Continuing Education Activity

Short stature is defined as a condition in which an individual's height is in the 3rd percentile for the mean height of a given age, sex, and population group. It can be assessed through instruments such as measuring tape, stadiometer, anthropometric rod, infantometer, etc. Various terminologies have been used to describe short stature based on the cause. These include Idiopathic short stature, familial short stature, constitutional short stature, constitutional delay of growth, adolescence, etc. Diagnosing short stature requires biochemical and radiological tests, including nutritional assessment, hormonal assessment, and estimation of bone age. The primary management of short stature aims at alleviating the underlying cause, including Gonadotropin-releasing hormone analogs (GnRHa), Aromatase inhibitors, Recombinant human insulin-like growth factor-1 (RhIGF-1), Low-dose androgen therapy, Recombinant human growth hormone (rhGH), etc. In addition to treating the underlying cause, individuals suffering from psychosocial distress should be provided with counseling aimed at imparting coping mechanisms. This activity highlights the different short-stature types, including discussing the underlying pathogenesis, diagnosis, and associated treatments. It reviews the interprofessional team's role in caring for this condition.

Objectives:

• Identify the underlying causes of short stature.

• Assess the diagnosis of short stature.

• Assess the approach to managing short stature.

• Examine the roles of the interprofessional team in managing short stature to enhance patient outcomes and quality of life.

Introduction

Short stature is defined as a condition in which an individual's height is in the 3rd percentile for the mean height of a given age, sex, and population group. It can be assessed through various anthropometric instruments. Short stature can be caused by hormonal, genetic, and developmental pathology. Diagnosing short stature requires biochemical and radiological tests, including nutritional and hormonal assessment and estimation of bone age. The primary management of short stature aims to alleviate the underlying cause and treat the associated psychosocial distress.

Stature is scientifically known as height vertex. It is defined as a person's height from the ground to the vertex when the head is held in the Frankfurt horizontal plane (F-H plane). It can be assessed through instruments such as measuring tape, stadiometer, anthropometric rod, infantometer, etc.[1] According to Ranke (1996), “Short stature is defined as a condition in which the height of an individual is 2 standard deviations (SD) below the corresponding mean height of a given age, sex, and population group.” In medical terminology, it is known as “dwarfism.” There are 2 short stature types: proportionate short stature and disproportionate short stature. Proportionate short stature is diagnosed when the individual has the usual proportion in the limbs and trunk height, whereas when this proportion is absent, and the individual shows a great difference in his sitting and standing height, the individual is said to have disproportionate short stature. In literature, various terminologies describe short stature based on the cause. These include idiopathic short stature, familial short stature, constitutional short stature, constitutional delay of growth, adolescence, etc.

Etiology

Stature is a hereditary trait controlled by genetic and environmental factors.[2] Short stature has 4 major causes:

1. Genetics: The height of a person is determined by their genetic makeup. If any of the parents have short stature or recorded it in their family history, then there is a greater possibility that they also have short stature. However, genetic short stature is applicable only if there is no underlying medical reason. This has also been categorized as familial short stature.[3] Individuals with a genetic makeup of short stature reach a height within the target height range. They have a normal growth rate and have no bone age delay.[4]
2. Constitutional growth delay: Constitutional growth delay deals with the tempo of growth or growth velocity. The tempo of growth throughout the growth process of these individuals may be slow or normal. Some children develop later than others, ie, delayed bone age. They are small for their age and enter puberty later than others. However, they usually catch up in adulthood, having short stature during childhood but a relatively normal height in adulthood. The reasons for this may include malnutrition during the gestational period and early childhood or could be genetic. Malnutrition is 1 factor affecting the tempo of growth and bone development, which may further aggravate short stature in a genetically predisposed individual.[5] Malnutrition during the gestational period results in underweight infants, whereas it causes stunted growth during childhood. Along with malnutrition, genetics play a crucial role in determining the tempo of growth. These individuals may be categorized as having constitutional delays in growth and adolescence.[3]
3. Early puberty: Short stature may also result from precocious puberty of the child.[6] Due to early puberty, the child may not realize their full growth potential. There are various reasons behind the attainment of early puberty, including earlier development of ovaries, adrenals, pituitary, cerebral, and central nervous system abnormalities, and the family history of the disease, showing a genetic nature.
4. Medical reasons: Several medical reasons can cause short stature. These include diseases and disorders, the most significant being hormonal deficiencies.
   • Endocrine disorder: The major medical cause of short stature is growth hormone deficiency. This may be categorized as an endocrine disorder. Growth hormones regulate human growth. The growth hormone-releasing hormone released by the hypothalamus stimulates the production and secretion of growth hormone from the anterior pituitary. These growth hormones act on the liver and other tissue and stimulate the secretion of insulin-like growth factor-1 (IGF-1), which further acts on the bones and promotes endochondral ossification. Pagani et al (2017) found a positive correlation between IGF-1 and stature, demonstrating lower levels of IGF-1 in individuals with short stature.[2] Another endocrine cause for short stature is androgen deficiency, causing decreased bone formation and development.
   • Genetic disorders: Various genetic disorders affect growth, including Down syndrome, Turner syndrome, 3M syndrome, Noonan syndrome, Prader-Willi syndrome, Aarskog syndrome, Silver-Russell syndrome, short stature homeobox gene deficiency, etc.[7][8][9][8][7] These genetic disorders affect the growth of an individual, resulting in short stature. They are also associated with hormonal imbalances, which may manifest as ovarian insufficiency, slowed growth, lack of growth spurts at expected times, irregular menstrual cycles, etc.
   • Bone diseases: Bone diseases affect bone growth, thus affecting the person's stature. These diseases include achondroplasia (short-limbed dwarfism), diastrophic dysplasia (short-limbed dwarfism), spondyloepiphyseal dysplasias (short-trunk dwarfism), rickets, etc.[10]
   • Chronic disorders: Chronic disorders also affect a person's overall growth, including stature. These disorders include cystic fibrosis, Crohn disease, juvenile idiopathic arthritis, anemia, chronic renal insufficiency, inflammatory bowel disorder, etc.
   • Environmental pollutants: Studies have shown that exposure to environmental pollutants such as lead, cadmium, hexachlorobenzene, polychlorinated biphenyl, etc, has been associated with reduced height.[11][12]

Epidemiology

Population Variations

A person's stature results from interactions between genetic adaptations and climatic conditions. The extremely cold climate favors short and round individuals, whereas individuals from hot climates are generally tall and thin, according to the Allen (1877) and Bergmann rules (1847). Following the Allen rule, the distal limb segments in Equatorial Africans are longer than those from more temperate climates.[13] Therefore, while an individual can have normal stature according to his population group, it can result in short stature relative to the entire population. Because of these population variations, an individual's mean height is always compared with the mean height of that specific population only. According to the definition, 97.5% of the population belongs to normal and tall stature, and only -2 SD, ie, 2.5% of the population has short stature. However, the prevalence rate may vary depending on the climatic conditions of the geographical area.

Prevalence of Short Stature

Saudi Arabia recorded a relatively high frequency of short stature, ie, in boys; the study found a prevalence of 11.3% in children and 1.8% in adolescents. In girls, short stature was prevalent in 10.5% of children and 1.2% of adolescents.[14] However, researchers found the prevalence rate of short stature in Jordan was 4.9%.[15]

A study on the Galician population from Spain has recorded 1% of children with short stature due to malnutrition among the 7438 recruited children.[16] In contrast, a longitudinal study conducted in Kobe, Japan, on 27228 infants born small for gestational age, documented that only 15 infants, ie, a prevalence rate of 0.06%, met the criteria for growth hormone treatment.[17] Only 555 out of 114881 children in the United States had short stature.[18]

A study from South India recorded a prevalence rate of 2.86% in school-going children. The study examined 15644 children, of which 448 (2.86%) had short stature. The major reasons behind short stature were genetics and constitutional delay in growth in 66.67% of children, whereas 13.79% and 9.20% had hypothyroidism and growth hormone deficiency, respectively. Only 6.69% of children were reported to have short stature caused by malnutrition.[19]

Sex-related Short Stature

A retrospective study in South China showed a difference in the frequency of hospital-reported cases. More boys were admitted than girls.[20] This may be due to the higher prevalence of social pressures and expectations from males compared to females. Meanwhile, the prevalence rate in Rosario, Argentina, was found to be statistically higher in females (16.4%) than in males (8.4%) (p<0.001).[21] Women's short stature was related to age, weight, and abdominal obesity.

Age-related Short Stature

Individuals who have not attained skeletal maturation, ie, the union of epiphyseal plates, can be affected.

History and Physical

The diagnosis requires in-depth interviews, anthropometric measurements, ancestry analysis, biochemical investigations, etc. The steps involved in the diagnosis are listed below:

1. Anthropometric measurements: Short stature can be diagnosed by measuring the height vertex, body weight, trunk height, and limb length of an individual. These are assessed relative to age, sex, and population.
2. Medical history: The medical history of an individual involves evaluation of relevant history - from the gestational period till birth, the emergence of milestones from early childhood to adolescence, as well as the emergence of puberty - to trace growth patterns and tempo of growth, history of the disease, nutritional diet chart, etc.
3. Family history: The family history includes pedigree analysis, history of short stature, etc.
4. Psychology-related questions: Questions assessing psychology would be asked, including behavioral changes, social relationships, family relationships, etc.

Evaluation

The medical investigation for diagnosis of short stature includes a range of biochemical and radiological tests that correlate with the clinical features. These include:

1. Medical tests: Medical tests are required for confirmation of diagnosis. These include nutritional assessment, assessment of growth hormones, insulin-like growth factor-1 levels in blood serum, and the complete blood count. Additional investigations include x-rays to estimate and correlate bone age with chronological age, etc. Traditionally, x-rays of the left hand are assessed using the Greulich-Pyle method to estimate bone age.[22]
2. Other symptoms: Clinical features associated with genetic and nutritional disorders and other diseases should be evaluated to help identify the underlying cause.

Treatment / Management

The primary management of short stature should aim at alleviating the underlying cause. Short stature caused by underlying hormonal deficiency should be managed with hormonal treatment. Short stature due to bone diseases should aim at treating the disease.

Various hormonal treatments are available today to treat the underlying hormonal condition that gives rise to short stature, and they should be prescribed as soon as possible. This treats the underlying cause, prevents the development of short stature, and prevents its psychosocial effects. These include treating growth hormonal deficiencies and constitutional growth delays with gonadotropin-releasing hormone analogs (GnRHa), aromatase inhibitors, recombinant human insulin-like growth factor- 1 (RhIGF-1), low-dose androgen therapy, recombinant human growth hormone (rhGH), etc.[6]

• GnRHa treatment is given in case of early or precocious puberty development. The administration of GnRHa suppresses gonadotropin, and gonadal steroid secretion allows for increased menarche development time. It leads to delayed bone maturation and fusion of the epiphyseal plates.[6] It also influences growth velocity.
• Low-dose androgen therapy, using oxandrolone, given to peri-pubertal males, has been shown to increase the growth potential but has no positive effect on stature. Animal models using oxandrolone have also been found to have good efficacy in preventing the development of osteopenia and short stature.[23]
• Maternal metformin treatment has been shown to improve fetal growth in animal-based studies. Metformin increases insulin sensitivity in the fetus, leading to higher glucose uptake by tissue and better development.[24]
• Recombinant human insulin-like growth factor- 1 (RhIGF-1) has been used in children to treat insulin-like growth factor-1 (IGF-1) deficiency and pregnancy-associated plasma protein A2 deficiency.[25]
• Aromatase inhibitors hamper the action of aromatase, an enzyme that converts androgens to estrogens, androstenedione to estrone, and testosterone to estradiol, thereby delaying puberty.[25] The studies suggested that it delays bone maturation and increases stature.[6]
• Recombinant C-natriuretic peptide (CNP) has been found to increase the growth velocity up to 42 months in treating achondroplasia.[25]

In addition to treating the underlying cause, individuals suffering from psychosocial distress due to their short stature should receive psychosocial counseling to acquire coping mechanisms.

Differential Diagnosis

Endocrine disorders: Growth hormone deficiency, insulin-like growth factor-1 (IGF-1), growth failure, constitutional growth delay, growth failure, stunted growth, structural brain abnormalities, or pituitary lesions, pituitary microadenomas, congenital hypothyroidism, idiopathic short stature, intrauterine growth deficiency, etc.[26]

Genetic disorders: Down syndrome, Turner syndrome, 3M syndrome, Noonan syndrome, Prader-Willi syndrome, Aarskog syndrome, Silver-Russell syndrome, etc.

Bone diseases: Dwarfism, achondroplasia (short-limbed dwarfism), diastrophic dysplasia (short-limbed dwarfism), spondylo-epiphyseal dysplasia (short-trunk dwarfism), rickets, etc

Chronic disorders: cystic fibrosis, Crohn disease, juvenile idiopathic arthritis, anemia, chronic renal insufficiency, inflammatory bowel disorder, chronic malnutrition, etc.

• Psychological distress
• Aarskog syndrome
• Achondroplasia
• Anemia
• Chronic malnutrition
• Chronic renal insufficiency
• Congenital hypothyroidism
• Constitutional growth delay
• Crohn disease
• Cystic fibrosis
• Diastrophic dysplasia
• Down syndrome
• Dwarfism
• Growth hormone deficiency
• Growth failure
• Idiopathic short stature
• Inflammatory bowel disorder
• Insulin-like growth factor-1
• Intrauterine growth deficiency
• Juvenile idiopathic arthritis
• Noonan syndrome
• Pituitary lesions
• Pituitary microadenomas
• Prader-Willi syndrome
• Psychological distress
• Rickets
• Silver-Russell syndrome
• Spondylo-epiphyseal dysplasia
• Structural brain abnormalities
• Stunted growth
• 3M syndrome
• Turner syndrome

Prognosis

Early diagnosis and management of preventable conditions can significantly improve the condition and accelerate growth to match their peers. Lionel Messi, regarded as 1 of the greatest footballers, reportedly underwent treatment for growth hormone deficiency with a positive outcome. While the prognosis for short stature in individuals who have attained skeletal maturity is extremely poor, the associated psychosocial stress is manageable with counseling.

Complications

The complications of short stature are often more dramatic in women, preventing the individual from bearing and giving birth to a child. This can further aggravate the anguish in an already distressed individual. Other complications include the stunted growth of internal organs, causing a predilection to various diseases and conditions.

Impact of short stature on psychology:

Numerous studies have shown that stature helps determine a person's personality. During the selection of partners for marriage, stature plays an important role. Tall statured individuals are mostly preferred. Despite this, short-statured individuals are always belittled by their peers and family in schools, colleges, and the workplace. They are often teased and bullied, resulting in social isolation, and thus, are at high risk of having psychosocial distress, especially during their adolescence.[27][28][29][30][31][32] They also encounter academic difficulties, family relationships, social relationships, office environment, etc.

Deterrence and Patient Education

The importance of patient education is 2-fold. The first is the detection and management of preventable conditions causing short stature. An equally important aspect of patient education is counseling patients and family members to improve the quality of life in individuals who have already attained full maturation. Counseling can also help individuals deal with the effects of bullying, social isolation, and stress associated with short stature.

Pearls and Other Issues

Clinical Significance

Stature is used to monitor physical growth and development during childhood. Stature is an indicator of malnutrition (including gestational malnutrition) and 1 of the constituents of BMI (body mass index); this can further help assess nutritional uptake. If the underlying cause of short stature is known, the related treatment can be provided. Short stature has a psychosocial impact on an individual, and therefore, a person's behavior (bullying behavior, isolated behavior, etc) can be improved by counseling.

Anthropological Significance

Anthropology is a human science, with human auxology or human growth and development being a major branch of biological anthropology. The focus of a biological anthropologist is the assessment of physical growth and development during life, which can be examined through the stature of an individual. Anthropologists study the various reasons behind short stature in a population and can assist in recording the family history, emergence of puberty, and genetic diseases. Anthropologists also help assess growth patterns and nutritional uptake among different population groups and help evaluate the risk factors, including diet, environment, and genetics.

Forensic Significance

Identification is an essential part of forensic investigations. Where identification cannot be established, forensic investigators develop the biological profile based on ancestry, age, sex, and stature. While stature alone cannot be used to establish identity, it assists in crime investigation by eliminating suspects, especially those with short stature.

Enhancing Healthcare Team Outcomes

Medical personnel, especially those working in child and maternal health, may be required to intervene in cases of short stature. Adequate knowledge of the underlying conditions, their treatment, and the need for counseling can greatly improve patient outcomes, prevent the development of short stature, and improve the quality of life of individuals who have already attained full maturation. These efforts require an interprofessional healthcare team that includes the primary care provider, nurses, and pharmacists. This team must coordinate their efforts and have open communication so that all team members are on the same page and can lend their expertise to guide optimal patient outcomes.