Evaluating breast ultrasonography as a complementary diagnostic method in girls with central precocious puberty.

BACKGROUND: Assessment of breast development by physical examination can be difficult in the early stages and in overweight girls. OBJECTIVE: To investigate ultrasonography (US) for evaluation of early breast development. MATERIALS AND METHODS: In a prospective study, 125 girls (age 7.1 ± 1.5 years) with breast development before 8 years underwent US breast staging, breast volume, and elastography, in addition to clinical/hormonal evaluation for precocious puberty. Accuracy of US for determining breast development and predicting progression to central precocious puberty was investigated. RESULTS: Physical examination revealed glandular breast enlargement in 100 and predominantly lipomastia in 25. Breast US in the former confirmed glandular breast development in 92 (group 1, physical examination and US positive), but not in 8 (group 2, physical examination positive, US negative). Comparison of the two groups demonstrated lower Tanner and US staging, bone age/chronological age, basal luteinizing hormone (LH), breast volume, and uterine volume in group 2. In the 25 lipomastia patients, US demonstrated no breast tissue in 19 (group 3, physical examination and US negative), but US stage ≥ II in 6 (group 4, physical examination negative, US positive) without differences in clinical parameters. After follow-up of 19.8 ± 4.2 months, 46/125 subjects were diagnosed with precocious puberty. US stage, total breast volume, and shear-wave speeds were significantly higher in these 46 patients. Multivariate analyses demonstrated breast volume > 3.4 cc had odds ratio of 11.0, sensitivity of 62%, and specificity of 89, in predicting progression to precocious puberty, being second only to stimulated LH for all variables. CONCLUSION: Breast US is a useful predictive tool for diagnosis of precocious puberty in girls. Higher US stages and higher breast volume on US increased the likelihood of eventual diagnosis of precocious puberty.

International consensus on mitotane treatment in pediatric patients with adrenal cortical tumors: indications, therapy, and management of adverse effects.

OBJECTIVE: Mitotane is an important cornerstone in the treatment of pediatric adrenal cortical tumors (pACC), but experience with the drug in the pediatric age group is still limited and current practice is not guided by robust evidence. Therefore, we have compiled international consensus statements from pACC experts on mitotane indications, therapy, and management of adverse effects. METHODS: A Delphi method with 3 rounds of questionnaires within the pACC expert consortium of the international network groups European Network for the Study of Adrenal Tumors pediatric working group (ENSAT-PACT) and International Consortium of pediatric adrenocortical tumors (ICPACT) was used to create 21 final consensus statements. RESULTS: We divided the statements into 4 groups: environment, indications, therapy, and adverse effects. We reached a clear consensus for mitotane treatment for advanced pACC with stages III and IV and with incomplete resection/tumor spillage. For stage II patients, mitotane is not generally indicated. The timing of initiating mitotane therapy depends on the clinical condition of the patient and the setting of the planned therapy. We recommend a starting dose of 50 mg/kg/d (1500 mg/m²/d) which can be increased up to 4000 mg/m2/d. Blood levels should range between 14 and 20 mg/L. Duration of mitotane treatment depends on the clinical risk profile and tolerability. Mitotane treatment causes adrenal insufficiency in virtually all patients requiring glucocorticoid replacement shortly after beginning. As the spectrum of adverse effects of mitotane is wide-ranging and can be life-threatening, frequent clinical and neurological examinations (every 2-4 weeks), along with evaluation and assessment of laboratory values, are required. CONCLUSIONS: The Delphi method enabled us to propose an expert consensus statement, which may guide clinicians, further adapted by local norms and the individual patient setting. In order to generate evidence, well-constructed studies should be the focus of future efforts.

Multi-stakeholder opinion statement on the care of individuals born with differences of sex development: common ground and opportunities for improvement.

BACKGROUND: In the last 15 years, the care provided for individuals born with differences of sex development (DSD) has evolved, with a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace the current model of care. This care model has also paid insufficient attention to socio-cultural differences and global inequalities. SUMMARY: This article is an opinion statement, resulting from in-depth discussions and reflection among clinicians, patients, and family support organizations based in the US and Europe, where we seek areas of common ground and try to identify opportunities to further develop resources. The product of these conversations is summarized in 10 panels. The corresponding sections provide additional discussion on some of the panel items. KEY MESSAGES: Participants identified areas of agreement and gained a deeper understanding of the reasons behind disagreements on certain matters and identified the necessary steps to foster future consensus. We offer preliminary recommendations for guiding clinical management and resource allocation. By promoting a broader consensus, we aim to enhance the quality of care and well-being for individuals of all ages who have a DSD.

Lack of NAD(P)+ transhydrogenase activity in patients with primary adrenal insufficiency due to NNT variants.

BACKGROUND: Pathogenic variants in the nicotinamide nucleotide transhydrogenase gene (NNT) are a rare cause of primary adrenal insufficiency (PAI), as well as functional impairment of the gonads. OBJECTIVE: Despite the description of different homozygous and compound heterozygous NNT variants in PAI patients, the extent to which the function and expression of the mature protein are compromised remains to be clarified. DESIGN: The activity and expression of mitochondrial NAD(P)+ transhydrogenase (NNT) were analyzed in blood samples obtained from patients diagnosed with PAI due to genetically confirmed variants of the NNT gene (n = 5), heterozygous carriers as their parents (n = 8), and healthy controls (n = 26). METHODS: NNT activity was assessed by a reverse reaction assay standardized for digitonin-permeabilized peripheral blood mononuclear cells (PBMCs). The enzymatic assay was validated in PBMC samples from a mouse model of NNT absence. Additionally, the PBMC samples were evaluated for NNT expression by western blotting and reverse transcription quantitative polymerase chain reaction and for mitochondrial oxygen consumption. RESULTS: NNT activity was undetectable (<4% of that of healthy controls) in PBMC samples from patients, independent of the pathogenic genetic variant. In patients' parents, NNT activity was approximately half that of the healthy controls. Mature NNT protein expression was lower in patients than in the control groups, while mRNA levels varied widely among genotypes. Moreover, pathogenic NNT variants did not impair mitochondrial bioenergetic function in PBMCs. CONCLUSIONS: The manifestation of PAI in NNT-mutated patients is associated with a complete lack of NNT activity. Evaluation of NNT activity can be useful to characterize disease-causing NNT variants.

An Overlooked Manifestation of Hypercortisolism: Cerebral Cortical Atrophy and Challenges in Identifying the Etiology of Hypercortisolism - A Report of 2 Pediatric Cases.

INTRODUCTION: Endogenous Cushing's syndrome (CS) is a rare, severe disease that can cause multiple systemic involvements and behavioral problems due to excessive cortisol production. Structural changes can be noted in the brain magnetic resonance imaging (MRI) scans of these cases. CASES: A 9-year-old girl and a 13-year-old boy were admitted with hypercortisolism. In the female patient, altered consciousness was prominent along with cerebral and cerebellar brain atrophy, and findings indicating posterior reversible encephalopathy syndrome were detected in the brain MRI. Although the male patient's neurological examination was normal, significant cerebral atrophy was seen in the brain MRI. Case 1 was diagnosed as having ectopic ACTH syndrome (EAS) due to a thymic carcinoid tumor. Case 2 underwent a pulmonary lobectomy upon detection of a bronchial lesion in the Ga-68 DOTATATE PET/CT scan while being examined for EAS due to a lack of suppression in the high-dose dexamethasone suppression test. However, hypercortisolism persisted despite the removal of the bronchial lesion, and subsequently, a diagnosis of Cushing's disease was established following bilateral inferior petrosal sinus sampling. DISCUSSION: Endogenous hypercortisolism may cause brain atrophy of varying severity. The central nervous system findings can be overlooked in children with CS. More comprehensive studies are needed to better understand the behavioral changes caused by the effects on the brain and to evaluate whether these changes are reversible. In addition, identifying the source of hypercortisolism can be difficult due to a lack of experience related to the rarity of the disease in children.

Bone Phenotype is Always Present But Androgen Excess is Less Frequently Seen in PAPSS2 Deficiency

3'-Phosphoadenosine 5'-phosphosulfate synthase 2 (PAPSS2) deficiency is a rare disorder due to biallelic pathogenic variants in the PAPSS2 gene. This disorder was first described in 1998 by Ahmad et al. and Faiyaz ul Haque et al. To date, 79 patients with PAPSS2 deficiency have been reported. The main reported features of these patients are related to bone abnormalities and clinical/biochemical androgen excess. Disproportionate short stature and symptoms associated with spondylar skeletal dysplasia are the most common clinical features that require clinical attention. Androgen excess has been described much less commonly. This review summarizes the currently published clinical, molecular, and biochemical features of patients with PAPSS2 deficiency.

Development of external genitalia during mini-puberty: is it related to somatic growth or reproductive hormones?

Although hypothalamo-pituitary-gonadal axis is active during mini-puberty, its relationship with somatic growth and the role on the development of external genitalia has not been fully elucidated. We aimed to evaluate the effects of somatic growth and reproductive hormones on the development of external genitalia during mini-puberty. Anthropometric data, pubertal assesment, serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), sex-hormone binding globulin (SHBG), estradiol (E2) and inhibin-B, testosterone (T), and anti-Mullerian Hormone (AMH) of healthy infants aged 1-4 months were evaluated. Free sex hormone index was calculated as T/SHBG for boys and E2/SHBG for girls. The mean age of 148 (74 female) infants included in the study was 2.31 ± 0.76 months. Tanner stage 2-3 sex steroid and gonadotropin levels were observed. A statistically significant difference was found between the weight, height, BMI, weight gain and serum FSH, LH, and A4 measurements of girls and boys (p < 0.05). Penile length was associated with weight (r = 0.24, p = 0.03), height (r = 0.25, p = 0.02), and AMH (r = 0.3, p = 0.01), but not with testosterone (p = 0.56 respectively). A negative correlation was found between weight and serum LH (r = - 0.26, p = 0.2) and T/SHBG levels in males (r = - 0.38, p = 0.015 respectively). Weight-SDS was negatively correlated with testosterone in males (r = - 0.25, p = 0.02). Testicular size and breast stage did not correlate with any of the hormonal and anthropometric parameters.  Conclusions: External genitalia in males during mini-puberty is related more to somatic growth rather than reproductive hormones. Similar to pubertal developmental stages, both total and free testosterone are negatively associated with higher weight during mini-puberty. What is Known: • Mini-puberty allows early assessment of HPG axis function in infancy. • There is an inverse relationship between the amount of adipose tissue and circulating testosterone levels in males during puberty and adulthood. • The potential effect of somatic growth and reproductive hormones on external genital development during mini-puberty remains unclear. What is New: • During mini-puberty, males' external genitalia is more related to somatic growth than to reproductive hormones, but this relationship is not observed in girls. • Both total and free testosterone are negatively associated with higher weight during mini-puberty, similar to the pubertal developmental stages.

Rare forms of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders due to pathogenic variants in genes encoding enzymes and cofactors involved in adrenal steroidogenesis. Although 21-hydroxylase, 11ß-hydroxylase, 3ß-hydroxysteroid dehydrogenase type 2, 17α-hydroxylase/17,20-lyase, P450 oxidoreductase, steroidogenic acute regulatory protein, cholesterol side-chain cleavage enzyme deficiencies are considered within the definition of CAH, the term 'CAH' is often used to refer to '21-hydroxylase deficiency (21OHD)' since 21OHD accounts for approximately 95% of CAH in most populations. The prevalence of the rare forms of CAH varies according to ethnicity and geographical location. In most cases, the biochemical fingerprint of impaired steroidogenesis points to the specific subtypes of CAH, and genetic testing is usually required to confirm the diagnosis. Despite there are significant variations in clinical characteristics and management, most data about the rare CAH forms are extrapolated from 21OHD. This review article aims to collate the currently available data about the diagnosis and the management of rare forms of CAH.

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

Venous thrombosis in a pseudohypoparathyroidism patient with a novel GNAS frameshift mutation and complete resolution of vascular calcifications with acetazolamide treatment.

Introduction Pseudohypoparathyroidism type IA (PHP1A) is characterized by end-organ resistance to multiple hormones and Albright's hereditary osteodystrophy (AHO). PHP1A is caused by inactivating mutations of the GNAS gene encoding the α-subunit of the stimulatory G protein (Gsα). In line with the underlying genetic defect, impaired inhibition of platelet aggregation has been demonstrated in some patients. However, no PHP1A case with thrombotic events has been described. Also, PHP1A cases typically have subcutaneous ossifications, but soft tissue calcifications are another common finding. Treatment options for those and other non-hormonal features of PHP1A are limited. Case Presentation A female patient presented with short stature, fatigue, and exercise-induced carpopedal spasms at age 117/12 years. Diagnosis of PHP1A was made based on hypocalcemia, hyperphosphatemia, elevated serum PTH, and AHO features, including short stature and brachydactyly. A novel frameshift variant was detected in the last exon of GNAS (c.1065_1068delGCGT, p.R356Tfs*47), showing complete loss of baseline and receptor-stimulated activity in transfected cells. The patient developed venous thrombosis and vascular and subcutaneous calcifications on both forearms after venous puncture on the right and extravasation of calcium gluconate during treatment on the left. The thrombosis and calcifications completely resolved following treatment with low molecular weight heparin and acetazolamide for 5 and 8 months, respectively. Conclusions This case represents the first PHP1A patient displaying thrombosis and the first successful use of acetazolamide for PHP1A-associated soft tissue calcifications, thus providing new insights into the treatment of non-endocrinological features in this disease.

Predictors of surgical complications in boys with hypospadias: data from an internationa registry.

Background: Complications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence. Methods: Data from boys with hypospadias born between 2000 and 2020 were obtained from the International Disorders of Sex Development (I-DSD) Registry. Logistic regressions, fisher's exact tests and spearman's correlation tests were performed on the data to assess associations between clinical factors and complication rates. Results: Of the 551 eligible boys, data were available on 160 (29%). Within the cohort, the median (range) External Masculinization Score (EMS) was 6 (2, 9). All presented with one or more additional genital malformation and 61 (38%) presented with additional extragenital malformations. Disorders of androgen action, androgen synthesis and gonadal development were diagnosed in 28 (18%), 22 (14%) and 9 (6%) boys, respectively. The remaining 101 (62%) patients were diagnosed as having non-specific 46,XY Disorders of Sex Development. Eighty (50%) boys had evidence of abnormal biochemistry, and gene variants were identified in 42 (26%). Median age at first hypospadias surgery was 2 years (0, 9), and median length of follow-up was 5 years (0, 17). Postsurgical complications were noted in 102 (64%) boys. There were no significant associations with postsurgical complications. Conclusions: Boys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation.

Molecular analysis of MKRN3 gene in Turkish girls with sporadic and familial idiopathic central precocious puberty.

OBJECTIVES: Central precocious puberty (CPP) develops as a result of early stimulation of the hypothalamic-pituitary-gonadal (HPG) axis. The loss-of-function mutations in the Makorin-ring-finger3 (MKRN3) gene appear to be the most common molecular cause of familial CPP. We aimed to identify MKRN3 gene mutations in our CPP cohort and to investigate the frequency of MKRN3 mutations. METHODS: 102 patients with CPP included. 53 of them had family history of CPP in the first and/or second-degree relatives. MKRN3 gene was analyzed by next-generation sequencing. RESULTS: Possible pathogenic variants were found in 2/53 patients with family history of CPP (3.8%) and 1/49 patient without family history (2%). A novel heterozygous c.1A>G (p.Met1Val) mutation, a novel heterozygous c.683_684delCA (p.Ser228*) and a previously reported c.482dupC (Ala162Glyfs*) frameshift variations were detected. The two novel variants are predicted to be pathogenic in silico analyses. CONCLUSIONS: In our cohort, possible pathogenic variants in MKRN3 gene were detected in 2.9% of the total cohort, 3.8% of the familial and 2% of the nonfamilial cases, slightly lower than that reported in the literature. Two novel variants detected contribute to the molecular repertoire of MKRN3 defects in CPP. Classical pattern of paternal inheritance has been demonstrated in all three cases. However, the father of the patient 3 did not have history of CPP suggesting that the father inherited this variant from his mother and had phenotype skipping. Therefore, we emphasize that the absence of history of CPP in the father does not exclude the possibility of a MKRN3 mutation.

Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls.

INTRODUCTION: Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls. METHODS: The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls. RESULTS: Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment. CONCLUSION: In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.

Challenges in the Management of a 7-Year-Old Child with Thyrotropin-Secreting Pituitary Adenoma and the Review of the Literature.

INTRODUCTION: Thyrotropin-producing pituitary adenoma (TSHoma) is a very rare disease, representing less than 1% of the pituitary tumours and presenting with elevated thyroid hormones and normal/high TSH concentrations. CASE PRESENTATION: A 7-year-old boy with nervousness was referred by his psychiatrist for elevated free T4, T3, and TSH levels. Initial evaluation revealed an elevated α-subunit. Pituitary magnetic resonance imaging (MRI) demonstrated a macroadenoma. The patient underwent a trans-sphenoidal tumour resection (TSS) which showed positive immunohistochemical staining for TSH, growth hormone, and prolactin in tumoral tissue. Euthyroidism was achieved for 1 year after TSS, then recurrence of tumour with elevated TSH and thyroid hormone levels necessitated a re-operation with TSS followed by gamma-knife radiosurgery. The euthyroid state was achieved and lasted for 2.5 years this time, but due to the recurrence, medical treatment had been commenced with cabergoline and octreotide. Euthyroidism was maintained for the last 4 years on monthly octreotide treatment. A repeat MRI demonstrated no pituitary mass, but a mass in the sphenoidal sinus had been detected. Removal of this mass by surgery did not achieve euthyroidism. 68Ga-DOTA-TATE positron emission tomography/computed tomography showed residual tissue extending from the pituitary region to the sphenoid sinus. The patient's bone age was advanced by 2 years at diagnosis which became 4 years in 1 year after the diagnosis and remained so throughout follow-up, leading to a final height of -3.3 SDS below his target height at the age of 16 years. CONCLUSION: The diagnosis, treatment, and follow-up of TSHomas are challenging, and short stature due to accelerated bone maturation is a complication of paediatric TSHomas.

Decline in the Age of Menarche in Istanbul Schoolgirls Over the Last 12 Years

Objective: Menarche is the endpoint of a sequence of maturational events of female puberty. The timing of menarche is a strongly heritable trait. However, secular trends suggest that lifestyle and environmental factors are important. To assess the trend in age at menarche (AAM), and its associated factors in Istanbul over the last 12 years. Methods: A cross-sectional study was carried out between March and April 2022 on schoolgirls aged 9-18 years. A predesigned and self-administered questionnaire was filled out anonymously by the students. The data of AAM was included in the statistical analysis if the time of AAM is remembered in both months and years. A probit model was used to calculate the median AAM. The findings were compared with those from a study performed 12 years ago in the same region of Istanbul. Results: Among 9000 girls to whom the questionnaire was distributed, 1749 (19.5%) responded. The median AAM of 1374 girls whose AAM information was considered valid was 12.04 years (95% confidence interval: 12.01-12.13), 0.7 years lower than was reported 12 years ago (p<0.0001). AAM was correlated positively with maternal AAM, and negatively with body mass index (BMI) standard deviation score and maternal educational status (p<0.0001, p<0.0001 and p=0.002), respectively. There was no correlation between the AAM and birth weight. Girls with BMI percentile ≥85% (n=251) had earlier menarche than the ones with BMI percentile <85% (n=1072) (11.5 vs. 12.1 years, p<0.0001). Among the mother-daughter pairs (n=1162), AAM of girls was 0.91 years (median 0.94 years) earlier than their mothers. Conclusion: The present study demonstrates a significant downward trend in the menarcheal age in Istanbul over the last twelve years. These findings support a strong contribution from genetic factors and BMI on AAM.

Non-hormonal Clitoromegaly due to Clitoral Priapism Caused by Appendicitis/Appendectomy

Clitoromegaly usually develops due to hyperandrogenism. There are a few cases of clitoromegaly described without clinical and biochemical hyperandrogenism. Clitoromegaly due to clitoral priapism and clitoral priapism after appendectomy have not been reported previously. A 7-year-old girl was referred for enlargement of the clitoris. She reported having a mild, pulsating clitoral pain starting three days after an appendectomy operation. Subsequently, painful swelling and an increase in the size of the clitoris was observed. Her growth and physical examination were otherwise normal. Causes of the clitoromegaly due to androgen excess were excluded after a comprehensive work-up. Color Doppler ultrasound revealed a high peak systolic velocity and resistance in the cavernosal artery, consistent with clitoral priapism. The clitoromegaly and associated symptoms improved significantly with oral pseudoephedrine and intracavernosal aspiration. This unique case illustrates that clitoral priapism is a rare, non-hormonal cause of clitoromegaly and may occur after appendectomy. Pseudoephedrine treatment is helpful in alleviating the symptoms.

Genotype of congenital adrenal hyperplasia patients with testicular adrenal rest tumor.

Testicular adrenal rest tumor (TART) is one of the important complications that can cause infertility in male patients with congenital adrenal hyperplasia (CAH) and should therefore be diagnosed and treated at an early age. The factors that result in TART in CAH have not been completely understood. The aim of this study is to evaluate the genotype-phenotype correlation in CAH patients with TART. METHOD: Among 230 malepatients with CAH who were followed upwith regular scrotal ultrasonography in 11 different centers in Turkey, 40 patients who developed TARTand whose CAH diagnosis was confirmed by genetic testing were included in this study. Different approaches and methods were used for genotype analysis in this multicenter study. A few centers first screened the patients for the ten most common mutations in CYP21A2 and performed Sanger sequencing for the remaining regions only if these prior results were inconclusive while the majority of the departments adopted Sanger sequencing for the whole coding regions and exon-intron boundaries as the primary molecular diagnostic approach for patients with either CYP21A2 orCYP11B1 deficiency. The age of CAH diagnosis and TART diagnosis, type of CAH, and identified mutations were recorded. RESULTS: TART was detected in 17.4% of the cohort [24 patients with salt-wasting (SW) type, four simple virilizing type, and one with nonclassical type with 21-hydroxylase (CYP21A2) deficiency and 11 patients with 11-beta hydroxylase (CYP11B1) deficiency]. The youngest patients with TART presenting with CYP11B1 and CYP21A2 deficiency were of 2 and 4 years, respectively. Eight different pathogenic variants in CYP21A2were identified. The most common genotypes were c.293-13C>G/c.293-13C>G (31%) followed by c.955C>T/c.955C>T(27.6%) and c.1069C>T/c.1069C>T (17.2%). Seven different pathogenic variants were identified in CYP11B1. The most common mutation in CYP11B1 in our study was c.896T>C (p.Leu299Pro). CONCLUSION: We found that 83% TART patients were affected with SW typeCYP21A2 deficiency,and the frequent mutations detected were c.955C>T (p.Gln319Ter), c.293-13C>G in CYP21A2 and c.896T>C (p.Leu299Pro) inCYP11B1. Patients with CYP11B1 deficiency may develop TART at an earlier age. This study that examined the genotype-phenotype correlation in TART may benefit further investigations in larger series.

Dysosteosclerosis: Clinical and Radiological Evolution Reflecting Genetic Heterogeneity.

Dysosteosclerosis (DSS), the term coined in 1968 for ultrarare dysplasia of the skeleton featuring platyspondyly with focal appendicular osteosclerosis, has become generic by encompassing the genetic heterogeneity recently reported for this phenotype. We studied four unrelated Turkish patients with DSS to advance understanding of the new nosology. Patient 1 suffered femur fractures beginning at age 1 year. DSS was suspected from marked metaphyseal osteosclerosis in early childhood and subsequently platyspondyly accompanying patchy osteosclerosis of her appendicular skeleton. She harbored in SLC29A3, in 2012 the first gene associated with DSS, a unique homozygous duplication (c.303_320dup, p.102_107dupYFESYL). Patient 2 presented similarly with fractures and metaphyseal osteosclerosis but with no platyspondyly at age 2 months. She was homozygous for a novel nonsense mutation in SLC29A3 (c.1284C>G, p.Tyr428*). Patient 3 had ocular disease at age 2 years, presented for short stature at age 11 years, and did not begin to fracture until age 16 years. Radiographs showed mild platyspondyly and focal metaphyseal and femoral osteosclerosis. She was homozygous for a unique splice site mutation in TNFRSF11A (c.616+3A>G). Patient 4 at age 2 years manifested developmental delay and frequent infections but did not fracture. He had unique metadiaphyseal splaying and osteosclerosis, vertebral end-plate osteosclerosis, and cortical thinning of long bones but no mutation was detected of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, or CSF1R associated with DSS. We find that DSS from defective SLC29A3 presents earliest and with fractures. DSS from compromised TNFRSF11A can lead to optic atrophy as an early finding. Negative mutation analysis in patient 4 suggests further genetic heterogeneity underlying the skeletal phenotype of DSS. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A homozygous Y443C variant in the RNPC3 is associated with severe syndromic congenital hypopituitarism and diffuse brain atrophy.

Biallelic RNPC3 variants have been reported in a few patients with growth hormone deficiency, either in isolation or in association with central hypothyroidism, congenital cataract, neuropathy, developmental delay/intellectual disability, hypogonadism, and pituitary hypoplasia. To describe a new patient with syndromic congenital hypopituitarism and diffuse brain atrophy due to RNPC3 mutations and to compare her clinical and molecular characteristics and pituitary functions with previously published patients. A 20-year-old female presented with severe growth, neuromotor, and developmental delay. Her weight, height, and head circumference were 5135 gr (-25.81 SDS), 68 cm (-16.17 SDS), and 34 cm (-17.03 SDS), respectively. She was prepubertal, and had dysmorphic facies, contractures, and spasticity in the extremities, and severe truncal hypotonia. There were no radiological signs of a skeletal dysplasia. The bone age was extremely delayed at 2 years. Investigation of pituitary function revealed growth hormone, prolactin, and thyroid-stimulating hormone deficiencies. Whole-exome sequencing revealed a novel homozygous missense (c.1328A > G; Y443C) variant in RNPC3. Cranial MRI revealed a hypoplastic anterior pituitary with diffuse cerebral and cerebellar atrophy. The Y443C variant in RNPC3 associated with syndromic congenital hypopituitarism and abnormal brain development. This report extends the RNPC3-related hypopituitarism phenotype with a severe neurodegenerative presentation.