Endocrine System

PART II

DISORDERS OF THE GONADS

NOONAN SYNDROME

• SHORT STATURE, webbing of the neck, pectus carinatum/excavatum, cubitus valgus, R sided congenital HD, characteristic facies.

• Hypertelorism, epicanthus, downward slanted palpebral fissures, ptosis, micrognathia, ear abnormalities

• Mean IQ 86 (53-127)• Verbal IQ> performance IQ

NOONAN SYNDROME

• PULMONARY VALVULAR STENOSIS, HYPERTROPHIC CM, ASD

• Hepatosplenomegaly, low clotting factors XI XII, ALL, CML• CRYPTORHIDISM, SMALL TESTES, hypogonadal or normal• Delayed puberty (2yrs), ADULT HEIGHT 2nd DECADE,

usually reaches the lowest limit of the normal population• PRENATAL DX: Normal karyotype, edema, hydrops and

short femur length• TREATMENT: HUMAN GH

KLINEFELTER SYNDROME

• 1/500 MALES: 47,XXY• ALL BOYS WITH MR and in children with PSYCHOSOCIAL,

LEARNING, or SCHOOL ADJUSTMENT problems• Tall, slim, underweight, long legs, body habitus can vary

markedly• Testes tend to be small for age, phallus tends to be smaller

than average, cryptorchidism or hypospadias may occur in a few patients; SPERMATOGENIC ARREST and SERTOLI CELL PREDOMINANCE

• GYNECOMASTIA (80%)• Height tends to be increased

12-yr-old boy with 48,XXXY/49,XXXXY mosaicism who has prognathism, epicanthal folds, scoliosis, small testes, severe mental retardation, clinodactyly, and radioulnar synostoses

KLINEFELTER SYNDROME

• Increased incidence of pulmonary disease, varicose veins, cancer of the breast

• Male breast cancer (7.5%), Mediastinal GCT, Leukemia, Lymphoma. Higher cancer risk (RR 2.7): 15-30y age group

KLINEFELTER SYNDROME

• Replacement therapy– Long-acting TESTOSTERONE preparation– 11-12 yrs of age– ENANTHATE ESTER 25-50mg IM q3-4w, 50mg increments q6-9mo until a maintenance

dose for adults achieved (200-250mg q3-4w)– TESTOSTERONE PATCHES/GEL

• Rapid increase in prostate volume and PSA levels

HYPOGONADOTROPIC HYPOGONADISM in the MALE

(SECONDARY HYPOGONADISM)• Deficiency of LH or FSH, or both• Primary defect: anterior pituitary/ hypothalamus – deficiency of GnRH• N testes, prepubertal • KALLMAN SYNDROME - +anosmia/hyposmia

– Xlinked mutation KAL gene – failure of the olfactory axons and GnRH-expressing neurons to migrate from their common origin in the olfactory placode to the brain

• TESTOSTERONE ENANTHATE 100mg IM qMo for 4-6mo increase in signs of secondary sexual characteristics, increase in growth velocity

• hCG 500-1000IU, SC or IM, 3x/wk growth of testes and spermatogenesis

• human menopausal gonadotrophin 37.5-150 IU, 3x/wk, may require 2yrs of tx

PSEUDOPRECOCITY resulting from Tumors of the testes

• Leydig Cell Tumors – REINKE CRYSTALLOIDS• Adrenal Rest Tumors– bilateral

• FRAGILE X SYNDROME– B Testicular enlargement MACROORCHIDISM, 40-

50mL

GYNECOMASTIA

• TRUE vs PSEUDOGYNECOMASTIA (adipose)• ESTROGEN-ANDROGEN IMBALANCE• Aromatase• Treatment: Reassurance– Medical: Anastrozole (Ar In) 1mg = placebo– Surgical: Removal ENDOSCOPICALLY ASSISTED

TRANSAXILLARY REMOVAL

HYPOFUNCTION OF THE OVARIESTURNER SYNDROME

• Sexual infantilism, webbed neck, cubitus valgus• Complete or partial absence of second X chr• BIRTH: edema of dorsum of hands & feet, loose skin

folds at the nape. LOW BW and DECREASED LENGTH• CHILDHOOD: webbing of the neck, low posterior

hairline, small mandible, prominent ears, epicanthal folds, high arched palate, broad chest, cubitus valgus, hyperconvex fingernails

• SHORT STATURE (US MAH: 143-144cm), MPH

Turner syndrome in a 15-yr-old girl exhibiting failure of sexual maturation, short stature, cubitus valgus, and a goiter. There is no webbing of the neck. Karyotyping revealed 45,X/46,XX chromosome complement

TURNER SYNDROME

• Isolated nonstenotic bicuspid aortic valves, aortic coarctation, AS, MVP

• Pelvic kidney, horseshoe kidney, double collecting system, complete absence of 1kidney, UPJ obstruction

• Autoimmune thyroid disease• IBD: Chron disease and UC• Sternal malformations• Recurrent Bilateral OM, SNH defects

TURNER SYNDROME

• Chromosomal Analysis• Ultrasonography• Plasma Gn: FSH• Thyroid antiPO Ab, T4, TSH• Treatment: RECOMBINANT hGH– Replacement E2 Therapy• Conjugated estrogen 0.3-0.625mg• Micronized E2 0.5mg daily x3-6mo

CONGENITAL ADRENAL HYPERPLASIA

• Ambiguous genitalia• 21-OH deficiency

Cholesterol

Pregnelonone Progesterone DOC Corticosterone 180H Corticosterone

Aldosterone

170H Pregnenolone

170H Progesterone 11 Deoxycortisol Cortisol

DHEA Androstenedione Testosterone Estradiol

P450sccP450c213(B)HSD P450c11 P450c11 P450c11

P450c17 P450c17

3(B)HSD

P450c21 P450c113(B)HSD

17(B)HSD P450aro

CONGENITAL ADRENAL HYPERPLASIA

• SALT WASTING • Progressive weight loss, anorexia, vomiting,

dehydration, weakness, hypOtension, hypOglycemia, hypOnatremia, hypErkalemia

• 2 Wks of age• GLUCOCORTICOID 15-20mg/m²/24 • FLUDROCORTISONE 0.1-0.3mg/day

WAGRWILMS TUMOR, ANIRIDIA,

GENITOURINARY MALFORMATIONS, RETARDATION

• Deletion c11p13 (aniridia gene PAX6, WT1)• 46,XY males have genital abnormalities• Cryptorchidism• Virilization

ANDROGEN INSENSITIVITY SYNDROMES

• 46,XY• Phenotypic females (COMPLETE AIS) to males with various

ambiguous genitals and undervirilization (PARTIAL)• Complete: female at birth, F external genitals, blind

vaginal pouch, absent uterus, FT remnants, intraabdominal testes. – Puberty: N breast development, female habitus, menstruation

does not occur, absent sexual hair– Adult height same with N males– N testosterone and DHT levels– Testicular removal (seminoma); ESTROGEN

DIABETES MELLITUS

Type 1 DM

• IDDM, juvenile diabetes• Low/ absent levels of endogenously produced insulin

and dependence on exogenous insulin to prevent DKA• 4 stages:

1. Preclinical β-cell autoimmunity with progressive defect of insulin secretion

2. Onset of clinical diabetes3. Transient remission “honeymoon period”4. Established diabetes associated with acute and chronic

complications and decreased life expectancy

Type 1 DM

• Onset: 7-15 y/o• Autoimmune destruction

T2 DM

• Usually obese but are not insulin dependent• NIDDM, adult-onset DM, MODY• More insidious• Excessive weight gain, fatigue• ACANTHOSIS NIGRICANS

T2 DM CRITERIA• OVERWEIGHT (BMI>85th % A,S; WFH>85th %; Wt>120% of ideal for ht)

PLUS:

Any 2 of the ff:• FH T2DM in 1st or 2nd degree relative• Race/Ethnicity• Signs of Insulin Resistance or conditions associated with insulin resistance (AN,

hypertension, dyslipidemia, PCOS)• Age of initiation: age 10yrs or at onset of puberty if puberty occurs at a younger

age• Frequency: every 2 yrs• Test: FPG preferred

TreatmentInsulin therapy

prepubertal 0.7 U/Kg/dmidpuberty 1.0 U/Kg/dend 1.2 U/Kg/d

Nutritional EducationImproved Exercise Level

Diagnosis• “inappropriate polyuria in any child with dehydration,

poor weight gain, or the flu”• RBS>200mg/dL (11.1

Long Term Complications

1. Microvascular– Retinopathy– Nephropathy

2. Macrovascular– CAD– CVD– PVD

3. Neuropathies– Peripheral– Autonomic

TRANSIENT DM of the NEWBORN

• 1st week of life• SGA• Hyperglycemia, pronounced glycosuria• Severe dehydration, metabolic acidosis but

with only minimal or no ketonemia/ketonuria• 1-2U/Kg/24h intermediate actingINSULIN

insulin

DEFECTS OF CARBOHYDRATE METABOLISM

Glycogen Storage Disease type I (GLUCOSE-6-PHOSPHATASE/ TRANSLOCASE/ VON GIERKE DISEASE)

• Neonatal period: Hypoglycemia and lactic acidosis• 3-4mo: hepatomegaly, hypoglycemic seizures• Doll like faces with fat cheeks, relatively thin

extremities, short stature, protruberant abdomen, enlarged kidneys

• Hypoglycemia, Lactic Acidosis, Hyperuricemia, Hyperlipidemia

• NORMAL transaminases• Tx: NGT infusion of glucose/ oral uncooked cornstarch

Glycogen Storage Disease type III (DEBRANCHER DEFICIENCY)

• Deficiency of glycogen debranching enzyme activity• Hepatomegaly, hypoglycemia, short stature, variable

skeletal myopathy, variable CM• BOTH LIVER AND MUSCLE INVOLVEMENT (IIIa)• LIVER (IIIb)• ELEVATION OF LIVER TRANSAMINASES• HEPATOCELLULAR CARCINOMA• Tx: Frequent meals with high in CHO, high CHON diet

GSDIIIbGrowth and development in a patient with type IIIb glycogen storage disease. The patient has debrancher deficiency in liver but normal activity in muscle. As a child, he had hepatomegaly, hypoglycemia, and growth retardation. After puberty, he no longer had hepatomegaly or hypoglycemia, and his final adult height is normal.He had no muscle weakness or atrophy; this is in contrast to type IIIa patients, in whom a progressive myopathy is seen in adulthood.

Glycogen Storage Disease type IV(Branching Enzyme Deficiency/ Amylopectinosis/ Andersen Disease)

• Accumulation of an abnormal glycogen with poor solubility

• Fewer branch points• Progressive cirrhosis of the liver• 1st 18 mo: hepatosplenomegaly, FTT• Cirrhosis progresses to portal HPN, ascites,

esophageal varices, liver failure• Death by 5 y/o• NO SPECIFIC TX, poor prognosis

Glycogen Storage Disease type II (LYSOSOMAL ACID a1-4-GLUCOSIDASE DEFICIENCY/ POMPE DISEASE)

• Lysosomal glycogen accumulation in multiple tissues, cardiac, skeleletal, SMOOTH MUSCLE CELLS

• Myopathy, “floppy infant appearance”, feeding difficulties, macroglossia, hepatomegaly, hypertrophic CM

• Slowly progressive proximal muscle weakness with truncal involvement

• LE> UE• Lab: elevated CK, AST, LDH; muscle def a-glucosidase• Tx: Supportive/ Palliative

GALACTOSEMIA (Galactose-1-Phosphate Uridyl Transferase Deficiency)

• 2nd half of the 1st week of life• Accumulation of galactose-1-phosphate

kidney/liver/brain injury• Jaundice, hepatomegaly, vomiting, hypoglycemia,

convulsions, lethargy, irritability, feeding difficulties, FTT, aminoaciduria, nuclear cataracts, vitreous hge, hepatic failure, liver cirrhosis, ascites, splenomegaly, mental retardation.

• Dx: Reducing substance in urine• Tx: Elimination of galactose from the diet

MUCOPOLYSACCHARIDOSIS IHURLER DISEASE

• 6 to 24 months old• Hepatosplenomegaly, coarse facial features,

corneal clouding, large tongue, prominent forehead, joint stiffness, short stature and skeletal dysplasia, developmental delay

MUCOPOLYSACCHARIDOSIS IIHUNTER DISEASE

• Almost exclusively in MALES• Same with Hurler EXCEPT for LACK OF

CORNEAL CLOUDING and somewhat SLOWER progression of somatic and CNS deterioration

MUCOPOLYSACCHARIDOSIS

• Treatment– BM transplantation– CORD BLOOD transplantation– Enzyme replacement

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