Unveiling “Verheij Syndrome”: MRI Findings Illuminate a Unique Clinical Feature

In the vast and intricate realm of human genetics, there exists a myriad of rare disorders that continue to challenge researchers and medical practitioners alike. One such puzzling condition is Verheij syndrome, a rare genetic disorder characterized by a unique set of symptoms and complexities. I have seen my fair share of rare and odd cases as an MRI technologist. However, a sweet boy with a rather larger head circumference, shorter limbs, and the most precious smile, was the first (and might be the only) case of Verheij I will come across in my career. His particular case added a set of new questions about the peculiar syndrome.

Understanding Verheij Syndrome

Verheij syndrome is an extremely rare genetic disorder with only a handful of cases reported worldwide. It is believed to be caused by a spontaneous mutation in the PUF60 gene located on the long arm (q) of chromosome 8, specifically in the q24.3 region, leading to an array of physical, developmental, and neurological abnormalities.

PUF60 gene diagram (above) indicates mutations in the second half of the coding region, apart from the single variant in exon 1

Low, K., Ansari, M., Abou Jamra, R. et al. PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal, and spinal features. Eur J Hum Genet 25, 552–559 (2017). [SOURCE]

The disorder appears to affect males and females without particular geographical or ethnic predilection. Due to its rarity, Verheij syndrome often goes undiagnosed or misdiagnosed, making it essential for healthcare professionals and researchers to raise awareness and deepen their understanding of the condition. For that sake, I have taken the liberty to contact the child’s parents and got their consent to develop this article and they contributed by providing details about the kid’s case including radiographic images, symptoms, hassles, and progress. Before proceeding with further details about the case, I would like to thank the parents for their cooperation which will inevitably benefit other parents, rad techs, or healthcare professionals to identify similar cases.

Clinical Features

The clinical manifestations of Verheij syndrome are highly variable and can present differently in each affected individual. However, some common features have been identified:

The gist: Verheij syndrome’s clinical manifestations are highly variable and may be presented differently in each individual, from developmental delays to intellectual disabilities, as well as physical characteristics.

Out of respect to the family and to preserve the privacy of the child, his mother and I have decided to refer to him as “Ethan” for this article. Ethan does have some common features mentioned above, immediately noticeable are the distinct facial features (a broader forehead), short neck, his arms and legs are shorter than they should be according to his torso length, his head is larger than the normal borderline of the head circumference scale (above 99th% for his age), and a micro-penis.

“Ethan does have some distinct physical characteristics noticed at birth, a broader forehead, short neck, arms and legs are shorter than the torso-limb scale, larger head circumference and a micro-penis.” [SOURCE]

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Imaging and Diagnosis

Diagnosing Verheij syndrome can be particularly challenging due to its rarity and variable presentation. Healthcare professionals may utilize genetic testing, imaging studies, and a thorough clinical evaluation to arrive at a definitive diagnosis. At birth, the pediatrician requested an MRI of the brain and spine to rule out hydrocephaly (due to the larger head circumference) or spinal dysraphism (due to the shorter structure).

The gist: MRI of the brain and spine were requested at birth to rule out the possibility of hydrocephaly, due to his larger head circumference and spinal dysraphism, due to his shorter structure.

The MRI used was a 1.5T Philips Ingenia, and a routine brain and spinal MR protocol was applied. Brain protocol includes 3D sagittal T2 weighted, 3D sagittal T1 weighted and 3D sagittal FLAIR, axial Diffusion-weighted imaging, as well as an axial susceptibility-weighted image (SWIp). Slice thickness 3 mm and 0 gap. Total spine protocol included 3D sagittal T1 and T2, T2 mDIXON (which is a fat saturation technique), and axial T1 and T2 weighted imaging.

The findings of the brain MRI were the following:

• Midline structures were in place
• No signal of recent ischemic cerebrovascular accident (or stroke)
• No hydrocephalus
• No mass
• No anomaly in the posterior fossa
• Fourth ventricle is median and of the usual volume

The findings of the spine MRI were the following:

• No spinal dysraphism
• No suspicious anomaly in the morphology of the vertebrae
• No compression with preserved vertebral height
• No anomaly of the peri-spinal soft tissues was noted
• No abnormal epidural infiltration
• The cervicothoracic marrow is homogeneous and of regular caliber

Consequently, the normal MRI result provided relief to his parents. Ethan went on to live his life like any normal baby, reaching a milestone after the other, all of course under observation and the occasional blood work and clinical examinations.

In the next few months after that, principal symptoms surfaced, borderline levels of Luteinizing Hormone (LH) and Follicle-stimulating hormone (FSH) appeared in blood tests, and his genitalia remained small (doctors were hoping it would grow on its own since there are many newborns that are born with micro-penis at the beginning). A pediatric endocrinologist suggested repeating all his blood tests as well as the MRI of the brain with a focus on the “pituitary gland” to check for abnormalities in the development and function of the gland that could be leading to hormonal deficiencies.

The gist: at 7 months of age, more distinct features have appeared, including borderline LH and FSH levels in the blood. Subsequently, a pituitary gland MRI was recommended to rule out abnormalities with its morphology and function that could be leading to hormonal deficiencies.

At 7 months of age, blood tests returned normal except for free T4 levels (lower than normal range); and an MRI of the pituitary was done. MRI used was a 3T Philips Ingenia, and the protocol included an axial T2 weighted image and an axial diffusion-weighted image along with a sagittal 3D FLAIR of the whole brain. As for the pituitary gland, sagittal T1 and T2 weighted images, coronal T1 and T2 weighted images, and a dynamic coronal T1 sequence were done with a post-contrast T1, all in thin 2.5-3mm slice thickness and 0 gaps.

The findings of the pituitary MR were the following:

Supra tentorial stage:

• Moderate cerebral atrophy with the significant widening of the subarachnoid spaces, in particular, the anterior frontal and temporopolar lobes (left>right)
• Absence of hydrocephalus
• Median structures in place: absence of signal anomaly on FLAIR sequence, absence of signal anomaly on diffusion-weighted image
• No mass effect detected

Pituitary:

• Pituitary gland and the Sella turcica are very small. The pituitary stalk is very hypoplastic, barely visible
• The posterior pituitary is not identified
• Chiasma in normal position with normal signal

At the level of the posterior fossa:

• Normal brainstem and cerebellar morphology without significant signal abnormality visible
• The fourth ventricle is the median of the usual volume
• Free aspect of the cistern base

A small pituitary gland, also known as a pituitary hypoplasia, can potentially affect its function and lead to various hormonal imbalances. The pituitary gland plays a crucial role in regulating several hormones that control different processes in the body. These hormones include:

• Growth hormone (GH) stimulates bone and tissue growth and development. Which could potentially explain the shorter stature of the Ethan’s extremities
• Thyroid-Stimulating Hormone (TSH): controls the function of the thyroid gland, which regulates metabolism. Ethan has shown a lower level of FT4 in recent blood work
• Adrenocorticotropic Hormone (ACTH): Stimulates the adrenal glands to produce cortisol, which is essential for managing stress and metabolism
• Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH): Regulate reproductive function and sex hormone production in both males and females. This also could be related to the small genitalia in Ethan’s case
• Prolactin: Stimulates milk production in lactating females and has other functions related to reproduction

The gist: the pituitary gland is responsible for regulating several hormones that control different processes in the body. In Ethan’s case however, the hypoplastic pituitary could potentially be the cause for the shorter stature, low level of FT4, and smaller genitalia.

When the pituitary gland is small and underdeveloped (hypoplastic), it may not produce enough of one or more of these hormones, leading to hormone deficiencies. The specific effects will depend on which hormones are affected and to what extent. Some potential consequences of a small pituitary gland’s functional impairment include growth issues (insufficient growth hormone can lead to growth disorders in children and adults), hypothyroidism, adrenal insufficiency, reproductive problems, and prolactin-related issues.

It’s important to note that the effects of a small pituitary gland can vary in severity depending on the individual and the specific hormone deficiencies. Treatment may involve hormone replacement therapy to restore normal hormone levels and manage the associated symptoms. Regular medical monitoring is essential to address any complications and ensure optimal health.

The gist: part of Ethan’s treatment may involve hormone replacement therapy to restore normal hormone levels and manage the associated symptoms.

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Management and Treatment

As of now, there is no specific treatment for Verheij syndrome, and management is largely supportive and symptomatic. Early intervention and therapeutic interventions, such as speech and occupational therapy, can help improve the quality of life for affected individuals. Seizures may be controlled with antiepileptic medications. Additionally, a multidisciplinary approach involving specialists from various fields, such as neurology, genetics, and developmental pediatrics, is crucial in providing comprehensive care for those with Verheij syndrome. In Ethan’s case, replacing the hormone deficiencies caused by the small pituitary gland could help manage the slow growth and TSH levels.

Subsequently, the committee decided to monitor his physical and intellectual growth milestones as well as his hormone levels. Ethan’s age now is 9 months, on his first birthday a full body x-ray will be conducted to observe his bone formation and development. Moreover, to compensate for the growth hormone (GH) deficiency, daily lifetime GH injections will be administered starting bewteen the age of 12 and 18 months. In addition to that, daily intake of levothyroxine (T4) will be introduced and shall be regular monitored. Finally, at puberty, sex hormone replacements will be required.

The gist: there is no specific treatment for Verheij syndrome for now, a committee of physician shall assess the situation and manage its apparent symptoms accordingly. In Ethan’s case, management will include monitoring milestones, occupational therapy and hormonal replacement therapy.

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Research and Future Perspectives

Given its rarity, research on Verheij syndrome has been limited. However, continued efforts to understand the genetic basis of the disorder, its pathophysiology, and its molecular mechanisms are essential for developing targeted therapies and improving patient outcomes. Some of the parents of children with Verheij have a Facebook group and share their experiences and knowledge about the syndrome, once Ethan’s parents shared his case of a hypoplastic pituitary gland, they were informed that only one other Verheij-diagnosed child had similar MRI finding was reported worldwide; specifically exhibiting a hypoplastic pituitary gland. Unfortunately, many of these children have never had an MRI screening of their brain or pituitary gland.

Ethan’s parents have found out through a Facebook group for parents with children with Verheij, that only one other case of hypoplastic pituitary was reported in the world, and that the majority of these children have never had MRI screenings of their brain and pituitary gland!” [Source]

Ethan’s case may have raised new questions about the rare syndrome. Does this mean that the common features of slow growth in Verheij could have been caused by the absence of proper pituitary function? Are other children with Verheij misdiagnosed because of a lack of awareness of the importance of MRI screening of brain and pituitary function? Should an MRI of the brain and pituitary gland with IV contrast become a standard diagnostic tool in screening children with growth delays and atypical hormone levels?

We hope the MRI images kindly given to us by Ethan’s parents raise awareness and help in research on the syndrome, and help add more information on the larger-scale genomic database that holds promise for uncovering the underlying genetic mutation responsible for Verheij syndrome. Furthermore, collaboration among researchers, clinicians, healthcare professionals, and affected families is crucial in gathering more comprehensive data and creating a global platform to exchange knowledge and insights related to this rare disorder.

The gist: we hope that sharing Ethan’s case help raise awareness of the importance of MRI screening of the brain and pituitary gland in children with growth delays and atypical hormone levels.

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Conclusion

Verheij syndrome remains a perplexing and understudied genetic disorder that challenges the medical community. Through increased awareness and concerted research efforts, we can hope to shed light on the mysteries surrounding this rare condition. Moreover, sharing radiologic studies and images can contribute to our knowledge of human genetic disorders and pave the way for targeted therapies, improving the lives of those living with rare enigmatic disorders.

References

• [LINK]
• The diverse pleiotropic effects of spliceosomal protein PUF60: A case series of Verheij syndrome. [LINK]
• Follicle-Stimulating Hormone Abnormalities. [LINK]
• [LINK]
• Low, K., Ansari, M., Abou Jamra, R. et al. PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features. Eur J Hum Genet 25, 552–559 (2017). [LINK]

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