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). Investigations The following investigations may be clinically indicated: \200 Left hand a nd wrist radiograph for bone age \200 Sex hormone levels (testosterone, estrogen, androst enedione, DHEAS), baseline and stimulated LH and FSH levels Karyotype \200 Serum IGF-1 and IGFBP-3 levels \200 Oral glucose tolerance test \200\224 GH levels normally suppress to low or undetectable levels (<1 mU/L) Speci \201 c molecular tests for overgrowth syndromes Management of tall stature After excluding abnormal pathology, often only reassurance and i nforma- tion on predicted \201 nal height are necessary. In younger children, early induc tion of puberty using low-dose sex steroids advances the pubertal growth spurt and promotes earlier epiphyseal fusion. In older children already in puberty, high-dose estrogen therapy in girls, or testosterone in boys, has been used to induce rapid skeletal maturation. However, theoretical side effec ts of high-dose estrogen therapy include thromboembolic disease and oncogenic risk. Further reading Carel JC, L ger J (2008). Precocious puberty N Engl J Med 358:2366 \200 \2232377. Clayton PE, Cianfarani S, Czernichow P, et aI. (2007). Management of the child born small f or ges- tational age child (SGA) through to adulthood: a consensus statement of the Interna tional Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 92(3):804 \200\223810. Clayton PE, Cuneo RC, Juul A, et al. (2005). Consensus statement on the management of the G H-treated adolescent in the transition to adult care. Eur J Endocrinol 152:165 \200\223170. Dattani M, Preece M (2004). Growth hormone de \201 ciency and related disorders: insights into causa- tion, diagnosis, and treatment. Lancet 363:1977 \200\2231987. De Waal WJ, Greyn-Fokker MH, Stijnen T, et al. (1996). Accuracy of \201 nal height predic tion and effect of growth-reductive therapy in 362 constitutionally tall children. J Clin E ndocrinol Metab 81:1206 \200\2231216. Growth Hormone Research Society (2000). Consensus guidelines for the diagnosis and treatmen t of growth (GH) de \201 ciency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 85:3990 \200\2233993. Saenger P, Wikland KA, Conway GS, et al. (2000). Recommendations for the diagnosis and man- agement of Turner \200\231s syndrome. J Clin Endocrinol Metab 86:3061 \200\2233069. 75-Draznin-Chap75.indd 446 4/1/2011 5:52:05 PM NORMAL PUBERTY 447447 Puberty Normal puberty Puberty is the sequence of physical and physiological changes occurring at a dolescence culminating in full sexual maturity. Age at onset Average age at onset of puberty is earlier in girls ( 11 years) than in boys ( 12 years) but varies widely ( 2 years from the mean age of onset) and is in \202 uenced by a number of factors: \200 Historical: Age of menarche has d this century from 17 year s in 1900 to 12.8 years today, presumably as a result of improved childhood nutrition and g rowth. Genetic: Age at onset of puberty is partly familial. \200 Ethnicity: Afro-Caribbean girls tend to have earlier puberty than whites. \200 Weight gain: Earlier puberty is seen in g irls who are overweight, whereas girls who engage in strenuous activity and are thin often have delayed puberty. Hormonal changes prior to and during puberty Adrenal androgens (DHEAS and androstenedione) rise 2 years before puberty starts (adrenarche). This usually causes no physical changes bu t occasionally results in early pubic hair and acne (premature adrenarche). Pulsatile secre tion of LHRH from the hypothalamus at night is the \201 rst step in the initiation of pub erty and occurs well before physical signs of puberty. This results in pulsatile secretion of LH and FSH from the pituit- ary, and the gonadotropin response to LHRH administration re verses from the prepubertal FSH predominance to a higher response in LH levels. Physical changes The \201 rst indication of puberty is typically breast development in gi rls and increase in testicular size in boys. In each sex, puberty then typically progresses in an orderly manner through distinct stages (see Table 76.1). Puberty rating by an experi enced observer involves identi \201 cation of pubertal stage, particularly breast developm ent in girls and testicular vol- ume (by comparison with an orchidometer) in boys. Pubertal growth spurt Increased estrogen levels in both boys and girls lead to i GH secreti on. Peak height velocity occurs at puberty stage 2 \200\2233 in girls and is later in boys, at stage 3 \200\2234 (testicular volume 10 \200\22312 mL). 76-Draznin-Chap76.indd 447 4/1/2011 5:46:07 PM CHAPTER 76 Puberty 448 Table 76.1 The normal stages of puberty (Tanner stages) Boys Stage Genitalia Pubic hair Other events I Prepubertal Vellus, not thicker than on abdomen TV * <4 mL II Enlargement of testes and scrotum Sparse long, pigmented strands at base of penis TV 4 \200\2238 mL Voice starts to change III Lengthening of penis Darker, curlier, and spreads over pubis TV 8 \200\22310 mL Axillary hair IV Increase in penis length and breadth Adult-type hair but covering a smaller area TV 10 \200\22315 mL Upper lip hair Peak height velocity V Adult shape and size Spread to medial thighs (Stage 6: spread up linea alba) TV 15 \200\22325 mL Facial hair spreads to cheeks Adult voice Girls Stage Genitalia Pubic hair Other events Elevation of papilla only Vellus, not thicker than on abdomen I II Breast bud stage: elevation of breast and papilla Sparse long, pigmented strands along labia Peak height velocity III Further elevation of breast and areola together Darker, curlier, and spreads over pubis IV Areola forms a second mound on top of breast Adult-type hair but covering a smaller area Menarche V Mature stage: areola recedes and only papilla projects Spread to medial thighs (Stage 6: spread up linea alba) TV, testicular volume: measured by size-comparison with a Prader orchidometer. Reprinted wi th permission from Tanner JM (1978). Growth at Adolescence , 2nd ed. Wiley- Blackwell. 76-Draznin-Chap76.indd 448 4/1/2011 5:46:07 PM PRECOCIOUS PUBERTY 449 Precocious puberty De \201 nition Early onset of puberty is de \201 ned as <8 years in girls and <9 years in boys. Gonadotropin-dependent ( \200\234central \200\235 or \200\234true \200\235) precoci ous puberty is characterized by early breast development in girls or testicular enlarge- me nt in boys. Gonadotropin-independent puberty occurs from abnormal peripheral sex hormone secretion, res ulting in isolated development of certain sec- ondary sexual characteristics. This may invo lve autonomous testosterone production in a boy or autonomous estrogen production in a girl . In add- ition, testosterone production from the adrenal or an ovarian tumor can induce vi rilization in a girl. Assessment of precocious puberty History \200 Age when secondary sexual development \201 rst noted \200 What features are present and in what order did they appear? E.g., virilization (pubic, axillary, or facial hair, acne, body odor), genital or breast en largement, galactorrhea (very rare), menarche, or cyclical mood changes? Is there evidence of recent growth acceleration? \200 Family history of early puberty? \200 Past history of adoption or early weight gain or prior CNS abnormality or insult (e.g., radiation)? Examination \200 Breast or genital and testicular size; degree of virilization (clitorome galy in girls indicates abnormal androgen levels) Neurological examination, particularly visual \201 eld assessment and fundoscopy Abdominal or testicular masses \200 Skin (?caf -au-lait patches \200\224McCune \200\223A lbright [ b see Chapter 85, McCune \200\223Albright syndrome, p. 486], or NF1) \200 Assess height and height velocity over 4 \200\2236 months. Investigations The following investigations may be clinically indicated: \200 Radiograph of left wrist and hand for bone age \200 Thyroid function \200 Sex hormone levels (test osterone, estrogen, androstenedione, DHEAS) LH, FSH, and estradiol levels (baseline and after SQ leuprolide) \200 17AOH progesterone levels (baseline and 60 minutes post IV cortrosyn) if congenital adrenal hyperplasia is suspected Tumor markers (AFP, BhCG) \200 Midnight salivary cortisol \200 Abdominal US scan (adren al glands; ovaries) \200 MRI scan (cranial; adrenal glands) 76-Draznin-Chap76.indd 449 4/1/2011 5:46:07 PM CHAPTER 76 Puberty 450 Central precocious puberty This is due to premature activation of pulsatile LHRH secretion from the hypothalamus, and the normal progression in physical changes is main- tained. As p recocious puberty is de \201 ned as occurring younger than 2 SD before the average age, in a normal distribution, 2.5% of children will have early-onset puberty. In practice, in girls, central precocious puberty is more likely to be idio- pathic or fami lial, whereas boys have a greater risk of intracranial or other pathology. Causes \200 Idiopathic or familial \200 Intracranial tumors, hydrocephalus, or other le sions \200 Post \200\223cranial irradiation or trauma \200 Intracranial tumors (in part icular, optic nerve glioma and hypothalamic germinoma), harmatoma, hydrocephalus, and nonsp eci \201 c brain injury (e.g., cerebral palsy) May also be triggered by long-standing elevation in sex hormones resulting from any periphe ral source or adrenal enzyme defect (e.g., late-presenting simple virilizing CAH or inadequ ately treated CAH) Hypothyroidism (elevated TRH stimulates FSH release) \200\224rare \200 Gonadotropin-secre ting tumors (e.g., pituitary adenoma or hepatoblastoma) are rare. Treatment The aims of treatment are as follows: \200 Avoid psychosocial problems for the child or family \200 Prevent reduced \201 nal height due to premature bone maturation a nd early epiphyseal fusion. A \201 nal height prediction is often necessary when consider ing the need for inhibition of puberty Pituitary LH and FSH secretion can be inhibited by the use of LHRH ana- logs, e.g., Lupron 0.3 mg/kg IM monthly (comes as 7.5, 11.25, or 15 mg doses). Treatment ef \201 cacy should be monitored regularly by clinical observa- tion. The dose m ay need to be increased if there is evidence of inadequate suppression of pubertal developm ent. Gonadotropin-independent precocious puberty At least two genetic syndromes have been identi \201 ed, both resulting in abnormal activation of gonadotropin receptors independent of n ormal lig- and binding. Thus, in these conditions, the gonads autonomously secrete sex horm ones and levels of LH and FSH are suppressed by feedback inhibition. McCune \200\223Albright syndrome b Also see Chapter 85, McCune \200\223Albright syndrome (p . 486). This is a sporadic condition due to a somatic activating mutation of the GSA protei n subunit that affects bones (polyostotic \201 brous dysplasia) and skin (caf -au- lait spots) and potentially contributes to multiple endocrinopathies. 76-Draznin-Chap76.indd 450 4/1/2011 5:46:07 PM PRECOCIOUS PUBERTY 451 A number of different hormone receptors share the same G protein \200\223 coupled cyclic AM P second messenger system, and hyperthyroidism or hyperparathyroidism may also be present. All cells descended from the mutated embryonic cell-line are affected, while cells descende d from nonmutated cells develop into normal tissues. Thus, the phenotype is highly variable in physical distribution and severity. Treatment is with an aromatase inhibitor (letrozole ). Testotoxicosis This is a rare familial condition resulting in precocious puberty only in bo ys, due to an activating LH receptor mutation. Testes show only lit- tle increase in size a nd on biopsy Leydig cell hyperplasia is characteristic. Treatment is with a combination of androgen receptor \200\223blocking agents (cyproterone acetate) and aromatase inhibitors or with ketoconazole. Peripheral sex hormone secretion Excessive peripheral androgen secretion may occur due to C AH or andro- gen-secreting adrenal or gonadal tumors. These children usually have rapid gro wth, advanced bone age, and moderate to severe virilization in the absence of testicular or breast development. (Note: a testicular tumor may cause asymmetrical enlargement). Peripheral estrogen production from ovarian tumors is a rare cause of precocious breast development in girls. Premature thelarche Premature breast development in the absence of other signs of puberty m ay present at any age from infancy. Breast size may \202 uctuate and is often asymmetrica l. The cause is unknown, although typically FSH levels (but not LH) are elevated and ovarian U S may reveal a single large cyst. Bone maturation, growth rate, and \201 nal height are u naffected. Thelarche variant This is an intermediate condition between premature thelarche and cen- tr al precocious puberty. The etiology is unknown. These girls demonstrate i height velocity and rate of bone maturation and ovarian US reveal s a more multicystic appearance, as seen in true puberty. There is probably a whole spectru m of presentations between premature thelarche and true precocious puberty. The decision to treat should take into account height velocity and \201 nal height predic tion as well as the rate of physical maturation and the sever- ity of accompanying pubertal features (e.g., mood swings and dif \201 cult behavior). Premature adrenarche and pubarche The normal onset of adrenal androgen secretion (adrenarch e) occurs 1 \200\2232 years before the onset of puberty. Premature or exaggerated adrenarch e is thought to be due to i androgen production or sensitivity and presents with mild featu res of virilization, such as onset of pubic hair (pubarche) or acne, in the absence of othe r features of puberty. 76-Draznin-Chap76.indd 451 4/1/2011 5:46:07 PM CHAPTER 76 Puberty 452 Clitoromegaly in girls suggests a more severe pathology with excessive androgen production (e.g., CAH or androgen-secreting tumor). The diagnosis is made in the presence of pubic hair and/or axillary hair; the absence of br east or testicular development in children aged <8 years. It is more common in girls. Management The management of premature adrenarche usually only requires reassur- ance after exclusion of other causes, as there is no signi \201 cant impact on \201 nal height and onset or progression of puberty. Some of these girls may subsequently develop features of polycystic ovary disease. In these cases, treatment should be directed at the present- ing feature (e.g., hirsutism, menstrua l irregularities). 76-Draznin-Chap76.indd 452 4/1/2011 5:46:07 PM DELAYED OR ABSENT PUBERTY 453 Delayed or absent puberty De \201 nition Delayed puberty is de \201 ned as failure to progress into puberty by >2 S D later than the average, i.e., >13 years in girls and >14 years in boys. Clinically, boys are more likely to present with delayed puberty than girls. In addition, some children pres ent with delay in progression from one pubertal stage to the next for >2 years. Psychological distress may be exacerbated by declining growth velocity relative to that of peers. In the long term, severe delay may be a risk factor for d bone mineral density and o steoporosis. Causes General \200 Constitutional delay of growth and puberty (this is the most common cause; b see Constitutional delay of growth and puberty, p. 436). Chronic childhood disease, malabsorption (e.g., celiac disease, in \202 ammatory bowel disease), or undernutrition Hypergonadotropic hypogonadism Gonadal failure may be either of the following: \200 Conge nital (e.g., Turner \200\231s syndrome in girls, Klinefelter \200\231s syndrome in boys) Acquired (e.g., following chemotherapy, local radiotherapy, infection, torsion) In these conditions, basal and stimulated gonadotropin levels are raised. Gonadotropin de \201 ciency \200 Kallman syndrome (including anosmia) \200 HP lesions (tumors, post-radiotherapy, dysplasia) \200 Rare inactivating mutations of genes encoding LH, FSH (or their receptors) These conditions may also present in the newborn period with micropenis and undescended tes tes in boys. Investigation The following investigations may be clinically indicated: \200 LH and FSH l evels \200 Plasma estrogen or testosterone levels \200 Measurement of androgen levels b efore and after hCG therapy may be used to indicate presence of functional testicular tissue in boys. Karyotype \200 Pelvic US in girls to determine ovarian morphology \200 US or MRI imagin g in boys to detect an intra-abdominal testes It may be dif \201 cult to distinguish betwe en constitutional delay and gonado- tropin de \201 ciency, as gonadotropin levels are low in both conditions. In these cases, pharmacological induction of puberty may be indicated w ith regular assessment of testicular growth in boys (which is independent of 76-Draznin-Chap76.indd 453 4/1/2011 5:46:07 PM CHAPTER 76 Puberty 454 testosterone therapy) followed by withdrawal of treatment and reassess- ment when \201 na l height is reached. Management Depending on the age and concern of the child and parents, short- course exogeno us sex steroids can be used to induce pubertal changes. If gonadotropin de \201 ciency is permanent or the gonads are dysfunctional or absent, then exogenous sex steroids are requir ed to induce and main- tain pubertal development ( b see Constitutional delay of growth and puberty, p. 436). Long-term treatment See Table 76.2. Boys Testosterone (by IM injection): 50 mg q4 \200\2236 weeks, gradually i to 250 mg q4 wee ks. \200 Monitor penile enlargement, pubic hair, height velocity, and adult body habitus. Side effects include severe acne and rarely priapism. Girls Estrogen (oral): Start at low dose (estradiol 0.5 mcg qod or Premarin 0.3 mg qod) and gradually increase. \200 Promotes breast development and adult body habitus \200 Proge sterone (oral) should be added if breakthrough bleeding occurs or when estrogen dose reaches 1 mcg/day. Table 76.2 Suggested schema for pubertal induction and maintenance in boys and girls Testosterone dose Testosterone Interval Estradiol dose (daily) Duration Duration 50 mg 4 weeks 6 months 0.5 mcg qod 6 months 100 mg 4 weeks 6 months 0.5 mcg qd 6 months 125 mg 4 weeks 6 months 1 mcg (+ a progesterone when bleed) 6 months 250 mg 3 \200\2234 weeks Onwards 2 mcg Onwards Treatment could be started at age 12 \200\22313 years in boys and 11 \200\22312 years in gi rls. Duration for each stage of treatment is determined by individual responses. 76-Draznin-Chap76.indd 454 4/1/2011 5:46:08 PM NORMAL SEXUAL DIFFERENTIATION 455 Sexual differentiation Normal sexual differentiation Gonadal development In the male or female embryo, the bipotential gonad develops as a thick - ening of mesenchymal cells and coelomic epithelium around the primitive kidney. This geni tal ridge is then colonized by primordial germ cells that migrate from the yolk sac to form the gonadal ridge . In the absence of a Y chromosome, the gonad will develop into an ovary . In the presence of a normal Y chromosome, immature Sertoli cells, germs cells, and seminife rous tubules can be recognized by 7 weeks, and testis differentiation is complete by 9 week s. The SRY gene is an essen- tial sex-determining region on the Y chromosome that signals f or testis differentiation. Internal genitalia Embryonic M llerian structures form the uterus, fallopian tubes, and up per 1/3 of the vagina. In males, by 6 weeks, anti-M llerian hormone is secreted by immature Sertoli cells in the testis, and this causes regression of the M llerian struc- tures. Leydig cells appear in t he testis around day 60 and produce testos- terone under placental hCG stimulation. Testosterone promotes growth and differentiation of the Wolf \201 an ducts to form the epididymis, vas deferens, and seminal vesicles. External genitalia In the absence of any androgen secretion, the labia majora, labia minora , and clitoris develop from the embryonic genital swelling, genital fold, and genital tuber cle, respectively. Development of normal male external genitalia requires testosterone production from the tes tis and its conversion to dihydrotestosterone by the enzyme 5 A -reductase. In the presence of dihydrotestosterone, the genital tubercle elongates to form the corpora cavernosa and g lans penis, the urethral fold forms the penile shaft, and the labioscrotal swelling forms t he scrotum. This process commences at around 9 weeks and is completed by 13 weeks. Testicular descent i n males occurs in the later two-thirds of gestation under control of fetal LH and testoster one. 77-Draznin-Chap77.indd 455 3/31/2011 8:46:55 PM CHAPTER 77 Sexual differentiation 456 Assessment of ambiguous genitalia Most cases of ambiguous genitalia present at birth. Invol vement of an experienced pediatric endocrinologist and surgeon should be sought as early as possible. History \200 Any maternal medications during pregnancy? \200 Are parents consanguineous , or is there a family history of ambiguous genitalia? Is there a neonatal history of hypoglycemia or prolonged jaundice? Examination \200 Assess clitoris or phallus size, degree of labial fusion, and position o f urethra and urogenital sinus (anterior or posterior). Are gonads palpable? Check along line of descent. \200 Are there any signs indicating pan hypopituitarism (e.g., midline defects, hypoglycemia, hypocortisolemia, prolonged jaundice)? Dysmorphic features of Turner \200\231s syndrome may be seen in XO/XY mosaicism. Investigations \200 Blood for karyotype, electrolytes, glucose, 17 A OH progesterone \200 US of pelvis and labial folds (for M llerian structures and gonads) \200 After the infant is 48 hours old, when the neonatal hormonal surge has decreased, repeat blood tests for 17 A OH progesterone, cortisol, LH, FSH, and androgen levels. Examination under anesthesia (EUA) and cystogram may be required. Speci \201 c tests \200 ACTH stimulation test may be required when CAH is suspected, to assess cortisol secretion and aid in diagnosis. 3-day HCG test in an undervirilized \200\234male \200\235 (testes present or 46, XY) assesses stimulated gonadal production of androgens and may be diagnostic of androgen b iosynthesis defects or androgen insensitivity. Glucagon test is an alternative test to examine cortisol and GH secretion. Androgen receptor function can be tested on cultured \201 broblasts from a genital skin biopsy. DNA analysis for androgen receptor mutation, CAH mutations, and androgen biosynthesis mutations 77-Draznin-Chap77.indd 456 3/31/2011 8:46:55 PM DISORDERS OF SEX DEVELOPMENT (DSD) 457 Disorders of sex development (DSD) Male and female internal and external genitalia develop from common embryonic structures. In the absence of male-differentiating signals, nor- mal female genitalia develop. Genital ambiguity may therefore occur as a result of chromosomal abnormality, gonadal dysge nesis, biochemical defects of androgen synthe- sis, inappropriate exposure to external andr ogens, or androgen receptor insensitivity. 46XX DSD Disorders of ovarian development Normal male differentiation can occur if the SRY gene has been translo- cated onto an autosome. Biochemical defects leading to androgen oversecretion Congenital adrenal hyperplasia (CAH, 21-hydroxylase de \201 ciency most commonly) is the most common cause of ambiguous genital ia in 46, XX. Maternal hyperandrogenism The female fetus may be virilized if maternal androgen levels exc eed the capacity of placental aromatase to convert these to estrogen. This may occur from maternal disease (e.g., CAH, adrenal and ovarian tumors) or use of andr ogenic medication in pregnancy or, rarely, placental aromatase de \201 ciency. 46XY DSD Disorders of testis development XY gonadal dysgenesis can be caused by mutations i n a number of genes controlling male sexual differentiation, including SRY, SF-1, WT-1, and SOX , and can present with normal external genitalia. There is early testicular failure resulting from torsion or infarction. Biochemical defects of androgen synthesis Rare de \201 ciencies of the enzymes 5 A -reduct ase, 17 -hydroxysteroid dehydrogenase, or 3 B -hydroxysteroid dehydrogenase, which are a lso associated with glucocorticoid and mineralocorticoid de \201 ciencies, are autosomal r ecessively inherited and may result in variable degrees of undervirilization. Androgen receptor insensitivity syndrome b Also see Androgen insensitivity syndrome (p. 335 ). Defects of the androgen receptor gene on the X chromosome, or auto- somal post-receptor sig naling genes, may result in complete or partial androgen insensitivity. Complete androgen insensitivity results in normal female external geni- talia and usually o nly presents with testicular prolapse in childhood or primary amenorrhea in adolescence. In partial androgen insensitivity, presentation may vary from mild virilization to micropen is, hypospadias, undescended testes, or only d spermatogenesis. 77-Draznin-Chap77.indd 457 3/31/2011 8:46:55 PM CHAPTER 77 Sexual differentiation 458 Gonadotropin defects Gonadotropin de \201 ciency may occur in hypopituitarism or may be as soci- ated with anosmia (Kallmann syndrome). It usually presents with delayed puberty but i s an occasional cause of micropenis and undescended testes. LH receptor gene defects are rare and result in complete absence of virilization, as the testes are unable to respond to placental hCG. Anti-M llerian hormone de \201 ciency or insensitivity Testes are usually undescended and uterus and fallopian tubes are present. Management of ambiguous genitalia In the newborn period, the infant should be monitored in the hospital for the following: \200 Hypoglycemia (until hypopituitarism is excluded) \200 Salt-wasting (until CAH is excluded) Explain to the parents that the infant appears t o be healthy but has a defect that interferes with determining sex. It is helpful to show t he par- ents the physical \201 ndings as you explain this. Advise them to postpone the re gistration of the birth until after further investigations, and discuss what they will say to relatives and friends. Sex assignment Decision on the sex of rearing should be based on the optimal expected outco me in terms of psychosexual and reproductive function. Parents should be allowed discussion with an endocrinologist, a surgeon specializ- ing in urogenital reconstruction, a psycholo gist, and a social worker. Following the necessary investigations and discussions, early gender assignment is thought to optimize the psychosexual outcome, but further research into this area is still required . Further management \200 If female sex is assigned, any testicular tissue should be remove d. \200 Reconstructive surgery may include clitoral reduction, gonadectomy, and vaginopla sty in girls, and phallus enlargement, hypospadias repair, and orchidopexy in boys. In both sexes, multiple-stage procedures may be required. Testosterone may enhance phallus size in male infants and a trial of therapy is sometimes useful before sex assignment. Hormone replacement therapy may also be required from puberty into adulthood. Continuing psychological support for the parents and child is very important. 77-Draznin-Chap77.indd 458 3/31/2011 8:46:55 PM CONGENITAL ADRENAL HYPERPLASIA 459 Congenital adrenal hyperplasia b Also see Chapter 47, Congenital adrenal hyperplasia in adu lts (p. 239). A number of autosomally inherited enzyme de \201 ciencies result in cor- tis ol de \201 ciency, excess pituitary ACTH secretion, and adrenal gland hyperplasia. 21-hydroxylase de \201 ciency (>90%) The most common cause of CAH results in cortisol and mineralocor- ticoid de \201 ciency, while the build-up of precursor steroids is channeled toward excess adrenal androgen synthesis. Different gene defects in the 21-hydroxylase gene (e.g., deletion, splice site, or point mutation) result in different degrees of enzyme dys function and thus wide variation in phenotypes. Clinical features Virilization of female fetuses may result in clitoromegaly and labial fus ion at birth. 75% have suf \201 cient mineralocorticoid de \201 ciency to cause renal sal t-wasting. Because males have normal genitalia at birth, they may present acutely ill in the neonatal period with vomiting, dehydration, collapse, hyponatremia, and hyperkalemia. Non-salt-wasti ng boys present with early genital enlargement, pubarche, and rapid growth. If untreated or poorly treated, both sexes may develop pubic hair, acne, rapid height veloc ity, advanced bone maturation, and precocious puberty that may result in very short \201 nal height. Nonclassic CAH is due to milder 21-hydroxylase de \201 ciency, and affected girls present in later childhood or adulthood with hirsutism, acne, prema- ture or exaggerated adrenarche , menstrual irregularities, and infertility. 11 BB -hydroxylase de \201 ciency ( 5%) This enzyme, which converts 11-deoxycortisol to cortisol, is the \201 nal step in cortisol syn thesis. In addition to excess adrenal androgens, the overpro- duced precursor corticosteron e has mineralocorticoid activity. Thus, in contrast to salt-wasting in 21-hydroxylase de \201 ciency, these subjects may have hypernatremia and hypokalemia. Hypertension is rarely seen in infancy but may develop during childhood and affects 50 \200\22360% of adults. Speci \201 c investigations for CAH b See also Assessment of ambiguous genitalia (p. 456). \200 Plasma 17A OH progesterone: An elevated level indicates 21-hydroxylase de \201 ciency. It may be dif \201 cult to distinguish this from the physi ological hormonal surge that occurs in the \201 rst 2 days of life. This test should ther efore be repeated (together with 11-deoxycortisol) after 48 hours of age. An ACTH stimulation test may be required to discriminate between the different enzyme de \201 ciencies. Plasma electrolytes may need to be monitored over the \201 rst 2 weeks. \200 Plasma ren in level is also useful to con \201 rm salt-wasting in those with normal serum sodium and relatively mild 21-hydroxylase de \201 ciency. 77-Draznin-Chap77.indd 459 3/31/2011 8:46:55 PM CHAPTER 77 Sexual differentiation 460 Other rare enzyme de \201 ciencies 17AA -Hydrolxylase de \201 ciency This impairs cortiso l, androgen, and estrogen synthesis, but overproduc- tion of mineralocorticoids leads to hy pokalemia and hypertension. 3 B -Hydroxysteroid dehydrogenase de \201 ciency This impairs cortisol, mineralocorticoid, and androgen biosynthesis. Males have hypospadias and undescen ded testes. However, excess DHEA, a weak androgen, may cause mild virilization in females. Steroid acute regulatory protein \200 STAR mutation: 46XY sex reversal and severe adrenal failure. Heterozygous defect. Extremely rare CYPIIAI (P450: side-chain cleavage cytochrome enzyme): 46XY sex reversal and severe adrenal failure. Heterozygous defect. Extremely rare P450 oxidoreductase de \201 ciency: Biochemical picture of combined 21-hydroxylase/17A - hydrolxylase/17, 20 Lyase de \201 ciencies. Spectrum of presentation from children with ambiguous genitalia, adrenal failure, and the Antley \200\223Bixler skel etal dysplasia through to mildly affected individuals with polycystic ovarian syndrome Management \200 Hydrocortisone (10 \200\22320 mg/m 2 per day orally in 3 divided doses). In