Pediatric Annals

Feature Article 

A Phenotypic Female Adolescent with Primary Amenorrhea and Dysmorphic Features

Diboro Kanabolo, BS; Joseph Rodriguez, MD; Darrel Waggoner, MD; Susan Tucker, MD; Dianne Deplewski, MD; Benjamin Kaumeyer, MD; Ricardo R. Lastra, MD; Mohan Gundeti, MD

Abstract

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495–e500.]

Abstract

We report on a case of a 14-year-old phenotypic female with a microdeletion at 13q31.1-q31.3, dysmorphic facial and limb features, and neurologic symptoms. She presented to her pediatrician with concerns for delayed puberty, and laboratory analysis revealed hypergonadotropic hypogonadism. She was found to have an XY karyotype and streak gonads. Further genetic studies did not reveal another cause for her gonadal dysgenesis and, to our knowledge, an association with her known 13q-microdeletion has not yet been reported. Given the risk of malignancy with XY gonadal dysgenesis, the patient had surgery to remove the gonads and had no postoperative complications after a 6-month follow-up visit. We also discuss the role of the pediatrician in cases of delayed puberty, from initial diagnosis to definitive management. [Pediatr Ann. 2019;48(12):e495–e500.]

Gonadal dysgenesis is a type of incomplete or defective gonadal development that falls under the heading of disorders of sexual differentiation (DSD). Complete 46, XY gonadal dysgenesis (Swyer syndrome) is associated with a female phenotype due to a complete lack of gonadal steroid production during embryogenesis.1 Only approximately 50% of 46, XY DSD cases can be explained by known sex chromosome anomalies or autosomal mutations.2 Various phenotypic abnormalities have been reported with 13q-deletion syndrome, including developmental delays, cognitive defects, behavior disorders, movement disorders, clinodactyly and other limb defects, and genitourinary tract malformations including cryptorchidism and micropenis.3 However, to the best of our knowledge, there have been no reports of gonadal dysgenesis associated with deletions in this region. We describe a case of complete 46, XY gonadal dysgenesis in a patient with a 13q31.1-q31.3 microdeletion and no other known genetic cause for DSD. We further expand upon current opinions and guidelines regarding the approach to delayed puberty, including endocrinological, genetic, and surgical considerations for pediatric providers.

Illustrative Case

A phenotypic female age 14 years 9 months was brought to her pediatrician by her concerned mother for evaluation of primary amenorrhea and delayed puberty. On diagnostic evaluation, her gonadotropin levels (luteinizing hormone [LH], follicle stimulating hormone [FSH]) were elevated, and her bone age was delayed. Thyroid function tests were normal. She was referred to the Section of Endocrinology at our hospital, where a pubertal examination revealed Tanner 1 breasts and axillary hair, and early Tanner 2 pubic hair. Dysmorphic physical features included a shortened neck with a low posterior hairline, cubitus valgus (wide carrying angle) of both arms, borderline brachydactyly of 4th digits bilaterally, brachyclinodactyly of 5th digits bilaterally, widely spaced nipples, increased truncal adiposity, and pes planus. She had a normal sense of smell.

The patient's past medical history was significant for developmental delays noted by age 2 years, with delays in gross and fine motor skills, as well as cognitive, speech, and social skills. At age 10 years, the patient demonstrated seizure-like activity, described as heavy breathing and nonsuppressible shaking movements of the head, neck, upper body, and limbs lasting up to 90 seconds per episode, up to 50 times per day. Epilepsy was suspected, but her electroencephalogram findings over several measurements were inconsistent with this finding, so she was diagnosed with an unspecified movement disorder.

Endocrine laboratory evaluation revealed elevated gonadotropins, as well as low estradiol, normal prolactin, and normal markers of growth hormone adequacy (insulin-like growth factor 1 and insulin-like growth factor-binding protein 3). Routine chromosome analysis revealed a 46, XY karyotype. Subsequent testosterone and dihydrotestosterone levels were found to be low. Microarray testing demonstrated evidence of a heterozygous autosomal microdeletion at 13q31.1-q31.3. Because this microdeletion includes a gene that has been found to correlate with movement disorders (SLITRK1, Tourette syndrome), and neighboring genes that have been reported to be associated with developmental delays, intellectual disability, and limb defects such as clinodactyly and brachydactyly (eg, MIR17HG, Feingold syndrome type 2), it was concluded at the time that her microdeletion was the cause of her neurologic phenotype. A 46, XY DSD panel (Table 1) was ordered but returned negative for known associated mutations. Pelvic ultrasound and review of a previous abdominal computed tomography scan were equivocal, initially concerning for Müllerian agenesis. She was then referred to urology for diagnostic laparoscopy and potential removal of nonfunctional gonadal tissue due to increased risk of malignancy.

Select Entries from the 72-Gene 46, XY DSD Panel at The University of Chicago

Table 1.

Select Entries from the 72-Gene 46, XY DSD Panel at The University of Chicago

Laparoscopy revealed Müllerian structures, including a uterus, with streak gonads thought to be ovarian in nature. Genetic analysis on this tissue also revealed a 46, XY genotype, effectively ruling out germline mosaicism. Pathologic examination of the streak gonads revealed small foci of estrogen receptor and WT-1–positive ovarian-type stroma without associated follicles (Figure 1). The decision was made to remove the gonads due to the risk of malignancy. Postoperatively, the patient has been managed on a feminizing protocol with estrogen replacement therapy. After 6 months of treatment, she has had no complications of surgery or medical management.

(A and B) Hematoxylin and eosin demonstrating a small focus of ovarian-type stroma within the right streak gonad without associated follicles. Immunohistochemistry for (C) estrogen receptor and (D) WT-1 demonstrate positive nuclear staining of the ovarian-type stroma.

Figure 1.

(A and B) Hematoxylin and eosin demonstrating a small focus of ovarian-type stroma within the right streak gonad without associated follicles. Immunohistochemistry for (C) estrogen receptor and (D) WT-1 demonstrate positive nuclear staining of the ovarian-type stroma.

Discussion

Approach to a Dysmorphic Adolescent with Delayed Puberty

Delayed puberty is defined as the absence of testicular enlargement in boys by age 14 years, or the absence of breast development in girls by age 13 years, or at an age that is 2 to 2.5 standard deviations later than the population mean.4

The most common cause of delayed puberty is constitutional delay of growth and maturation. Other less common causes of delayed puberty include primary or secondary hypogonadism, both of which are characterized by low levels of gonadal hormones (testosterone in boys, estrogen in girls). Serum LH and FSH levels are elevated in primary hypogonadism (defect in the gonad), and low in secondary hypogonadism.5 Secondary hypogonadism can occur due to low levels of serum LH and/or FSH secretion or low levels of gonadotropin-releasing hormone (GnRH), as a result of chronic illness, hypothyroidism, and pituitary or hypothalamic neoplasm.

The initial evaluation of delayed puberty should include a thorough history and physical examination. The clinician should ask questions that assess growth pattern, height velocity, nutrition, exercise, underlying disorders, congenital or neurologic symptoms, family pubertal history, and hyposmia/anosmia. Physical examination should include a thorough pubertal examination, assessment of body mass index, anthropometrics (such as arm span), and evaluation for any dysmorphic features. The patient and guardian(s) can often miss initial signs of sexual development. These early signs include breast buds with glandular tissue for girls or testicular volume at or above 3 mL for boys.4

After conducting a complete history and physical examination, further studies include a bone age and biochemical analysis as indicated. Depending on availability of a laboratory capable of performing sensitive pediatric hormonal assays and the clinician's level of comfort in the diagnosis of delayed puberty, the pediatrician may either start the biochemical analysis or refer to pediatric endocrinology for consultation. Initial endocrine testing includes early morning LH, FSH, and serum testosterone/estradiol testing in a laboratory that performs sensitive pediatric hormonal assays. Other tests include prolactin, thyrotropin, and free thyroxine. Additional testing to consider after consultation with a pediatric endocrinologist includes a pelvic ultrasound or chromosome analysis. Other tests that may be performed in consultation with a pediatric endocrinologist include GnRH and/or human chorionic gonadotropin stimulation testing, and/or brain magnetic resonance imaging if the patient presents with neurologic symptoms.4 Treatment will depend on the cause of the delayed puberty.

Genotype Clarification

Male patients with primary hypogonadism present with signs of altered androgen activity, such as delayed puberty, cryptorchidism, and gynecomastia. Female patients with primary hypogonadism present with delayed puberty and primary amenorrhea. In either case, karyotype and comparative genomic hybridization arrays should be considered to assess for syndromic causes of gonadal dysgenesis and chromosomal abnormalities.6

13q-deletion syndrome is associated with a diverse list of phenotypic abnormalities. Review of a case series describing eight patients with 13q31-32 deletions showed an 80% to 100% incidence of microcephaly, intellectual disability, genital malformations, and hand anomalies.7 The case we present here, of a 46, XY phenotypic female with disordered gonadal development with concurrent autosomal isolated genetic microdeletion, is uniquely important because it has been documented that in cases with disorders of gonadal development, small deletions or duplications that can likely be causative may be found in 25% of cases where other organ systems are affected (as opposed to only 6% in partial DSD cases with only testicular development).8 The patient described here showed heterogeneous signs of dysgenesis, which included delayed puberty, dysmorphic limb features, and neurologic symptoms. Gonadal dysgenesis associated with 13q-deletion has not previously been reported.

Surgical Considerations

Delayed puberty in females may result from multiple genetic causes (Table 2). A female with a Y chromosome may be at higher risk of gonadoblastoma, and in many situations gonadectomy is advised. Although no universally accepted guidelines exist as to the timing of gonadectomy in female patients with a 46, XY DSD, it is recognized that tumor risk increases with age and is modified by the specific subtype of DSD. For example, for 46, XY patients with structurally normal gonads, as in androgen insensitivity syndrome (AIS), tumor risk ranges from 5.5% to 25%, compared to 25% to 70% in gonadal dysgenesis.9–12 In patients with dysgenetic gonads, the risk of malignancy has been reported to increase to 50% to 70% by the 3rd decade of life, and to 80% by the 4th decade of life. Consequently, management for patients with 46, XY gonadal dysgenesis should include gonadectomy as soon as possible after a diagnosis of XY gonadal dysgenesis. Provided thorough assessment has shown no evidence of active malignancy in patients with AIS in particular, the reportedly lower risk described above has prompted some experts to recommend postponing prophylactic gonadectomy until secondary sex characteristics have developed.13 In some cases of 46, XY DSD, simultaneous removal of adnexal structures (adnexectomy) is warranted, particularly when the gonads are attenuated, elongated, or closely approximate the fallopian tube.9 After gonadectomy, long-term, low-dose hormone replacement therapy is generally recommended.10

Classification of Delayed Pubertal Signs in a Phenotypic Female

Table 2.

Classification of Delayed Pubertal Signs in a Phenotypic Female

A 2016 review conducted by Calvo et al.14 demonstrated that laparoscopy has gained wide acceptance over traditional laparotomy for the surgical diagnosis and treatment of 46, XY DSD in the pediatric population. This may be attributed to its favorable cosmetic outcomes and minimally invasive nature. The combination of these factors has been shown to reduce psychological trauma in children undergoing surgery.15 In all literature related to 46, XY DSD that we reviewed in the preceding 10 years, 100% of procedures were successfully conducted with laparoscopy, without conversion to open surgery or increase in intraoperative complications. A breakdown of reported postoperative complications include a 2% incidence of both umbilical port infection and pelvic abscess, both treated successfully with antibiotics.14 Regarding the decision to preserve Müllerian structures, routine resection is generally recommended by the European Society for Pediatric Urology and the Societies for Pediatric Urology in 46, XY patients with persistent Müllerian remnants in the setting of urological symptoms, such as infection and dysuria, and unwanted gynecologic symptoms such as menses.16

Conclusion

We described a phenotypic female with delayed puberty who was found to have complete XY gonadal dysgenesis with persistent Müllerian structures. Genetic testing was negative for known causes of 46, XY DSD, but the patient did have a coincident microdeletion at 13q31.1-q31.3. We cannot conclude definitively that the existing microdeletion was causative of this patient's DSD. What is apparent is that the gonadal dysgenesis happened early enough in embryogenesis that secretion of anti-Müllerian hormone, if present at all, was insufficient to avoid the development of Müllerian structures. There is also no evidence of testosterone secretion at any point in development or thereafter. Because the genetic cause of approximately 50% of cases of 46, XY DSD remains unknown, intensive research must continue to add to the understanding of how a growing list of genes regulate development of the gonads. The prevention of gonadoblastoma in patients with XY-gonadal dysgenesis may be accomplished with exhaustive assessment for evidence of active malignancy, followed by scrupulous dissection and careful retrieval of gonads with adherent adnexa as necessary.

References

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Select Entries from the 72-Gene 46, XY DSD Panel at The University of Chicago

Gene Location Function
AMH 19p13.3 Results in development of male internal and external genitalia, and regression of the Müllerian structures (fallopian tubes, uterus, vagina)
AMHR2 12q13.13 Receptor for anti-Müllerian hormone
AR Xq12 Steroid hormone activated transcription factor. After binding its steroid hormone (ie, testosterone, androstenedione), it translocates to the nucleus, where it then dimerizes and stimulates transcription of androgen-responsive genes
AKR1C2 10p15.1 Involved in regulation of fetal testosterone synthesis by catalyzing conversion of aldehydes and ketones to corresponding alcohols
ARX Xp21.3 Involved in central nervous system development, plays central role in neuronal migration. Expansion of the polyalanine tract in the gene and other mutations associated with X-linked cognitive disability
ATRX Xq21.1 Transcription factor involved in gene regulation and chromosomal segregation, diverse patterns of gene expression in developmental processes
B3GALTL 13q12.3 Encodes beta-1,3-glucosyltransferase, type II membrane protein. Defect or mutation affects the eye chamber, limbs, facial features, and gross stature
CYB5A 18q22.3 Cytochrome B5 is a redox partner to 17,20-lyase
CYP11A1 15q24.1 Catalyzes many reactions involved in the synthesis of cholesterol, steroids, and other lipids, catalyzes conversion of cholesterol to pregnenolone
CYP17A1 10q24.32 Has both 17-alpha hydroxylase and 17, 20 lyase activities and is a key enzyme in producing progestins, mineralocorticoids, androgens, and estrogens
DHCR7 11q13.4 Transmembrane protein localizes to endoplasmic reticulum membrane and nuclear outer membrane; syndrome that is metabolically characterized by reduced serum cholesterol and elevated serum 7-dehydrocholesterol levels
DHH 12q13.12 Encodes signaling molecules that play an important role in regulating morphogenesis
DYNC2H1 11q22.3 Large cytoplasmic dynein involved in retrograde transport in the cilium, a process required for ciliary/flagellar assembly
GATA4 8p23.1 Zinc-finger transcription factor thought to regulate genes involved in embryogenesis; necessary for normal testicular development
HCCS Xp22.2 Protein encoded by this gene is an enzyme that covalently links a heme group to the apoprotein of cytochrome c
HSD17B3 9q22.32 Isoform of 17 beta-hydroxysteroid dehydrogenase expressed predominantly in the testis and catalyzes the conversion of androstenedione to testosterone
LHCGR 2p16.3 Luteinizing hormone and choriogonadotropin receptor mutations associated with disorders of male secondary sex characteristic developments
MAMLD1 Xq28 Functions as a transcriptional coactivator; associated with X-linked hypospadias
MAP3K1 5q11.2 Serine/threonine kinase and is part of multiple signal transduction cascades; associated with several published cases of 46, XY disorders of sexual differentiation
NR5A1 9q33.3 Transcriptional activator involved in sex determination. Binds DNA. Defects are a cause of XY sex reversal with or without adrenal failure and adrenocortical insufficiency
OPHN1 Xq12 Rho-GTPase activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction
SOX9 17q24.3 Acts during chondrocyte differentiation and, with NR5A1, regulates transcription factor 1; regulates transcription of anti-Müllerian hormone
SRD5A2 2p23.1 Encoded protein active at acidic pH, sensitive to the 4-azasteroid inhibitor finasteride. Deficiencies in this gene can result in genital anomalies such as pseudovaginal perineoscrotal hypospadias
SRY Yp11.2 Testis-determining-factor, initiates males sex determination
WT1 11p13 Has an essential role in the normal development of the urogenital system, activation of SRY is only observed with co-expression of WT1
ZFPM2 8q23.1 Zinc finger protein, modulates expression of GATA-target genes

Classification of Delayed Pubertal Signs in a Phenotypic Female

Syndrome Genotype Physical Examination Laboratory Results
Turner syndrome 45, XO Variable breast development depending on ovarian function Normal uterus and vagina Widely spaced nipples Low posterior hairline Short stature Short 4th and 5th metacarpals and metatarsals High LH, FSH Low estradiol Testosterone in normal female range
Müllerian agenesis (Mayer-Rokitansky-Kuster-Hauser syndrome) 46, XX Secondary sexual characteristics present Hypoplasia of the upper vagina Complete or partial absence of cervix and uterus Normal LH, FSH, estradiol Testosterone in normal female range
Kallmann syndrome (hypogonadotropic hypogonadism) 46, XX Anosmia may be present Arm span exceeds height Secondary sexual characteristics absent Low LH, FSH, estradiol, and testosterone
Androgen insensitivity syndrome 46, XY Complete androgen insensitivity syndrome   Breast development present   Phenotypically female external genitalia   Little or no axillary or pubic hair   Short vagina, absent uterus   Testes present in the abdomen or inguinal canals Partial androgen insensitivity syndrome   Breast development present   Variable ambiguous genitalia   Inguinal testes   Sparse pubic hair Normal or high LH Normal FSH Low estradiol High testosterone, normal testosterone to DHT ratio
Swyer syndrome 46, XY 46, XY gonadal dysgenesis is associated with a female phenotype due to a complete lack of gonadal steroid production during embryogenesis High LH High FSH Low estradiol Low testosterone
Authors

Diboro Kanabolo, BS, is a Medical Student, Pritzker School of Medicine. Joseph Rodriguez, MD, is a Resident Physician, Department of Surgery, Section of Urology. Darrel Waggoner, MD, is a Professor, Department of Human Genetics and Pediatrics. Susan Tucker, MD, is a Fellow, Department of Pediatrics, Section of Endocrinology. Dianne Deplewski, MD, is an Associate Professor, Department of Pediatrics, Section of Endocrinology. Benjamin Kaumeyer, MD, is Resident Physician, Department of Pathology. Ricardo R. Lastra, MD, is an Assistant Professor, Department of Pathology. Mohan Gundeti, MD, is a Professor, Department of Surgery, Section of Urology. All authors are affiliated with The University of Chicago Medicine.

Address correspondence to Mohan Gundeti, MD, Department of Surgery, Section of Urology, The University of Chicago Medicine, 5841 South Maryland Avenue, MC6038, Chicago, IL 60637; email: mgundeti@surgery.bsd.uchicago.edu.

Disclosure: Mohan Gundeti is the Course Director for Intuitive Surgical. The remaining authors have no relevant financial relationships to disclose.

10.3928/19382359-20191118-02

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