Natural history in Malan syndrome: survey of 28 adults and literature review.

BACKGROUND: Malan syndrome (MALNS), previously referred to as "Sotos syndrome 2" due to its resemblance to Sotos syndrome (SS), is an ultra-rare neurodevelopmental disorder characterized by overgrowth, typical craniofacial features, intellectual disability (ID), and a range of psychobehavioral, musculoskeletal, vision and neurological signs. As MALNS and SS partly overlap, it is essential to more accurately profile their clinical presentations and highlight their differences in order to improve syndrome specific management. An increasing number of individuals with MALNS reach adult-age though the natural history of the disorder is poorly characterized due to the small number of adult individuals described so far. As a consequence, current guidelines are limited to the pediatric population. Further delineation of MALNS is essential to optimize care in adulthood. RESULTS: A mixed approach based on cross-sectional data collection with a survey disseminated to caregivers of adults with molecularly confirmed MALNS and literature review was conducted. Twenty-eight caregivers completed the survey. Clinical presentation in adulthood is multisystemic and defined by psychobehavioral comorbidities (96%), musculoskeletal involvement (96%), vision impairment (96%) and neurological complications (86%). The most common signs were anxiety (79%), hypotonia (75%), movement difficulty (75%), scoliosis (64%), problems with coordination (61%), strabismus (57%), constipation (54%), breastbone abnormalities (54%) and advanced bone age during childhood (54%). Impaired vision was complicated by vision decline (36%) and optic atrophy (32%). We report some previously unidentified features, including high pain threshold (46%), incontinence (25%), tremors (21%), muscle hypoplasia (18%) and tics (18%). CONCLUSIONS: This survey in the adult population has allowed a more complete description of the natural history of MALNS. Our findings will contribute to the development and improvement of standards of care for adults with MALNS to assure optimal health monitoring and treatment of evolutive complications. We propose additional recommendations to the previous dataset of clinical evaluations specifically applied to adults. The comparison of MALNS and SS adult presentation highlights significant differences in terms of prevalence and severity of ID, behavioral issues, and vision problems, confirming that a proper differential diagnosis between the two conditions is indispensable to guide physicians and mental health professionals to syndrome specific management.

Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes.

BACKGROUND: Ultrarare Marshall-Smith and Malan syndromes, caused by changes of the gene nuclear factor I X (NFIX), are characterised by intellectual disability (ID) and behavioural problems, although questions remain. Here, development and behaviour are studied and compared in a cross-sectional study, and results are presented with genetic findings. METHODS: Behavioural phenotypes are compared of eight individuals with Marshall-Smith syndrome (three male individuals) and seven with Malan syndrome (four male individuals). Long-term follow-up assessment of cognition and adaptive behaviour was possible in three individuals with Marshall-Smith syndrome. RESULTS: Marshall-Smith syndrome individuals have more severe ID, less adaptive behaviour, more impaired speech and less reciprocal interaction compared with individuals with Malan syndrome. Sensory processing difficulties occur in both syndromes. Follow-up measurement of cognition and adaptive behaviour in Marshall-Smith syndrome shows different individual learning curves over time. CONCLUSIONS: Results show significant between and within syndrome variability. Different NFIX variants underlie distinct clinical phenotypes leading to separate entities. Cognitive, adaptive and sensory impairments are common in both syndromes and increase the risk of challenging behaviour. This study highlights the value of considering behaviour within developmental and environmental context. To improve quality of life, adaptations to environment and treatment are suggested to create a better person-environment fit.

Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.

Safety and efficacy of oxandrolone in growth hormone-treated girls with Turner syndrome: evidence from recent studies and recommendations for use.

There has been no consensus regarding the efficacy and safety of oxandrolone (Ox) in addition to growth hormone (GH) in girls with Turner syndrome (TS), the optimal age of starting this treatment, or the optimal dose. This collaborative venture between Dutch, UK and US centers is intended to give a summary of the data from three recently published randomized, placebo-controlled, double-blind studies on the effects of Ox. The published papers from these studies were reviewed within the group of authors to reach consensus about the recommendations. The addition of Ox to GH treatment leads to an increase in adult height, on average 2.3­4.6 cm. If Ox dosages<0.06 mg/kg/day are used, side effects are modest. The most relevant safety concerns are virilization(including clitoromegaly and voice deepening) and a transient delay of breast development. We advise monitoring signs of virilization breast development and possibly blood lipids during Ox treatment, in addition to regular follow-up assessments for TS. In girls with TS who are severely short for age, in whom very short adult stature is anticipated,or in whom the growth rate is modest despite good compliance with GH, adjunctive treatment with Ox at a dosage of 0.03­0.05 mg/kg/day starting from the age of 8­10 years onward scan be considered.

Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A.

BACKGROUND: A severe and challenging complication in the treatment of hemophilia A is the development of inhibiting antibodies (inhibitors) directed towards factor VIII (FVIII). Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. OBJECTIVES: In a large cohort study in patients with mild/moderate hemophilia A we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. PATIENTS/METHODS: Longitudinal clinical data from 138 mild/moderate hemophilia A patients were retrospectively collected from 1 January 1980 to 1 January 2008 and analyzed by multivariate analysis using Poisson regression. RESULTS: Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients; the remaining 86 patients had 26 other missense mutations. Sixty-three (46%) patients received intensive FVIII concentrate administration, 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. Compared with the other patients, those with the Arg593Cys mutation had a 10-fold increased risk of developing inhibitors (RR 10; 95% CI, 0.9-119).The other two inhibitor patients had the newly detected mutations Pro1761Gln and Glu2228Asp. In both these patients and in five patients with genotype Arg593Cys, inhibitors developed after intensive peri-operative use of FVIII concentrate (RR 186; 95% CI, 25-1403). In five of the 10 inhibitor patients FVIII was administered by continuous infusion during surgery (RR 13; 95% CI, 1.9-86). CONCLUSION: The Arg593Cys genotype and intensive peri-operative use of FVIII, especially when administered by continuous infusion, are associated with an increased risk for inhibitor development in mild/moderate hemophilia A.