eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Microphallus

Author: Karen S Vogt, MD, Pediatric Endocrinologist, Department of Pediatrics, Division of Endocrinology, Walter Reed Army Medical Center
Coauthor(s): Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; Andrew J Bauer, MD, Program Director, Department of Pediatrics, Division of Pediatric Endocrinology, Uniformed Services University of the Health Sciences; Michael J Bourgeois, MD, Director of Pediatric Undergraduate Medical Education, Associate Professor, Department of Pediatrics, Division of Pediatric Endocrinology and Metabolism, Texas Tech University School of Medicine
Contributor Information and Disclosures

Updated: Jul 9, 2008

Introduction

Background

Microphallus, or micropenis, is defined as a stretched penile length of less than 2.5 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 full-term newborn male is 3.5 cm. Measurements of less than 2.5 cm (2.5 SDs below the mean) in a full-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:¹

Penile length in centimeters = 2.27 + 0.16 X (gestational age in weeks)

Although micropenis can be considered a form of ambiguous genitalia, the presence of a normal scrotum and palpable testes indicates a high probability of a normal male karyotype. 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 should be performed.

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 2.5 SDs below the mean for various age groups can be found in the popular Harriet Lane Handbook (table 9-26, 17th ed).²

Occasionally, older boys are brought to physicians for evaluation because of concerns of small genitalia. These boys are usually prepubertal and obese. Most often, these individuals have normal penis size based on stretched penile length, and the apparent smallness is secondary to the penis being concealed in the suprapubic fat pad. However, if the penis does measure less than 2.5 SDs below the mean (approximately 4 cm), further evaluation is 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 luteinizing hormone (LH) receptor. By approximately 14 weeks' gestation, the fetal hypothalamic-pituitary-gonadal axis is active, and testosterone production falls under the influence of fetal LH. Therefore, penile growth after the first trimester depends on fetal testosterone production. Testosterone is  peripherally converted by the enzyme 5-alpha reductase to the more potent androgen DHT, which is responsible for virilization of the male external genitalia. Finally, intact peripheral androgen receptors are necessary for normal male development.

Shortly after birth, gonadotropin (LH and follicle stimulating hormone [FSH]) and testosterone production decrease. Beginning at about age 1 week, gonadotropin and testosterone levels begin to rise again to pubertal levels, peaking at age 1-3 months, and then decreasing to prepubertal levels by age 6 months. After age 6 months, the little subsequent penile growth that occurs parallels general somatic growth. With the onset of puberty penis growth resumes because of increases in testosterone production. Growth hormone also plays a role in penis growth because micropenis has been observed in children with isolated growth hormone deficiency.

Micropenis may be caused by a defect anywhere along the hypothalamic-pituitary-gonadal axis, a defect in peripheral androgen action, isolated growth hormone deficiency, or a primary structural anomaly or it may be part of a genetic syndrome. The most common cause of micropenis is abnormal hypothalamic or pituitary function. In the absence of normal hypothalamic or pituitary function, a normally shaped penis may develop due to maternal hCG effect on fetal testosterone production, but adequate penile growth does not occur after 14 weeks' gestation when testosterone production depends on intact fetal pituitary LH secretion.  Failure of adequate testosterone production toward the end of gestation due to a primary testicular disorder can also result in inadequate penis growth. 

Micropenis can also occur in children with LH-receptor defects and defects in testosterone biosynthesis (eg, 17-beta hydrosysteroid dehydrogenase deficiency). The genitalia of individuals with LH-receptor defects vary from a normal female appearance to a male with micropenis. Individuals with 17-beta hydroxysteroid dehydrogenase deficiency most often have female-appearing genitalia and, less often, ambiguous genitalia. 

Defects in peripheral androgen action include 5-alpha reductase deficiency (failure of conversion of testosterone to DHT) and partial androgen insensitivity syndrome (PAIS) due to an androgen receptor defect. However, most children with these conditions have varying degrees of incomplete labioscrotal fusion, resulting in hypospadias and genital ambiguity.

Lastly, genetic syndromes in which micropenis may be a feature include Prader-Willi, Klinefelter, and Noonan syndromes, among others (see Causes).

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 because 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, 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

History

• Neonatal hypoglycemia, often in the first 24 hours of life, is associated with other pituitary hormone deficiencies, including panhypopituitarism, growth hormone deficiency, and adrenal insufficiency. Other features that may be associated with hypopituitarism during the neonatal period include breech delivery, optic nerve hypoplasia or aplasia, nystagmus, other midline defects, and cholestasis with prolonged direct hyperbilirubinemia.
• Poor growth or failure to thrive is also associated with other pituitary hormone deficiencies.
• An abnormal sense of smell (anosmia or hyposmia) suggests Kallmann syndrome (hypogonadotropic hypogonadism with abnormal olfaction).
• Other congenital anomalies may provide clues to a genetic syndrome.
• Family history of similarly affected children could suggest a familial form of hormonal deficiency (autosomal recessive), defect in steroidogenesis (autosomal recessive), or androgen insensitivity (X-linked). Family history of unexplained death in the first year of life could also suggest pituitary hormone deficiencies, adrenal insufficiency, or both.

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 location and size of the testes, 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.
  • One or both testes may be abnormally descended because testosterone also plays a role in testicular descent.

Causes

Most cases of micropenis are due to fetal testosterone deficiency. Testosterone deficiency may be caused by a defect anywhere along the hypothalamic-pituitary-gonadal axis or a defect in peripheral androgen action (5-alpha reductase deficiency or PAIS). Micropenis may also be caused by isolated growth hormone deficiency. Additionally, it can occur as a primary idiopathic structural anomaly or may be associated with a genetic syndrome. The most common cause of micropenis is abnormal hypothalamic or pituitary function that leads to hypogonadotropic hypogonadism. The next most common cause is a primary testicular disorder that leads to hypergonadotropic hypogonadism.

• Conditions associated with hypogonadotropic hypogonadism
  • Multiple pituitary hormone deficiency: This condition may be secondary to transcription factor mutations (eg, PROP-1, LHX3); however, 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 of Kallmann syndrome, which occurs in 1 per 10,000 males. The underlying abnormality is failure of migration of gonadotropin-releasing hormone (GnRH) and olfactory neurons from the olfactory placode to their proper locations in the hypothalamus and olfactory bulb, respectively. About half of males with Kallmann syndrome are born with a micropenis. The inheritance pattern is autosomal dominant (FGFR1/KAL-2 gene), autosomal recessive, or X-linked recessive (KAL-1 gene). Associated anomalies may 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. Abnormal or absent olfactory bulbs or sulci (folds) are seen on brain MRI in 90% of patients.
  • Septo-optic dysplasia (SOD): Major features of SOD 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 years. Mutations in the HESX1 gene (RPX) have been associated with SOD.
  • Idiopathic hypogonadotropic hypogonadism: The sense of smell is normal in this condition, differentiating it from Kallman syndrome.
• Conditions associated with decreased testosterone production and hypergonadotropic hypogonadism
  • Anorchia: In this condition of absent testes in an individual with a normal male karyotype, micropenis results when testicular degeneration occurs after approximately 12-14 weeks' gestation. The testicular degeneration is due to torsion or other vaso-occlusive event in utero.
  • LH-receptor defects: Autosomal recessive mutations are found in the LHCGR gene in this rare condition and cause Leydig cell hypoplasia in males. The genital phenotype varies from normal-appearing female to male with micropenis.
  • Defects in testosterone steroidogenesis: Incomplete forms of 17 beta-hydroxysteroid dehydrogenase deficiency type 3 can cause micropenis, but the genitalia are most often female in appearance or less often ambiguous. The enzyme 17-beta-hydroxysteroid dehydrogenase normally converts androstenedione to testosterone. In the deficiency state, the androstenedione-to-testosterone ratio is elevated (after hCG stimulation in the prepubertal state) and is expressed as a testosterone-to-androstenedione ratio of less than 0.8. These individuals undergo profound virilization at puberty.
• Deficiency of 5-alpha reductase: 5-alpha reductase peripherally converts testosterone to the more potent DHT, which is necessary for virilization of the male external genitalia. The genitalia in most children with this autosomal recessive condition are usually more ambiguous, with varying degrees of incomplete labioscrotal fusion and hypospadias. The hallmark biochemical abnormality is an elevated testosterone-to-DHT ratio (usually >30:1) after hCG stimulation if prepubertal. These individuals also undergo profound virilization at puberty.
• PAIS: PAIS is due to a defect in the androgen receptor. Isolated micropenis is not typically a manifestation of PAIS because the genitalia are usually more ambiguous. Gonadotropin and testosterone levels are elevated in this condition. Because the gene that codes for the androgen receptor is located on the X chromosome, PAIS is inherited in an X-linked manner.
• Growth hormone deficiency
• Genetic syndromes
  • Klinefelter syndrome (47,XXY) and other poly X syndromes: Features of this syndrome include hypergonadotropic hypogonadism, tall stature, gynecomastia, small firm testes, increased leg length, and increased risk for learning difficulties.
  • Prader-Willi syndrome: Features of this syndrome include hypogonadotropic hypogonadism, cryptorchidism, hypotonia in infancy, failure to thrive in infancy with later hypothalamic obesity, developmental delay, short stature, small hands and feet, emotional instability (perseveration, obesessions and compulsions), almond-shaped eyes, and triangular mouth. This syndrome occurs in 1:20,000 live births.
  • Bardet-Biedl syndrome: Features of this syndrome include hypogonadotropic hypogonadism, developmental delay, retinitis pigmentosa, obesity, short stature, polydactyly, renal dysplasia leading to end-stage renal disease, hepatic fibrosis, and hearing loss. Inheritance of this syndrome is in an autosomal recessive pattern.
  • Noonan syndrome: Features of this syndrome include short stature, webbed neck, hypertelorism, ptosis, low posterior hairline, low-set ears, pectus excavatum, cryptorchidism, valvular pulmonary stenosis, lymphedema, and bleeding abnormalities. Noonan syndrome is inherited in an autosomal dominant manner, although approximately half of all cases represent new mutations. 
  • CHARGE syndrome: The syndrome is defined by coloboma, heart disease, atresia choanae, retarded growth and development, genital anomalies and hypogonadism, and ear anomalies and deafness. Neuropathic bladder, hydronephrosis, vesicoureteral reflux, and ureteropelvic junction obstruction may also be observed. Given the renal and urinary tract abnormalities that can occur, bladder and renal ultrasonography and voiding cystourethrography (VCUG) are indicated in those suspected of having this syndrome.
  • Robinow syndrome: Features of the syndrome include hypergonadotropic hypogonadism, cryptorchidism, hypoplastic or absent genitalia, flat facial profile with prominent nares, hypertelorism, low-set ears, short forearms, rib abnormalities, and spinal abnormalities. The inheritance pattern of this syndrome is autosomal dominant.  
  • Rud syndrome: Features of this syndrome include hyposmia, developmental delay, congenital ichthyosis, epilepsy, and short stature.

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