Microphallus

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 by 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 control of fetal LH. Penile growth after the first trimester depends on fetal gonadotropin 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.[11, 12]

After an initial surge of LH and testosterone at birth, lasting about 12 hours, gonadotropin (LH and follicle stimulating hormone [FSH]) and testosterone levels are low during the first few days of life. At about 1 week of age, gonadotropin and testosterone levels begin to rise to pubertal levels, peaking at age 1-3 months, and then decreasing to prepubertal levels by age 6 months.[13, 14] 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 increased testosterone production. Growth hormone also plays a role in penis growth as 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, a primary structural anomaly, or 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 (e.g. 17-beta hydroxysteroid dehydrogenase deficiency).[13] The genitalia of individuals with LH-receptor defects vary from normal female-appearing to male-appearing with micropenis. Individuals with 17-beta hydroxysteroid dehydrogenase deficiency most often have female-appearing genitalia and, less often, ambiguous genitalia.[15]

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.[15, 16]

Lastly, genetic syndromes in which micropenis may be a feature include Prader-Willi, Klinefelter, and Noonan syndromes, among others (see Causes).[15, 17]

Sex

By definition, microphallus is an exclusively male condition. However, distinguishing between a male with micropenis and bilateral 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.

Neonatal hypoglycemia 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, 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 hypogonadism or other hormone deficiency, defect in steroidogenesis (autosomal recessive), or androgen insensitivity (X-linked). Family history of unexplained death in the first year of life could suggest pituitary hormone deficiencies, adrenal insufficiency, or both.

The infant or child with micropenis should be thoroughly examined for dysmorphic features and other congenital anomalies.

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 after the first 6-12 months of life 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, position of the urethral opening, and location and size of the testes, is important. One or both testes may be abnormally descended because testosterone also plays a role in testicular descent.

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.[2]

An alternate, less traumatic method is to use the index finger of one hand as a gauge pressed against the symphysis. As 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.

A literature review by López-Soto et al indicated that while methodologic aspects in the diagnosis of micropenis, as performed using newborns’ stretched penile length, seem to be similar and consistent between studies, independent variables exist. Such variables appear to consist mainly of ethnic group and gestational age, with the investigators suggesting that in place of classic cutoff points, customized reference charts be created for use with each specific population.[18]

Micropenis most often results from 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. 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

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, among others), autosomal recessive, or X-linked recessive (KAL-1 gene). Associated anomalies may include cleft lip and palate, renal agenesis, sensorineural hearing loss, visual abnormalities, synkinesia (mirror image movements), cerebellar ataxia, agenesis of the corpus callosum, short metacarpals, or pes cavus. Abnormal or absent olfactory bulbs or sulci (folds) are seen on brain MRI in 90% of patients.[19, 20]

Isolated hypogonadotropic hypogonadism

Sense of smell is normal in this condition, differentiating it from Kallmann syndrome.[19]  An observational cohort study by Bonomi et al indicated that there is a greater tendency for a severe and complex phenotype to arise in Kallmann syndrome than in normosmic isolated hypogonadotropic hypogonadism.[21]

Multiple pituitary hormone deficiencies

Hypoglycemia may occur due to growth hormone and adrenocorticotrophic hormone (ACTH) deficiencies. Midline defects and cholestatic liver disease can be associated. Hypopituitarism 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.[22, 23]

Septo-optic dysplasia (SOD)

Major features of SOD include the triad of absent septum pellucidum, optic nerve hypoplasia, and hypopituitarism. Wandering nystagmus may be present. 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.[22, 23]

Conditions associated with decreased testosterone production and hypergonadotropic hypogonadism

Anorchia

In this condition, also known as vanishing testes or testicular regression syndrome, testes are absent in an individual with a normal male karyotype. Micropenis results when testicular degeneration occurs after 12-14 weeks' gestation. The testicular degeneration is likely due to torsion or other vaso-occlusive event in utero.[11, 12]

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.[17, 24]

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.[11, 25, 26]

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. Genetic testing for SRD5A2 gene mutations is commercially available.[16, 27, 28]

Partial androgen insensitivity syndrome

PAIS is caused by 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.[12]

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 in proportion to height, and increased risk for learning difficulties.[29]

Prader-Willi syndrome (PWS)

Hypogonadism is a feature of PWS and usually manifests in males as cryptorchidism and an underdeveloped scrotum. Some also have a micropenis. Characteristic features of PWS include hypotonia, weak suck, feeding difficulties and failure to thrive in infancy with later development of hypothalamic hyperphagia and often obesity. Motor and language developmental delay, short stature, small hands and feet, emotional instability (perseveration, obsessions and compulsions), almond-shaped eyes, and triangular mouth are additional features. PWS occurs in 1:20,000 live births. The underlying genetic abnormality is the lack of expression of genes on the Prader-Willi critical region, 15q11.2-13, of the paternally inherited chromosome 15, which may be due to deletion (70%), maternal uniparental disomy (25%), or a imprinting defect (5%).[30]

Bardet-Biedl syndrome

Features of this syndrome include hypogonadotropic hypogonadism, rod-cone dystrophy with progressive visual impairment, obesity, short stature, polydactyly, developmental delay, renal anomalies leading to end-stage renal disease, and hepatic fibrosis. Inheritance of this syndrome is in an autosomal recessive pattern and mutations in 14 genes have been implicated.[31]

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. Mutations in the PTPN11 gene are found in 50% and smaller percentages have mutations in KRAS, SOS1, and RAF1.[32]

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 occur. Given these potential renal and urinary tract abnormalities, bladder and renal ultrasonography and voiding cystourethrography (VCUG) are indicated in those suspected of having this syndrome. Sixty to seventy percent have a mutation in the CHD7 gene.[33, 34]

Other

More rare genetic syndromes associated with micropenis include Robinow syndrome, Rud syndrome, and IMAGe syndrome.[15]

A karyotype is recommended to confirm chromosomal sex. If PWS is suspected, methylation studies should be performed, and if positive, further genetic analysis for the specific genetic defect is indicated.

Gonadotropins (LH and FSH) reach pubertal levels in healthy male infants, peaking at age 1-3 months and declining by about age 6 months. Excessively high or low values during this "minipuberty" help to narrow the differential diagnoses.

Anti-Müllerian hormone (Müllerian inhibitory substance) and inhibin B are markers of Sertoli cell function and can be useful as indicators of the presence of testicular tissue in the setting of bilateral cryptorchidism.

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).

Given the possibility of panhypopituitarism, observe all infants with micropenis for hypoglycemia and evidence of other 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 hypoglycemia or suspected hypopituitarism, other pituitary hormone function should be evaluated. Evaluation of the thyroid axis should include measurement of total or free thyroxine (T4) as well as thyrotropin stimulating hormone (TSH). Growth hormone and cortisol levels may need to be measured after stimulation (eg, with glucagon for growth hormone and cortisol or ACTH for cortisol).

In situations of genital ambiguity, pelvic ultrasonography is often helpful. The presence of a uterus and ovaries strongly suggests a virilized female (46,XX) infant.

When hypopituitarism is suspected, an MRI scan of the head should be obtained to evaluate the hypothalamic and pituitary areas. In Kallmann syndrome, abnormalities of the olfactory system may be seen.

Testosterone therapy (testosterone enanthate or cypionate) 25 mg every month for 3 months has diagnostic and therapeutic implications. No appreciable increase in penis size (< 0.9 cm) with androgen therapy suggests androgen insensitivity.[13]

Testosterone therapy in the form of 3 monthly intramuscular (IM) injections 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.[3]  With appropriate pubertal and adult replacement, patients achieved normal adult penis size and reported sexual activity and appropriate gender identity.[3] Thus, evidence suggests that treatment with testosterone during infancy or childhood primes the penis for later growth during puberty.

Infants with other hormonal deficiencies (growth hormone deficiency, hypothyroidism, adrenal insufficiency) should receive appropriate hormonal replacements.

A study by Becker et al of three related 46,XY males with PAIS found mixed results from the treatment of micropenis with topical dihydrotestosterone (4-month course of daily gel application). In the prepubertal patient, stretched penile length (SPL) increased from 2.5 cm to 3.5 cm, while in the peripubertal patient, it increased from 3.5 cm to 5.7 cm. However, an adult patient who had already undergone 1 year of weekly, high-dose testosterone treatment demonstrated no additional increase in SPL following topical therapy.[36]

A study by Xu et al supported the efficacy of short-term, low-dose, percutaneous dihydrotestosterone administration in the treatment of children with micropenis. Average stretched penile lengths in the study increased from 1.68 cm before treatment to 2.2, 2.6, and 2.9 cm following 1, 3, and 6 months of therapy, respectively. In 14 out of 23 cases (61%), standard penile length range was achieved. However, despite a lack of significant side effects in the study, aside from elevated serum dihydrotestosterone levels, the investigators urged caution in the use of this treatment, since long-term studies and determination of ideal dosage are still needed.[37]

A study by Stoupa et al of six infants with micropenis—due to isolated congenital hypogonadotropic hypogonadism (CHH; 4 patients), panhypopituitarism (1 patient), or PAIS (1 patient)—indicated that early postnatal infusion of gonadotropins is a safe and effective therapy. Micropenis resolved in all but one patient, with the stretched penile length in the CHH patients increasing from an initial 13.8 mm to 42.6 mm and in the PAIS patient from an initial 13 mm to 38 mm.[38]

A literature review by Krishnan et al indicated that in males with hypospadias, preoperative testosterone therapy can increase penile length and circumference, providing adequate tissue in patients with microphallus for successful urethral reconstruction. Evidence suggested that in patients undergoing the repair operation, preoperative testosterone treatment leads to fewer complications and improved cosmesis. The investigators added, however, that no consensus exists as to whether the testosterone would better be administered topically or parenterally.[39]

A study of 10 patients by Papadimitriou et al indicated that in infants with congenital hypogonadotropic hypogonadism, daily subcutaneous injections of luteinizing hormone/follicle-stimulating hormone (LH/FSH) (75/150 IU) for 3 months can successfully treat micropenis and cryptorchidism, with the regimen producing a mimicking of male minipuberty. While the pretreatment levels of LH and FSH were undetectable, LH attained a high-normal posttreatment level of 4.45 IU/L, and FSH, a supranormal level of 83 IU/L. Median anti-Müllerian hormone, inhibin B, and testosterone levels increased to normal, and stretched penile length, with a pretreatment median of 2 cm, increased to 3.8 cm. By the end of the third month, all patients had descended testes.[40]

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.[9, 10]

Circumcision should be avoided, or at least delayed, until appropriate evaluation, gender assignment, and therapy are completed. If associated with penile growth, testosterone therapy may facilitate the circumcision (see Medical Care).

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.

Testosterone therapy has been shown to increase phallus size in infants with micropenis.[41]

Class Summary

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 to include increased erythropoietin, increased protein production, and increased retention of calcium. Testosterone is a schedule C-III controlled substance.

Testosterone cypionate or enanthate (Andro-LA, Delatest, Depo-Testosterone)

Testosterone cypionate or enanthate promotes and maintains secondary sex characteristics in males with androgen deficiency.

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. In these cases, testosterone is used to initiate puberty, with the dosage gradually increased to an adult replacement dose in a manner that mimics natural puberty.

In those with hypogonadotropic hypogonadism who desire fertility, hCG and recombinant FSH can be given to promote testosterone secretion and spermatogenesis at the appropriate time by a specialist in reproductive medicine.

Appropriate counseling should be provided.

In the newborn nursery, any infant with microphallus should be closely monitored for hypoglycemia. Hypoglycemia should prompt evaluation for other pituitary hormone deficiencies.

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.[3, 17]

Prognosis is much more guarded in children with androgen insensitivity, especially with significant genital ambiguity.

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 can be associated with 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 should be intimately involved in this decision, and counseling from a center with a multidisciplinary team skilled at gender reassignment should be pursued.

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, the parents should play a key role in the decision process.