Faculty Bibliography

OBJECTIVES/OBJECTIVE:Hashimoto's thyroiditis (HT) is characterized by lymphocytic thyroid infiltration. Gradual thyroid failure can occur due to thyroid cell apoptosis. Rarely neurological autoimmunity due to glutamic acid decarboxylase (GAD) antigen can co exist with HT. CASE PRESENTATION/METHODS:A seven-year-old male presented with tiredness, weight loss, frequent falls, tachycardia, firm thyromegaly, and abnormal gait. Biochemical markers and thyroid ultrasound (TUS) showed autoimmune hyperthyroidism. Methimazole (MMI) was started and continued for 2.2 years. MRI brain was normal and neurological symptoms resolved. At nine years, he became hypothyroid and levothyroxine (LT4) was started. Serial TUS showed progressive thyroid atrophy. At 14.8 years, he developed epilepsy and fourth cranial nerve palsy, and diagnosed with GAD-65 central nervous system disease. At 15.3 years, TUS showed complete atrophy of right lobe with involuting left lobe volume. CONCLUSIONS:This is an unusual form of atrophic thyroiditis (AT) with coexisting neurological autoimmunity. GAD-65 CNS autoimmunity should be considered in children with AT presenting with neurological signs.

Objective/UNASSIGNED:Neutropenia can occur from untreated autoimmune hyperthyroidism (AIH) or methimazole (MMI); starting MMI in children and adolescents with AIH and neutropenia could thus be worrisome. We aimed to describe the prevalence of neutropenia in children and adolescents with AIH prior to treatment with antithyroid drugs and to assess the effect of antithyroid drugs on the neutrophil count. Methods/UNASSIGNED:This was a retrospective study of patients with AIH seen at a Pediatric Endocrinology clinic. ANC data at presentation and during anti-thyroid treatment for up to 24 weeks was collected. AIH was defined as elevated fT4 or fT3, suppressed TSH, and positive thyroid autoantibodies. Neutropenia was defined as ANC <1500 cells/μl. Results/UNASSIGNED:31 patients were included: 71% females, 29% males, median age 14.71 years (IQR 11.89-17.10). Neither fT4 nor fT3 levels significantly correlated with ANC at presentation (rs = 0.22, p = 0.24 and rs = 0.13, p = 0.54, respectively). 26/31 (84%) had normal baseline ANC; none developed neutropenia with thionamides. 5/31 (16%) had baseline neutropenia (median 1,200/μl; IQR 874-1200); 4/5 patients started MMI at diagnosis; 1/5 started propranolol only then added MMI 1 week later; all normalized ANC within 24 weeks. Conclusion/UNASSIGNED:A small percentage of AIH patients may have neutropenia at presentation, but it resolves in the short term and does not worsen with thionamides. Thionamides may be used with caution in these patients with close monitoring of blood counts.

Objectives BACKGROUND: X-linked hypophosphatemia (XLH) in children is a rare genetic disorder characterized by renal phosphate wasting, hypophosphatemia, rickets, growth impairment and elevated serum fibroblast growth factor 23 (FGF23). We present a mother and daughter pair diagnosed with XLH and discuss the benefits of anti FGR23 human monoclonal antibody (Burosumab) versus conventional therapy (CT) with oral phosphate and calcitriol. Methods CLINICAL CASE: Mother: An 8 yr old girl presented with short stature, pain and deformities of lower extremities (LE). Family history was negative for bone disease. On exam height (Ht) 108cm (Z score -4.89), weight (Wt) 18.8kg (Z score -2.22) and bilateral genu varum. Lab data revealed serum Ca 9.6 (N 8.0-10.4mg/dL), P 2.2 (N 2.7-4.5mg/dL), ALP 275 (N 25-100 U/L), PTH 69 (N 14-72 pg/mL) and low TmP/GFR 2.2 (normal 2.9-6.5mg/dL). She was diagnosed with XLH and started on CT. She required multiple bilateral tibial and femoral osteotomies. She is now 24 yrs old, her final Ht is 139.4cm (Z score -3.70) with long standing rickets that has failed to respond to CT. Daughter: A 3 yr old presented with bowing and pain in LE and poor linear growth (GV 2cm/yr) for 1 yr. She was born at term with normal Wt and length. On exam Ht was 87.7cm (Z score -1.74) and Wt was 15.5kg (Z score 0.57), she had bowing of LE. Dentition and systemic exam were normal. Lab data revealed serum Ca 9.6, P 2.7, ALP 473, PTH 61 and low TmP/GFR 2.7. X-Ray confirmed rickets with Rickets Severity Score (RSS) of 4 points. RSS for knee progresses from zero (normal) to 6 points (severe). Patient was diagnosed with XLH and placed on CT for 23 months. During this time she had poor linear growth 3cm/yr, pain and bowing of lower extremities making ambulation difficult with worsening of RSS to 6 points hence she was switched to the recently FDA approved Burosumab at 5 yrs of age. Results Burosumab was started at 0.62mg/kg subcutaneously every 2 weeks. Continued improvements were noted at 20, 32 and 48 weeks. At 48 weeks serum P 3.3mg/dL, ALP 383 U/L, PTH 111.5 pg/mL, TmP/GFR 3.3mg/dL and Knee x-ray showed normal RSS score of 0. A brief episode of mild headache and malaise was noted after first injection. Serious adverse events did not occur. Conclusions XLH can cause substantial, progressive disabilities and impaired quality of life. Burosumab is a promising option to treat XLH by noteworthy improvement in bone healing, rickets severity, linear growth, physical function and pain

Objectives Methimazole (MMI) is the anti-thyroid drug of choice for autoimmune hyperthyroidism (AIH). Agranulocytosis is a rare but serious adverse reaction to thionamides (0.2-0.5% incidence). This is thought to be due to direct toxicity when the drug is oxidized by neutrophils, or to immune-mediated mechanisms. However, untreated hyperthyroidism can itself cause neutropenia and even pancytopenia. Baseline neutropenia in a patient with hyperthyroidism could be worrisome given the concern for potential agranulocytosis as a side effect of thionamides. This study aimed to determine the prevalence of pre-treatment neutropenia in children with AIH and the effect of thionamides on the absolute neutrophil count (ANC). Methods This was a retrospective study of patients diagnosed with AIH seen at the Pediatric Endocrinology clinic. Data up to 24 weeks after treatment was collected. AIH was defined based on elevated fT4 (N: 0.7-1.5 ng/dL) or fT3 (N: 1.71-3.71 pg/mL), suppressed TSH (N: 0.4-4.5 mIU/L), and positive thyroid autoantibodies. Neutropenia was defined as ANC <1500/mul. Group A was the control group, and Group B included patients with pre-treatment neutropenia. Results A total of 31 patients with AIH were included. Mean age was 13.3 +/- 5 yrs. Majority were either Hispanic (48%) or Asian (32%). Neither fT4 nor fT3 levels significantly correlated with ANC at presentation (r = 0.29, p = 0.11 and r = 0.07, p = 0.7, respectively). Group A: 26/31 patients (84%) had normal baseline ANC (mean 4,297 +/- 2,118/mul). Mean fT4 was 4.2 +/- 2.3 ng/dL (n = 26) and fT3 13.21 +/- 6.4 pg/mL (n = 23). None of the patients developed neutropenia after starting thionamides. Group B: 5/31 patients (16%) had baseline neutropenia (mean 1,026 +/- 407/mul). Mean fT4 was 2.37 +/- 0.9 ng/dL (n = 5) and fT3 11.3 +/- 6.9 pg/mL (n = 3). In 4/5 patients, MMI was started at diagnosis; 1/5 was started on propranolol only followed by MMI 1 week later. All 5 cases normalized their ANC within 24 weeks. 4/5 cases had normal ANC by 4 weeks (1 patient developed a transient drop in ANC at week 9 which again normalized at 21 weeks). 1/5 continued to have neutropenia at 12 weeks and normalized by 24 weeks. 3/5 patients had anti-neutrophil cytoplasmic antibodies checked and were negative. Conclusions A small percentage of patients with AIH may have neutropenia at presentation, but it resolves in the short term and does not worsen with thionamides. Thionamides may be used with caution in these patients with close monitoring of blood counts. (Table Presented)

Context Preimplantation genetic diagnosis (PGD) is currently used for over 400 monogenic diseases. Some endocrine conditions that occur due to monogenic defects are either life-threatening or can cause severe morbidities; thus, PGD may be an option to avoid the occurrence of such diseases. Evidence acquisition An initial search in PubMed/Medline search was done to identify monogenic endocrine conditions using appropriate search terms. Eleven articles (1999-2018) reported 15 cases using PGD for monogenic endocrine diseases performed at major reproductive centers. Clinical and outcome data of these cases were reviewed with respect to the number of PGD cycles, successful pregnancy rates, live births and their genetic status. Evidence synthesis Fifteen couples underwent 32 PGD cycles (one to nine per couple), of which 17 resulted in a pregnancy. Seven couples underwent a single PGD cycle. Four couples had successful pregnancies each resulting in live births, one couple had an unsuccessful pregnancy, one needed medical termination of pregnancy and the outcome data were not reported in one. The remaining eight couples underwent multiple PGD cycles (two to nine per couple) and all had successful pregnancies in at least one cycle resulting in 16 live births. Of the total live births, 60% were genetically unaffected and 40% were carriers of the autosomal recessive gene mutation. Conclusions PGD may be a potential tool for preventing the inheritance of severe monogenic endocrine diseases in future generations. Currently, the use of PGD in endocrine disorders is rare but provides a promising option on a case-by-case basis, provided the optimal resources are available.

The use of antiretroviral (ARV) medications has successfully reduced maternal transmission of human immunodeficiency virus (HIV)-1 to newborns, but metabolic and mitochondrial toxicities in newborns continue to be a concern. We report the case of a 10-day-old full-term female infant born to an HIV-positive mother presenting with lethargy and respiratory distress. Maternal ARV medications included nucleoside reverse transcriptase inhibitors (NRTIs) and an integrase strand transcriptase inhibitors (INSTIs). Infant ARV prophylaxis included two NRTIs and a nonnucleoside reverse transcriptase inhibitor. At presentation, laboratory tests were significant for hyponatremia, hyperkalemia, severe metabolic acidosis, and acute kidney injury. She was resuscitated with fluids and a stress dose of hydrocortisone (HC), which resulted in improvement of her condition within 48 h. Adrenal profile on the day of admission revealed elevated levels of 17-hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione, aldosterone, and elevated plasma renin activity. HC was tapered and the patient was discharged on the day of life (DOL) 26. Adrenocorticotropic hormone (ACTH) stimulation test off HC for one night that was performed on DOL31 showed a normal cortisol response of 35.8 mcg/dL at 60 min. HC was later discontinued. A repeat ACTH stimulation test off HC for 7 days that was performed on DOL59 yielded a normal cortisol response of 27.6 mcg/dL at 60 min. This report reveals severe metabolic disturbances suggestive of adrenal insufficiency (AI) in a neonate exposed to a combination of ARV medications in utero and postnatally with improvement of symptoms after glucocorticoid treatment. The AI was transient in nature, which resolved after cessation of ARV therapy.

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

Context: Nearly half of Turner Syndrome (TS) patients have a 45 X karyotype. The second most frequent is the isodicentric chromosome idic(Xp) (18% of TS). Research showed that the clustering of 4 breakpoints (BP1,2,3,4) of idic(Xp) are located in the region of Xp11.1-p11.22, within a 6Mb region (from 52-58 Mb). Using cell lines, it was suggested that this region is filled with repetitive gene clusters and segments with duplications, which may predispose to breakage and rearrangement. Objective: To study the BP interval and elucidate the molecular mechanism of formation of idic(Xp) in TS patients and to review the literature of isodicentric X chromosome in TS with respect to different breakpoints. Methods: Patient A was a 7yr female with TS and short stature (Z score:height -1.99, weight 0.27) short 4thmetacarpals, cubitus valgus, spoon shaped nails, astigmatism, learning disability and ovarian dysgenesis. She had normal renal, cardiac and autoimmunity evaluation. The karyotype revealed 46, X, idic(X)(p11.22) [4/20 cell]; X(45, X) [16/20 cell]. Patient B was a 6.5 year old female with TS and short stature, (Z score:height -1.96, weight 0.21) cubitus valgus, madelung deformity of arms, short 4th metacarpals, developmental delay, autoimmune hypothyroidism and alopecia areata. Her ovarian, renal and cardiac evaluations were To further refine the breakpoint, an array based comparative genomic hybridization (aCGH) was performed. The data was plotted on X chromosome ideogram from NCBI reference sequence collection (RefSeq). Results: aCGH analysis: Patient A: A 51Mb loss at Xp22.33-p11.22 (305449 to 52102355 basepairs). It also revealed a mosaic loss of 102Mb with a copy number at Xp11.22-q28 (52570755 to 155232863 basepairs). The size of the breakpoint at Xp11.22 was 468.4 Kb, located at BP-3, and contained both structural variation [copy number variation(CNV)] and segmental duplication [low copy repeats(LCR)]. Patient B: A 55Mb loss at Xp22.33-p11.21 (291285 to 55466476 basepairs) and a mosaic 100 Mb gain with the copy number at Xp11.21-q28 (55556198 to 155226073 basepairs). The actual location of the breakpoint was at Xp11.22 (Not p11.23 as per karyotype). The size of the breakpoint was 89.7 Kb, located at BP-2, and contained both structural variation (CNV) and segmental duplication (LCR). Also, duplication of chromosome 1q44 was revealed. A review literature showed the most common breakpoints occur at Xp11. Breakpoints at Xq13 & Xq10 correlates with hematologic malignancy and at Xq22 correlates with ovarian failure. Conclusion: Our report further supports that breakpoints in isodicentric chromosome in TS are not random and are potentially due to specific structural rearrangements in basepairs. Further research is needed to gain the knowledge about position of breakpoints and their clinical correlation

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.