Faculty Bibliography

Background: Netherton Syndrome (NS) is a genodermatosis that presents with icthyosiform erythroderma, atopic manifestations and hair abnormalities. It is autosomal recessive, caused by mutation in the SPINK5 gene, which encodes the lymphoepithelial Kazal-type-related inhibitor (LEKTI). Dysfunction of LEKTI leads to increased activity of serine proteases in the stratum corneum, including the Kallikreins (KLK5, KLK7 and KLK14) which are involved in desquamation and epidermal remodeling. Weakening of the skin's lipid permeability barrier in NS predisposes to avid absorption of topical medications such as steroids that can lead to exogenous Cushing Syndrome. Clinical Case: A 3 month old girl with congenital hydrocephalus, absent septum pellucidum and presumed seborrheic dermatitis treated with mid-potency topical 0.1% mometasone ointment for 2 weeks presented to the emergency department with emesis. Pediatric endocrinology consult for evaluation of central panhypopituitarism due to the known structural brain abnormalities revealed a random serum cortisol <0.2ug/dl, with normal LH, FSH, ACTH, TSH, IGF-1, and Prolactin. ACTH stimulation test with 125mg cosyntropin resulted in serum cortisol of hypothalamicpituitary- adrenal (HPA) axis suppression due to exogenous steroid use. Family history was significant for consanguinity, being parents first cousins, and similar skin lesions in the paternal aunt, uncle and first cousin. The Pediatric Dermatologist noted that the paternal aunt had icthyosis linearis circumflex and the hair shaft abnormality trichorrhexis invaginata, both pathognomonic findings of NS. On examination at 3 months, baby had normal growth (height 9th, weight 25th percentile) and cushingoid facies. She had severe erythema and seborrheic crusting involving the scalp, trunk and intertriginous creases with superimposed bacterial infection. A skin biopsy showed epidermal hyperplasia with scaling concerning for NS. Microscopic examination of sampled hair was normal however the hair shaft abnormalities of NS may not manifest until 1 year of age. Genetic testing for SPINK 5 mutation seen in NS is still pending. Result: 1. Skin lesions: The patient continued careful and cautious use of low potency topical steroids (2.5%Hydrocortisone ointment) intermittently, with improvement over 6 months. The baby continues to feed and grow well (height 22th, weight 20th percentile). 2. Suppression of HPA axis: Previously low serum cortisol showed some improvement over 6 months, (at 9 months Serum cortisol 3.9ug/dl,). The patient was advised to use stress doses of hydrocortisone when necessary. Conclusion: Patient's with NS have defective stratum corneum that increases absorption of even low potency topical steroids. Cautious use of topical steroids is advised in cases of NS as it may lead to suppression of HPA axis

BACKGROUND:Allergic and non-allergic skin reactions to recombinant human growth hormone (rhGH) are uncommon and infrequently reported. However, physicians should be aware of these potential side effects to determine whether the reactions constitute true allergies and how to proceed with growth hormone therapy. To review allergic and non-allergic skin reactions caused by rhGH and subsequent diagnostic workup and management options. CASE PRESENTATION/METHODS:We report the case of a 12-year-old healthy male presenting with idiopathic short stature. He developed an itchy skin rash over the chest and abdomen, 15 min after administration of the first dose of rhGH, leading us to review allergic and non-allergic skin reactions to rhGH. In our patient, an immediate skin reaction after administration of rhGH prompted a concern about a type I hypersensitivity reaction (HS) and the discontinuation of rhGH. However, after a dermatologic evaluation and observed administration of rhGH without subsequent rash, the initial eruption was likely an exacerbation of his underlying atopic dermatitis and a type I HS was felt to be unlikely. The rhGH was resumed and he has been on rhGH for the past 1 year with no recurrence of rash and with improvement in growth velocity. CONCLUSIONS:Though rare, allergic and non-allergic skin reactions are known to occur with rhGH. It is important to know if the allergic reaction was due to the growth hormone molecule or one of the preservatives. It is also important to consider a non-allergic reaction due to flare up of underlying skin disorders as in our patient.

Treatment to induce puberty in boys is indicated in those who do not undergo spontaneous development at a normal age. Stimulating development of the secondary sex characteristics is possible using gradually increasing doses of testosterone esters (TEs) via intramuscular (IM) administration, which is the most widely used method of testosterone (T) supplementation. When TEs are administered as monthly injection, serum T levels exhibit large fluctuations with supraphysiologic levels seen immediately after the injection followed by a decrease into the low range. Transdermal T (TT) has also been used for replacement therapy in adult males with hypogonadism and this provides steadier serum T levels. We report three adolescent boys with delayed puberty who were treated with TT gel for pubertal induction/continuation. This route was chosen as an alternative therapy due to their hepatic dysfunction, as is known that TT avoids the hepatic first-pass metabolism.

BACKGROUND: The hypothalamic-pituitary-gonadal axis is transiently activated during the postnatal months in boys, a phenomenon termed "minipuberty" of infancy, when serum testosterone (T) increases to pubertal levels. Despite high circulating T there are no signs of virilization. We hypothesize that free T as measured in saliva is low, which would explain the absence of virilization. METHODS: We measured serum total T and free T in saliva using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 30 infant boys, aged 1-6 months, and in 12 adolescents, aged 11-17 years. RESULTS: Total serum T in all infants was, as expected, high (172 +/- 78 ng/dL) while salivary T was low (7.7 +/- 4 pg/mL or 0.45 +/- 0.20%). In contrast, salivary T in the adolescents was much higher (41 +/- 18 pg/mL or 1.3 +/- 0.36%) in relation to their total serum T (323 +/- 117 ng/dL). We provide for the first time reference data for salivary T in infants. CONCLUSION: Measurement of salivary T by LC-MS/MS is a promising noninvasive technique to reflect free T in infants. The low free T explains the absence of virilization. The minipuberty of infancy is more likely of intragonadal than peripheral significance..

Management of central diabetes insipidus in infancy is challenging. The various forms of desmopressin, oral, subcutaneous, and intranasal, have variability in the duration of action. Infants consume most of their calories as liquids which with desmopressin puts them at risk for hyponatremia and seizures. There are few cases reporting chlorothiazide as a temporizing measure for central diabetes insipidus in infancy. A male infant presented on day of life 30 with holoprosencephaly, cleft lip and palate, and poor weight gain to endocrine clinic. Biochemical tests and urine output were consistent with central diabetes insipidus. The patient required approximately 2.5 times the normal fluid intake to keep up with the urine output. Patient was started on low renal solute load formula and oral chlorothiazide. There were normalization of serum sodium, decrease in fluid intake close to 1.3 times the normal, and improved urine output. There were no episodes of hyponatremia/hypernatremia inpatient. The patient had 2 episodes of hypernatremia in the first year of life resolving with few hours of hydration. Oral chlorothiazide is a potential bridging agent for treatment of central DI along with low renal solute load formula in early infancy. It can help achieve adequate control of DI without wide serum sodium fluctuations.

Fractures are uncommon in young, nonambulatory infants. The differential diagnosis includes nonaccidental injury (NAI) and metabolic bone disease, including rickets. While rickets typically present after six months of age, multiple cases have been reported in younger infants. We report a case of an 11-week-old male infant who presented with a spiral fracture of the humerus and no radiologic evidence of rickets. A detailed psychosocial assessment failed to reveal any risk factors for NAI. The patient had elevated alkaline phosphatase and PTH with low 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D levels. Additionally, the mother was noncompliant with prenatal vitamins, exclusively breastfeeding without vitamin D supplementation, and had markedly low vitamin D levels 15 weeks postpartum. The biochemical data and history were consistent with rickets. Given the diagnostic dilemma, the working diagnosis was rickets and the patient was started on ergocalciferol with subsequent normalization of his laboratory values and healing of the fracture. These findings are consistent with nutritional rickets largely due to maternal-fetal hypovitaminosis D. This case highlights that in young infants rickets should be considered even in the absence of positive radiologic findings. Additionally, it illustrates the importance of maintaining adequate vitamin D supplementation during pregnancy and early infancy.

Gonadotropin independent sexual precocity (SP) may be due to congenital adrenal hyperplasia (CAH), and its timing usually depends on the type of mutation in the CYP21A2 gene. Compound heterozygotes are common and express phenotypes of varying severity. The objective of this case report was to investigate the hormonal pattern and unusual genetic profile in a 7-year-old boy who presented with pubic hair, acne, an enlarged phallus, slightly increased testicular volume and advanced bone age. Clinical, hormonal and genetic studies were undertaken in the patient as well as his parents. We found elevated serum 17-hydroxyprogesterone (17-OHP) and androstenedione that were suppressed with dexamethasone, and elevated testosterone that actually rose after giving dexamethasone, indicating activity of the hypothalamic-pituitary-gonadal (HPG) axis. An initial search for common mutations was negative, but a more detailed genetic analysis of the CYP21A2 gene revealed two mutations including R341W, a non-classical mutation inherited from his mother, and g.823G>A, a novel not previously reported consensus donor splice site mutation inherited from his father, which is predicted to be salt wasting. However, the child had a normal plasma renin activity. He was effectively treated with low-dose dexamethasone and a GnRH agonist. His father was an unaffected carrier, but his mother had evidence of mild non-classical CAH. In a male child presenting with gonadotropin independent SP it is important to investigate adrenal function with respect to the androgen profile, and to carry out appropriate genetic studies.

Transient hyperinsulinism and thrombocytopenia can occur in neonates following exposure to perinatal stress and birth asphyxia. However, little is known about whether there is a direct association between neonatal hyperinsulinism and thrombocytopenia. We report a case of transient hyperinsulinism and thrombocytopenia, both of which improved after administration of diazoxide in a full-term neonate born by emergency cesarean section and required resuscitation. The newborn had severe hypoglycemia at 8 h of life and continued to have episodes of hypoglycemia while on a continuous glucose infusion rate. The glucagon stimulation test was positive confirming hyperinsulinism and the patient was started on diazoxide. Concomitantly, the neonate also had severe thrombocytopenia and required four platelet transfusions in the first 8 days. Within 24 h after starting diazoxide, both blood glucose and platelet counts improved. We speculate a possible association of hyperinsulinism with thrombocytopenia

BACKGROUND: Diagnosis of adolescent polycystic ovary syndrome (PCOS) remains a challenge despite several existing criteria, and may be difficult to distinguish from pubertal changes. Different parameters to study ovarian function using ultrasonography have been proposed, but there is still no consensus about their diagnostic value. OBJECTIVE: To evaluate the role of ultrasonography in the diagnosis of adolescent PCOS by reviewing available studies that assessed the ovarian volume (OV) and other ovarian morphological features such as location and number of follicles, stromal area, and volume. METHODS: MEDLINE/PubMed database were searched to identify studies that assessed ovarian characteristics of adolescent PCOS patients by ultrasound. Studies on adults were also reviewed if study population included adolescents and stromal characteristics were assessed by three-dimensional (3D) sonogram. RESULTS: Five studies, including 262 PCOS adolescents (10-19 years of age) and two-dimensional (2D) ultrasound analysis, were identified. Mean OV was 9.29 cm3 for PCOS patients and 4.77 cm3 for controls. The morphology of ovarian follicles, when reported, showed multiple (>10) peripheral follicles in 83% of cases. Two studies, including 157 PCOS adolescents and young women (15-35 years of age) and 2D and 3D ultrasound analysis, were identified. Patients with PCOS patients had a MOV 13.1 cm3, multiple follicles (>15), and a statistically significant greater S/A ratio compared to controls. Stromal volume indices were positively correlated with hyperandrogenemia in PCOS patients. CONCLUSION: Pelvic ultrasound is an increasingly important aid in the diagnosis of PCOS in adolescents. Besides ovarian volume, ovarian morphology must be assessed with 2D ultrasound to look for peripherally located multiple follicles. Further studies are warranted to evaluate the utility of 3D ultrasonographic assessment in adolescents with PCOS.