This is the first study providing data on the natural history and management of MALNS, and its impact on QoL in the largest molecularly confirmed cohort of adult individuals with MALNS (N = 28) from the perspectives of caregivers.

Our data indicate that adult individuals with MALNS may present with different occurrence of some cardinal features of the disorder with respect to childhood and adolescence. MALNS is an overgrowth disorder in which a height higher than two SD is observed in more than half of the children and adolescents [5]. In our cohort, only nine individuals (32%; 5 men/4 women) showed a height higher than two SD. Among these subjects, two had spinal surgery. Our results confirm that overgrowth is less prominent in adulthood. On the other hand, macrocephaly still remains the most distinctive sign of overgrowth in MALNS, as head circumference (OFC) was above two SD in all individuals (N = 16) whose OFC was reported.

This survey also allowed us to highlight some interesting data in adaptive functioning skills with a relevant data in communication abilities in MALNS. As expected by previous reports, [20], all participants indicate impaired language skills in childhood, but the majority of the adults are able to communicate verbally (23/28; 82%). Unexpectedly, 76% of individuals (16/21) showed improvement in speech, meaning that language skills can become better with age. This information suggests partial recovery and/or late improvement of speech, which should be considered when counseling families diagnosed with MALNS in childhood. Adaptive functioning assessment is usually performed with the Vineland adaptive behavior scale—second edition (VABS-II), which specifically explores abilities in three different domains (communication, socialization and daily living skills). Apparent contrasting results for the two other domains (i.e.: socialization and daily living skills) has previously been evidenced between pediatric and adult MALNS populations [20, 26] Specifically, adult MALNS have been found to gradually improve with time in daily living skills eventually reaching an average score later than typical and, in general, performing better than expected [26].

When considering the most frequent medical problems, the clinical presentation in adulthood is mainly characterized by a high prevalence of psychobehavioral comorbidities (96%). They include anxiety (79%), limited interests, repetitive movements and echolalia (50%), autistic traits (46%) and mood abnormalities (39%). These observations show consistency with previous literature, which reported a prevalence between 52 and 94%, mainly represented by anxiety and autistic-like behavior [5, 7, 21]. Notably, despite the high rate, more than half of the individuals (N = 15) were not under direct care and follow-up of mental health professionals. This result may be traced back to several causes. The transition from pediatric to adult healthcare system remains challenging for affected individuals with neurodevelopmental disorders as they (and indirectly their families/caregivers) invariably encounter several obstacles. They are frequently forced to change referring specialists who, in most cases, do not have experience in dealing with rare diseases and their dedicated care. [27, 28] In MALNS individuals, the high anxiety levels in the medical setting and examinations by unfamiliar physicians could lead to less willingness to apply to adult healthcare services. Eventually, these factors put affected individuals at risk of discontinuous and non-adequate support. [27].

In the present cohort, the treatment of psychobehavioral comorbidities was mainly pharmacological (14/27; 52%) whereas only a few individuals received non-pharmacological treatments, such as psychotherapy and psychoeducation (N = 5). A slightly higher pharmacological treatment has been reported in individuals diagnosed with Fragile X syndrome (63%), whereas prevalence of psychotropic usage in Prader-Willi syndrome (37%) appears to be less [29, 30]. Mental health services are more prone to prescribe psychotropic medication, mainly antipsychotics, in adults with ID even in the absence of concurrent psychiatric symptoms [31]. High doses and polypharmacy are also common practice in this population [32]. The use of psychotropic drugs is much higher than in the general population [33]. Based on these clinically relevant findings, we suggest that pharmacological treatment should only be prescribed after proper interdisciplinary assessment, under close monitoring of efficacy and side-effects. Psychological therapy is also suggested to be moderately effective in people with ID. However, concerns regarding lack of experience with this population amongst mental health professionals and the notion that their cognitive problems are a barrier for proper engagement limit the inclusion of psychotherapy in psychobehavioral management [34]. Half of the caregivers reported that drug therapy was effective whereas the other half did not provide an answer (Fig. 4B). This suggests that caregivers find it difficult to define effectiveness of drug therapy and/or how they improved their child’s behavior. The benefit of different psychotropic drugs varies tremendously, which highlights the complexity of behavior in individuals with MALNS as seen in Supplementary Table 5 (see Additional file 3). The importance of a proper psychobehavioral assessment in MALNS has been previously underlined to aid clinicians in timely diagnosis and early intervention at all ages [20, 21]. Our results confirm the usefulness of psychological surveillance also in adulthood. When considering the significant impact of psychobehavioral issues on adult QoL, the need to include a mental health professional in management of adult individuals is highly recommended.

Involvement of the musculoskeletal system is characteristic of MALNS. Previous reports have identified hypotonia (50–76%), abnormal spine curvatures (32–75%), advanced bone age (80%) and flat feet (69%) as common features [5, 7]. We found consistent results regarding hypotonia (75%) and spine anomalies (including scoliosis and/or kyphosis) (64%). These numbers are in line with those in the pediatric cohort [7]. Only half of the adults had an advanced bone age during childhood. As bone age is assessed in children who present with growth abnormalities, those who show overgrowth are more likely to be evaluated and diagnosed [35]. Indeed, there is evidence that advanced bone age is hard to be properly confirmed after early infancy so it might be likely that this specific feature has not been investigated in individuals with MALNS who were molecularly diagnosed in late childhood or adolescence. Five individuals had bone fractures, which mostly occurred during childhood. Despite the small number of associated osteoporosis (N = 3), the increased risk of skeletal fractures suggests that further investigations on bone mineral density in adolescent and adult individuals should be required, as previously reported, [7] and that vitamin D supplementation should be considered.

Problems with coordination was a commonly observed symptom with a higher prevalence compared to the pediatric population. Seventeen individuals (61%) experienced this problem compared to three cases reported in the study by Macchiaiolo et al. (19%). The latter were evaluated by medical professionals and findings were objectified. Moreover, the authors recorded ataxia as sporadic episodes and part of a spectrum of neurovegetative signs [7]. In the present survey, coordination problems were initially defined as “ataxia” and might be misinterpreted by caregivers. The discrepancies between previous data and the present findings can be explained due to this difference in perception by caregivers. They were specifically re- interviewed on this topic, but they could not provide a real distinction between general coordination problems and a medical diagnosis of ataxia. As we cannot objectively verify the occurrence of ataxia in the present adult cohort, it is likely that coordination problems are due, in part, to concomitant visuospatial and visuomotor deficiencies that are invariably observed in MALNS [7, 20].

Seizures/EEG anomalies were present in 46% of the individuals (13/28), while previous studies reported a prevalence of 26.5% and 63% [5, 7]. EEG anomalies were not constantly associated with seizures, in line with previous observations considering other cohorts of individuals with other neurodevelopmental disorders [36, 37]. In the present survey, both features were incorporated into a single question, and therefore could not be separated into two categories. Ten out of thirteen adults (77%) were treated with antiepileptics and were presumed to have developed seizures, whereas the remaining three were asymptomatic. This finding is in contrast with what had previously been reported in the pediatric population [7], which evidenced a high prevalence of EEG anomalies without development of seizures. Overall these findings indicate that late manifestation of seizures should be carefully monitored in adult individuals. In particular, late adult-onset of seizures occurred in three subjects (Table 1), who carried a pathogenic intragenic NFIX variant. While, previous reports suggested that deletions involving the CACNA1A gene could play a role and potentially increase the risk of developing seizures, [5, 14, 38] the present findings highlight the need for continuous monitoring of possible seizures in adulthood regardless of type of mutation or microdeletion.

Brain abnormalities, such as wide ventricles, corpus callosum hypoplasia, Chiari malformation and brain atrophy have been reported in MALNS [5]. We observed only one individual with Chiari malformation who was diagnosed at 17 years. As we did not ascertain whether all adults have had an MRI nor did we include a separate question in the survey, these features may have been underreported.

The other frequently described features of MALNS in adulthood included visual problems (96%). We observed strabismus in 57% of the adults, comparable with previous reports (63%) [7], all diagnosed in either infancy or childhood. Refractive disorders were less prevalent (21% vs. 75–81%) [5, 7]. We also report relatively high rates of ONA/ONH (32%) and vision decline (10/28; 36%). ONH/ONA are congenital conditions that have been previously reported with a prevalence of 21–25% in pediatric MALNS individuals [5, 7]. Individuals with ONH usually develop nystagmus and strabismus at an early age [39]. ONA was not reported separately before and was grouped under ONH in previous surveys thus we cannot properly verify if there is an increased occurrence in adulthood [5, 7]. ONA refers to irreversible loss of nerve fibers caused by a wide range of diseases and patients often present with a loss of visual field [40]. This might suggest that those with vision decline could potentially have underlying ONA. Over half of the adults (6/10; 60%) with vision decline were also diagnosed with ONA. Three individuals were diagnosed with vision decline in adulthood mainly due to adult-related complications (cataracts and presbyopia), while the rest manifested during childhood. Despite the observed vision decline, no cause was determined in two patients. The exams to determine ONA include visual field tests, magnetic resonance imaging and optical coherence tomography [40]. However due to their anxiety and ID, consultation of ophthalmologists and subsequent examinations may be limited in individuals with MALNS. All these observations, together with the high prevalence of visual impairment in the adult MALNS population, highlights the importance of routine ophthalmologic evaluations at all ages, as previously suggested [7]. This is anticipated to aid in identifying causes that can be accommodated/treated before significant vision loss occurs.

Adults display a lower prevalence of hypersensitivity to noise with respect to children and young adults (46% vs. 67–81%) [7, 21]. This could be explained by the difficulty to secure an accurate diagnosis that is obtained through audiometry to verify the level of discomfort in decibels, together with dedicated questionnaires to assess severity [41]. It is possible that individuals in our cohort have not all been properly evaluated, and the number could be much higher. However, our findings suggest that hypersensitivity to noise might decrease with age.

Other observations include constipation in more than half of the cases (54%). This is consistent with the pediatric prevalence (50%) [7], confirming that it is a significant symptom to adequately treat either early in childhood or in adulthood. Due to ID and language difficulties, it may be challenging for individuals with MALNS to express discomfort or pain. Manifestations of constipation can often present as sleep or behavioral problems [42]. Other gastrointestinal symptoms were not described in previous adult case reports.

We report a high frequency of sleep problems in MALNS (20/28; 71%). This issue seems not to have been reported in the literature. Sleep abnormalities are common in individuals with ID across all ages and impaired sleep is associated with challenging behavior [43]. It is also possible that anxiety may worsen sleep problems, and this could explain the high occurrence of this issue in the adult MALNS population. Based on both high frequencies of constipation and sleep anomalies, we strongly suggest proper evaluation of gastrointestinal and sleep issues in the adults with MALNS who present with psychobehavioral comorbidities.

High pain threshold (46%), skin issues (32%), incontinence (25%), tremors (21%), muscle hypoplasia (18%) and tics (18%) had not previously been reported in MALNS. Three out five adults with tics presented with coexistent seizures for which antiepileptic therapy was required. This might suggest that medication could possibly contribute to the manifestation of tics, as previously reported [44].

A high pain threshold is characteristic of Prader-Willi syndrome caused by dysfunction of the hypothalamus [45]. For MALNS it remains unclear whether the parents’ reported high pain threshold is consistent with a higher threshold point at which a stimulus becomes painful or that it underlies altered pain tolerance or reactions. As mentioned before, individuals with ID do not always provide reliable self-reporting of pain and have to rely on their caregivers to observe behavior that indicates pain [46]. Children and adolescents with ID display a higher prevalence of incontinence [47]. It is possible that there is a correlation between pain perception and incontinence as affected individuals might be less aware of the sensory signals of a full bladder. Caregivers and professionals should keep an altered pain perception in mind when evaluating any medical issues.

Skin issues could not be properly specified to obtain possible occurrence of dermatologic conditions. They generally occurred during childhood. Therefore, an age-related association seems less likely. A recurrent finding were eczemas, which are a relatively common in the general population [48].

Six individuals presented with “tremors” as an additional feature with variable onset varied (from birth to adulthood) and possibly related to different triggering events, including anti-psychotic drugs. Follow-up with a neurologist is desired to accurately objectify these tremors and further examine associations with psychobehavioral comorbidities and seizures.

A diminished volume in muscle tissue has been observed in a minority of individuals (5/28; 18%). This sign is invariably associated with low BMI (see below). Although we do not have a clear explanation about this feature, we might hypothesize a connection between the two signs. NFIX plays an important role in skeletal muscle development, regulating the switch from embryonic to fetal myogenesis by specifically activating fetal genes [49]. This crucial role has been also established in the mouse model of the disorder in which an inhibitory mechanism at the promoter of the gene that encodes for myostatin, a TGF-β family member with anti-myogenic properties, has been evidenced [50]. This finding is consistent with the hypothesis that MALNS individuals could show a reduced muscular mass due to the inability to gain weight despite adequate nutrient intake [7]. On the other hand, it might be possible that a diminished muscular mass might be also related to decreased mobility and diminished physical activity due to movement and coordination problems, which are frequently observed in these subjects. Further studies are needed to confirm a possible concomitant effect of these causes on muscle volume in MALNS.

Our survey evidenced some age-related signs diagnosed at a younger age than normally expected. We observed three individuals affected with cataracts at 4, 13 and 22 years of age. Cataract surveillance should be performed at all ages in MALNS population due to possible anticipation of early-onset in these individuals.

The oldest individual (60 years old) presented with a relatively stable health and reported adult-onset features, such as presbyopia, dilated left ventricle and hypertension. Signs such as acid reflux and inflammatory bowel disease were also sporadically reported in adulthood. Again, these issues might not be directly related to MALNS, as these are complications statistically normally occurring in the general adult population [51,52,53]. Cancer, macular degeneration, and stroke were not reported.

We observed obesity in three individuals (11%), which is in contrast to slender habitus and low BMI typical of pediatric MALNS [5, 7]. Underweight/low BMI was also observed in six adult individuals (21%). Among them, one individual required nasogastric tube feeding and involvement of a dietitian. Tube feeding-dependence had previously been reported [16]. These observations indicate that weight and BMI should be evaluated at every follow-up appointment, and stress the importance of sufficient calorie intake, with the potential help of a dietitian, to prevent complications and possibly avoid tube feeding.

MALNS is currently not classified as a disorder predisposing for cardiovascular disease. Previous series have reported dilatation of large blood vessels; among them, one had dilatation of the pulmonary arteries and five presented with dilatation of the aorta [5, 13, 54]. One individual showed progression of the aortic dilatation between 35 and 38 years of age with dissection [13]. Macchiaiolo et al. [7] evaluated 16 pediatric individuals with echocardiography and only observed mitral regurgitation in 31%. We report three individuals with aortic dilatation diagnosed at various ages (birth, 10 years, and 30 years). Clinical significance and progression of dilatation cannot be determined yet, but these observations signify the importance of cardiological evaluation in all affected individuals at diagnosis and follow-up.

The 1-year surveillance study by Macchiaiolo et al. provided a set of recommendations for management and follow-up of all individuals with MALNS [7]. Based on the presently collected data, we propose additional recommendations focused on adulthood (Table 3).

Strengths of this study include close collaboration with the international patient advocacy group, the Malan Syndrome Foundation, and the Italian and Dutch MALNS centers of expertise, which allowed easy access to recruit all known caregivers of adult individuals with MALNS. Additionally, combined input from these organized entities has helped to interpret open answers and establish uniform definition of symptoms.

In general, we observed a high response rate of 18/28 adult individuals (64%) who were registered at the Malan Syndrome Foundation. Despite the small number of participants, the present cohort is representative with respect to the prevalence of this ultra-rare disorder. The adapted survey was extensive, and questions covered a wide range of aspects of health, behavior, daily functioning, and treatments. The cross-sectional approach allowed us to quickly collect data in a short period of time and establish prevalence of multiple signs and symptoms. However, this approach also has some limitations such as the inability to objectively assess signs and symptoms and determine their prevalence. There is also recall bias risk as participants may not always be able to remember information correctly. We also had some missing data, mostly concerning age of onset or diagnosis and, type and outcomes of treatments, as not all questions were required to be answered.