Associate Professor Justin H Davies

Consultant Paediatric Endocrinologist & Hon. Associate Professor, Southampton Children’s Hospital; Faculty of Medicine, University of Southampton, UK.

Personalised medicine for hypophosphataemic rickets – a new era

Hypophosphataemic rickets

Rickets results from impaired mineralisation of the growth plate. Hypophosphataemia is common to all forms of rickets as hypophosphataemia impairs both hydroxyapatite formation and failure of apoptosis of the hypertrophied chondrocytes1. Hypophosphataemic rickets (HR) is rare and has several causes, many with an underlying genetic basis (Table). It is necessary to establish the cause of hypophosphataemia to enable institution of targeted therapy. This mini review focuses on the commonest cause of HR, X-linked hypophosphataemia (XLH).

XLH affects approximately one in 20,000 individuals and is caused by loss of function of the PHEX gene, mainly expressed by osteocytes. The PHEX gene is located on the X chromosome; thus an affected mother will have a 50% chance of passing the condition on to her child and an affected father will have affected daughters but no affected sons. The genotype–phenotype relationship is highly variable even within affected families2.

Loss of PHEX function leads to increased secretion of fibroblast growth factor (FGF)23. Elevated FGF23 levels cause hypophosphataemia by enhanced renal phosphate excretion (by inhibition of the sodium-phosphate co-transporters NaPi2a and NaPi2c) in the proximal renal tubule, and by inhibiting 1,25-dihydroxyvitamin D3 synthesis resulting in reduced dietary phosphate absorption1.

XLH is diagnosed because of a family history (present in 60%) or as a de novo case presenting with clinical features, usually in the first 2 years of life. Early recognition is essential to optimise outcomes. The diagnosis of XLH is based on a combination of clinical, biochemical and radiographical features. Typical clinical features at presentation are lower limb deformity, wrist and ankle swelling, delayed motor development, waddling gait, dental abscesses, short stature and bone/joint pain. Rarer associations include craniosynostosis and Chiari malformation.

Serum phosphate is usually low and must be interpreted in the context of an age-specific reference range. Key investigations include serum phosphate, creatinine, calcium, alkaline phosphatase, parathyroid hormone (PTH), and 25-hydroxyvitamin D, and urine phosphate and creatinine. Renal phosphate wasting should be assessed by calculating the tubular maximum reabsorption of phosphate per glomerular filtration rate (TmP/GFR), and a wider tubulopathy secondary to Fanconi syndrome must be excluded. Measurement of FGF23 may be helpful to distinguish FGF23-mediated causes and FGF23-independent causes2 (Table). The biochemical characteristics of XLH are renal phosphate wasting, elevated alkaline phosphatase, elevated FGF23 and inappropriately low or normal 1,25-dihydroxyvitamin D3. Mutation analysis of the PHEX gene is recommended to confirm a clinical diagnosis of XLH.

Table. Causes of hypophosphataemia (Genetic basis)

  • FGF23-mediated
    • X-linked hypophosphataemia (PHEX)
    • Autosomal dominant HR (DMP1)
    • Autosomal recessive HR types 1, 2, 3 (FGF23, ENPP1, FAM20C)
    • Fibrous dysplasia (GNAS)
    • Tumour induced osteomalacia
    • Iron polymaltose infusions
  • Non-FGF23-mediated
    • Primary hyperparathyroidism
    • Hereditary hypophosphataemic rickets with hypercalciuria (SLC34A3)
    • Vitamin D dependent rickets (type 1A, 1B, 2A, 3)
    • Causes of Fanconi syndrome

The goals of therapy are to correct lower limb deformities to reduce the requirement for surgery, optimise linear growth, minimise pain and improve dental health, necessitating a multidisciplinary approach. A current focus has been to improve the recognition of the XLH, as the earlier therapy is instituted the better the long-term outcomes. There are currently two medical treatment strategies, conventional therapy or anti-FGF23 monoclonal antibody.

Conventional therapy

Conventional therapy consists of multiple doses of oral phosphate (4–6 times per day) and an activated vitamin D analogue (calcitriol or alphacalcidol once a day). Higher doses are needed during phases of rapid linear growth. Medicine nonadherence and intolerance are frequent. Adverse effects include secondary hyperparathyroidism, nephrocalcinosis and cardiovascular abnormalities. Treatment monitoring is with serum alkaline phosphatase (ALP), PTH, severity of rickets assessed by X-ray (hand or knee) and intercondylar and/or intermalleolar distance, and growth. Treatment is continued until cessation of linear growth.

Conventional therapy does not fully correct the biochemical derangement nor symptoms of XLH. A limitation is that as serum phosphate levels are increased, FGF23 levels are further increased with consequent increased renal phosphate wasting, potentially reducing treatment efficacy.

Anti-FGF23 monoclonal antibody (burosumab)

Burosumab, a recombinant IgG1 monoclonal antibody, directly inhibits FGF23 activity and thus increases TmP/GFR and indirectly enhances intestinal phosphate and calcium absorption. The EMA granted marketing authorisation in 2018 for treatment for children older than 1 year with XLH and radiographical evidence of rickets; the FDA approved usage in children and adults. Burosumab is given subcutaneously every 2 weeks and is well tolerated with a reassuring safety profile. Side effects include a mild reaction at the site of injection, headache and cough. Fasting serum phosphate should be monitored regularly to achieve a phosphate in the lower end of the age-specific reference range. The monitoring required includes serum ALP, TmP/GFR and wrist X-ray, annual renal ultrasound and urine calcium: creatinine ratio3.

Compared to conventional therapy, burosumab resulted in superior improvements in radiological rickets healing, serum phosphate, growth, pain, reduction in renal phosphate wasting and functional outcomes4,5.

Early diagnosis of XLH is a key management step to enable access to targeted therapy to reduce long-term morbidity. Anti-FGF23 therapy is a preferable treatment compared to conventional therapy.


  1. Beck-Nielsen SS, Mughal Z, Haffner D, Nilsson O, Levtchenko E, Ariceta G, et al. FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis 2019; 14: 58 doi: 10.1186/s13023-019-1014-8
  2. Haffner D, Emma F, Eastwood DM, Duplan MB, Bacchetta J, Schnabel D, et al. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2019; 15: 435–455
  3. Padidela R, Cheung MS, Saraff V, Dharmaraj P. Clinical guidelines for burosumab in the treatment of XLH in children and adolescents: British paediatric and adolescent bone group recommendations Endocr Connect 2020; 9: 1051–1056
  4. Imel EA, Glorieux FH, Whyte MP, Munns CF, Ward LM, Nilsson O, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet 2019; 393: 2416–2427
  5. Linglart A, Imel EA, Whyte MP, Portale AA, Högler W, Boot AM, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children With X-linked hypophosphatemia. J Clin Endocrinol Metab 2022; 107: 813–824

Professor Helen Storr

Professor of Paediatric Endocrinology, Barts and the London School of Medicine, Queen Mary University London, UK.

Identification of GH insensitivity among short children with normal GH secretion


The evaluation of children presenting with short stature includes detailed clinical, phenotypic, auxological and biochemical assessments with genetic analyses in selected cases. Advances in molecular technologies and bioinformatic pipelines have broadened the genetic testing available to clinicians and unveiled numerous genetic causes for growth failure. This work has advanced the understanding of the physiology of normal human linear growth, identified new genetic causes of short stature and enhanced patient diagnosis.

Approximately 80% of children referred with short stature do not obtain a specific diagnosis despite detailed evaluation and many children with undiagnosed short stature have normal growth hormone (GH) secretion. The finding of a low serum IGF-I concentration in association with sufficient GH levels, particularly when there is severe short stature, is suggestive of growth hormone insensitivity (GHI) (1). Evidence of GHI is reported in approximately 30% of children referred for investigation of short stature.

Growth hormone insensitivity (GHI) in children is characterised by short stature, functional IGF-I deficiency and normal or elevated serum GH concentrations. GHI encompasses a spectrum of defects of GH action presenting in childhood with growth failure. In its severe form, GHI is associated with extreme short stature, dysmorphic features and metabolic abnormalities (2). In recent years, the clinical, biochemical and genetic characteristics of GHI and other overlapping short stature syndromes have rapidly expanded. This can be attributed to advancing genetic techniques and a greater awareness of this group of disorders.

Genetic defects of the GH-IGF-I axis are an established cause of GHI; however, their exact prevalence is not well established. “Laron syndrome” or “classical” GHI due to homozygous or compound heterozygous defects of the GH receptor gene (GHR) presents at the extreme end of the spectrum with marked postnatal growth failure and IGF-I deficiency due to severe GH resistance. To date, more than 90 homozygous, compound heterozygous, missense, nonsense, and splice site GHR mutations have been identified with significant phenotypic and biochemical variability (3).

Genetic defects have also been discovered in key downstream GH-IGF-I axis genes such as STAT5B, IGFI, IGF2, IGFALS and PAPPA2 and we can now conceptualize a spectrum of GHI presentations in patients from very mild to very severe. Each known defect in the GH pathway has a distinct clinical, biochemical, metabolic and/or genetic signature. Other molecular defects impacting GH signalling and causing GHI phenotypes include STAT3, IKBKB, IL2RG, PIL3R1 and FGF21 mutations (4).

Our recent published series of patients presenting with short stature and apparent GHI, indicated that genetic variants in the GH-IGF-I axis comprised the most common cause, accounting for 56% of patients in whom a diagnosis was made (1). This was not unexpected, given the biochemical phenotype and high incidence of consanguinity (34%) in our cohort.

Interestingly, we also identified a wide range of additional genetic diagnoses and 44% had “overlapping” short stature syndromes/disorders (1). This included single diagnoses in individuals of nine disorders not previously linked to GHI. Patients with diagnoses external to the GH-IGF-I axis were more likely to be born small for gestational age as many of these disorders, such as 3M and Silver-Russell syndromes, cause both pre- and post-natal growth restriction.

GHI comprises a spectrum of clinical entities caused by genetic defects in and external to the GH-IGF-I axis. Clinical diagnosis can be challenging as the predominant, consistent feature of many of these conditions is short stature. The associated dysmorphic features can frequently be subtle, non-specific and overlap with other disorders. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management (5). The identification of an underlying genetic defect can enable access to treatments, genetic counselling, early detection of likely comorbidities and will inform prognosis.

Figure 1. The range of genetic diagnoses identified in a cohort of 149 patients with short stature and suspected growth hormone insensitivity

Genetic diagnoses were identified in a total of 80/149 individuals. Of the 80 with a genetic diagnosis: 45 had growth hormone-insulin-like growth factor-I (GH-IGF-I) axis gene variants (GHR n=40, IGFALS n=4 and IGFIR n=1), 10 had 3M syndrome genetic variants (OBSL1 n=7, CUL7 n=2 and CCDC8 n=1) and four had Noonan syndrome (NS) genetic variants (PTPN11 n=2, SOS1 n=1 and SOS2 n=1). Two patients were diagnosed with Silver-Russell syndrome (SRS) (Loss of methylation on chromosome 11p15, uniparental disomy for chromosome 7). Class 3-5 copy number variations (CNVs) were identified in 10 patients (Class 4 1q21 deletion n=2, Class 5 12q14 deletion n=1, Class 3 5q12 deletion n=1, Class 4 Xq26 duplication n=1, duplication of Chromosome 10 n=1, Class 3 7q21 and Class 4 7q31 deletion n=1), Class 3 7q21 duplication and Xp22 duplication n=1, Class 3 7q36 duplication n=1, Class 3 3p22 deletion and 15q13 duplication n=1). Additional overlapping disorders were diagnosed in nine individuals (Barth syndrome, Autoimmune lymphoproliferative syndrome, Microcephalic osteodysplastic primordial dwarfism Type II, Achondroplasia, Glycogen storage disease Type IXb, Lysinuric protein intolerance, Multiminicore disease, MACS syndrome and Bloom syndrome).

  1. Andrews A, Maharaj A, Cottrell E, Chatterjee S, Shah P, Denvir L, et al. Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes. J Clin Endocrinol Metab 2021; 106: e4716–e4733
  2. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008; 93: 4210–4217
  3. Storr HL, Chatterjee S, Metherell LA, Foley C, Rosenfeld RG, Backeljauw PF, et al. Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action. Endocr Rev 2019; 40: 476–505
  4. Cottrell E, Cabrera CP, Ishida M, Chatterjee S, Greening J, Wright N, et al. Rare CNVs provide novel insights into the molecular basis of GH and IGF-1 Insensitivity. Eur J Endocrinol 2020; 183: 581–595
  5. Collett-Solberg PF, Ambler G, Backeljauw PF, Bidlingmaier M, Biller BMK, Boguszewski MCS, et al. Diagnosis, Genetics, and Therapy of Short Stature in Children: A Growth Hormone Research Society International Perspective. Horm Res Paediatr 2019; 92: 1–14.

Sasha R Howard and Leo Dunkel

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK

Changes in the timing of puberty: clinically significant, genetic or environmental?


Amongst healthy adolescents, there is a near-normal distribution of the timing of puberty, with the mean age of onset in boys being 11.5 years and in girls 11 years, but wide inter-individual variation (age range 9–14 years in boys; 8–13 years in girls) (1). The timing of puberty is strongly heritable, and evidence from twin and other epidemiological studies has demonstrated that genetic regulation is an important element in determining when healthy individuals enter puberty. Such studies suggest that 50–80% of this variation in the general population is under genetic regulation. However, an individual’s nutritional status, adoption, geographical location and emotional well-being also have an effect on pubertal timing.

Figure 1. Secular trend in the age of onset of puberty, as demonstrated by first breast development in girls (thelarche, Tanner stage B2), panel (a) and of testicular volume (TV) ≥ 3 mL in boys, panel (b). From (7).Click to view

The timing of puberty in most developed countries exhibited a rapid decrease in the first half of the 20th century. This was most notable in girls (Figure 1, panel A), but has also been documented in boys (Figure 1, panel B). This has resulted in an increase in both the number of cases of central precocious puberty and in the incidence of normal variants of puberty (premature thelarche and adrenarche) (1). This observed secular trend towards an earlier age of pubertal onset has been the subject of intense discussion. In view of the timeframe, it is thought not to be genetically determined, but likely due to increasing rates of obesity in children and other environmental influences.

There are clear data supporting the influence of nutritional changes on pubertal timing, as shown by the clear correlation between age at puberty onset and childhood body size, particularly in girls. A larger gain in body mass index (BMI), particularly between 2 and 8 years of age, is positively associated with first breast development (2) and fat mass percentage during a similar period in mid-childhood has been shown to be associated with increased risk of precocious puberty in boys (3). In boys, the data suggest a complex relationship between fat mass and pubertal timing, with overweight status associated with earlier pubertal onset but severe obesity correlated with later onset (4), potentially due to suppression of the hypothalamic–pituitary–gonadal (HPG) axis.

In conclusion, the observed increase in the incidence of both central precocious puberty and benign pubertal variants is most likely due to increasing BMI of children in the developed world and a possible influence of EDCs. This has clinical significance as earlier pubertal development has associations with poor adult health, including risk of type 2 diabetes, cardiovascular disease and breast cancer, as well as psychosocial difficulties in adolescence and beyond (1).

  1. Brauner EV, Busch AS, Eckert-Lind C, et al. Trends in the incidence of central precocious puberty and normal variant puberty among children in Denmark, 1998 to 2017. JAMA Netw Open 2020; 3: e2015665
  2. He Q, Karlberg J. BMI in childhood and its association with height gain, timing of puberty, and final height. Pediatr Res 2001; 49: 244–251
  3. Pereira A, Busch AS, Solares F, et al. Total and central adiposity are associated with age at gonadarche and incidence of precocious gonadarche in boys. J Clin Endocrinol Metab 2021; 106: 1352–1361
  4. Lee JM, Wasserman R, Kaciroti N, et al. Timing of puberty in overweight versus obese boys. Pediatrics 2016; 137: e20150164
  5. Parent AS, Franssen D, Fudvoye J,et al. Developmental variations in environmental influences including endocrine disruptors on pubertal timing and neuroendocrine control: Revision of human observations and mechanistic insight from rodents. Front Neuroendocrinol 2015; 38: 12–36
  6. Mouritsen A, Aksglaede L, Sorensen K, et al. Hypothesis: exposure to endocrine-disrupting chemicals may interfere with timing of puberty. Int J Androl 2010; 33: 346–59
  7. Sorensen K, Mouritsen A, Aksglaede L, et al. Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty. Horm Res Paediatr 2012; 77: 137–145

Ana Claudia Latronico MD, PhD.

Internal Medicine Department, Division of Endocrinology & Metabolism, Sao Paulo Medical School, Sao Paulo University, Brazil.

Increasing global incidence of central precocious puberty

Precocious puberty is a prevalent endocrine disorder that affects children globally. Classically, precocious puberty is defined as the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys and it has a clear female predominance. The premature activation of hypothalamic gonadotropin-releasing hormone secretion leads to central precocious puberty (CPP), the most common mechanism of abnormal premature sexual development. Epidemiological studies based on national registries have estimated the prevalence and incidence of CPP in children originating from different populations in the last 2 decades (1–4).

Table: Four longitudinal epidemiologic studies on the incidence and prevalence of precocious pubertal development based on national registries. Click to view

A Danish study (1993–2001) involving 670 children with precocious pubertal development estimated that 0.2% of girls and <0.05% of boys had some form of precocious pubertal development (1). More recently, a new Danish study (1998–2017) involving a very large group of patients (8596 children) with CPP, premature thelarche and premature adrenarche was reported (2). The 20-year mean annual incidence rate of CPP was 9.2 per 10,000 girls and 0.9 per 10,000 boys. There was a sixfold increase in incidence for girls, from 2.6 per 10,000 to 14.6 per 10,000, and a 15-fold increase for boys, from 0.1 per 10,000 to 2.1 per 10,000. These findings strongly suggested that the annual incidence of CPP has substantially increased in Denmark during the last 20 years.

Similarly, two epidemiological longitudinal studies demonstrated a significant increase of CPP in children from Korea (3–4). The first study (2004–2010) estimated the prevalence of CPP at 55.9 per 100,000 girls and 1.7 per 100,000 boys. Notably, the annual incidence of CPP in girls also significantly increased from 3.3 to 50.4 per 100,000 girls in this initial study, especially in the older age group (>6 years of age). The second Korean study (2008–2014) involved a very large number of Korean children from both sexes (37,890 girls and 1220 boys). It showed an overall incidence of CPP of 193.2 per 100,000 children (girls 410.6 and boys 10.9).

Multiple factors can influence the timing and tempo of puberty, including genetics, lifestyle, nutrition and environmental exposures. The mechanisms underlying the increasing trend in incidence of CPP are uncertain. The growing influence of nutritional status (overweight or obesity) has been highlighted as a major influence on the premature pubertal development, especially in girls. Other potential mechanisms include prenatal and postnatal exposures to endocrine disruptors, international adoption, physical activity, use of electronic devices and psychological influence. Very recently, an increased incidence of precocious and accelerated puberty was demonstrated in a small cohort of Italian girls during and after lockdown for the coronavirus 2019 (5). This fact was potentially related to weight gain, frequent use of electronic devices and stress.Notably, earlier age at puberty has been associated with a higher risk of metabolic, oncologic (breast cancer in girls) and cardiovascular disorders during adulthood. Therefore, the evidence of increasing prevalence and incidence of CPP can amplify the occurrence of other diseases, resulting in adverse long-term health outcomes.
1. Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries. Teilmann G, Pedersen CB, Jensen TK, Skakkebaek NE, Juul A. Pediatrics 2005; 116: 1323–13282. Trends in the incidence of central precocious puberty and normal variant puberty among children in Denmark, 1998 to 2017. Bräuner EV, Busch AS, Eckert-Lind C, Koch T, Hickey M, Juul A. JAMA Netw Open 2020; 3: e20156653. A significant increase in the incidence of central precocious puberty among Korean Girls from 2004 to 2010. Kim SH, Huh K, Won S, Lee KW, Park MJ. PLoS One 2015; 10: e01418444. Incidence and prevalence of central precocious puberty in Korea: An Epidemiologic Study Based on a National Database. Kim YJ, Kwon A, Jung MK, Kim KE, Suh J, et al. J Pediatr 2019; 208: 221–2285. Increased incidence of precocious and accelerated puberty in females during and after the Italian lockdown for the coronavirus 2019 (COVID-19) pandemic. Stagi S, Mais S, Bencini E, Losi S, Paci S, Parpagnoli M, Ricci F, Ciofi ,Azzari C. Ital J Pediatr 2020; 46: 165.

Martin Savage

Idiopathic short stature is not a diagnosis: A strategy is needed to identify the true pathogenesis in cases of unexplained short stature


The designation “Idiopathic short stature” (ISS) was first used in the 1980s as a description for short children who had normal growth hormone (GH) secretion and otherwise unexplained short stature. ISS acquired clinical significance following the introduction of recombinant human (h)GH in 1985 and the approval of GH deficiency (GHD) by the FDA and EMA for hGH replacement therapy. Trials of hGH in ISS subjects were started, guided by collaborations between pharma companies and academic institutions, because patients with the ISS label were shown to have comparable degrees of short stature to GHD patients.

These short children therefore deserved an opportunity to possibly benefit from hGH prescribed in a higher pharmacological dose. Positive data demonstrated efficacy of hGH in the ISS subjects in randomised placebo-controlled trials. Although the growth responses were highly variable, highlighting the heterogeneous nature of these patients, the overall positive responses and absence of safety signals led to successful applications to the FDA and, in 2003, ISS became an approved indication for hGH therapy. Similar applications by pharma companies to the EMA were rejected, largely due to the absence of improvement in quality of life variables. Consequently, ISS is not a reimbursable condition in countries not covered by FDA jurisdictions.

Figure 1. Investigation scheme for children with ISS showing equal status of clinical, endocrine and genetic assessment. Click to view Figure 1

The clinical entity of ISS has acquired scientific respectability, despite the absence of identification of pathogenesis in the majority of patients. Clinicians have continued to use the ISS label for their patients with unexplained short stature and a Consensus Statement on the management of ISS was published in 2008 (1), highlighting the heterogeneity of such patients and giving guidelines for their investigation and management. Patients with familial short stature (FSS), non-familial short stature (NFSS) and constitutional delay of growth and puberty (CDGP) were also included in the definition of ISS.

Since the emergence of molecular biological investigation of patients with growth disorders, which started in the late 1980s and accelerated considerably in the 1990s and through to the 21st century, genetic defects have repeatedly been discovered in children previously labelled as having ISS. Initial genetic studies were mainly in the GH–insulin-like growth factor (IGF)-1 axis, where defects in pituitary development and in genes coding for functional proteins in the pathway of GH action were identified. Examples are monogenic defects in the following genes: GH receptor (GHR); STAT5B; IGF1; IGFALS; IGF1R and PAPPA2 (2). However, recent attention has focused on genes involved in chondrogenesis and growth plate function as a key mechanism regulating normal linear growth (3). Genetic defects in the following growth plate genes have been identified in children carrying the label of ISS: SHOX; ACAN; NPR2; IHH; FGFR3.
In view of these recent discoveries, patients labelled as ISS deserve further investigation in an attempt to define their true pathogenesis. “ISS” is not a diagnosis, but a statement of diagnostic uncertainty. It is now clear that the three disciplines of diagnostic assessment, namely clinical evaluation, endocrine characterisation and genetic investigation, need to have equal status in the hierarchy of the short stature protocol (Figure 1). Clinical assessment is of crucial importance with essential documentation of family history, parental, grandparental and sibling height data, dysmorphology and body disproportion examination, in addition to developmental, feeding and behavioural milestones (4). General paediatric disorders, such as celiac disease and Turner syndrome need to be excluded. Endocrine evaluation should document GH and IGF-1 status. Genetic investigations should centre around the search for monogenic defects with major growth effects, rather than polygenic defects with multiple minor effects.A working relationship should be established between the clinician and a molecular biologist for discussion of which short patients should undergo genetic tests, which are the appropriate techniques to use and how can the results of the tests be best interpreted. Such a relationship will bring considerable dividends in terms of academic learning, patient care and research opportunities. For example, candidate gene sequencing, indicated when a phenotype suggests a specific genetic diagnosis, is largely being replaced by the hypothesis-free approach of whole-exome sequencing using specific gene panels, which have given diagnostic yields in ~35% of unexplained short stature patients in some reports (5).
ISS is a convenient term for patients with unexplained short stature and is likely to remain in clinical usage. The scheme proposed in Figure 1 gives equality to the three diagnostic disciplines of clinical, endocrine and genetic studies to pursue the primary cause of short stature in unexplained cases. This approach has the realistic chance of clarifying the molecular pathogenesis of known or novel growth disorders. By explaining the basic mechanistic defects, genetic results can guide therapy and thereby enhance progression to optimisation of clinical management.
1. Baron J, Sävendahl L, De Luca F, Dauber A, Phillip M, et al. Short and tall stature: a new paradigm emerges. Nat Rev Endocrinol 2015; 11: 735–746. doi: 10.1038/nrendo.2015.165.2. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab 2008; 93: 4210–4217. doi: 10.1210/jc.2008-05093. Storr HL, Chatterjee S, Metherell LA, Foley C, Rosenfeld RG, et al. Nonclassical GH Insensitivity: Characterization of Mild Abnormalities of GH Action. Endocr Rev 2019; 40: 476–505. doi: 10.1210/er.2018-00146.4. Wit JM, Kamp GA, Oostdijk W. on behalf of the Dutch Working Group on Triage and Diagnosis of Growth Disorders in Children. Towards a Rational and Efficient Diagnostic Approach in Children Referred for Growth Failure to the General Paediatrician. Horm Res Paediatr 2019; 91: 223–240 doi: 10.1159/000499915.5. Hauer NN, Popp B, Schoeller E, Schuhmann S, Heath KE, et al. Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature. Genet Med 2018; 20: 630–638. doi: 10.1038/gim.2017.159.

Kate Davies

Supporting families of paediatric patients with adrenal disease


While adrenal disease in children is quite rare (Simpson et al., 2018), healthcare professionals today working in paediatric endocrinology departments are experts in managing the care of children with adrenal disease. Congenital adrenal hyperplasia (CAH) is the most common; primary adrenal insufficiency and Cushing’s syndrome are also rare but important disorders.

It is useful for families to learn more detail on what is involved in CAH from this helpful video from the patient support group “Living with CAH.”

Families should have a paediatric endocrine nurse specialist (PENS) to help with communication and to coordinate care. Such a person can act as a resource and a liaison between various members of the multidisciplinary team that they may encounter.

It is very important that the prescribed medications are taken correctly and on time, as children may have a life-threatening adrenal crisis if they do not have enough of the hormone cortisol in their system (Miller et al., 2020). Babies will have to take extra liquid salt supplements every day until they are fully weaned (Padidela & Hindmarsh, 2010), and it is important that parents know the correct pharmacy to obtain this from. Fludrocortisone tablets are given to treat reduced levels of aldosterone, and hydrocortisone replacement is also needed for basic cortisol replacement, given at different times throughout the day. The tablets can be crushed and mixed with water to obtain the correct dose, which can be quite small in children (Watson et al., 2018), or there is a paediatric-specific formulation, which comes as capsules that can be broken open and the small grains administered (Porter, Withe, & Ross, 2018).When children are unwell, hydrocortisone doses will need to be doubled or trebled until clinical improvement occurs. In an emergency, an injection of hydrocortisone needs to be administered, and the PENS can help train the family for this eventuality. A useful app (Tollerfield, Atterbury, Langham, Morris, & Farrell, 2017) formulated by the team at Great Ormond Street Hospital also demonstrates the injection (see image), and the team have other useful information at the following links:

Education in the primary disorder will underpin the understanding of families to have a full stock of the medication at home. The PENS can help liaise with nurseries and schools and agree on a management plan regarding medication and potential emergency scenarios. A steroid therapy card should always be with the child and the PENS can formulate hand-held emergency management plans to be kept at school, with both parents, at grandparents’ houses etc. Medic alert bracelets are also advised to be worn at all times.Travel advice can also be given by the PENS, focusing on when to take the medication across different time zones, advice for travelling with an emergency kit on an aeroplane, emergency plans in relevant languages, and possibly the contact details of the local paediatric endocrine team (Moloney, Murphy, & Collin, 2015).It is vital that families and healthcare professionals from a multidisciplinary team work together: the diagnosis can be alarming, but support from other families and support groups can be invaluable (Moloney et al., 2015), with education being the key to optimum and safe management (Bowden & Henry, 2018).
Bowden, S. A., & Henry, R. (2018). Pediatric Adrenal Insufficiency: Diagnosis, Management, and New Therapies. Int J Pediatr 2018; 1739831. doi:10.1155/2018/1739831Miller, B. S., Spencer, S. P., Geffner, M. E., Gourgari, E., Lahoti, A., Kamboj, M. K., Sarafoglou, K. Emergency management of adrenal insufficiency in children: advocating for treatment options in outpatient and field settings. J Investig Med 2020; 68: 16–25. doi:10.1136/jim-2019-000999Moloney, S., Murphy, N., & Collin, J. An overview of the nursing issues involved in caring for a child with adrenal insufficiency. Nurs Child Young People 2015; 27; 28–36. doi:10.7748/ncyp.27.7.28.e609Padidela, R., & Hindmarsh, P. C. Mineralocorticoid deficiency and treatment in congenital adrenal hyperplasia. Int J Pediatr Endocrinol 2010; 656925. doi:10.1155/2010/656925Porter, J., Withe, M., & Ross, R. J. Immediate-release granule formulation of hydrocortisone, Alkindi(R), for treatment of paediatric adrenal insufficiency (Infacort development programme). Expert Rev Endocrinol Metab 2018; 13: 119–124. doi:10.1080/17446651.2018.1455496Simpson, A., Ross, R., Porter, J., Dixon, S., Whitaker, M. J., & Hunter, A. Adrenal Insufficiency in Young Children: a Mixed Methods Study of Parents’ Experiences. J Genet Couns 2018; 27: 1447–1458. doi:10.1007/s10897-018-0278-9Tollerfield, S., Atterbury, A., Langham, S., Morris, S., & Farrell, N. C1.4 My cortisol, development of a life saving app. Arch Dis Child 2017; 102; A5. doi:10.1136/archdischild-2017-084620.12Watson, C., Webb, E. A., Kerr, S., Davies, J. H., Stirling, H., & Batchelor, H. How close is the dose? Manipulation of 10mg hydrocortisone tablets to provide appropriate doses to children. Int J Pharm 2018; 545: 57–63. doi:10.1016/j.ijpharm.2018.04.054

Professor Ieuan Hughes and Dr Rieko Tadokoro-Cuccaro

Medical management of congenital adrenal hyperplasia: can conventional therapy be replaced by novel treatments?


Congenital adrenal hyperplasia (CAH) is a disorder of decreased cortisol production coupled with an increase in androgens from a compensatory adrenocorticotropic hormone (ACTH) drive. Glucocorticoid and mineralocorticoid replacement is the standard treatment for CAH. The optimal goal is to ensure well-being, prevent adrenal crises and suppress excess androgens but this is unrealistic using conventional treatment. The price paid is childhood growth suppression and adult morbidity associated with obesity and cardiovascular disease. How can this conundrum be solved?

Immediate-release HC granules, Alkindi (Diurnal Ltd, UK), were developed for infants and children (1). They provide small dosing, flexibility and easy administration. Pharmacokinetic studies showed bioequivalence of Alkindi to the HC tablet.Two modified-release HC preparations are in clinical trials to try to match endogenous cortisol rhythm: Plenadren (immediate and delayed release; Shire Pharmaceuticals Ltd, UK) and Chronocort (delayed and prolonged release; Diurnal Ltd, UK). A morning dose of Plenadren in 16 healthy adults produced a similar cortisol exposure to three times daily HC, except later in the day (2). A supplementary dose of HC would still be needed.Chronocort was designed to mimic increasing cortisol levels overnight, peaking on awakening and falling to a nadir later in the day. Chronocort is taken twice daily in “toothbrush” mode at bedtime and on awakening. A phase 2 study in 16 adults with CAH showed profiles similar to endogenous cortisol; this resulted in reduced conventional HC doses and decreased androgens (3). A larger phase 3 study in 122 patients failed to confirm superiority over conventional treatment but the manufacturers of this agent have nevertheless been given permission to apply for EMA marketing authorization.
As an alternative to suppressing ACTH-induced androgens with modified HC, why not use a top-down approach to block ACTH? (Figure). The hypothalamic–pituitary–adrenal (HPA) axis is orchestrated by corticotrophin-releasing hormone or factor (CRH or CRF). Consequently, blocking this factor or the receptor to which it binds on the cell membrane of pituitary corticotroph cells would inhibit ACTH synthesis and reduce adrenal steroid production. A CRF1 receptor antagonist was studied in eight women with CAH in a phase 1b clinical trial (4), where a bedtime dose significantly reduced morning ACTH levels in a dose-dependent manner. In turn, this decreased concentrations of precursor steroids such as 17OH-progesterone and induced a reduction of androgens. Further studies of a novel approach to medical adrenalectomy are required but the results are promising.Perhaps a complete shutdown of adrenocortical function can be achieved safely and replacement doses of HC and a mineralocorticoid added. This form of block and replace regimen would be akin to the non-surgical treatment of hyperthyroidism.Other examples of non-conventional treatments for CAH include inhibiting the enzyme for adrenal androgen biosynthesis with abiraterone (5), blocking the action of androgens and oestrogens with steroid receptor antagonists (6), continuous infusion of HC by pump therapy similar to that used to treat insulin-dependent diabetes (7) and bilateral adrenalectomy (8). Such therapies have merit at an individual level, but are not suited for routine management of CAH.
Use of HC granules sprinkled on soft food is a practical step forward for infants and young children with CAH. Attempts to deliver HC to replicate endogenous cortisol secretion are progressing with some success. The more radical option of a neuroendocrine approach to the HPA axis by blocking CRH action also has exciting potential for the future medical management of CAH.
Support from the National Institute for Health Research Cambridge Biomedical Centre. R T-C is supported by the Cambridge Children’s Kidney Research Fund.
  • Neumann U, Whitaker MJ, Wiegand S, et al. Absorption and tolerability of taste-masked hydrocortisone granules in neonates, infants and children under 6 years of age with adrenal insufficiency. Clin Endocrinol 2018; doi:10.1111/cen.13447
  • Johannsson G, Bergthorsdottir R, Nilsson AG, et al.Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol 2009; doi: 10.1530/EJE-09-0170
  • Mallappa A, Sinaii N, Kumar P, et al. A phase 2 study of Chronocort, a modified-release formulation of hydrocortisone, in the treatment of adults with classic congenital adrenal hyperplasia. J Clin Endocrinol Metab 2015; doi:10.1210/jc.2014-3809
  • Turcu AF, Spencer-Segal JL, Farber RH, et al. Single-dose study of a corticotropin-releasing factor receptor-1 antagonist in women with 21-hydroxylase deficiency. J Clin Endocrinol Metab; doi:10.1210/jc.2015-3574
  • Auchus RJ, Buschur EO, Chang AY, et al.Abiraterone acetate to lower androgens in women with classic 21-hydroxylase deficiency. J Clin Endocrinol Metab 2014; doi:10.1210/jc.2014-1258
  • Auchus RJ.Management considerations for the adult with congenital adrenal hyperplasia. Mol Cell Endocrinol 2015; doi:10.1016/j.mce.2015.01.039
  • Nella AA, Mallappa A, Perritt AF, et al. A phase 2 Study of continuous subcutaneous hydrocortisone infusion in adults with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2016; doi: 10.1210/jc.2016-1916
  • MacKay D, Nordenström A, Falhammar H. Bilateral adrenalectomy in congenital adrenal hyperplasia: A systematic review and meta-analysis. J Clin Endocrinol Metab 2018; doi: 10.1210/jc.2018-00217

Dr Alexander A L Jorge


Noonan syndrome (NS) is a relatively common autosomal dominant disorder (1:1000 to 1:2500 live births) characterised by facial dysmorphism, short stature, chest deformities and congenital heart defects. Variable developmental delay and intellectual disability are also observed in some patients.

Disease-causing mutations in genes of the RAS/MAPK pathway are identified in 70–80% of affected patients (1). PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) gene was the first causative gene identified in this condition and encodes a tyrosine phosphatase protein. Nearly 40–50% of patients with NS harbour heterozygous pathogenic variants in this gene.

The diagnosis of NS is based on classical clinic features and can be confirmed by the identification of a heterozygous pathogenic variant in one of the causative genes.

Currently, the diagnosis has been established mainly by multigene sequencing analysis (whole exome or target panel sequencing).

rhGH has been shown to be safe for patients with NS, mainly based on data from retrospective studies with a limited number of patients (3). For this reason, some concerns still remain about an increase in cancer risk and worsening of hypertrophic myocardiopathy in patients with NS treated with rhGH (4). Patients with specific mutations in PTPN11, KRAS and RIT1 can have a high rate of myeloproliferative disorder during the first 5 years of life. In those patients with genetic variants highly associated with myeloproliferative disorders, the decision to start rhGH therapy should be carefully discussed and only begun after the age of 5 years. Future studies are necessary to better define the impact of specific genotypes on growth response and safety of patients with NS treated with rhGH. However, some insights are already possible by identifying the molecular basis of a patient with NS.
  • Tajan M, Paccoud R, Branka S, et al. The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway. Endocr Rev doi: 10.1210/er.2017-00232
  • Malaquias AC, Brasil AS, Pereira AC, et al. Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway. Am J Med Genet A 2012; doi: 10.1002/ajmg/a/35519
  • Noonan JA, Kappelgaard AM. The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence. Horm Res Paediatr 2015; doi: 10.1159/000369012
  • Malaquias AC, Noronha RM, Souza TTO, et al. Impact of Growth Hormone Therapy on Adult Height in Patients with PTPN11 Mutations Related to Noonan Syndrome. Horm Res Paediatr 2019: doi: 10.1159/000500264
  • US Food & Drug Administration. Somatropin Information, as of 23 July 2015.
  • Binder G, Wittekindt N, Ranke MB. Noonan Syndrome: Genetics and Responsiveness to Growth Hormone Therapy. Horm Res Paediatr 2007; doi: 10.1159/000097552

Dr Sasha Howard


Delayed puberty (DP) is common in the developed world, affecting over 2% of adolescents, and is associated with adverse health outcomes including short stature, reduced bone mineral density and compromised psychosocial health. The majority of patients have constitutional or self-limited DP, which is often familial, most commonly segregating in an autosomal dominant pattern. However, the key genetic regulators in self-limited DP are largely unknown [1], Figure 1.

Figure 1 – Schematic representing the genes (encircled) known to be involved in the pathogenesis of self-limited DP, and their overlap with cHH and loci identified by genome-wide association studies of age of puberty in the general population. Important genes identified in precocious puberty (DLK1 and MKRN3) and the Kisspeptin gene (KISS1) and its receptor (KISS1R) are also included.

Ieuan Hughes, MD FRCP FRCPCH FMedSci

Congenital adrenal hyperplasia: optimising cardiometabolic outcomes

The introduction of glucocorticoid replacement for congenital adrenal hyperplasia (CAH) has revolutionised the outlook for patients with this lifelong condition, preventing life-threatening salt-wasting crises. However, accumulating evidence shows persistently increased morbidity, and even mortality, in CAH patients, and links it not only to the disease, but also to the treatment.

Here we review key publications, selected by Ieuan Hughes, Emeritus Professor of Paediatrics from Addenbrooke’s Hospital in Cambridge, UK, which summarise the current knowledge and show how clinicians and the pharmaceutical industry are beginning to respond to this challenge.

For patients with the salt-wasting (classical) form of CAH, the introduction of glucocorticoid treatment in the 1950s turned the condition into a chronic illness, rather than a guarantee of early death.And Hughes says that CAH was initially viewed as simple to treat: “Take your hydrocortisone, go away, no problem.”Yet a 2014 Swedish registry study showed that the problem of salt-wasting crises was reduced, rather than entirely vanquished.1 The mortality rate was 3.9% among 588 CAH patients, compared with 1.6% among nearly 59,000 controls, and 42% of the deaths in CAH patients were due to adrenal crises. Other causes of death were cardiovascular, cancer, accident and suicide, and occurred at a similar rate as in controls. However, study authors Henrik Falhammar (Karolinska University Hospital, Stockholm, Sweden) and colleagues noted that half the cardiovascular deaths in CAH patients occurred concurrently with a severe infection, suggesting that an adrenal crisis could have contributed to these deaths.The findings imply suboptimal glucocorticoid treatment, a point highlighted in a study of 203 CAH patients treated at specialist endocrine centres in the UK.2 Levels of the androgen precursor andostenedione were suppressed in between 10% and 29% of patients and elevated in around a third. Researcher Wiebke Arlt (University of Birmingham, UK) and colleagues found that, overall, only a third of patients had levels within the target range, and the same was true of renin levels in patients receiving mineralocorticoid replacement.“Paediatricians have prided themselves – allegedly anyway – including myself, that we’ve done a good job,” says Hughes.Paediatricians were not only keeping CAH patients alive, he says, but also achieving fairly good growth, helping them attain adult heights that, although lower than expected for their family, were still well within population norms.“And then of course we hand them over to the adult physicians and they come back to us – quite rightly…”
Because the adult physicians, making detailed study of their patients’ health, were becoming aware of increased cardiometabolic morbidity in adult CAH patients. For example, Arlt et al found CAH patients were more often obese relative to the UK population, and frequently had metabolic abnormalities, with 46% having hypercholesterolaemia and 29% having insulin resistance, while around a third had osteopenia.Similarly, Falhammar et al followed up their mortality study with a look at cardiometabolic morbidities, finding that these were almost fourfold more likely to occur in CAH patients relative to controls from the Swedish population, while cardiovascular disease was nearly threefold more common.3 Specific conditions that were elevated in CAH patients included thyrotoxicosis, venous thromboembolism, atrial fibrillation, obesity and diabetes.Another study found evidence of cardiovascular morbidity in CAH patients at a worryingly young age.4 Ivani Silva (Universidade Federal de Minas Gerais, Belo Horizonte, Brazil) and team assessed 38 pubertal CAH patients, aged 20 years or younger, and controls matched for age, gender and pubertal status. They showed that, relative to the controls, the CAH patients had significantly increased carotid intima-media thickness – an early sign of atherosclerosis. This was not restricted to overweight patients, but was seen only in females.So cardiometabolic morbidity is “something that’s now being taken very seriously,” says Hughes.These studies have not only flagged high cardiometabolic risk in CAH patients, they have also begun to link it directly to CAH treatment. A cross-sectional study of 196 adults with CAH found that patients with more severe disease received higher glucocorticoid doses without achieving better disease control – higher dose was actually associated with higher androgen levels.5 Moreover, the increased glucocorticoid doses were also associated with elevated blood pressure.Although researcher Richard Ross (Royal Hallamshire Hospital, Sheffield, UK) and team found that dexamethasone – the most potent of the glucocorticoids used in the study patients – was associated with the lowest androgen levels, this came at the expense of greater insulin resistance.A study from Hughes’ own group took a closer look at insulin resistance in 37 CAH patients and 41 healthy controls.6 The 25 patients with classical CAH, which is diagnosed and treated early in life, had significantly greater fat mass than the controls, which the researchers attributed to the long-term effects of glucocorticoid treatment.“Add to that the obesity epidemic and you’ve got a pretty powerful cocktail of problems,” observes Hughes.By contrast, the 12 children with nonclassical CAH, which is usually diagnosed later in childhood, had greater lean body mass and blood pressure than the controls, and significant increases in several measures of insulin resistance. Hughes attributes these changes to the patients’ prolonged exposure to excess androgen levels in early childhood, saying that androgen “in itself is a pretty potent stimulator of insulin resistance.”
The most recent guidelines for CAH management, from 2010, acknowledge the difficulty of optimising treatment, calling it “a difficult balance between hyperandrogenism and hypercortisolism”, and noting that efforts to completely normalise androgen levels “typically result in overtreatment”.7The guidelines also advise against long-acting glucocorticoids in children, because of their growth-suppressing effects, instead recommending hydrocortisone three times daily at the lowest possible dose to avoid compromising growth.Hughes believes that paediatric endocrinologists “are doing much better now than we used to”, saying that the daily hydrocortisone dose, which “in the past has been too much”, has been brought down. “And that’s being translated into better growth and outcome in the short term.”However, paediatric CAH patients experience the usual deluge of childhood colds and illnesses, each one placing the body under stress and prompting a temporary increase in hydrocortisone dose. Necessary though this is, Hughes wonders if “collectively, we have been overdosing them.”Added to that is the highly variable pharmacokinetics of hydrocortisone, not only between different stages of childhood, but also between different children, aptly demonstrated in a paper from Peter Hindmarsh (UCL Institute of Child Health, London, UK) and Evangelia Charmandari (University of Athens Medical School, Greece).8 The researchers gave 48 children the same hydrocortisone bolus, but found that its half-life in the different patients ranged from 40 to 225 minutes. Although all children attained a similar peak plasma cortisol concentration, the speed of absorption varied widely, with time to peak concentration ranging from 20 to 118 minutes and the additional time taken for the concentration to fall below 100 nmol/L ranging from 140 to 540 minutes.This suggests that hydrocortisone dosing should be highly individualised, and perhaps more frequent, with the study authors moving towards four doses per day on the basis of their findings.
But in some cases, clearance of hydrocortisone may be so rapid that even a six-times-daily dosing schedule is insufficient to achieve androgen control. An ingenious solution for this is continuous delivery via an adapted insulin pump, as illustrated in a case study, also by Hindmarsh.9Pump delivery avoids gaps in hydrocortisone exposure and increased need for hydrocortisone during physiological stress can be managed simply by increasing the infusion rate or using the bolus function. Hindmarsh’s team has implemented this in three children, achieving 24-hour cortisol levels within the normal range, normalised 17-hydroxyprogesterone (17-OHP) levels and large improvements in school attendance and quality of life.Although an effective means of mimicking physiological hormone production, an insulin pump cannot match the simplicity of oral treatment. And pharmaceutical companies are beginning to develop oral drug formulations that more closely replicate physiological production. Two slow-release formulations are currently undergoing clinical testing: Plenadren (ViroPharma SPRL, Brussels, Belgium) and Chronocort (Diurnal Ltd, Cardiff, UK).In a phase II study of Chronocort, Ashwini Mallappa (National Institutes of Health Clinical Center, Bethesda, Maryland, USA) and colleagues found that the rates of elevated androstenedione and 17-OHP levels among 16 adult CAH patients decreased significantly with Chronocort treatment relative to conventional therapy (33.7 vs 12.0% and 33.2 vs 12.0%, respectively).10 After 6 months of Chronocort treatment, 73% and 59% had normal androstenedione and 17-OHP levels, respectively.Hughes highlights that the more physiological replacement appeared to allow further dose reductions, with eight of the 16 patients requiring a dose reduction (although two other patients needed a dose increase).Chronocort is taken twice daily, and therefore suppresses the overnight rise in adrenocorticotrophic hormone (ACTH) seen with Plenadren, which is taken just once daily.11Hughes says that combating the overnight ACTH rise “probably is important, but on the other hand, if you want to be a pragmatist you’re more likely to take your medicine if it’s a once-daily thing as opposed to a twice-daily thing.”Plenadran is a little further down the clinical testing route than Chronocort, being approved and now the subject of a post-authorisation safety registry, which includes CAH patients.12 But both formulations still need to be tested in paediatric patients.“I hope that perhaps getting these so-called more physiological replacement regimens will in due course improve morbidity in adult life,” says Hughes.But he adds: “It will take a generation to see that.”

Andrew Dauber, MD, MMSc

The genetic toolbox: dissecting pathways to growth

The role of growth hormone (GH) has been established for many decades, but it is only with the advent of advanced molecular genetic techniques that researchers have started to piece together the precise pathways leading to growth.

Here we review seven key papers, chosen by Professor Andrew Dauber, from Cincinnati Children’s Hospital Medical Center in Ohio, USA, which document the pivotal findings that shed light on the process of signalling through the GH/insulin-like growth factor (IGF)-I axis.

The research largely represents the extreme end of the growth disorder spectrum, with a single mutation having a profound effect on a patient’s height, but Dauber stresses that “they teach us a lot about the underlying physiology and the role that those genes play in normal biology.”

Origin/Period of study Size of sample/


Incidence Prevalence Registry




50–70 new cases per year 23 per 10,000 in girls

<5 per 10,000 in boys

Danish National Patient Registry




9.2 per 10,000 in girls

0.9 per 10,000 in boys#





50.4 per 100,000 girls

1.2 per 100,000 boys

55.9 per 100,000 girls

0.6 per 100,000 boys

Health Insurance Review and Assessment Service in Korea




262.8 per 100,000 girls

7.0 per 100,000 boys

410.6 per 100,000 girls

10.9 per 100,000 boys