6 Increased Growth Velocity and/or Tall Stature Pushpa Viswanathan and Bianca Pinto P. Viswanathan () University of Pittsburgh School of Medicine, Department of Endocrinology, UPMC Children’s Hospital Pittsburgh, Pittsburgh, PA, USA e-mail: pushpa.viswanathan@chp.edu B. Pinto Division of Pediatric Endocrinology, University of Pittsburgh, UPMC Children’s Hospital Pittsburgh, Pittsburgh, PA, USA e-mail: bianca.pinto@chp.edu © Springer Nature Switzerland AG 2021 T. Stanley, M. Misra (eds.), Endocrine Conditions in Pediatrics, https://doi. org/10.1007/978-3-030-52215-5_2 Normal Growth A careful measurement of height and growth velocity is a sensitive indicator of health and well-being and therefore an essential part of every well child visit to the primary care physician. A complete growth evaluation includes an accurate measurement of recumbent length or height, assessment of height based on mid-parental target height and ethnicity, and monitoring of growth velocity. The Centers for Disease Control and Prevention (CDC) recommends using theWorld Health Organization (WHO) growth charts for children 0–2 years of age and CDC growth charts for children 2 years of age and older [1]. Clinical Tool In children 2 years and younger, recumbent length should be measured with an infantometer. In children older than 2 years, a wall-mounted stadiometer should be used to measure height [3]. Growth velocity should be measured using at least two accurately measured heights obtained at least 3–6 months apart. An infant’s length at birth is a reflection of the maternal and uterine factors affecting fetal nutrition and insulin availability. Hormones like growth hormone and thyroid hormone only have a modest influence. It is not uncommon to see “genetic channeling,” where one might see an upward or downward crossing of percentiles to move toward the child’s genetic potential. This is usually seen around 12 months to 24 months of age [2]. Crossing growth percentiles in this age range is therefore normal. The recumbent length of a small baby, who was exposed to an adverse prenatal environment, with tall parents will channel up across percentiles, while a large baby (e.g., infant of a diabetic mother with uncontrolled blood sugars, who was exposed to large amounts of insulin in utero) born to short parents will channel down. After about 36 months, children who are growing normally should then follow a consistent height percentile during pre-pubertal years. Growth velocity changes throughout childhood (Table 1). Growth should be interpreted in the context of pubertal status, and providers must ensure that the growth velocity is appropriate for the different growth phases – infancy, childhood, and pubertal growth. Tall Stature Tall stature is defined as linear height above the 97th percentile or more than two standard deviations above the mean for age and sex. Concern over tall stature is a relatively rare initial presentation to a primary care office. However, it is not uncommon to see a rapid increase in growth velocity during a well visit. A relative increase in growth velocity can be seen in endocrine conditions such as premature adrenarche, precocious puberty, hyperthyroidism, and growth hormone excess (Table 2). In addition to hormonal disorders that increase the rate of growth and body size, there are overgrowth syndromes that can Table 1: Growth velocity during childhood and adolescence. Age range Growth velocity Birth – 1 year ~ 25 cm/year 1–2 years ~ 10 cm/year 2–4 years 5–10 cm/year 4 years – Puberty 5–6 cm/year Puberty – Final height 8–12 cm/year Endocrine Encounters: Endocrine Disorders in Pediatric Subpopulation
7 Endocrinology Excellence Table 2: Differential diagnosis. Diagnosis Clinical features Normal variant Familial/constitutional tall stature Most common cause of tall stature. Due to genetic potential from family history of tall stature. Otherwise healthy child with normal physical exam. Endocrine/hormonal causes Exogenous obesity Second most common cause of tall stature in childhood. Increased linear growth and weight gain from increased nutritional intake. Precocious puberty (gonadotropin-dependent or gonadotropin-independent) Pubertal changes in boys prior to age 9 years or girls prior to age 8 years. Accelerated linear growth in childhood secondary to pubertal growth spurt occurring at a young age. Androgen insensitivity syndrome (rare) Phenotypical females with XY karyotype. May present with inguinal hernias in childhood or with amenorrhea at pubertal age. Adult height is usually taller than women without the syndrome, but shorter than typical males. Growth hormone excess (rare) Caused by overproduction of GH, often from a GH-secreting tumor. This may be an isolated finding or in association with conditions like McCune Albright syndrome, Carney complex, tuberous sclerosis, familial isolated pituitary adenoma. Hyperthyroidism Increase in growth rate in uncontrolled hyperthyroidism. Estrogen resistance and aromatase deficiency [6, 7] (rare) Suspect if continued growth well after puberty. Due to resistance at the estrogen receptor level (estrogen resistance) or low level of estradiol (aromatase deficiency). Bony epiphyses remain open into adulthood. Familial glucocorticoid deficiency (rare) Patients with point mutations in the ACTH receptor gene are usually noted to be of tall stature. McCune Albright syndrome (rare) Precocious puberty, café au lait lesions, fibrous dysplasia. Tall stature from any hormone over secretion – estradiol, thyroid, growth hormone. Generalized lipodystrophy, XY males with 17 alpha-hydroxylase deficiency inactivating mutations of FGFR3, and others [8] (rare) Tall stature in these conditions with causes including phenotypic females with a Y chromosome, hyperinsulinemia, or mutations in receptor pathways affecting growth. Genetic/overgrowth syndromes (non-hormonal) Klinefelter syndrome (47 XXY) Relatively common. Clinical manifestations include tall stature, small testes, infertility, gynecomastia, and intellectual disability [9]. Neurofibromatosis type 1 [10] Associated with café-au lait spots, neurofibromas, freckling. While many patients have poor growth, tall stature due to GH excess has been reported. Fragile X syndrome Tall stature, large ears, macroorchidism in males [11]. Beckwith-Wiedemann [12] Congenital overgrowth disorder. Infants are large at birth with macroglossia, omphalocele, and hypoglycemia. Growth rate may slow down after the first few years. Increased risk of embryonal tumors, such as Wilms’ tumor, neuroblastoma, and others. Sotos syndrome (cerebral gigantism) (rare) Born LGA with increased growth rate that continues into childhood. Prominent forehead, prominent ears, down-slanting palpebral fissures, narrow jaw, large hands, high-arched palate. Macrocephaly present at all ages. Abnormal body proportions with arm span exceeding height [12]. Weaver syndrome (rare) Excessive growth both prenatally and postnatally. Features resemble Sotos syndrome. Macrocephaly and tall stature. Marfan syndrome and other fibrillinopathies [13] Marfan syndrome is an autosomal dominant disorder of collagen metabolism associated with tall stature with abnormal body proportions due to long extremities, subluxation of lens of the eye, and dilation of the ascending aorta. Homocystinuria (rare) Autosomal recessive disorder similar to Marfan syndrome including tall stature and lens subluxation. 47, XYY syndrome Tall stature with possible behavioral problems or intellectual disability. Simpson-Golabi-Behmel syndrome (SGBS), Partington, and other syndromes [8] (rare) Macrocephaly +/− intellectual disability, visceromegaly.
8 Endocrinology Excellence cause tall stature. These are mainly non-hormonal/genetic conditions. Overgrowth is defined by extreme physical size and stature including tall stature or generalized/localized overgrowth of tissues and/or increased head circumference (macrocephaly). A degree of intellectual disability may be present, as well as associated dysmorphic features, although intelligence may be normal in some overgrowth syndromes. History: Important Clarifying Questions Age of onset of tall stature z Intrauterine overgrowth is seen in multiple genetic syndromes including Beckwith-Wiedemann and Sotos syndrome. z In addition to prenatal overgrowth, rapid growth rate in the first 3–4 years of life is also seen in genetics syndromes such as Sotos and Weaver syndrome. z Tall stature in later childhood may suggest exogenous obesity or hormonal causes. Pubertal history z Age at first signs of puberty including pubic hair, breast development, and testicular development will aid in the diagnosis of precocious/delayed puberty. Developmental milestones/academic performance z May be delayed in various genetic conditions. Past medical history including prenatal and perinatal history z Many genetic syndromes are associated with multiple medical conditions. For example, lens dislocation and aortic dilation in Marfan syndrome. z Birth weight to assess for intrauterine overgrowth; neonatal hypoglycemia from hyperinsulinemia is important to diagnose conditions like Beckwith-Wiedemann syndrome. Family history z Calculation of mid-parental height and parental ages of puberty will help make the diagnosis of familial/constitutional tall stature. z Family history of genetic diagnoses, congenital disorders, endocrinopathies. Important Aspects of the Physical Exam Vitals z Tachycardia and hypertension in hyperthyroidism. Height and growth velocity z Is the growth rate normal or too fast? Acceleration unexpected from familial pattern? z Growth velocity can be estimated from two linear measurements separated by months and calculated as cm/year and compared to the normal velocities for age (Table 1). z Increased growth velocity and/or tall stature may be the only manifestation of a growth hormone (GH) secreting tumor . Children might not have acromegalic features [4]. Weight z Overnutrition is a common cause for linear growth acceleration. z Weight gain precedes and increases more rapidly than height gain in exogenous obesity. Endocrine causes of excessive weight gain usually lead to deceleration in growth velocity. z Children with obesity from overnutrition will have increased height velocity and therefore are taller than their lean peers. Skeletal maturation in this group will be advanced with possible early epiphyseal fusion. Body proportion and dysmorphic features z Measurement of head circumference, upper-to-lower body segment ratio, and arm span is useful to identify some causes of tall stature such as Marfan syndrome and Klinefelter syndrome. z Identification of coarse/dysmorphic features like large head and visceromegaly might give clues to the diagnosis of overgrowth syndromes. Pubertal exam z Pubertal staging is important in tall stature as this may suggest precocious or delayed puberty. Thyroid exam z Goiter in hyperthyroidism. Visual field evaluation z May be abnormal in GH-secreting tumor. Skin/musculoskeletal z Coarse facial features, large hands, and feet (acromegaloid features) may suggest GH excess z Birthmarks and neurocutaneous findings may suggest a genetic diagnosis. For example, café au lait spots for McCune Albright syndrome, neurofibromatosis with GH excess, blue nevi for Carney complex [5].
9 Endocrinology Excellence Clinical Key Peak height velocity is reached 2 years earlier in girls than boys and is dependent on pubertal status. Height velocity should be correlated with pubertal exam, making breast evaluation in females and testicular evaluation in males a vital component of the pediatric evaluation. Consideration for Further Evaluation Baseline evaluation z Bone age study: X-ray of the left hand and wrist for a child over 3 years of age. A normal bone age in a tall child growing in concordance with genetic potential is very reassuring. Laboratory testing is not routinely required in cases of familial/constitutional tall stature, especially if bone age evaluation is normal. z Insulin-like growth factor (IGF)-1, Insulin-like growth factor binding protein 3 (IGFBP-3). z TSH, Free T4. z Karyotype: Especially in tall stature associated with absent or markedly delayed puberty, primary amenorrhea, or small testicular volume, to rule out conditions such as androgen insensitivity, 47 XXY (Klinefelter), 47 XXX (Trisomy X), 47 XYY. Specific investigations based on history and examfindings (Table 2) z Gonadotropins (LH, FSH) and sex hormone levels (testosterone, estradiol) if indicated by pubertal exam findings. z Serum (and urine) homocysteine is advisable in patients with intellectual disability, central nervous system (CNS) abnormalities, or Marfan-like phenotype. z Molecular studies for overgrowth syndromes if indicated by exam findings (or referral to genetics). z Prolactin and other pituitary hormones if GH-secreting tumor suspected. z Glucose suppression test, performed by Endocrinology, is the gold standard diagnosing GH excess – lack of suppression of GH levels to an oral glucose load using an oral glucose tolerance test. z MRI of the pituitary if GH excess is suspected. z Morning serum cortisol level in the rare event of tall stature with features of adrenal insufficiency (fatigue, weight loss, hypoglycemia). Summary of Approach to Tall Stature Not all tall stature is pathological; however as tall stature is socially acceptable and often desirable, pathological causes of tall stature and increased growth velocity can often be missed due to a lack of concern and subsequent workup. Familial/constitutional tall stature is most common and is characterized by a normal history, exam, and growth velocity. There are not early signs of puberty. Parents will also be tall. A thorough family history, therefore, is critical for the diagnosis. Familial/ constitutional tall stature is non-pathological, and generally reassurance is appropriate. Acceleration of height in constitutional tall stature is seen as early as the first 3 years of life with height plots crossing up percentiles towards genetic potential. Normal body proportions will be maintained, and pubertal timing will be based on family pattern. Growth after 3 years of age may be parallel to, but above, the 95th or 97th percentiles. Psychosocial concerns with tall stature are important to address and may be more common in females. Exogenous obesity, caused by a mismatch between caloric intake and caloric expenditure, is a common cause of increased growth velocity in childhood. Usually final height prediction does not exceed mid-parental target height range, as there is proportionate bone age advancement. Exogenous obesity may be associated with premature adrenarche, which may further advance bone age. Healthy weight loss through diet and exercise should be instituted and will prevent further bone age advancement. Increased growth velocity and weight gain from excessive nutritional intake are usually seen later in childhood. If intrauterine or perinatal obesity is identified, it becomes important to rule out overgrowth syndromes that are associated with future risk of tumors and require long-term surveillance. As noted in Table 2, findings such as body disproportion with long extremities, delayed development, and intellectual disability are common in multiple genetic syndromes associated with tall stature. More specific findings can help pinpoint particular diagnoses, such as the overgrowth in infancy seen in Beckwith-Wiedemann and Sotos syndrome, lens dislocation and aortic dilation in Marfan syndrome, and neurocutaneous markers including café au lait spots seen in neurofibromatosis and McCune Albright syndrome. Clinical Key Children with precocious puberty will be tall during childhood; however if left untreated, these children may become short adults due to premature closure of the growth plates. Referral to endocrinology is indicated for evaluation for pubertal suppression. Uncontrolled hyperthyroidism will cause increased growth velocity in children. Identification of symptoms and signs including weight loss, diarrhea, tachycardia, palpitations, and goiter could lead to lab work and timely treatment, leading to normalization of
10 Endocrinology Excellence growth without significant bone age advancement. Similarly, with precocious puberty, although children may be tall or relatively tall for familial pattern, there is advanced skeletal maturation with premature fusion of bony epiphyses and final height will usually be compromised in the absence of intervention. To evaluate for growth hormone excess, a high index of suspicion is needed with careful review of systems. Although physical exam may reveal coarse facial features and large hands and feet, rapid growth rate might be the only clue for the primary care provider. This reemphasizes the importance of proper linear measurement of a child with careful attention to growth velocity in primary care offices. When to Consult Endocrinology? z Growth velocity significantly higher than expected for age and pubertal status. z Tall stature with inappropriate pubertal status for age (precocious puberty, premature adrenarche). z Height prediction corrected for bone age places at a much higher percentile than mid-parental height. z Detection of abnormal body proportions, dysmorphology with tall stature. z If a diagnosis of familial/constitutional tall stature cannot be confidently made, labs and bone age should be obtained, and endocrine consult placed. References 1. Growth Charts - Homepage [Internet]. Centers for Disease Control and Prevention. Centers for Disease Control and Prevention; 2010 [cited 2019Oct14]. Available from: https://www.cdc.gov/growthcharts/ index.htm. 2. Smith DW, TruogW, Rogers JE, Greitzer LJ, Skinner AL, Mccann JJ, et al. Shifting linear growth during infancy: illustration of genetic factors in growth from fetal life through infancy. J Pediatr. 1976;89(2):225–30. 3. A health professional’s guide to using growth charts. Paediatr Child Health. 2004;9(3):174–6. 4. Bowden S, Sotos J, Stratakis C, Weil R. Successful treatment of an invasive growth hormone-secreting pituitary macroadenoma in an 8 year-old boy. J Pediatr Endocrinol Metab. 2007;20(5):643–7. 5. Correa R, Salpea P, Stratakis CA. Carney complex: an update. Eur J Endocrinol. 2015;173(4):M85. 6. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994;331(16):1056–61. 7. Jones ME, Boon WC, Mcinnes K, Maffei L, Carani C, Simpson ER. Recognizing rare disorders: aromatase deficiency. Nat Clin Pract Endocrinol Metab. 2007;3(5):414–21. 8. Sotos JF, Argente J. Overgrowth disorders associated with tall stature. Adv Pediatr. 2008;55(1):213–54. 9. Davis S, Howell S, Wilson R, Tanda T, Ross J, Zeitler P, et al. Advances in the interdisciplinary care of children with Klinefelter syndrome. Adv Pediatr. 2016;63(1):15–46. 10. Cambiaso P, Galassi S, Palmiero M, Mastronuzzi A, Bufalo FD, Capolino R, et al. Growth hormone excess in children with neurofibromatosis type-1 and optic glioma. Am J Med Genet A. 2017;173(9):2353–8. 11. Hersh JH, Saul RA. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127(5):994–1006. 12. Ko JM. Genetic syndromes associated with overgrowth in childhood. Ann Pediatr Endocrinol Metabol. 2013;18(3):101. 13. Hayward C, Brock DJH. Fibrillin-1 mutations in Marfan syndrome and other type-1 fibrillinopathies. Hum Mutat. 1997;10(6):415–23. Source: Viswanathan, P., Pinto, B. (2021). Increased Growth Velocity and/or Tall Stature. In: Stanley, T., Misra, M. (eds) Endocrine Conditions in Pediatrics. Springer, Cham. https://doi.org/10.1007/978-3-030-52215-5_2. © Springer Nature Switzerland AG 2021.
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