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 therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

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.

Genetic characteristics and long-term follow-up of 11 patients with congenital hyperinsulinism followed in a single center.

BACKGROUND: Congenital hyperinsulinism (CHI) is a rare disease with an estimated incidence of 1:40,000 live births. Here, we characterize 11 patients treated at Munich Children's Hospital Schwabing. METHODS: We analyzed data on birth, treatment and laboratory results including genetic testing and evaluated the long-term course with a follow-up visit. RESULTS: All patients had severe, diazoxide-(DZX)-resistant hypoglycemia, beginning immediately after birth. Two patients were treated by medical therapy, eight underwent subtotal pancreatectomy and one had a partial resection. Both patients who had medical therapy still suffer from occasional hypoglycemia. Six patients with subtotal pancreatectomy were affected by mild hypoglycemia. Seventy-five percent of patients who had surgical treatment developed diabetes mellitus (DM) at a median age of 10.5 (8-13) years. In 89% of patients with available genetic testing, mutations of the ABCC8 gene were detected. CONCLUSIONS: The majority of CHI-patients not responding to DZX underwent surgery. After subtotal pancreatectomy, patients typically developed diabetes around early puberty.

A levothyroxine dose recommendation for the treatment of children and adolescents with autoimmune thyroiditis induced hypothyroidism.

OBJECTIVE: To determine a levothyroxine (T4) dose recommendation for the treatment of autoimmune thyroiditis (AIT)-induced hypothyroidism. METHODS: T4 doses in 75 children and adolescents with newly diagnosed AIT were prospectively collected and compared to T4 doses of patients with congenital hypothyroidism (CH, n=22). RESULTS: Sixty-four patients with AIT and 22 patients with CH were included in the analysis. The thyroid-stimulating hormone declined significantly from 25.8 ± 50.1 to 2.1 ± 1.5 µIU/mL (AIT group; p<0.01) and from 338.7 ± 380.7 to 1.9 ± 1.6 µIU/mL (CH group; p<0.01). The required T4 dose for patients with AIT was 1.5 ± 0.5 µg/kg per day (≥ 6 to <10 years: 2.0 ± 0.4 µg T4/kg per day; ≥ 10 to <12 years: 1.6 ± 0.4 µg T4/kg per day; ≥ 12 to <14 years: 1.5 ± 0.6 µg T4/kg per day; ≥ 14 years: 1.4 ± 0.6 µg T4/kg per day). It deviated significantly from the CH patients' mean T4 dose of 2.8 ± 0.7 µg T4/kg per day, p<0.01. CH patients with athyreosis required an average dose of 3.1 ± 0.5 µg T4/kg per day; patients with ectopia, 2.6 ± 0.7 µg T4/kg per day; and patients with dyshormonogenesis, 2.5 ± 0.6 µg T4/kg per day. CONCLUSION: Juvenile patients with AIT require significantly lower T4 doses than patients with CH.

Visual loss without headache in children with pseudotumor cerebri and growth hormone treatment.

We report on two prepubescent girls with visual loss due to idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, both treated with recombinant human growth hormone for growth failure. The interval from starting hormone therapy to diagnosis of IIH was 3 and 18 months, respectively. Both girls did not complain of headache and nausea. They were neither obese nor did they suffer from renal insufficiency. In both patients, we observed bilateral optic disc edema with visual loss and elevated cerebrospinal fluid (CSF) pressures. Other causes of IIH were excluded with neuroimaging and CSF examination. Cessation of drug administration is often sufficient for symptom resolution in cases of hormone therapy-associated IIH. However, visual field defects in one girl remained unchanged during follow-up of 8 months. In children with IIH, the spectrum of neurologic and visual manifestations might be variable and unspecific. Diagnosis and management of IIH can be difficult in the absence of headache. Blurred or double vision due to cranial nerve palsy might be the only symptom rather than complaints about reduced visual acuity. Therefore, regular clinical monitoring of visual function and fundus appearance is essential for early diagnosis, efficient management, and improvement of visual outcome in children receiving recombinant human growth hormone.

Avoiding harmful procedures in patients with elevated α-fetoprotein concentrations: hereditary persistence of α-fetoprotein is an important and benign differential diagnosis!

BACKGROUND: Hereditary persistence of α-fetoprotein (AFP) is a rare but benign condition. OBSERVATION: A 13-year-old girl presented with dysmenorrhoic complaints and irregular cycles. Diagnostic workup revealed a cystic lesion of the ovary and elevated AFP; ß-human chorionic gonadotrophin was negative. Right-sided ovarectomy was performed. Postsurgery AFP concentration did not decline. The patient underwent further diagnostic workup with negative results. Histology revealed follicular cysts but no tumor. Finally, hereditary persistence of AFP was suspected and AFP testing was performed in the family. CONCLUSIONS: It is important to include hereditary persistence of AFP in the differential diagnosis of elevated AFP concentrations to avoid harmful procedures.

A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature.

The LHX3 LIM-homeodomain transcription factor gene is required for normal pituitary and motoneuron development. LHX3 mutations are associated with growth hormone, prolactin, gonadotropin, and TSH deficiency; abnormal pituitary morphology; and may be accompanied with limited neck rotation and sensorineural hearing loss. We report on a boy, who presented with hypoglycemia in the newborn period. He is the second child of healthy unrelated parents. Short neck, growth hormone deficiency, and central hypothyroidism were diagnosed at a general pediatric hospital. Growth hormone and levothyroxine treatment were started, and blood sugar normalized with this treatment. On cerebral MRI, the anterior pituitary gland was hypoplastic. Sensorineural hearing loss was diagnosed by auditory testing. During follow-up, six repeatedly low morning cortisol levels (<1 µg/dl) and low ACTH levels (<10 pg/ml) were documented, so ACTH deficiency had developed over time and therefore hydrocortisone replacement was started at 1.5 years of age. Mutation analysis of the LHX3 gene revealed a homozygous stop mutation in exon 2: c.229C>T (CGA > TGA), Arg77stop (R77X). A complete loss of function is assumed with this homozygous stop mutation. We report a novel LHX3 mutation, which is associated with combined pituitary hormone deficiency including ACTH deficiency, short neck, and sensorineural hearing loss. All patients with LHX3 defects should undergo longitudinal screening for ACTH deficiency, since corticotrope function may decline over time. All patients should have auditory testing to allow for regular speech development.

Reassessment of the optimal growth hormone cut-off level in insulin tolerance testing for growth hormone secretion in patients with childhood-onset growth hormone deficiency during transition to adulthood.

CONTEXT: Retesting of patients with childhood-onset growth hormone deficiency (CO-GHD) is recommended after completion of growth hormone (GH) treatment. AIM: To identify patients who are at risk of persistent GHD, and to evaluate the most reliable cut-off level for GH secretion using the insulin tolerance test (ITT) in the transition from childhood to adulthood. RESULTS: Ninety patients (22 female) with CO-GHD were retested using the ITT 1.1 +/- 1.1 years after discontinuation of therapy. Fifty-eight of 77 patients (75%) initially diagnosed with idiopathic GHD showed normalization of GH secretion. Thirteen patients were diagnosed with multiple pituitary hormone deficiency (MPHD) and diagnosis was reconfirmed in all of them, except for one patient. IGF-I levels of patients with persistent GHD were significantly lower (112 +/- 74 ng/ml [range 22-283] vs 245 +/- 107 ng/ml [range 31-505], p<0.01). IGF-I levels correlated positively with GH peak during ITT (r = 0.54, p <0.01), but the wide range of IGF-I levels shows that IGF-I alone cannot replace retesting in many cases. The best sensitivity and specificity scores were obtained when a GH cutoff level below 5.0 ng/ml for patients in the transition phase was used. ROC analysis demonstrates that ITT is a reliable test for evaluation of GH secretion in the transition phase (ROC-AUC 0.97). CONCLUSIONS: Patients with CO-GHD should be retested after discontinuation of therapy to identify those who may profit from further replacement therapy. Patients with organic or genetic GHD or MPHD are likely to have persistent GHD, whereas 75% of our patients with idiopathic GHD showed normalization of growth hormone secretion. IGF-I levels alone are not reliable in the diagnosis of adult GHD in many cases. The best sensitivity and specificity scores were found when a GH cut-off level below 5.0 ng/ml was used in patients with GHD in the transition from childhood to adulthood.

Recurrent hypoglycemic seizures and obesity: delayed diagnosis of an insulinoma in a 15 year-old boy--final diagnostic localization with endosonography.

Insulinoma in children and adolescents is extremely rare. In adults diagnosis is frequently delayed due to frequent neuropsychiatric symptoms that are misunderstood. Diagnostic localization is sometimes extremely difficult. We present a case of insulinoma with onset of symptoms at the age of 12.5 years. Diagnosis was made very soon after the first symptoms, but diagnostic localization was delayed, since conventional MRI did not reveal the insulinoma. The patient suffered from recurrent hypoglycemic seizures and gained 54 kg in weight until diagnostic localization was made with abdominal MRI, octreotate-PET and finally successful endosonography. A solitary insulinoma in the pancreatic tail was enucleated laparoscopically.

Virilising adrenocortical tumours in children.

UNLABELLED: Adrenocortical tumours (ACT) are a rare but important cause of virilisation in infancy and childhood. Four cases of virilising ACT are presented. Two girls (age 0.9 years and 3.9 years) and two boys (age 6.2 years and 6.4 years) had symptoms and signs of virilisation before the age of 6 years. Diagnosis of a virilising adrenal tumour was confirmed by laboratory tests, diagnostic imaging and histology. However, one female patient was misdiagnosed and treated for 3 months as atypical congenital adrenal hyperplasia. Ultrasonography of the adrenal region could not visualise the tumour in three out of four cases. The most sensitive method of diagnostic imaging was MRI. In all cases, treatment consisted of complete surgical resection of the adrenal tumour by open abdominal surgery. Immunohistochemistry was performed in all patients and in two patients there was an overexpression of p53, indicating p53 mutation and in three cases the ki67 proliferation index was greater than 5%. The classification of ACT in childhood is extremely difficult. Histology scores adapted from adrenal tumours in adults and molecular markers are under investigation, but there is still not enough clinical experience since ACT are so rare. CONCLUSION: Long-term follow-up is mandatory not only because of the uncertainty in classification of adrenocortical tumours, but also for observation of growth and pubertal development.