Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.

Expanding the clinical and molecular spectrum of FOXG1- and ZBTB18-associated neurodevelopmental disorders.

Introduction The zinc finger BTB domain-containing protein ZBTB18 binds to FOXG1 to form a transcriptional repressive complex involved in neuronal differentiation. Disruption of the components of this complex results in chromosome 1q43-q44 deletion syndrome/intellectual developmental disorder 22 or in FOXG1 syndrome. Case presentation This study reports on five patients with cognitive and behavioral impairment, seizures, microcephaly, and/or congenital brain abnormalities. Whole exome sequencing identified deleterious ZBTB18 variants in three patients and deleterious FOXG1 variants in the remaining patients. We have detected a missense variant within the BTB domain of ZBTB18 in two affected monozygotic twins. In addition, we observed agenesis of the septum pellucidum in a missense FOXG1 carrier with a severe FOXG1 syndrome. Conclusion Although the ZBTB18 zinc finger domains harbor the majority of known deleterious variants, we report a novel de novo rare missense variant within the BTB domain. The agenesis of the septum pellucidum observed in a missense FOXG1 carrier could be considered as a novel clinical feature associated with FOXG1 syndrome. The severe FOXG1 syndrome in this patient contrasts with the milder phenotype expected for a missense. Genetic or environmental factors may explain this phenotypic variability in FOXG1 syndrome.

Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder.

The few proximal 4q chromosomal aberrations identified in patients with neurodevelopmental phenotypes that have been published to date are variable in type, size and breakpoints and, therefore, encompass different chromosome bands and genes, making the establishment of genotype-phenotype correlations a challenging task. Here, microarray-based copy number analysis allowed us the detection of two novel and partially overlapping deletions in two unrelated families. In Family 1, a 4q13.1-q13.2 deletion of 3.84 Mb was identified in a mother with mild intellectual disability and in her two children, both with mild intellectual disability and attention deficit hyperactivity disorder. In Family 2, a de novo 4q13.2-q13.3 deletion of 6.81 Mb was detected in a female patient, born to unaffected parents, with a diagnosis of mild intellectual disability, behavioral disorder and facial dysmorphism. The shortest region of overlap between these two aberrations is located at chromosome 4q13.2 and includes 17 genes amongst of which we suggest UBA6 (ubiquitin-like modifier-activating enzyme 6) as a strong candidate gene for these phenotypes.

Juvenile xanthogranuloma of the cauda equina.

Juvenile xanthogranuloma is a form of histiocytic proliferative disorder that usually affects the skin and tends to occur during infancy. On rare occasions, it has been reported at extracutaneous sites and in other age groups. Isolated juvenile xanthogranuloma of the nervous system is extremely rare, especially in the cauda equina. A case of juvenile xanthogranuloma of the cauda equina in a 14-year-old boy is reported, and the literature is reviewed.

Muscle myostatin expression in children with muscle diseases.

The demonstration that myostatin may negatively regulate muscle mass in adult individuals has raised the possibility of targeting the myostatin pathway to increase muscle growth in a variety of muscle-degenerative and -wasting conditions. To gain further insight into the possible role of myostatin in primary muscle diseases, the authors investigated the expression of muscle myostatin in children with congenital fiber type 1 disproportion, in others with neurogenic muscular atrophy, in others with myotonia congenita, in others with infantile glycogenosis type II, in others with Prader-Willi syndrome, and in 4 age-matched controls. No differences in the pattern of myostatin expression were found in any case, even in those patients with prominent muscular atrophy or hypertrophy. These findings suggest that muscle alterations that can be observed in primary muscle diseases do not depend on changes in myostatin expression.

Evolution of subclinical hypothyroidism in children treated with antiepileptic drugs.

The concentration levels of serum free thyroxine, serum free triiodothyronine, and thyroid-stimulating hormone were measured in 20 children receiving carbamazepine, 32 children receiving valproic acid, and 5 children receiving phenobarbital at the following times: (1) during chronic treatment, and (2) 3 months after the end of treatment with antiepileptic drugs. Patients during chronic treatment revealed significant changes in serum thyroid hormones, especially the children treated with carbamazepine and valproic acid. A number of children receiving long-term therapy with the two last antiepileptic drugs had varying grades of subclinical hypothyroidism. Three months after the end of treatment, a complete return to normal of all parameters was observed. These data demonstrate that the changes induced by these drugs are transient and reversible.

Copy number variation analysis of patients with intellectual disability from North-West Spain.

Intellectual disability (ID) is a complex and phenotypically heterogeneous neurodevelopmental disorder characterized by significant deficits in cognitive and adaptive skills, debuting during the developmental period. In the last decade, microarray-based copy number variation (CNV) analysis has been proved as a strategy particularly useful in the discovery of loci and candidate genes associated with these phenotypes and is widely used in the clinics with a diagnostic purpose. In this study, we evaluated the usefulness of two genome-wide high density SNP microarrays -Cytogenetics Whole-Genome 2.7M SNP array (n=126 patients; Group 1) and CytoScan High-Density SNP array (n=447 patients; Group 2)- in the detection of clinically relevant CNVs in a cohort of ID patients from Galicia (NW Spain). In 159 (27.7%) patients, we detected 186 rare exonic chromosomal imbalances, that were grouped into the following classes: Clinically relevant (67/186; 36.0%), of unknown clinical significance (93/186; 50.0%) and benign (26/186; 14.0%). The 67 pathogenic CNVs were identified in 64 patients, which means an overall diagnostic yield of 11.2%. Overall, we confirmed that ID is a genetically heterogeneous condition and emphasized the importance of using genome-wide high density SNP microarrays in the detection of its genetic causes. Additionally, we provided clinical and molecular data of patients with pathogenic or likely pathogenic CNVs and discussed the potential implication in neurodevelopmental disorders of genes located within these variants.

Treatment of mitochondrial encephalomyopathies with a xanthine oxidase inhibitor.

Five females with mitochondrial encephalomyopathies were treated for 3 to 7 years with a xanthine oxidase inhibitor (allopurinol, oral route, 20 mg/kg/day, in 2 or 3 doses daily). Clinical course was monitored in all patients. In addition, various metabolic variables, namely blood lactic acid, blood adenosine triphosphate, adenosine diphosphate, and adenosine monophosphate were monitored, as well as energy charge. Data obtained were compared with data for an age-matched control group of 10 healthy children. Four of the five patients manifested clinical improvement, and the remaining patient exhibited slower disease progression. Three of the four patients who exhibited clinical improvement also had normalization of blood lactic acid level. All five patients had an increase in blood adenosine triphosphate levels and a decline in blood adenosine monophosphate; four of the five manifested a decline in blood adenosine diphosphate and increased energy charge. Mean blood adenosine triphosphate was significantly increased with respect to pretreatment levels and with respect to the control group; mean energy charge displayed an increase, though this was not statistically significant. In one patient, reduction of the allopurinol dose to 10 mg/kg/day was followed by a decline in both blood adenosine triphosphate level and energy charge, and by clinical worsening. In conclusion, the xanthine oxidase inhibitor allopurinol appears to have had beneficial effects in these patients in terms of both energy metabolism and clinical course.

The influence of valproic acid and carbamazepine treatment on serum biotin and zinc levels and on biotinidase activity.

We determined the serum concentration of biotin, zinc, antiepileptic drugs, and biotinidase enzyme activity in 20 children treated with valproic acid, in 10 children treated with carbamazepine, and in 75 age- and sex-matched healthy controls. There were no significant differences in the serum levels of biotin, and biotinidase enzyme activity between the patients treated with valproic acid, the patients treated with carbamazepine, and the control group. Zinc serum levels were lower in the patients treated with valproic acid and with carbamazepine than in the control group, but within the normal range. Hair loss was observed in 3 patients treated with valproic acid, with normal serum levels of biotin, zinc, and biotinidase activity, and the alopecia disappeared with the oral administration of biotin (10 mg/d) in 3 months. These results suggest that the treatment with valproic acid does not alter the serum levels of biotin, zinc, and biotinidase enzyme activity.

Primary adenosine monophosphate (AMP) deaminase deficiency in a hypotonic infant.

The spectrum of the adenosine monophosphate (AMP) deaminase deficiency ranges from asymptomatic carriers to patients who manifest exercise-induced muscle pain, occasionally rhabdomyolysis, and idiopathic hyperCKemia. However, previous to the introduction of molecular techniques, rare cases with congenital weakness and hypotonia have also been reported. We report a 6-month-old girl with the association of congenital muscle weakness and hypotonia, muscle deficiency of adenosine monophosphate deaminase, and the homozygous C to T mutation at nucleotide 34 of the adenosine monophosphate deaminase-1 gene. This observation indicates the possible existence of a primary adenosine monophosphate deaminase deficiency manifested by congenital muscle weakness and hypotonia.

Congenital hypothyroidism with neurological and respiratory alterations: a case detected using a variable diagnostic threshold for TSH.

We report a case of congenital hypothyroidism (CH) with neurological and respiratory alterations due to a heterozygotic c.374-1G > A mutation of TITF1/NKX2-1. The hypothyroidism was detected using a neonatal screening protocol in which the thyroid stimulating hormone (TSH) threshold is re-set each day on the basis of within-day variability and between-day variation. In this case, the threshold on the day of the initial analysis was 8.2 mIU/L, and the measured TSH level in heel-prick blood was 8.3 mIU/L.

Hashimoto encephalopathy in a preschool girl.

Hashimoto encephalopathy is a steroid-responsive encephalopathy associated with elevated blood concentrations of antithyroid antibodies. The patients are usually euthyroid or mildly hypothyroid. The clinical picture is pleomorphic, presenting with variable symptoms ranging from behavioral and cognitive changes, myoclonus, seizures, pyramidal tract dysfunction, involuntary movements, and cerebellar signs to psychosis and coma, with relapsing and progressive course. The diagnosis is often overlooked at presentation but is crucial, given that this is a treatable disease. Described here, with a literature review, is the youngest patient reported to date with Hashimoto encephalopathy.

Serum biotinidase activity in children treated with valproic acid and carbamazepine.

There is evidence that valproic acid causes a reduction of serum biotinidase enzyme activity. We determined the serum concentration of antiepileptic drugs, transaminases, gamma-glutamyl transferase, ammonia, and biotinidase enzyme activity in 57 children treated with valproic acid, in 17 children treated with carbamazepine, and in 75 age- and sex-matched healthy controls. There were no significant differences in the serum biotinidase enzyme activity between the patients treated with valproic acid, the patients treated with carbamazepine, and the control group. Hyperammonemia was detected in 8 patients treated with valproic acid. Hair loss was observed in 3 female patients treated with valproic acid, and the alopecia disappeared with the oral administration of biotin (10 mg/ d) in 3 months. These results suggest that the treatment with valproic acid does not alter the serum biotinidase enzyme activity.

Respiratory chain complex I deficiency in an infant with Ohtahara syndrome.

We report an infant with complex I deficiency of the mitochondrial respiratory chain whose most conspicuous symptom at presentation was an Ohtahara syndrome. Review of the literature suggest that association of these two conditions is extremely rare. Despite the few cases reported, in our view Ohtahara syndrome should be considered as one of the forms of presentation of mitochondrial dysfunction.