Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Quality Improvement in Concussion Care: Influence of Guideline-Based Education.

OBJECTIVE: To evaluate the potential impact of a concussion management education program on community-practicing pediatricians. STUDY DESIGN: We prospectively surveyed 210 pediatricians before and 18 months after participation in an evidence-based, concussion education program. Pediatricians were part of a network of 38 clinically integrated practices in metro-Atlanta. Participation was mandatory for at least 1 pediatrician in each practice. We assessed pediatricians' self-reported concussion knowledge, use of guidelines, and comfort level, as well as self-reported referral patterns for computed tomography (CT) and/or emergency department (ED) evaluation of children who sustained concussion. RESULTS: Based on responses from 120 pediatricians participating in the 2 surveys and intervention (response rate, 57.1%), the program had significant positive effects from pre- to postintervention on knowledge of concussions (-0.26 to 0.56 on -3 to +1 scale; P < .001), guideline use (0.73-.06 on 0-6 scale; P < .01), and comfort level in managing concussions (3.76-4.16 on 1-5 scale; P < .01). Posteducation, pediatricians were significantly less likely to self-report referral for CT (1.64-1.07; P < .001) and CT/ED (4.73-3.97; P < .01), but not ED referral alone (3.07-3.09; P = ns). CONCLUSIONS: Adoption of a multifaceted, evidence-based, education program translated into a positive modification of self-reported practice behavior for youth concussion case management. Given the surging demand for community-based youth concussion care, this program can serve as a model for improving the quality of pediatric concussion management.

Seizure Recurrence in Developmentally and Neurologically Normal Children With a Newly Diagnosed Unprovoked Seizure.

This study aims to assess recurrence risk in developmentally and neurologically normal children with a newly diagnosed unprovoked seizure. The medical record was retrospectively reviewed in 393 children who had a newly diagnosed, unprovoked seizure. A total of 152 children met inclusion criteria. The relationship between seizure recurrence and variables was examined. Seventy cases had recurrent seizures. Total 113 cases had follow-up data and 70 cases of these (63.7%) experienced recurrent seizures. EEG was abnormal in 65 (44.8%): focal epileptiform abnormality in 34 cases (23.4%) and generalized epileptiform abnormality in 23 cases (15.9%). Brain MRI revealed any structural abnormality in 14 of 86 cases (16.3%). Neither EEG abnormality nor brain MRI abnormality was statistically significantly associated with increased seizure recurrence in this cohort. Further study is required to confirm the EEG and brain MRI findings in otherwise normal children with a newly diagnosed unprovoked seizure.

Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations.

OBJECTIVE: To study the clinical and radiologic spectrum and genotype-phenotype correlation of 4H (hypomyelination, hypodontia, hypogonadotropic hypogonadism) leukodystrophy caused by mutations in POLR3A or POLR3B. METHODS: We performed a multinational cross-sectional observational study of the clinical, radiologic, and molecular characteristics of 105 mutation-proven cases. RESULTS: The majority of patients presented before 6 years with gross motor delay or regression. Ten percent had an onset beyond 10 years. The disease course was milder in patients with POLR3B than in patients with POLR3A mutations. Other than the typical neurologic, dental, and endocrine features, myopia was seen in almost all and short stature in 50%. Dental and hormonal findings were not invariably present. Mutations in POLR3A and POLR3B were distributed throughout the genes. Except for French Canadian patients, patients from European backgrounds were more likely to have POLR3B mutations than other populations. Most patients carried the common c.1568T>A POLR3B mutation on one allele, homozygosity for which causes a mild phenotype. Systematic MRI review revealed that the combination of hypomyelination with relative T2 hypointensity of the ventrolateral thalamus, optic radiation, globus pallidus, and dentate nucleus, cerebellar atrophy, and thinning of the corpus callosum suggests the diagnosis. CONCLUSIONS: 4H is a well-recognizable clinical entity if all features are present. Mutations in POLR3A are associated with a more severe clinical course. MRI characteristics are helpful in addressing the diagnosis, especially if patients lack the cardinal non-neurologic features.

Characteristics of early MRI in children and adolescents with vanishing white matter.

OBJECTIVE: MRI in vanishing white matter typically shows diffuse abnormality of the cerebral white matter, which becomes increasingly rarefied and cystic. We investigated the MRI characteristics preceding this stage. DESIGN: In a retrospective observational study, we evaluated all available MRIs in our database of DNA-confirmed VWM patients and selected MRIs without diffuse cerebral white matter abnormalities and without signs of rarefaction or cystic degeneration in patients below 20 years of age. A previously established scoring list was used to evaluate the MRIs. RESULTS: An MRI of seven patients fulfilled the criteria. All had confluent and symmetrical abnormalities in the periventricular and bordering deep white matter. In young patients, myelination was delayed. The inner rim of the corpus callosum was affected in all patients. CONCLUSIONS: In early stages of VWM, MRI does not necessarily display diffuse cerebral white matter involvement and rarefaction or cystic degeneration. If the MRI abnormalities do not meet the criteria for VWM, it helps to look at the corpus callosum. If the inner rim (the callosal-septal interface) is affected, VWM should be considered.