Clinical characteristics.

NFIX-related Malan syndrome (MALNS) is characterized by prenatal and postnatal overgrowth, macrocephaly, advanced bone age and/or skeletal anomalies (scoliosis, pes planus), slender body habitus, developmental delay / intellectual disability (typically in the moderate-to-severe range), behavioral problems (including a specific anxious profile and attention-deficit/hyperactivity disorder [ADHD]), and ocular findings (most commonly strabismus, refractive errors, and blue sclerae). Affected individuals typically have distinctive facial features, including a long and triangular face, high anterior hair line with prominent forehead, depressed nasal bridge, deep-set eyes, downslanted palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open, thin vermilion of the upper lip, an everted lower lip, and a prominent chin. Other findings may include autonomic signs (episodic ataxia with dizziness and nausea and/or postural fainting), seizures or EEG abnormalities, hypotonia, dental anomalies, long bone fractures, and (rarely) congenital heart defects. Four individuals with aortic root dilatation have been reported, with one adult individual experiencing progressive aortic dilation and dissection at age 38 years. Additionally, one individual with rib osteosarcoma and another with Wilms tumor have been reported (an overall prevalence of malignancy of about 2%). Therefore, MALNS appears to be in the same low risk group as Sotos syndrome and Weaver syndrome with respect to a low likelihood of developing cancer.

Diagnosis/testing.

The diagnosis of MALNS is established in a proband with suggestive findings and either a heterozygous pathogenic variant in NFIX (~75% of affected individuals) OR a heterozygous deletion of 19p13.2 that includes NFIX (~25% of affected individuals) identified by molecular genetic testing.

Management.

Treatment of manifestations: Feeding therapy with a low threshold for clinical feeding evaluation &/or radiographic swallowing study for those with clinical signs or symptoms of dysphagia; gastrostomy tube placement may be required for persistent feeding issues. Stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation. Symptomatic treatment for autonomic signs based on the underlying cause. Cognitive behavioral therapy (CBT) may be used to treat anxiety and ADHD. Symptomatic aids (i.e., colored glasses, low voice tone) may reduce anxiety outbursts. Hearing aids may be helpful per otolaryngologist. Standard treatment for epilepsy, Chari I malformation, developmental delay / intellectual disability, scoliosis/kyphosis, pes planus, pectus anomalies, refractive error, strabismus, tooth anomalies / malocclusion, aortic root dilatation / valvular issues, and cryptorchidism.

Surveillance: At each visit, measure growth parameters and evaluate nutritional status and safety of oral intake; monitor for signs/symptoms of constipation, Chari I malformation, and subtle and nonspecific neurovegetative findings; and assess for new manifestations, such as seizures and changes in tone. The first BMI evaluation should be performed after age two years; assess caloric intake and BMI every six months during the first two years of life, then at least annually. Monitor developmental progress, educational needs, and psychopathologic symptoms annually from age 12 months to age 36 months and then approximately every two years from age three to six years. Annual ophthalmology evaluation until puberty and then periodically in adults to evaluate for late-onset optic nerve degeneration. Annual audiology evaluation in childhood or as clinically indicated. At least annual routine dental/orthodontic evaluation. Consider DXA scan for bone mineral density periodically in those with a history of multiple fractures or previous low bone mineral density. If the baseline cardiovascular evaluation is normal, consider annual cardiology follow up; limited data on aortic root progression is available for adults. No tumor screening protocols have been proposed or recommended for individuals with MALNS.

Genetic counseling.

MALNS is an autosomal dominant disorder typically caused by a de novo genetic alteration. Therefore, the risk to other family members is presumed to be low. Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported. Once an NFIX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MALNS should be suspected in individuals with at least five out of the following eight features [Priolo et al 2018, Mulder et al 2020, Alfieri et al 2022, Macchiaiolo et al 2022]:

• Prenatal overgrowth, often with a diagnosis of being large for gestational age
• Postnatal overgrowth (length/height and/or head circumference ≥2 standard deviations [SD] above mean for age and sex)
• Developmental delay / intellectual disability
• Behavioral problems
• Distinctive facial features (See Clinical Description.)
• Advanced bone age and/or skeletal anomalies, such as scoliosis, pes planus, and pectus anomaly
• Slender body habitus
• Ocular findings, most commonly strabismus, refractive errors, and blue sclerae

Family history may be consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MALNS is established in a proband with suggestive findings and one of the following on molecular genetic testing (see Table 1):

• A heterozygous pathogenic (or likely pathogenic) variant in NFIX (~75% of affected individuals)
• A heterozygous deletion of 19p13.2 that includes NFIX (~25% of affected individuals)

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous NFIX variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with overgrowth and/or intellectual disability are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

NFIX-related Malan syndrome (MALNS) was first reported in three individuals with overgrowth and heterozygous pathogenic variants in NFIX in 2010 [Malan et al 2010]. Since that time, at least 100 individuals have been identified with MALNS [Priolo et al 2012, Yoneda et al 2012, Klaassens et al 2015, Gurrieri et al 2015, Martinez et al 2015, Jezela-Stanek et al 2016, Oshima et al 2017, Priolo et al 2018, Hancarova et al 2019, Sihombing et al 2020, Tabata et al 2020, Langley et al 2022, Macchiaiolo et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Facial features. Distinctive facial features are generally present in all affected individuals identified to date. The facial features include a long and triangular face, high anterior hair line with prominent forehead, depressed nasal bridge, deep-set eyes, downslanted palpebral fissures, short nose with anteverted nares and upturned tip, long philtrum, small mouth that is often held open, thin vermilion of the upper lip, an everted lower lip, and a prominent chin (see Figure 1). Other less frequent features are high-arched palate, dental crowding, sparse hair, loose and soft skin, and facial asymmetry [Priolo et al 2018, Alfieri et al 2022, Macchiaiolo et al 2022].

Figure 1.

Clinical features of individuals with Malan syndrome at different ages, with evolving facial appearance. Note long and triangular face, high anterior hair line with prominent forehead, downslanted palpebral fissures, small mouth, everted lower lip, and (more...)

Growth

• Macrocephaly is observed in all reported individuals to date [Priolo et al 2018, Priolo 2019, Macchiaiolo et al 2022]. Dolichocephaly is also usually present.
  • Approximately 41% of newborns with MALNS have a head circumference >2 standard deviations (SD) above the mean for sex.
  • At least 77% of adults maintain a head circumference >2 SD above the mean for sex.
• Prenatal and postnatal overgrowth
  • About 15% of affected newborns will be characterized as large for gestational age (weight at birth >2 SD above the mean for sex), but weight is reported to be above the mean for about 90% of affected newborns.
  • Postnatal overgrowth is generally recognized in childhood and adolescence, with a length/height >2 SD above the mean for age and sex reported in 56% of affected individuals.
  • About one third of affected individuals’ final adult height is >2 SD above the mean [Priolo et al 2018, Priolo et al 2019, Macchiaiolo et al 2022].
• Body mass index (BMI) falls <2 SD below the mean for age and sex in at least one third of affected individuals, despite normal micro- and macronutrient intake for age [Macchiaiolo et al 2022]. This finding may be due to the overall slender body habitus (see Musculoskeletal below).

Developmental delay (DD) and intellectual disability (ID). Cognitive impairment and DD are invariably present and may range from moderate to severe. Rarely, mild ID has been reported.

• Typically, affected individuals show both low cognitive and adaptive functioning, with communication skills being the most affected.
• The level of intellectual impairment generally remains stable throughout life.
• A dedicated diagnostic battery of tests has been proposed to carefully assess the impairment in different domains (for a full review of the battery of tests recommended, see Alfieri et al [2022] and Alfieri et al [2023]).
• Aadaptive functioning is usually lower than normal, generally ranging from moderately to severely impaired, with communication skills the most affected.
• Verbal language skills are usually the most severely impacted, with receptive language more preserved than expressive language [Mulder et al 2020, Alfieri et al 2022, Alfieri et al 2023].

Other neurodevelopmental features

• Hypotonia. At least 65% of individuals with MALNS have been reported to have hypotonia. This finding may cause, together with DD, feeding difficulties and drooling in infancy. Hypotonia may persist during childhood and slowly improve with time.
• Autonomic findings. Recurring autonomic signs have been reported in at least 25% of affected individuals. Symptoms may be subtle or nonspecific (e.g., vomiting/nausea, dizziness, fainting). These signs may be occasional or triggered by external causes (stress, anxiety, provoking situations).
  The same signs, sometimes associated with gait disturbances (e.g., broad-based gait, toe-walking), have also been occasionally described in affected individuals with Chiari I malformations, but they may be also observed in individuals with MALNS who do not have Chiari I malformations. For this reason, individuals with MALNS should be first assessed for Chiari I malformations through neuorimaging and then for other causes (e.g., cardiac/otologic evaluation) of these nonspecific symptoms.

Epilepsy. Seizures and electroencephalogram (EEG) anomalies are common and more frequently observed among individuals with continuous gene deletions that include NFIX and surrounding genes. Individuals with NFIX intragenic pathogenic variants are prone to develop nonspecific EEG anomalies, which usually do not require anti-seizure medication (ASM) [Macchiaiolo et al 2022]. The exact types and severity of epilepsy in individuals with this condition have not been well characterized to date.

Neurobehavioral/psychiatric manifestations affect most individuals with MALNS. Behavioral problems characterized by a specific anxious profile are seen in more than 80% of affected individuals. Anxiety does not appear to affect individuals in any specific age range but may worsen over time.

The most prevalent psychiatric comorbidities include generalized anxiety disorder; separation anxiety with specific phobias; attention-deficit/hyperactivity disorder; and behavioral issues (e.g., impaired socialization) that may resemble those of individuals with autism but are different from classic autistic behavior.

Some affected individuals may be given a clinical diagnosis of an autism spectrum disorder primarily because of their expressive language difficulties. However, most affected individuals do not have true impairment in social interactions outside of their deficient communication skills [Mulder et al 2020, Alfieri et al 2022, Alfieri et al 2023].

Additional neuropsychiatric hallmarks include difficulty with visuomotor integration; hypersensitivity to visual and auditory stimuli (noise hypersensitivity and photophobia), both of which may contribute to psychopathology; and challenging behaviors with panic crises and, rarely, outbursts of hetero-aggression and self-injurious behavior.

Neuroimaging. Brain MRI abnormalities are identified in at least half of individuals with MALNS. Ventricular dilatation and corpus callosum hypoplasia are the most frequent findings, present in 8/16 (50%) individuals reported by Macchiaiolo et al [2022]. Chiari I malformation has been identified in 6/16 (38%) affected individuals. In the study by Macchiaiolo et al [2022], about 25% of affected individuals had various degrees of optic nerve hypoplasia; however, data from patient registries suggest that this latter figure might be an underestimate [Sanford CoRDS patient registry for Malan syndrome].

Musculoskeletal features may include the following:

• Slender body habitus (almost all individuals)
• Advanced bone age (at least 76%)
• Scoliosis (75%)
• Hyperkyphosis or hyperlordosis (~30%)
• Pes planus (69%)
• Pectus anomaly (excavatum, carinatum, or mixed) (63%)
• Long bone fracture
  • Individuals with MALNS have a slightly increased risk of bone fractures during childhood as compared to the general population [Macchiaiolo et al 2022].
  • Rarely, mild osteopenia has been identified by DXA scan, which quickly resolved after vitamin D₃ supplementation (see Management) [Macchiaiolo et al 2022, Sanford CoRDS patient registry for Malan syndrome].

Ophthalmologic findings, including strabismus and refractive errors (such as myopia, hypermetropia, and astigmatism), occur with an overall frequency of about 75%. About 70% of affected individuals have blue sclerae. There is some evidence to suggest that adults with MALNS may be at risk for late-onset optic nerve degeneration. Other findings may include:

• Nystagmus (31%)
• Polar posterior cataract (13%)
• Optic nerve hypoplasia and optic disk pallor (25%)

Cardiovascular anomalies have been reported in a small proportion of individuals with MALNS. Four individuals with aortic root dilatation and one with pulmonary artery dilatation have been reported [Nimmakayalu et al 2013, Oshima et al 2017, Priolo et al 2018]. There is limited data available on aortic root z scores or on whether aortic dilation was static or progressive; however, one affected adult experienced progressive aortic dilation and dissection at age 38 years [Oshima et al 2017]. Minor cardiac anomalies, such as low-grade mitral regurgitation, have been frequently observed [Macchiaiolo et al 2022]. Other major cardiac findings have been reported in a minority of reported individuals.

Gastrointestinal issues. Isolated hepatomegaly has been observed in about one quarter of individuals with MALNS either during childhood or adulthood. It is not generally associated with liver dysfunction.

Different degrees of constipation, sometimes requiring pharmacologic therapy (see Management), have been observed in almost half of individuals.

Hearing. Two individuals with MALNS have been reported with bilateral moderate-to-severe sensorineural hearing impairment [Priolo et al 2018, Sanford CoRDS patient registry for Malan syndrome]. Many individuals with this condition are sensitive to noise (see Neurobehavioral/psychiatric manifestations above).

Genitourinary. A minority of affected males have had cryptorchidism. Renomegaly might be observed as an incidental finding.

Malignancy. To date, one individual with rib osteosarcoma and another with Wilms tumor have been reported (an overall prevalence of malignancy of about 2%). Therefore, MALNS appears to be in the same low risk group as Sotos syndrome and Weaver syndrome with respect to a low likelihood of developing cancer [Villani et al 2017, Priolo et al 2018, Brioude et al 2019, Macchiaiolo et al 2022]. Therefore, no tumor screening protocols have been proposed or recommended for individuals with MALNS.

Prognosis. It is unknown whether the life span in MALNS is abnormal. Two reported individuals are alive at age 40 and 60 years, respectively [M Priolo, personal observation], demonstrating that survival into adulthood is possible. Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Genotype-Phenotype Correlations

Deletion of 19p13.2. At least 25% of individuals with MALNS have a deletion of the 19p13.2 region that includes NFIX and other adjacent genes. There is no significant difference in growth pattern, cognitive impairment, facial characteristics, or skeletal manifestations in those with larger deletions that include NFIX compared to those with intragenic NFIX pathogenic variants. However, individuals with a deletion containing NFIX and adjacent genes are more likely to have seizures and EEG abnormalities compared to those with intragenic NFIX pathogenic variants, which may be due to deletion of CACNA1A, which is located about 109 kilobases (kb) from NFIX [Priolo et al 2018].

NFIX intragenic pathogenic variants. There are no significant genotype-phenotype correlations for individuals with intragenic NFIX pathogenic variants (see Molecular Genetics). MALNS-associated frameshift pathogenic variants are expected to produce mRNA that undergoes nonsense-mediated decay (NMD) [Priolo et al 2018]. In contrast to this, Marshall-Smith syndrome-associated mutated mRNA typically is not predicted to undergo NMD [Malan et al 2010; Schanze et al 2014] (see Genetically Related Disorders).

Nomenclature

NFIX-related Malan syndrome (MALNS) has previously been referred to as Sotos syndrome 2. This term is now outdated and should no longer be used.

Prevalence

Based on the number of known affected individuals, the prevalence of MALNS is estimated to be about 1:1,000,000 [Macchiaiolo et al 2022]. However, data from association registries strongly support that the exact prevalence of the condition is highly underestimated [M Priolo, unpublished data; Sanford CoRDS patient registry for Malan syndrome].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MALNS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for MALNS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

NFIX-related Malan syndrome (MALNS) is an autosomal dominant disorder typically caused by a de novo genetic alteration.

Risk to Family Members

Parents of a proband

• Almost all individuals diagnosed with MALNS whose parents have undergone molecular genetic testing have the disorder as the result of a de novo genetic alternation (either a pathogenic variant in NFIX or a heterozygous deletion of 19p13.2 that includes NFIX).
• Rarely, individuals diagnosed with MALNS have the disorder as the result of a genetic alteration inherited from a mosaic parent. Families with sib recurrence due to parental gonadal (or somatic and gonadal) mosaicism have been reported [Priolo et al 2018, Hancarova et al 2019, Sihombing et al 2020, Langley et al 2022].
• If the proband appears to be the only affected family member (i.e., a simplex case), genetic testing capable of identifying the genetic alternation identified in the proband is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the genetic alteration identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo genetic alteration.
  • The proband inherited a genetic alteration from a parent with gonadal (or somatic and gonadal) mosaicism [Priolo et al 2018, Hancarova et al 2019, Sihombing et al 2020, Langley et al 2022]. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.
    * A parent with somatic and gonadal mosaicism for an NFIX pathogenic variant or 19p13.2 deletion may be mildly/minimally affected. Parental somatic and gonadal mosaicism has been reported in one family to date [Priolo et al 2018]. Presumed parental gonadal mosaicism was described in all other reported families with sib recurrence [Hancarova et al 2019, Sihombing et al 2020, Langley et al 2022].

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the NFIX pathogenic variant or 19p13.2 deletion identified in the proband, the risk to the sibs of inheriting the genetic alteration is 50%.
• If the genetic alteration identified in the proband cannot be detected in the leukocyte DNA of either parent and – if the proband has a deletion – neither parent has a balanced chromosome rearrangement involving the 19p13.2 region, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental gonadal mosaicism [Priolo et al 2018, Hancarova et al 2019, Sihombing et al 2020, Langley et al 2022].

Offspring of a proband. Each child of an individual with MALNS has a 50% chance of inheriting the MALNS-related genetic alteration; however, reproductive fitness in MALNS is extremely low due to severe intellectual disability and, to date, individuals with MALNS are not known to reproduce.

Other family members. Given that all probands with MALNS reported to date have the disorder as the result of an NFIX pathogenic variant or 19p13.2 deletion that occurred de novo in the proband or in a mosaic parent, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the MALNS-related genetic alternation has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Nuclear factor 1 X-type (NFIX) belongs to the nuclear factor 1 (NFI) family of transcription factors. Members of this family act as homodimers and heterodimers and bind with high affinity to the palindromic consensus sequence TTGGC(N5)GCCAA. In vertebrates, the Nfi gene family consists of four closely related genes (Nfia, Nfib, Nfic, and Nfix).They encode proteins with a conserved N-terminal DNA binding and dimerization domain and a C-terminal transactivation/repression domain. Almost all the pathogenic variants in NFIX are located in the DNA binding and dimerization domain, with few exceptions. Most pathogenic variants are nonsense, frameshift, and splice site pathogenic variants predicting premature stop codons, mostly in the 5’ part of the mRNA. These pathogenic variants likely activate nonsense-mediated decay (NMD) of the respective mutated mRNA, thereby leading to haploinsufficiency. Conversely, all other observed missense pathogenic variants affect highly conserved residues within the DNA binding and dimerization domain that are expected to be crucial for protein function. A number of NFIX pathogenic missense variants involving positively charged amino acids (at positions Lys113, Arg115, Arg116, Arg121, Lys125, and Arg128) are clustered in a small region of 15 residues that is crucial for protein activity. The replacement of these positively charged residues by negatively charged residues suggest abnormal DNA binding.

NFIX pathogenic variants that cause NFIX-related Malan syndrome (MALNS) are typically located in exons coding for the DNA binding and dimerization domain (exons 2 to 5), with few exceptions. Some affected individuals have pathogenic variants located at the 3’ end of the gene (in exons 6, 7, and 8). Their phenotypes do not differ in any way from the phenotype in other individuals with MALNS.

Mechanism of disease causation. Loss of function

Acknowledgments

The author gratefully acknowledges the patients, their families, and the support associations that have generously participated in the research described and referenced here. The author would also like to thank the clinician collaborator teams of physicians, genetic counselors, nurses, therapists, and trainees who have generously cared for these patients and contributed to produce guidelines for diagnosis and management of individuals with NFIX-related Malan syndrome (MALNS).

Revision History

• 1 August 2024 (ma) Review posted live
• 17 February 2023 (mp) Original submission

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