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Introduction Beckwith-Wiedemann Syndrome (BWS) is the most common overgrowth syndrome with up to 50% of infants found to have hypoglycemia which has been believed to be related to hyperinsulinemia. However, our case report highlights a patient with the unusual presentation of concurrent BWS and T1DM along with the discussion of genetic factors that may contribute to the pathogenesis. Clinical Case We present the case of a 4-year-old African American female with a past medical history of BWS, twin gestation, prematurity, omphalocele, and patent ductus arteriosus. Her BWS had been diagnosed at birth via genetic testing which found a loss of methylation on the maternal chromosome at imprinting center 2 (IC2) on chromosome 11. During her newborn period, she did not have hypoglycemia. She presented to her primary care physician with a 2.4-kilogram weight loss, new-onset headaches, polyuria, and polydipsia for three months. She also had a viral upper respiratory tract infection a month prior to presentation. Her twin sister did not have similar complaints. Her physical exam including vital signs was reassuring. With the concern for diabetes, further work-up was done which showed an elevated serum glucose level of 681 mg/dL, and hemoglobin A1C of 12.4%. She was admitted for new-onset diabetes. Further labs on admission also showed elevated transglutaminase IgG and positive glutamic acid decarboxylase 65 (GAD65) antibody (level: 444 nmol/L, normal: ≤0.02 nmol/L). Notably, no acidosis was detected in the initial investigations and, unfortunately, due to laboratory error the diabetes antibody panel was cancelled. She was started on a basal-bolus insulin regimen with the diagnosis of new-onset T1DM without ketoacidosis. BWS does not have T1DM as a known characteristic. Hypoglycemia secondary to hyperinsulinemia rather than the opposite, such as our case, is associated with BWS. Due to this, our case is rare, and we found a case report from Europe describing a similar phenomenon. Our patient had a GAD65 antibody being positive which explains having T1DM although there are no studies showing the association of BWS with a positive GAD65 antibody. Our patient also had a viral infection prior to the diagnosis of T1DM which may have triggered autoimmunity. Further, IC2 loss of methylation present in our patient regulates the expression of CDKN1C which has been previously reported to be associated with diabetes. Conclusion Further studies will be required to identify the possible case of T1DM in a patient with BWS. We plan on obtaining a diabetes antibody panel to further assess the genetics of our patient.

Behavioral aspects of organized sports activity for pediatric athletes are considered in a world consumed with winning at all costs. In the first part of this treatise, we deal with a number of themes faced by our children in their sports play. These concepts include the lure of sports, sports attrition, the mental health of pediatric athletes (i.e., effects of stress, anxiety, depression, suicide in athletes, ADHD and stimulants, coping with injuries, drug use, and eating disorders), violence in sports (i.e., concepts of the abused athlete including sexual abuse), dealing with supervisors (i.e., coaches, parents), peers, the talented athlete, early sports specialization and sports clubs. In the second part of this discussion, we cover ergolytic agents consumed by young athletes in attempts to win at all costs. Sports doping agents covered include anabolic steroids (anabolic-androgenic steroids or AAS), androstenedione, dehydroepiandrostenedione (DHEA), human growth hormone (hGH; also its human recombinant homologue: rhGH), clenbuterol, creatine, gamma hydroxybutyrate (GHB), amphetamines, caffeine and ephedrine. Also considered are blood doping that includes erythropoietin (EPO) and concepts of gene doping. In the last section of this discussion, we look at disabled pediatric athletes that include such concepts as athletes with spinal cord injuries (SCIs), myelomeningocele, cerebral palsy, wheelchair athletes, and amputee athletes; also covered are pediatric athletes with visual impairment, deafness, and those with intellectual disability including Down syndrome. In addition, concepts of autonomic dysreflexia, boosting and atlantoaxial instability are emphasized. We conclude that clinicians and society should protect our precious pediatric athletes who face many challenges in their involvement with organized sports in a world obsessed with winning. There is much we can do to help our young athletes find benefit from sports play while avoiding or blunting negative consequences of organized sport activities.

Ovarian neoplasms constitute 1% of childhood tumors. The majority of them are teratomas and usually are asymptomatic or present with paraneoplastic syndromes. Our case is a 16-year-old female who presented with chronic abdominal pain, virilization and oligomenorrhea and found to have a complex cystic mass of the left ovary, more likely cystic teratoma on abdomen and pelvis CT. Further work-up revealed significantly elevated serum total and free testosterone. The patient subsequently underwent left salpingo-oophorectomy confirming the radiological findings. Within two week after surgery, serum testosterone normalized and the patient started having regular menstrual cycles. In summary, ovarian teratomas should be include in the differential diagnosis of abdominal pain and menstrual abnormalities in female adolescents. Further studies are needed to determine the role of ovarian-sparing surgery in this patient population.

Abnormal calcium/calcinosis/creatinine in Down syndrome (ABCD syndrome) is a very rare condition with no clear etiology. In this paper, we describe our clinical encounter with this disease. We report the case of an 11-month-old male infant with Down syndrome (DS) who presented to the hospital with intractable vomiting and decreased oral intake and urine output. The evaluation revealed an acute kidney injury (AKI) and hypercalcemia. Although his AKI improved with intravenous hydration, his hypercalcemia persisted. Extensive studies were notable for an elevated urinary excretion of calcium and bilateral medullary nephrocalcinosis seen on renal ultrasound (US). As a result, he was diagnosed with ABCD syndrome. Dietary calcium restriction was implemented. During his follow-up visit with a pediatric endocrinologist, his serum calcium was found to be normalized. To our knowledge, this is only the seventh case report on ABCD syndrome in the literature.

Background: There has been a well-documented link showing that pre-existing diabetes worsens outcomes in Covid-19 infection in adults. However, researchers have postulated that this relationship is reciprocal, where infection with Covid-19 may trigger new onset diabetes. Data on pediatric new onset type 1 diabetes mellitus (T1DM) and Covid-19 remains scarce. Furthermore, the results are conflicting; some studies showed increased rate of new onset T1DM in children with Covid-19 and the others did not find any difference in 2020 compared to previous years. The aim of this study is to elucidate the relationship between pediatric new onset T1DM and diabetic ketoacidosis (DKA) with Covid-19 infection in a single center. Methods: We conducted a retrospective chart review of 50 pediatric diabetes cases admitted to the Bronson Children’s Hospital between March 2020 and December 2020. Results: From the total of 50 patients, 42 had new onset T1DM. Of these 42, 33 (78.6%) presented with DKA, and 17 (40.5%) met hospital criteria for Covid-19 testing, with 16 of those producing a negative result. There was only 1 (5.9% of tested, 2.4% of T1DM cases) patient with new onset T1DM associated with a positive Covid-19 test. Conclusion: The low number of positive cases identified in this study suggests that there may be no link between Covid-19 viral illness and new onset T1DM in the pediatric population. Major limitations include the single center localization of the study and inability to test all cases for Covid-19 at this facility. Due to the scarcity of test kits and lab personnel especially early during the pandemic, only patients that met symptomatic criteria were tested. It is possible and likely that some of the patients were infected with Covid-19 but remained asymptomatic. Disclosure D. Rowland: None. N. D. O. Lee: None. B. Ergun-longmire: None.

Prader-Willi syndrome (PWS) is a rare and complex genomic imprinting disorder caused by an absence of expression of paternal genes from chromosome 15q11.2-q13. Clinical manifestations of PWS depends on age. In early infancy, PWS patients is characterized by hypotonia and failure to thrive. Later in life, they can also exhibit hyperphagia, obesity, short stature, hypogonadism, behavioral issues and cognitive disability. Multiple sleep abnormalities including obstructive and/or central sleep apnea, daytime hypersomnolence, and impaired responses to hypercapnia and hypoxia have been described in patients with PWS. Recent studies also demonstrated an increased risk of seizures in PWS patients. Electrical status epilepticus in sleep (ESES) is an age-limited epilepsy with various seizure types, neurophysiological and motor impairment. The classic electroencephalogram (EEG) pattern of ESES involves continuous epileptic activity at 2–3 Hz occupying greater than 85% of non-rapid eye movement (REM) sleep. Treatment of the ESES syndrome consists of anti-epileptic drugs in routine cases, and corticosteroids, gamma globulins, the ketogenic diet, and surgery in refractory cases. In this project, we describe ESES during polysomnography in a 5-year-old female with PWS and no history of seizure disorder. To the best of our knowledge, this is the first case report on ESES in a PWS patient.

Introduction: Majority of children and adolescents diagnosed with Type 1 Diabetes Mellitus (T1D) present with the classic symptoms of polyuria, polydipsia and polyphagia, associated with hyperglycemia. Concurrent conditions at the time of T1D diagnosis may alter its presentation and potentially lead to challenges in diagnosis and management. Clinical Case: We present a 17-year-old male with worsening fatigue and unintentional weight loss for two months, then one week of emesis and abdominal pain. Initial work-up by his primary care provider showed sodium 125 mmol/L (133–145), potassium 5.7 mmol/L (3.5–5.1), HCO3 20 mmol/L (21–31), anion gap 13 mmol/L (9–18), random glucose 141 mg/dL (70–199). Due to hyponatremia and dehydration, he was sent to a local emergency room where he was found to be mildly hypotensive at 87/57 mmHg. He received intravenous fluids for hydration and was sent home. On out-patient follow up, he appeared well despite being hypotensive. His additional labs revealed a random glucose of 330 mg/dl and elevated HbA1C of 8.3% (4.4–5.6). His urine was positive for glucose but negative for ketones. He was admitted for further management of new onset diabetes. On admission, he was well appearing and in no acute distress. Blood pressure was 86/57 mmHg, heart rate was 109 bpm, and other physical exam findings were unremarkable. Although his hyperglycemia improved after initiation of insulin therapy, his electrolyte abnormalities persisted, raising suspicion for adrenal insufficiency. An ACTH stimulation test was performed, with both baseline and 60-minute cortisol levels low at 1 ug/dl and 0.9 ug/dl, respectively, confirming adrenal insufficiency. He responded well to glucocorticoid and mineralocorticoid replacement. His electrolytes and blood pressure normalized. Further testing confirmed elevated levels of Glutamic Acid Decarboxylase antibodies 0.19 nmol/L (less than 0.02), Islet Antigen 2 Antibodies: 3.38 nmol/L (less than 0.02), and 21-Hydroxylase antibodies, consistent with T1D with concomitant Addison’s disease (AD). Conclusion: About 0.5% of patients with T1D have AD, but the diagnosis of T1D typically precedes AD for several years, thus the coexistence of both autoimmune conditions at diagnosis is rare.

Diabetes mellitus is the most common abnormal carbohydrate metabolism disorder affecting millions of people worldwide. It is characterized by hyperglycemia as a result of s-cell destruction or dysfunction by both genetic and environmental factors. Over time chronic hyperglycemia leads to microvascular (i.e., retinopathy, nephropathy and neuropathy) and macrovascular (i.e., ischemic heart disease, peripheral vascular disease, and cerebrovascular disease) complications of diabetes. Diabetes complication trials showed the importance of achieving near-normal glycemic control to prevent and/or reduce diabetes-related morbidity and mortality. There is a staggering rate of increased incidence of diabetes in youth, raising concerns for future generations’ health, quality of life and its enormous economic burden. Despite advancements in the technology, diabetes management remains cumbersome. Training individuals with diabetes to gain life-long survival skills requires a comprehensive and ongoing diabetes education by a multidisciplinary team. Diabetes education and training start at the time of diagnosis of diabetes and should be continuous throughout the course of disease. The goal is to empower the individuals and families to gain diabetes self-management skills. Diabetes education must be individualized depending on the individual's age, education, family dynamics, and support. In this article, we review the history of diabetes, etiopathogenesis and clinical presentation of both type 1 and type 2 diabetes in children as well as adolescents. We then focus on diabetes management with education methods and materials.

Introduction: Primary adrenal insufficiency (PAI), also known as Addison’s disease, is a disorder of the adrenal glands characterized by decreased levels of glucocorticoids and mineralocorticoids. It is a rare condition with a prevalence of 120 cases per million and is less frequently seen in the pediatric population. Here, we report a previously healthy 15-year-old patient with acute kidney injury (AKI) and PAI. Case Presentation: The patient was admitted to the hospital after findings of abnormal laboratory studies, which included an elevated BUN (53 mg/dL), creatinine (1.39 mg/dL), calcium (11.3 mg/dL), potassium (5.6 mmol/L), and hyponatremia (126 mmol/L). These were performed at an outpatient visit due to three-week history of back pain, fatigue and emesis. On admission, he had stable vital signs. Physical examination revealed generalized darkening of skin, more noticeable on the knuckles and palmar creases, with hyperpigmented patches in oral mucosa and both upper extremities. Although his renal function, serum potassium and calcium levels normalized after intravenous hydration with normal saline, hyponatremia (128 mmol/L) continued. His urine analysis and renal ultrasound were normal. Due to his hyperpigmentation and persistent hyponatremia, PAI was suspected. An ACTH stimulation test revealed that basal and stimulated serum cortisol levels were low, 2.6 mcg/dL and 2.9 mcg/dL, respectively. His plasma ACTH level was elevated at 1,625 pg/mL and serum aldosterone level was low at Discussion: PAI is well described in the literature, though reports in pediatrics vary. Patients may present with nonspecific symptoms such as unexplained weight loss, fatigue, diffuse abdominal pain, nausea, vomiting and muscular weakness. These symptoms may be of insidious onset, which often leads to delayed diagnosis. Physical signs include hypotension and hyperpigmentation. Characteristic biochemical findings are hyponatremia, hyperkalemia and hypoglycemia. Despite the electrolyte derangements, AKI is not a common presentation of PAI. There are only a few case reports associating these two diseases. In this case, his symptoms and abnormal electrolytes were initially considered to be the result of AKI of unknown origin. PAI only became a suspicion after a careful physical exam and persistent hyponatremia despite improvement of his AKI with fluid resuscitation. His low serum cortisol and aldosterone levels with elevated plasma ACTH confirmed the diagnosis of PAI. Conclusion: This case highlights a unique presentation of PAI in an adolescent. A timely diagnosis reduces the risk of unwanted and potentially life-threatening complications such as an Addisonian crisis.

Background: Hypercalcemia secondary to primary hyperparathyroidism (PHPT) is less common in children than adults. Single parathyroid adenoma is commonly the cause of primary hyperparathyroidism in children. Clinical Case: We present a 15-year-old female with one-week history of abdominal pain despite taking over the counter antacids. Her initial work up by her primary care provider revealed serum calcium of 11.8 mg/dL (9.0–11.5) and creatinine of 0.8 mg/dL (0.4–1.2). A week later, she presented to the emergency department with same complaint. In ED, she was found to have hypercalcemia (12.8 mg/dl) with elevated parathyroid hormone (PTH) at 78.5 pg/mL (15–65). Her random urine calcium creatinine ratio was high at 2.1. Her 25OHD was 25 ng/mL (30–100). She had negative urine pregnancy test but had trace ketones, leukocyte esterase, blood and bacteria. CBC and CMP were otherwise unremarkable. She continued to complain abdominal pain with nausea, decrease appetite, fatigue, and general muscle weakness. There was no known family history of calcium or metabolic bone disorders. Her vital signs and physical exam were normal. Subsequent labs showed mild improvement of calcium between (11–12.3 mg/dL), PTH between 54.5 and 77 pg/mL, normal thyroid function. Ionized calcium was mildly elevated 6.0 mg/dL (4.5–5.3) but her repeat 25OHD was low at18 ng/mL. Serum phosphorus levels were relatively normal with lowest level of 2.5 mg/dL (2.7–4.5). Gliadin Deamidated IgA was detectable 15 U/mL (< 15.0 U/). Ultrasound of abdomen was significant for nonspecific mild hepatomegaly; kidneys were normal in size and appearance. Ultrasound of thyroid was significant for probably intrathyroid parathyroid, measuring 6 x 8 x 8 mm. Tc-Sestamibi scan did not confirm a parathyroid adenoma. Genetic testing for MEN-1 was negative. FHH- related genes (i.e. CASR) was positive for p.R990G variant resulting in a mild gain of function of the calcium-sensing receptor. Although previous Tc-Sestamibi scan was unremarkable, an over read of it raised a concern for questionable uptake in the left superior lobe. SPEC-CT demonstrated possible abnormal parathyroid tissue in the upper pole of the left thyroid. FNA of the left thyroid nodule confirmed likely intrathyroidal parathyroid adenoma. Subsequent follow up and treatment, including parathyroidectomy, was done by another institution. She underwent a left parathyroidectomy with normalization of serum calcium and PTH levels post operatively (10.1 mg/dl and 8 pg/mL, respectively) and has complete resolution of her previous abdominal and gastrointestinal symptoms. Conclusion: PHPT is uncommon in children and adolescents and is typically associated with a single parathyroid adenoma. High index of suspicion is key for early diagnosis of PHPT despite a negative Tc-Sestamibi initially.

Congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH. Aim To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD. Methods A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations. Results The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2–8.7 years) and were assigned as male due to severe masculinization. Twenty one patients have reached adult height and sixteen were ultimately short due to delayed diagnosis. Two male patients had testicular microlithiasis and 5 (35.7%) patients had testicular adrenal rest tumor during follow up. Four patients (28.6%) had gynecomastia. Mutation analyses in 25 index patients revealed thirteen different mutations in CYP11B1 gene, 4 of which were novel (c.393 + 3A > G, c.428G > C, c.1398 + 2T > A, c.1449_1451delGGT). The most frequent mutations were c.896T > C with 32%, c.954G > A with 16% and c.1179_1180dupGA with 12% in frequency. There was not a good correlation between genotype and phenotype; phenotypic variability was observed among the patients with same mutation. Conclusion This study presents the high allelic heterogeneity of CYP11B1 mutations in CAH patients from Turkey. Three dimensional protein simulations may provide additional support for the pathogenicity of the genetic alterations. Our results provide reliable information for genetic counseling, preventive and therapeutic strategies for the families.

Chronic mucocutaneous candidiasis (CMC) is frequently associated with T cell immunodeficiencies. Specifically, the proinflammatory IL-17A–producing Th17 subset is implicated in protection against fungi at epithelial surfaces. In autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED, or autoimmune polyendocrine syndrome 1), CMC is often the first sign, but the underlying immunodeficiency is a long-standing puzzle. In contrast, the subsequent endocrine features are clearly autoimmune, resulting from defects in thymic self-tolerance induction caused by mutations in the autoimmune regulator (AIRE). We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlying CMC in both patient groups has an autoimmune basis.

Context: GH deficiency is common in childhood cancer survivors. In a previous report, although we did not find an increase in the risk of disease recurrence in survivors treated with GH, GH-treated survivors did have an increased risk of developing a second neoplasm (SN) (rate ratio, 3.21). Objective: In this analysis, we have reassessed the risk of GH-treated survivors developing an SN after an additional 32 months of follow-up. Design and Setting: We conducted a retrospective cohort multicenter study. Patients: Among a total of 14,108 survivors who were enrolled in the Childhood Cancer Survivor Study, a retrospective cohort of 5-yr survivors of childhood cancer, we identified 361 who were treated with GH. Main Outcome: We assessed the risk of developing an SN. Results: During the extended follow-up, five new SN developed in survivors treated with GH, for a total of 20 SN, all solid tumors. Using a time-dependent Cox model, the rate ratio of GH-treated survivors developing an SN, compared with non-GH-treated survivors, was 2.15 (95% confidence interval, 1.3–3.5; P < 0.002). Meningiomas were the most common SN (n = 9) among the GH-treated group. Conclusion: Although cancer survivors treated with GH appear to have an increased risk of developing SN compared with survivors not so treated, the elevation of risk due to GH use appears to diminish with increasing length of follow-up. Continued surveillance is essential.

Repeated ingestion of insulin has been suggested as an immune tolerization therapy to prevent immune-mediated (type 1) diabetes. We performed a placebo-controlled, two-dose, oral insulin tolerance trial in newly diagnosed (< 2 years) diabetic patients who had required insulin replacement for less than 4 weeks and were found to have cytoplasmic islet cell autoantibodies (ICAs). No oral hypoglycemic agents were permitted during the trial. Endogenous insulin reserves were estimated at six-month intervals by plasma C-peptide responses to a mixed meal. Positive ICAs were found in 262 (31%) of the 846 patients screened. Of the 197 who agreed to participate, 187 could be followed for 6 to 36 months. Endogenous insulin retention was dependent upon initial stimulated C-peptide response, age at diabetes onset, and numbers of specific islet cell autoantibodies found. Oral insulin improved plasma C-peptide responses in patients diagnosed at ages greater than 20 years, best seen at the low (1 mg/day) over the high (10 mg/day) insulin dose (P = .003 and P = .01, respectively). In patients diagnosed before age 20 years, the 1 mg dose was ineffective, whereas the 10 mg dose actually accelerated C-peptide loss (P = .003). There were no adverse effects. If confirmed, these findings suggest that diabetic patients over age 20 years with ICA evidence of late-onset immune-mediated diabetes should be considered for oral insulin at 1 mg/day to better retain endogenous insulin secretion.

Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-α cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-ω but not IFN-α showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.

Objective To evaluate the effects of protease inhibitors (PIs) as antiretroviral therapy in comparison with other antiretroviral (non-PI) medications on glucose tolerance, lipid metabolism, and body fat distribution in human immunodeficiency virus (HIV)-infected young patients. Methods We conducted a cross-sectional clinical study in an outpatient HIV clinic. The study population consisted of 21 patients (15 female and 6 male) who had had at least 6 months of antiretroviral treatment. The mean age of the patients was 11.9 years (range, 6 to 16.5). Results Fifteen patients treated with PIs and 6 patients treated with non-PIs were enrolled in the study. We found no significant differences in the lipid panel and insulin resistance, as determined by using the Quantitative Insulin Sensitivity Check Index formula, in the PI group in comparison with the non-PI group. Lipodystrophy was observed in 47% (7 of 15) of the PI group and 33% (2 of 6) of the non-PI group (P = 0.66). In the presence of lipodystrophy, serum triglyceride levels were higher in the PI group than in the non-PI group (P = 0.046). No such difference was found between the treatment groups when no lipodystrophy was present. There was no significant difference in insulin resistance between the treatment groups in the presence or absence of lipodystrophy. Conclusion Our study found the presence of lipodystrophy in HIV-infected young patients regardless of whether they were taking PIs or not. In the patients who had lipodystrophy, those treated with PIs had higher serum triglyceride levels than those not treated with PIs. (Endocr Pract. 2006;12:514-521)

Context: Congenital adrenal hyperplasia resulting from 17α-hydroxylase deficiency (17OHD) is a rare disorder associated with hypertension. Subject and Methods: We describe a phenotypically and hormonally affected female patient with 17OHD. DNA sequencing of her CYP17 gene revealed a maternal heterozygous mutation in exon 2 (R125Q) and a paternal heterozygous mutation in exon 8 (R416H). These are novel mutations in the CYP17 gene that completely eliminate enzyme activity. Conclusion: Identification of novel mutations in the CYP17 gene is vital in understanding the molecular mechanisms of its deficiency and in providing additional information about the structure and enzymatic functions of P450c17.

The main factor influencing the sex determination of an embryo is the genetic sex determined by the presence or absence of the Y chromosome. However, some individuals carry a Y chromosome but are phenotypically female (46,XY females) or have a female karyotype but are phenotypically male (46,XX males). 46,XX maleness is a rare sex reversal syndrome affecting 1 in 20,000 newborn males. Molecular analysis of sex-reversed patients led to the discovery of the SRY gene (sex-determining region on Y). The presence of SRY causes the bipotential gonad to develop into a testis. The majority of 46, SRY-positive XX males have normal genitalia; in contrast SRY-negative XX males usually have genital ambiguity. A small number of SRY-positive XX males also present with ambiguous genitalia. Phenotypic variability observed in 46,XX sex reversed patients cannot be explained only by the presence or absence of SRY despite the fact that SRY is considered to be the major regulatory factor for testis determination. There must be some other genes either in the Y or other autosomal chromosomes involved in the definition of phenotype. In this article, we evaluate four patients with 46,XX male syndrome with various phenotypes. Two of these cases are among the first reported to be diagnosed prenatally.