

a Other than history suggestive of CNS pathology, and normally timed adrenarche, clinical features pertain to youth with congenital not acquired forms of permanent hypogonadotropic hypogonadism.

b Frequency rates based upon published cohorts ( 1-4 , 10 ).

c Majority of youth with Klinefelter syndrome will enter spontaneous puberty but some will present with failure of pubertal progression or stalled puberty ( 13 ).

A large variety of both acquired and congenital conditions comprise the 4 diagnostic groupings ( Table 1 ). Points to highlight include that chromosomal disorders, Turner syndrome in girls and Klinefelter syndrome in boys, are the most common causes of hypergonadotropic hypogonadism ( 10 , 41 ). While the majority of boys with Klinefelter syndrome ( 42 ) and up to 30% of girls with Turner syndrome ( 43 ) will undergo spontaneous onset of gonadarche, a significant proportion will fail to progress completely through puberty with evidence of low sex hormone concentrations and elevated gonadotropins. Further understanding of the genetic regulation of puberty is rapidly advancing and includes the identification of a growing number of pathogenic mutations that underlie primary ovarian insufficiency, decreasing the number of youth who are labeled as having an idiopathic condition ( 44 , 45 ) ( Table 1 ).

It is also important to note that isolated CHH is a heterogeneous entity. Approximately 50% of cases are associated with anosmia or hyposmia (known as Kallmann syndrome) ( 46 ); other features of this syndrome include bimanual synkinesia, dental agenesis, hearing impairment and cleft lip/palate ( 47 , 48 ). As previously discussed, an increasing number of genetic loci involved in either the development and migration of GnRH neurons, or the secretion and action of GnRH, have been implicated in CHH ( 10-13 , 31 ) ( Table 1 ). Autosomal recessive and dominant, X-linked recessive, and imprinting modes of inheritance have been described. Oligogenic inheritance (where more than one gene mutation is present with synergistic effects between the genes) can also occur ( 49 ). The wide variety of pathogenic mutations and their variable penetrance contribute to the significant clinical heterogeneity observed between and within families, ranging from complete lack of pubertal development to partial hypogonadism to even reversible CHH.

CDGP also has a strong genetic component, with a family history of delayed puberty, often in an autosomal dominant manner, reported in 50% to 75% of cases ( 27 , 33 , 50 , 51 ). CDGP also occurs more commonly in family members of individuals with CHH, compared to the general population ( 50 ).As highlighted in Table 1 and previously discussed, rare variants in genes involved in GnRH migration have been described in patients with CDGP ( 27-30 ), with CDGP appearing to have a generally distinct genetic profile from CHH

It is noted that functional hypogonadotropic hypogonadism (FHH) is also heterogeneous and can arise from a variety of chronic conditions (eg, Crohn’s disease, renal failure, restrictive eating disorder etc.), acute illness, excessive exercise, medications (eg, glucocorticoids) or endocrine disorders such as hyperprolactinemia. Nutrition and inflammation have direct effects on GnRH pulsatile secretion ( 52 , 53 ), as has excessive exercise independent of body weight changes ( 54 ). In addition, there is increasing awareness of the genetic interplay with environmental factors in the development of FHH, with higher rates of rare genetic variants associated with CHH found in women with hypothalamic amenorrhea ( 55 ).

The evaluation of the youth with delayed puberty begins with a complete history, including family history of illness and pubertal timing; as well as physical examination ( 1 , 10 , 40 , 56 ). A bone age is usually obtained to permit counseling around predicted adult height, with additional laboratory testing as described below.

We find it helpful to organize the evaluation by around the differential diagnosis. For example, clues to hypergonadotropic hypogonadism would include a history of chemotherapy, radiation, gonadal trauma, or infection; a past diagnosis of a difference in sexual differentiation; or symptoms of underlying syndromes such as Turner syndrome. Behavioral difficulties or developmental delay may lead to an earlier diagnosis in some children with Klinefelter syndrome. Suggestive physical examination findings include characteristic syndromic features such as short stature, cubitus valgus, low hair line or findings suggestive of a difference/disorder of sexual development. However, in many cases the history and physical examination are unrevealing; thus, we recommend measurement of LH and FSH in all youth with unexplained pubertal delay ( 40 ) ( Fig. 1 ).

Diagnostic clinical approach to youth with delayed puberty. Abbreviations: CDGP, constitutional delay of growth and puberty; CHH congenital hypogonadotropic hypogonadism; CNS, central nervous system; FHH, functional hypogonadotropic hypogonadism; HH hypogonadotropic hypogonadism; HPG, hypothalamic-pituitary-gonadal; MRI, magnetic resonance imaging.

To discriminate among the causes of hypogonadotropic hypogonadism, history can again be informative ( Table 1 ). Bilateral cryptorchidism may be the single feature most suggestive of CHH ( 3 ), but other findings such as micropenis at birth and family history of CHH, delayed puberty, anosmia, or infertility are also important. Multiple syndromes are associated with CHH ( 10 ) and features of these conditions (eg, absent/reduced sense of smell in Kallmann syndrome, choanal atresia, or hearing loss in CHARGE anomaly, morbid obesity in Prader-Willi syndrome, blindness in septo-optic dysplasia) can be important clues. On examination, midline defects, dysmorphic features, or visual field abnormalities may suggest the underlying diagnosis; testicular volume of ≤ 1 mL has a reported sensitivity and specificity of 100% and 91%, respectively, for CHH ( 3 ). There is no definitive laboratory test for CHH, but LH will typically be in the prepubertal range in hypogonadotropic hypogonadism, recognizing that FSH is a better test for diagnosis of gonadal insufficiency and LH is a better marker for the onset of puberty. Other neuroendocrine deficiencies, such as growth hormone or adrenal insufficiency, may have already been diagnosed. Acquired forms of permanent hypogonadotropic hypogonadism may be signaled by headaches ( 57-59 ); visual, cognitive, or behavioral changes; seizures; or history of central nervous system trauma or radiation. Supportive findings include abnormalities on the neurologic and/or visual field examination.

As noted, transient FHH can be secondary to a wide array of underlying conditions ( Table 1 ). Clues to the diagnosis of FHH include a history of abdominal pain/constipation/diarrhea suggestive of a gastrointestinal disorder such as inflammatory bowel disease or celiac disease; weight gain/loss or temperature intolerance suggestive of a thyroid disorder; disordered body image or eating suggestive of a restrictive eating disorder; substantially slowed growth suggestive of growth hormone deficiency; or involvement in high demand athletics (gymnastics, ballet, long distance running etc.) that suggest physiologic suppression of the HPG axis. On physical examination, youth with FHH may be underweight for height or have physical findings consistent with a particular disorder (goiter or abdominal distention, for example).

The most common form of transient hypogonadotropic hypogonadism, CDGP, is a diagnosis of exclusion. It is suggested by the lack of findings consistent with the conditions already discussed. There is often a family history of delayed or relatively delayed puberty in fathers and/or mothers ( 27 , 31 , 50 , 51 , 60 ). The growth chart may show gradual downward crossing of centiles as linear growth slows compared to peers who are entering puberty. Development of pubic hair (adrenarche) may also be delayed in CDGP as opposed to CHH where adrenarche occurs at the normal age for population ( 2 , 8 , 9 ).

Second-line investigations can further define the cause of delayed puberty ( Fig. 1 ). For example, in hypergonadotropic hypogonadism, a karyotype or comparative genomic hybridization (CGH) (to allow detection of lower levels of mosaicism) can make the diagnosis of Turner or Klinefelter syndrome. For FHH, it is less clear which second-line tests are indicated. In one case series, more than 25 different disorders were identified as leading to FHH ( 2 ). Thus, some advocate for broad screening for such disorders, while others (we included) recommend targeted testing guided by the history and physical examination ( 40 ). In a clinic audit, practice varied greatly, with the numbers of tests conducted during initial evaluations ranging from three to 27 (mean of 16), but identified abnormalities were rare ( 40 ). Targeted diagnostic tests may be warranted in some cases to investigate further causes of FHH, such as anti-transglutaminase IgA for celiac disease or insulin-like growth factor (IGF1) in cases with growth velocity below prepubertal norms ( 1 ). Measurement of IGF binding protein 3 (IFGBP3) levels can be considered in conjunction with IGF1 in youth with poor nutritional status.

The most challenging clinical scenario is the diagnosis of CHH, especially when the clinical presentation overlaps with CDGP and provides no diagnostic clues. Clinical observation until age 18 years for evidence of endogenous activation of the HPG axis (progressive testicular enlargement or breast development) is, as such, the “gold standard” to distinguish between these 2 conditions. Diagnostic tests to identify the child with CHH at an earlier age, to limit the period of clinical observation and to help initiate timely sex steroid replacement, have been extensively investigated, but to date continue to have limitations. Basal LH concentrations ≥ 0.3 IU/L have good diagnostic accuracy in identifying activation of the HPG axis, particularly in the setting of children with precocious puberty ( 61 , 62 ). LH levels have not, however, been shown to be a good discriminator between adolescents with CHH and CDGP, with concentrations < 0.3 IU/L having a poor specificity and sensitivity for youth with CHH and partial CHH, respectively ( 63-65 ). Similarly, the utility of GnRH, GnRH agonist, and human chorionic gonadotropin (hCG) stimulated gonadotropin and sex steroid concentrations to distinguish youth with CHH from CDGP is limited, with significant overlap in diagnostic thresholds ( 65 ). Initial studies assessing the role of basal inhibin B concentrations were promising ( 66 ) but have not been validated, with significant variability in the cutoff level of inhibin B to distinguish between CHH and CDGP ( 67 ).

Two new biochemical approaches to identify youth with CHH have been published. FSH stimulated inhibin B concentrations < 116 pmol/L have been demonstrated in a study of adolescents with delayed puberty to have excellent diagnostic discrimination ( 68 ). Another proposed approach is the use of the neuropeptide kisspeptin, an upstream stimulator of GnRH release. Kisspeptin-stimulated LH concentrations ≤ 0.4 mIU/ml in 15 youth with delayed puberty had a 100% ability to distinguish CHH from CDGP ( 69 , 70 ). These developments are promising, but the need to validate diagnostic thresholds, as well as potential issues around the length of the test, availability, and cost, currently limit the clinical uptake of these tests. Further investigation of biochemical tests to distinguish between CHH and CDGP remains an area of important ongoing investigation ( 71 ).

With an increasing number of genes associated with CHH, genetic testing is an emerging tool for the clinical investigation of the youth with delayed puberty. In the child with additional phenotypic features such as anosmia/hyposmia, synkinesia, or hearing loss, the probability of detecting a pathogenic variant on testing is increased ( 48 , 72 ). Greater utility may also be seen in older adolescents, with deleterious genetic variants found in 33% of a delayed puberty cohort assessed at a median of 16 years ( 73 ). There remains, however, some challenges in using genetic testing as a discriminatory test between CHH and CDGP in the child without suggestive phenotypic features. Pathogenic variants in patients with CHH are only detected in approximately 50% of cases ( 10 , 12 , 13 ) and, while genetic profiles of CHH and CDGP are generally distinct ( 12 ), there is some overlap between these 2 conditions ( 11 , 33 ). Due to these limitations, routine clinical use of genetic testing remains problematic, but as a second-line investigation, particularly in the youth with a higher pre-test probability of CHH (older age or phenotypic features associated with CHH), genetic analysis may be more valuable.

Magnetic resonance imaging (MRI) has a larger role. MRI of the pituitary gland and olfactory structures can both exclude an acquired form of hypogonadism (eg, CNS tumor) and help look for features of CHH (eg, absence of the olfactory bulbs). MRI is obtained in any patient with suggestive clinical features of intracranial pathology. Absent such concerns, we strike a balance between potential for undiagnosed disorders and resource utilization by waiting until youth are older (girls > 14 years and boys > 15 years) but then routinely perform MRI in youth without evidence of endogenous puberty.

The treatment of delayed puberty has been reviewed recently ( 1 , 74-77 ), and the reader is referred to these sources for further details regarding side effects, pros/cons, and unanswered questions regarding interventions. A general approach to the treatment of delayed puberty in males is outlined in Fig. 2 .

Approach to the management of delayed puberty in males. Abbreviations: CDGP, constitutional delay of growth and puberty; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; SC, subcutaneous.

For the most common scenario, a young man with CDGP, medical treatment is often not needed. Instead, reassurance about expected spontaneous pubertal onset, estimated adult height and the lack of underlying pathology may be all that is needed/requested other than expectant observation. In other cases, concerns raised by negative interactions with peers, poor self-esteem, and/or body habitus may lead to initiation of low dose testosterone supplementation. In the case previously presented, a young man who was recently cut from his hockey team due to relative short stature and lack of muscle mass, intervention may be appropriate. Treatment most commonly involves monthly intramuscular injection of testosterone esters (testosterone enanthate, cypionate, or propionate). A common protocol is to start with 50 mg monthly for 3 to 6 months; if spontaneous puberty does not ensue (as evidenced by increase in testicular size), another course with 25 to 50 mg dose increment can be administered. When doses do not exceed 100 mg per month, rapid advancement of bone age or reduced adult height do not typically occur ( 78-80 ). Side effects are also rare, though priapism can occur in those with sickle cell disease. We also intervene with testosterone in cases where stature is a primary concern as it will promote linear growth in the short-term. Neither growth hormone, which offers at most modest additional benefit, nor aromatase inhibitors, which await long-term data for this indication, are recommended for routine use ( 74 ). For select cases, where the predicted adult height is well below minus 2 SDs, a discussion with the family around potential use of these therapies, as well as their limitations and potential adverse effects, may be warranted.

For youth who do not progress into endogenous puberty after 12 months, testosterone doses can be gradually increased to adult replacement over ~3 years to promote full masculinization. At these higher doses, the interval between intramuscular injections is usually shortened to every other week. Ongoing monitoring for endogenous puberty is recommended—for example, every 6 months through examination of testicular volume and measurement of LH and testosterone levels 1 month post the last injection. If endogenous puberty does not ensue by age 18 years, permanent hypogonadotropic hypogonadism is diagnosed.

Though simple, this approach does have drawbacks. Monthly or biweekly injections are associated with nonphysiologic peaks after and troughs before the injection. Intramuscular injections are also painful and inconvenient as they are difficult for patients/caregivers to administer at home. These concerns have led to consideration of other options, including more frequent subcutaneous injections ( 81 , 82 ), oral ( 4 ) and long-lasting injections of testosterone undecanoate ( 83 ), transdermal gels, and intranasal testosterone. These alternatives likely have a larger role when the hypogonadism and need for supplementation are permanent, although longer term efficacy and safety data in adolescents is still needed ( Fig. 2 ) ( 84 , 85 ). For CDGP, where treatment is short-term and experience with other agents is still limited, routine management continues to rely on testosterone esters, with some regional and provider variability ( 4 ).

Experience and evidence are insufficient to recommend agents other than androgens for routine use in treatment of delayed puberty. These options include: (a) synthetic kisspeptin, which could be administered to promote GnRH secretion and HPG axis function in youth without hypergonadotropic hypogonadism or hypothalamic or pituitary lesions ( 86 ); and (b) letrozole, which has shown efficacy in one trial as an alternative to low dose testosterone for treatment of CDGP ( 87 , 88 ). In individuals with permanent hypogonadotropic hypogonadism, administration of pulsatile GnRH, FSH injections with or without human chorionic gonadotropin (hCG), or purified human menopausal gonadotropin (hMG) is required for testicular growth and spermatogenesis. However, it has yet to be demonstrated that administration of these agents for initiation of puberty in youth with hypogonadotropic hypogonadism improves long-term fertility ( 71 , 74 ).

A similar approach is used for girls presenting with delayed puberty albeit with the use of transdermal or oral estrogen. The most common and preferred form of estrogen replacement is 17-β estradiol, given the increased risk of thrombophlebotic events with conjugated equine estrogen and ethinyl estradiol ( 89 , 90 ). Due to its mode of administration, transdermal 17-β estradiol bypasses hepatic metabolism and has been shown to result in more stable serum estradiol concentrations without lower insulin-like growth factor (IGF1) concentrations as well as decreased potentially genotoxic estrogen metabolites compared to the oral forms ( 91-93 ). Given these effects, as well as a lower thrombotic risk, transdermal 17-β estradiol has been proposed as the recommended form of estrogen replacement, particularly in girls with Turner syndrome ( 41 ). However, studies directly comparing oral and transdermal estrogen have not demonstrated a significant difference in body composition, height, or bone mineralization ( 91 , 94 ), and some find use of oral agents more convenient at lower doses and if intervention may be short-term. Depot monthly estradiol injections are also available in some countries ( 95 ) although they are not as widely used.

In the girl with likely CDGP, when intervention is requested, low dose estrogen replacement for 3 to 6 months can be trialed with the aim of initiating breast development while awaiting endogenous pubertal progression. A typical starting dose of estrogen is 0.25 to 0.5 mg of oral 17-β estradiol (or 5 microgram/kg) daily or, if the transdermal route is preferred, 3.1 to 6.2 mcg (1/8 to 1/4 of a 25 mcg/24h 17-β estradiol patch) can be used ( 1 , 75 , 77 ). Unlike boys, in whom increase in testicular size is indicative of hypothalamic-pituitary gonadal axis activation, the presence of thelarche does not distinguish between the effect of the exogenous vs endogenous estrogen. After the initial treatment course, clinical monitoring for further breast development off replacement and/or measurement of LH and estradiol is needed to assess for onset of endogenous puberty.

When there is no evidence of subsequent endogenous pubertal progression, or in the girl with known hypergonadotropic hypogonadism or permanent hypogonadotropic hypogonadism, estrogen doses are increased over approximately 3 years, with intermittent assessment for endogenous puberty if warranted. In girls with a uterus, a progestin should be added after 2 years of estrogen therapy, or earlier if breakthrough bleeding occurs, to induce endometrial cycling to help reduce the risk for irregular bleeding, endometrial hyperplasia, and endometrial cancer. Another use of progestins, to enhance breast development, is controversial and awaits additional evidence.

The stereotypical case presentation of delayed puberty is the 14-year-old boy with absence of pubertal signs. Indeed, males are much more likely to be seen in academic centers for assessment of delayed puberty, constituting 67% to 71% of patients in published cohorts ( 2 , 3 , 5 ). However, one wonders whether there are additional considerations if, for example, the youth is female rather than male or older or younger that the classic presentation?

Although CDGP is the most common single diagnosis in both boys and girls, girls require greater scrutiny given the higher rates of both hypergonadotropic hypogonadism and FHH ( 2-5 , 40 ) ( Table 1 ). Careful screening for a history consistent with underlying conditions, weight loss, or excessive exercise are especially important given that FHH represents 20% to 30% of cases of delayed puberty in girls.

Approach to the management of pubertal delay can also differ between boys and girls. In a survey of 184 pediatric endocrinologists, 45% reported that they would initiate a trial of sex steroids for a potential diagnosis of CDGP sooner in boys compared to girls ( 96 ). There were also differences in the reasons to initiate a trial of treatment; patient and parental distress and growth concerns were cited as reasons more commonly in boys compared to girls while increasing bone mineral density was noted more frequently in girls. There is evidence supporting increased psychological distress in some boys with delayed puberty ( 97 , 98 ), but data comparing distress between males and females is lacking. While males represent the majority of youth assessed for delayed puberty in tertiary centers ( 2 , 3 , 5 ), to what degree this represents referral bias vs true preponderance of males with delayed puberty compared to females, is unknown. Whether differences in the approach to management of delayed puberty between sexes reflect a greater level of comfort in managing boys compared to girls, that males are truly more distressed and warrant earlier intervention, or that there are other influencing factors such as unconscious biases present, warrants greater study.

The older youth with delayed puberty raises additional questions. Consider, for example, the 16-year-old young man who is prepubertal with 3 mL testes or the 14-year-old young woman with Tanner stage 1 breasts. In rare instances, youth present at these ages for initial evaluation; in other cases, the pediatric endocrinologist may have been following them for presumed CDGP. As depicted in Fig. 3 , these youth prompt a need to reconsider the likely diagnoses. Robust data are lacking, but it is reasonable to assume that the further one gets away from the average age of pubertal onset in the general population, the less likely a diagnosis of CDGP becomes. Other etiologies increase in likelihood and should be considered more strongly, if not already addressed. In cases where diagnosis of CDGP vs persistent hypogonadotropic hypogonadism remains unclear, MRI of the brain should be considered to rule out underlying pathology. Older youth may also present a greater indication for genetic testing as causative genes for CHH and CDGP are identified more often in older youth ( 73 ), although as noted earlier some favor limiting genetic evaluation in such cases to the research setting ( 56 , 99 ).

Change in likelihood of different etiologies of delayed puberty by age. For illustrative purposes, the timing of puberty is depicted as a “normal” or Gaussian distribution; however, it is likely that the true distribution is somewhat skewed ( 17 ).

Even if a definitive diagnosis of “constitutional delay” could be made, these youth raise the question of whether all individuals with idiopathic, self-limited delayed activation of the HPG axis have the same underlying physiology/diagnosis ( 5 ). Do all such individuals have “CDGP” or do different etiologies comprise the far end of the age distribution ( Fig. 3 )? The high heritability of pubertal timing, family histories of delayed puberty among individuals with CDGP, and the demonstrated influence of single nucleotide polymorphisms on puberty timing are all consistent with the possibility that the composition of different common genetic variants underlies the splay in pubertal timing within the general population and within CDGP ( 20 , 26 , 100 , 101 ). Indeed, depending on the number and effect size of the variants present (and their modulation by environmental influences), one could theoretically experience pubertal onset that is either relatively or extremely delayed. However, this “common variant” hypothesis for CDGP has not been empirically demonstrated to underlie the majority of cases, and the increasing number of single gene defects known to cause self-limited delayed puberty ( 10-13 ) implicates additional genetic mechanisms. Clinical scenarios among this population also vary. For example, some youth exhibit longitudinal growth trajectories consistent with the decades-old delayed case curves produced by L. Bayer and N. Bayley ( 102 ); other youth grow along the population-based cross-sectional curves until adolescence when they cross percentiles more acutely as their peers experience puberty and increased growth velocities; still others display an intermediate growth pattern. It remains unresolved whether these patterns reflect different compositions of common genetic variants and environmental influences or different etiologies all together.

Conversely, consider the 13-year-old male or 12-year-old female who has not entered puberty. They too raise questions about age cutoffs and treatment. Population data demonstrate that the onset of puberty is occurring at earlier ages than when the traditional cutoffs for delayed puberty were determined ( 103-105 ). Thus, one wonders if whether new age cutoffs should be established, including whether racial/ethnic group-specific cutoffs should be included. Reconsidering age cutoffs is especially pertinent for females, as the magnitude and uniformity of downward age trends are greater for girls ( 104 , 106 , 107 ) than boys ( 108 , 109 ).

Consensus-based age revisions are lacking, but 2 lines of evidence argue against decreasing traditional ages too much. First, although the timing of puberty approaches a normal distribution in the general population ( 110 ), the model is only approximate, necessitating some caution in using distribution-based statistics to define cutoffs. Second, probability curves for attainment of Tanner stage 2 breast development display a uniform shift toward younger ages when comparing 2006-2008 vs 1991-1993 within the Copenhagen Puberty Study ( 110 ). However, the downward trend of gonadarche in males (testicular volume > 3 mL) is skewed; with a small proportion of youth exhibiting a greater leftward shift toward younger age of onset, while timing of onset among the oldest 5% to 10% shows very little change ( 110 ). Consistent with greater age changes in females, some have advocated for changing the age cutoffs to 12 years for girls (12 months earlier) and 13 years and 6 months for boys (6 months earlier). On the other hand, a recent survey of pediatric endocrinologists in North America revealed that > 50% utilize the current age cutoffs, with smaller percentages advocating equally for either younger or older age designations ( 96 ). Absent a consensus process we, like most survey respondents, continue to use the 13- and 14-year-old definitions.

The high rates of underlying conditions among youth with delayed puberty indicate that all youth presenting with delayed puberty warrant careful evaluation. We work to avoid medicalizing normal variations in growth; however, if an underlying condition is identified prior to traditional diagnostic age cutoffs, initiation of sex steroid supplementation should be considered so that youth can experience pubertal development along with peers, potentially lessening psychosocial and later-life medical ramifications of delayed puberty ( 97 , 98 , 111 ).

Delayed puberty is one of the most common clinical scenarios encountered by pediatric endocrinologists. In this article, we have presented an approach to day-to day clinical evaluation and management of these youth, informed by review of recent literature. In many ways, despite recent research advances, the general clinical approach remains relatively unchanged, but change does seem to be on the horizon driven by areas of challenge and opportunity.

Over the next 5 years, we anticipate that more genes will be identified that underlie CDGP and CHH, increasing the yield of such analyses. These discoveries, along with decreasing costs, will increase use of genetic testing in the day-to-day management of youth with delayed puberty. We envision that these expanded sequencing efforts will also lead to new discoveries regarding the etiology of hypogonadotropic hypogonadism and CDGP and functioning of the HPG axis. In addition, ongoing research regarding practical and reliable biochemical tests to distinguish youth with CDGP from those with CHH may allow for earlier identification of underlying diagnoses, informing both clinical management and counseling for youth and families ( 71 ). A consensus may also emerge regarding new age cutoffs for diagnosis of delayed puberty and parameters guiding intervention at earlier ages.

In addition to age at onset, use of statistical models that allow for pubertal progression to be assessed compared with expected norms for age may increase ( 4 , 112 , 113 ). Such tools are particularly useful in assessment of halted or slowly progressing development. Finally, new modes of therapy are being actively investigated for CDGP and CHH. All these new developments will facilitate a more personalized-medicine approach to evaluation and management of youths with delayed puberty.

Abbreviations

constitutional delay of growth and puberty

congenital hypogonadotropic hypogonadism

functional hypogonadotropic hypogonadism

follicle-stimulating hormone

gonadotropin-releasing hormone

genome-wide association studies

hypothalamic-pituitary-gonadal

insulin-like growth factor 1

luteinizing hormone

magnetic resonance imaging

polycomb group protein

No specific funding/support.

The authors have no conflicts of interest to disclose.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

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Constitutional Growth Delay Differential Diagnoses

• Author: Pamela A Clark, MD; Chief Editor: Sasigarn A Bowden, MD, FAAP  more...
• Sections Constitutional Growth Delay
• Practice Essentials
• Pathophysiology
• Epidemiology
• Laboratory Studies
• Imaging Studies
• Medical Care
• Medication Summary
• Anabolic steroids
• Further Outpatient Care
• Inpatient & Outpatient Medications
• Complications
• Patient Education
• Questions & Answers

Differential Diagnoses

Anorexia Nervosa

Autoimmune disease

Cystic Fibrosis

Growth Failure

Growth hormone (GH) insensitivity

Inflammatory Bowel Disease

Kallmann Syndrome and Idiopathic Hypogonadotropic Hypogonadism

Klinefelter Syndrome

Noonan Syndrome

Nutritional Considerations in Failure to Thrive

Occult malignancy

• Pediatric Growth Hormone Deficiency
• Pediatric Hypopituitarism

Pediatric Hypothyroidism

Prader-Willi Syndrome

Pseudohypoparathyroidism

Renal tubular acidosis

Short Stature

Silver-Russell Syndrome

Turner Syndrome

Sultan M, Afzal M, Qureshi SM, et al. Etiology of short stature in children. J Coll Physicians Surg Pak . 2008 Aug. 18(8):493-7. [QxMD MEDLINE Link] .

Aguilar D, Castano G. Constitutional Growth Delay. StatPearls . 2023 Jun 26. [QxMD MEDLINE Link] . [Full Text] .

Rohani F, Alai MR, Moradi S, Amirkashani D. Evaluation of near final height in boys with constitutional delay in growth and puberty. Endocr Connect . 2018 Mar. 7 (3):456-9. [QxMD MEDLINE Link] . [Full Text] .

Rogol AD, Hayden GF. Etiologies and early diagnosis of short stature and growth failure in children and adolescents. J Pediatr . 2014 May. 164(5 Suppl):S1-14.e6. [QxMD MEDLINE Link] .

Banerjee I, Hanson D, Perveen R, Whatmore A, Black GC, Clayton PE. Constitutional delay of growth and puberty is not commonly associated with mutations in the acid labile subunit gene. Eur J Endocrinol . 2008 Apr. 158(4):473-7. [QxMD MEDLINE Link] .

Rothermel J, Lass N, Toschke C, Reinehr T. Progressive Decline in Height Standard Deviation Scores in the First 5 Years of Life Distinguished Idiopathic Growth Hormone Deficiency from Familial Short Stature and Constitutional Delay of Growth. Horm Res Paediatr . 2016. 86 (2):117-25. [QxMD MEDLINE Link] .

Reinehr T, Hoffmann E, Rothermel J, Lehrian TJ, Binder G. Characteristic dynamics of height and weight in preschool boys with constitutional delay of growth and puberty or hypogonadotropic hypogonadism. Clin Endocrinol (Oxf) . 2019 Sep. 91 (3):424-31. [QxMD MEDLINE Link] .

Howard SR. Genes underlying delayed puberty. Mol Cell Endocrinol . 2018 Nov 15. 476:119-28. [QxMD MEDLINE Link] . [Full Text] .

Barroso PS, Jorge AAL, Lerario AM, et al. Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort. Neuroendocrinology . 2019 Nov 15. [QxMD MEDLINE Link] .

Duckett K, Williamson A, Kincaid JWR, et al. Prevalence of Deleterious Variants in MC3R in Patients With Constitutional Delay of Growth and Puberty. J Clin Endocrinol Metab . 2023 Nov 17. 108 (12):e1580-7. [QxMD MEDLINE Link] . [Full Text] .

Gunn KC, Cutfield WS, Hofman PL, Jefferies CA, Albert BB, Gunn AJ. Constitutional delay influences the auxological response to growth hormone treatment in children with short stature and growth hormone sufficiency. Sci Rep . 2014 Aug 14. 4:6061. [QxMD MEDLINE Link] .

Bozzola M, Bozzola E, Montalbano C, Stamati FA, Ferrara P, Villani A. Delayed puberty versus hypogonadism: a challenge for the pediatrician. Ann Pediatr Endocrinol Metab . 2018 Jun. 23 (2):57-61. [QxMD MEDLINE Link] . [Full Text] .

Rohayem J, Nieschlag E, Kliesch S, Zitzmann M. Inhibin B, AMH, but not INSL3, IGF1 or DHEAS support differentiation between constitutional delay of growth and puberty and hypogonadotropic hypogonadism. Andrology . 2015 Sep. 3 (5):882-7. [QxMD MEDLINE Link] .

Varimo T, Miettinen PJ, Kansakoski J, Raivio T, Hero M. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod . 2017 Jan. 32 (1):147-53. [QxMD MEDLINE Link] .

Giri D, Patil P, Blair J, et al. Testosterone Therapy Improves the First Year Height Velocity in Adolescent Boys with Constitutional Delay of Growth and Puberty. Int J Endocrinol Metab . 2017 Apr. 15 (2):e42311. [QxMD MEDLINE Link] . [Full Text] .

Chioma L, Papucci G, Fintini D, Cappa M. Use of testosterone gel compared to intramuscular formulation for puberty induction in males with constitutional delay of growth and puberty: a preliminary study. J Endocrinol Invest . 2018 Feb. 41 (2):259-63. [QxMD MEDLINE Link] .

McGrath N, O'Grady MJ. Aromatase inhibitors for short stature in male children and adolescents. Cochrane Database Syst Rev . 2015 Oct 8. 10:CD010888. [QxMD MEDLINE Link] .

Harrington J, Palmert MR. Clinical review: Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: critical appraisal of available diagnostic tests. J Clin Endocrinol Metab . 2012 Sep. 97(9):3056-67. [QxMD MEDLINE Link] .

Krebs A, Moske-Eick O, Doerfer J, Roemer-Pergher C, van der Werf-Grohmann N, Schwab KO. Marked increase of final height by long-term aromatase inhibition in a boy with idiopathic short stature. J Pediatr Endocrinol Metab . 2012. 25(5-6):581-5. [QxMD MEDLINE Link] .

Cook DM, Rose SR. A review of guidelines for use of growth hormone in pediatric and transition patients. Pituitary . 2012 Sep. 15 (3):301-10. [QxMD MEDLINE Link] .

[Guideline] Wilson TA, Rose SR, Cohen P, et al. Update of guidelines for the use of growth hormone in children: the Lawson Wilkins Pediatric Endocrinology Society Drug and Therapeutics Committee. J Pediatr . 2003 Oct. 143(4):415-21. [QxMD MEDLINE Link] .

Doneray H, Orbak Z. Association between bone turnover markers and bone mineral density in puberty and constitutional delay of growth and puberty. West Indian Med J . 2008 Jan. 57(1):33-9. [QxMD MEDLINE Link] .

• Comparison of the growth patterns between idiopathic short stature and constitutional growth delay.

Contributor Information and Disclosures

Pamela A Clark, MD Consulting Staff, McLeod Physician Associates; Consulting Staff, McLeod Pediatric Subspecialists Pamela A Clark, MD is a member of the following medical societies: American Academy of Pediatrics , American Association of Clinical Endocrinology , Pediatric Endocrine Society Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Nothing to disclose.

Barry B Bercu, MD Professor, Departments of Pediatrics, Molecular Pharmacology and Physiology, University of South Florida College of Medicine, All Children's Hospital Barry B Bercu, MD is a member of the following medical societies: American Academy of Pediatrics , American Association of Clinical Endocrinology , American Medical Association , American Pediatric Society , Association of Clinical Scientists , Endocrine Society , Florida Medical Association , Pediatric Endocrine Society , Society for Pediatric Research , Southern Society for Pediatric Research , Society for the Study of Reproduction , American Federation for Clinical Research , Pituitary Society Disclosure: Nothing to disclose.

Sasigarn A Bowden, MD, FAAP Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital Sasigarn A Bowden, MD, FAAP is a member of the following medical societies: American Society for Bone and Mineral Research , Central Ohio Pediatric Society, Endocrine Society , International Society for Pediatric and Adolescent Diabetes , Pediatric Endocrine Society , Society for Pediatric Research Disclosure: Nothing to disclose.

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics , American College of Epidemiology , American Pediatric Society , Endocrine Society , Pediatric Endocrine Society , Society for Pediatric Research , Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society , International Society for Pediatric and Adolescent Diabetes Disclosure: Nothing to disclose.

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• v.25(3); May-Jun 2021

Etiological Profile of Short Stature in Children and Adolescents

Rajesh rajput.

Department of Endocrinology, Pt. B. D. Sharma PGIMS, Rohtak, Haryana, India

1 Department of Medicine, Pt. B. D. Sharma PGIMS, Rohtak, Haryana, India

Meena Rajput

2 Department of Social and Preventive Medicine, Pt. B. D. Sharma PGIMS, Rohtak, Haryana, India

Rakesh Garg

3 Department of Medicine, Pt. B. D. Sharma PGIMS, Rohtak, Haryana, India

The delayed growth of a child is a major cause of concern for the parents. There is a multitude of etiological factors which must be considered in relation to this common aspect of healthcare.

The study was done to evaluate the etiological profile of short stature in children and adolescents.

Settings and Design:

The cross-sectional study was conducted for 12 months including 111 cases of short stature (out of the 1,058 cases screened), at the endocrinology outpatient department (OPD) of a tertiary care institute in Haryana.

Subjects and Methods:

As per the inclusion criteria, cases with age <18 years were enrolled. The examination and anthropometric measurements were performed in the presence of parents/guardians.

Out of the 1,058 cases screened; 111 cases of short stature were recruited as per the inclusion and exclusion criteria. The prevalence was about 10.49% of the total population. The mean age of the sample was 12.34 ± 3.19 years. The endocrine causes were the most common followed by normal variants of growth and delay, chronic systemic illness, and nutritional and skeletal causes. Among the endocrine causes, hypothyroidism was the most common followed by growth hormone deficiency and type 1 diabetes mellitus (T1DM).

Conclusions:

The mean chronological age of 12.34 ± 3.19 years suggests the delayed detection of short stature in the population. This highlights the importance of educating parents so that timely therapeutic intervention can be done to achieve the potential height.

I NTRODUCTION

Short stature is defined as a height of less than the 3 rd percentile or 2 or more standard deviations (SDs) below the mean height for age and gender.[ 1 ] There is a multitude of etiological factors which must be considered in relation to this common aspect of healthcare. The causes are broadly classified into normal variants and pathological causes. The normal variants including familial short stature and constitutional growth delay (CGD) are the commonest. The pathological causes include endocrine diseases, chronic diseases, metabolic diseases, and clinically defined syndromes.[ 2 , 3 ]

Therefore, the present study was planned considering its impact on the healthcare of children and adolescents.

S UBJECTS AND M ETHODS

The present cross-sectional study was done at the endocrinology outpatient department (OPD) of a tertiary care institute to evaluate the etiological profile of short stature in children and adolescents in Haryana. The study was conducted for 12 months after approval from the institutional ethics committee. As per the inclusion criteria, cases of either gender with age less than 18 years and a height less than the 3 rd percentile for age and gender or growth velocity less than the 25 th percentile were enrolled. The written informed consent was obtained from the parents/guardians before the inclusion of the cases into the study. The cases with contractures and deformities, fused epiphysis on hand X-ray, and cases under treatment from the outside hospital were excluded from the study. A total of 1,058 cases of short stature were screened, and 111 cases were recruited for the study based on the inclusion and exclusion criteria.

The examination and all anthropometric measurements were performed in the presence of the parents/guardians after informed consent. The height (H) was measured in centimeters using a stadiometer and recorded on the the Indian Academy of Pediatrics-World Health Organization (IAP-WHO) growth chart. The body weight (W) was measured in kilograms with the help of an electronic balance. The body mass index (BMI) was calculated by dividing the weight (kilograms) by the square of the height (meters). The lower segment was measured by a vertical ruler as the distance from the top of the symphysis pubis to the floor. The upper segment was derived by subtracting the lower segment from the total height, and the ratio of the upper and lower segment was calculated.

The mid-parental height (MPH)/target height (TH) was calculated using the following formula:

• MPH for boys = (mother's height + father's height)/2 + 6.5 cm ± 8 cm
• MPH for girls = (mother's height + father's height)/2 – 6.5 cm ± 8 cm

The detailed history, family history of short stature, and parental age at puberty were enquired from each case. The general physical examination and routine investigations were done in all the cases. The X-ray of the non-dominant (left) hand with the wrist joint was done for determining the bone age using Greulich and Pyle's atlas of skeletal development.[ 4 ] The height age was determined as the age which corresponded to the height in centimeters along the 50 th percentile curve on the growth chart. The sexual maturity rating and stages of puberty were recorded based on Marshall and Tanner's staging.[ 5 , 6 ]

The serum follicle-stimulating hormone test (measured by chemiluminescence immunoassay, Immulite-1000, Siemens) was done in all the females presenting with short stature. The thyroid function tests were done to detect hypothyroidism. The serum thyroid-stimulating hormone (TSH) was measured by immuno-radiometric assay (IRMA, Immunotech, Beckman Coulter). The serum T3 (triiodothyronine) and T4 (tetraiodothyronine) were measured by radio-immunoassay (RIA, Immunotech, Beckman Coulter). The growth hormone deficiency (GHD) was diagnosed if the peak serum growth hormone levels were <10 ng/L after growth hormone stimulation (estimated by chemiluminescence immunoassay, Immulite-1000, Siemens) and low-serum insulin-like growth factor-1[ 7 ] (measured by chemiluminescence immunoassay, Immulite-1000, Siemens). The growth hormone stimulation was done by tablet clonidine (0.15 mg/m 2 ). The diagnosis and assessment of the severity of anemia were done based on the cut-off defined by the WHO).[ 8 ] Severe anemia was defined as a hemoglobin level of less than 7 g/dL in children under 5 years of age, and less than 8 g/dL for children over 5 years of age.[ 8 ]

The familial short stature (FSS) was diagnosed if a child was short in comparison to the reference population but remained within the range of the TH with no bone age delay and normal growth velocity.[ 9 ] The constitutional delay of growth and puberty (CDGP) was detected by the presence of short stature, bone age delay (≥2 years), delayed puberty (onset at ≥13 years in girls and ≥14 years in boys) with normal growth velocity, and family history of delayed puberty.[ 9 ] Whereas, the idiopathic short stature (ISS) was detected by the presence of a subnormal growth rate, delayed bone age without any apparent medical cause for growth failure, and normal growth hormone response to provocative testing.[ 10 ]

The data analysis was done using a statistical package for social sciences (SPSS) version 21.0. The normality of the data was tested by the Kolmogorov–Smirnov test. If the normality was rejected; then a nonparametric test was used. The quantitative variables were compared using the independent t -test/Mann–Whitney test (when the data sets were not distributed normally) between the two groups. The qualitative variables were correlated using the Chi-square test/Fisher's exact test. A P value of <0.05 was considered statistically significant.

In the present cross-sectional study, out of a total of 1,058 cases screened; 111 cases were diagnosed as having short stature. The recorded height and weight of the study subjects were plotted on the growth charts. The calculated prevalence of short stature was about 10.49% of the total population.

The males 50.45% (56 cases) with mean age 13.3 ± 3.03 years were found to be affected slightly more than the females 49.55% (55 cases) with mean age 11.36 ± 3.08 years. A significant difference was seen in the age distribution between the males and females ( P 0.016). The majority of the females were in the age group less than 12 years; whereas the majority of males were more than 12 years. The observed mean (SD) of the chronological age (CA) of the sample was 12.34 ± 3.19 years. The mean (SD) values of height (H), weight (W), height age (HA), and bone age (BA) of the study subjects are listed in Table 1 .

Auxological parameters of study subjects (sample size=111)

*SD: standard deviation; † IQR: inter-quartile range; ‡ BMI: body mass index; § BW: birth weight

Among the 111 subjects diagnosed as having short stature, the endocrine causes were found in 42.34% of the cases. Among the endocrine causes, the most commonly observed etiology was hypothyroidism accounting for 30.63% of the cases [ Table 2 ]; where the females (38.18% cases) were found to be affected more than the males (23.21% cases) with no significant difference ( P 0.053). The ISS, i.e., where no pathology was found (including familial and constitutional delay) was found to be present in 43 cases (38.74%); among them, FSS was seen in 35 cases (31.53%) while CDGP was found in 8 cases (7.21%). The GHD was found in 8.11% cases (12.50% males and 3.64% females with a non-significant difference; P 0.085). Type 1 diabetes mellitus (T1DM) was found to be present in 7.21% of the cases (12.73% females and 1.79% males with a significant difference; P 0.02).

Frequency distribution of different etiology of short stature

*CDGP: constitutional delay of growth and puberty; † CHD: congenital heart disease; ‡ GHD: Growth hormone deficiency; § TIDM: Type 1 diabetes mellitus

Chronic systemic illness (CSI) as the cause of short stature was found among 38 cases (34.23%). In this group, a majority of the cases were related to celiac disease (29 cases; 26.13%). The hemoglobinopathies (thalassemia major) were seen in 6.31% of the cases followed by bronchial asthma in 2.70% of the cases and congenital heart disease (CHD) in 1.80% of the cases in decreasing order of frequency. The next important cause of short stature was nutritional disorders (6.31% cases); among them, rickets was found in 2.70% of the cases followed by severe anemia and malnutrition in two cases each (1.80%). The skeletal causes were present in 0.90% of the cases as achondroplasia [ Table 2 ].

Among the 111 subjects diagnosed as short stature, 95.50% (106 cases) were having proportionate short stature; while only about 4.50% (5 cases) were having disproportionate short stature. Among the cases of short stature with hypothyroidism (30.63%), an equal ratio of the upper and lower body segments was observed in 9.80% of the cases while 76.19% of the cases were having a ratio >1 and 33.33% of the cases had a ratio <1 with a significant difference in observations ( P 0.0001). Among the cases of short stature with GHD (8.11%), an equal ratio of the upper and lower body segments was observed in 1.96% of the cases while 20.51% of the cases were having a ratio <1 with a significant difference in observations ( P 0.002).

Among 26.13% of the subjects with short stature in whom celiac disease (CD) was found; 26.47% of the cases were associated with hypothyroidism while no association was observed between the two in 25.97% of the cases; with no significant difference seen in the observations ( P 0.956).

Among 7.21% of the subjects with short stature in whom T1DM was found, 8.82% of the cases were associated with hypothyroidism. Among 26.13% (29 cases) of the subjects with short stature in whom CD was found, 87.50% cases were associated with T1DM while no association was observed between the two in 21.36% of the cases, with a significant difference in the observations present ( P 0.0003).

D ISCUSSION

The delayed growth of the child is a major cause of concern for the parents. The short stature, itself, is a manifestation of many underlying diseases. A delay in the diagnosis and initiation of treatment for these underlying disorders may result in the failure to achieve the genetic potential in height. Therefore, early diagnosis and intervention carry important significance to address the problem of short stature.

The available studies reflect a different prevalence of short stature based on geographical, environmental, and socioeconomic factors. In the present study, the calculated prevalence of short stature was about 10.49% of the total population. The endocrine causes were the most common cause of short stature, of them, hypothyroidism was the most common followed by GHD and T1DM. The extent of the short stature as reflected in this study (a prevalence of 10.49%) was higher than reported by Colaco[ 11 ] (prevalence of 5.6% in 2,500 children admitted in hospitals and 10% in children attending outpatient services). However, Garg[ 12 ] (out of a total of 625 children screened with age 3–15 years attending OPD of a community-level hospital; 86 cases were identified as having short stature) had reported 13.8% prevalence of short stature, higher than that of our study (out of a total of 1,058 cases screened, 111 cases were diagnosed as having short stature with a prevalence of 10.49%).

The assessment of short stature before the epiphyseal fusion is a prerequisite for timely medical management. Unlike the previous Indian studies, the maximum number of short children presented in the 9–15 years age group (64.56%). This reflects the lack of awareness regarding the problem of short stature among the general population. Bhadada,[ 13 , 14 ] et al. reported normal variants as the predominant cause of short stature. Also, they observed pituitary disorders in 19.2%, CD in 13.7%, and hypothyroidism among 13.7% of the cases of short stature in 2005–2007,[ 13 ] compared to their findings of hypothyroidism in 18.4%, pituitary disorders in 15.21%, and nutritional disorders in 17.4% of the cases of short stature in 1995–1996.[ 14 ] The prevalence of hypothyroidism (30.63%) in our study was higher than that reported by Bhadada et al[ 14 ]. (18.4%). This variation in the etiological profile could be due to a difference in the study population, geographical and social factors, and healthcare facilities. Bhadada et al. showed normal variants of growth and delay as the most common cause followed by endocrine causes; while endocrine causes were most common in our study followed by normal variants. The etiological profile of the two studies could not be compared because of the different sample sizes. Both studies were done in different populations and at different intervals.

Zargar,[ 15 ] et al. , from the department of endocrinology, Sher-I-Kashmir Institute of Medical Sciences, determined the causes of short stature in a retrospective study including 193 subjects. The GHD was the commonest identifiable cause of short stature accounting for 22.8% of the cases; in contrast to our study where hypothyroidism was the most common cause of short stature found in 34 cases (30.63%) while GHD was seen only in 9 cases (8.11%).

Thirty-six subjects (18.7%) had a normal variant short stature, while in our study, the normal variant as a cause of short stature was seen in 43 cases (38.74%). Al-Jurayyan,[ 16 ] et al. , 2012, reported a retrospective study of short stature cases referred to the pediatric endocrine clinic. Their study reported short stature as a common referral problem, with FSS being the commonest and seen in 57 (51.8%) patients while in the other 53 (48.2%) patients, variable endocrine and nutritional causes were noted. In our study, the endocrine causes were the commonest (42.34%), followed by normal variant short stature (38.74%).

Lashari[ 17 ] et al. , 2014, in a descriptive cross-sectional study conducted from January 2007 to July 2007, found CGD and FSS as the most common causes of short stature, accounting for 55% of all the short stature cases. They concluded that the most common etiological factors in the order of frequency were normal variants of growth (CGD, FSS), CSI, hypothyroidism, GHD, and CD. In our study, the most common etiological factors in the decreasing order of frequency were endocrine causes, normal variants of growth (CGD, FSS), CSI, and nutritional causes followed by skeletal causes.

Ullah[ 9 ] et al. , 2016, in a descriptive cross-sectional study described GHD, CDGP, FSS, and hypothyroidism as the most common causes of short stature in the decreasing order of frequency; while in our study, the maximum cases were related to normal variant short stature followed by hypothyroidism and GHD. The normal variant short stature was comparable in both the studies. A slight male preponderance was observed in both the studies. Hussein[ 18 ] et al. , 2017, in their descriptive observational study from May 2012 to December 2015 determined the frequency of etiological factors causing short stature. In our study, the cases of CD were higher while that of GHD were lower than Hussein's study. They recommended that growth hormone treatment in children, however, should be promptly initiated with specific clinical indications.

The small sample size was the major limitation of this study. As the study was done at a tertiary care institute, the selected sample is not a true representation of the general population. This highlights the need for a large-scale population-based study for better representation of the problem of short stature in a defined geographical area.

The study results suggest that the frequency of endocrine causes is higher in the endocrine referral center. The mean CA of the study sample of 12.34 ± 3.19 years suggests delayed recognition of the problem in the population. This highlights the need and importance of educating parents along with the serial screening of height and weight to identify a significant growth delay in short children at an earlier age, so that timely therapeutic intervention can be done to achieve the potential height. The growth charts serve as an inexpensive tool for monitoring growth in children and promptly identify significant delays in growth. The study findings can frame our mindset to remain vigilant about the problem for detection at its earliest stage to achieve maximum benefit from the available treatment.

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Conflicts of interest.

There are no conflicts of interest.

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