Symposium on Adolescent Medicine
The Problem of Delayed Puberty H. Verdain Barnes, M.D.*
The attainment of an age-appropriate height, weight, and secondary sexual development is a compelling desire of all adolescents, although their concern is often not clearly verbalized. No problem of puberty is of greater personal importance or embarrassment to the teenager than to remain short and/or sexually infantile while one's peers are rapidly developing. Delayed puberty is defined medically for boys as having not reached genital stage 2 (G2) by 13.7 years of age or having not progressed from stage G2 to G3 within 2.2 years, G3 to G4 in 1.6 years, or G4 to G5 in 1.9 years (Tables 3, 4, p. 1310). In girls it is defined as not having begun breast development (stage B2) by 13.4 years of age or not having progressed from stage B2 to B3 within 1.0 years or B3 to B4 in 2.2 years, or not having menarche within 5.0 years of attaining breast stage B2. 14 • 15 In the patient's mind, however, delayed puberty is more simply defined as lagging behind one's peers in growth and development, which does not necessarily correlate with the medical definition. Regardless, for the patient the problem is no less real. Failing or seeming to fail in maturation usually incites remarkable degrees of anxiety and depression in the adolescent. All patients complaining of delayed or inadequate maturation must be carefully evaluated by history and physical examination and, then, thoughtfully counseled. In counseling it is important to provide detail as to normal variations in maturation as well as future expectations for growth and development. The necessity for this type of counseling cannot be overemphasized.
DIFFERENTIAL DIAGNOSIS Delayed puberty is estimated to occur in perhaps 2 to 3 per cent of adolescents. 11 The differential diagnosis of delayed puberty, including primary amenorrhea, is found in Table 1. The focus of this article is on the most common of these disorders, the constitutional delay of puberty. ':'Formerly Director, Adolescent Medicine. and Assistant Professor of Medicine. Pediatrics. and Radiology. The Johns Hopkins Hospital; Presently Associate Professor of Medicine and Pediatrics. and Director of Adolescent Medicine. University of Iowa Hospitals and Clinics. Iowa City. Iowa Medical Clinics of North America- Vo!' 59. No. 6. November 1975
1337
1338
H.
Table 1.
VERDAIN BARNES
Potential Causes of Delayed Puberty
I. Constitutional Delay of Puberty
Il. Hypothalamic Disorders 1. Congenital deficiency of gonadotropin-releasing hormone Familial Sporadic Kallman's syndrome Laurence- Moon- Biedl syndrome Prader-Willie syndrome Friedreich's ataxia(?) 2. Acquired gonadotropin-releasing hormone deficiency A. Infections Post viral encephalitis Sarcoidosis Tuberculosis B. Neoplasms Primary hypothalamic tumors Craniopharyngioma Pinealoma Histiocytosis Ill. Pituitary Disorders 1. Congenital deficiency of gonadotropin(s) Idiopathic panhypopituitarism Isolated LH and/or FSH deficiency Microcephaly 2. Acquired gonadotropin(s) deficiency A. Infections Sarcoidosis Tuberculosis B. Neoplasms Primary pituitary adenomas Primary and secondary pituitary carcinoma Craniopharyngioma Histiocytosis C. Post traumatic IV. Gonadal Disorders 1. Congenital Turner's syndrome (45XO and Mosaics) Klinefelter's syndrome (47XXY and Mosaics) Gonadal agenesis Reifensteins' syndrome Weinstein's syndrome Male Turner's syndrome Myotonia dystrophic a 2. Acquired A. Infections Gonorrhea (male) Tuberculosis (male) Viral orchitis (primarily mumps) B. Mechanical postoperative or radiation Bilateral ovarian or testicular torsion Oophorectomy (bilateral) Orchiectomy (bilateral) Post orchiopexy testicular atrophy post irradiation necrosis
1339
DELAYED PUBERTY
Table 1.
Potential Causes of Delayed Puberty (Continued)
C. Posttraumatic Testicular atrophy Spinal cord damage V. Chronic Systemic Diseases Congenital heart disease (usually cyanotic) Severe acquired mitral or aortic valve disease Bronchial asthma Regional enteritis Ulcerative colitis Chronic renal failure Renal tubular acidosis Sickle cell anemia Hyperthyroidism Hypothyroidism Uncontrolled diabetes mellitus Juvenile rheumatoid arthritis Systemic lupus erythematosus Tuberculosis Anorexia nervosa Socioeconomic malnutrition VI. Some Causes of Primary Amenorrhea Associated With Normal or Partial Secondary Sexual Development Pregnancy Cryptomenorrhea Uterine agenesis Vaginal agenesis Pure gonadal dysgenesis (46XY or 46XX) Testicular feminization Functional ovarian tumors True hermaphrodite
Constitutional Delay of Puberty l3,
16, 17
In our clinic, over 90 per cent of the adolescents seeking medical attention for delayed puberty are normal but slow in their maturation. The precise cause of constitutional delay of puberty is not known, but current evidence suggests that there is a physiologic delay in the maturation of the central nervous system which results (1) in a delay in the normal hypothalamic-pituitary unit's decrease in sensitivity to prepubertal levels of the sex hormones and (2) in a delay in the initiation of the unique pubertal hypothalamic-pituitary, sleep-associated LH secretory pattern. 10, 13 Constitutional delay of puberty occurs in both males and females. Males, however, more often seek medical attention since, in our society, they are more likely to be openly ridiculed, abused, bullied by peers, denied peer group membership, or excluded from social and athletic activities because of inappropriate size and development for chronologic age. A tentative diagnosis of constitutional delay of puberty is made by exclusion and confirmed in retrospect after the patient has progressed to adult maturation. The major clinical criteria for making a presumptive
1340 Table 2.
H. VERDAIN BARNES The Criteria for Making a Presumptive Diagnosis of Constitutional Delay of Puberty
1. Negative review of systems for neurologic, cardiovascular, renal, gastrointestinal, musculoskeletal, and endocrine signs or symptoms 2. History of appropriate nutrition and eating habits 3. Normal physical examination, including upper lower body segment ratio, arm span, and genitalia 4. Delay in bone age (1.5 to 4.0 years) 5. Linear growth rate of at least 3.75 cm per year (average 5.0 cm per year) 6. Normal hemogram, erythrocyte sedimentation rate, urinalysis, total serum thyroxine, and skull x-ray
diagnosis of constitutional delay of puberty are shown in Table 2. In addition, about 90 per cent of both males and females are short in stature with heights near the third percentile for chronologic age and close to 60 per cent have a positive family history for pubertal delay. When present, these features add support to the diagnosis. Patients who do not meet all of the major criteria or who fail to progress through puberty at a satisfactory rate require further evaluation. The majority of the other causes of delayed puberty are almost invariably suggested by the history and/or physical examination. In our experience, the following disorders, however, may be difficult to differentiate from constitutional delay of puberty and, in fact, the diagnosis may be initially missed: gonadal dysgenesis (particularly Turner's syndrome), Klinefelter's syndrome, hypo gonadotropic hypogonadism, renal tubular acidosis, early inflammatory bowel disease particularly regional enteritis, and early hypothyroidism.
Turner's Syndrome!. 10. 17.21 Adolescent age females who are below the third percentile in height with stage 3 pubic hair have a high probability of being a classic (45 XO) or mosaic (XO/XX, XO/XXX, etc.) Turner's syndrome, particularly in the absence of breast development. In evaluating such girls it is important to recognize that: (1) many Turner's patients, particularly mosaics, have only a suspicion of or no typical somatic manifestations of the syndrome, (2) many mosaics have a normal female (chromatin positive) buccal smear, and (3) mixed patterns of gonadal dysgenesis are important to identify since the presence of a Y chromosome in the karyotype increases the potential for developing a gonadoblastoma. To rule in or out the diagnosis of Turner's syndrome often requires chromosomal analysis. Hormonally, these girls have elevated levels of serum LH and FSH for their stage of secondary sexual development and, in fact, the levels are frequently in the postmenopausal range. Two other congenital disorders may be clinically confusing, pure gonadal dysgenesis and testicular feminization. In pure gonadal dysgenesis, the phenotype and karyotype (46XX) are female, but gonadal streaks rather than ovaries are present. The serum LH and FSH pattern is identical to that in the Turner's phenotype. In testicular feminization, the phenotype is female but the karyotype is male. The primary defect is
1341
DELAYED PUBERTY
androgen insensitivity. These patients have normal female breast development and scant or no pubic hair growth. They often present complaining of primary amenorrhea. Anatomically, these patients have intra-abdominal, inguinal, or labial testes and a short blind pouch vagina. Chemically, serum testosterone values are usually in the adult male range, as are serum and estrogen levels. The LH is elevated while FSH is usually normal. These patients are at high risk for developing gonadoblastomas; therefore, the testes should be removed. Klinefelter's Syndrome1 • 10, 17, 21 Males with a height at or greater than the fiftieth percentile, an arm span exceeding height by more than 2.5 cm, a decreased upper to lower body segment ratio, eunuchoid fat distribution, true gynecomastia, or firm prepubertal size testes and/or disproportionately small testes for pubic hair stage should be evaluated for classic (47 XXY) or mosaic (XX/XXY, XO/XY/XXY, etc.) Klinefelter's syndrome. These patients may be diagnosed by the presence of a chromatin positive buccal smear (normal female) or multiple chromatin bodies; however, some mosaics are chromatin negative (normal male.) Consequently, the disorder cannot be ruled out without a chromosome analysis. Serum LH and FSH levels are disproportionately high for the stage of secondary sexual development. Testosterone levels are usually low for the developmental stage though an occasional patient may have a low normal value. A rare phenotypic male will have a 46 XX karyotype but will otherwise be clinically or chemically indistinguishable from patients with Klinefelter's syndrome. Males who are below the third percentile in height should be carefully examined for the somatic features of Turner's syndrome. The presence of short stature and one or more typical somatic features suggests the male variant of Turner's syndrome.
Hypogonadotropic Hypogonadism10 ,
13, 17,21
Patients with one of the congenital hypo gonadotropic syndromes will almost invariably exhibit some or all of the typical somatic characteristics of the syndrome. It is beyond the scope of this article to detail the characteristics of each syndrome; however, there are two notable exceptions which must be discussed: Kallman's syndrome and isolated gonadotropin deficiency of hypothalamic or pituitary origin. In the olfactory genital syndrome, Kallman's syndrome, the only distinct characteristic may be some degree of anosmia. Consequently, the sense of smell should be tested in all patients having delayed puberty. In isolated gonadotropin deficiency, there are unfort~nately no telltale clues other than pubertal delay or arrest. The acquired causes of hypothalamic or pituitary dysfunction are often subtle, but a careful past history will usually suggest the post infectious or post traumatic etiologies. Neoplastic causes are often occult particularly in their early stages when the tumor is small or when the process is infiltrative as in histocy~ tosis X. The review of systems may offer no suggestion of neurologic, psychologic, antidiuretic hormone, or other trophic hormone deficiencies. The physical examination is usually entirely normal except for
1342
H.
VERDAIN BARNES
delayed pubertal development for age. In fact, these patients may initially meet all the major criteria for a presumptive diagnosis of constitutional delay of puberty. Congenital isolated absence of gonadotropin releasing hormone or gonadotropins or with acquired deficiencies is the most difficult to distinguish from constitutional delay of puberty; in fact, these disorders are often impossible to differentiate until the mid teen years. Testing for hypo gonadotropic hypogonadism is in order for females and males who are still prepubertal at age 15 and 16 respectively as well as those patients who are carrying a presumptive diagnosis of constitutional delay of puberty but have not progressed in their secondary sexual development according to the guidelines in Tables 3 and 4 (p. 1310). Hormonally, LH and FSH levels are prepubertal or inappropriately low for the stage of sexual development as are the sex hormones. Some potentially useful differential tests are shown in Table 3. As is immediately obvious, only two available tests are of potential help. The clomiphene test is useful after mid pubertal development is reached and the adolescent nocturnal secretory pattern determination is of help when it is present. If either test shows a normal response, hypo gonadotropic hypogonadism is ruled out; if no response, the question remains unresolved.
Renal Tubular Acidosis 1H Both the proximal and distal types of renal tubular acidosis may have their onset just prior to or during puberty. Renal tubular acidosis of both types may occur as primary sporadic or hereditary abnormalities, or arise secondary to a variety of systemic diseases and toxins. Primary distal renal tubular acidosis inherited as an autosomal dominant trait, is the most likely to present in adolescence or adult life. The incidence is greater in females than in males. Proximal renal tubular acidosis is most often secondary. In the adolescent, the most likely associated disorders or toxins are Wilson's disease, primary hyperparathyroidism, or the ingestion of outdated tetracycline. Both types are characterized by a sustained metabolic acidosis. It is the acidosis which is apparently responsible for the retardation of growth and development. IS The exact mechanism by which acidosis retards growth is unknown, but the clinical correction of the acidosis is followed by a resumption of growth. The key laboratory features in distal renal tubular acidosis are acidosis, hypocarbia, hyperchloremia, and an alkaline urine (pH 6.0 or greater). In proximal disease, the urine pH may be appropriately acid when hypocarbia is severe or the pH may be alkaline if the plasma bicarbonate exceeds the renal threshold. In proximal disease, hypokalemia is an almost invariable finding. The classic Fanconi syndrome is not uncommon in association with secondary proximal renal tubular acidosis and should be sought in these patients. The clinical features of renal tubular acidosis other than growth retardation are often subtle but a careful history and physical examination may uncover varying degrees of polydipsia, polyuria, a history of easy dehydration with mild intercurrent illnesses, tachypnea, and/or muscle weakness.
Abn N
N
N N
N
E
N
N
Abn N
E
Abn/N
A N N Abn
0
N Abn
N
A N N N N
DIN DIN DIN DIN
0
N Abn
Abn
A N(D) N N N
DIN DIN DIN DIN
N
N N
N
N N N N A N I N N
Regional Enteritis
N
N N
N
N N N N Yes N N N N
Renal Tubular Acidosis
N
N N
N
N N N N A D N N N
Hypothyroidism
SYSTEMIC DISEASES
3,10
2,5,7,10,13,17,20,21, 23 2,5,6,10,13,17,21,22 2,5,6,7,10,13,17,21
2,5,6,7,10,13,17,21 2,5,6,7,10,13,17,21 2,6,10,13,17,21 6,7,10,17,21 18,21 8,21 4 1,2,6,7,10,13,17,21 1,2,7,17,21
REFERENCES
N-Normal for development stage, A-Absent, D-Decreased, I-Increased, E-Exaggerated increase, Abn-abnormal for developmental stage; (1) erythrocyte sedimentation rate elevated about 90 per cent with regional enteritis and is often elevated in other chronic systemic diseases; (2)(3) Gonadotropin releasing hormone and human chorionic gonadotropin-response varies with pubertal stage; (4) only laboratory marker for pubertal progression-is of no use until mid puberty; (5) test of choice to determine whether hypothalamic-pituitary puberty has begun.
HCG(3) Clomiphene(4) Adolescent Nocturnal Secretory Pattern(5)
Abn/N
D A N N Abn
Nil DII
I
Pituitary Dysfunction
HYPOGONADOTROPISM
Hypothalamic DysTurner's Klinefelter's Syndrome Syndrome function
N N N N A N N N N
Constitutional Delay Puberty
HYPOGONADISM
Selected Laboratory Tests in the Evaluation of Several Etiologies of Delayed Puberty
Blood LH FSH Testosterone Estradiol Acidosis Total T4 ESR(1) Chromosome Analysis Buccal Smear Stimulation Tests GnRH(2)
TESTS
Table 3.
to
tJ t"'
.... ~
~
....
"">
The Problem of Delayed Puberty H. Verdain Barnes, M.D.*
The attainment of an age-appropriate height, weight, and secondary sexual development is a compelling desire of all adolescents, although their concern is often not clearly verbalized. No problem of puberty is of greater personal importance or embarrassment to the teenager than to remain short and/or sexually infantile while one's peers are rapidly developing. Delayed puberty is defined medically for boys as having not reached genital stage 2 (G2) by 13.7 years of age or having not progressed from stage G2 to G3 within 2.2 years, G3 to G4 in 1.6 years, or G4 to G5 in 1.9 years (Tables 3, 4, p. 1310). In girls it is defined as not having begun breast development (stage B2) by 13.4 years of age or not having progressed from stage B2 to B3 within 1.0 years or B3 to B4 in 2.2 years, or not having menarche within 5.0 years of attaining breast stage B2. 14 • 15 In the patient's mind, however, delayed puberty is more simply defined as lagging behind one's peers in growth and development, which does not necessarily correlate with the medical definition. Regardless, for the patient the problem is no less real. Failing or seeming to fail in maturation usually incites remarkable degrees of anxiety and depression in the adolescent. All patients complaining of delayed or inadequate maturation must be carefully evaluated by history and physical examination and, then, thoughtfully counseled. In counseling it is important to provide detail as to normal variations in maturation as well as future expectations for growth and development. The necessity for this type of counseling cannot be overemphasized.
DIFFERENTIAL DIAGNOSIS Delayed puberty is estimated to occur in perhaps 2 to 3 per cent of adolescents. 11 The differential diagnosis of delayed puberty, including primary amenorrhea, is found in Table 1. The focus of this article is on the most common of these disorders, the constitutional delay of puberty. ':'Formerly Director, Adolescent Medicine. and Assistant Professor of Medicine. Pediatrics. and Radiology. The Johns Hopkins Hospital; Presently Associate Professor of Medicine and Pediatrics. and Director of Adolescent Medicine. University of Iowa Hospitals and Clinics. Iowa City. Iowa Medical Clinics of North America- Vo!' 59. No. 6. November 1975
1337
1338
H.
Table 1.
VERDAIN BARNES
Potential Causes of Delayed Puberty
I. Constitutional Delay of Puberty
Il. Hypothalamic Disorders 1. Congenital deficiency of gonadotropin-releasing hormone Familial Sporadic Kallman's syndrome Laurence- Moon- Biedl syndrome Prader-Willie syndrome Friedreich's ataxia(?) 2. Acquired gonadotropin-releasing hormone deficiency A. Infections Post viral encephalitis Sarcoidosis Tuberculosis B. Neoplasms Primary hypothalamic tumors Craniopharyngioma Pinealoma Histiocytosis Ill. Pituitary Disorders 1. Congenital deficiency of gonadotropin(s) Idiopathic panhypopituitarism Isolated LH and/or FSH deficiency Microcephaly 2. Acquired gonadotropin(s) deficiency A. Infections Sarcoidosis Tuberculosis B. Neoplasms Primary pituitary adenomas Primary and secondary pituitary carcinoma Craniopharyngioma Histiocytosis C. Post traumatic IV. Gonadal Disorders 1. Congenital Turner's syndrome (45XO and Mosaics) Klinefelter's syndrome (47XXY and Mosaics) Gonadal agenesis Reifensteins' syndrome Weinstein's syndrome Male Turner's syndrome Myotonia dystrophic a 2. Acquired A. Infections Gonorrhea (male) Tuberculosis (male) Viral orchitis (primarily mumps) B. Mechanical postoperative or radiation Bilateral ovarian or testicular torsion Oophorectomy (bilateral) Orchiectomy (bilateral) Post orchiopexy testicular atrophy post irradiation necrosis
1339
DELAYED PUBERTY
Table 1.
Potential Causes of Delayed Puberty (Continued)
C. Posttraumatic Testicular atrophy Spinal cord damage V. Chronic Systemic Diseases Congenital heart disease (usually cyanotic) Severe acquired mitral or aortic valve disease Bronchial asthma Regional enteritis Ulcerative colitis Chronic renal failure Renal tubular acidosis Sickle cell anemia Hyperthyroidism Hypothyroidism Uncontrolled diabetes mellitus Juvenile rheumatoid arthritis Systemic lupus erythematosus Tuberculosis Anorexia nervosa Socioeconomic malnutrition VI. Some Causes of Primary Amenorrhea Associated With Normal or Partial Secondary Sexual Development Pregnancy Cryptomenorrhea Uterine agenesis Vaginal agenesis Pure gonadal dysgenesis (46XY or 46XX) Testicular feminization Functional ovarian tumors True hermaphrodite
Constitutional Delay of Puberty l3,
16, 17
In our clinic, over 90 per cent of the adolescents seeking medical attention for delayed puberty are normal but slow in their maturation. The precise cause of constitutional delay of puberty is not known, but current evidence suggests that there is a physiologic delay in the maturation of the central nervous system which results (1) in a delay in the normal hypothalamic-pituitary unit's decrease in sensitivity to prepubertal levels of the sex hormones and (2) in a delay in the initiation of the unique pubertal hypothalamic-pituitary, sleep-associated LH secretory pattern. 10, 13 Constitutional delay of puberty occurs in both males and females. Males, however, more often seek medical attention since, in our society, they are more likely to be openly ridiculed, abused, bullied by peers, denied peer group membership, or excluded from social and athletic activities because of inappropriate size and development for chronologic age. A tentative diagnosis of constitutional delay of puberty is made by exclusion and confirmed in retrospect after the patient has progressed to adult maturation. The major clinical criteria for making a presumptive
1340 Table 2.
H. VERDAIN BARNES The Criteria for Making a Presumptive Diagnosis of Constitutional Delay of Puberty
1. Negative review of systems for neurologic, cardiovascular, renal, gastrointestinal, musculoskeletal, and endocrine signs or symptoms 2. History of appropriate nutrition and eating habits 3. Normal physical examination, including upper lower body segment ratio, arm span, and genitalia 4. Delay in bone age (1.5 to 4.0 years) 5. Linear growth rate of at least 3.75 cm per year (average 5.0 cm per year) 6. Normal hemogram, erythrocyte sedimentation rate, urinalysis, total serum thyroxine, and skull x-ray
diagnosis of constitutional delay of puberty are shown in Table 2. In addition, about 90 per cent of both males and females are short in stature with heights near the third percentile for chronologic age and close to 60 per cent have a positive family history for pubertal delay. When present, these features add support to the diagnosis. Patients who do not meet all of the major criteria or who fail to progress through puberty at a satisfactory rate require further evaluation. The majority of the other causes of delayed puberty are almost invariably suggested by the history and/or physical examination. In our experience, the following disorders, however, may be difficult to differentiate from constitutional delay of puberty and, in fact, the diagnosis may be initially missed: gonadal dysgenesis (particularly Turner's syndrome), Klinefelter's syndrome, hypo gonadotropic hypogonadism, renal tubular acidosis, early inflammatory bowel disease particularly regional enteritis, and early hypothyroidism.
Turner's Syndrome!. 10. 17.21 Adolescent age females who are below the third percentile in height with stage 3 pubic hair have a high probability of being a classic (45 XO) or mosaic (XO/XX, XO/XXX, etc.) Turner's syndrome, particularly in the absence of breast development. In evaluating such girls it is important to recognize that: (1) many Turner's patients, particularly mosaics, have only a suspicion of or no typical somatic manifestations of the syndrome, (2) many mosaics have a normal female (chromatin positive) buccal smear, and (3) mixed patterns of gonadal dysgenesis are important to identify since the presence of a Y chromosome in the karyotype increases the potential for developing a gonadoblastoma. To rule in or out the diagnosis of Turner's syndrome often requires chromosomal analysis. Hormonally, these girls have elevated levels of serum LH and FSH for their stage of secondary sexual development and, in fact, the levels are frequently in the postmenopausal range. Two other congenital disorders may be clinically confusing, pure gonadal dysgenesis and testicular feminization. In pure gonadal dysgenesis, the phenotype and karyotype (46XX) are female, but gonadal streaks rather than ovaries are present. The serum LH and FSH pattern is identical to that in the Turner's phenotype. In testicular feminization, the phenotype is female but the karyotype is male. The primary defect is
1341
DELAYED PUBERTY
androgen insensitivity. These patients have normal female breast development and scant or no pubic hair growth. They often present complaining of primary amenorrhea. Anatomically, these patients have intra-abdominal, inguinal, or labial testes and a short blind pouch vagina. Chemically, serum testosterone values are usually in the adult male range, as are serum and estrogen levels. The LH is elevated while FSH is usually normal. These patients are at high risk for developing gonadoblastomas; therefore, the testes should be removed. Klinefelter's Syndrome1 • 10, 17, 21 Males with a height at or greater than the fiftieth percentile, an arm span exceeding height by more than 2.5 cm, a decreased upper to lower body segment ratio, eunuchoid fat distribution, true gynecomastia, or firm prepubertal size testes and/or disproportionately small testes for pubic hair stage should be evaluated for classic (47 XXY) or mosaic (XX/XXY, XO/XY/XXY, etc.) Klinefelter's syndrome. These patients may be diagnosed by the presence of a chromatin positive buccal smear (normal female) or multiple chromatin bodies; however, some mosaics are chromatin negative (normal male.) Consequently, the disorder cannot be ruled out without a chromosome analysis. Serum LH and FSH levels are disproportionately high for the stage of secondary sexual development. Testosterone levels are usually low for the developmental stage though an occasional patient may have a low normal value. A rare phenotypic male will have a 46 XX karyotype but will otherwise be clinically or chemically indistinguishable from patients with Klinefelter's syndrome. Males who are below the third percentile in height should be carefully examined for the somatic features of Turner's syndrome. The presence of short stature and one or more typical somatic features suggests the male variant of Turner's syndrome.
Hypogonadotropic Hypogonadism10 ,
13, 17,21
Patients with one of the congenital hypo gonadotropic syndromes will almost invariably exhibit some or all of the typical somatic characteristics of the syndrome. It is beyond the scope of this article to detail the characteristics of each syndrome; however, there are two notable exceptions which must be discussed: Kallman's syndrome and isolated gonadotropin deficiency of hypothalamic or pituitary origin. In the olfactory genital syndrome, Kallman's syndrome, the only distinct characteristic may be some degree of anosmia. Consequently, the sense of smell should be tested in all patients having delayed puberty. In isolated gonadotropin deficiency, there are unfort~nately no telltale clues other than pubertal delay or arrest. The acquired causes of hypothalamic or pituitary dysfunction are often subtle, but a careful past history will usually suggest the post infectious or post traumatic etiologies. Neoplastic causes are often occult particularly in their early stages when the tumor is small or when the process is infiltrative as in histocy~ tosis X. The review of systems may offer no suggestion of neurologic, psychologic, antidiuretic hormone, or other trophic hormone deficiencies. The physical examination is usually entirely normal except for
1342
H.
VERDAIN BARNES
delayed pubertal development for age. In fact, these patients may initially meet all the major criteria for a presumptive diagnosis of constitutional delay of puberty. Congenital isolated absence of gonadotropin releasing hormone or gonadotropins or with acquired deficiencies is the most difficult to distinguish from constitutional delay of puberty; in fact, these disorders are often impossible to differentiate until the mid teen years. Testing for hypo gonadotropic hypogonadism is in order for females and males who are still prepubertal at age 15 and 16 respectively as well as those patients who are carrying a presumptive diagnosis of constitutional delay of puberty but have not progressed in their secondary sexual development according to the guidelines in Tables 3 and 4 (p. 1310). Hormonally, LH and FSH levels are prepubertal or inappropriately low for the stage of sexual development as are the sex hormones. Some potentially useful differential tests are shown in Table 3. As is immediately obvious, only two available tests are of potential help. The clomiphene test is useful after mid pubertal development is reached and the adolescent nocturnal secretory pattern determination is of help when it is present. If either test shows a normal response, hypo gonadotropic hypogonadism is ruled out; if no response, the question remains unresolved.
Renal Tubular Acidosis 1H Both the proximal and distal types of renal tubular acidosis may have their onset just prior to or during puberty. Renal tubular acidosis of both types may occur as primary sporadic or hereditary abnormalities, or arise secondary to a variety of systemic diseases and toxins. Primary distal renal tubular acidosis inherited as an autosomal dominant trait, is the most likely to present in adolescence or adult life. The incidence is greater in females than in males. Proximal renal tubular acidosis is most often secondary. In the adolescent, the most likely associated disorders or toxins are Wilson's disease, primary hyperparathyroidism, or the ingestion of outdated tetracycline. Both types are characterized by a sustained metabolic acidosis. It is the acidosis which is apparently responsible for the retardation of growth and development. IS The exact mechanism by which acidosis retards growth is unknown, but the clinical correction of the acidosis is followed by a resumption of growth. The key laboratory features in distal renal tubular acidosis are acidosis, hypocarbia, hyperchloremia, and an alkaline urine (pH 6.0 or greater). In proximal disease, the urine pH may be appropriately acid when hypocarbia is severe or the pH may be alkaline if the plasma bicarbonate exceeds the renal threshold. In proximal disease, hypokalemia is an almost invariable finding. The classic Fanconi syndrome is not uncommon in association with secondary proximal renal tubular acidosis and should be sought in these patients. The clinical features of renal tubular acidosis other than growth retardation are often subtle but a careful history and physical examination may uncover varying degrees of polydipsia, polyuria, a history of easy dehydration with mild intercurrent illnesses, tachypnea, and/or muscle weakness.
Abn N
N
N N
N
E
N
N
Abn N
E
Abn/N
A N N Abn
0
N Abn
N
A N N N N
DIN DIN DIN DIN
0
N Abn
Abn
A N(D) N N N
DIN DIN DIN DIN
N
N N
N
N N N N A N I N N
Regional Enteritis
N
N N
N
N N N N Yes N N N N
Renal Tubular Acidosis
N
N N
N
N N N N A D N N N
Hypothyroidism
SYSTEMIC DISEASES
3,10
2,5,7,10,13,17,20,21, 23 2,5,6,10,13,17,21,22 2,5,6,7,10,13,17,21
2,5,6,7,10,13,17,21 2,5,6,7,10,13,17,21 2,6,10,13,17,21 6,7,10,17,21 18,21 8,21 4 1,2,6,7,10,13,17,21 1,2,7,17,21
REFERENCES
N-Normal for development stage, A-Absent, D-Decreased, I-Increased, E-Exaggerated increase, Abn-abnormal for developmental stage; (1) erythrocyte sedimentation rate elevated about 90 per cent with regional enteritis and is often elevated in other chronic systemic diseases; (2)(3) Gonadotropin releasing hormone and human chorionic gonadotropin-response varies with pubertal stage; (4) only laboratory marker for pubertal progression-is of no use until mid puberty; (5) test of choice to determine whether hypothalamic-pituitary puberty has begun.
HCG(3) Clomiphene(4) Adolescent Nocturnal Secretory Pattern(5)
Abn/N
D A N N Abn
Nil DII
I
Pituitary Dysfunction
HYPOGONADOTROPISM
Hypothalamic DysTurner's Klinefelter's Syndrome Syndrome function
N N N N A N N N N
Constitutional Delay Puberty
HYPOGONADISM
Selected Laboratory Tests in the Evaluation of Several Etiologies of Delayed Puberty
Blood LH FSH Testosterone Estradiol Acidosis Total T4 ESR(1) Chromosome Analysis Buccal Smear Stimulation Tests GnRH(2)
TESTS
Table 3.
to
tJ t"'
.... ~
~
....
"">
