Others are not able to replicate this. Epidemiology Paget \200\231s disease is present in about 2% of the UK population over the a ge of 55. Its prevalence increases with age and it is more common in men than women. Only a bout 10% of affected patients will have symptomatic disease. It is most common in the UK or in migrants of British descent in North America and Australa sia, but is rare in Africa. Recent studies in the UK and New Zealand have suggested that th e prevalence may be declining with time. Clinical features \200 90% asymptomatic \200 The most notable feature is pain. This is frequently multifactorial: i Metabolic activity of the bone \200 Changes in bone shape \200 Fissure fractures \200 Nerve compression \200 Arthritis Pagetic bones tend to increase in size or to become bowed (16% cases): bowing can be so sev ere as to interfere with function. Fractures (either complete or \201 ssure) are present in 10%. 73-Draznin-Chap73.indd 422 3/31/2011 3:59:53 PM INVESTIGATION 423 Investigation The diagnosis of Paget \200\231s disease is primarily radiological (Box 73.1) Box 73.1 Radiological features of Paget \200\231s disease Early disease \200\224primarily lytic \200 V-shaped \200\230cutting cone \200\231 in lo ng bones \200 Osteoporosis circumscripta in skull Combined phase (mixed lytic and sclerot ic) \200 Cortical thickening \200 Loss of corticomedullary distinction \200 Accentuat ed trabecular markings Late phase \200\224primarily sclerotic \200 Thickening of long bon es \200 Increase in bone size \200 Sclerosis An isotope bone scan is frequently helpful in assessing the extent of skeletal involvement with Paget \200\231s disease. It is partic ularly important to identify Paget \200\231s disease in a weight-bearing bone because of th e risk of fracture. The uptake of tracer depends on the disease activity, and iso- tope bon e scans can also be used to assess the response to therapy. In active disease, plasma alkaline phosphatase activity is usually (85%) elevated. An excep tion to this is in monostotic disease, when there may be insuf \201 cient bone involved to raise the enzyme levels above normal. Alkaline phosphatase activity responds to successful treatment. There is little advantage i n using the more modern markers of bone turnover over the total alkaline phosphatase activi ty for the monitoring of pagetic activity. A possible exception to this is in patients with liver disease, where changes in bone alkaline phosphatase might be masked by the liver iso enzyme. 73-Draznin-Chap73.indd 423 3/31/2011 3:59:53 PM CHAPTER 73 Paget \200\231s disease 424 Complications Deafness is present in up to 1/2 of cases of skull base Paget \200\231s. Othe r neu- rological complications are rare. These can include the following: \200 Compressio n of other cranial nerves with skull base disease \200 Spinal cord compression is most co mmon with involvement of the thoracic spine and is thought to result as much from a vascula r steal syndrome as from physical compression. It frequently responds to medical therapy wi thout need for surgical decompression. Platybasia, which can lead to an obstructive hydrocephalus that may require surgical drainage Osteogenic sarcoma: \200 Very rare complication of Paget \200\231s disease \200 Rarely amenable to treatment \200 Presents with i pain and radiological evidence of tumor, and a mass Any increase of pain in a patient with Paget \200\231s disease should arouse sus- pic ion of sarcomatous degeneration. A more common cause, however, is resumption of activity of disease. Pagetic sarcomas are most frequently found in the humerus or femur but can affect any bone involved with Paget \200\231s disease. 73-Draznin-Chap73.indd 424 3/31/2011 3:59:53 PM TREATMENT 425 Treatment Treatment with agents that decrease bone turnover reduces disease activ- ity as i ndicated by bone turnover markers and isotope bone scans. There is evidence to suggest that such treatment leads to the deposition of his- tologically normal bone. Although such treatment has been shown to help pain, there is little evidence that it bene \201 ts the other consequences of Paget \200\231s disease. In par- ticular, the deafness o f Paget \200\231s disease does not regress after treatment, although its progression may be halted. Nonetheless, it has become generally accepted to treat patients in the hope that future com plications of the disease will be avoided. Typical indi- cations for treatment of Paget \200\231s disease are listed in Box 73.2. The bisphosphonates have become the mainstay of treatment (Table 73.1). Calcitonin and plicamycin are no longer used. Patients should also be fully replete in both calcium and vitamin D before and during treatment. Goals of treatment \200 Normalize bone turnover \200 Alkaline phosphatase in normal ran ge \200 The more aggressive the initial therapy, the longer the disease remission. Minimize symptoms \200 Prevent long-term complications \200 No actual evidence that tre atment achieves this Box 73.2 Indications for treating Paget \200\231s disease \200 Pain \200 Neurological c omplications (e.g., deafness, spinal cord compression) \200 Disease in weight-bearing bon es \200 Prevention of long-term complications (e.g., bone deformation, osteoarthritis) \200 Young patients \200 In preparation for surgery \200 Hypercalcemi a \200 Following fracture 73-Draznin-Chap73.indd 425 3/31/2011 3:59:53 PM CHAPTER 73 Paget \200\231s disease 426 Table 73.1 Biophosphonates licensed in the U.S. for Paget \200\231s disease Duration of treatment Drug Dose Side effects 6 months Nausea Diarrhea Bone pain i Focal osteomalacia Etidronate 5 mg/kg per day orally in middle of 4-hour fast (max 400 mg) Pamidronate 3 x 60 mg IV infusion or 6 x 30 mg IV infusion 2-week interval Weekly interval In \202 uenza-like symptoms i Bone pain Iritis Risedronate 30 mg orally on rising and wait 30 minutes before breakfast 2 months Increased bone pain Nausea Tiludronate 400 mg/day and wait 2 hours before food in the morning 3 months, and 3 months post- treatment observation period Increased bone pain Nausea Zoledronic acid 5 mg IV Single dose Flu-like symptoms i Bone pain Upper GI side effects Bone pain Alendronate 40 mg orally on rising, wait 30 minutes upright before eating 6 months Monitoring therapy \200 Plasma alkaline phosphatase every 6 months \200 Clinical assess ment Re-treat if symptoms recur with objective evidence of disease recur- rence (alkaline phosph atase or positive isotope scan). If treating for asymp- tomatic disease, re-treat if alkali ne phosphatase increases 25% > nadir. Further reading Bilezikian, JP, Watts JT Jr, Fuleihan Gel-H, et al. (2002). Summary stateme nt from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin Endocrinol Metab 87(12):5353 \200\2235561. Davies M, Fraser WD, Hosking DJ (2002). The management of primaryhyperparathyroidism. Clin Endocrinol (Oxf) 57(2):145 \200\223155. Ralston SH, et al (2008). Pathogenous and management of Paget \200\231s disease of Core. 37 2:155 \200\223163. Selby PL, Davie MW, Ralston SH, et al. (2002). National Association for the Relief of Paget \200\231s Disease: guidelines on the management of Paget \200\231s disease of the bone. Bo ne 31(3):366 \200\223373. 73-Draznin-Chap73.indd 426 3/31/2011 3:59:53 PM OSTEOGENESIS IMPERFECTA 427 Inherited disorders of bone Osteogenesis imperfecta Osteogenesis imperfecta is an inherited form of osteoporosis in whi ch there is a genetic defect in one of the two genes ( COLIA1 and COLIA2 ) encoding the A-c hain of collagen type I collagen production. Several different mutations are recognized, and these produce differ- ent clinical pictures . These are generally separated into four and, more recently, seven different types ( b see Table 74.1). In addition to the osteoporosis and easy-fracture predisposition, there may also be abnorma lities of the teeth (dentigenesis imperfecta), blue sclerae, hearing loss, hypermobility, a nd cardiac valvular lesions. Radiological features include the following: Generalized osteopenia \200 Multiple fractures with deformity \200 Abnormal shape of lo ng bones \200 Wormian bones in skull Diagnosis \200 Features (as above) and family history \200 Analysis of collagen type I genes (detect 90%) \200 Differential diagnosis includes Brock syndrome, panostotic \201 brous dysplasia, hyper- and hypophatasia, and idiopathic juvenile osteoporosis. There are three criteria: \200 Three fragility fractures aged <20 years \200 At least o ne of the following: blue sclerae, scoliosis, hearing loss, joint laxity, dentinogenesis imperfecta, and affected family member Osteoporosis Recent studies have demonstrated that infusions of pamidronate lead to i bone mass and reduced fracture incidence in affected children. Patients with milder disease migh t only be recognized in adulthood. It appears that oral bisphosphonates may be helpful in t heir disease management. Prenatal diagnosis of severe types is possible from US, and genetic coun- seling should be offered to at-risk families. Further reading Rauch F, Glorieux FH (2004). Osteogenesis imperfecta. Lancet 363(9418):1377 \200\2231385. 74-Draznin-Chap74.indd 427 3/31/2011 4:00:12 PM 7 4 D r a z n i n C h a p 4 2 8 7 4 . i n d d Table 74.1 Classi \201 cation of osteogenesis imperfecta C H A P T E R 4 2 8 Type Inheritance Stature Teeth Sclerae Hearing Genetic defect I AD Normal Normal Blue Variable loss Substitution for glycine in COL1A1 and COL1A2 7 4 I n h e r i t e d II AD/AR Lethal deformity Rearrangement of COL1A1 and COL1A2 III AD/AR (Very short severe scaliosis) Abnormal Variable (growth) Loss common Glycine substitution is COL1A1 and COL1A2 IV AD Mild Abnormal Normal Occasional loss Point mutations in a2(I) or a1(I) d i s o r d e r s o f b o n e 3 / 3 1 / 2 0 1 1 4 : 0 0 : 1 2 P M 429 Part 7 Pediatric endocrinology Kristen Nadeau 75 Growth and stature 76 Puberty 77 Sexual differentiation 430 447 455 75-Draznin-Chap75.indd 429 4/1/2011 5:51:56 PM CHAPTER 75 Growth and stature 430 Growth and stature Growth Regulation of growth Normal human growth can be divided into three overlapping stages (the Karlberg model), each under the control of different factors. Infancy Growth is largely under nutritional regulation, and wide interindividual vari- atio n in rates of growth is seen. Many infants show signi \201 cant \200\234catch-up \200\235 or \200\234catch-down \200\235 in weight and length, and by 2 years, length is much more predictive of \201 nal adult height than at birth. Childhood Growth is regulated by growth hormone (GH) and thyroxine. It is char- acterized b y alternating periods of mini-growth spurts with intervening stasis, each phase lasting sev eral weeks. However, over years, a child will tend to maintain their centile position on he ight charts with a height vel- ocity between the 25th and 75th centiles. Puberty The combination of GH and sex hormones promotes bone maturation and a rapid growth acceleration, or growth spurt. In both sexes estrogen even- tually causes epiphyseal fusion , resulting in the attainment of \201 nal height. Sex differences Adult heights differ between men and women by on average 13 cm. During chil dhood, onset of the pubertal growth spurt is earlier in girls, who are thus on average tall er than boys between the ages of 10 \200\22313 years. Tempo Within each sex there may also be marked interindividual differences in tempo of grow th (or rate of attainment of \201 nal height) and the timing of puberty. Delay or advance of bone maturation is linked with timing of puberty. Constitutional delay in growth and pu berty often runs in families, re \202 ecting probable genetic factors. Comparison of bone age (estimated from a hand and wrist radiograph) with chronological age is thus an important part of growth assessment. Final height Final height is estimated as the height reached when growth velocity slows to <2 cm/year and can be con \201 rmed by \201 nding epiphyseal fusion on hand or wrist rad iograph knee radiograph. Final height is largely genetically determined, and a target height can be estimated in each individual from their parent \200\231s heights. 75-Draznin-Chap75.indd 430 4/1/2011 5:51:57 PM GROWTH 431 Assessment of growth Measurement From birth to 2 years old, supine length is measured ideally using a meas- urin g board (e.g., Harpenden neonatometer). Two adults are needed to ensure that the child is l ying straight with legs extended. From 2 years old, standing height is measured against a wall-mounted or free-standing stadi ometer with the measurer applying moderate upward neck traction and the child looking forwa rd in the horizontal plane. To minimize error in the calculation of height velocity (cm/year), height measurements shou ld be taken at least 6 months apart using the same equipment and by the same person. Measurement of sitting height and comparison with leg length (standing height \200\223 sitting height) allows an estimate of body proportion. Growth charts (Figs. 75.1 and 75.2) Height and weight velocity should be compared to age- a nd sex-appropri- ate reference data by plotting values on standard growth charts (e.g., US 2000 CDC Growth Charts: http://www.cdc.gov/growthcharts/). 190 180 Boys 170 Girls 160 150 140 130 ) m c ( 120 t h g e i 110H 100 90 80 70 60 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Age (years) Fig. 75.1 Typical individual height-attained curves for boys and girls (supine length to th e ages of 2; integrated curves of Fig. 75.2 ). 75-Draznin-Chap75.indd 431 4/1/2011 5:51:57 PM CHAPTER 75 Growth and stature 432 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 ) m c ( t h g e H i Boys Girls 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Age (years) Fig. 75.2 Typical individual velocity curves for supine length or height in boys and girls. These curves represent the velocity of the typical boy and girl at any given instant. Mid-parental height (MPH) MPH is an estimate of the child \200\231s genetic height potentia l and is calculated as [(mother \200\231s height + father \200\231s height)/2] + 7 cm (for boys) or \200\223 7 cm (for girls). It can be used to estimate a child \200\231s expected \201 nal height, but there is a wid e target range (MPH 10 cm for boys and 8.5 cm for girls), and it is more commonly use d to assess whether the child \200\231s current height centile is consistent with genetic e xpectation. Bone age Skeletal maturation proceeds in an orderly manner from the \201 rst appear- ance of each epiphyseal center to the fusion of the long bones. From chronological age 3 \200 \2234 years, bone age may be quanti \201 ed from radiographs of the left hand and wrist by comparison with standard photographs (e.g., 75-Draznin-Chap75.indd 432 4/1/2011 5:51:58 PM GROWTH 433 Greulich and Pyle method) or by an individual bone scoring system (e.g., Tanner \200\223Whi tehouse method). The difference between bone age and chronological age is an estimation of tempo of growth. The initiation of puberty usually coincides with a bone age around 10.5 \200\22311 years in girls and 11 \200\22311.5 years in boys, although the correlation between bone age and pub ertal timing is approximate. Girls reach skeletal maturity at a bone age of 15 years and boys when bone age is 17 years. Thus, bone age allows an estimation of remaining growth potential and can be used to aid i n the prediction of \201 nal adult height. Final height prediction Predictions of \201 nal height can be derived from information on current height, age, pubertal status, and bone age using calculations described by Tanner and Whitehouse, or Bailey and Pinneau, among others (b see Further reading, p. 446, De Waal et al., 1996). Secular trends Population growth references used should be appropriate to the popula- tion studied and may occasionally need to be updated. 75-Draznin-Chap75.indd 433 4/1/2011 5:52:00 PM CHAPTER 75 Growth and stature 434 Short stature De \201 nition Short stature is de \201 ned as height at least 2 standard deviations (SD) below the mean for age and sex or at least 2 SD below the predicted MPH. However, abnormal ities of growth may be present long before attained height falls below this level and may b e detected much earlier by assessing growth velocity and observing height measurements Assessment History \200 Who is concerned, the child or parents? \200 What are the parental heights ? \200 Has the child always been small, or does the history suggest recent growth failure ? Try to obtain previous measurements (e.g., from parents, primary care physician, school). Ask about maternal illness in pregnancy, drug intake and possible sub- stance abuse in preg nancy, gestation at delivery, size at birth (weight, length, and head circumference), child hood illnesses, medication, and developmental milestones. \200 Conduct a systematic inqui ry regarding headaches, visual disturbance, asthma and respiratory symptoms, abdominal symp toms, and diet. Is there a family history of short stature or pubertal delay? \200 What are the psychosoc ial circumstances of the child and the family? Examination \200 Assess height and height velocity over at least 6 months. \200 Measure sitting height and derive subischial leg length (standing height \200\223 sitting height [cm] if skeletal disproportion suspected). Assess for the presence and severity of chronic disease. Low weight- for-height suggests a nutritional diagnosis, GI cause, or other signi \201 cant systemic d isease. Pubertal stage using Tanner \200\231s criteria \200 Observe for dysmorphic features and s igns of endocrinopathy, and presence and severity of chronic disease. \200 Measure parents \200\231 heights and calcu late MPH. Investigations Laboratory tests should include CBC, ESR, electrolytes, thyroid func- tion, calcium, phosphate, tissue transglutaminase antibodies, IGF-1 and IGF BP-3 levels, karyotyp e (of particular importance in girls), and urinalysis. The following tests may also be clinically indicated: GH provocation testing (e.g., arginin e, clonidine, or glucagon) (see Table 75.1) with other anterior pituitary function tests, M RI scan with speci \201 c reference to the hypothalamus and pituitary, skeletal survey (fo r bone dysplasia), and, very rarely, an IGF-1 generation test (b for GH resistance, see Gro wth hor- mone de \201 ciency, p. 437). 75-Draznin-Chap75.indd 434 4/1/2011 5:52:00 PM SHORT STATURE 435 Table 75.1 Comparison of GH provocation tests l-arginine (IV) Clonidine (oral) Glucagon (IM) Advantages Safe Simple and safe Safe Also tests ACTH- cortisol axis Disadvantages Requires IV infusion Postural hypotension and somnolence Nausea may last 3 \200\2234 hours Possible late hypoglycemia Other agents (e.g., L-dopa or Insulin) are less commonly used. Measurement of GH levels aft er exercise has poor sensitivity and speci \201 city for detecting GH de \201 ciency. Causes \200 Genetic short stature \200 Constitutional delay in growth and puberty These \201 rst two together account for 40% of cases. Chronic illness (including untreated celiac disease, congenital heart disease, chronic renal failure, in \202 ammatory bowel disease) Psychosocial deprivation (which may be associated with reversible GH de \201 ciency) Small for gestational age (SGA), including intrauterine growth restriction (IUGR) (7.5%). Dysmorphic syndromes (e.g., Turner \200\231s, Noonan, or Down syndrome) \200 Malnutrition GH de \201 ciency (8%) \200 Unde \201 ned etiology (idiopathic, including those with a bnormal pituitary morphology on MRI) Congenital malformation in the hypothalamus and pituitary (HP) (e.g., septo-optic dysplasia) or acquired HP disorders (e.g., craniopharyngioma, traum a), the GH-1 gene or GH-releasing hormone receptor gene, or rarely, mutations in transcript ion factors controlling pituitary development GH resistance (rare genetic mutations in the GH receptor or GH signaling molecules) Endocrine disorders (hypothyroidism, hypoparathyroidism, Cushing \200\231s syndrome) Other \200 Skeletal dysplasia (e.g., achondroplasia, hypochondroplasia) \200 Metabolic bone disease (e.g., nutritional or hypophosphatemic rickets) 75-Draznin-Chap75.indd 435 4/1/2011 5:52:00 PM CHAPTER 75 Growth and stature 436 Genetic short stature Although stature does not follow strict Mendelian laws of inheritance , it does relate to parental height and is probably a polygenic trait. It should be remembe red that short parents may themselves have an unidenti \201 ed dominantly inherited condit ion (e.g., hypochondroplasia). Constitutional delay of growth and puberty Clinical features This condition often presents in adolescence but may also be recognized i n earlier childhood and is more prevalent in boys. Characteristic features include short stature and delay in pubertal devel- opment by >2 SD and/or bone age delay in an otherwise healthy child. In the adolescent years, short sitting height percentile compared to that of leg length is typical. There is often a family histo ry of delayed puberty. Bone age delay may also develop in a number of other conditions, but in constitutional dela y, bone age delay usually remains consistent over time, and height velocity is normal for t he bone age. Final height may not reach target height. GH secretion is usually normal, although provocation tests should be primed by prior admini stration of exogenous sex hormones if bone age is >10 years. Management Often only reassurance is necessary. Treatment is sometimes indicated in adolesc ent boys who have dif \201 culty coping with their short stature or delayed sexual maturat ion. \200 For the older boy (>14 years) with concerns about puberty: testosterone (50 \200\223100 mg IM, monthly for 3 \200\2236 months) For the older girl (>13 years) with concerns about puberty: estradiol (0.5 mcg qod for 3 \200\2236 months) or Premarin 0.3 mg qod. 75-Draznin-Chap75.indd 436 4/1/2011 5:52:01 PM GROWTH HORMONE DEFICIENCY 437 Growth hormone de \201 ciency Primary GH de \201 ciency Primary GH de \201 ciency is usu ally sporadic, but rarely it may be inherited as autosomal dominant, recessive, or X-linked recessive and may be associ- ated with other pituitary hormone de \201 ciencies. It may r epresent a defect in homeobox genes (e.g., Pit1 [leading to GH, TSH, and PRL de \201 cienc y], Prop1 [leading to GH, TSH, PRL, gonadotropin, and later ACTH de \201 cien- cies], or H esx1 ) that control HP development. Mutation in Hesx1 has been associated with midline defects, such as optic nerve hypoplasia and corpus callosum defects (i.e., septo-optic dys- plasia). GH de \201 ciency usually ari ses because of failure of release of GHRH from the hypothalamus. Clinical features Infancy GH de \201 ciency may present with hypoglycemia. Coexisting ACTH, TSH, and gonadot ropin de \201 ciencies may cause prolonged hyperbilirubinemia and micropenis. Size may be normal, as fetal and infancy growth are more dependent on nutrition and other growth factor s than on GH. Childhood Typical features include slow growth velocity, short stature, d muscle mass, and i SC fat. Underdevelopment of the mid-facial bones, relative protrusion of the frontal bone s because of mid-facial hypoplasia, delayed dental eruption, and delayed closure of the ant erior fontanelle may be seen. These children have delayed bone age and delayed puberty. Secondary GH de \201 ciency Brain tumors and cranial irradiation Pituitary or hypothalamic tumors may impair GH secreti on, and de \201 cien- cies of other pituitary hormones may coexist. Cranial irradiation, u sed to treat intracranial tumors, facial tumors, and acute leukemia, may also cause GH de \201 ciency. Risk of HP damage is related to total dose administered, fractionation (single dose more to xic than divided), location of the irradiated tissue, and age (younger children are more se nsitive to radiation damage). GH secretion is most sensitive to radiation damage, followed by gonadotropins, TSH, and ACT H. Central precocious puberty may also occur and may mask GH de \201 ciency by promoting g rowth but will com- promise \201 nal height if untreated. At-risk children should therefo re be screened regularly by careful examination and multiple pituitary hor- mone testing. These survivors of childhood cancer may also have other endocrine problems, including gonad al damage related to concomitant chemother- apy or radiation scatter, hypothyroidism relate d to spinal radiation, or glucose intolerance related to total body irradiation. It is reco mmended that all such patients undergo endocrine surveillance. 75-Draznin-Chap75.indd 437 4/1/2011 5:52:01 PM CHAPTER 75 Growth and stature 438 Psychosocial deprivation Severe psychosocial deprivation may cause reversible disturbance o f GH secretion and growth failure. GH secretion improves within 3 weeks of hospitalization or removal from the adverse environment and catch-up growth is often dramatic (see Fig. 75. 3 ), although these children may con- tinue to exhibit other features of emotional disturba nce. Treatment of GH de \201 ciency (Fig. 75.4) Recombinant human GH has been available since 1 985 and is administered by daily SC injection. Dose The replacement dose for childhood GH de \201 ciency is 0.3 mg/kg per week, divided i nto 7 days/week. Catch-up growth is optimized if GH is com- menced early. A higher dose can be used in puberty, re \202 ecting the normal elevation in GH levels at Tanner stage 3 \200\2234. F 190 97 90 75 50 25 10 3 BOYS Height 180 M 97 170 Longitudinal standards 50 160 3 150 140 130 ) m c ( 120 t h g e H i 110 100 90 80 5+ 4+ 3+ 2+ 5+ 4+ 3+ 2+ 12 ml 4 ml Penis stage Pubic hair stage Testes vol. 70 97 90 75 50 25 10 3 60 97 90 75 50 25 10 3 97 90 75 50 25 10 3 50 12 13 14 15 16 17 18 19 1 2 3 4 5 6 7 8 9 10 11 Age (years) Fig. 75.3 Height of child with psychosocial short stature. Note catch-up on removal, marked by arrow, from parental home. Reprinted with permission from Brook C (2001). Brook \200 \231s Clinical Pediatric Endocrinology . Wiley-Blackwell. 75-Draznin-Chap75.indd 438 4/1/2011 5:52:01 PM GROWTH HORMONE DEFICIENCY 439 190 97 90 75 50 25 10 3 M BOYS Height 180 F 97 170 Longitudinal standards 50 160 3 150 140 130 ) m c ( 120 t h g e H i 110 100 90 80 70 human growth hormone 60 50 1 2 3 4 5 6 7 8 9 10 11 Age (years) 12 13 14 15 16 17 18 19 Fig. 75.4 Heights of two brothers with isolated GH de \201 ciency treated with human GH fr om ages 6 years and 2 years. Catch-up of older brother is partly by high velocity and partl y by prolonged growth and is incomplete. Younger brother shows true complete catch-up. F an d M, parents \200\231 height centiles; vertical thick line, range of expected heights for f amily. Reprinted with permission from Brook C (2001). Brook \200\231s Clinical Pediatric En docrinology . Wiley-Blackwell. Side effects Local lipoatrophy and benign intracranial hypertension occur rarely. Slipped u pper femoral epiphyses are associated with GH de \201 ciency, but the incidence is similar before or after GH treatment. Other pituitary hormone de \201 ciencies may be unmasked by GH therapy, and thyroid functi on should be checked within 4 \200\2236 weeks of commencing therapy. Retesting in adulthood Once \201 nal height is achieved, GH secretion should be retested, as a sig- ni \201 cant percentage of subjects (25 \200\22380%) with GH de \201 ciency in childhood subsequently have normal GH secretion in adulthood. In those with con \201 rmed GH de \201 ciency, continuation of GH treatment (at a dose of 3 \200\2236 mcg/kg/day) through the late adolescent years into early 75-Draznin-Chap75.indd 439 4/1/2011 5:52:02 PM CHAPTER 75 Growth and stature 440 adulthood (the transition phase) is recommended in order to complete somatic development (i ncreasing lean body mass and muscular strength, reducing fat mass, improving bone density, and maintaining a healthy lipid pro \201 le). GH treatment may need to be continued beyond this phase, as adult GH replacement. The transition from pediatric to adult care is an important time to not only re-evaluate GH status but also reassess other pituitary function and management of any underlying disorde r. It is also recommended that assessment of bone mineral density, body composition, fasting l ipid pro \201 le, and QoL by questionnaire be under- taken at this time and repeated at 3- to 5-year intervals for those restart- ing GH treatment. GH resistance GH resistance may arise from primary GH receptor defects or post-re- ceptor d efects secondary to malnutrition, liver disease, type 1 diabetes, or, very rarely, circulat ing GH antibodies. Laron syndrome is a rare autosomal recessive condition caused by a genetic defect of the GH receptor. Affected individuals have extreme short stature, high levels of GH, low levels o f IGF-1, and impaired GH-induced IGF-1 generation (b see Box 75.1, p. 440). Treatment with recombinant IGF-1 is available. Hypothyroidism (Fig. 75.5) Congenital primary hypothyroidism is detected by neonatal screen ing. Hypothyroidism presenting in childhood is usually autoimmune in origin. Incidence is h igher in girls and those with personal or family history of other autoimmune disease. Box 75.1 GH assessment GH is normally secreted overnight in regular pulses (pulse frequency 180 minutes). Frequent ly sampled overnight GH pro \201 les are costly and labori- ous, thus standardized stimula tion tests are more commonly useful. There can be large variation between different GH assay methods and exact cut-offs must be locally validated. A number of different agents may be used to stimulate GH secretion (arginine, clonidine, gl ucagon, or insulin; see Table 75.1, p. 435). All tests should be performed in the morning f ollowing an overnight fast, and serial blood samples are collected over 90 \200\223180 minu tes. An IGF-1 and IGF BP-3 level should also be measured in the baseline sample, as an additional marker of GH status. IGF-1 generation test In those with high basal and stimulated GH levels and low IGF-1 level s, measurement of IGF-1 levels before and following administration of GH 0.1 IU/kg (30 mcg/ kg/day) daily SC for 4 days allows an assessment of GH sensitivity and resistance. This tes t is rarely necessary. 75-Draznin-Chap75.indd 440 4/1/2011 5:52:03 PM GROWTH HORMONE DEFICIENCY 441 190 GIRLS Height 180 97 90 75 50 25 10 3 97 170 Longitudinal standards 50 160 3 150 140 130 ) m c ( 120 t h g e H i 110 100 Thyroxine 90 5+ 4+ 3+ 2+ 5+ 4+ 3+ 2+ 80 Breast stage 70 97 90 75 50 25 10 3 Pubic hair stage Menarche 60 97 90 75 50 25 10 3 97 90 75 50 25 10 3 50 12 13 14 15 16 17 18 19 1 2 3 4 5 6 7 8 9 10 11 Age (years) Fig. 75.5 Response of hypothyroid child treated with thyroxine. Solid circles, height for a ge; open circles, height for bone age. Reprinted with permission from Brook C (2001). Brook \200\231s Clinical Pediatric Endocrinology . Wiley-Blackwell. In childhood, hypothyroidism may present with growth failure alone, and bone age is often d isproportionately delayed. Very rarely, early puberty may occur. Investigations show low T 4 and T 3 , high TSH, positive anti-thyroglobulin, and antithyroid peroxidase (microsomal) antibodies. Replacement therapy with oral levothyroxine (100 mcg/m 2 per day titrated with thyroid function) results in catch-up growth unless diagnosis is late. Celiac disease This is more common in children with other autoimmune disorders. Although th e classical childhood presentation is an irritable toddler with poor weight gain, diarrhea, abdominal pain, and distension, in later child- hood poor growth with bone age delay may b e the presenting feature. Measurement of tissue transglutaminase is a valuable screening test, but diagnosis needs to be con \201 rmed by small-bowel biopsy. Catch-up growth usually follows commencement of a gluten-free diet. 75-Draznin-Chap75.indd 441 4/1/2011 5:52:03 PM CHAPTER 75 Growth and stature 442 Skeletal dysplasias This heterogeneous group of mostly dominantly inherited disorders inclu des achondroplasia and hypochondroplasia. These children usually have severe disproportionate short stature and a positive or suspicious family history. Radiological assessment by skeletal survey often allows a speci \201 c diag- nosis to be made. High-dose GH therapy has been used in these disorders, with variable success. Surgical leg- lengthening procedures before and/or after puberty are also an additional option. Small for gestational age (SGA) and intrauterine growth restriction (IUGR) SGA is de \201 ned as birth weight and/or length at least 2 SD below the mean for gestational age. IUGR is de \201 ned as growth failure on serial antenatal US scans, and that would usually lead t o a baby being born SGA. However, IUGR in late gestation may result in a baby who is within 2 SD of the mean for birth weight or length. Ninety percent of infants with SGA show catch-up growth by age 3 years; 8% of subjects born SGA will remain small at 18 years of age. Catch-up growth is more common in infants with r elative sparing of birth length and head circumference (>10th centile). In severe IUGR, length and head circumference are also reduced. Severe IUGR may be due to m aternal factors such as hypertension in pregnancy, placental dysfunction, or a wide range o f chromosomal or genetic condi- tions in the fetus. Russell-Silver syndrome is characterized by severe IUGR, lateral asym- metry, triangular fa cies, clinodactyly, and extremely poor infancy feeding and postnatal weight gain. Children with severe IUGR who do not undergo catch-up growth may have early-onset puberty d espite bone age delay and therefore achieve a very poor \201 nal height. Numerous epidemiological studies have shown a relationship between low birth weight and an i risk of a number of disorders in later life, includ- ing hypertension, ischemic heart dis ease, cerebrovascular disease, meta- bolic syndrome, and type 2 diabetes. The risk is i wit h rapid postnatal weight gain. These associations relate to relatively low birth weight and not exclusively to those born SGA. Management GH therapy is used in the SGA/IUGR child who has failed to show catch-up growth by age 3 years. GH (at doses of 0.48 mg/kg/week) can increase growth velocity and \201 na l height. The effect of GH on later risk of insulin resistance as type 2 diabetes is not kn own. Turner \200\231s syndrome b Also see Box 50.1 (p. 258). Turner \200\231s syndrome should always be considered in a girl who is short for her parent al target. The classical dysmorphic features may be dif \201 - cult to identify at younger ages. Karyotype usually con \201 rms the diagnosis, 75-Draznin-Chap75.indd 442 4/1/2011 5:52:04 PM GROWTH HORMONE DEFICIENCY 443 Turner syndrome 180 170 160 +2SD +1SD x \210\2221SD \210\2222SD 150 140 ) 130 m c ( t h g e H 120 i 110 Height SDS 100 90 80 70 2 4 6 8 10 12 14 16 18 20 Age (years) Fig. 75.6 Height SDs for chronological age extrapolated to \201 nal height. Reprinted wit h permission from Brook C (2001). Brook \200\231s Clinical Pediatric Endocrinology . Wiley- Blackwell. although suf \201 cient cells (>30) should be examined to exclude the possi- bility of mos aicism. Clinical features There may be a history of lymphedema in the newborn period. Typically, gr owth velocity starts to decline from 3 to 5 years old (Fig. 75.6) and gonadal failure combi ned with a degree of skeletal dysplasia results in loss of the pubertal growth spurt. Mean \201 nal height is consistently 7.9 inches below the normal average within each population (4 ft 8 inches in the U.S). GH secretion is normal, although IGF-1 levels may be low. Ten percent progress through pube rty spontaneously but only 1% develop ovulatory cycles. Management High-dose GH therapy (0.375 mg/kg/week) increases \201 nal height, although in dividual responses are variable. The height gained is related to time on GH treatment, and thus GH therapy should be started early. If the diagnosis has been made in early life, trea tment is usually started at 3 to 5 years of age. 75-Draznin-Chap75.indd 443 4/1/2011 5:52:04 PM CHAPTER 75 Growth and stature 444 Oral estrogen is started between 12 and 14 years of age, tailored to the individual patient , to promote secondary sexual development and puber- tal growth. It should be started in lo w dose (estradiol 0.5 mcg qod or Premarin 0.6 mg qod), and gradually i with age. Progesterone should be added if breakthrough bleeding occurs or when estrogen dose reaches estradiol 1 mg/day or Premarin 0.6 mg/day. 75-Draznin-Chap75.indd 444 4/1/2011 5:52:05 PM TALL STATURE AND RAPID GROWTH 445 Tall stature and rapid growth De \201 nition Although statistically as many children have heights >2 SD above the mean a s have heights >2 SD below the mean, referral for evaluation of tall stat- ure is much less common than for short stature. Socially, for boys heights up to 6 ft 9 in are typically considered accept- able, whereas f or girls heights >6 ft may be problematic. Tall stature and particularly accelerated growth rates in early childhood can indicate an underlying hormonal disorder, such as precocious puberty. For causes, see Box 75.2. Assessment History \200 Is tall stature long-standing, or does the history suggest recent growth acceleration? Try to obtain previous measurements. Inquire about size at birth, infancy weight gain, intellectual development, and neurological development. Inquire about headaches, visual disturbance, and evidence of puberty. \200 Is there a fam ily history of tall stature or early puberty? Box 75.2 Causes of tall stature in childhood Normal variants \200 Familial tall stature \200 Early maturation (largely familial but also promoted by early- childhood nutrition and obesity. Height is not excessive for bone age, which is advanced) Hormonal \200 See Precocious puberty (p. 449) \200 GH or GHRH excess (pituitary giganti sm) resulting from pituitary adenoma or ectopic adenomas is a very rare cause of tall statu re ( b p. 110). Other hormonal excess, e.g., hyperthyroidism, congenital adrenal hyperplasia (associated with signs of virilization), familial glucocorticoid de \201 ciency Rarely, estrogen receptor or aromatase de \201 ciencies delay puberty and epiphyseal fusion, resulting in tall adult height. Chromosomal abnormalities \200 XXY (Klinefelter \200\231s syndrome) \200 XYY, XYYY (eac h extra Y confers on average 13 cm additional height) Other rare syndromes Overgrowth and d ysmorphic features are seen in Marfan syndrome, homocystinuria, Sotos syndrome, Beckwith \200\223Wiedemann syndrome, and Weaver syndrome. 75-Draznin-Chap75.indd 445 4/1/2011 5:52:05 PM CHAPTER 75 Growth and stature 446 Examination \200 Assess height and height velocity over at least 4 \200\2236 months. \200 Measure sitting height and arm span. \200 Pubertal stage? \200 Dysmorphic feature s? \200 Measure parents \200\231 heights and calculate MPH (b see Assessment of growth, p. 445).