Familial Tall Stature Research Articles

Genetic Testing of Children With Familial Tall Stature: Is it Worth Doing?

Familial tall stature (FTS) is considered to be a benign variant of growth with a presumed polygenic etiology. However, monogenic disorders with possible associated pathological features could also be hidden under the FTS phenotype. To elucidate the genetic etiology in families with FTS and to describe their phenotype in detail. Children with FTS (the life-maximum height in both the child and his/her taller parent > 2 SD for age and sex) referred to the Endocrinology center of Motol University Hospital were enrolled into the study. Their DNA was examined cytogenetically and via a next-generation sequencing panel of 786 genes associated with growth. The genetic results were evaluated by the American College of Molecular Genetics and Genomics guidelines. All of the participants underwent standard endocrinological examination followed by specialized anthropometric evaluation. In total, 34 children (19 girls) with FTS were enrolled in the study. Their median height and their taller parent's height were 3.1 SD and 2.5 SD, respectively. The genetic cause of FTS was elucidated in 11/34 (32.4%) children (47,XXX and 47,XYY karyotypes, SHOX duplication, and causative variants in NSD1 [in 2], SUZ12 [in 2], FGFR3, CHD8, GPC3, and PPP2R5D genes). Ten children had absent syndromic signs and 24 had dysmorphic features. Monogenic (and cytogenetic) etiology of FTS can be found among children with FTS. Genetic examination should be considered in all children with FTS regardless of the presence of dysmorphic features.

Tall Stature: A Challenge for Clinicians.

Clinicians generally use the term “tall stature” to define a height more than two standard deviations above the mean for age and sex. In most cases, these subjects present with familial tall stature or a constitutional advance of growth which is diagnosed by excluding the other conditions associated with overgrowth. Nevertheless, it is necessary to be able to identify situations in which tall stature or an accelerated growth rate indicate an underlying disorder. A careful physical evaluation allows the classification of tall patients into two groups: those with a normal appearance and those with an abnormal appearance including disproportion or dysmorphism. In the first case, the growth rate has to be evaluated and, if it is normal for age and sex, the subjects may be considered as having familial tall stature or constitutional advance of growth or they may be obese, while if the growth rate is increased, pubertal status and thyroid function should be evaluated. In turn, tall subjects having an abnormal appearance can be divided into proportionate and disproportionate syndromic patients. Before initiating further investigations, the clinician needs to perform both a careful physical examination and growth evaluation. To exclude pathological conditions, the cause of tall stature needs to be considered, although most children are healthy and generally do not require treatment to inhibit growth progression.In particular cases, familial tall stature subject can be treated by inducing puberty early and leading to a complete fusion of the epiphyses, so final height is reached. This review aims to provide proposals about the management of tall children.

The Evaluation and Treatment of Tall Stature in Preadolescent Girls: A Case Report

Families may approach primary care providers for advice and treatment for tall stature (height more than two standard deviations above the mean height for a given age) in pre-pubertal children. The following case report describes an 11-year-old girl who was referred to an endocrinology specialist for familial tall stature. Potential pathological causes for tall stature are reviewed. The assessment, management, and risks and benefits of treatment for this condition are described. Finally, the role of the pediatric nurse practitioner in caring for youth with this chief complaint is discussed.

Exploration d’une avance staturale chez l’enfant : conduite à tenir pratique, principales étiologies à évoquer

Tall stature is not a common motive for medical consultation, even though by definition 2.5 % of children in the general population are concerned. It is usually defined as height greater than+2 standard deviations (SD) using the appropriate growth chart for age and gender, or a difference greater than +2 SD between actual height and target height. With a patient presenting tall stature, the physician has to determine whether it is a benign feature or a disease. Indeed, making the diagnosis is essential for hormonal disease or genetic overgrowth syndromes. The past medical history including parents’ height, prenatal and birth data, physical examination along with anthropometry (height, weight, head circumference, body mass index), and growth chart evaluation with the detailed growth pattern are generally sufficient to make the diagnosis such as familial tall stature, obesity, or early puberty. Bone age estimation may be helpful for some specific etiologies and is also necessary to help predict final adult height. After exclusion of common causes, further investigation is required. Sudden growth acceleration often reveals endocrine pathology such as early puberty, hyperthyroidism, or acrogigantism. Tall stature accompanied by dysmorphic features, congenital malformations, developmental delay, or a family medical history may be related to genetic disorders such as Marfan, Sotos, or Wiedemann-Beckwith syndromes. We relate here the most frequent etiologies of overgrowth syndromes.

What treatment for a child with tall stature?

Tall stature is statistically defined as a height standard deviation score (SDS) above 2 for a given age, sex and population group. The most common cause of tall stature is constitutional (often familial) tall stature. However, underlying endocrine or genetic disorders must be considered as some of them may require specific treatment or management. In constitutional tall stature, healthy children are referred to discuss treatment aiming at reducing adult height. The indications of treatment are rare and usually discussed in girls with extremely tall stature (height SDS>4, corresponding to 185cm in girls). The treatment options for tall children are limited and concerns have been raised about their long-term safety. Indeed, recent studies have suggested that high-dose estrogens in adolescent girls may be associated with an increased risk of infertility, as well as increased risk of cancer. Surgical epiphysiodesis has also been reported to reduce adult height but this invasive procedure in healthy children can be questionable and further data on its safety profile are required.

MANAGEMENT OF ENDOCRINE DISEASE: Diagnostic and therapeutic approach of tall stature.

Tall stature is defined as a height of more than 2 standard deviations (s.d.) above average for same sex and age. Tall individuals are usually referred to endocrinologists so that hormonal disorders leading to abnormal growth are excluded. However, the majority of these patients have familial tall stature or constitutional advance of growth (generally associated with obesity), both of which are diagnoses of exclusion. It is necessary to have familiarity with a large number of rarer overgrowth syndromes, especially because some of them may have severe complications such as aortic aneurysm, thromboembolism and tumor predisposition and demand-specific follow-up approaches. Additionally, endocrine disorders associated with tall stature have specific treatments and for this reason their recognition is mandatory. With this review, we intend to provide an up-to-date summary of the genetic conditions associated with overgrowth to emphasize a practical diagnostic approach of patients with tall stature and to discuss the limitations of current growth interruption treatment options.

Cyclopes and Giants: From Homer's Odyssey to contemporary genetic diagnosis.

Giants are humanlike creatures of prodigious size and strength present in the myths and legends of many cultures. Cyclopes were a race of giants depicted in ancient Greek mythology and literature. Apart from their extraordinary stature, they were also characterised by the presence of one single eye, located in the centre of their forehead. One of them, Polyphemus, plays a central role in one of the most exiting episodes of Homer’s Odyssey. Besides, descriptions of cases of extremely tall individuals appear in the medical literature as early as in the 16 th century A.D. Post mortem evidence of pituitary tumors were identified in most of these cases, pointing towards acromegaly / gigantism as the most likely cause. More recent case reports on real life giants enriched with the use of radiographic imaging have yielded similar results and even familial cases have been identified. Today, pituitary adenomas over secreting growth hormone (GH) are recognised as the most common cause of acromegaly and advances have been made in understanding their aetiology and pathogenesis. Medical interpretation of the case of Cyclopes covers the differential diagnosis of familial tall stature concurrent with vision impairment in the form of bitemporal hemianopia. Combining textual evidence from Homer’s Odyssey with current scientific data has led us to the conclusion that gigantism in the context of Familial Isolated Pituitary Adenoma (FIPA) or X-linked acro-gigantism (X-LAG) due to mutations either in AIP or GPR101 is the possible culprit: a change in DNA sequence functioning as a link between myth and reality, proving not only that Cyclopes could have really existed, but also that giants are still living among us.

Diagnostic Work-up and Follow-up in Children with Tall Stature: A Simplified Algorithm for Clinical Practice.

Objective:No evidence-based guideline has been published about optimal referral criteria and diagnostic work-up for tall stature in children. The aim of our study was to describe auxological and clinical characteristics of a cohort of children referred for tall stature, to identify potential candidates for adult height reduction, and to use these observations for developing a simple algorithm for diagnostic work-up and follow-up in clinical practice.Methods:Data regarding family and medical history, auxological measurements, bone age development, physical examination, additional diagnostic work-up, and final diagnosis were collected from all children referred for tall stature, irrespective of their actual height standard deviation score (HSDS). Predicted adult height (PAH) was calculated in children above 10 years. Characteristics of patients with an indication for adult height reduction were determined.Results:Hundred thirty-two children (43 boys) with a mean ± SD age of 10.9±3.2 (range 0.5-16.9) years were included in the study. Fifty percent of the referred children had an HSDS ≤2.0 (n=66). Two pathological cases (1.5%) were found (HSDS 2.3 and 0.9). Tall children without pathology were diagnosed as idiopathic tall, further classified as familial tall stature (80%), constitutional advancement of growth (5%), or unexplained non-familial tall stature (15%). Of the 74 children in whom PAH was calculated, epiphysiodesis was considered in six (8%) and performed in four (5%) patients.Conclusion:The incidence of pathology was very low in children referred for tall stature, and few children were potential candidates for adult height reduction. We propose a simple diagnostic algorithm for clinical practice.

XYY syndrome: a 13-year-old boy with tall stature.

When evaluating the underlying causes of tall stature, it is important to differentiate pathologic tall stature from familial tall stature. Various pathologic conditions leading to adult tall stature include excess growth hormone secretion, Marfan syndrome, androgen or estrogen deficiency, testicular feminization, and sex chromosome anomaly, such as Klinefelter syndrome and XYY syndrome. Men with 47,XYY syndrome can exhibit multiple phenotypes. A 13-year-old boy visited the hospital for evaluation of tall stature. The boy had no other physical abnormalities except tall stature. All biochemical and imaging studies were within the normal ranges. He was diagnosed with XYY syndrome in this chromosome study. When evaluating men with tall stature, XYY syndrome should be ruled out.

Tall stature in children: differential diagnosis and management

Tall stature in children: differential diagnosis and management

No effect of ethinylestradiol treatment on melatonin secretion in healthy pubertal girls.

The present study investigated the impact of high estrogen doses on melatonin blood concentrations in healthy young girls. Melatonin secretion was investigated in 7 girls (chronological age 13.2 +/- 0.2 years; bone age 12.8 +/- 0.2 years) before and during treatment with ethinylestradiol (EE2, daily dose 0.5 mg/d orally) aimed at the reduction of final prospective height in familial tall stature. Melatonin, LH, FSH, E2 and EE2 were measured by radioimmunoassay. In all subjects, LH and FSH were completely suppressed, but melatonin secretion, day/night plasma values as well as the area under the curve (AUC) remained unchanged under pharmacological administration of ethinylestradiol. We therefore conclude that melatonin secretion is not affected by pharmacological doses of the synthetic estrogen derivative ethinylestradiol in healthy young girls. The decrease of melatonin blood concentrations during puberty is not caused by increasing concentrations of estrogens but must be due to some other process.

Referrals for tall stature in children: A 25‐year personal experience

Extreme tall stature may lead to a variety of concerns in tall children and their parents, leading to requests for treatment to reduce final height in some children. This study reviews referrals for tall stature to a single pediatric endocrinologist and results of treatment over 25 years from 1980 to 2004. Diagnoses, heights, target heights and estimated final heights at presentation, and final heights and complications in treated patients, were examined by retrospective chart review. Of 345 referrals, 244 (71%) were girls and 101 (29%) were boys. Of the 68 (19.7%) treated, 53 (78%) were girls and 15 (22%) were boys. Most children had familial tall stature. Treated children were tall for their already tall families. Treatment reduced final heights compared with estimated final heights by (mean +/- standard error of the mean) 4.2 +/- 0.5 cm (P = 0.001) in girls and 5.1 +/- 0.8 cm (P < 0.001) in boys. Minor complications occurred in 27 (51%) girls, including 5 (9.4%) who stopped treatment because of weight gain, and 5 (33%) of boys. In more recent years, girls (but not boys) presented less frequently, were taller at presentation and opted for treatment less often, and at taller estimated final heights than in the earlier years. Any benefits of high-dose sex steroid treatment of tall children in terms of reduced final height and improved self-image are at the expense of complications in many. Fewer tall girls being referred and treated probably reflects altered attitudes to tallness in society. Such treatment should seldom - if ever - be used in the future.

Somatostatin Analog and Estrogen Treatment in a Tall Girl

A girl aged 10 years and 7months who was 168.9 cm tall was diagnosed as having familial tall stature and was treated with a combination of octreotide acetate (50 μg. sc injection three times daily) and Kaufmann therapy (Premarin 2.5 mg/day for 26 days a month with Provera 10 mg for the last 7 days with Premarin, cyclically) for 25 months to reduce final height. Serum insulin-like growth factor I (IGF-I) and the urinary growth hormone (GH) level decreased and serum gonadotropins were completely suppressed during the treatment. After discontinuation of the treatment, serum IGF-I, urinary GH, and gonadotropins returned to the pubertal level. Her height velocity decreased and bone age advanced from 11.4 years to 14 years during the 25-month treatment. When the treatment was discontinued at the chronological age of 12 years and 11 months, her bone age was 14 years and her height was 176.4 cm. She has almost stopped growing at 13 years and 11 months, and has reached a final height of 177.6 cm.Since the patient grew only 7.9 cm during puberty, it can be concluded that the combination treatment was very effective in reduction of final height.

Growth hormone secretion in children and adolescents with familial tall stature

Sixty-five patients (22 boys and 43 girls) presenting with familial tall stature were investigated with regard to growth hormone (GH) secretion, both physiological and after stimulation with thyrotropin releasing hormone (TRH) and growth hormone releasing hormone (GHRH). Plasma insulin-like growth factor-I (IGF-I) was also measured. Two groups of patients were distinguished according to their physiological secretion of GH: a high secretory group (n = 49) with a mean 24 h integrated concentration of GH (IC-GH) of 5.4 +/- 2.3 micrograms/l per minute and a large number of peaks (5.1 +/- 1.6 in 24 h), and a low secretory group (n = 16) with a mean 24 h IC-GH of 2.1 +/- 0.5 micrograms/l per minute and few peaks (3.3 +/- 1.3 in 24 h). Plasma IGF-I levels and GH peak values after the TRH test were significantly higher in the high secretory group. These results indicate that familial tall stature is the consequence either of hypersecretion of GH or of hypersensitivity to this hormone (IGF-I levels being normal in spite of low GH levels).

Growth hormone secretion in children and adolescents with familial tall stature

Growth hormone secretion in children and adolescents with familial tall stature

Clinical use of the long acting somatostatin analogue octreotide in pediatrics

Preliminary data of the use of the long-acting somatostatin analog octreotide (Sandostatin) in pediatrics are reported. In nesidioblastosis and other hyperinsulinemic conditions, timely treatment with octreotide can protect cerebral function and may reduce mortality. The acute use of octreotide produces prompt elevation of blood glucose, even in patients who fail to respond to diazoxide. In addition, it may be possible to avoid the need for partial or subtotal pancreatectomy by the long-term use of octreotide. As in adults, octreotide should find a place in the symptomatic treatment of secretory diarrhea, notably the watery diarrhea hypokalemia-achlorhydria complex and pancreatic cholera syndrome. Octreotide has been shown to be effective in the treatment of familial tall stature by reducing height velocity and final height. Responses to octreotide therapy vary and the individual responsiveness must be extensively studied.

Accelerated growth in children

Many tall-statured children will display variations of normal growth patterns, such as familial tall stature or familial rapid maturation. However, precocious puberty and a number of rarer diseases that can cause accelerated growth require the earliest possible detection and treatment to ensure that underlying problems are appropriately treated and optimum final adult height is attained. Most of these syndromes are rare. Nevertheless, the pediatric nurse practitioner should be acquainted with them to make timely and appropriate referrals to endocrinologists, geneticists, cardiologists, or orthopedists.

Bromocriptine treatment in adolescent boys with familial tall stature: a pair-matched controlled study.

Recently, bromocriptine has been proposed as a novel agent for the treatment of excessively tall stature in adolescents. To further test its value, we treated nine boys, aged 10.0-15.4 yr, for 1 yr with bromocriptine (7.5 mg/day). A paradoxical plasma GH response to TRH was demonstrated in four of eight boys before and in five boys after 6 months of bromocriptine treatment. At the onset of therapy, the mean adult height prediction was 202.2 +/- 4.3 (+/- SD) cm (Bayley-Pinneau), 202.1 +/- 4.7 cm (TW Mark II), and 198.6 +/- 5.3 cm (Roche-Wainer-Thissen). After 1 yr of therapy, the mean adult height prediction had changed by -4.5 +/- 2.6 cm (Bayley-Pinneau), -3.4 +/- 2.2 cm (TW Mark II), and -2.6 +/- 1.2 cm (Roche-Wainer-Thissen). These reductions were solely due to a decrease in growth velocity and not to an increased skeletal maturation rate. To substantiate these findings, each treated boy was pair-matched with an untreated tall boy so that their chronological and skeletal ages differed by less than 1 yr. After 1 yr of follow-up, height predictions in the treated boys compared with those in the matched control boys gave significantly reduced results with the Bayley-Pinneau and the Roche-Wainer-Thissen, but not with the TW Mark II, method. Because of this discrepancy it is uncertain whether final height in tall boys will really be reduced by treatment with bromocriptine.

Estrogen-induced weight gain cannot be predicted in individuals.

The effect of high estrogen doses on weight was studied in 36 adolescent girls with familial tall stature treated to reduce adult height. Mean weight gain during the first year was 9.0 +/- 3.6 kg. Thereafter, there was no or minimal gain on continued treatment. The largest weight velocity occurred during the first 6 months. Within that period, it was most marked during the first 5 weeks, probably due to early water retention. The gain (total, in different groups of patients and in treatment periods of different duration) did not correlate with height and weight before treatment expressed in absolute values or standard deviation scores. It is concluded that the weight gain induced by long-term estrogen treatment cannot be predicted quantitatively before treatment in individuals, and that heavy or fat girls do not necessarily gain more weight than light and lean girls.

Salivary and Plasma Progesterone in Female Adolescents

The distribution of plasma values of sexual steroids is log normal during the menstrual cycle (Kletzky et al. 1975). After log transformation of simultaneously determined salivary (SP) and plasma progesterone (PP) values, we found a significant correlation between SP and PP in 69 healthy adolescents (r=0.562,p<0.001). Chronologic age (CA) was 10.6.-21.4, bone age (BA) 10.5-18years. This series comprises girls with ovulatory (follicular-FP-and luteal phase-LP) and anovulatory cycles, premenarchal girls and patients with familial tall stature before and after hormonal treatment. For the whole group, the relation between the transformed data was y=0.03459±1.43085× (y=PP,x=SP). With respect to the FP period, the coefficient of correlation between SP and PP was r=0.432 (n=58, p<0.001). The equation was y=4.05524±0.51879×. Considering the progesterone levels in the LP only, the correlation between SP and PP was r=0.783 (n=11, p<0.01) The regression equation was y=3.49863±1.14611×. Provisional normal ranges for SP and PP during the ovulatory cycles were provided by data from 6 regularly menstruating girls (CA 13-21.4, BA 13-18, gynecologic age 0.3-7 yrs; cycle length 26-35 days). The Wilcoxon test for pair differences was significant between progesterone in FP and LP (SP p<0.05,PPp<0.001). Conclusion: Knowing the cycle length, longitudinal analyses of SP are suited to characterise phase and type of a cycle. Because of the high correlation it is possible to calculate PP during LP based on SP.