Margaret F. Keil

Context: Height outcome in patients with classic congenital adrenal hyperplasia (CAH) is suboptimal due to glucocorticoid and androgen excess. Methods: In an open, randomized, controlled trial, children with classic CAH were randomized to receive a combination regimen of antiandrogen, aromatase inhibitor, reduced hydrocortisone, and fludrocortisone prior to puberty or standard therapy (hydrocortisone, fludrocortisone). Females continued on antiandrogen during puberty. The primary endpoint was adult height. Results: Of 62 children randomized, 45 completed the study. Adult height SDS did not differ between the investigational and control groups (−0.34 [0.93] vs −0.60 [0.89], respectively), mean difference 0.26 [95% CI −0.29, 0.82], P = .35), irrespective of midparental height, but was greater than the predicted adult height pretreatment in both groups (P < .001). Growth rate and rate of bone maturation were reduced in the investigational group prior to puberty, despite lower hydrocortisone dose (7.6 [1.5] vs 15.0 [3.6] mg/m2/day, P < .001), and improvement in predicted adult height appeared greater at pubertal onset (P = .049) compared to standard therapy. Antiandrogen treatment during puberty in girls allowed for lower-dose glucocorticoid, and improved height outcome (adult minus midparental height: −0.7 [4.6] vs −5.6 [5.2] cm, mean difference 4.9 [95% CI 0.09, 9.7], P = .046). Those who received GnRHa had lower growth rate (P = .023) and longer years of unchanged bone age (P = .017), regardless of treatment. Conclusion: Prepubertal antiandrogen, aromatase inhibitor combination with reduced hydrocortisone improves short-term predicted height for children with CAH but does not result in taller adult stature than those treated with standard therapy, and is not recommended. Females may benefit from antiandrogen treatment during puberty.

Objective To investigate the effect of hypercortisolism on the developing brain we performed clinical, cognitive, and psychological evaluation of children with Cushing disease (CD) at diagnosis and 1 year after remission. Study Design Prospective study of 41 children with CD. Children completed diverse sets of cognitive measures before and 1 year after remission. Neuropsychological evaluation included the Wechsler Intelligence Scale, California Verbal Learning Test, Trail Making Test, the combined subset scores of Wide Range Achievement Test and Woodcock-Johnson Psychoeducational Battery Test of Achievement, and the Behavioral Assessment System for Children. Results Comprehensive cognitive evaluations at baseline and 1 year following cure revealed significant decline mostly in nonverbal skills. Decrements occurred in most of the various indices that measure all aspects of cognitive function and younger age and early pubertal stage largely contributed to most of this decline. Results indicated that age at baseline was associated with positive regression weights for changes in scores for verbal, performance, and full intelligence quotient (IQ) scores and for subtests arithmetic, picture completion, coding, block design, scores; indicating that older age at baseline was associated with less of a deterioration in cognitive scores from pre- to posttreatment. Conclusion Our findings suggest that chronic glucocorticoid excess and accompanying secondary hormonal imbalances followed by eucortisolemia have detrimental effects on cognitive function in the developing brain; younger age and pubertal stage are risk factors for increased vulnerability, while older adolescents have cognitive vulnerabilities like that of adult patients affected with CD.

Background: After adoption, children exposed to institutionalized care show significant improvement, but incomplete recovery of growth and developmental milestones. There is a paucity of data regarding risk and protective factors in children adopted from institutionalized care. This prospective study followed children recently adopted from institutionalized care to investigate the relationship between family environment, executive function, and behavioral outcomes. Methods: Anthropometric measurements, physical examination, endocrine and bone age evaluations, neurocognitive testing, and behavioral questionnaires were evaluated over a 2-year period with children adopted from institutionalized care and non-adopted controls. Results: Adopted children had significant deficits in growth, cognitive, and developmental measurements compared to controls that improved; however, residual deficits remained. Family cohesiveness and expressiveness were protective influences, associated with less behavioral problems, while family conflict and greater emphasis on rules were associated with greater risk for executive dysfunction. Conclusions: Our data suggest that a cohesive and expressive family environment moderated the effect of pre-adoption adversity on cognitive and behavioral development in toddlers, while family conflict and greater emphasis on rules were associated with greater risk for executive dysfunction. Early assessment of child temperament and parenting context may serve to optimize the fit between parenting style, family environment, and the child’s development. Impact: Children who experience institutionalized care are at increased risk for significant deficits in developmental, cognitive, and social functioning associated with a disruption in the development of the prefrontal cortex. Aspects of the family caregiving environment moderate the effect of early life social deprivation in children. Family cohesiveness and expressiveness were protective influences, while family conflict and greater emphasis on rules were associated with a greater risk for executive dysfunction problems. This study should be viewed as preliminary data to be referenced by larger studies investigating developmental and behavioral outcomes of children adopted from institutional care.

Context Germline loss-of-function CDKN1B gene variants cause the autosomal dominant syndrome of multiple endocrine neoplasia type 4 (MEN4). Even though pituitary neuroendocrine tumors are a well-known component of the syndrome, only 2 cases of Cushing’s disease (CD) have so far been described in this setting. Aim To screen a large cohort of CD patients for CDKN1B gene defects and to determine their functional effects. Patients We screened 211 CD patients (94.3% pediatric) by germline whole-exome sequencing (WES) only (n = 157), germline and tumor WES (n = 27), Sanger sequencing (n = 6), and/or germline copy number variant (CNV) analysis (n = 194). Sixty cases were previously unpublished. Variant segregation was investigated in the patients’ families, and putative pathogenic variants were functionally characterized. Results Five variants of interest were found in 1 patient each: 1 truncating (p.Q107Rfs*12) and 4 nontruncating variants, including 3 missense changes affecting the CDKN1B protein scatter domain (p.I119T, p.E126Q, and p.D136G) and one 5’ untranslated region (UTR) deletion (c.-29_-26delAGAG). No CNVs were found. All cases presented early (10.5 ± 1.3 years) and apparently sporadically. Aside from colon adenocarcinoma in 1 carrier, no additional neoplasms were detected in the probands or their families. In vitro assays demonstrated protein instability and disruption of the scatter domain of CDKN1B for all variants tested. Conclusions Five patients with CD and germline CDKN1B variants of uncertain significance (n = 2) or pathogenic/likely pathogenic (n = 3) were identified, accounting for 2.6% of the patients screened. Our finding that germline CDKN1B loss-of-function may present as apparently sporadic, isolated pediatric CD has important implications for clinical screening and genetic counselling.

This review focuses on the anxiety related to cyclic AMP (cAMP)/protein kinase A (PKA) signaling pathway that regulates stress responses. PKA regulates an array of diverse signals that interact with various neurotransmitter systems associated with alertness, mood, and acute and social anxiety-like states. Recent mouse studies support the involvement of the PKA pathway in common neuropsychiatric disorders characterized by heightened activation of the amygdala. The amygdala is critical for adaptive responses leading to fear learning and aberrant fear memory and its heightened activation is widely thought to underpin a variety of anxiety disorders. Stress-induced plasticity within the amygdala is involved in the transition from normal vigilance responses to emotional reactivity, fear over- generalization, and deficits in fear inhibition resulting in pathological anxiety and conditions, such as panic and depression. Human studies of PKA signaling defects also report an increased incidence of psychiatric disorders, including anxiety, depression, bipolar disorder, learning disorders, and attention deficit hyperactivity disorder. We speculate that the PKA system is uniquely suited for selective, molecularly targeted intervention that may be proven effective in anxiolytic therapies.

Endogenous Cushing syndrome (CS) may have different effects in children than what has been described in adults. Previous studies of children and adolescents with CS have identified cognitive decline despite reversal of brain atrophy after remission of CS. Although the observations of parents of children and adolescents with CS support personality changes, significant psychopathology has not been described in the literature. We report 9 children who underwent successful surgery (transsphenoidal surgery [TSS] or resection of bronchial carcinoid) for treatment of CS and subsequently developed significant affective pathology. Affective symptoms included anger–rage outbursts, suicidal ideation, irritability, anxiety, and depression. One child, who committed suicide 60 months after TSS, had recently discontinued antidepressant medication. She had a history of anxiety during active CS and was treated with an anxiolytic. The 7 patients with onset of symptoms within 7 months of TSS were on glucocorticoid replacement, and 1-year follow-up evaluation showed recovery of hypothalamic–pituitary–adrenal axis and biochemical evidence of remission. The 2 patients who presented with onset of symptoms at 48 months or later underwent endocrine evaluation that showed biochemical evidence of remission and normal anterior pituitary hormone levels. This is the first report of affective symptoms and behavioral dysregulation, including suicidal ideation, in a subgroup of children and adolescents after remission of CS. Health care providers caring for children with CS who have been cured should continue to screen for mental illness, monitor for changes in behavior, and refer as appropriate to mental health professionals.