A Rare Differences of Sex Development: Male Sex Reversal Syndrome (NonSyndromic 46, XX with Negative Sex-Determining Region of Y Chromosome Gene).

46, XX testicular differences of sex development (DSD) is a rare cause of DSD presenting as a phenotypical male with chromosomal sex of 46, XX. Sex-determining region of the Y chromosome (SRY)-positive 46, XX DSDs have a well-characterized pathogenetic mechanism, whereas in SRY-negative 46, XX DSDs, the pathogenesis is not clearly delineated. Herein, we present a case of a 3½-year-old child who presented with ambiguous genitalia and bilateral palpable gonads. On the basis of a karyotype and fluorescent in situ hybridization, we arrived at a diagnosis of SRY-negative 46, XX testicular DSD. Basal serum estradiol and human menopausal gonadotrophin stimulated estradiol levels and inhibin A blood levels were against the presence of any ovarian tissue. Imaging of the gonads showed bilateral normal-looking testis. A clinical exome sequencing revealed a heterozygous missense variant NR5A1:c275G>A (p. Arg92gln) located at exon 4 in the affected child. Protein structure analysis was further performed, and the variant was found to be highly conserved. Sanger's sequencing showed that the mother was heterozygous for the variant detected in the child. This case highlights the rarity of SRY-negative 46, XX testicular DSD with a unique variant. Largely under characterized, this group of DSDs needs to be reported and analyzed to add to the spectrum of presentation and genetic characteristics. Our case is expected to add to the database, knowledge, and approach to cases of 46, XX testicular DSD.

Cytological findings of phosphaturic mesenchymal tumor: Report of a case with summary of prior published cases.

Phosphaturic mesenchymal tumor (PMT) is a rare neoplasm causing tumor-induced osteomalacia (TIO) and is characterized by secretion of FGF23, renal phosphate wasting and hypophosphataemia. It can be completely cured by resection and therefore its diagnosis is of utmost importance. Although the histology is well described, there is sparse literature on cytology of PMT and only three cases have been described so far. A 45-year-old lady presented with a non-tender mass in hard palate for 2 years from which fine-needle aspiration was done. The smears were paucicellular and showed bland spindle cells embedded in osteoid-like stromal matrix in a hemorrhagic background. Here we take the opportunity to describe the cytological findings of PMT along with its cytological differentials and a summary of prior published cases.

Toe brachial index and not ankle brachial index is appropriate in initial evaluation of peripheral arterial disease in type 2 diabetes.

BACKGROUND: Non-invasive clinic-based tools for assessing PAD are not without limitations. Therefore, costly tests like Doppler study, CT angiography and MR angiography are often required to make a diagnosis. Ankle brachial index (ABI), commonly used for assessment of PAD, has high false positivity rates in sclerosed, calcified arteries which render them non-compressible. Toe brachial index (TBI) can be an alternative, as digital arteries are relatively unaffected by these changes. AIM: To compare the reliability of ABI and TBI in diagnosing PAD in type 2 diabetes using CT angiography (CTA) as the reference. METHODS: 175 adults with T2D were selected. ABI &TBI were measured with an automated vascular Doppler XT 6 ports bilaterally for all subjects. For any subject, the limb with lower ABI and TBI was included for analysis. ABI < 0.9 & TBI < 0.6 were taken as evidence of PAD. CTA showing > 50% narrowing was taken as evidence of PAD. RESULTS: 24% of our study subjects had CTA confirmed PAD. ABI has low sensitivity of 35.29% (95% CI 0.21-0.52) compared to TBI being 82.35% (95% CI 0.66-0.92). The specificity however was similar. ABI < 0.9 was able to detect CTA confirmed PAD, but ABI > 0.9, including the so-called normal ABI (0.9-1.3) was unable to detect PAD. ROC showed ABI at 1.005 has sensitivity 64.71% (95% CI 0.48- 0.79) and specificity 61.7% (95% CI 0.53-0.69) and TBI at 0.6 has sensitivity 82.35% (95% CI 0.66-0.92) & specificity 92% (95% CI 0.87-0.96). Utilizing Cohen's Kappa, the reliability of ABI with respect to CTA showed fair agreement (K = 0.225, p = 0.001), whereas the reliability of TBI with respect to CTA showed substantial agreement (K = 0.759, p < 0.0001). CONCLUSION: ABI < 0.9 detects PAD reliably, but presence of PAD in patients with ABI > 9.0 including the normal of ABI (0.9-1.3) can be confirmed with TBI, which correlated strongly with CTA. TBI is also non-inferior for PAD detection, when ABI < 0.9. TBI and not ABI can be utilized for initial assessment of PAD in subjects with T2D.

Hypercalcemia in an Infant with Primary Hyperoxaluria Type 2: A Novel Association.

Hypercalcemia in infants presents with a variety of clinical features and the etiology of hypercalcemia varies with age. Here we present a case of hypercalcemia in an infant presenting with nephrocalcinosis and nephrolithiasis. Our investigations led us to a diagnosis of primary hyperoxaluria (PH) type 2, a rare metabolic disorder, along with hypercalcemia, a never before reported association. A 9-month-old female presented with urinary tract infection and systemic features requiring hospitalization and parenteral antibiotics. Investigations revealed bilateral medullary nephrocalcinosis. Genetic testing revealed a diagnosis of Primary hyperoxaluria type 2 with two possible mutations. Sanger sequencing of the parents identified the pathogenic mutation in the mother. This is the first report of a genetically proven case of primary hyperoxaluria type 2 associated with hypercalcemia.

Rickets in proximal renal tubular acidosis: a case series of six distinct etiologies.

OBJECTIVES: Proximal renal tubular acidosis (pRTA) is characterized by a defect in the ability of the proximal convoluted tubule to reabsorb bicarbonate. The biochemical hallmark of pRTA is hyperchloremic metabolic acidosis with a normal anion gap, accompanied by appropriate acidification of the urine (simultaneous urine pH <5.3). Isolated defects in bicarbonate transport are rare, and pRTA is more often associated with Fanconi syndrome (FS), which is characterized by urinary loss of phosphate, uric acid, glucose, amino acids, low-molecular-weight proteins, and bicarbonate. Children with pRTA may present with rickets, but pRTA is often overlooked as an underlying cause of this condition. CASE PRESENTATION: We report six children with rickets and short stature due to pRTA. One case was idiopathic, while the remaining five had a specific underlying condition: Fanconi-Bickel syndrome, Dent's disease, nephropathic cystinosis, type 1 tyrosinemia, and sodium-bicarbonate cotransporter 1-A (NBC1-A) defect. CONCLUSIONS: Five of these six children had features of FS, while the one with NBC1-A defect had isolated pRTA.

Leydig Cell Tumor-Induced Gonadotropin-Independent Precocious Puberty Progressing to Gonadotropin-Dependent Precocious Puberty Post Orchiectomy: Out of the Frying Pan Into the Fire.

Many pathologies can cause gonadotropin-independent precocious puberty (GIPP) in prepubertal boys. Leydig cell tumor is one rare cause of this presentation. Here we present a six-year-old boy with features of isosexual precocious puberty, high testosterone levels, low gonadotropin levels, and bone age advancement. Testicular USG revealed a left-sided testicular tumor. The left testis was removed surgically, and the Leydig cell tumor was confirmed on histopathology. Post orchiectomy, the boy had elevated testosterone levels with raised luteinizing hormone (LH) levels. A diagnosis of gonadotropin-dependent precocious puberty (GDPP) was made. He has been initiated on monthly gonadotropin-releasing hormone (GnRH) agonist therapy.

Van Wyk-Grumbach syndrome: a rare presentation of a common endocrine disorder.

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Glial Cell Missing Homolog 2 Mutation Causing Severe Hypoparathyroidism: Report of Two Cases With Novel Mutations.

Hypoparathyroidism is a common encounter in endocrinology practice. A thorough search for the etiology is generally futile, and most cases are labeled as idiopathic. Familial idiopathic hypoparathyroidism is a large chunk of these idiopathic cases. Here we present 2 cases who presented with features of hypocalcemia and were eventually diagnosed with hypoparathyroidism. Our first case is that of a middle-age woman who presented with spontaneous tetany and perioral numbness. She had very low serum calcium values, low serum magnesium, hypokalemia, hypercalciuria, and undetectable parathormone levels. She was initially managed with parenteral calcium, magnesium, and oral potassium chloride, which was shifted to oral replacements once stabilized. Focused exome sequencing for causes of hypoparathyroidism and hypocalcemia revealed a frameshift mutation in glial cell missing homolog 2 (GCM2) (NM_004752.4) on chromosome 6, c737dupA variant (p. Asp246Glufs*25) located at exon 5. The second case presented is that of a 1-month-old infant presenting with hypocalcemic seizures, severe hypocalcemia, hyperphosphatemia, and low parathormone levels. The infant was stabilized with parenteral calcium and trial of subcutaneous teriparatide for further improvement. Oral calcium and calcitriol were instituted once stabilized, and teriparatide was tapered off. Focused exome sequencing revealed a homozygous mutation involving GCM2 (ENST0000379491.5) on chromosome 6, variant CM2 chr6:10876558_10877139insT located on exon1-2. Both of these mutations are novel and underscore the profound effect of GCM2 on parathyroid gland development in infants and maintenance in adults.

Aromatase deficiency in a tall man: Case report of two novel mutations and review of literature.

Aromatase (CYP19A1) is the only enzyme known to catalyse the conversion of androgen to estrogen. Aromatase deficiency occurs due to mutation in CYP19A1gene which has an autosomal recessive inheritance pattern. It leads to decrease in estrogen synthesis and delayed epiphyseal closure, eunuchoid habitus and osteopenia. We are presenting here, a 24 years old male, with history of progressive increase in height and knock knees. X-ray showed open wrist and knee epiphysis. The serum testosterone level was normal and serum estradiol level was undetectable. Semen analysis showed azoospermia. Clinical exome sequencing gave two novel mutations in CYP19A1. The first variant was a novel single nucleotide deletion of thiamine at 570th base of the cDNA (c.570delT) of CYP19A1 gene. The second variant detected was again a novel one in the same gene in Exon 5 corresponding 344th base of the cDNA (c344G>A) resulting in a missense mutation of 115th arginine to glutamine in the protein. Sanger sequencing showed that the later mutation was inherited from the father. The patient was started on oral estradiol valerate for epiphyseal closure to prevent further increase in height. Only 15 mutations have been reported in the aromatase gene in males till date, our report of these novel mutations will be an add-on to the literature.

Late onset hypogonadism in type 2 diabetic and nondiabetic male: a comparative study.

Sexual dysfunction in diabetic men can result from a variety of causes of which late onset hypogonadism is now a recognised entity. The study described here was conducted to determine this entity by comparing diabetic men with age matched controls. A significant number of diabetic men had low levels of testosterone and free testosterone. Among the patients with low testosterone a large percentage had low pituitary gonadotrophic hormones signifying that the disorder was actually hypogonadotrophic hypogonadism. This finding was then correlated with various risk factors present in the diabetic patients and positive correlations were found for many parameters.

Comparison of left ventricular mass in normotensive type 2 diabetes mellitus patients with that in the nondiabetic population.

Cardiovascular disease is increased in individuals with type 1 or type 2 diabetes mellitus (DM). Left ventricular hypertrophy (LVH), which is an ominous prognostic sign and an independent risk factor for cardiac events, is often present in type 2 DM patients. The aim of our cross-sectional study was to evaluate the prevalence of LVH, and risk factors for its development, in normotensive type 2 diabetic patients without antihypertensive medication. The objectives of the study were to find out the prevalence of high left ventricular mass (LVM) in normotensive type 2 diabetic patients and compare it with nondiabetics and to uncover the risk factors for the development of high LVM in normotensive type 2 diabetic patients. A total of 130 age- and sex-matched subjects were selected (65 cases, diabetic normotensive, and 65 controls, nondiabetic normotensive) and baseline data were collected. LVM and left ventricular mass index (LVMI) were calculated using echocardigraphic parameters and body surface area. LVMI was significantly higher in patients with type 2 DM compared with age-, sex-matched healthy population (104.9 ± 21 vs. 78.5 ± 22.7 g/m(2), respectively; P < 0.05). BMI, HbA1c, and duration of diabetes were significantly associated with LVH whereas sexes, age, PPBS, were not.