9 year-old Boy with Precocious Puberty - UChicago...

9 year9 year--old Boy with Precocious old Boy with Precocious PubertyPuberty

Katie O’Sullivan, M.D.Fellow, Med/Peds EndocrinologyUniversity of ChicagoThursday, September 12th, 2013

Chief ComplaintChief Complaint

9 year and 2 month-old boy who presents with pubertal changes since 8 years 0 months of age

This is a second opinion.

History of Present IllnessHistory of Present Illness

8 yrs: Patient developed pubic hair

8 yrs 6 mos: Parents noted penile enlargement

8 yrs 10 mos: Deepening of voice

is noted

-> Pediatrician Visit:◦

Physical Exam:

No acne, facial hair, axillary hair or body odor

Tanner 3 pubic hair

Accelerated linear growth

More HistoryMore History……

Birth History:◦

Mother received routine prenatal care

◦

Uncomplicated pregnancy and delivery

◦

Full-term

◦

Birth Weight 8 lbs, 4 oz (AGA)

Past Medical/Surgical History:

None

Allergies:

None

Immunizations:

Up-To-Date

Developmental History:◦

No delayed milestones

Medications:

None

◦

No herbs/supplements

◦

No exogenous steroid exposure

◦

No lavender/tea-tree oil

Social History:◦

Entering 4th grade this fall, good student

◦

Hobbies: Excels in gymnastics and karate

◦

Lives with Mother, Father, brother (10y) and sister (2y)

◦

Mother is an obstetrics nurse, Father is a paramedic

Family History:◦

No family history of precocious puberty.

Mother with menarche at 12 years old.

Father started shaving after high school.

◦

Great-great grandparents with DM. Grandparents with CAD.

Review of SystemsReview of Systems

Constitutional:

Negative for fever, diaphoresis. +increased appetite, +weight gain, +fatigue.

HENT:

Negative for congestion, rhinorrhea, sore throat, neck swelling or difficulty swallowing. +deepening of voice.

Eyes:

Negative for visual disturbance.

Respiratory:

Negative for cough or shortness of breath.

Cardiovascular:

Negative for palpitations or chest pain.

Gastrointestinal:

Negative for abdominal pain, nausea, vomiting, diarrhea. +intermittent constipation.

Review of Systems ContinuedReview of Systems Continued

Genitourinary:

Negative for urgency, frequency and enuresis. +enlarged phallus. +pubic hair.

Musculoskeletal:

Negative for arthralgias, edema.

Skin:

Negative for acne, rash. +dry skin.

Neurological:

Negative for headaches. +intermittent light-headedness with gymnastics.

Psychiatric/Behavioral:

Negative for behavioral problems. +some anxiety, +nail-biter

Physical ExamPhysical Exam

Vitals:◦

T 35.8C, P 72, BP 85/50◦

Weight: 35.7 kg (85.1%)◦

Length: 137.5 cm (67.5%)◦

BMI 18.9 kg/m2 (85.6%)

Growth Chart: Length for AgeGrowth Chart: Length for Age

Height Age – 10 yo

Growth Chart: Weight for AgeGrowth Chart: Weight for Age

Growth VelocityGrowth Velocity

Constitutional:

Appears well-developed and well-nourished. Active. No distress.

Head/Face:

No dysmorphic features. No facial hair. No acne.

Mouth/Throat:

Mucous membranes are moist. Dentition is normal. Oropharynx is clear.

Eyes:

Conjunctivae and EOM are normal. Pupils are equal, round, and reactive to light.

Neck:

Neck supple. No adenopathy. No thyromegaly.

Cardiovascular:

Normal rate and regular rhythm. Pulses are strong. No murmur heard.

Pulmonary/Chest:

Effort normal. There is normal air entry. No wheezes. Minimal breast tissue. No provoked discharge from nipples.

Axilla:

Tanner 2 axillary hair.

Abdominal:

Soft, no distension. No hepatosplenomegaly. No masses. No tenderness. Normal bowel sounds,

Genitourinary:

Tanner 3 pubic hair.

circumcised adult-appearing phallus, pigmented scrotum, testes descended bilaterally, left 4 cm and right 4.5 cm in long diameter (Tanner 4 genitalia).

No testicular masses.

Musculoskeletal:

Normal range of motion. There is no edema and no tenderness.

Neurological:

Exhibits normal muscle tone. No motor weakness. 2+ Patellar DTRs. No tremor on outstretched hands. Balance and gait in tact. Coordination in tact.

Skin:

Skin is warm. No acanthosis nigricans. +eczematous skin. +hypo-pigmented patches on face.

Initial Assessment and WorkInitial Assessment and Work--UpUp

Precocious PubertyPrecocious Puberty

Definition:

Premature beginning of sexual

characteristics before 9 years in boys and before 8 years in girls1

(age still debated)2

Prevalence3:◦

Girls: 0.2%◦

Boys: <0.05%

1. Rosenfield and Ghai. “Disorders of Pubertal Development…” 1994.2. Walvoord EC. Journal of Adolescent Health. 2010.

3. Teilmann G et al. Pediatrics. 2005.

Differential Diagnosis of Precocious Differential Diagnosis of Precocious PubertyPuberty

Central Precocious Puberty◦

premature reactivation of the GnRH pulse generation and the pituitary-gonadotropin axis

= GnRH-dependent

GnRH-Independent Puberty◦

Increase in sex steroids outside of the HPG axis◦

Isosexual vs. contrasexual

Central Precocious PubertyCentral Precocious Puberty

Idiopathic

Neurogenic Etiology: CNS Disorders

Chronic exposure to sex steroids

Kisspeptin/Kisspeptin receptor gain-of-

function mutation

Lifshitz. Pediatric Endocrinology. 2007

Bone AgeBone Age

Chronologic Age: 9 years and 1 months◦

> Bone Age ~ 12 years and 6 months old◦

> Beyond 2 standard deviations from mean

for a patient with chronologic age 9 years

Laboratory Studies at 9 yrs 0 mosLaboratory Studies at 9 yrs 0 mosValue Range

LH 4.9 IU/LT II: 0.0 – 3.6; T III: 0.2 - 6.4

Tanner IV-V: 0.9 - 8.3

FSH 6.2 IU/LT II: 0.5 - 4.8; T III: 1.0 – 6.4

Tanner IV-V: 1.0 - 8.1

Total Testosterone 640 ng/dLTanner IV: 165 – 854 ng/dLTanner V: 194 – 783 mgdL

SHBG 52 nmol/L 28 – 190 nmol/L

Free Testosterone 96 pg/mLTanner IV: 35-169 ng/dLTanner V: 41–239 ng/dL

DHEA 0.921 ng/mLT II: 0.37-3.66 ng/mL; T III: 0.75-5.24 ng/mL; T IV-V:

1.22-6.73 ng/mL

17-OH Progesterone 63 ng/dLMale 7-9yr: <63 ng/dL

Male 10-12yr: <79 ng/dL Male 13-15yr: 9-140 ng/dL

What Study Would you Like Next?What Study Would you Like Next?

MRI Brain: Sagittal ImagingMRI Brain: Sagittal Imaging

MRI Brain: T2 Axial ImagingMRI Brain: T2 Axial Imaging

12.5 x 7.8 x 10.6 cm

SummarySummary9 yr 2 mo boy with central precocious puberty

due to suprasellar arachnoid cyst.

Evaluated by ophthalmology◦

Has normal vision, including peripheral fields, and normal optic discs

Evaluated by 3 neurosurgeons◦

Consensus: No surgical intervention at this time

Pituitary hormones were evaluated and determined to be normal

Initiated Lupron

Clinical QuestionsClinical Questions1.

What are the most common causes of central precocious puberty in boys?

2.

What is the mechanism of precocious puberty in patients with large arachnoid cysts?

3.

What is the appropriate treatment of patients with large arachnoid cysts presenting with precocious puberty?

Distribution of Diagnoses of Patients with Distribution of Diagnoses of Patients with Central Precocious PubertyCentral Precocious Puberty

Pescovitz et al. Journal of Pediatrics. 1986.

Arachnoid CystArachnoid Cyst

Abnormality of the arachnoid membrane caused by accumulation of CSF

Typically congenital, but not always

Rare, account for only 1% of intracranial mass lesions

Sellar/Suprasellar Cysts◦

9-15% of all Arachnoid Cysts

◦

Wide range of endocrine dysfunction

◦

33% present with CPP

Chung et al. RadioGraphics. 2012. Huang et al. Pediatric Neurology. 2004. Mohn et al. Pediatric Neurosurgery. 1999.http://weillcornellbrainandspine.org/condition/arachnoid-cysts-intracranial-cysts

Exact Mechanism of CPP is UnknownExact Mechanism of CPP is Unknown

Endocrinopathies correlate with proximity of the cyst to the H-P area

Proposed Mechanisms:

1.

Disruption of the neural pathway that normally inhibits the GnRH pulse generator

Direct physical compression of portions of H-P axis

Pressure effects on the pressure-sensitive hypothalamus

2.

Direct release of hormones into the pituitary portal circulation

Adan et al. European Journal of Pediatrics. 2000Chung et al. RadioGraphics. 2012.

Management: Medical vs. SurgicalManagement: Medical vs. Surgical

GnRH Agonist

successfully halts pubertal development in this patient population

Surgical Management

is controversial for arachnoid cysts, in general◦

Complication Rate 15-58%◦

Recurrence Rate 15-30%

Outcomes after surgical management for CPP is mixed:◦

At least 6 Case Reports suggest cessation of puberty after surgery◦

10-40% endocrine disorders persist despite surgery

Boutarbouch et al. Clinical Neurology and Neurosurgery. 2008.Ozek MO and Urgun K. World Neurosurgery. 2013.

Works CitedWorks Cited

1.

Boutarbouch et al. “Management of intracranial arachnoid cysts: institutional experience with intial 32 cases and review of the literature.”

Clinical Neurology and Neurosurgery. 2008. 110(1):1-7.2.

Chung et al. “From the Radiologic Pathology Archives: Precocious Puberty: Radiologic-Pathologic Correlation.”

RadioGraphics. 2012. 32: 2071-2099.

3.

Gangemi et al. “Suprasellar arachnoid cysts: endoscopy versus microsurgical cyst

excision and shunting.”

British Journal of Neurosurgery. 207; 21(3): 276-280.

4.

Guzel et al. “Suprasellar Arachnoid Cyst: A 20-year Follow-Up after Stereotactic Internal Drainage: Case Report and Review of the Literature.”

Turkish Neurosurgery. 2007. 17 (3):211-218.5.

Huang et al. “Arachnoid Cyst with Gn-RH-dependent sexual precocity and growth hormone deficiency.”

Pediatric Neurology. 2004. (30)2:143-145.6.

Lifshitz. “Puberty and its Disorders.”

Pediatric Endocrinology, 5th

Edition. Informa Healthcare INC. New York, NY. 2007, p. 273-303.

7.

Mohn et al. “The Endocrine Spectrum of Arachnoid Cysts in Childhood.”

Pediatric Neurosurgery. 1999. 31: 316-321.

8.

Ozek MO and Urgun K. “Neuroendoscopic Management of Suprasellar Arachnoid Cysts.”

World Neurosurgery. 2013. 79 (2S):S19.13-S19.e18.

9.

Pescovitz et al. “The NIH Experience with precocious puberty: Diagnostic subgroups

and response to short-term luteinizing hormone releasing hormone analogue therapy.”

1986. Journal of Pediatrics. 108(1): 47-54.

10.

Rosenfield and Ghai. “Disorders of Pubertal Development: Too Early, Too Much, Too Late, or Too Little.”

Adolescent Medicine: State of the Art Reviews. 1994. Hanley & Belfus, INC. Philadelphia, PA. 1994, p. 19-24.

11.

Teilmann G et al. “Prevalence and incidence of precocious pubertal development in Denmark: an epidemiologic study based on national registries.”

Pediatrics. 2005. 116:1323-1328.12.

Walvoord EC. “The Timing of Puberty: is it changing? Does it matter?”

2010. Journal of Adolescent Health. 47:433-439.

Case Report Case Report --

20072007

3 year-old female with precocious puberty

35 x 25 mm suprasellar arachnoid cyst

s/p cystoventriculography

Breast tissue disappeared in 1 year

Guzel et al. Turkish Neurosurgery. 2007.

Additional Laboratory StudiesAdditional Laboratory StudiesValue Range

Cortisol* 2.7 mcg/dL 3-23

Prolactin 10.8 ng/mL 0.7-15.8

IGF-1 212 ng/mLTanner I: 52 – 391

Tanner II, III: 39-648Tanner IV, V: 277-434

IGFBP-3 3690 ng/mL

Tanner I: 1878-6190Tanner II: 2112-6208Tanner III: 2372-6602

Tanner IV, V: 2336-6414

obtained at 5:30pm from ARUP Laboratories

Additional Laboratory StudiesAdditional Laboratory Studies

141 106 12

0.72284.789

6.6 4.1

0.2

1522

803Calcium – 8.8

Mohn et al. Pediatric Neurosurgery. 1999.

CNS lesions causing CPP and moreCNS lesions causing CPP and more……

Mohn et al. Pediatric Neurosurgery. 1999.

CNS DisordersCNS Disorders

Acquired:◦

Abscess/Encephalitis/Meningitis◦

Inflammation◦

Chemo/Radiation◦

Surgical/Trauma

Congenital anomalies:◦

Hypothalamic harmartoma◦

Arachnoid

cysts◦

Hydrocephalus◦

SOD◦

Suprasellar

cyst◦

Myelomeningocele◦

Tuberous Sclerosis

CNS Tumors:◦

Craniopharyngiomas◦

Astrocytomas◦

Pinealomas◦

Ependymomas◦

Gliomas

Optic-Pathway (NF-1)◦

LH-secreting adenoma