AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

The criterion for microphallus, or micropenis, is a stretched penile length of less than 2 standard deviations (SDs) below the mean for age. Traditionally, the term micropenis refers to a penis that is otherwise normally formed, and the term microphallus has been used when associated hypospadia is present.

The mean stretched penile length in a term newborn male is 3.5 cm. Measurements of less than 2.5 cm (2 SD below the mean) in a term newborn male meet the definition of micropenis and warrant evaluation. Penile growth is essentially linear during mid-to-late gestation. Tuladhar et al (1998) reported the following formula to describe the relationship between penile length and gestational age for infants born at 24-36 weeks' gestation:

Although micropenis can be defined as a form of ambiguous genitalia, the presence of a normal scrotum and palpable testes indicates a high probability of a normal male karyotype. In contrast, if the testes are not palpable, the penile urethra is absent, or both, the examination is better described as ambiguous, and an evaluation and counseling for disorders of sexual development need to be undertaken.

After the first few years of life, the penis grows very little until puberty, when testosterone levels begin to rise. Mean stretched penile lengths and SDs below 2.5 for various age groups can be found in the popular Harriet Lane Handbook (table 9-26, 17th ed).

Occasionally, older boys are brought to physicians for evaluation because of concerns of small genitalia. These boys are usually prepubertal and obese. Almost invariably, these individuals have normal penis sizes based on stretched penile length; the apparent smallness is secondary to the penis being concealed in the prepubic fat pad. However, if the penis does measure less than 2 SDs below the mean (approximately 4 cm), further evaluation may be indicated.

Pathophysiology

Fetal production of testosterone and its peripheral conversion to dihydrotestosterone (DHT) is necessary for normal male development. Early in gestation, placental human chorionic gonadotropin (hCG) stimulates the developing testes to produce testosterone through binding to the LH receptor. At approximately 14 weeks' gestation, the fetal hypothalamic-pituitary-gonadal axis is activated, and testosterone production falls under the influence of fetal luteinizing hormone (LH). In the absence of normal hypothalamic or pituitary function, a normally shaped penis may develop, but adequate penile growth does not occur. Failure of adequate testosterone production toward the end of gestation, due to a primary testicular disorder, can also result in inadequate penis growth.

In addition, microphallus can also occur in children with androgen receptor defects or 5-alpha reductase deficiency (failure of conversion of testosterone to DHT). However, most children with these defects have varying degrees of incomplete labioscrotal fusion, resulting in hypospadias and genital ambiguity.

Shortly after birth, gonadotropin and testosterone production decrease. Beginning at about age 1 week, gonadotropin and testosterone levels begin to rise again to pubertal levels, peaking at age 1-2 months, and then decreasing to prepubertal levels by age 6 months. The subsequent limited penis growth is probably related to generalized somatic growth. With the advent of puberty and increases in testosterone production, penis growth resumes.

Micropenis has also been observed in children with isolated growth hormone deficiency, indicating a role for growth hormone in penis growth. Lastly, micropenis may be a feature in genetic syndromes, such as Prader-Willi, Klinefelter, and Noonan syndromes.

Mortality/Morbidity

• When micropenis is associated with hypopituitarism and hypoadrenalism, the infant can develop hypoglycemia, electrolyte abnormalities, hypotension, and shock. Infants with midline defects and those with optic nerve hypoplasia or aplasia deserve particular attention, as these defects may point to pituitary hormone deficiencies. Failure to recognize this association in an ill neonate can result in death. Infants who survive the newborn period may exhibit varying degrees of poor growth and failure to thrive, depending on potential associated hormone deficiencies or genetic syndrome.
• Psychosocial concerns can arise over issues such as gender identity, normal standing urination, physical appearance, and sexual performance. These concerns should be addressed with early evaluation and treatment and counseling, if appropriate.
• In cases of extreme micropenis, especially if associated with other genital anomalies (eg, cryptorchidism, hypospadias), gender reassignment is sometimes considered. However, the family needs to be intimately involved in this decision, and counseling from a center with a multidisciplinary team skilled at gender reassignment should be pursued.

Sex

By definition, microphallus is an exclusively male condition. However, distinguishing between a male with micropenis and cryptorchidism and a female with clitoromegaly is important and may be difficult.

Age

Micropenis is most often recognized and evaluated in the immediate newborn period, but delays in evaluation may also occur.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Neonatal hypoglycemia is associated with other pituitary hormone deficiencies, including panhypopituitarism, growth hormone deficiency, and adrenal insufficiency. Infants with other midline defects and those with optic nerve hypoplasia or aplasia deserve particular attention, as these defects may point to pituitary hormone deficiencies.
• Poor growth or failure to thrive is also associated with other pituitary hormone deficiencies.
• Lack of a sense of smell suggests Kallmann syndrome (anosmia and hypogonadotropic hypogonadism).
• Other congenital anomalies may provide clues to a genetic syndrome.
• Family history of similarly affected children could suggest a familial form of hormonal deficiency, defect in steroidogenesis, or androgen insensitivity. Family history of unexplained death in the first year of life could also suggest pituitary hormone deficiencies and/or adrenal insufficiency.

Physical

• The infant or child with micropenis should be thoroughly examined for dysmorphic features and other congenital defects. This examination should include careful inspection of the face and mouth for cleft lip or palate or other indications of midfacial hypoplasia.
• Abnormal growth velocity suggests growth hormone deficiency with or without other pituitary hormone deficiencies.
• A thorough examination of the genitalia, including proper measurements of the stretched penis length and testicular size, is important.
• • The proper technique for measuring the penis is to use a rigid ruler held firmly against the symphysis pubis at a right angle.
  • Firm but gentle traction is placed on the penis to stretch it upward along the ruler to the point of increased resistance
  • An alternate, less traumatic method is to use the index finger of one hand as a gauge pressed against the symphysis.
  • Gentle traction is placed on the penis, the index finger of the other hand is used to mark the length on the gauge finger, and a tape measure is used to determine the length.

Causes

Most cases of micropenis are due to fetal testosterone deficiency. This condition can occur in gonadotropin deficiency, either as an isolated finding or in conjunction with multiple pituitary hormone deficiencies. Other causes include decreased synthesis of testosterone or conversion of testosterone to DHT, decreased testosterone sensitivity, and growth hormone deficiency. Micropenis can occur as an isolated idiopathic anomaly or in association with other anomalies.

• Conditions associated with hypogonadotropic hypogonadism include the following:
• • Multiple pituitary hormone deficiency: This may be secondary to transcription factor mutations (eg, PROP-1), although, in most instances, genetic evaluation is not part of the routine diagnostic evaluation.
  • Kallmann syndrome: Anosmia (lack of sense of smell) or hyposmia is a prominent feature. The inheritance pattern is autosomal dominant (FGFR1 gene), autosomal recessive, or X-linked recessive (KAL gene). Associated anomalies include cleft lip and palate, congenital heart disease, renal agenesis, sensorineural deafness, visual abnormalities, synkinesia (mirror image movements), cerebellar ataxia, short metacarpals, or pes cavus.
  • Septo-optic dysplasia: Major features include the triad of absent septum pellucidum, optic nerve hypoplasia, and hypopituitarism. Wandering nystagmus may be noted. The multiple pituitary hormone deficiencies may be present at birth or develop over a number of years.
  • Idiopathic hypogonadotropic hypogonadism: The sense of smell is normal.
• Conditions associated with decreased testosterone production include the following:
• • Anorchia: Micropenis results when testicular degeneration occurs after 12 weeks' gestation.
  • Defects in testosterone steroidogenesis: Incomplete forms of 17 beta-hydroxysteroid dehydrogenase deficiency can cause micropenis, but the genitalia are often more feminine appearing or ambiguous.
  • Luteinizing hormone (LH) receptor defects are associated.
• Partial androgen insensitivity: The genitalia are sometimes more ambiguous.
• Deficiency of 5-alpha reductase: The genitalia are usually more ambiguous.
• Growth hormone deficiency
• Other syndromes include the following:
• • Klinefelter syndrome (47, XXY) and other poly X syndromes - Hypergonadotropic hypogonadism
  • Prader-Willi syndrome - Hypogonadotropic hypogonadism, hypotonia in infancy, failure to thrive in infancy with later hypothalamic obesity, developmental delay, short stature, small hands and feet
  • Bardet-Biedl syndrome - Hypogonadotropic hypogonadism, developmental delay, retinitis pigmentosa, obesity, short stature, polydactyly
  • Noonan syndrome - Short stature, webbed neck, pectus excavatum, cryptorchidism, pulmonary stenosis
  • CHARGE syndrome - Coloboma, heart disease, atresia choanae, retarded growth and development, genital anomalies and hypogonadism, ear anomalies and deafness
  • Robinow syndrome - Flat facial profile, short forearms, hypoplastic genitalia
  • Rud syndrome - Hyposmia, developmental delay, congenital ichthyosis, epilepsy, short stature

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

X-linked adrenal hypoplasia congenita: Hypogonadotropic hypogonadism is associated with X-linked adrenal hypoplasia congenita and usually presents with lack of pubertal development. Primary adrenal failure occurs in infancy or early childhood. Mutations in the DAX1 gene are implicated.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Chromosomal analysis is recommended to confirm chromosomal sex and to evaluate for associated genetic syndromes. If Prader-Willi syndrome is suspected, chromosomal analysis looking for a 15q11-13 band deletion of the paternally derived chromosome (70%), maternal uniparental disomy (25%), or methylation-specific paternal defect (5%) should be undertaken.
• Gonadotropins (LH and follicle-stimulating hormone [FSH]) reach pubertal levels in healthy male infants, peaking at age 1-2 months. Excessively high or low values help to narrow the differential diagnoses.
• Testosterone and DHT levels, before and after hCG stimulation, can be measured to evaluate the responsiveness of the testes to gonadotropin stimulation and for 5-alpha reductase deficiency (indicated by an increased testosterone-to-DHT ratio).
• Observe infants with micropenis (especially if other abnormalities associated with hypopituitarism are present) for evidence of metabolic derangements.
• • If hypoglycemia occurs, obtain a critical sample immediately before intravenous glucose is administered.
  • The critical sample should include glucose, insulin, growth hormone, and cortisol levels.
• In infants with suspected hypopituitarism, growth hormone and cortisol levels can be measured after glucagon stimulation.
• In infants with suspected hypopituitarism, measure total and free thyroxine (T4) levels to check for hypothyroidism. Thyrotropin-stimulating hormone (TSH) levels are low in secondary and tertiary hypothyroidism. Of interest, these children rarely have positive screen results for hypothyroidism in the newborn period.

Imaging Studies

• In situations of genital ambiguity, pelvic ultrasonography is often helpful. The presence of a uterus and ovaries strongly suggests a virilized female (XX) infant.
• When hypopituitarism is suspected, an MRI of the head should be obtained to evaluate the hypothalamic and pituitary areas. In Kallmann syndrome, abnormalities of the olfactory system may be seen on MRI.

Other Tests

• A gonadotropin-releasing hormone (GnRH) stimulation test can be performed to evaluate the pituitary gland's ability to respond and produce LH and FSH.
• Testosterone therapy (testosterone enanthate or cypionate 25-50 mg every month for 3 to 6 months) has diagnostic and therapeutic implications. No appreciable increase in penis size with androgen therapy suggests androgen insensitivity.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Testosterone therapy in various forms (eg, injections, creams, patches) has been used to increase penis size in infants and children.
• Testosterone therapy has generally been found effective in treating micropenis due to testosterone deficiency.
• • In 1999, Bin-Abbas et al showed that 1 or 2 courses of 3 testosterone injections (25-50 mg) administered at 4-week intervals in infancy or childhood resulted in sufficient increase in penis sizes to reach the reference range for age.
  • With appropriate pubertal and adult replacement, patients achieved normal adult penis size and reported sexual activity and appropriate gender identity.
• Infants with other hormonal deficiencies (growth hormone deficiency, hypothyroidism, adrenal insufficiency) should receive appropriate hormonal replacements.

Surgical Care

• Gender reassignment with appropriate genitoplasty has been performed. Because most boys with micropenis and descended testes are sensitive to testosterone therapy, consider genitoplasty only in extreme situations in which testosterone insensitivity is demonstrated. Even then, some authors question the wisdom of gender reassignment.
• Circumcision should be avoided, or at least delayed, until appropriate evaluation, gender assignment, and therapy are completed. If associated with penile growth, testosterone therapy (see Medical Care) may facilitate the circumcision.

Consultations

• As soon as an infant is discovered to have micropenis, a pediatric endocrinologist should be consulted.
• In some cases, the involvement of a pediatric urologist can also be helpful.
• Psychological support and social services assistance may be useful.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Testosterone therapy has been shown to increase phallus size in infants with micropenis.

Drug Category: Androgenic hormones

Testosterone is the main androgenic hormone predominantly formed in the interstitial (Leydig) cells of the testes. In target tissues, it is converted to the more active form (DHT) by 5-alpha reductase. Testosterone controls the development and maintenance of the male sex organs and the male secondary sex characteristics. It also produces systemic anabolic effects (increased retention of nitrogen, calcium, sodium, potassium, chloride, and phosphate).

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Monitor infants with isolated micropenis for subsequent growth and development problems. If any problems arise, evaluate and treat appropriately.
• Many children with micropenis, especially those with gonadotropin deficiency, do not have spontaneous or complete puberty.
• Appropriate counseling and testosterone therapy should be provided.

Prognosis

• The prognosis of boys with micropenis secondary to gonadotropin or testosterone deficiency is usually good. These individuals generally respond well to testosterone therapy and function normally as adults. However, despite the potential for near-normal adult phallic size and sensitivity, infertility is generally expected.
• Prognosis is much more guarded in children with androgen insensitivity, especially with significant genital ambiguity

Patient Education

• Provide parents with a clear picture of the cause of their child's problems, including expectations from treatment. In situations in which gender assignment is being contemplated, include parents in the decision process.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The importance of appropriate gender assignment cannot be overemphasized.
• Evaluate any genital abnormality carefully and early on, using appropriate consultations.
• • Girls with congenital adrenal hyperplasia have been labeled boys prematurely based on the appearance of their genitalia.
  • Some males have been gender assigned as girls and put through genital surgery when androgen therapy may have been a simpler and more appropriate treatment.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Achermann JC, Ozisik G, Meeks JJ. Genetic causes of human reproductive disease. J Clin Endocrinol Metab. 2002;87:2447-2454. [Medline].
• Arrigo T, De Luca F, Maghnie M. Relationships between neuroradiological and clinical features in apparently idiopathic hypopituitarism. Eur J Endocrinol. Jul 1998;139(1):84-8. [Medline].
• Bin-Abbas B, Conte FA, Grumbach MM. Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated. J Pediatr. May 1999;134(5):579-83. [Medline].
• Bourgeois MJ, Jones B, Waagner DC. Micropenis and congenital adrenal hypoplasia. Am J Perinatol. Jan 1989;6(1):69-71. [Medline].
• Brinkmann A, Jenster G, Ris-Stalpers C. Molecular basis of androgen insensitivity. Steroids. Apr 1996;61(4):172-5. [Medline].
• Calikoglu AS. Should boys with micropenis be reared as girls? [editorial]. J Pediatr. May 1999;134(5):537-8. [Medline].
• Danon M, Friedman SC. Ambiguous genitalia, micropenis, hypospadias, and cryptorchidism. In: Pediatric Endocrinology. 3rd ed. Philadelphia, Pa:. WB Saunders;1996:297-301.
• Dissaneevate P, Warne GL, Zacharin MR. Clinical evaluation in isolated hypogonadotrophic hypogonadism (Kallmann syndrome). J Pediatr Endocrinol Metab. Sep-Oct 1998;11(5):631-8. [Medline].
• Feldman KW, Smith DW. Fetal phallic growth and penile standards for newborn male infants. J Pediatr. Mar 1975;86(3):395-8. [Medline].
• Gad YZ, Nasr H, Mazen I. 5 alpha-reductase deficiency in patients with micropenis. J Inherit Metab Dis. Mar 1997;20(1):95-101. [Medline].
• Hamilton J, Blaser S, Daneman D. MR imaging in idiopathic growth hormone deficiency. AJNR Am J Neuroradiol. Oct 1998;19(9):1609-15. [Medline].
• Hayes FJ, Seminara SB, Crowley WF. Hypogonadotropic hypogonadism. Endocrinol Metab Clin North Am. 1998;27:739-763. [Medline].
• Quigley CA. Editorial: The postnatal gonadotropin and sex steroid surge - Insights from the androgen insensitivity syndrome. J Clin Endocrinol Metab. 2002;87:24-28. [Medline].
• Ragan DC, Casale AJ, Rink RC. Genitourinary anomalies in the CHARGE association. J Urol. Feb 1999;161(2):622-5. [Medline].
• Robertson J, Shilkofski N. Mean Stretched Penile Length. The Harriet Lane Handbook. 2005;277.
• Schonfeld WA, Beebe GW. Normal growth and variation in male genitalia from birth to maturity. J Urol. 1942;64:759-777.
• Sinnecker GH, Hiort O, Dibbelt L. Phenotypic classification of male pseudohermaphroditism due to steroid 5 alpha-reductase 2 deficiency. Am J Med Genet. May 3 1996;63(1):223-30. [Medline].
• Tsigos C, Latronico C, Chrousos GP. Luteinizing hormone resistance syndromes. Ann N Y Acad Sci. Jun 17 1997;816:263-73. [Medline].
• Tuladhar R, Davis PG, Batch J. Establishment of a normal range of penile length in preterm infants. J Paediatr Child Health. Oct 1998;34(5):471-3. [Medline].
• Wessells H, Lue TF, McAninch JW. Penile length in the flaccid and erect states: guidelines for penile augmentation. J Urol. Sep 1996;156(3):995-7. [Medline].

Article Last Updated: Aug 7, 2006