Tall stature: a difficult diagnosis?

Firstly, tall stature is defined as a height more than two standard deviations (SD) above the mean for age, i.e. greater than the 97th percentile for sex and age. It is important to take into account the ethnic background of the patient and use the appropriate growth charts when measuring a child. Secondly, a child can also be considered tall in relation to his/her midparental height (MPH), when his/her height is more than two SD over the MPH (height standard deviation score (SDS)-MPH SDS >2.0). Therefore, a detailed familial history of tallness in one or both parents is essential in order to not miss a diagnosis.

After a careful physical evaluation, tall subjects may be divided into two groups (Figs. 1 and 2): tall subjects with normal appearance and tall subjects with abnormal appearance.

In the case of normal appearance (Fig. 1), the paediatric endocrinologist will have to evaluate growth rate. If growth velocity is normal for age and sex, the subject grows according to his/her MPH and his/her body mass index (BMI) is within the normal ranges, he may be classified as familial tall stature and a family history of tallness in one or both parents should have been previously reported. The height of these subjects is usually within the target centile range calculated from the parents’ height [9]. No further investigation is required as long as the child normally develops and has a normal physical examination.

On the contrary, if the difference height SDS-MPH SDS is >2 and the BMI is above the normal range (>95th percentile), the subject has to be classified as obese. Obese children are sometimes taller than average for their age and, if maturity is also advanced, puberty may occasionally occur earlier [10]. However, their final height will usually be normal.

If the BMI is normal an aromatase deficiency may be suspected. This is a rare disease with autosomal recessive inheritance. In males the diagnosis is made later in adulthood, when there is a tall stature, incomplete epiphyseal closure, eunucoid proportion of the skeleton, osteoporosis and obesity. Oestrogen levels are low, while follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone increased slightly. The most intriguing features are the presence of steatohepatitis, insulin resistance with acanthosis nigricans and high concentrations of triglycerides. The administration of low-dose oestrogen allows complete bone maturation after the complete closure of the epiphysis and produces an increase in bone density. More than 30 mutations (point mutations, deletions and insertions) have been found in the gene CYP19A1, which encodes for the human P450 aromatase enzyme located in the membrane of the endoplasmic reticulum of several tissues, such as gonad, brain, placental syncytiotrophoblast, breast, and adipose tissue and catalyzes biosynthesis of oestrogens from androgens [11].

Rare cases of oestrogen receptor α (ER α ) deficiency have been described and the phenotype is very similar to that of aromatase deficiency with tall stature and eunucoid body proportions, continued linear growth into adulthood due to incomplete epiphyseal closure and osteoporosis in males [12] and absent breast development and markedly elevated serum oestrogen levels and multicystic ovaries in females [13]. Both oestrogen-resistant patients had homozygous point mutations in the ERα gene [12, 13].

When an increase in growth velocity is observed, it is essential to evaluate pubertal status and thyroid status. In fact, tall subjects with normal appearance and high growth velocity may be divided into two groups according to the absence or presence of pubertal signs (Fig. 1).

If there are pubertal signs, subjects may show precocious puberty in the presence of the appearance of the breast (Tanner stage 2) before 8 years in females and enlargement of testicular volume (>4 ml) before the age of 9 years in males, in both associated with advanced bone age. Gonadotropin releasing hormone (GnRH) stimulation test is necessary to confirm the diagnosis of precocious puberty and therapy with GnRH analogues should be promptly started in order to block pituitary gonadotropin secretion. The presence of pubertal signs may also suggest an early pseudoprecocious puberty with high steroid, androgen or oestrogen secretion, secondary to an ovarian cyst in females or, more rarely to testis or ovary cancer, or a congenital adrenal hyperplasia. Congenital adrenal hyperplasia is mainly (90% of cases) due to a 21-hydroxylase deficit encoded by the gene GYP21A2 and tall stature, premature pubarche, irregular menstruation, acne, hirsutism and bone age advancement characterize the late-onset form of this condition.

Tall children without pubertal signs and increase of growth rate include children with constitutional advance of growth (CAG). They present an accelerated growth after birth reaching peak centile by 2–4 years of age, and then they grow along 97th centile until 9 year when their growth rate drops to 50th percentile [14, 15]. These children are different from those with familial tall stature since they are born with an above average birth length and they are tall for their parental height [2, 16]. Sometimes CAG can be associated with obesity and it has been suggested that could predict late onset of childhood obesity in non-obese children [16]. Puberty is often earlier in these children. An increase in insulin-like growth factor (IGF)-II secretion and a higher IGFs/IGF binding proteins (BPs) molar ratio prior to puberty may be a possible mechanism of tall stature in CAG children [17].

In the absence of pubertal signs associated with a growth rate increase a condition of GH excess or hyperthyroidism may be considered. The former occurs before epiphyseal fusion and is characterized by rapid growth not associated with advanced bone age, metabolic changes similar to those observed in acromegalic patients and elevated serum IGF-I values. Furthermore, serum GH values are not suppressed by glucose oral administration. Since a GH-secreting tumour may be present, radiologic evaluation of the hypothalamus and pituitary by magnetic resonance imaging is requested. In a condition of hyperthyroidism, an increase in growth rate associated with advanced bone age is present. The diagnosis is made by measuring free thyroxine and thyroid stimulating hormone (TSH) levels.

McCune-Albright Syndrome (MAS) is a rare cause of precocious pseudopuberty and GH excess. It is a genetic disorder originally characterized as the triad of polyostotic fibrous dysplasia of bone, precocious puberty and café-au-lait skin pigmentation. Moreover, other associated endocrinopathies have been recognized, including hyperthyroidism, GH excess, FGF23-mediated phosphate wasting and hypercortisolism. Skin manifestations are common and are usually present at or shortly after birth. The café-au-lait spots typically have irregular margins giving them a “coast of Maine” appearance, and usually show an association with the midline of the body. In MAS, fibrous dysplasia of bone typically occurs at several sites (polyostotic), and commonly presents with fracture, deformity and/or bone pain. Radiographs show characteristic expansile lesions with a “ground glass” appearance. Craniofacial fibrous dysplasia can be severe in individuals who have pituitary disorders leading to GH hypersecretion. In girls, precocious pseudopuberty is a common initial manifestation, with recurrent ovarian cysts leading to episodes of vaginal bleeding and breast development, while it is less common in boys, presenting with penile enlargement, pubic and axillary hair, acne, body odour, and sexual behaviour. However, in both girls and boys, there is a high frequency of gonadal pathology (ovarian abnormalities in girls, and testicular abnormalities in boys) [18]. McCune-Albright Syndrome is caused by an activating mutation in the GNAS gene, which encodes the alpha subunit of the stimulatory G protein involved in G-protein signalling. The mutation arises early in embryogenesis and is distributed in a mosaic pattern.

In many syndromes with dysmorphisms, severe complications may be associated with tall stature. Anthropometric measurement such as height, weight, BMI, arm span, sitting height and head circumference allow a classification of proportionate and disproportionate tall stature, although this cannot be an absolute division (Fig. 2). Physical examination can focus on dysmorphic features including supernumerary nipples such as in Simpson-Golabi-Behmel syndrome or macroglossia such as in Beckwith-Wiedemann syndrome.

Sotos syndrome (cerebral gigantism): children with this syndrome at birth have increased length, weight and head circumference [2]. They are large-for-gestational age infants and have rapid growth in early childhood with advanced bone age, but do not attain excessively tall adult height. Characteristic features include a large dolichocephaly, macrocephaly, prominent forehead, down-slanting palpebral fissures, mild hypertelorism, high-arched palate, prominent ears, jaw and small pointed chin, large hands and feet, and acromegalic appearance. Most have subnormal intelligence and motor incoordination. Although they continue to rapidly grow during the early years of life, puberty is early and causes premature epiphyseal fusion leading to normal final height. They have normal GH and IGF-I secretion, thyroid, adrenal and gonadal function. Deletions and point mutations in the NSD1 gene, with consequent loss of function, account for the majority of cases and there may be autosomal dominant transmission.

Weaver syndrome subjects present prenatal and postnatal overgrowth, typical features including large ears, depressed nasal bridge, downslating palpebral fissures, dimpled chin, prominent wide philtrum and micrognathia. Advanced skeletal maturation and camptodactyly are observed. Many patients present developmental delay and learning difficulties. Missense and truncating mutation in the EZH2 gene, encoding for histone methyltransferase, are reported [19].

Fragile X syndrome is a genetic disorder that includes intellectual disability and features such as a long and narrow face, protruding ears, flexible fingers, hypotonia and large testicles (macroorchidism). These patients show increased growth velocity in peripubertal period, but it decreases after puberty. The patients often present autism, delayed speech and hyperactivity. Fragile X syndrome occurs in about 1 in 4000 males and 1 in 8000 females. Partial or complete loss-of-function mutations in the FMR1 gene, mapped on chromosome Xq27.3, cause fragile X syndrome. Most affected patients show hypermethylated CGG-repeat stretch in the 50-untranslated region of the FMR1 exon 1 [20]. This hypermethylation results in constriction of the X chromosome which appears ‘fragile’ under the microscope at that point, a phenomenon that gave the syndrome its name. Fragile X syndrome has traditionally been considered an X-linked dominant condition with variable expressivity. Prenatal testing with chorionic villous sampling or amniocentesis allows diagnosis of FMR1 mutations while the foetus is in uterus and appears to be reliable [21].

Simpson-Golabi-Behmel syndrome is a rare inherited congenital disorder that can cause craniofacial, skeletal, cardiac and renal abnormalities. Possible symptoms and associated conditions are macrosomia, macroglossia, advanced bone age, organomegaly, neonatal hypoglycaemia, congenital diaphragmatic hernia, “bulldog” or “coarse” face, short and broad hands and feet with dysplastic nails, polydactyly, pectus excavatum, talipes, vertebral segmentation defects, hypernumerary nipples, structural and conductive cardiac defects, multicystic dysplastic kidneys, hypotonia, brain malformations, developmental disabilities and, rarely, mental retardation. The syndrome is inherited in an X-linked recessive fashion, where males express the phenotype and females usually do not or may express varying degrees of the phenotype. The first signs of Simpson-Golabi-Behmel syndrome may be observed as early as 16 weeks of gestation [22, 23]. These patients show an increased risk of neoplasms, in particular in the abdominal region, such as Wilms tumour and hepatoblastoma. In Simpson-Golabi-Behmel syndrome type I patients, a mutation of the GPC3 gene (especially expressed in kidney, liver and lung) on the X chromosome locus q26.1 has been described, while Simpson-Golabi-Behmel syndrome type II may be caused by duplication of the GPC4 gene, which helps to regulate cell division and growth.

Marfan syndrome is an autosomal-dominant condition resulting from a mutation in the FBN-1 gene on chromosome 15q, encoding for a 350-kDa extracellular matrix glycoprotein that takes part in the formation of microfibrils, which are important for elasticity and structural support of numerous tissues [24]. It affects approximately 1 in 5000 people. They have long limbs with narrow hands and long slender fingers. Arm span is greater than height and the lower segment is much greater than the upper segment. Other features include mild hyperextensible joints, skin striae, kyphoscoloiosis, deformities of the rib cage, high arch palate and lens dislocation. Aortic root dilatation, aortic aneurysms, and mitral valve prolapse are important cardiac features and associated with increased mortality in early adult life. Death from a dissecting aneurysm may occur in early adult life. Echographic and ophthalmic assessment should be undertaken in a child with marfanoid features. Two important clinical findings in making the diagnosis are the wrist sign and thumb sign. The “wrist sign” is positive when the thumb overlaps the fifth finger when grasping the contralateral wrist. The “thumb sign” is positive when the thumb extends well beyond the ulnar border of the hand when overlapped by the fingers [25].

Homocystinuria is a rare (1:250,000) autosomal-recessive disorder caused by an absence of the enzyme cystathionine β-synthase (CBS). Phenotypically, patients resemble those with Marfan syndrome, but they usually have subnormal intelligence, osteopoenia, and a tendency to fatal thromboembolism. Lenticular dislocation also occurs, usually in downward direction. A multitude of genes are related to homocystinuria, but mutations in the gene that encodes for CBS are the prevalent. Alterations in CBS result in the disruption of enzyme activity, which consequently leads to elevated homocysteine, a potentially toxic aminoacid responsible for clinical manifestations observed in homocystinuric patients. To date, 150 CBS mutations have been identified and 67% are missense mutations [26].

Triple X (XXX) syndrome . The incidence of this syndrome is 1 in 1000 birth females, but the majority are not recognized due to considerable variation in the phenotype [27]. About 10% of subjects may be mosaicisms (i.e. 46 XX/47 XXX, 47 XXX/48 XXXX, 45 X/47 XXX, 45 X/46 XX/47 XXX). Features include increased linear growth in mid-childhood, tall stature, epicanthal folds, hypertelorism, upslanting palpebral fissures, clinodactily, hypotonia, joint hyperextensibility, genitourinary abnormalities, congenital hip dysplasia, premature ovarian failure, congenital heart defects, seizure disorders and electroencephalogram abnormalities. Fertility is normal. Increased risk for attention deficit and early developmental delays, mainly in speech-language disorders may be present.

Other rare conditions are characterized by tall stature:

Proteus syndrome is mainly caused by activating mutations of AKT1 and PTEN genes and the characteristic signs are macrocephaly with frontotemporal exostosis, large hands and feet with macrodactyly, normal psychomotor development, predisposition to cancer and thromboembolic diseases.

In conclusion, to investigate a syndromic subject with tall stature, the following assessments should be initially requested on the basis of diagnostic suspicion:

Human growth and adult height are highly heritable (h2 = 0.80–0.90) polygenic traits [28, 29]. Initially, the study of genetics of height mainly focused on short stature, with many possible candidate genes identified. Recently, some studies focused on genetics in extremely tall individuals and found some common genetic variations. Exome sequencing has been demonstrated to be useful for identifying novel genes involved in aetiology of tall stature.

For example, a common polymorphism in the high-mobility group A2 (HMGA2) gene was significantly associated with tall stature [30]. Furthermore, overproduction of C-type natriuretic peptide by chromosomal translocation [31, 32] and gain-of-function mutations in natriuretic peptide receptor-2 (NPR2) gene have been reported to be responsible for overgrowth syndromes [33, 34] or extremely tall stature without skeletal deformities [35]. Heterozygous los-of-function mutations of fibroblast growth factor receptor-3 (FGFR3) gene results in a aphenotype characterized by camptodactyly, tall stature and hearing loss (CATSHL syndrome [36, 37]. Finally, a recent article identified an association of a novel homozygous mutation in Sec23 homolog A (SEC23A) gene and a previously reported homozygous mutation in mannosidase alpha class 1B member 1 (MAN1B1) gene in two patients, from a consanguineous family of Lebanese origin, presenting somatic overgrowth, macrocephaly, mild dysmorphic features, hypertelorism, maloccluded teeth, intellectual disability and flat feet [38].

In our recent in-press paper, we found significantly higher GH receptor gene expression levels in tall children compared with short and normal statures ones, suggesting that GH sensitivity could be involved in the mechanisms on the basis of tall stature [39].

Generally, tall stature is not a pathological condition and does not need treatment.

Children and their parents may seek treatment to reduce growth if they find the predicted adult height unacceptable but treatment is generally only considered for adolescents whose predicted adult height is more than 2.5 SD above the population mean.

Social impact in tall patients may be a cause of anxiety in parents who request treatment to cease growth progression. Specific therapy depends on the prevision of the final height. Various types of treatment, either hormonal or surgical, have been used to reduce growth.

The most accepted and effective treatment for an excessive height prediction is inducing puberty early and leading to a complete fusion of the epiphyses and achievement of final height, using testosterone in males and oestrogens in females.

In males, testosterone enanthate is usually used at the doses of 250–500 mg/ 2 week for 6-9 months. Side effects as aggressive behaviour, painful erections, severe forms of acne and increased risk of developing prostatic cancer may be observed [40].

In females, the most accepted treatment is 17β-estradiol at the dose of 0.2–4 mg/die, adding a progestin (10 mg) for 1 week a month. Treated patients may show weight increase, headache, hypertension, increased risk of thromboembolic events or of developing breast cancer and melanoma [41]. Furthermore, it is important to exclude a mutation of the Villebrand factor gene before start the treatment.

Furthermore, late negative effects on fertility in females have been reported. High dose testosterone in boys is less effective than oestrogen treatment in girls, but the achieved height reduction depends on the bone age at which treatment is started.

It has been reported that a nocturnal infusion of octreotide, a somatostatin analogue (201–995), reduces GH secretion and height prediction in tall children [42, 43]. However, a more recent study, showed that long-term treatment with analogue of somatostatin (201–995) does not reduce final height in a manner sufficient to justify the treatment in tall stature [44].

The most common surgical procedure for reducing growth is bilateral percutaneous epiphysiodesis of the distal femur and proximal tibia and fibula. Epiphysiodesis is a surgical intervention for reducing final height by 5 cm, which is performed at a bone age exceeding 12.5 years in girls with a stature of 170 cm and 14 years in boys with a stature more than 185 cm [2, 45, 46]. The procedure itself is short (about 60–70 min) and patients are allowed to stand on their legs directly afterwards but are advised not to engage in athletic activities for 4 weeks. In experienced hands, few complications are seen.