b p.468) b pp.111, 468) b p.470) b p.424), b pp.469, 948) b p.941) b p.936) \200 \200 b p.336) b pp.366 \200\223369) b p.469): in \202 ammatory bowel \200 b p.766): achondroplasia/hypochrondroplasia Investigations The following baseline screening tests should be carried out: \200 \200 \200 \200 \200 \200 \200 \200 U&E (renal function). FBC and CRP (chronic disease/in \202 ammation). Calcium and phosphat e (bone disorder). Karyotype (chromosomal abnormalities, especially Turner \200\231s syndro me). Thyroid function tests. Serum IGF-I (and IGFBP-3) (GH de \201 ciency). Coeliac diseas e antibody screen. Urinalysis. Where clinically indicated: \200 \200 Bone age X-ray. GH provocation test. Management This will depend on the underlying cause (see later sections of this chap- ter). The diagnosis of a child with short stature is often a shock to the family, and they shoul d be offered detailed, reliable information about their child \200\231s condition and infor med where to get additional support and advice. In the UK the Restricted Growth Foundation (www.restricted- growth.co.uk) is a good resource. Familial short stature does not require any speci \201 c treatment. Note: Most short children are psychologically well adjusted. Where there are problems from being teased and bullied at school or poor self- esteem, psychological intervention measure s may be needed. 13_McClure_13.indd 467 11/14/2012 11:29:34 PM CHAPTER 13 Growth and puberty 468 Constitutional delay in growth and puberty Relative short stature occurs because of a delay in the timing of onset of puberty. It is a variation in the timing of normal puberty, rath er than an abnormal condition. It usually presents in early adolescence, although it may be recognized in earlier childhood. There is often a familial basis, of- ten having occurred in one of the parents. It is much commoner in males, although this may re \202 ect a bias in the level of concern. Characteristic features include short stature and delayed pubertal development by greater t han 2 SDs. Typically, there is a mild degree of skeletal disproportion with evidence of a s horter back (sitting height per- centile) relative to leg length. There is invariably delay in BA maturation, which usually remains consistent over time. Height velocity is appropria te for BA. Laboratory investigations are normal, including GH provocation tests. Management Usually no treatment is required as the onset of puberty and the accompa- nying growth spurt will occur spontaneously and an appropriate \201 nal adult target height is achieved. Treatment is sometimes indicated in those adolescents who have dif- \201 culty coping wit h their short stature or with the delayed physical devel- opment. Administration of sex ste roids for a period of 3 \200\2236mths can be used to induce pubertal changes and to acceler ate growth rate (boys: testosterone 50 \200\223100mg IM every 4wks). Intrauterine growth retardation See also b p.111. IUGR refers to reduction and restriction in expected fetal growth pattern. IUGR affects 3 \200\22310% of pregnancies and 20% of stil l- born infants are thought to have evidence of IUGR. Perinatal mortality rates are 4 \200 \2238 times higher for growth-retarded infants, and morbidity is present in 50% of survivin g infants. Growth outcome In placental causes of IUGR, \200\230catch-up growth \200\231 occurs after birth in the majority of infants during the \201 rst 1 \200\2232yrs of life, with infants regaining their genetically determined weight and height centiles. However, in approxi- ma tely 15 \200\22320% of infants with IUGR, catch-up growth does not occur and patients are a t risk of short stature. Recent studies also implicate IUGR in adult onset of hypertension and CHD, and in early onset obesity, polycys- tic ovarian disease, and type 2 diabetes. The se studies suggest that IUGR has long-term effects on insulin sensitivity and on endocrine function. 13_McClure_13.indd 468 11/14/2012 11:29:34 PM TURNER \200\231S SYNDROME 469 Turner \200\231s syndrome See also b p.948. This condition must always be considered in gir ls pre- senting with short stature, or height below parental target height range. Karyotype con \201 rms the diagnosis. The majority of girls with Turner \200\231s syndrome will not have the classi- cal phenotyp e of dysmorphic features and it may be dif \201 cult to identify, particularly where there is mosaicism in the karyotype. \200 Short stature is frequent. Typically growth rate begins to falter from age 3 \200\2235yrs a nd is due to an underlying skeletal dysplasia. Ovarian dygenesis and consequent gonadal fai lure result in loss of the pubertal growth spurt. Mean \201 nal height is consistently 20 cm below the norm. Treatment with daily SC injections of high dose recombinant human growth hormone (rhGH 10mg /m2/wk) increases \201 nal height, although individual responses are variable. Oral estro gen (ethinylestradiol) is required to induce puberty between ages 12 and 14yrs. Combination therapy, which also includes the anabolic steroid, oxandrolone, may fur- ther improve \201 nal height. Coeliac disease Also see b p.336. Coeliac disease may be asymptomatic or atypical in its pr esentation with few if any gastrointestinal symptoms or signs. Poor height velocity and evo lving short stature may be a presenting feature. Chronic in \202 ammatory disorders Poor growth and short stature is a common feature of lo ng-term in \202 am- matory conditions such as in \202 ammatory bowel disease and rheumati c dis- orders. It may be a presenting feature in Crohn \200\231s disease when GI symp- toms are initially minimal (see b p.332). Short stature is due to long-term use of immunosuppressive agents (e.g. corticosteroids) an d to the generation of in \202 ammatory factors (e.g. IL-6). Both lead to GH/IGF-I resista nce and suppression of bone growth. Management should be aimed at minimizing in \202 ammation, and reducing immunosuppressive therapy. rhGH may have a role in treatment. Skeletal dysplasias This heterogeneous group of disorders includes achondroplasia and hypoc hrondroplasia. Most disorders are characterized by severe short stature and often evidence of disproportion in body segment develop- ment. Skeletal survey may allow identi \201 cati on of speci \201 c condition (see b pp.766 \200\223767, 950). 13_McClure_13.indd 469 11/14/2012 11:29:34 PM CHAPTER 13 Growth and puberty 470 Growth hormone de \201 ciency Physiology: secretion GH is secreted from the somatomammotro pic cells of the anterior pitu- itary gland in a pulsatile pattern. Secretion is diurnal an d largely noctur- nal and is controlled by a rhythmically changing equilibrium between two hormones secreted by the hypothalamus: GH releasing hormone (GHRH) and GH-inhibiting hormon e (or somatostatin). GHRH induces GH syn- thesis and secretion whenever somatostatin is low . Different factors act at the level of the hypothalamus to regulate GH hormone secretion. GH secretion is regulated by negative feedback by circulating insulin-like growth factor-I (IGF-I) at the pituitary and hypothalamus, and by short loop-feedback by GH on the hypothal amus. Causes of growth hormone de \201 ciency These may be primary (or congenital) or secondary (acquired) in origin. In clinical practice the most frequent cause of GH de \201 ciency is s to cranial radiotherapy (Box 13.2). Box 13.2 Causes of GH de \201 ciency Primary or congenital causes \200 \200 \200 Idiopathic/isolated Congenital hypopituitarism (see Midline brain anomalies b p.449) Secondary or acquired causes \200 \200 \200 \200 \200 Intracranial tumors: c Cranial irradiation/radiotherapy Psychosocial deprivation Traumatic brain injury In \202 ammatory/in \201 ltrative disease: \200 Langerhan \200\231s cell h istiocytosis \200 sarcoidosis Intracranial infection raniopharyngioma Clinical features Presentation depends on the age of onset of GH de \201 ciency. GH de \201 ciency in infancy May present with hypoglycaemia. Co-existing de \201 ciencies in the adrenal, thyroid, and gonadal axes may cause prolonged jaundice and micropenis. Siz e at birth and growth during the 1st year of life may be normal as growth during this perio d is not GH-dependent. GH de \201 ciency in childhood Typically presents with slow growth rate and short stature. Other charac- teristics include increased subcutaneous fat, truncal obesity, and decreased 13_McClure_13.indd 470 11/14/2012 11:29:34 PM GROWTH HORMONE DEFICIENCY 471 muscle mass. Children with congenital GH de \201 ciency develop relative hypoplasia of the mid-facial bones, frontal bone protrusion, and delayed dental eruption. Delayed closure of the anterior fontanelle may also be observed. Investigations Laboratory \200 Baseline/random serum IGF-I and IGFBP-3: low in GH de \201 ciency, but normal levels do no t exclude GH de \201 ciency. GH provocation tests. GH-dependent and may be All tests should be performed in the morning after an overnight fast and serial blood sampl es are collected. The insulin tolerance test (ITT) is con- sidered the gold-standard test. GH provocation test should only be per- formed in those centers with experience and with ap propriate technical and laboratory support. Assessment commonly used in children/adolescents Pharmacological stimulation tests \200 \200 \200 \200 \211 5yrs) Insulin tolerance test (gold standard; children aged Glucagon stimulation tests Clonidine t est Arginine test Physiological tests \200 \200 \200 Exercise Overnight or 24hr GH serum pro \201 les Random serum IGF-1 and/or IGFBP3 level Radiological \200 Bone age \200 MRI scan of brain (hypothalamic/pituitary structures) NICE criteria for diagnosis of GH de \201 ciency1 \200 GHD is primarily a clinical diagnosis supported by auxological, biochemical, and radiologic al \201 ndings. Con \201 rmation of the diagnosis is usually by GH provocation testing T wo such tests should be used in children with suspected isolated GH de \201 ciency togethe r with evaluation of other aspects of pituitary function De \201 nition of a normal GH res ponse remains arbitrary as there is a continuous spectrum of GH secretory ability in childh ood \200\224peak GH concentrations <20mIU/L (7microgram/L) have traditionally been used to support the diagnosis Reference 1 NICE (2010). Guidance on the use of human growth hormone (somatropin) in childr en with growth failure, Technology Appraisal Guidance, No. 188. London: NICE. 13_McClure_13.indd 471 11/14/2012 11:29:34 PM CHAPTER 13 Growth and puberty 472 Growth hormone de \201 ciency: management GH de \201 ciency is treated with rhGH, which i s administered as a once daily SC injection (0.7 \200\2231.0mg/m2/day or 23 \200\22339micro gram/kg/day). \200 Treatment should be undertaken in experienced centers. \200 Response s to treatment (height velocity increase) and dose adjustments should be reviewed once ever y 6mths. Catch up growth optimal if GH therapy is started as early as possible. Transition to GH de \201 ciency care in adulthood Treatment with rhGH is continued until \201 nal adult height is achieved. At this point the GH de \201 ciency should be recon \201 rmed, particularly in those with isolated or so-called idiopathic GH de \201 ciency w here the cause is unclear. Up to 50% of patients with the latter may have normal GH secre- tion when retested in early adulthood. Those patients with persisting GH de \201 ciency sh ould be offered the opportunity to continue rhGH therapy (0.2 \200\2230.5mg/day). Studies h ave demonstrated that rhGH replacement in adulthood may maintain lean body mass, muscle str ength, and bone min- eral density. In addition, improved quality of life has been reported with treatment. Cranial irradiation and GH de \201 ciency Cranial radiotherapy used in the treatment of tu mors (intracranial, face, and nasopharynx) may cause GH de \201 ciency. The GH axis is the most sensitive to radiotherapy, followed by the gonadal and adrenal axes, and \201 nally the thyroid axis, which is least sensitive. There is a good corre- lation between radiothe rapy dose and the occurrence of hypothalamic \200\223 pituitary dysfunction (Table 13.2). R isk of dysfunction is also related to dose fractionation (single is more toxic than divided ), and age (younger more sensitive). Table 13.2 Correlation between radiotherapy dose and GH de \201 ciency Radiotherapy dose (Gy) % GH-de \201 cient* 18 24 55 25 \200\22345 68 \200\22376 >45 100% Assessed 4yrs after radiotherapy. 13_McClure_13.indd 472 11/14/2012 11:29:34 PM GROWTH HORMONE DEFICIENCY: MANAGEMENT 473 Pyschosocial deprivation Children subjected to physical or emotional abuse may exhibit grow th failure. This may be due to a reversible inhibition of GH secretion that improves within 3 \200\2234wks of being removed from the adverse environment. Catch-up growth is usually d ramatic. GH insensitivity syndrome Moderate to severe short stature may be due to GH resistance. Thi s may be due to a defect in the GH receptor or to a defect in post-receptor GH signaling. Complete GH insensitivity syndrome (GHIS) results in severe short stature. It may be inheri ted as an autosomal recessive trait (Laron syn- drome). Affected individuals have high GH l evels and low circulating IGF- I levels. Exogenous rhGH administration fails to increase IG F-I levels further (IGF-I generation test). 13_McClure_13.indd 473 11/14/2012 11:29:34 PM CHAPTER 13 Growth and puberty 474 Tall stature Referral for tall stature is much less common than that for short stature. Soc ially, it is more acceptable to be tall, particularly for boys. Nevertheless, tall stature, particularly when it is associated with inappropriately increased growth rates, may indica te an underlying growth disorder. Causes of tall stature In the majority tall stature is genetic in origin and inherited from tall par- ents. Other causes, although rare, need to be considered: \200 \200 \200 \200 Familial. Early (normal) puberty. Obesity. Endocrine disorders: \200 \200 \200 \200 \200 \200 \200 \200 Chromosomal abnormalities: Klinefelter \200\231s syndrome (XXY ); XYY; XYYY (b p.938). Other syndromes: Wiedemann (b p.949). b p.480); precocious puberty (see GH excess; pituitary adenoma; androgen excess; congenital adrenal h yperplasia ( hyperthyroidism ( aromatase enzyme de \201 ciency (very rare); estrogen recep tor defects (very rare). b p.436); b p.425); Marfan (b p.940), homocystinuria, Soto, Beckwith \200\223 History A detailed history should be obtained. Perinatal/infancy history \200 \200 \200 Size at birth. Birth weight (head circumference). Feeding and weight gain. Systematic enquiry E.g. headaches/visual disturbance. Growth history \200 \200 \200 Examine previous growth records if available. Recent growth acceleration. Signs of puberty. Neurodevelopmental \200 \200 Developmental delay. School performance. Family history \200 Tall stature. \200 Early puberty. \200 Endocrine disease. 13_McClure_13.indd 474 11/14/2012 11:29:34 PM TALL STATURE 475 Examination \200 Measure: \200 height; \200 weight; \200 head circumference. Pubert y staging (Tanner). Observe dysmorphic features; goiter. Assess growth velocity over a mini mum 6-monthly interval. Measure parents \200\231 heights and calculate: \200 \200 \200 \200 \200 MPH; family height target. Investigations The following baseline screening tests should be carried out: \200 \200 \200 \200 \200 Karyotype (chromosomal abnormalities \200\224Klinefelter \200\231s syndrome). Thyroid funct ion tests/serum IGF-I (and IGFBP-3). Sex hormone/LH and FSH levels. Androgen levels (DHEAS; 17-OH progesterone). BA X-ray. Where clinically indicated GH suppression test (i.e. modi \201 ed oral glucose tolerance t est; GH levels normally suppressed to low levels). Management In familial tall stature, reassurance and information about predicted \201 nal height are usually suf \201 cient. Early induction of puberty using low dose sex-steroid to advance the pubertal growth spurt and to cause earlier epiphyseal closure is occasionall y considered. However, this produces variable results and there is a theoretical risk of co mplications (including thromboembolic disease and oncogenic risk). 13_McClure_13.indd 475 11/14/2012 11:29:35 PM CHAPTER 13 Growth and puberty 476 Delayed puberty: assessment This is de \201 ned as the lack of initiation and progress of pubertal develop- ment > +2 SD later than the average age of onset of puberty for the pop- ulation. In the UK, this is to >14yrs for females and >16yrs for males. The causes of delayed puberty are shown in Box 13.3. History A detailed history should screen for the many possible physical and func- tional ca uses of delayed puberty. Make careful enquiry about age at puber- ty onset (including menar che in females) in other family members. Examination \200 \200 \200 \200 Measure height, weight, head circumference. Puberty (Tanner) staging. Review previous growt h records if available. Measure parents \200\231 heights and calculate MPH and family heigh t target. Investigations The following baseline screening tests should be carried out. Blood \200 \200 \200 \200 \200 LH and FSH levels. Sex hormone: Karyotype (chromosomal abnormalities). Thyroid function tes ts. Routine biochemistry and in \202 ammatory markers (e.g. CRP). estrogen/testosterone. Radiological \200 BA X-ray. \200 Pelvic US (ovarian morphology). \200 Abdominal US (e .g. intra-abdominal testes). \200 MRI scan brain. Tests \200 hCG stimulation test (3- or 21-day test): pre- and post-hCG (as indicator of functional tes ticular tissue). GnRH (LHRH) test: levels (an indicator of hypothalamic \200\223pituitary f unction). measurement of testosterone measurement of basal and post-GnRH LH and FSH Note: It is dif \201 cult to distinguish constitutional delay in growth and pu- berty (CDG P) from other causes of hypogonadotrophic hypogonadism (HH) using current tests. In both co nditions basal and stimulated go- nadotrophin (LH/FSH) levels are low. Differentiation may only be pos- sible after induction of puberty with sex steroid therapy and attainment of \201 nal height, when reassessment of the hypothalamic \200\223pituitary gonadal axis shoul d be repeated after withdrawal of treatment. 13_McClure_13.indd 476 11/14/2012 11:29:35 PM DELAYED PUBERTY: ASSESSMENT 477 Box 13.3 Causes of pubertal delay Constitutional delay of growth and puberty Hypogonadotrophic hypogonadism Low/undetectable basal and stimulated gonadotrophin levels: \200 Congenital: \200 \200 \200 \200 \200 Kallman \200\231s syndrome congenital hypopituitarism (e.g. LHX-3; PROP-1; see isolated LH de \201 ciency isolated FSH de \201 ciency other causes of gonadotrophin de \201 ciency, e.g. congenital adrenal hypoplasia (DAX-1 gene) syndromic associations, e.g. Prader \200 \223Willi syndrome b p.449) Acquired: \200 \200 \200 \200 \200 \200 \200 intracranial tumors (e.g. craniopharyngioma) cranial irradiation traumatic brain injury Lan gerhan \200\231s cell histiocytosis anorexia nervosa excess physical training chronic child hood disease, e.g. in \202 ammatory bowel disease Primary gonadal failure (hypergonadotrophic hypogonadism) High basal and stimulated gonadot rophin levels \200 Congenital: \200 chromosomal disorders, Turner \200\231s syndrome, Klinefelter \200\231s syndrome gonadal dy sgenesis LH resistance disorders of steroid biosynthesis (e.g. congenital adrenal hyperplas ia: StAR; CYP17; 3BHSD (see b p.436)) \200 \200 Acquired: \200 \200 \200 \200 \200 \200 chemotherapy gonadal irradiation (local radiotherapy) gonadal infection (e.g. mumps orchiti s) gonadal trauma/gonadal torsion cranial irradiation autoimmune (ovarian) 13_McClure_13.indd 477 11/14/2012 11:29:35 PM CHAPTER 13 Growth and puberty 478 Delayed puberty: management \200 Children with CDGP may be treated with a short course of sex steroid therapy to promote phy sical development and growth (see Constitutional delay of growth and puberty). Children wit h permanent gonadotrophin de \201 ciency or gonadal failure requiring complete induction o f puberty and thus long-term treatment can have puberty induced with gradually increasing d oses of sex steroids over a period of 2 \200\2233yrs. \200 Boys: dose, starting from 50mg every 4 \200\2236wks to 250mg every 3 \200\2234wks. Girls: e thinylestradiol, oral. Increasing doses every 6mths, starting from 2micrograms/day increasi ng to 5 \200\22320micrograms/day. A progesterone (e.g. norethisterone or levonorgestrel giv en on days 14 to 21 of the cycle only) should be added when the dose of ethinylestradiol is 10 \200\22315micrograms/day or when vaginal bleeding or spotting is \201 rst observed. testosterone esters by IM injection. Incremental increases in The aim of long-term sex steroid therapy is the maintenance of secondary sexual features, l ibido, and menstruation in females. There are also positive bene \201 ts in terms of bone mineralization and cardiovascular health. Note. In males, testosterone therapy does not promote testicular growth and testicular size remains prepubertal unless spontaneous puberty occurs. Constitutional delay of growth and puberty This is the most common cause of delayed puberty . Usually observed in boys, this condition re \202 ects a delay in the timing mechanisms t hat regulate the onset of puberty. There is often a family history of delayed puberty in pa rents or siblings. \200 \200 \200 Children presenting with CDGP are invariably healthy. Onset and progress through puberty wi ll occur normally with time. Children achieve a \201 nal adult height in keeping with the ir predicted familial target range. It is likely that most children with CDGP are not referred for medical attention, as they a nd their parents will not perceive that there is a prob- lem. However, for many others, con cerns about the lack of physical devel- opment and the lack of anticipated adolescent growt h spurt would be a source of much anxiety and psychological stress. There is often evidence of delayed or slow growth in childhood, which is most pronounced in the peripubertal years due to lack of anticipated growth spurt. Children will also have ev idence of delayed skeletal matura- tion on bone age assessment. 13_McClure_13.indd 478 11/14/2012 11:29:35 PM DELAYED PUBERTY: MANAGEMENT 479 No speci \201 c therapy is required. For many children and families, explana- tion of the benign nature of the condition and reassurance that puberty will occur normally is suf \201 cient. However, children who are experienc- ing signi \201 cant social or psychologic al dif \201 culties may request treatment. In this situation, low dose sex steroids may be used (e.g. boys: testosterone, 50mg IM monthly for 4 \200\2236mths). This approach will: \200 \200 \200 induce sexual development; promote an increase in growth rate; stimulate activation of the hypothalamic \200\223pituitary \200\223gonadal axis. Thus puberty may continue once the administration of sex steroids has been stopped. Any decision regarding whether therapy is required or not must include the views of the chi ld and their parents, who should be part of the deci- sion process. Hypogonadotrophic hypogonadism This indicates impaired gonadotrophin release from the pitui tary gland. Congenital and acquired causes are recognized (see Box 13.3, b p.477). The cond ition is characterized by low or undetectable gonadotrophin lev- els either under basal or stimulated (GnRH test) conditions. Congenital causes of HH may be characterized by micropenis and unde- scended testis at birth in boys, whereas in girls physical signs are absent. Kallmann syndrome (KS) A genetic disorder characterized by the association of HH and anosmi a (absent sense of smell). This arises due to a defect in the co-migration of GnRH releasin g neurons and olfactory neurons that occurs during early fetal development. X-linked, autos omal dominant, and autosomal reces- sive modes of inheritance are recognized. The X-linked form of KS results from a mutation in the KAL gene (encoding the glycoprotein, anosmin-1). It is also characterized by a range of clinical features including synkinesia (mirror-image movements), renal agensis, and visual problems as well as craniofacial anomalies, although their expression is highly variable. 13_McClure_13.indd 479 11/14/2012 11:29:35 PM CHAPTER 13 Growth and puberty 480 Precocious puberty This is de \201 ned as the early onset and rapid progression of puberty . Age criteria vary. In White European children, precocious puberty (PP) is de \201 ned as <8yrs in females and <9yrs in males. Classi \201 cation and causes PP is either central or peripheral in origin. The various ca uses of PP are as follows. Central (true) PP (gonadotrophin-dependent) \200 \200 Idiopathic (familial/non-familial). Intracranial tumors: astrocytoma, optic glioma. Other C NS lesions: injury, cranial irradiation. early maturation of the hypothalamic \200\223pitui tary \200\223 Secondary central PP: gonadal axis due to long-term sex steroid exposure, e.g . congenital adrenal hyperplasia (CAH), McCune \200\223Albright syndrome. e.g. hypothalamic hamartoma, craniopharyngioma, hydrocephalus, arachnoid cysts, traumatic brain Puberty occurs as a consequence of early physiological (true) activation of the hypothalami c \200\223pituitary \200\223gonadal axis (central). A normal sequence of pubertal developme nt is observed. Central PP may also be idiopathic and familial. Girls with central PP are more likely to ha ve idiopathic central PP, whereas in boys there is a much greater risk of intracranial tumo rs. Peripheral PP (gonadotrophin-independent) \200 Gonadal: McCune \200\223Albright syndrome; ovarian tumors (e.g. benign cyst; granulosa cell tumor); testicular tumor; familial testitoxicosis (LH receptor-activating mutation). Adren al: Human chorionic gonadotrophin (HCG)-secreting tumors: (chorioepithelioma; dysgerminoma) . Iatrogenic (exogenous sex-steroid administration). \200 CAH; adrenal tumor (carcinoma; adenoma). e.g. CNS Puberty is due to mechanisms that do not involve physiological gonado- trophin secretion fr om the pituitary. The source of sex steroid may be endogenous (gonadal or extragonadal) or exogenous. Endogenous hor- mone production is independent of hypothalamic \200\223pituitary \200\223gonadal activ- ity. An abnormal sequence of pubertal development is usually observ ed. 13_McClure_13.indd 480 11/14/2012 11:29:35 PM PRECOCIOUS PUBERTY 481 Assessment History A detailed history should be obtained: \200 \200 Age when \201 rst signs of pubertal development observed. Which features of puberty are p resent and in what order did they appear? Evidence of growth acceleration. Family history: careful enquiry about the age of onset of puberty (including age of menarche in females) wi thin other family members. \200 Examination \200 \200 \200 \200 \200 \200 \200 Puberty (Tanner) staging. Measure height; weight; head circumference. Review previous growt h records if available. Measure parents \200\231 heights and calculate MPH/family height ta rget. Skin lesions: Abdominal/testicular masses. Neurological examination: e.g. caf -au-lait marks (McCune \200\223Albright; NF-1). visual \201 elds; fundoscopy. Investigations Baseline screening tests should be considered. \200 \200 \200 Plasma LH and FSH levels. Plasma sex hormone: Other serum androgen levels: androstendione. estrogen/testosterone. e.g. 17-OH progesterone, DHEAS, In addition, undertake the following: \200 \200 \200 \200 \200 \200 Urine: BA X-ray. Pelvic US (ovarian morphology; testicular masses). Abdominal US, e.g. adre nal glands. MRI scan brain. GnRH (LHRH) test: levels as indicator of hypothalamic \200\223p ituitary function. steroid pro \201 le (sex/adrenal steroids). measurement of basal and post-GnRH LH, and FSH 13_McClure_13.indd 481 11/14/2012 11:29:35 PM CHAPTER 13 Growth and puberty 482 Precocious puberty: management Diagnosis The diagnosis is based on demonstrating progressiv e pubertal develop- ment and increased growth rate, together with laboratory evidence of in creased sex steroid production. Distinguishing central and peripheral PP and PP from other normal variants of pubertal development may be dif \201 - cult (see Table 13.3). In CPP th ere is evidence of consonance in sequence of pubertal development in keeping with the norma l physiological activa- tion of puberty. Table 13.3 Characteristic \201 ndings of disorders of pubertal development Sequence of pubertal changes Height velocity Sex steroids LH/FSH (basal/ stimulated) BA Central PP Consonant ++ ++ ++, LH predominant ++ Peripheral PP Usually non- consonant ++ ++ Pre-pubertal; suppressed ++ Premature thelarche Breast tissue only N N Pre-pubertal/ FSH + N Thelarche \200\230variant \200\231 Breast tissue only + N Pre-pubertal/ FSH + N/+ Premature adrenarche Pubic hair; skin changes only N N/DHEAS + Pre-pubertal; N suppressed BA, Bone age; +, slightly raised or advanced; ++, raised or advanced; N, normal. 13_McClure_13.indd 482 11/14/2012 11:29:35 PM PRECOCIOUS PUBERTY: MANAGEMENT 483 Management The management of precocious puberty is aimed at the following: \200 Detection and treatment of underlying pathological causes of PP: this is especially importa nt in males in whom early puberty is invariably due to organic disease. Reducing the rate o f skeletal maturation, if necessary: accelerated skeletal maturation and growth rate occur and will result in the affected child being tall during childhood relative to peers. Howeve r, skeletal maturation exceeds concominant growth and thus growth potential is reduced, gro wth is complete prematurely, and \201 nal adult height is reduced and potentially below t he predicted expected familial target height range. Reducing development. Addressing potent ial behavioral and psychological dif \201 culties: sexual and reproductive characteristics advance inappropriately for age, leading to mature appearance. Early menstruation occurs i n girls, and spermatogenesis and ejaculation in boys. Sexualized behavior may occur and int eractions with age-peers and adults may be based on assumed, but age-inappropriate, mental and social expectations. and halting, if necessary, the rate of physical pubertal Before therapy is considered, it is essential that an explanation of the physiology and phy sical consequences of precocious puberty should be discussed with the parents and the child . The decision on therapy should be made jointly with the parents. Treatment of precocious puberty Central PP \200 Suppression of the hypothalamic \200\223pituitary \200\223gonadal axis with a long- acting GnRH analog is the only currently effective treatment for central PP. These agents work by providing continuous stimulation of the GnRH receptor on the pituitary gonadotrophes, resul ting in down- regulation of the receptor and thus decreased LH and FSH secretion. GnRH anal ogs are administered by either SC or IM injection, monthly (or 3-monthly in depot preparati ons). Treatment ef \201 cacy should be assessed by monitoring growth rate and pubertal sta ge. In addition, serum LH and FSH levels (basal and stimulated) should be measured to ensur e hypothalamic \200\223pituitary \200\223 gonadal axis suppression. 13_McClure_13.indd 483 11/14/2012 11:29:35 PM CHAPTER 13 Growth and puberty 484 Variants of normal puberty These include premature thelarche and premature adrenarche. Neit her condition is associated with pubertal activation of the hypothalamic \200\223pitu- itar y \200\223gonadal axis. Premature thelarche \200 Isolated premature breast development occurring in the absence of any other signs of pubert y. Typically, females present in infancy and usually by 2yrs of age. Breast development is due to the action of physiological or mild increases in the amounts of circulating estrogen . \200 The clinical course is characterized by a waxing and waning of breast size, normal growth ( height) rate, and the absence of any further sexual devel- opment. Breast development may b e asymmetrical, and there is usually a resolution of any breast enlargement by age 4 \200 \2235yrs. The cause is unknown, but small increases in basal and stimulated serum FSH levels are usua lly observed. In contrast LH levels remain suppressed in the prepubertal range. Ovarian fol licle development is often observed, but no changes in ovarian or uterine size are seen. Se rum oestradiol levels are increased when measured by sensitive assays, but typically within nor- mal range by standard radioimmunoassay. The condition is benign. Bone maturation, age of onset of menarche, and \201 nal adult he ight are not affected. Management is conservative with re-evaluation of growth and puberty stage at 3 \200\2236-monthly intervals. Thelarche variant \200 An intermediate condition between premature thelarche and central precocious puberty. It re presents a non-progressive form of early pubertal development. Patients have evidence of breast development, increased growth rate, and advanced skeletal maturation on bone age assessment. There may also be evidence of ovarian enlargement and ra ised serum oestradiol levels. For most patients the tempo of progression of pubertal develo pment will be slow and they will have laboratory \201 ndings within normal range for age. Management is usually conservative with regular re-evaluation of growth and pubertal statu s at 3 \200\2236 monthly intervals. Decisions to treat (as for central PP) are based on hei ght velocity and \201 nal height predictions. 13_McClure_13.indd 484 11/14/2012 11:29:36 PM VARIANTS OF NORMAL PUBERTY 485 Premature adrenarche Early onset of pubertal adrenal androgen secretion is a common variati on of normal pubertal development. Premature adenarche is the result of premature secretion of androgens from the zona reticualris of the adre- nal gland. \200 Children typically present with premature appearance of androgen- dependent s sexual hair d evelopment (axillary hair, pubic hair, or both), acne, and axillary (body) odor. Patients m ay have mild acceleration in height velocity and slight increase in BA. Laboratory investig ations reveal an increase in serum DHEAS levels that are appropriate for pubic hair stage r ather for than age. Serum concentrations of testosterone and 17-OH progesterone are normal. When evaluating patients for premature adrenarche it is important to assess for clinical si gns and symptoms that might indicate another cause of excess androgen production (e.g. adre nal tumor; congenital adrenal hyperplasia). The later are characterized with signs of viril ization, rapid growth rate, and signi \201 cantly advanced bone age. Premature adrenarche is a benign condition. The timing of onset of true puberty is normal a nd \201 nal adult height is unaffected. Management is conservative with reassurance after exclusion of other causes of adrenal androgen excess. Symptomatic treatment may be require d if adrenarche is pronounced, particularly in females who may go on to develop features of ovarian hyperandrogenism and the polycystic ovarian syndrome. 13_McClure_13.indd 485 11/14/2012 11:29:36 PM CHAPTER 13 Growth and puberty 486 Disorders of sex development Terminology \200 Sexual determination refers to the process that occurs from the time of conception until th e fetal bipotential gonad has been fully determined as either an ovary or testis. Sexual go nadal sex is determined until s sexual characteristics are fully expressed and fertility ac hieved. differentiation refers to the process that occurs from the time Disorders of sexual development The complex process of sexual determination and differentia tion may be interrupted. Numerous disorders that can result in genital ambiguity and uncert ainty about an infant \200\231s sex are recognized. Disorders of sexual dif- ferentiation m ay be classi \201 ed as genetic defects of gonadal determination (Box 13.4) or defects in androgen biosynthesis, metabolism, and action (excess or de \201 ciency). Box 13.4 Genetic disorders of gonadal determination \200 Gonadal dysgenesis: \200 \200 \200 \200 True hermaphroditism 46 XX or 46 XY sex rev ersal Camptomelic dysplasia (SOX-9 mutation) DAX-1 mutation Denys \200\223Drash syndrome (W T-1 mutation) 45 XO (gonadal dysgenesis) 46 XY (gonadal dysgenesis) 46 XX (gonadal dysgenesis) 45 XO/46 X Y (mixed gonadal dysgenesis) \200 \200 \200 \200 Virilization of 46 XX infants (female pseudohermaphrodite) \200 congenital adrenal hyperplasia \200\22421A- Excessive androgen production: hydroxylase de \201 ciency; 11B-hydroxylase de \201 ciency ; 3BHSD Defect in androgen exposure: Maternal steroid exposure \200 placental \200\223fetal aromatase de \201 ciency Under-virilization of 46 XY male (male pseudohermaphrodite) \200 Defect in testosterone production: \200 Leydig cell hypoplasia/agenesis defects of testic ular and adrenal steroidogenesis \200 17A-hydroxylase/17,20 lyase de \201 ciency \200\224StAR; 3BHSD; \200 5A-reductase de \201 ciency androgen insensitivity syndrome: Defect in testosterone metabolism: Defects in testosterone action: complete or partial 13_McClure_13.indd 486 11/14/2012 11:29:36 PM DISORDERS OF SEX DEVELOPMENT 487 Assessment History A detailed history should be obtained and should include: \200 Family history: inguinal hernia. Prenatal history: maternal virilization during pregnancy. History of previous stillbirths or neonatal death? ambiguous genitalia; disorders/problems of puberty; maternal health; drugs taken during pregnancy; Examination \200 dysmorphic features or midline defects; state of General examination: hydration; BP. Are the gonads palpable? ovotestes. Assess the degree o f virilization: \200 Prader stage (Fig 13.2). \200 External masculinization score. Meas ure the length of the phallus: \200 If \200\230yes \200\231 they are likely to be testes or Normal term penis is about 3cm (stretched length from pubic tubercle to tip of penis). Micr openis is a length <2.0 \200\2232.5cm. Penis: Vagina: Appearance of labioscrotal folds. Position of urethral opening. Skin \200 \224pigmentation of genital skin: adrenocorticotrophin (ACTH) and opiomelanocortin in CAH. \200 \200 \200 \200 presence of chordee. locate opening? hyperpigmentation with excessive In preterm girls clitoris and labia minora are relatively prominent. In pre- term boys, tes tes remain undescended until 34wks gestation. Fig. 13.2 Prader staging: virilization. Reproduced from Prader A. (1058). Die Hau \201 gke it der kongenitalen adrenigenitalen syndrome. Helv Paediatr Acta 13: 5 \200\22314 and 426 \200\22331. With kind permission of Springer Science and Business Media. 13_McClure_13.indd 487 11/14/2012 11:29:36 PM CHAPTER 13 Growth and puberty 488 Disorders of sex development: management Investigations Laboratory \200 Genetic sex determination: (takes 3 \200\2235 days). Serum electrolytes. Blood sugar (hypog lycaemia). Adrenal androgens: steroid pro \201 le; LH and FSH. Molecular genetic studies; blood (DNA). FISH for Y and X chromosomes; karyotype \200 \200 plasma testosterone; 17-OH progesterone; urine