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.

A comparison of the early motor repertoire of very preterm infants and term infants.

OBJECTIVE: To obtain reference data on the early motor repertoire of very preterm infants compared with healthy term infants at three months' post-term age. STUDY DESIGN: In this observational study, using Prechtl's method on the assessment of the early motor repertoire, we compared the quality of fidgety movements and the concurrent motor optimality score - revised of infants with a gestational age <30 weeks and/or a birth weight <1000 g with healthy infants with a gestational age of 37-42 weeks. RESULTS: One hundred eighty very preterm and 180 healthy term infants participated. The median motor optimality scores - revised of very preterm infants were significantly lower in comparison to those of term infants, with scores of 24 (25th-75th percentiles: 23-26) and 26 (25th-75th percentiles: 26-28), respectively. Fidgety movements were aberrant (abnormal or absent) more often in very preterm infants than in term infants. The odds ratio was 4.59 (95% CI, 1.51-13.92). Compared with term infants, very preterm infants had poorer scores on the subscales age-adequate movement repertoire, observed postural patterns, and movement character with odds ratios ≥2.97. We found no differences regarding observed movement patterns. CONCLUSION: This study provides reference data on the early motor repertoire of very preterm and healthy term infants. It demonstrates that the early motor repertoire of very preterm infants is poorer than that of term infants, a finding consistent with existing knowledge that prematurity increases the risk of poor neurodevelopment.

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.

Associations between developmental trajectories of movement variety and visual attention in fullterm and preterm infants during the first six months postterm.

BACKGROUND: During early infancy major developmental changes, both in the variety of body movements and in visual attention, help the infant to explore its surroundings. Both behaviours depend on a gradual shift from subcortical to cortical functioning. AIMS: First, to determine whether preterms reach mature levels of movement variety (the number of different movement patterns) and visual attention earlier than fullterms. Second, to determine whether individual developmental trajectories of movement variety and visual attention were associated. Finally, we compared the associations of developmental trajectories between fullterm and preterm infants. STUDY DESIGN: In this longitudinal study, 20 fullterm and 9 low-risk preterm infants performed a visual disengagement task every four weeks from six weeks until six months postterm. For each infant we drew up developmental trajectories for movement variety, and for frequencies and latencies of looks. We analyzed the developmental trajectories by means of general linear model (GLM) repeated measures and Monte Carlo analyses. RESULTS: In comparison to fullterms, preterm infants showed a similar increase in movement variety over time (F(4,108)=0.27; partial eta(2)=0.01; P=.90). Visual attention reached mature levels four weeks earlier than movement variety. This effect was stronger in fullterm infants. Neither in fullterm nor in preterm infants did we find an association between the developmental trajectories of movement variety and visual attention. P values ranged from .37 to .99. CONCLUSIONS: During the first 6 months postterm, movement variety and visual attention developed independently. Temporarily, preterm exposure to the extrauterine environment led to shorter latencies of looks but it did not affect developmental trajectories of frequencies of looks and movement variety.

Infants with Tyrosinemia Type 1: Should phenylalanine be supplemented?

Tyrosinemia type 1 (HT1) is an inborn error of tyrosine catabolism caused by fumarylacetoacetase deficiency. Biochemically, this results in accumulation of toxic metabolites including succinylacetone. Clinically, HT1 is characterized by severe liver, kidney, and neurological problems. Treatment with NTBC and dietary restriction of tyrosine and phenylalanine have strongly improved outcome, but impaired neurocognitive development has been reported. Whether impaired neurocognitive outcome results from high blood tyrosine or low blood phenylalanine concentrations is currently unknown. In this report, two HT1 newborns, diagnosed by neonatal screening, are presented. The first patient showed low phenylalanine concentrations, growth retardation, neurological impairments, and skin problems, clearly improving after institution of phenylalanine supplementation (~30 mg/kg/day) at age 6 months, while both blood phenylalanine and tyrosine concentrations increased. In the second patient, phenylalanine supplementation (~20 mg/kg/day) was initiated as soon as low phenylalanine concentrations were observed at age 19 days. On this regimen, blood phenylalanine concentrations increased, and hypophenylalaninemia was less frequently observed than in the first patient, whereas blood tyrosine concentrations tended to increase. Clinically, no growth, neurological, or skin problems have been observed. The combination of knowledge obtained from these cases suggests that hypophenylalaninemia rather than hypertyrosinemia during the first months of life may impair neurocognitive development in young HT1 infants. Phenylalanine supplementation should really be considered in HT1 patients with consistently low blood phenylalanine concentrations during the first months of life. However, the minimal phenylalanine concentrations acceptable and the optimal phenylalanine supplementation regimen require further investigation.

Early visual attention in preterm and fullterm infants in relation to cognitive and motor outcomes at school age: an exploratory study.

OBJECTIVE: Preterm infants are exposed to the visual environment earlier than fullterm infants, but whether early exposure affects later development is unclear. Our aim was to investigate whether the development of visual disengagement capacity during the first 6 months postterm was associated with cognitive and motor outcomes at school age, and whether associations differed between fullterms and low-risk preterms. METHOD: Seventeen fullterms and ten low-risk preterms were tested in a gaze shifting task every 4 weeks until 6 months postterm. The longitudinal data were converted into single continuous variables by fitting the data with an S-shaped curve (frequencies of looks) or an inverse model (latencies of looks). Neuropsychological test results at school age were converted into composite z scores. We then performed linear regression analyses for each functional domain at school age with the variables measuring infant visual attention as separate predictors and adjusting for maternal level of education and group (fullterms versus preterms). We included an interaction term, visual attention*group, to determine whether predictive relations differed between fullterms and preterms. RESULTS: A slower development of disengagement predicted poorer performance on attention, motor skills, and handwriting, irrespective of fullterm or preterm birth. Predictive relationships differed marginally between fullterms and preterms for inhibitory attentional control (P = 0.054) and comprehensive reading (P = 0.064). CONCLUSION: This exploratory study yielded no indications of a clear advantage or disadvantage of the extra visual exposure in healthy preterm infants. We tentatively conclude that additional visual exposure does not interfere with the ongoing development of neuronal networks during this vulnerable period of brain development.

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.

Motor development in 3-month-old healthy term-born infants is associated with cognitive and behavioural outcomes at early school age.

AIM: To determine whether motor development at 3 months of age is associated with cognitive, motor, and behavioural outcomes in healthy children at early school age. METHOD: In this cohort study, we included 74 term-born, healthy children (44 males, 30 females; median gestational age 40.1 wks, range 38.0-42.6 wks). From video recordings (median 12.9 wks, range 9.3-18.6 wks), we assessed the quality of fidgety movements, and calculated a motor optimality score. At school age (median 5 y 11 mo, range 5 y 8 mo-7 y 6 mo), we performed detailed cognitive, motor, and behavioural assessments. We examined whether aspects of motor development were associated with functional outcomes. RESULTS: An age-adequate motor repertoire, in particular the presence of antigravity, midline leg, and manipulation movements, was related to poorer cognition, whereas variable finger postures was related to better cognition. Children with a monotonous concurrent motor repertoire had better ball skills but experienced more behavioural problems. The presence of antigravity movements tended to be associated with abnormal recognition (odds ratio [OR] 4.4, 95% confidence interval [CI], 0.9-21; R(2) =0.17; p=0.070), where the absence of variable finger postures was associated with borderline and abnormal visual-spatial perception (OR 20, 95% CI, 1.7-238; R(2) =0.39; p=0.018). INTERPRETATION: Detailed aspects of motor development at 3 months of age are associated with cognition and behaviour, but not with motor outcome, in healthy children at early school age. Our findings suggest that early motor development may be the basis for later cognitive and behavioural performance. Since the associations were only moderate, possible environmental influences should be acknowledged.

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.

Prenatal exposure to polychlorinated biphenyls and their hydroxylated metabolites is associated with motor development of three-month-old infants.

BACKGROUND: Polychlorinated biphenyls (PCBs) are ubiquitous environmental pollutants that are potentially toxic to the developing brain. Hydroxylated metabolites of PCBs (OH-PCBs) are suggested to be even more toxic. Little is known about their short-term effects on human health. OBJECTIVES: To determine whether prenatal background exposure to PCBs and OH-PCBs was associated with the motor development of three-month-old infants. METHODS: Ninety-seven mother-infant pairs participated in this Dutch, observational cohort study. We determined the concentrations of PCBs and OH-PCBs in cord blood samples. When the infants were three months old we evaluated their motor development by assessing the presence and performance of spontaneous movement patterns from video recordings. We calculated a Motor Optimality Score (MOS). The score could range from low (5) to high (28) optimality. We explored the correlations between PCB and OH-PCB levels and MOS. Subsequently, we tested whether the levels differed between infants with a low (<26) or high (≥26) MOS and whether the levels associated with detailed aspects of their motor repertoires. RESULTS: We found several associations between PCB and OH-PCB levels and MOS, including detailed aspects of the early motor development. High 4-OH-PCB-107 levels were associated with a low MOS (P=.013). High PCB-187 levels were associated with reduced midline arm and leg movements (P=.047 and P=.043, respectively). High 4'-OH-PCB-172 levels were associated with more manipulation (P=.033). CONCLUSIONS: Prenatal exposure to high background levels of most PCBs and 4-OH-PCB-107 seems to impair early motor development, whereas only 4'-OH-PCB-172 showed the opposite.

Favorable outcome in a newborn with molybdenum cofactor type A deficiency treated with cPMP.

Molybdenum cofactor deficiency (MoCD) is a lethal autosomal recessive inborn error of metabolism with devastating neurologic manifestations. Currently, experimental treatment with cyclic pyranopterin monophosphate (cPMP) is available for patients with MoCD type A caused by a mutation in the MOCS-1 gene. Here we report the first case of an infant, prenatally diagnosed with MoCD type A, whom we started on treatment with cPMP 4 hours after birth. The most reliable method to evaluate neurologic functioning in early infancy is to assess the quality of general movements (GMs) and fidgety movements (FMs). After a brief period of seizures and cramped-synchronized GMs on the first day, our patient showed no further clinical signs of neurologic deterioration. Her quality of GMs was normal by the end of the first week. Rapid improvement of GM quality together with normal FMs at 3 months is highly predictive of normal neurologic outcome. We demonstrated that a daily cPMP dose of even 80 µg/kg in the first 12 days reduced the effects of neurodegenerative damage even when seizures and cramped-synchronized GMs were already present. We strongly recommend starting cPMP treatment as soon as possible after birth in infants diagnosed with MoCD type A.

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.