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The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from sixteen CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype–phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.

Purpose Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. Methods Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the NIH (ClinicalTrials.gov identifier: NCT02890342). Results Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P

Introduction Congenital facial weakness (CFW) can result from facial nerve paresis with or without other cranial nerve and systemic involvement, or generalized neuropathic and myopathic disorders. Moebius syndrome is one type of CFW. In this study we explored the utility of electrodiagnostic studies (EDx) in the evaluation of individuals with CFW. Methods Forty-three subjects enrolled prospectively into a dedicated clinical protocol and had EDx evaluations, including blink reflex and facial and peripheral nerve conduction studies, with optional needle electromyography. Results MBS and hereditary congenital facial paresis (HCFP) subjects had low-amplitude cranial nerve 7 responses without other neuropathic or myopathic findings. Carriers of specific pathogenic variants in TUBB3 had, in addition, a generalized sensorimotor axonal polyneuropathy with demyelinating features. Myopathic findings were detected in individuals with Carey-Fineman-Ziter syndrome, myotonic dystrophy, other undefined myopathies, or CFW with arthrogryposis, ophthalmoplegia, and other system involvement. Discussion EDx in CFW subjects can assist in characterizing the underlying pathogenesis, as well as guide diagnosis and genetic counseling.

Treatment of congenital adrenal hyperplasia (CAH) is suboptimal. Inadequate suppression of androgens and glucocorticoid excess are common and current glucocorticoid formulations cannot replace the cortisol circadian rhythm.The primary objective was to characterize the pharmacokinetic profile of Chronocort, a modified-release hydrocortisone formulation, in adults with CAH. Secondary objectives included examining disease control following 6 months of Chronocort with dose titration.Sixteen adults (eight females) with classic CAH participated in an open-label, nonrandomized, Phase 2 study at the National Institutes of Health Clinical Center. Twenty-four-hour blood sampling was performed on conventional glucocorticoids and following 6 months of Chronocort. Chronocort was initiated at 10 mg (0700 h) and 20 mg (2300 h). Dose titration was performed based on androstenedione and 17-hydroxyprogresterone (17-OHP) levels and clinical symptomatology.The primary outcome was cortisol pharmacokinetics of Chronocort and secondary outcomes included biomarkers of CAH control (androstenedione and 17-OHP).In patients with CAH, Chronocort cortisol profiles were similar to physiologic cortisol secretion. Compared with conventional therapy, 6 months of Chronocort resulted in a decrease in hydrocortisone dose equivalent (28 ± 11.8 vs 25.9 ± 7.1 mg/d), with lower 24-hour (P = .004), morning (0700-1500 h; P = .002), and afternoon (1500-2300 h; P = .011) androstenedione area under the curve (AUC) and lower 24-hour (P = .023) and morning (0700-1500 h; P = .02) 17-OHP AUC.Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.

Described more than 150 years ago by Thomas Addison, adrenal gland dysfunction, while treatable, remains a clinically significant and potentially fatal disease. Vague and non-specific symptomatology can delay diagnosis of adrenal insufficiency and lead to adrenal crisis. Affected individuals may delay self-management due to knowledge deficits or lack of required therapies. Advanced practice nurses must remain vigilant for signs and symptoms of adrenal insufficiency and prevention of crisis. Education of patients and their caregivers/family members must emphasize early intervention with regards to adrenal insufficiency in order to prevent adrenal crisis. Repetition of education about sick day rules and demonstration of intramuscular injections should be incorporated as part of the routine follow-up care of all individuals to enhance their confidence and self-efficacy in self-management of adrenal insufficiency.

A 20-month-old female presented with bloody discharge in her diaper. Significant findings on her physical examination included length greater than the 95th percentile, Tanner stage 2 breasts, and a large, light brown macule on her lower back near the crease of her buttocks with jagged edges that did not cross the midline. Pelvic ultrasound showed a large unilateral ovarian cyst. Skeletal maturity (bone age) was advanced. A 5-year-old male presented with leg pain and limp following a minor fall during a pillow fight with his brother. Radiographs showed a fracture at the site of a fibrous dysplastic lesion in the femoral neck with “ground glass” appearance. He had two light brown birthmarks with irregular borders on his posterior neck and chest. Neither crossed the midline of his body nor had changed much in size. These children had different clinical presentations, but they share the diagnosis of McCune–Albright syndrome. An overview of the clinical features of McCune–Albright syndrome follows.

Patients with congenital adrenal hyperplasia (CAH) often suffer from long-term complications secondary to chronic glucocorticoid therapy and suboptimal treatment regimens.The aim of the study was to describe clinical characteristics of a large cohort of pediatric and adult CAH patients.We conducted a cross-sectional study of 244 CAH patients [183 classic, 61 nonclassic (NC)] included in a Natural History Study at the National Institutes of Health.Outcome variables of interest were height sd score, obesity, hypertensive blood pressure (BP), insulin resistance, metabolic syndrome, bone mineral density, hirsutism (females), and testicular adrenal rest (TART).The majority had elevated or suppressed androgens, with varied treatment regimens. Mean adult height SD score was -1.0 ± 1.1 for classic vs. -0.4 ± 0.9 for NC patients (P = 0.015). Obesity was present in approximately one third of patients, across phenotypes. Elevated BP was more common in classic than NC patients (P ≤ 0.01); pediatric hypertensive BP was associated with suppressed plasma renin activity (P = 0.001). Insulin resistance was common in classic children (27%) and adults (38% classic, 20% NC); 18% of adults had metabolic syndrome. The majority (61%) had low vitamin D; 37% of adults had low bone mineral density. Hirsutism was common (32% classic; 59% NC women). TART was found in classic males (33% boys; 44% men).Poor hormonal control and adverse outcomes are common in CAH, necessitating new treatments. Routine monitoring of classic children should include measuring BP and plasma renin activity. Osteoporosis prophylaxis and TART screening should begin during childhood. A longitudinal study is under way.

Adrenalectomy is an experimental treatment option for select patients with congenital adrenal hyperplasia who have failed medical therapy. After adrenalectomy, adrenal rest tissue can remain in extraadrenal locations, cause recurrent hyperandrogenism, and be difficult to localize.The aim of the study was to investigate the usefulness of positron emission tomography/computerized tomography (PET/CT) in identifying adrenal rest tissue.A female with salt-wasting 21-hydroxylase deficiency who had bilateral adrenalectomy at age 17 yr presented with hyperandrogenism at age 32 yr. Pelvic magnetic resonance imaging and ultrasound imaging were nondiagnostic for the source of androgen production.A baseline F-18 labeled fluoro-2-deoxy-d-glucose (18F-FDG) PET/CT scan showed no active uptake; however, a second scan preceded by a 250-μg cosyntropin injection identified three areas of active uptake near both ovaries. Subsequent ovarian venous sampling showed elevations in 17-hydroxyprogesterone, androstenedione, and 21-deoxycortisol in both ovarian veins compared to a peripheral vein at baseline and more so after cosyntropin administration. At laparoscopy, three well-circumscribed nodules (2.4 × 0.9 × 1.3 cm, 1.2 × 1.5 × 1.5 cm, and 2 × 1.5 × 1 cm) lying lateral to the fallopian tubes adjacent to the broad ligaments were removed. The paraovarian nodules and previously removed adrenal glands had similar histology and immunohistochemistry. Postoperatively, androgen concentrations were undetectable, with no response to cosyntropin stimulation.Patients with CAH after an adrenalectomy may experience recurrent hyperandrogenism due to adrenal rest tissue. 18F-FDG PET/CT with cosyntropin stimulation accurately identified adrenal rest tissue not visualized with conventional imaging, allowing for successful surgical resection.

Adrenal insufficiency (AI) is defined as clinically deficient production or action of glucocorticoids (Bornstein, 2009). Cortisol is the major glucocorticoid hormone and is produced by the adrenal cortex. Inability to produce sufficient amounts of cortisol is associated with increased morbidity and mortality (Zaloga &Marik, 2001). AI is a lifethreatening disorder resulting from disruption of the hypothalamic–pituitary–adrenal (HPA) axis. Depending on which part of this pathway is affected, the disorder is classified as primary or secondary. AI can be congenital or acquired and a lifelong or temporary diagnosis. Appropriate care must be taken to assess for signs and symptoms of acute AI and prevent acute adrenal crisis that can be fatal. Health care providers must educate patients with known AI to prevent untimely deaths from adrenal crisis. Both cortisol and aldosterone are produced in the adrenal cortex and regulate normal physiologic functions, such as blood pressure, glucose levels, and sodium and fluid balance. Symptoms of adrenocortical insufficiency include weakness, fatigue, anorexia, abdominal pain, orthostatic hypotension, salt cravings, and darkening of the skin (Bornstein, 2009). Secondary AI results when the hypothalamus or pituitary gland is affected, disrupting the HPA axis. Primary adrenal insufficiency (PAI) is rare in the western population and estimated to be around 90–140 per million (Arlt & Allolio, 2003). The most common cause of PAI is the endocrine disorder congenital adrenal hyperplasia (CAH). This disease is an autosomal recessive disorder of cortisol biosynthesis with or without aldosterone deficiency and has an estimated incidence of 1 in 15,000 (Merke & Bornstein

The gene for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, CYP21A2, is flanked by the gene encoding tenascin-X (TNXB), a connective tissue extracellular matrix protein that has been linked to both autosomal dominant and autosomal recessive Ehlers-Danlos syndrome (EDS). A contiguous deletion of CYP21A2 and TNXB has been described.The objective of the study was to determine the frequency and clinical significance of TNXB haploinsufficiency in CAH patients.A total of 192 consecutive unrelated CAH patients being seen as part of an observational study at the National Institutes of Health Clinical Center (Bethesda, MD) were prospectively studied during 2006-2010. Patients were evaluated for clinical evidence of EDS, including cardiac evaluation. DNA was analyzed by PCR, multiplex ligation-dependent probe amplification, Southern blot, and TNXB sequencing. Tenascin-X expression was evaluated by Western blot analysis of fibroblasts and immunostaining of the skin. CAH patients with TNXB haploinsufficiency were compared with age-matched CAH patients with normal TNXB (controls). Phenotyping of 7 parents with TNXB haploinsufficiency was performed.The frequency of TNXB haploinsufficiency among CAH patients and the frequency of EDS symptomatology among CAH patients with TNXB haploinsufficiency and controls.TNXB haploinsufficiency, here termed CAH-X syndrome, was present in 7% of CAH patients. Twelve of 91 patients carrying a CYP21A2 deletion (13%) carried a contiguous deletion that extended into TNXB. One patient carried a TNXB premature stop codon. Twelve of 13 patients with CAH-X had EDS clinical features. Patients with CAH-X were more likely than age-matched controls to have joint hypermobility (P.001), chronic joint pain (P = .003), multiple joint dislocations (P = .004), a structural cardiac valve abnormality by echocardiography (P = .02), and reduced tenascin-X expression by Western blot and immunostaining. A subset of parents had clinical findings.Clinical evaluation for connective tissue dysplasia should be routinely performed in CAH patients, especially those harboring a CYP21A2 deletion.

Little is known about how steroid hormones contribute to the beneficial effect of incentives on cognitive control during adolescent development. In this study, 27 adolescents with Congenital Adrenal Hyperplasia (CAH, mean age 15.6 years, 12 female), a disorder of cortisol deficiency and androgen excess, and 36 healthy participants (mean age 16.3 years, 18 female) completed a reward-based antisaccade task. In this mixed-saccade task, participants performed eye movements towards (prosaccades) or away (antisaccades) from a peripherally occuring stimulus. On incentive trials, monetary reward was provided for correct performance, while no such reward was provided on no-incentive trials. Consistent with the hypothesis, the results showed that healthy, but not CAH adolescents, significantly improved their inhibitory control (antisaccade accuracy) during incentive trials relative to no-incentive trials. These findings were not driven by severity of CAH (salt wasters vs. simple virilizers), individual hormone levels, sex, age-at-diagnosis, or medication type (dexamethasone vs. hydrocortisone). In addition, no significant differences between groups were found on orienting responses (prosaccades). Additional analyses revealed an impact of glucocorticoid (GC) dosage, such that higher GC dose predicted better antisaccade performance. However, this effect did not impact incentive processing. The data are discussed within the context of steroid hormone mediated effects on cognitive control and reward processing.

BACKGROUND Chimeric CYP21A1P/CYP21A2 genes, caused by homologous recombination between CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) and its highly homologous pseudogene CYP21A1P (cytochrome P450, family 21, subfamily A, polypeptide 1 pseudogene), are common in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). A comprehensive junction site analysis of chimeric CYP21A1P/CYP21A2 genes is needed for optimizing genetic analysis strategy and determining clinical relevance. METHODS We conducted a comprehensive genetic analysis of chimeric CYP21A1P/CYP21A2 genes in a cohort of 202 unrelated 21-OHD patients. Targeted CYP21A2 mutation analysis was performed, and genotyping of chimeric CYP21A1P/CYP21A2 genes was cross-confirmed with Southern blot, RFLP, and multiplex ligation-dependent probe amplification analyses. Junction sites of chimera genes were determined by sequencing the long-PCR products amplified with primers CYP779f and Tena32F. An updated bioinformatics survey of Chi-like sequences was also performed. RESULTS Of 100 probands with a chimeric allele, 96 had a chimera associated with the severe classic salt-wasting form of CAH, and the remaining 4 carried an uncommon attenuated chimera with junction sites upstream of In2G (c.293–13A/C>G), which is associated with a milder phenotype. In addition to 6 of 7 reported chimeras, we identified a novel classic chimera (CH-8) and a novel attenuated chimera (CH-9). Attenuated chimeras explained prior genotype–phenotype discrepancies in 3 of the patients. Sequencing the CYP779f/Tena32F amplicons accurately differentiated between classic and attenuated chimeras. The bioinformatics survey revealed enrichment of Chi-like sequences within or in the vicinity of intron 2. CONCLUSIONS Junction site analysis can explain some genotype–phenotype discrepancies. Sequencing the well-established CYP779f/Tena32F amplicons is an unequivocal strategy for detecting attenuated chimeric CYP21A1P/CYP21A2 genes, which are clinically relevant.

ObjectiveTo comprehensively phenotype parents identified with nonclassic congenital adrenal hyperplasia (NCCAH) by family genetic studies, termed here as cryptic NCCAH and to define the incidence of cryptic NCCAH in the parents of a large cohort of patients with 21-hydroxylase deficiency.DesignGenotyping was performed on 249 parents of 145 unrelated congenital adrenal hyperplasia (CAH) patients. Parents with two CYP21A2 mutations underwent extensive evaluation.ResultsOf the 249 parents, ten (4%; seven females and three males) were identified as having cryptic NCCAH. The majority was of ethnicities previously reported to have a higher incidence of NCCAH. Cosyntropin stimulation performed in eight parents provided biochemical confirmation (17-hydroxyprogesterone range 56–364 nmol/l) and cortisol response was ≤500 nmol/l in three parents (38%). Of the seven women (27–54 years) with cryptic NCCAH, four had prior infertility, two reported irregular menses, two had treatment for hirsutism, one had androgenic alopecia. Men were asymptomatic. All cryptic NCCAH parents reported normal puberty and had normal height. Adrenal hypertrophy and a small adrenal myelolipoma were observed in two parents; testicular adrenal rest tissue was not found.ConclusionsParents diagnosed with NCCAH by genetic testing are mostly asymptomatic. Temporary female infertility and suboptimal cortisol response were commonly observed. Ongoing glucocorticoid therapy is not indicated in adults with CAH identified by family genotype studies unless symptomatic, but glucocorticoid stress coverage should be considered in select cases. Parents of a child with CAH have a 1:25 risk of having NCCAH; if the mother of a child with CAH has infertility, evaluation for NCCAH is indicated.

Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.

A 6 1/2-year-old Caucasian female presents for her annual pediatric checkup with her mother. Her mother reports some increased moodiness, but otherwise, there are no complaints. The girl has always been tall for her age, but in the past 6 months, she has grown taller than her 8-year-old sister. The nurse practitioner notes the following on physical examination: height = 131 cm (N97th percentile), weight = 23 kg (75th percentile), Tanner I breasts, Tanner II pubic hair. Examination is otherwise normal. Looking at the growth chart, the nurse practitioner sees that the growth has accelerated from the 90th percentile to the 97th percentile for height. She orders a bone-age x-ray of the left hand and tells the mother that she is going to speak to an endocrinologist about this case.

Congenital adrenal hyperplasia (CAH) describes a group of genetic, autosomal recessive conditions, where there is a block in cortisol biosynthesis. Approximately 95 percent of cases are due to 21-hydroxylase deficiency, which is discussed in this article. Patients with the severe or classic form of CAH have epinephrine deficiency in addition to cortisol deficiency. Both epinephrine and cortisol are important counterregulatory hormones and help prevent hypoglycemia during physical stress. This is the first prospective study to evaluate the incidence of hypoglycemia during acute illness in children with classic CAH. Our objective was to examine blood glucose levels and symptoms of these children during the physical stressor of a typical acute illness managed at home. Twenty patients, ages 3 to 10 years with classic CAH participated. Parents were instructed regarding management of illnesses, home blood glucose monitoring and questionnaire completion. Over 29 months, 20 patients completed questionnaires and 6 patients performed home blood glucose monitoring. A blood glucose of60 mg/dL was documented in 3 out of 8 monitored acute illness episodes, and in 2 out of 6 of monitored children. The acute illness episodes with documented blood glucose60 mg/dL were not associated with vomiting. Our data suggest that children with classic CAH may experience lowering of blood glucose during illnesses, and patient education regarding the management of common childhood illness should include glucose supplementation.