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

Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man

notes: PMCID: PMC3887257This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Understanding transcriptional regulation of pancreatic development is required to advance current efforts in developing beta cell replacement therapies for patients with diabetes. Current knowledge of key transcriptional regulators has predominantly come from mouse studies, with rare, naturally occurring mutations establishing their relevance in man. This study used a combination of homozygosity analysis and Sanger sequencing in 37 consanguineous patients with permanent neonatal diabetes to search for homozygous mutations in 29 transcription factor genes important for murine pancreatic development. We identified homozygous mutations in 7 different genes in 11 unrelated patients and show that NKX2-2 and MNX1 are etiological genes for neonatal diabetes, thus confirming their key role in development of the human pancreas. The similar phenotype of the patients with recessive mutations and mice with inactivation of a transcription factor gene support there being common steps critical for pancreatic development and validate the use of rodent models for beta cell development.Wellcome TrustDiabetes UKEuropean Community’s Seventh Framework Programme (FP7/2007-2013

Familial central precocious puberty suggests autosomal dominant inheritance

The prevalence of precocious puberty is higher in certain ethnic groups, and some cases may be familial. The aim of this study was to investigate the mode of inheritance of familial precocious puberty and to identify characteristics that distinguish familial from isolated precocious puberty. Of the 453 children referred to our center for suspected precocious puberty between January 1, 1997, and December 31, 2000, 156 (147 girls and 9 boys) were found to have idiopathic central precocious puberty, which was familial in 43 (42 girls and 1 boy) (27.5%). Data of the familial and sporadic cases were compared. The familial group was characterized by a significantly lower maternal age at menarche than the sporadic group (mean, 11.47 ؎ 1.96 vs. 12.66 ؎ 1.18 yr; P ‫؍‬ 0.0001) and more advanced puberty at admission (Tanner stage 2, 56.5% vs. 78.1%; P ‫؍‬ 0.006). Segregation analysis was used to study the mode of inheritance. The segregation ratio for precocious puberty was 0. (1) demonstrated that puberty may occur at an earlier age than previously thought, with a rate of early puberty four times higher in African-American girls than in Caucasian girls. This observation suggested a genetic regulation of the timing of puberty. Some pediatric endocrinologists believe that the pubertal pattern may be influenced by familial trends, such that families with one member with precocious puberty have a higher than normal probability of having another. However, scientific support for this assumption remains sparse. We found only a few published descriptions of cases of familial central precocious puberty (2-6) and only one study (3) of the prevalence of familial cases in a series of 58 patients with central precocious puberty. In the present study, we sought to determine the mode of inheritance of familial precocious puberty (FPP) in families with central precocious puberty and to identify specific clinical or laboratory features that distinguish familial from sporadic cases. We also calculated the prevalence of FPP at our tertiary care center in a given period of time. Patients and Methods Patients Of the 453 children evaluated in our clinic for precocious secondary sexual development between January 1, 1997, and December 31, 2000, 156 were found to have idiopathic central precocious puberty. The rest presented with precocious adrenarche (n ϭ 101), early puberty (n ϭ 89), premature thelarche (n ϭ 58), obesity associated with pseudothelarche (n ϭ 19), and other diagnoses (n ϭ 26); four were lost to follow-up. The diagnosis of precocious puberty was based on the presence of secondary sexual characteristics before age 8 yr in females and 9 yr in males. In girls, central precocious puberty was diagnosed on the basis of clinical characteristics, including appearance of breast buds before 8 yr of age accompanied by the presence of one or more of the following findings: menses, pubic hair, accelerated growth velocity, or bone age greater than 2 sd above chronological age. When the clinical picture was not obvious, the patients were followed for at least 6 months before the diagnosis was made. Adopted girls were excluded, as were girls with chronic disease, bone dysplasia, organic brain disease, congenital adrenal hyperplasia or other endocrinological abnormalities, and girls who had received radiation therapy and/or chemotherapy. Written informed consent was obtained from all families. The study was approved by the institutional human research committee. Methods At the first visit, the pedigree was determined, detailing medical illnesses and timing of puberty in family members. The parents completed a structured questionnaire including items on puberty in first-, second-, and third-degree relatives, and they were asked to contact directly the children's grandparents, aunts, uncles, and cousins to determine the age of puberty directly from them. We collected the data by contacting the parents by phone. First-degree relatives were defined as mother, father, brother(s), and sister(s); second-degree relatives as grandparents, aunt(s), and uncle(s); and third-degree relatives as cousins. Females were asked about age at appearance of breast buds and age at menarche and males about age at onset of pubertal changes and age at initiation of full-face shaving. Those who met the following criteria were included in the study group of FPP: 1) presentation with gonadotropin-dependent central precocious puberty, as described above; and 2) at least one of the following: menarche at age 10 yr or earlier in a first-, second-, or third-degree female relative; clinically documented precocious puberty, as described above, in a first-, second-, or third-degree relative; or full puberty, including full facial shaving, earlier than age 13 yr in a first-, second-, or third-degree male relative. [For Jewish males, age 13 (bar mitzvah) is a significant and well-remembered milestone.] Girls with idiopathic central precocious puberty without a family history were considered to have sporadic precocious puberty (SPP). All patients underwent clinical, biochemical, and bone age evaluation on admission. Pubertal stage was determined according to Marshall and Abbreviations: BMI, Body mass index; FPP, familial precocious puberty; SDS, sd score; SPP, sporadic precocious puberty. JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community

The Natural History of Metabolic Comorbidities in Turner Syndrome from Childhood to Early Adulthood: Comparison between 45,X Monosomy and Other Karyotypes

ObjectivePatients with Turner syndrome (TS) are at increased risk for metabolic disorders. We aimed to delineate the occurrence and evolution of metabolic comorbidities in TS patients and to determine whether these differ in 45,X monosomy and other karyotypes.MethodsA longitudinal and cross-sectional retrospective cohort study was conducted in a tertiary pediatric endocrine unit during 1980–2016. Ninety-eight TS patients, 30 with 45,X monosomy were followed from childhood to early adulthood. Outcome measures included weight status, blood pressure (BP), glucose metabolism, and lipid profile.ResultsLongitudinal analysis showed a significant change in body mass index (BMI) percentiles over time [F(3,115) = 4.8, P = 0.003]. Age was associated with evolution of elevated BP [systolic BP: odds ratio (OR) = 0.91, P = 0.003; diastolic BP: OR = 0.93, P = 0.023], impaired glucose metabolism (HbA1c: OR = 1.08, P = 0.029; impaired glucose tolerance: OR = 1.12, P = 0.029), and abnormal lipid profile (cholesterol: OR = 1.06, P = 0.01; low-density lipoprotein cholesterol: OR = 1.07, P = 0.041; high-density lipoprotein cholesterol: OR = 1.07, P = 0.033). The occurrence of metabolic comorbidities was similar in 45,X monosomy and other karyotypes. Coexistence of multiple metabolic comorbidities was significantly higher in 45,X monosomy [F(1,72) = 4.81, P = 0.032]. BMI percentiles were positively correlated with metabolic comorbidities (occurrence and number) in each patient (r = 0.35, P = 0.002 and r = 0.383, P = 0.001, respectively).ConclusionOur longitudinal study provides unique insights into the evolution of weight gain and metabolic disorders from childhood to early adulthood in TS patients. Since overweight and increasing age aggravate the risk for metabolic comorbidities, careful surveillance is warranted to prevent and control obesity already from childhood. The more prominent clustering of metabolic comorbidities in 45,X monosomy underscores the importance of a more vigorous intervention in this group

Homozygous truncating PTPRF mutation causes athelia

Athelia is a very rare entity that is defined by the absence of the nipple-areola complex. It can affect either sex and is mostly part of syndromes including other congenital or ectodermal anomalies, such as limb-mammary syndrome, scalp-ear-nipple syndrome, or ectodermal dysplasias. Here, we report on three children from two branches of an extended consanguineous Israeli Arab family, a girl and two boys, who presented with a spectrum of nipple anomalies ranging from unilateral hypothelia to bilateral athelia but no other consistently associated anomalies except a characteristic eyebrow shape. Using homozygosity mapping after single nucleotide polymorphism (SNP) array genotyping and candidate gene sequencing we identified a homozygous frameshift mutation in PTPRF as the likely cause of nipple anomalies in this family. PTPRF encodes a receptor-type protein phosphatase that localizes to adherens junctions and may be involved in the regulation of epithelial cell-cell contacts, peptide growth factor signaling, and the canonical Wnt pathway. Together with previous reports on female mutant Ptprf mice, which have a lactation defect, and disruption of one allele of PTPRF by a balanced translocation in a woman with amastia, our results indicate a key role for PTPRF in the development of the nipple-areola region

Consensus statement on the use of gonadotropin-releasing hormone analogs in children.

OBJECTIVE: Gonadotropin-releasing hormone analogs revolutionized the treatment of central precocious puberty. However, questions remain regarding their optimal use in central precocious puberty and other conditions. The Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology convened a consensus conference to review the clinical use of gonadotropin-releasing hormone analogs in children and adolescents. PARTICIPANTS: When selecting the 30 participants, consideration was given to equal representation from North America (United States and Canada) and Europe, an equal male/female ratio, and a balanced spectrum of professional seniority and expertise. EVIDENCE: Preference was given to articles written in English with long-term outcome data. The US Public Health grading system was used to grade evidence and rate the strength of conclusions. When evidence was insufficient, conclusions were based on expert opinion. CONSENSUS PROCESS: Participants were put into working groups with assigned topics and specific questions. Written materials were prepared and distributed before the conference, revised on the basis of input during the meeting, and presented to the full assembly for final review. If consensus could not be reached, conclusions were based on majority vote. All participants approved the final statement. CONCLUSIONS: The efficacy of gonadotropin-releasing hormone analogs in increasing adult height is undisputed only in early-onset (girls <6 years old) central precocious puberty. Other key areas, such as the psychosocial effects of central precocious puberty and their alteration by gonadotropin-releasing hormone analogs, need additional study. Few controlled prospective studies have been performed with gonadotropin-releasing hormone analogs in children, and many conclusions rely in part on collective expert opinion. The conference did not endorse commonly voiced concerns regarding the use of gonadotropin-releasing hormone analogs, such as promotion of weight gain or long-term diminution of bone mineral density. Use of gonadotropin-releasing hormone analogs for conditions other than central precocious puberty requires additional investigation and cannot be suggested routinely

Surgical Practice in Girls with Congenital Adrenal Hyperplasia: An International Registry Study.

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life