Nancy G. Greger

Bloody Nipple Discharge in an Infant and a Proposed Diagnostic Approach

Bloody nipple discharge is a rare finding in infants and is associated most often with benign mammary duct ectasia. The rarity of this symptom in infants and its association with breast carcinoma in adults can lead to unnecessary investigation and treatment. Here we describe a 4-month-old boy with bilateral bloody nipple discharge that resolved spontaneously without treatment by 6 months of age. Furthermore, we propose a strategic method for the evaluation of such infants.

Lipids and apolipoproteins in growth hormone-deficient children during treatment☆☆☆

The role of growth hormone (GH) in regulating the transport of plasma lipoproteins has not been clearly defined, but past studies suggest that GH may influence cholesterol levels. This protocol was designed to evaluate possible changes in lipid and apolipoprotein status in GH-deficient children and children with neurosecretory dysfunction (NS) before GH therapy and at intervals after GH therapy was started. Twenty children with classic GH deficiency were evaluated, and 28% were hyperlipidemic at the onset of the study. Seven children were evaluated in the NS group, and only one (14%) showed an elevated total cholesterol (TC) greater than 200 mg/dL. The mean TC for all the GH-deficient children was elevated above the normal range, but not for the NS group. The mean apolipoprotein (apo) C-III level and its heparin-precipitated fraction (HP) were also elevated in the GH-deficient group, but only the apo C-III HP was elevated in the NS group. A standard replacement dose of recombinant methionyl GH was used, and therapy had no significant effect on TC or triglyceride (TG) levels. Apo C-III HP, a marker of hypertriglyceridemia, increased after the start of therapy, but no other lipoprotein levels changed significantly in the GH-deficient group. No changes were seen with treatment in the NS group. The longitudinal design of this study allowed demonstration of the later changes in the apolipoproteins and the presence of a distinct subset of patients with both GH deficiency and hypercholesterolemia. This study supports the role of GH in modulating lipid metabolism.

High-density lipoprotein response to 5-α-dihydrotestosterone and testosterone in Macaca fascicularis: A hormone-responsive primate model for the study of atherosclerosis☆☆☆

A decrease in high-density lipoprotein cholesterol (HDL-C), a major risk factor for coronary artery disease, occurs during puberty in males. Previous studies have shown this decrease with testosterone (T) therapy for adolescent males, but the mechanism of this effect is unknown and has not been studied in a non-human primate. Two adult male monkeys (Macaca fascicularis) were studied to determine simultaneous changes in plasma androgens and HDL-C during the phases precastration (Ci); postcastration (Cx); Cx and T therapy; Cx and dihydrotestosterone (DHT) therapy; and T and 5-alpha-reductase inhibitor therapy (4-MA). After castration, the HDL-C concentrations increased significantly in both animals (monkey A, 57.0 +/- 1.8 mg/dL SE to 66.6 +/- 2.2, P less than .005; monkey B, 62.9 +/- 1.6 to 80.2 +/- 1.7, P less than .001). T-propionate treatment produced a significant decrease in HDL-C (monkey A, 48.0 +/- 5.0, P less than .01; monkey B, 43.5 +/- 0.5, P less than .001), which was similar to HDL-C reductions seen when treated with a nonaromatizeable androgen, DHT-propionate (monkey A, 47.5 +/- 1.5, P less than .005; monkey B, 44.5 +/- 3.5, P less than .001). T and the 5-alpha-reductase inhibitor therapy did not increase HDL-C from the levels with T therapy alone (monkey A, 55.7 +/- 1.9, NS; monkey B, 57.3 +/- 0.3, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Cytosol androgen receptor (AR) in human skin fibroblasts: Characterization of the binding reaction and differentiation from androgen binding molecules of lower affinity

Androgen binding was studied in cytosol of human fibroblasts at 4 degrees C. When 5 alpha-dihydrotestosterone (DHT) was the ligand, a curvilinear Scatchard plot was seen, which was resolved into two components: I the androgen receptor (AR), Kd = 0.12-0.44 nM, and II a low affinity species, Kd = 6.3-28 nM. The same cytosol demonstrated only type I binding for 3H-methyltrienolone (MTr), Kd = 0.10-0.40 nM. The AR, i.e., 3H-MTr binding activity, eluted at 440,000 d by gel filtration chromatography in pre-labeling and post-labeling experiments. When the ligand was 3H-DHT, binding activity in the 10,000-45,000 d range was seen in addition to AR. Thus, saturable nonreceptor steroid binding was seen for DHT but not for MTr. The latter is the preferred ligand for the study of the AR in this system.

Familial Infantile Diabetes and Autoimmune Enteropathy: Clue to a Possible X-Linked Multiple Autoimmune Disease Syndrome 423

We report a case of a child diagnosed with insulin dependent diabetes mellitus at 12 days of age who was subsequently diagnosed as having autoimmune enteropathy. He presented at five years of age with intractable diarrhea which was unresponsive to steroids and gluten free diet. Biopsy of the mucosa of the small bowel showed total villous atrophy. Anti-enterocyte antibodies were present. The enteropathy was eventually controlled with cyclosporine. The child had also been diagnosed with autoimmune glomerulonephritis. The patients family history revealed a maternal uncle who had been diagnosed with insulin dependent diabetes at 38 days of age and who had manifested symptoms of other autoimmune disease. Because we were aware of reports of infantile diabetes and autoimmune enteropathy occurring in an apparent familial X-linked recessive pattern, we undertook a review of the medical literature to attempt to identify additional such patients. We used the following criteria to identify probable cases of this syndrome: The patient must have had autoimmune enteropathy and/or infantile diabetes; both disorders must be present in the patient and/or the patients family history, and there must be more than one affected family member. According to this criteria, we identified a total of 31 probable cases in nine kindreds (including our cases), all occurring in males. Three reported kindreds demonstrated an X-linked recessive pattern of inheritance, accounting for 19 of the 31 cases. Because of the rarity of these disorders, their occurrence together in a family is strong evidence for the presence of a single genetic pathogenesis for the observed autoimmune disease, and we believe that these patients therefore all suffer from a single unique previously undefined X-linked syndrome. The above listed criteria represent the optimum clinical basis upon which these patients may be identified. We also make the following recommendations: 1. A careful family history for infantile diabetes and autoimmune enteropathy should be obtained in all cases of males diagnosed with either of these disorders. 2. All males with infantile diabetes and a positive family history should be closely observed for the development of other autoimmune disorders, particularly autoimmune enteropathy. 3. All patients diagnosed with autoimmune enteropathy who meet the above criteria should be treated aggressively. 4. Further research is needed to determine the precise nature of the genetic and immune system defects that result in this disorder.

Hypothalamic Hypodipsia with No Central Nervous System Lesion 469

Hypothalamic hypodipsia is usually associated with distinct anatomic disease. We have followed three patients with similar clinical presentations, who had no demonstrable central nervous system lesion. The first patient presented at nine years of age with an approximate weight gain of 20 kg in four months. Initial serum sodium was 160 8:00 am, 4:00 pm and 24 hour urine cortisols were normal. A TSH test showed hypothalamic hypothyroidism with a basal prolactin of 195 pg/ml. Fasting triglycerides were as high as 5000 on several occasions. Pneumoencephalogram, CT scan, and subsequent MRI of the head showed no lesions. An episode of rhabdomyolysis due to hypernatremia led to renal failure and subsequent renal transplantation which did not correct the hypernatremia or hypodipsia. Death occurred at age 27 after an auto accident. No post mortem exam was obtained.

LIPOPROTEIN RESPONSE TO 5DIHYDROTESTOSTERONE(DHT) AND TESTOSTERONE(T) IN MACACA FASCICULARIS

A decrease in high density lipoprotein cholesterol (HDLc), one of the major risk factors for coronary artery disease, occurs during puberty in males. Previous studies have shown this effect with T therapy for adolescent males at puberty (Kirkland, RT, et al;JAMA, in press). The mechanism of action is unknown.Two adult male monkeys (Macaca fascicularis) were studied to determine simultaneous changes in plasma androgens and HDLc during 5 phases- Precastration(Ci); Postcastration(Cx); Cx & T therapy; Cx & DHT; Cx, T & 5αreductase inhibitor (4-MA, Merck, 2-5mg/kg). Normal ranges for T, DHT, HDLc for this species were established. After Cx, androgens decreased and HDLc increased significantly. Therapy with T and a nonaromatizeable androgen(DHT) after Cx both produced a significant decrease in HDLc. Simultaneous therapy with T and 4-MA did not increase HDLc from Cx+ T levels.*This primate model shows hormone responsive lipoprotein changes similar to humans. 5αreductase and aromatase (estrogen) activity do not appear to be necessary for this response. This model will allow further study of the mechanism of action and benefits or side effects of therapeutic intervention with antiandrogens.