Endocrine manifestations in adults with 22q11.2 deletion syndrome: a retrospective single-center cohort study.

INTRODUCTION AND OBJECTIVE: Patients with the 22q11.2 deletion syndrome (22q11DS) frequently display cardiological and psychiatric diseases, but are also at increased risk for endocrine manifestations. The aim of this study was to evaluate the screening, prevalence, and management of hypoparathyroidism and thyroid disease in patients with 22q11DS, to evaluate the metabolic profile, and to compare these results with current literature and guidelines. DESIGN: We performed a retrospective study of patients with genetically confirmed 22q11DS, followed at the center for human genetics of the University Hospitals Leuven, resulting in a cohort of 75 patients. Medical history, medication, and laboratory results concerning hypoparathyroidism, thyroid dysfunction, and the metabolic profile were collected. RESULTS: Of the total cohort, 26 patients (35%) had at least one hypocalcaemic episode. During hypocalcaemia, parathyroid hormone (PTH) was measured in only 12 patients with 11 having normal or low PTH, confirming a diagnosis of hypoparathyroidism. Recurrent episodes of hypocalcaemia occurred in seventeen patients (23%). Adherence to the guidelines was low, with 13% of patients having a yearly serum calcium evaluation, 12% receiving daily calcium supplements, and 20% receiving non-active vitamin D. Hypothyroidism was present in 31 patients (44%) and hyperthyroidism in 6 patients (8%). Information on body mass index (BMI) was available in 52 patients (69%), of which 38% were obese (BMI ≥ 30 kg/m2). CONCLUSION: Hypoparathyroidism, hypothyroidism, and obesity are common endocrine manifestations in patients with 22q11DS but are probably underdiagnosed and undertreated, indicating the need for multidisciplinary follow-up including an endocrinologist.

An Endocrinological Perspective on 22q11.2 Deletion Syndrome: A Single-center Experience

Objective: 22q11.2 deletion syndrome (22q11.2 DS) is the most common chromosomal microdeletion disorder. Associated problems in 22q11.2 DS may include cardiac abnormalities, immune dysfunction, facial dysmorphism, with endocrine, genitourinary and gastrointestinal problems, and developmental delay. The aim of this study was to evaluate and present all endocrinological findings of patients with 22q11.2 DS from a single center. Methods: All participants had confirmed 22q11.2 DS by fluorescence in situ hybridization with hypoparathyroidism. Data were retrieved by retrospective review of patient records. Results: A total of 17 patients were reviewed. On physical examination, all patients had similar dysmorphic features. The median age at diagnosis was 45 days (1 day-13 years). Most cases (64.7%, 11/17) were diagnosed with hypoparathyroidism incidentally after routine tests. At the time of diagnosis, mean calcium was 7.04±0.80 mg/dL, phosphorus was 6.2±1.1 mg/dL, and median parathyroid hormone (PTH) was 11.5 (3.7-47.6) ng/L. Transient hypoparathyroidism was detected in five cases (29.4%). There was no significant difference between patients with permanent or transient hypoparathyroidism regarding gender, age at diagnosis, calcium, phosphorus, and PTH levels. However, vitamin D levels were significantly lower in the transient group (p=0.036). During follow-up, short stature, obesity, and type 2 diabetes mellitus were absent. Thyroid autoantibodies were detected in two patients with normal thyroid function tests. Despite there being no pathological short stature, final stature was shorter than the general population (mean height standard deviation score: -0.94±0.83). Conclusion: Hypocalcemia may be detected during acute illness in some cases where hypocalcemia appears at later ages. There was no significant difference between permanent and transient hypoparathyroidism cases in terms of PTH level. Recognition of the more specific facial findings is important to trigger investigation of genetic variants, additional anomalies, and for follow-up.

Abnormal development of early auditory processing in 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (22q11.2 DS) is one of the highest genetic risk factors for the development of schizophrenia spectrum disorders. In schizophrenia, reduced amplitude of the frequency mismatch negativity (fMMN) has been proposed as a promising neurophysiological marker for progressive brain pathology. In this longitudinal study in 22q11.2 DS, we investigate the progression of fMMN between childhood and adolescence, a vulnerable period for brain maturation. We measured evoked potentials to auditory oddball stimuli in the same sample of 16 patients with 22q11.2 DS and 14 age-matched controls in childhood and adolescence. In addition, we cross-sectionally compared an increased sample of 51 participants with 22q11.2 DS and 50 controls divided into two groups (8-14 and 14-20 years). The reported results are obtained using the fMMN difference waveforms. In the longitudinal design, the 22q11.2 deletion carriers exhibit a significant reduction in amplitude and a change in topographic patterns of the mismatch negativity response from childhood to adolescence. The same effect, reduced mismatch amplitude in adolescence, while preserved during childhood, is observed in the cross-sectional study. These results point towards functional changes within the brain network responsible for the fMMN. In addition, the adolescents with 22q11.2 DS displayed a significant increase in amplitude over central electrodes during the auditory N1 component. No such differences, reduced mismatch response nor increased N1, were observed in the typically developing group. These findings suggest different developmental trajectories of early auditory sensory processing in 22q11.2 DS and functional changes that emerge during the critical period of increased risk for schizophrenia spectrum disorders.

Rare complication of milk-alkali ingestion: severe pancreatitis and acute kidney injury in a chronic hypocalcaemic patient with DiGeorge's syndrome.

Injudicious use of over-the-counter calcium supplements has resulted in increased incidences of hypercalcaemia and related complications. We present a case of acute pancreatitis in a chronic hypocalcaemic patient of DiGeorge's syndrome. The patient came into the ED with sepsis syndrome, right upper quadrant and epigastric pain and no obvious source of infection. Lab results and imaging were indicative of acute pancreatitis. There was severe renal dysfunction. The patient needed haemodialysis and had a prolonged stay in intensive care. The medical history was negative for biliary duct pathology or alcohol use. The patient had vomiting and diarrhoea in the nursing home for about a week, but she continued to receive her regular medications that included the calcium supplements and thiazide diuretics. It is likely that a complex interplay between calcium supplementation, dehydration and thiazide diuretics resulted in the development of acute pancreatitis and severe renal dysfunction in a chronic hypocalcaemic patient.

Ictus emeticus presenting as an unusual seizure type in chromosome 22q11.2 deletion syndrome.

We present a case study of a patient with chromosome 22q11.2 deletion syndrome presenting with ictus emeticus, together with a review of the relevant literature. The patient developed generalized tonic-clonic seizures at 3 months old, and seizures eventually remitted after calcium therapy. He then experienced vigorous vomiting that occurred during sleep, with glassy eyes and legs flexion. Video-EEG recordings exhibited a switch in background activity from organized reactivity during normal sleep to left lateralized temporal delta activity, which was bilaterally synchronized during an emetic attack. The ictal vomiting ceased following management with oxcarbazepine, high-dose phenobarbital, and a ketogenic diet. The unique seizure type and rare ictal EEG findings are the first reported in a child with chromosome 22q11.2 deletion syndrome. This case highlights that ictus emeticus without detectable epileptic discharge on EEG is one potential epileptic presentation in this genetic syndrome. [Published with video sequence on www.epilepticdisorders.com].

Indicated prevention with long-chain polyunsaturated omega-3 fatty acids in patients with 22q11DS genetically at high risk for psychosis. Protocol of a randomized, double-blind, placebo-controlled treatment trial.

AIM: It has been found that long-chain omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of progression to first episode of psychosis (FEP) and may offer a safe and efficacious strategy for selective and indicated prevention in young people with ultra-high-risk (UHR) states. An opportunity for exploring the trajectory of FEP and for investigating the efficacy of preventive treatments exists in 22q11.2 deletion syndrome (22q11DS), which has a 30% psychotic transition rate. The fact that 22q11DS patients are more homogeneous than other UHR groups and are characterized by high level of negative symptoms provides a strong rationale for the use of PUFAs. The principal aim of the present trial is to investigate the effects of PUFAs in individuals with 22q11DS who are at UHR for developing FEP. METHODS: A prospective, randomized, double-blind, placebo-controlled, single-centre study design will be used. Eighty individuals aged 12-26 will be randomly assigned to two treatment conditions. RESULTS: The experimental group will receive PUFAs. The placebo group will receive paraffin oil. Standard clinical assessments and neuropsychological tests will be performed at baseline and at 8-, 12-, 26- and 52-week follow-up. Blood samples will be collected at baseline and after 12 weeks. This study is registered as an International Standard RCT, number 02070211. The corresponding author is supported by a NARSAD Young Investigator Award. CONCLUSIONS: This is the protocol of a planned study that aims to test the efficacy of PUFAs in the prodromal phase of FEP, in a specific syndrome where there is strong evidence that a high genetic load is involved in the disorder.

Altered auditory processing in frontal and left temporal cortex in 22q11.2 deletion syndrome: a group at high genetic risk for schizophrenia.

In order to investigate electroencephalographic (EEG) biomarkers of auditory processing for schizophrenia, we studied a group with a well known high-risk profile: patients with 22q11.2 deletion syndrome (22q11 DS) have a 30% risk of developing schizophrenia during adulthood. We performed high-density EEG source imaging to measure auditory gating of the P50 component of the evoked potential and middle to late latency auditory processing in 21 participants with the 22q11.2 deletion and 17 age-matched healthy controls. While we found no indication of altered P50 suppression in 22q11 DS, we observed marked differences for the first N1 component with increased amplitudes on central electrodes, corresponding to increased activations in dorsal anterior cingulate and medial frontal cortex. We also found a left lateralized reduction of activation of primary and secondary auditory cortex during the second N1 (120ms) and the P2 component in 22q11 DS. Our results show that sensory gating and activations until 50ms were preserved in 22q11 DS, while impairments appear at latencies that correspond to higher order auditory processing. While the increased activation of cingulate and medial frontal cortex could reflect developmental changes in 22q11 DS, the reduced activity seen in left auditory cortex might serve as a biomarker for the development of schizophrenia, if confirmed by longitudinal research protocols.

Hypocalcaemia as presenting symptom of velocardiofacial syndrome.

Hypocalcaemia due to hypoparathyroidism is a rare finding in adults. The coexistence of cardiac abnormalities may be suggestive of a hereditary syndrome. We describe a case of velocardiofacial syndrome in a woman without a family history of this disorder. The hypocalcaemia was treated with calcium and vitamin D supplementation.