Early diagnosis of Malan syndrome in an infant presenting with macrocephaly

Abstract

We present an infant with persistent macrocephaly and developmental delay. There is a wide range of differential diagnoses for this presentation, including many rare genetic conditions. Here, a diagnosis of Malan syndrome was made—a rare overgrowth syndrome caused by haploinsufficiency of NFIX and features affecting the neurological and musculoskeletal systems. Improvements in genomic medicine technologies and clinical services have revolutionised the way clinicians diagnose rare diseases. We highlight the importance of early genetic testing, particularly if there are red flag features such as developmental delay, and the need for a coordinated strategy to improve the management of rare diseases like Malan syndrome.

Background

Macrocephaly is defined as a head circumference of more than 2 SD above the mean for gestational age and sex, which is above the 97th percentile.¹ It has a prevalence of 2%–3% in the general population,² and is a common presentation to the neonatal outpatient clinic.

Macrocephaly is caused by enlargement of any component of the cranium—brain (megalencephaly), cerebrospinal fluid (CSF), blood or bone—or an increase in intracranial pressure. Most cases of mild macrocephaly, particularly if the child has normal development, are attributed to benign familial macrocephaly. However, macrocephaly can be a sign of many conditions, such as infections of the central nervous system, bone dysplasia, space-occupying lesions, arteriovenous malformations, haemorrhages, neurocutaneous disorders, overgrowth syndromes, fragile X syndrome or lysosomal storage disorders.¹

Malan syndrome, also known as Sotos-like syndrome, is an overgrowth syndrome that was first described in 2010,³ and fewer than 100 cases have been reported in the literature.^4–6 It is a multisystemic disease characterised by overgrowth, macrocephaly, developmental delay, epilepsy, dysmorphic facies and musculoskeletal abnormalities (figure 1).⁴ Facial features include a prominent forehead, long triangular face, down-slanting palpebral fissures and deep-set eyes.⁴ In addition, visual problems, such as strabismus, myopia and hypermetropia, affect 76% of patients.⁴ Most reported cases of Malan syndrome are sporadic. De novo heterozygous variants or deletions involving Nuclear Factor 1-X, the nuclear factor I/X gene located at chromosome 19p13.2,³ cause NFIX haploinsufficiency which gives rise to the disease phenotype.^{3 4 7}

Figure 1.

Clinical features of Malan syndrome.^{3 4} Created by Natasha G with BioRender.com.

As part of the NHS long-term plan, the NHS Genomic Medicine Service has been established. This aims to widen access to genetic testing and provides equitable genomic medicine healthcare throughout the country, with a goal of sequencing 500 000 whole genomes by 2023/2024.⁸ This will not only facilitate a greater number of genetic diagnoses but also enable these diagnoses to be reached quicker, thereby preventing many paediatric patients with rare diseases and their families from enduring years of uncertainty—the ‘diagnostic odyssey’. In this case, we highlight a rare genetic condition, Malan syndrome, diagnosed in an infant who presented to the outpatient clinic with macrocephaly and developmental delay.

Case presentation

A male neonate was followed up in the clinic with persistent macrocephaly (his head circumference was between the 98th and 99.6th centile) and a weight between the 75th and 91st centile. His fontanelle was soft, there was no ridging to suggest synostosis and there were no obvious dysmorphic features, peripheral stigmata or skin lesions. Cardiorespiratory, abdominal and neurological examinations were all normal, aside from pectus excavatum. Notably, he had normal tone, symmetrical reflexes and his pupils were equal and reactive to light. He was feeding well via a bottle and was initially reaching his early developmental milestones.

The patient was born at term in good condition with a head circumference in the 99th centile. Antenatally, he was noted to have possible ventricular dilatation, but a postnatal cranial ultrasound scan was normal. He had a normal newborn hearing screen. The only family history of note was maternal epilepsy.

The patient remained clinically well in the neonatal period, and had serial monthly head circumference measurements in the community showing a gradually increasing macrocephaly, above 99.9th centile (figure 2). There were no early concerns regarding development, or clinical signs of raised intracranial pressure. He underwent MRI brain accordingly (figure 3), which demonstrated global dilatation of extracerebral CSF spaces. Dilatation was marked around the frontal and temporal lobes, and there was prominent dilation of the frontal horns and trigones of the lateral ventricles. There were no focal abnormalities of the brain parenchyma. In view of benign enlargement of subarachnoid spaces, he was reviewed by the neurosurgeons, who advised continued head circumference monitoring. Ophthalmology review demonstrated healthy optic discs and no evidence of papilloedema.

Figure 2.

Growth chart demonstrating persistent macrocephaly. created by Natasha G.

Figure 3.

(A) T1-weighted sagittal and (B) T2-weighted axial MRI brain images showing enlargement of cerebrospinal fluid spaces, including ventricular dilatation.

On review during mid-infancy, delayed motor development was noted—he was able to roll but not crawl or sit independently. A further review in late infancy showed his development was delayed globally—he was not able to sit independently, or weight bear and he did not make any babbling noises. The patient’s mother also reported that he had experienced several staring episodes, although subsequent EEG was normal. Given the clinical findings of developmental delay and persistent macrocephaly, but in the absence of characteristics suggestive of a known syndrome, non-directed genetic screening was performed. The microarray revealed a copy number loss in the short arm of chromosome 19 with break points within 19p13.2, confirming a diagnosis of Malan syndrome (figure 4).

Figure 4.

Diagrammatic timeline summarising the patient’s clinical course. Created by Lydia Seed and Natasha G with Microsoft PowerPoint.

Outcome and follow-up

His development continued to be globally delayed as a toddler. From a gross motor perspective, he was able to sit unsupported with a curved back but not able to weight bear, with skills equivalent of a child in early infancy. He was able to hold objects and transfer them from one hand to another and had fine motor skills of a child in mid-infancy. In terms of his visual skills, he was able to fix and follow but not beyond 90°. His language and communication skills were also delayed—he made occasional grunting noises but was not able to babble.

He was reviewed by the paediatric respiratory team in view of recurrent chest infections and severe pectus excavatum. Aside from macrocephaly, he was also noted to have mild dysmorphic features, including a long triangular face with a prominent forehead. He was also noted to have thoracolumbar scoliosis. He was started on co-amoxiclav prophylaxis and is being followed up by the complex chest clinic in view of his aspiration risk.

The management of Malan syndrome is supportive and requires a multidisciplinary approach; the care for this patient has included input from neonatologists, community paediatricians, neurosurgeons, paediatric neurologists, paediatric respiratory team, clinical geneticists, physiotherapists, ophthalmologists and audiologists. Establishing a genetic diagnosis early has enabled the multidisciplinary team to coordinate appropriate monitoring of the disease. For example, after reaching a molecular diagnosis of Malan syndrome, a multidisciplinary clinic appointment with paediatric neurology and clinical genetics was made. This enabled further investigation into the patient’s suspected absent seizures, and allowed the patient’s parents to promptly seek advice regarding the risk of recurrence in future pregnancies, empowering them to make well-informed family planning decisions.

An early genetic diagnosis has not only been beneficial clinically, but it has also facilitated early access to additional support and allowed for coordinated long-term planning. For instance, the patient currently attends a specialist nursery and arrangements have been made to support anticipated learning needs through an educational healthcare plan. Further, the family have been directed to patient support groups, such as the Malan Syndrome Foundation and the Cambridge Rare Disease Network.

Discussion

Malan syndrome is an overgrowth syndrome. In this disease, while both postnatal head circumference and height are usually over 2 SDs, only macrocephaly is preserved with age,⁴ mimicking the growth pattern of Sotos syndrome—initial overgrowth followed by a degree of ‘normalisation’ of height in adulthood with a persistent macrocephaly.⁹ Other key features of both Malan syndrome and Sotos syndrome include a distinctive facial appearance, notably with a prominent forehead and moderate developmental delay.¹⁰

Sotos syndrome is caused by haploinsufficiency of NSD1, a histone methyltransferase,¹¹ whereas Malan syndrome is caused by haploinsufficiency of NFIX by way of non-sense or mis-sense point mutations or, as reported in the case herein, whole gene deletions.3 4 10 12 Malan syndrome is allelic to Marshall-Smith syndrome, which is caused by frameshift and splice-site variants in exons 6–8 of NFIX that are believed to avoid non-sense-mediated decay.¹⁰ In contrast to Malan syndrome, Marshall-Smith syndrome is characterised by a failure to thrive and short stature.¹³ However, like Malan syndrome, Marshall-Smith syndrome patients also exhibit developmental delay and unusual facial features, including a high forehead.¹³

Although haploinsufficiency of NFIX has been established as the underlying cause of Malan syndrome, the mechanism of disease has not yet been fully established. Studies have employed NFIX heterozygous mouse models to advance our understanding; NFIX-deficient mice have been shown to develop brain malformations including ventriculomegaly and partial agenesis of the corpus callosum.^{3 14} Adult NFIX heterozygous mice exhibit a significantly increased brain volume compared with wildtypes, suggesting that megalencephaly may underlie the macrocephaly that is clinically observed in patients with Malan syndrome.¹⁵ Additionally, these mice exhibited behavioural deficits that model intellectual disability.¹⁵ Aberrant cortical connectivity was detected in this mouse model which may contribute to the intellectual disability observed in patients with Malan syndrome.¹⁵

In the case described herein, a diagnosis of Malan syndrome was reached during infancy; typically, patients are diagnosed later in childhood, or even during adulthood.3–5 7 10 Like all diseases, earlier diagnosis improves patient outcomes. This case illustrates some of the benefits afforded by early genetic testing—a shortened diagnostic journey, which can otherwise have a significant negative impact on mental health; a care plan involving expertise from all relevant clinical specialties; appropriate monitoring of disease progression; informed decision-making regarding future plans for the patient and their family; and improved psychosocial support. Additional benefits of early genomic diagnoses in other cases might include early access to appropriate targeted treatments or clinical trials exploring novel therapies.

However, there are risks associated with early genetic testing, particularly when employing sequencing technologies rather than a microarray assay as in this case. The clinical phenotypes of some rare diseases take several years to fully develop. Genomic investigations initiated based on the presence of a small cluster of clinical features may involve testing a large number of genes that are implicated in a wide range of conditions, such that an agnostic approach is taken. This increases the level of uncertainty in interpreting results—there is a greater risk of incidental findings and identifying variants of uncertain significance, which are challenging to clinically interpret and communicate.¹⁶

Here, the perspective from the patient’s mother anecdotally highlights that robust systems need to be in place to support patients and families affected by rare disease: ‘I just feel as though I’ve been dropped’. Caring for someone with a rare disease and coordinating care from a plethora of healthcare professionals has a significant impact on the well-being of patients and their families.^{17 18} Although by definition a rare disease affects fewer than 1 in 2000 people, collectively rare diseases are common, affecting 1 in 17 people.¹⁹ Access to genomic testing continues to expand through the NHS Genomic Medicine Service, and with the possible expansion of newborn screening to include whole genome sequencing in the coming years, the demand for these supportive services is expected to increase. Of note, the recent national public dialogue on the implications of the use of WGS for newborn screening found ‘participants were supportive of the potential use of WGS for newborn screening’ provided that ‘genetic counselling and mental health assistance’ is ‘available for those who receive a confirmed diagnosis to help them understand the health condition and to provide emotional and psychological support’.²⁰ Furthermore, a recent inquiry conducted by the All Party Parliamentary Group on Rare Genetic and Undiagnosed Conditions found that mental healthcare is rarely incorporated as part of the multidisciplinary team approach to caring for patients with rare diseases.¹⁸ One of the recommendations from this inquiry is that ‘coordinated rare disease services should include assessment of mental health needs and access to mental health services’, which ‘should be extended to carers’.¹⁸ Rare disease patients and carers, as well as the general public, believe that access to professional psychological support for people affected by rare disease is profoundly important and there is a pressing need for improvement.

This case of an infant with Malan syndrome highlights the importance of early access to genetic testing, particularly in the presence of red flag features, such as developmental delay. This improves clinical outcomes, informs family planning decisions and broadens the support available for patients and their families. While improved access to genomic testing may shorten the diagnostic odyssey for many rare disease patients, a coordinated strategy to improve the holistic management of rare diseases, which includes mental health support, is warranted.

Patient’s perspective.

Telephone conversation with the patient’s mother.

When we got the diagnosis, I was really upset, especially because with COVID-19 I was the only one who could go in to receive the diagnosis. That was a lot – to deal with that on your own with a screaming child, trying to take it all in.

But at first, I was just always told, ‘Oh, it’s because you’re a first-time parent’. They would always ask me that and always assume that, but I’ve already got an older one. And then they’d say, ‘Well you shouldn’t compare’. But of course you do compare… and when he wasn’t holding his head up at a certain time, he wasn’t smiling, he was going floppy… I just knew something wasn’t right.

When we go to medical appointments, no one knows. It’s quite a lot… it’s frustrating. Everyone we’ve been to… they haven’t read his notes beforehand and they don’t know what Malan syndrome is. I just feel like I’ve been left… it’s so hard. I just get told to go and Google it, when they should be looking into it and trying to explain it in detail. So when we go in, we have to spend most of the appointment talking about everything that’s happened to him and explain the condition

They did well in diagnosing him. And they have referred him for physio… and… that’s it really. I just feel as though I’ve been dropped.

Learning points.

• Neonates and infants with macrocephaly should be followed up closely.

• Genetic testing should be considered early, particularly if there are red flag features like developmental delay, to improve biopsychosocial patient outcomes.

• Living with and caring for individuals with rare diseases has a significant impact on the mental health of patients and their families.

• A coordinated strategy that includes mental health support is needed to help improve the holistic management patients with rare diseases like Malan syndrome.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).