Expanding the phenotype of anauxetic dysplasia caused by biallelic NEPRO mutations: A case report.

The cartilage hair hypoplasia and anauxetic dysplasia (CHH-AD) spectrum encompasses a group of rare skeletal disorders, with anauxetic dysplasia (ANXD) at the most severe end of the spectrum. Biallelic variants in RMRP, POP1, and NEPRO (C3orf17) have previously been associated with the three currently recognized ANXD types. Generally, all types are characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility and dislocations, and extensive skeletal abnormalities visible on radiological evaluation. Thus far, only five patients with type 3 anauxetic dysplasia (ANXD3) have been reported. Here, we describe one additional ANXD3 patient. We provide a detailed physical and radiological evaluation of this patient, in whom we identified a homozygous variant, c.280C > T, p.(Arg94Cys), in NEPRO. Our patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly. We provide an overview of the literature on ANXD3 and discuss our patient's characteristics in the context of previously described patients. This study expands the phenotypic spectrum of ANXD, particularly ANXD3. Greater awareness of the possibility of atlantoaxial subluxation, dental anomalies, and craniosynostosis may lead to more timely diagnosis and treatment.

Primrose syndrome: Characterization of the phenotype in 42 patients.

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.

Mutations in PIK3C2A cause syndromic short stature, skeletal abnormalities, and cataracts associated with ciliary dysfunction.

PIK3C2A is a class II member of the phosphoinositide 3-kinase (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and the phosphorylation of PI(4)P into PI(3,4)P2. At the cellular level, PIK3C2A is critical for the formation of cilia and for receptor mediated endocytosis, among other biological functions. We identified homozygous loss-of-function mutations in PIK3C2A in children from three independent consanguineous families with short stature, coarse facial features, cataracts with secondary glaucoma, multiple skeletal abnormalities, neurological manifestations, among other findings. Cellular studies of patient-derived fibroblasts found that they lacked PIK3C2A protein, had impaired cilia formation and function, and demonstrated reduced proliferative capacity. Collectively, the genetic and molecular data implicate mutations in PIK3C2A in a new Mendelian disorder of PI metabolism, thereby shedding light on the critical role of a class II PI3K in growth, vision, skeletal formation and neurological development. In particular, the considerable phenotypic overlap, yet distinct features, between this syndrome and Lowe's syndrome, which is caused by mutations in the PI-5-phosphatase OCRL, highlight the key role of PI metabolizing enzymes in specific developmental processes and demonstrate the unique non-redundant functions of each enzyme. This discovery expands what is known about disorders of PI metabolism and helps unravel the role of PIK3C2A and class II PI3Ks in health and disease.

The quality of general movements after treatment with low-dose dexamethasone in preterm infants at risk of bronchopulmonary dysplasia.

BACKGROUND: High-dose dexamethasone (DXM) treatment of preterms at risk of bronchopulmonary dysplasia leads to a deterioration in quality of their general movements (GMs). It is unknown whether low-dose DXM affects GM quality similarly. OBJECTIVES: To assess the effect of low-dose DXM treatment on the quality of GMs and fidgety GMs (FMs). METHODS: A prospective study of preterms admitted to our NICU between 2010 and 2012, and treated with DXM (starting dose 0.25 mg/kg/day). We assessed GM/FM quality and calculated their motor optimality score (MOS) before, during, and after treatment up to 3 months postterm. Neurological follow-up was performed between 12 and 36 months. We related risk factors with infants' GM trajectories and MOSs. At 3 months we compared the MOSs of low-dose DXM infants and a historical cohort of infants treated with high-dose DXM or hydrocortisone. RESULTS: 17 infants were included. GM/FM quality improved in 9 out of 13 initially abnormal infants (p = 0.004). Shorter periods of mechanical ventilation and higher birth weights were associated with better GM trajectories (p = 0.032 and p = 0.042, respectively). Infants starting treatment later had higher MOSs on day 7 (p = 0.047). Low-dose DXM infants had higher MOSs than high-dose DXM infants (ß = -0.535; 95% CI -0.594 to -0.132; p = 0.003). Out of 17 infants, 2 died, 14 developed normally, and 1 developed with mild neurodevelopmental impairments. Infants whose GMs/FMs remained normal or improved had better outcomes than infants whose GMs/FMs remained abnormal (p = 0.019). CONCLUSIONS: Out of the 17 infants treated with low-dose DXM, 2 died. Of the surviving infants, neurological functioning improved with the majority having normal neurodevelopment at the age of 12-36 months.

Functional outcome at school age of preterm-born children treated with high-dose dexamethasone.

BACKGROUND: Postnatal dexamethasone (DXM) treatment is associated with adverse motor outcome. It is largely unknown as to what extent functional outcome at school age is affected. AIMS: Our first aim was to determine motor, cognitive, and behavioural outcome at school age of preterm-born children treated with high-dose DXM for pulmonary problems. Our second aim was to identify DXM-related risk factors for adverse outcome. STUDY DESIGN: In this cohort study, we included 53 very preterm-born children treated with DXM (starting dose 0.5mg/kg/d) after the first week of life. At the median age of 9 years, we performed a detailed neuropsychological assessment. RESULTS: Compared to the norm population, DXM-treated children scored worse on the Movement-ABC (abnormal fine motor, ball skills and balance: 59%, 47% and 30%, respectively). They more often had total (36%), verbal (32%) and performance IQs (55%) below 85 (P<.001, P=.002, P<.001, respectively). On each of the remaining measures, DXM-treated children scored worse than the norm population, except for verbal long-term memory and verbal recognition memory. DXM-related risk factors were associated with poorer performance. CONCLUSIONS: At school age, multiple domains of functional outcome were affected in DXM-treated children. Risk factors related to the use of DXM should be considered as serious potentiaters of adverse outcome in children treated with high-dose DXM.

Development of fine motor skills in preterm infants.

Fine motor skills are related to functioning in daily life and at school. We reviewed the status of knowledge, in preterm children, on the development of fine motor skills, the relation with gross motor skills, and risk factors for impaired fine motor skills. We searched the past 15 years in PubMed, using ['motor skills' or 'fine motor function' and 'preterm infant'] as the search string. Impaired gross and fine motor skills are among the most frequently occurring problems encountered by preterm children who do not develop cerebral palsy. The prevalence is around 40% for mild to moderate impairment and 20% for moderate impairment. Fine motor skill scores on the Movement Assessment Battery for Children are about 0.62 of a standard deviation lower compared with term children. Risk factors for fine motor impairments include moderately preterm birth (odds ratio [OR] 2.0) and, among very preterm children (<32 wk gestation), intra-uterine growth restriction (ORs 2-3), inflammatory conditions (late-onset sepsis and necrotizing enterocolitis, ORs 3-5), and dexamethasone therapy for bronchopulmonary dysplasia (OR 2.7). A better understanding of factors that play a role in the development of and recovery from brain injury could guide future intervention attempts aimed at improving fine motor skills of preterm children.

Hydrocortisone vs. dexamethasone treatment for bronchopulmonary dysplasia and their effects on general movements in preterm infants.

INTRODUCTION: Hydrocortisone (HC) and dexamethasone (DXM) are used to treat preterm infants at risk for bronchopulmonary dysplasia (BPD). This may, however, affect their long-term neurological development. We aimed to determine the effect of HC and DXM therapy in preterm infants on neurological functioning as assessed by the quality of general movements (GMs) until 3 months after term. RESULTS: We found no difference in the quality of GMs between HC and DXM infants until term age. At 3 months, HC infants had a higher median motor optimality score (MOS) than DXM infants (25 vs. 21, P = 0.015). In the DXM group, MOS on the first day of treatment was lower than before treatment (10 vs. 11, P = 0.030). DISCUSSION: MOS decreased in DXM infants on the first day following treatment and at 3 months after term. This was not the case in HC infants. Our study suggests that neurological functioning at 3 months after term is better in infants treated with HC than in infants treated with DXM. METHODS: We performed a longitudinal, observational study including 56 preterm infants (n = 17 HC, n = 17 DXM, n = 22 controls). GM quality, videoed before and after treatment, was assessed. In addition, a MOS was assigned to details of the GMs.