278 Arch Dis Child 1998;78:278–284

RECENT ADVANCES Arch Dis Child: first published as 10.1136/adc.78.3.278 on 1 March 1998. Downloaded from

Advances in

Peter E Clayton, Vallo Tillmann

New developments in endocrinology, in com- DISORDERS OF G-PROTEINS AND G-PROTEIN mon with many specialised branches of medi- COUPLED RECEPTORS cine, have been dominated by advances in The majority of polypeptide signal molecular genetics. Although these investiga- to their target cells through G-protein coupled tions relate to rare single disorders, they receptors (GPCRs), which are characterised by have resulted in major breakthroughs in many seven transmembrane helices connected by fields of endocrinology, significantly contribut- extracellular and intracellular loops. The ing to our understanding of the cellular N-terminal extracellular domain and one or mechanisms of action. However it is more extracellular loops are involved in ligand not just the minute detail of single gene disor- binding while the intracellular loops and the ders and hormone action that has caught the C-terminal tail are coupled to specific attention of endocrinologists in recent years. G-protein complexes, composed of á, â, and ã This review will also focus on two broader subunits. There are many á subunit , health issues, one epidemiological and the whose protein products may be associated with

other therapeutic. stimulation (Gsá) or inhibition (Gi). Activation The studies of Barker and colleagues have of a GPCR leads to the dissociation of the introduced the concept that disease in adult life G-protein trimer and modulation of the activ- has its origin in the fetal environment, and that ity of enzymes, such as adenylate cyclase, or ion this process can be attributed to changes in the channels by the á subunit and/or the âã dimer. programming of fetal endocrine axes. On the Over the last few years, it has been recognised therapeutic agenda, the most dramatic advance that either gain or loss of function of G-protein in endocrinology occurred over a decade ago intracellular signalling mechanisms due to

with the introduction of recombinant human mutations either in the GPCR or in the http://adc.bmj.com/ (hGH). This created wide G-proteins can generate a wide spectrum of interest in the use of growth hormone treat- human endocrine disease. ment in growth disorders with or without asso- For instance, both loss and gain of function ciated . It is appropriate there- have been described with mutations of genes fore to summarise our long term experiences encoding the receptors of many hormones (for with hGH as the first generation of these chil- example adrenocorticotrophic hormone dren achieve final height. (ACTH), growth hormone releasing hormone Finally the isolation and characterisation of a (GHRH), vasopressin, luteinising hormone, on September 25, 2021 by guest. Protected copyright. new hormone is a rare event in the 1990s. follicle stimulating hormone, and thyroid Therefore the discovery of the satiety factor, stimulating hormone). Mutations of the leptin, initially heralded as a potential cure for ACTH receptor cause resistance to ACTH , has attracted considerable media as which is characterised by but well as scientific interest and merits due not mineralocorticoid deficiency. Some cases consideration in this review. are associated with missense, nonsense or frameshift mutations within the ACTH recep- tor (ACTHR) gene,35 53 while others with the features of ACTH resistance (for example the Molecular investigation and diagnosis triple A syndrome) have no identified ACTHR The tools to treat endocrine disorders have not mutation,53 implying that postreceptor defects changed dramatically in recent years, but what could be responsible. Loss of function in the has changed is our understanding of the GHRH receptor is responsible for the “little” molecular abnormalities that generate these mouse,54 but has now been linked to familial Department of Child conditions. Endocrinologists have come to rely isolated growth hormone deficiency, with a Health, University of heavily on molecular diagnostic techniques. homozygous nonsense mutation in the GHRH Manchester, Royal 1 Manchester Children’s For many disorders, it is insuYcient to charac- receptor gene. Nephrogenic insipidus Hospital, Pendlebury, terise the disease only on clinical and bio- (NDI) is associated with mutations in the V2 Manchester M27 4HA chemical grounds. A full appraisal requires a vasopressin receptor39 (X linked) or in the P E Clayton molecular diagnosis. There are many indi- aquaporin-2 gene41 (autosomal recessive). V Tillmann vidual examples of significant molecular devel- Rapid identification of these mutations should Correspondence to: opments in endocrinology (table 1). A few lead to the early diagnosis and appropriate Dr Clayton. examples will be discussed. management of NDI, hopefully avoiding Advances in endocrinology 279

repeated episodes of dehydration, which can terised by insensitivity to parathyroid hormone Arch Dis Child: first published as 10.1136/adc.78.3.278 on 1 March 1998. Downloaded from cause growth failure and mental retardation. with or without osteodystrophy and general- Mutations within the sixth transmembrane ised hormone resistance. Defects can occur in 33 34 domain of the luteinising the Gsá protein or in the association of have recently been linked to male G-protein subunits with adenylate cyclase or pseudohermaphroditism17 (female external further down the signalling pathway in the genitalia, primary amenorrhoea, a short blind intracellular action of cAMP.

ending vagina, and absence of müllerian struc- Gsá mutations may generate simultaneously tures with a 46XY karyotype). It is possible loss of function in one tissue (pseudohypopara- however that other less critical luteinising hor- thyroidism) and gain in another (gonado- mone receptor mutations may account for trophin independent precocious ), as milder clinical forms of this disorder (for described in two unrelated boys.55 Expression example hypergonadotrophic of the mutant protein showed that it was and ). In contrast activating muta- rapidly degraded at 37oC (that is a loss of func- tions in the luteinising hormone receptor gene tion mutation) explaining the pseudohypopar- cause familial male precocious puberty which athyroidism phenotype, but at 32oC (compat- is inherited in an autosomal dominant, male ible with the temperature in the testis) the limited pattern.16 A missense mutation, again protein was constitutively activated causing the in the sixth transmembrane domain of the precocious puberty by stimulating Leydig cell luteinising hormone receptor, has been found cAMP formation. Another example of disease most commonly. Interestingly, no clinical associated with an activating mutation of the 56 manifestations have been reported in female Gsá gene is the McCune-Albright syndrome, carriers of the mutant receptor gene. classically defined by polyostotic fibrous dys- Endocrine disease is also generated by plasia, cafe-au-lait spots, sexual precocity, and abnormal G-protein signal transduction. One other hyperfunctional endocrinopathies. Acti-

such example is , a vating mutations of the Gsá gene have been disease with a wide clinical spectrum charac- found in various tissues, which appear to cause

Table 1 Examples of a wide range of conditions, relevant to endocrine practice, where the target gene has recently been identified, are shown. References are given for each disorder

System Mutated target gene Endocrine disorder Growth GHRH receptor Familial GH deficiency1 GH-1 with bioinactive GH2 Pit-1 Combined pituitary hormone deficiency3–5 GH receptor GH insensitivity in familial short stature6 IGF-I Intrauterine and postnatal growth retardation with IGF-I deficiency7 SHOX Turner’s syndrome, idiopathic short stature8 Sex diVerentiation, SRY XY female with gonadal dysgenesis9–11 12 puberty, and fertility DAX1 Hypogonadotropic hypogonadism http://adc.bmj.com/ SOX9 Campomelic dysplasia with sex reversal13 AMH receptor Persistent müllerian structures in a male14 KAL X linked Kallmann’s syndrome15 LH receptor: Activation Familial male precocious puberty16 Inactivation Male pseudohermaphroditism17 FSH receptor: Activation Sustained spermatogenesis in a male with treated hypopituitarism18 Inactivation Hypergonadotropic ovarian dysgenesis19 LH Male hypogonadism20 on September 25, 2021 by guest. Protected copyright. FSH Female infertility21 Oestrogen receptor Tall stature in male22 Aromatase P450 (CYP19) Tall stature in a male and female pseudohermaphroditism23 Gs-protein McCune-Albright syndrome24 Thyroid TSH receptor: Inactivation Familial hypothyroidism25 Activation Non-autoimmune hyperthyroidism26 27 Hyperfunctioning thyroid adenomas28 Calcium homoeostasis PTH Hypoparathyroidism29 30 Calcium sensing receptor: Inactivation Familial hypocalciuric hypercalcaemia and severe neonatal primary hyperparathyroidism31 Activation Familial hypocalcaemia32 Gs-protein Pseudohypoparathyroidism33 34 Adrenal axis ACTH receptor Familial ACTH resistance35 36 DAX1 X linked congenital adrenal hypoplasia12 Water balance Prepro-AVP-NPII Autosomal dominant neurogenic diabetes insipidus37 38 39 V2 vasopressin receptor X linked nephrogenic diabetes insipidus Aquaporin-2 Autosomal recessive nephrogenic diabetes insipidus40 41 Bones FGFR-3 Achondroplasia42 43 Thanatophoric dysplasia44 Hypochondroplasia45 Diastrophic dysplasia sulphate transporter Diastrophic dysplasia46 Achondrogenesis type 1B47 Atelosteogenesis type II48 PEX X linked hypophosphatemic rickets49 PTH receptor Jansen’s metaphyseal chondrodysplasia50 51 52 Pancreas Sulphonylurea receptor and KATP channel Persistent hyperinsulinaemic hypoglycaemia of infancy

ACTH=adrenocorticotrophic hormone; AMH = anti-müllerian hormone; AVP = vasopressin; FGFR = fibroblast ; FSH=follicle stimulating hormone; GH=growth hormone; GHRH=growth hormone releasing hormone; IGF=insulin-like growth factor; LH=luteinising hormone; NP = neuro- physin; PTH=parathyroid hormone; TSH=thyroid stimulating hormone. 280 Clayton, Tillmann

widespread disease manifestations if they occur Fetal origin of adult disease Arch Dis Child: first published as 10.1136/adc.78.3.278 on 1 March 1998. Downloaded from early in embryogenesis, but result in focal dis- Restricted fetal and early infant growth has ease if activated later in development. been associated with the later development of significant risk factors for cardiovascular dis- ease, in particular hypertension.63 These rela- ABNORMALITIES IN GROWTH HORMONE SIGNAL tionships were initially demonstrated using ret- TRANSDUCTION rospective data on cohorts born earlier this Interest in the wider therapeutic applications of century in the UK, on whom detailed obstetric growth hormone has parallelled a rapid ad- and perinatal growth data were available vance in our understanding of the cellular (reviewed in Barker64). The association be- mechanisms of growth hormone action. In tween low birth weight and postnatal develop- contrast to the G-protein coupled receptors ment of hypertension has been demonstrated listed above, the prospectively in rat models.65 The relationship (GHR) belongs to the class I cytokine receptor has not been confirmed in UK adolescents.66 superfamily, whose members possess extracel- The timing of the growth restriction and hence lular, transmembrane and intracellular do- the body phenotype generated are proposed to mains, but lack any intrinsic tyrosine kinase influence the risk of other conditions in activity. Signalling molecules are recruited addition to raised blood pressure. Thus syn- from the cytoplasm on activation of the recep- drome X (hypertension, impaired glucose tor to associate with the intracellular domain. tolerance, non-insulin-dependent diabetes In the case of the GHR, the pivotal signalling mellitus (NIDDM), hypertriglyceridaemia, molecule is the Janus kinase, Jak 2. Its low high density lipoprotein-cholesterol, and activation causes a sequence of phosphoryla- central obesity) is more likely to occur in those tion events down distinct signalling pathways, with mid-trimester growth retardation, who are leading to phosphorylation of mitogen acti- thin at birth but regain normal weight by one vated protein kinase, signal transducers and year, while abnormal lipid and haemostatic activators of transcription, and profiles occur in those with poor growth in late substrate and eventually changes in nuclear pregnancy, who have reduced abdominal cir- events.57 cumference, are short at birth and remain so 64 It has been recognised for many years that postnatally. Although many studies support mutations within the GHR gene,58 that prevent the fetal origin hypothesis, it has been sug- expression of GHR, can generate growth gested that selection bias, confounding vari- ables, and inconsistency between studies have hormone insensitivity, characterised by ex- 67 68 treme short stature and a phenotype similar to not been fully eliminated. It is important that of severe growth hormone deficiency. This therefore to continue to rigorously test the condition (Laron’s syndrome) is very rare, hypothesis, and to unravel the mechanisms that usually follows an autosomal recessive inherit- generate these associations. It is postulated that alterations in fetal nutri-

ance pattern but has been identified through- http://adc.bmj.com/ tion lead to permanent changes in hormone out the world. An increasing number of muta- 69 tions within the GHR are being recognised,59 sensitivity. Evidence that programming within the insulin and growth hormone- including instances where the GHR is ex- insulin-like growth factor (IGF) axes to gener- pressed but dysfunctional60 or where the GHR ate a multihormone resistant syndrome is appears to be functioning normally but the sig- accumulating both from studies in animals70 71 nal transduction pathway is defective.61 and in children who have suVered intrauterine Most importantly this rare disorder has led 72 73

growth retardation (IUGR). Such studies on September 25, 2021 by guest. Protected copyright. to the recognition that lesser degrees of GHR have demonstrated that growth retarded ne- dysfunction may be relevant to some cases of 62 onates can develop altered insulin:glucose idiopathic short stature, where clear endo- ratios, indicative of insulin resistance, raised crine deficits have not been identified. Al- growth hormone and IGF-I concentrations, though screening has revealed a low incidence suggesting insensitivity within the growth axis, of heterozygous GHR mutations in idiopathic and raised IGF binding protein-1 levels, that short stature (ISS), the concept of a range of may reduce IGF-I bioavailability. Persistence growth hormone sensitivity has been intro- of these abnormalities may permanently reset duced. Such data demonstrate how rapidly the homoeostatic control of hormonal axes, lead- molecular characterisation of a candidate ing to a clinically significant insulin resistant disease, in this case growth hormone insensitiv- syndrome in adulthood. In both UK and ity, can then be used to assess another common Indian children, serum IGF-I concentrations disorder, namely ISS. in early to mid-childhood were higher in taller Overall these developments in our under- and heavier children, but also inversely related standing of the molecular basis for defects in to birth weight.74 Thus children with low birth hormone receptor signalling have provided: (i) weight had higher IGF-I levels than would be the potential for prenatal diagnosis in aVected expected for their size. The development of families, (ii) the opportunity to make an accu- NIDDM in subjects, who had disproportionate rate molecular diagnosis where clinical/ IUGR but became obese adults, provides biochemical uncertainty exists, and most im- further evidence for a link between prenatal portantly (iii) the recognition of the key and postnatal growth.75 Additionally there is receptor sequences or signalling molecules rel- some evidence that the adrenal axis may be evant to human disease and therefore the programmed: adrenal androgen and glucocor- potential to design specific treatments. ticoid excretion, assessed in mid-childhood, Advances in endocrinology 281

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was raised in those with low birth weights. with individuals gaining at best >15 cm of extra Arch Dis Child: first published as 10.1136/adc.78.3.278 on 1 March 1998. Downloaded from One caveat to these data is that all these com- height. Factors influencing this gain include mon health problems will usually occur in the timing of pubertal induction and the length those without a history of IUGR; fetal environ- of growth hormone treatment. The adjuvant ment is but one of many other factors (lifestyle, use of oxandrolone would appear to provide activity, diet, and smoking) that contribute. only a small additional benefit to final height. This is an area with considerable implica- Despite these studies, the optimal times for tions not only to obstetricians and neonatolo- starting growth hormone treatment and for the gists but to all paediatricians. An understand- induction of puberty have not been defined, ing of the key events involved in nor has the wide range of individual response reprogramming an endocrine axis oVers the to growth hormone been adequately explained. possibility that therapeutic manipulation of the Coordinated treatment policies across the prenatal or postnatal environment could growth centres in the UK may help to address modify the incidence of some of the most com- these issues over the next decade. mon disorders of Western society. Final height data after growth hormone are also being reported in those children, variably EYcacy of long term growth hormone classified as short normal, normal variant, or treatment idiopathic short stature.85–87 These cohorts are Although molecular investigation has domi- not growth hormone deficient by classical nated most specialised areas of paediatrics, criteria. Their early response to growth hor- accumulating knowledge on practical thera- mone was encouraging, but in some studies peutic issues should not overlooked. This is of this has not been maintained to final height, particular relevance to the field of growth hor- with insignificant increments in height above mone treatment. It is just over a decade since that predicted (for example mean 2.5 cm in the first recombinant (r)hGH was issued a girls and 2.8 cm in boys87). Those with chronic license in the UK for the treatment of growth renal failure88 and with IUGR89 have also been hormone deficiency. Since that time, many targeted for growth hormone treatment, but as other conditions associated with growth failure yet final height data are not available in signifi- have been treated with growth hormone. As cant numbers. Certainly growth rate can be many of these children are now approaching improved by supraphysiological doses of final height, it is pertinent to review our experi- growth hormone, but experience with short ences with growth hormone and decide just normal children might suggest that we should how eVective such treatment has been. be cautious in our predictions for final height. The final height prognosis of those with iso- Biosynthetic hGH would appear to be a safe lated growth hormone deficiency or multiple agent with undisputed benefit in congenital pituitary hormone deficiency has improved and acquired growth hormone deficiency. In over the last decade, in part related to the opti- fact the lifelong metabolic consequences of misation of growth hormone administration growth hormone deficiency have led to its schedules, including adjustment of growth introduction as replacement therapy in the http://adc.bmj.com/ hormone dose according to body size. Most adult growth hormone deficient population. In will achieve a height within the normal range, all non-growth hormone deficient growth but still below that predicted from parental tar- disorders, there would appear to be a range of get range.77–79 In a study of children who sensitivity to growth hormone with potential received rhGH from the prepubertal years to benefits to many of the recipients. It remains near adult height, factors that influenced the our task to work out which individuals with

adult height achieved included the duration of which conditions are the most appropriate tar- on September 25, 2021 by guest. Protected copyright. growth hormone treatment, age at starting gets for treatment. treatment (the younger the child at the start, the greater the adult height), height at the start and growth rate in the first year.79 These data Regulation of leptin clearly indicate that prompt diagnosis and ini- In 1994 a new hormone, exclusively expressed tiation of growth hormone treatment are the in , was characterised and cloned principal factors that can be modified in order from the genetically obese (ob/ob) mouse.90 to improve further the eYcacy of growth The hormone, named leptin (leptos = thin), hormone in growth hormone deficiency. was rapidly identified as a potent modulator of Growth hormone has been licensed to appetite and thermogenesis. Its administration promote growth in Turner’s syndrome since to the ob/ob mouse resulted in a marked 1989; this indication accounts for up to 25% of reduction in food intake and hence weight the caseload in growth clinics. Studies from the loss.91–94 The leptin receptor was soon cloned,95 USA, Canada, and Europe are now reporting and mutations in this gene result in the obese final heights after four to 10 years of growth phenotype of the db/db mouse.96 97 It had been hormone treatment80–84 : the parameter used to postulated for many years that a factor judge success has been the gain in height over produced in fat may exist, which would be that projected from disease specific growth capable of signalling to central mechanisms charts at the start of treatment, a technique that governing appetite. Leptin appears to be a can- can be compromised by secular trends and didate for such a role, but its actions may be application of national standards to a diVerent even more significant in that it also has an population. Nevertheless growth hormone additional direct eVect on the reproductive treatment would appear to promote an average system.98 It is also present in significant gain in height above that predicted of 3–8cm, amounts in amniotic fluid and cord blood,99 the 282 Clayton, Tillmann

level in the latter correlating with birth and molecular diagnosis for rare disorders as a fast Arch Dis Child: first published as 10.1136/adc.78.3.278 on 1 March 1998. Downloaded from placental weight, suggesting that it may have a reliable clinical service. In addition under- role in fetal growth and metabolism. standing the molecular mechanisms of disease Leptin mRNA is expressed exclusively in is likely to direct a search for new treatments. adipose tissue, while the leptin receptor (a For instance, calcium channel blockers have member of class I cytokine family) is found in been used in nesidoblastosis to reduce the a range of tissues, which include the hypothala- hypersecretion of insulin, as a result of the rec- mus, choroid plexus but also lung and gonadal ognition of the role that calcium has in the tissues.100 Circulating concentrations of leptin function of the â-cell ATP sensitive K+ in humans are most closely correlated to body channel.116 fat mass101 102 and are acutely regulated by star- Although the potential benefits of hGH are vation, insulin, and (reviewed now being clearly defined in a range of growth 103 in Saladin et al ). It is postulated that leptin disorders, the treatment is invasive and expen- exerts its central eVects on appetite through a sive. It is likely that future endocrine therapeu- long feedback loop from the periphery to the tic developments could include slow release central nervous system to decrease the expres- growth hormone preparations, orally active 104 sion of neuropeptide-Y and hence appetite growth hormone mimetics, or even hormone (reviewed in Campfield et al105 and Rohner- 106 production from an ectopic viral cDNA vector. Jeanrenaud et al ). Its potential therapeutic The next “advances in endocrinology” will also role as an anorectic factor, however, is reveal whether leptin will have a therapeutic confounded by the fact that the majority of role in appetite control or even the modulation cases of human obesity appear to be associated of pubertal development. with a leptin resistant state. Nevertheless it is thought that 5% of those with obesity may have a leptin concentration lower than expected for 1 Wajnrajch MP, Gertner JM, Harbison MD, et al. Nonsense 107 mutation in the human growth hormone-releasing hor- their fat mass. Of particular interest to mone receptor causes growth failure analogous to the little paediatricians is the recent discovery of the first (lit) mouse. Nat Genet 1996;12:88–90. cases of the Ob gene mutation, analogous to 2 Takahashi Y, Hidesuke K, Okumura Y, et al. Short stature caused by a mutant growth hormone. N Engl J Med 1996; that found in the ob/ob mouse, in two 334:432–6. massively obese children from a consanguine- 3 Tatsumi K, Miyai K, Notomi T, et al. Cretinism with com- 108 bined hormone deficiency caused by a mutation in the ous family. Although very rare, this diagnosis PIT1 gene. Nat Genet 1992;1:56–8. should be considered in children, who develop 4 Radovick S, Nations M, Du Y, et al. A mutation in the POU-homeodomain of Pit-1 responsible for combined progressive severe obesity in infancy. pituitary hormone deficiency. Science 1992;257:1115–8. The ob/ob mouse is recognised to be sterile, 5PfäZe RW, DiMattia GE, Parks JS, et al. Mutation of the POU-specific domain of Pit-1 and hypopituitarism without but it was found that parenteral administration pituitary hypoplasia. Science 1992;257:1118–21. of leptin not only induced weight loss but also 6 Ayling RM, Ross R, Towner P, et al. A dominant-negative 109 mutation of the growth hormone receptor causes familial stimulated the reproductive system and short stature. 1997;16:13–4. 98 110 Nat Genet restored fertility. A series of experiments in 7 Woods KA, Camacho-Hübner C, Savage MO, et al. Intrau- terine growth retardation and postnatal growth failure http://adc.bmj.com/ normal rats and mice have demonstrated con- associated with deletion of the insulin-like growth factor I clusively that leptin administration is also able gene. N Engl J Med 1996;335:1363–7. to bring forward the age at which reproductive 8 Rao E, Weiss B, Fukami M, et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause ability is achieved, despite lowering body growth failure in idiopathic short stature and Turner weight.111–113 It will also partially reverse the syndrome. Nat Genet 1997;15:54–63. 9 Pivnick EK, Wachtel S, Woods D, et al. Mutations in the relative hypopituitarism induced by starvation conserved domain of SRY are uncommon in XY gonadal of mice.114 These eVects are likely to be dysgenesis. Hum Genet 1992;90:308–10. 10 Jager RJ, Harley VR, PfeiVer RA, et al. A familial mutation in

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