Phenotypic variability in two siblings with Poretti-Boltshauser syndrome

Abstract

Introduction

Poretti-Boltshauser Syndrome (PBS) is a rare neuro-ophthalmological disorder with autosomal recessive inheritance. It is characterized by non-progressive cerebellar ataxia, delay in neuropsychomotor development, intellectual disability, and vision abnormalities. PBS is caused by mutations in the LAMA1 gene, resulting in cerebellar abnormalities, including cerebellar cysts in most cases.

Case presentation

We present two siblings with LAMA1 mutations and distinct phenotypic presentation, with one of them showing no evidence of cerebellar cysts on magnetic resonance imaging (MRI).

Conclusion

This study highlights intrafamilial variability in patients with Poretti-Boltshauser Syndrome (PBS). Patient 1 exhibits more pronounced cerebellar dysplasia (with cysts) and oculomotor apraxia, while Patient 2 shows milder cerebellar dysplasia (without cysts) and a macular hole. These findings underscore the importance of comprehensive evaluation and genetic testing for accurate diagnosis and management of PBS.

Introduction

Poretti-Boltshauser syndrome (PBS) is an autosomal recessive disorder due to pathogenic variants in the LAMA1 gene. Clinical presentation spectrum consists in neurological and ophthalmological manifestations, including non-progressive cerebellar ataxia, oculomotor apraxia, language impairment, intellectual disability, high myopia, abnormal eye movements, retinal dystrophy and cerebellar dysplasia with cysts.

We report two siblings with LAMA1 mutations and distinct phenotypic presentations.

Case reports

Case 1

H.S.P (patient 1), male, second child of non-consanguineous parents. Mother was 36 years old at delivery time, with a history of gestational diabetes and systemic lupus erythematosus. She denied the use of medications, alcohol consumption or smoking during pregnancy. Serologies were negative, and prenatal ultrasonographic studies were unremarkable. The child was delivered by cesarean section due to acute fetal distress, at a gestational age of 38 weeks and 3 days, birth weight of 3225 g (22nd percentile), length of 51 cm (53rd percentile) and head circumference of 35 cm (51st percentile). The baby cried at birth, no resuscitation maneuvers were needed, and APGAR scores were 9/10. Pulse oximetry, hearing, ocular and biological screening (including Phenylketonuria, Congenital Hypothyroidism, Sickle Cell Disease and other hemoglobinopathies, Cystic Fibrosis, Congenital Adrenal Hyperplasia, and Biotinidase Deficiency) were unremarkable. Discharged from hospital at 3 days of age.

At 2 months of age, he was evaluated by a pediatric neurologist due to head tremors in a "denial" movement, which ceased at 8 months of age. At 2 years old, he underwent an electroencephalogram (EEG) with normal results and a brain magnetic resonance imaging (MRI) with a complex malformation of the cerebellar vermis/hemispheres, leading to a diagnosis of cerebellar dysplasia with cerebellar cysts (Fig. 1). Ophthalmologic evaluation revealed convergent strabismus and high-grade myopia (Fig. 2), with the right eye at −13.50 diopters and the left eye at −12.00 diopters.

Fig. 1.

Brain MRI of patient 1 at 2 years old. (a), (b), (c) - Axial T2 / (e), (f) - Coronal T2 - show disorganization of the cerebellar folia (cerebellar dysplasia), with the formation of subcortical cysts in the hemispheres and vermis. There is involvement of the anterior and posterior lobes of the cerebellum, without any predominance. The cerebellar vermis is present with hypoplasia of the inferior part. There is elongation of the superior cerebellar peduncles. (d) - Sagittal T1 with contrast media shows the fourth ventricle increased in volume/elongated with loss of the usual rhomboid shape assuming a rectangular shape. The brainstem shows preserved shape and signal. There are no additional supratentorial findings.

Fig. 2.

Brain magnetic resonance imaging (MRI) image of patient 1 at 2 years old. (g) - Axial T2 - increased anteroposterior diameter of the eyeballs, consistent with the high-grade myopia.

Regarding neuropsychomotor development, he achieved head control at 6 months, sat without support at 1 year and 2 months, walked without support at 1 year and 11 months, spoke his first words at 1 year and 5 months, and formed sentences after 2 years old. Neurological evaluation at 3 years old showed ataxia and oculomotor apraxia. At 7 years old, he exhibited mild dysarthria, with no nystagmus or ataxia detected. He started using Ritalin for a suspected diagnosis of Attention Deficit Hyperactivity Disorder (ADHD).

At the age of 6, the school´s report described the child as with no autonomy to carry out activities independently, which were performed with the assistance of the teacher, as the child completed their activities slowly and with distraction, requiring an extended period of time.

The child is at the syllabic-alphabetic level, reads words and phrases with difficulty, writes his own name and struggles with learning involving numerals and addition/subtraction operations.

On dysmorphological physical examination, at the age of 6 years and 7 months, he was observed to be normocephalic, with a medium hairline on the forehead, straight palpebral fissures, mild convergent strabismus, thick lips, normally positioned ears, hands with normal creases and bilateral clinodactyly of the 5th fingers. Anthropometric measurements showed a weight of 25.9 kg (91st percentile), height of 116.5 cm (38th percentile), and head circumference of 52 cm (20th percentile).

Case 2

A.S.P (patient 2), male, first child of non-consanguineous couple. Mother was 26 years old at delivery time, underwent high-risk prenatal care due to a previous diagnosis of systemic lupus erythematosus. Pregnancy was uneventful with no history of smoking, alcohol consumption or medication use. The child was born by vaginal delivery at 38 weeks gestation, weighing 3200 g (22nd percentile) and measuring 50 cm in length (33rd percentile). He did not cry at birth, required resuscitation with positive pressure ventilation, Apgar scores of 6/7. He remained hospitalized for 10 days due to pneumonia possibly resulting from meconium aspiration. Neonatal screenings were unremarkable.

The mother reports that, like his younger brother, A.S.P began experiencing head tremors with a denial movement at 2 months of age, which ceased at 6 months. At 3 months, he was diagnosed with strabismus. At 6 months, he was diagnosed with high myopia. At 12 years old, during a routine ophthalmological examination, a macular hole was detected, and laser photocoagulation was performed.

Regarding neuropsychomotor development, A.S.P had head support at 4 months, sat without support at 8 months, walked without support at 1 year and 4 months, spoke his first words at 1 year, and formed sentences around 2 years and 6 months. In the early school years, he was diagnosed with attention deficit disorder and had learning difficulties. He is currently attending the senior year of high school without academic difficulties.

On physical examination, A.S.P, like his brother, presents without significant dysmorphisms: medium hairline on the forehead, eyes with straight palpebral slits, deep palpebral fissures, nose with medium root and dorsum, broad base, thick lips, high palate, normally implanted ears with anteriorized lobes, cervical acanthosis nigricans, normal hand creases, with the 5th digit somewhat short. Pubertal development was normal.

At 17 years old, A.S.P underwent a brain MRI that showed cerebellar dysplasia, but without the presence of cerebellar cysts (Fig. 3). In the most recent ophthalmological evaluation, high myopia was detected, with the right eye at −12.00 diopters and the left eye at −11.50 diopters (Fig. 4).

Fig. 3.

Brain MRI of patient 2 at 17 years old. (h), (i), (j) - axial T2 / (l), (m) - coronal T2 - show foliation disorders with disarrangements of the primary and horizontal fissures (cerebellar dysplasia. There are no parenchymal cysts. (k) - volumetric sagittal T1 - brainstem, cerebellar vermis, and fourth ventricle with preserved in shapes. There are no additional supratentorial findings.

Fig. 4.

Brain MRI of patient 2 at 17 years old. (n) - Axial T2 - increased anteroposterior diameter of the eyeballs, consistent with the high myopia.

Genetic analysis

For diagnostic elucidation, genetic tests were performed on both siblings. The genetic panel performed by Next Generation Sequencing (NGS) revealed two pathogenic variants, c .3881 G>A (p.Trp1294 *) and a deletion (exons 31–32), identified in the LAMA1 gene.

The first variant sequence change creates a premature stop codon (p.Trp1294 *) in the LAMA1 gene. It is expected to result in the absence of the protein product. Loss-of-function variants in LAMA1 are known to be pathogenic (PMID: 25105227, 26932191). This variant is not present in population databases (gnomAD with no frequency) and has not been reported in the literature in individuals affected by conditions related to LAMA1.

The second variant is a deletion of the genomic region encompassing exons 31–32 of the LAMA1 gene. This deletion is out-of-frame and is expected to create a premature stop codon, resulting in the absence of the protein product. Loss-of-function variants in LAMA1 are known to be pathogenic (PMID: 25105227, 26932191). A similar copy number variant (CNV) was observed in individuals with Poretti-Boltshauser syndrome (PMID: 26932191).

Literature review

Poretti-Boltshauser syndrome (PBS), first described in 2014, is a rare neuro-ophthalmological disease with autosomal recessive inheritance, characterized by phenotypes that may include non-progressive cerebellar ataxia, delay in neuropsychomotor development (mainly in language), variable degrees of intellectual disability, and abnormalities of vision [1], [2].

PBS is caused by homozygous or compound heterozygous mutations in the LAMA1 gene, which encodes the α1 subunit of the laminin protein. Laminins are heterotrimeric glycoproteins that connect basement membranes and the extracellular matrix to the cell, maintaining tissue integrity. It is also known that laminins play a critical role in embryonic development, associated with the proliferation and migration of granule cell precursors in the cerebellum and the development of the retina. A deficient LAMA1 protein typically results in a disruption of the cerebellar folia. Of the twelve genes encoding laminin subunits, nine are associated with disease in humans, including the LAMA1 gene [1], [2], [3], [4], [5], [6], [7].

Ophthalmologic findings may include oculomotor apraxia, nystagmus, strabismus, high myopia, cataracts, and retinal manifestations such as chorioretinal atrophy, retinal avascularization, retinal neovascularization, and pigmentary changes [1], [3], [5]. A previously described report in the literature of two siblings with PBS exhibited a retinal phenotype similar to familial exudative vitreoretinopathy (FEVR). Basic scientific studies in mice have implicated LAMA1 in angiogenesis and retinal vasculopathy and have shown that tetraspanin, one of the proteins in the Wnt pathway implicated in FEVR, associates with a laminin-binding receptor to mediate retinal angiogenesis [8].

The phenotype of Poretti-Boltshauser Syndrome also includes cases of autism spectrum disorder (usually mild), neuropsychiatric symptoms (simple and complex tics, obsessive-compulsive traits, generalized anxiety disorder), syndactyly, kyphoscoliosis, alopecia areata with parietal defect of the scalp, and congenital heart malformation (total anomalous pulmonary venous drainage and atrial and ventricular septal defects) [1], [2], [4], [7], [9], [10]. Additionally, there is a published case report describing a patient who presented at 2 months old with a type of head tremor called titubation, which improved spontaneously around 8 months followed by the appearance of oculomotor apraxia. [11] Oculomotor apraxia was reported as part of the phenotype in PBS in the initial description [12]. Differential diagnoses should be evaluated using brain MRI and it includes Joubert syndrome, haploinsufficiency of the SUFU gene, disorders related to the NPHP1 gene, and tubulinopathies [13]. Furthermore, oculomotor apraxia has been reported in cases of other brain malformations, such as agenesis of the corpus callosum and brainstem dysgenesis [12].

Regarding prenatal diagnosis, there are four patients described with ventriculomegaly and one with esophageal atresia, all detected on prenatal ultrasound scans [10], [14], [15]. Overall, 7 to 12 % of fetuses diagnosed prenatally with isolated mild ventriculomegaly present associated abnormalities postnatally, mainly central nervous system malformations. These prenatal findings suggest that ventriculomegaly may be within the phenotypic spectrum of fetuses with PBS. However, esophageal atresia may not be related to the syndrome, as it is a common congenital malformation, with an estimated prevalence of approximately 2.8 per 10,000 births [15].

Magnetic resonance imaging of the brain mainly shows cerebellar dysplasia, hypoplasia of the cerebellar vermis, and cerebellar cysts that can vary in size, quantity, and location. Cortical and subcortical cysts are most frequently found in the superior and anterior cerebellar vermis and in the superior and posterior cerebellar hemispheres. It is not known yet whether cerebellar cysts in Poretti-Boltshauser Syndrome are already present in the neonatal period or develop later. An enlarged, elongated and square-shaped fourth ventricle, elevated and open superior cerebellar peduncles, short pons, thin isthmus, enlarged tectum, arachnoid cyst, large globes and changes in the cortical white matter have also been described in the literature [1], [2], [6], [11], [16].

Cerebellar cysts are uncommon in pediatric neuroimaging. They are usually associated with dystroglycanopathies, although they have occasionally been observed in cases of Aicardi syndrome and, rarely, in pontocerebellar hypoplasia type 6. Additionally, cerebellar cysts have been described in children with mutations in the GPR56 gene, accompanied by cerebellar dysplasia, cerebellar hypoplasia, and brainstem abnormalities. In these cases, patients also presented with bilateral frontoparietal polymicrogyria in anteroposterior distribution and bilateral irregularities in white matter [12].

In database searches, there are few reports in the literature (about 42 published cases), suggesting that the syndrome may not be recognized or misdiagnosed as other conditions, such as Joubert syndrome (JS), a clinically heterogeneous condition with over 38 known genetic causes [1], [15], [17].

Joubert syndrome and PBS can present very similarly in childhood, leading to diagnostic confusion. The main clinical similarities between Joubert Syndrome and Poretti-Boltshauser syndrome are delays in neuropsychomotor development, oculomotor apraxia, ataxia, hypotonia, intellectual disability, retinal dystrophy, nystagmus, and strabismus. However, Joubert Syndrome differs clinically by presenting abnormal respiratory patterns (alternating tachypnea and apnea), nephronophthisis, hepatic fibrosis, and skeletal dysplasia [1], [4].

Another difference between the two syndromes is related to the brain MRI appearance. Poretti-Boltshauser Syndrome shows cerebellar dysplasia, cerebellar cysts, and hypoplasia of the cerebellar vermis. In contrast, Joubert syndrome is a neurodevelopmental disorder typically defined by a pathognomonic brain malformation: "the molar tooth sign," which consists of hypoplasia of the cerebellar vermis, thick and horizontally oriented superior cerebellar peduncles, and sometimes a deep interpeduncular fossa. At diffusion tensor (DTI) studies have shown an absence of superior cerebellar peduncle decussation. Therefore, recognizing radiological patterns is important for the identification and distinction of the two syndromes. However, while careful examination of the retina and brain MRI can adequately classify most individuals, genetic testing should be the most definitive way to separate the disorders [1], [4], [17].

The neuroimaging features of PBS can also resemble findings observed in α-dystroglycanopathies (cerebellar dysplasia with cysts); however, the symptomatology in α-dystroglycanopathies generally does not include ataxia, oculomotor apraxia, and retinopathy. Additionally, in PBS, supratentorial malformations are not observed, muscle weakness is infrequent, seizures are rare, and serum creatine kinase levels is normal or slightly increased [6].

The oldest patient diagnosed with PBS was a 65-year-old Japanese woman. She had mild intellectual disability but had graduated from high school and worked in factories. At the age of 60, she began to experience difficulty walking, associated with a slow and broad-based gait. At the age of 64, she noticed memory loss and attention deficit. At the age of 65, during a general medical examination, she was diagnosed with cognitive impairment and cerebellar hypoplasia on brain MRI. Neurological examination revealed left conductive hearing loss, mild impairment of eye movement, mild cerebellar ataxia, and hyperreflexia in the lower limbs. She also had cataracts in her left eye but did not have myopia or retinal involvement. Brain MRI revealed cerebellar dysplasia with multiple cysts in the anterosuperior vermis and posterosuperior aspects of the hemispheres, vermis hypoplasia, fourth ventricle dilatation, open superior cerebellar peduncles, and short pons [18].

Discussion

Although the phenotype of patients with LAMA1 mutation is generally homogeneous, we observed relevant intrafamilial variability in this study.

Regarding neuroimaging, it can be concluded that patient 1 presents with a more extensive and severe form of cerebellar dysplasia than patient 2. In patient 1, there is involvement of the anterior and posterior lobes and both cerebellar hemispheres, associated with the presence of cysts. There is also hypoplasia of the cerebellar vermis and elongation of the superior cerebellar peduncles, as well as an enlarged and abnormally shaped fourth ventricle. In contrast, patient 2 exhibits cerebellar dysplasia is predominantly in the posterior lobe, without the presence of cerebellar cysts. The cerebellar vermis and fourth ventricle maintain a preserved shape.

Only three other cases have been reported in the literature of Poretti-Boltshauser Syndrome without the presence of cerebellar cysts. A boy aged 2 years and 7 months at the time of evaluation had cerebellar dysplasia with enlargement of the fourth ventricle, without evidence of cerebellar cysts. His genotype was described as compound heterozygosity in the LAMA1 gene, variants c .6151 C>T and c.1494_1504del, both classified as likely pathogenic according to ACMG/AMG guidelines [9], [19] Another study described two brothers with compound heterozygous variants in the LAMA1 gene, c.2816_2817delAT and c .555 T > G, classified as pathogenic according to the ACMG/AMG guidelines [19]. The first sibling, 2 years and 1 month old at the time of evaluation, had cerebellar dysplasia with vermis hypoplasia, slightly enlarged fourth ventricle, arachnoid cyst, interpeduncular and suprasellar cysts and absence of cerebellar cysts. The second sibling, 5 months old at the time of evaluation, had cerebellar dysplasia with hypoplasia of the vermis, normal fourth ventricle and absence of cerebellar cysts. [4].

In reviewing the literature, Geerts et al. found that all reported patients exhibited some degree of cerebellar involvement on brain MRI. The main cerebellar anomalies observed were dysplasia (100%) and cysts (93%). Other findings included increased size (87%) and abnormal shape (87%) of the fourth ventricle. Overall, 57% of patients had hypoplasia of the cerebellar vermis. Less commonly, structural abnormalities were observed in the brainstem (37%) and supratentorial region (29%), such as ventriculomegaly (14%) and signal abnormalities in the white matter (24%), usually affecting the periventricular area [15].

The initial MRI of 1-year-old’s brain from a patient reported by Faizi et al. showed discrete signs of periventricular leukomalacia and asymmetry of the upper portion of the cerebellar vermis. At the age of 17, a new MRI of the brain was performed,showing abnormal cerebellar foliation, cerebellar corticosubcortical cysts, atrophy of the superior cerebellum, and an enlarged, square fourth ventricle. Genetic analysis revealed a homozygous pathogenic variant c .8446 C>T in the LAMA1 gene. This case suggests that cerebellar cysts in BPS may develop over time, but further investigation is needed for clarification [20].

Patient 1 presented delays in motor development (walked without support at 1 year and 5 months) and language development (first words at 1 year and 5 months, formed sentences after 2 years). In contrast, patient 2 had adequate neuropsychomotor development, but both had learning difficulties in childhood and attention deficit disorder. Overall, 93% of patients with BPS experience some degree of developmental delay, including 86% in motor skills and 85% in speech. Mild cognitive impairment was observed in 74% of cases [15].

A study published in 2022 described three adult siblings (37, 40 and 42 years old) diagnosed with Poretti-Boltshauser Syndrome [21]. Genetic analysis revealed a homozygous frameshift variant c.1492del in the LAMA1 gene, classified as likely pathogenic according to ACMG/AMG guidelines [19]. Two of the three siblings had speech or language delay, but no other developmental or intellectual disabilities were present.

In the present study, both siblings presented head tremor in the first months of life. This tremor was only recorded in one patient in the literature, appearing around 2 months old and improving by 8 months old, a temporal pattern similar to that observed in the siblings reported in our study. [11]. This early phenomenon may be underestimated due to its transient nature, which could explain the rarity of the description. Therefore, careful assessment of early clinical history may suggest that the presence of head titubation may lead to an earlier diagnosis of PBS.

Patient 1 at 3 years old had ataxia, which normalized at 7 years old. Patient 2, up to the present moment, has not manifested this symptom. Only 3% of patients with PBS do not exhibit ataxia [15].

Both siblings had high myopia and strabismus. These findings are present in about 77% and 53% of patients with PBS, respectively [15]. In contrast, only patient 1 exhibited oculomotor apraxia, while neither of the siblings exhibited nystagmus. These findings are present in about 69% and 59% of patients with PBS, respectively [15].

Unlike patient 1, who has had a normal fundoscopy so far, patient 2 has a history of a macular hole. Two siblings described in the literature, both under 5 years old, had a small atrophic hole at the edge of the inferotemporal avascular retina on ophthalmologic evaluation [8]. Another child at 5 years old had holes resulting in rhegmatogenous retinal detachment. Severe retinal thinning in the avascular retina can result in small round atrophic holes that may be difficult to detect clinically [21].

About 61% of patients with PBS will present with retinal abnormalities/dystrophy [15]. It is important to note that ocular signs in PBS can be its first manifestation. Therefore, ophthalmologists should be aware of this diagnostic entity, which requires molecular confirmation and subsequent referral to neurology and genetics services for management and treatment of associated neurological complications [3].

The patient described by Faizi et al. was initially evaluated at 1 year of age presenting with high myopia and horizontal nystagmus. The anterior segment was initially normal, but she developed cataracts at age 14 [20]. Aldinger et al. reported a case of cataracts development at age 22, and Ikeda et al. reported a patient with cataracts at age 64 [4], [18]. These findings reinforce the importance of long-term ophthalmological follow-up.

Given the limited number of cases reported in the literature, data regarding prognosis in PBS is scarce; however, there is evidence of adult patients with normal IQ levels who attend college and achieve financial independence [1]. Currently, patient 2 has overcome the early childhood learning difficulties and is completing high school, with plans to attend college.

Conclusion

The study highlights intrafamilial variability in patients with Poretti-Boltshauser Syndrome (PBS). Patient 1 exhibits more pronounced cerebellar dysplasia (with cysts) and oculomotor apraxia, while patient 2 presents milder cerebellar dysplasia (without cysts) and a macular hole. These findings underscore the importance of comprehensive evaluations and genetic testing for accurate diagnosis and PBS management.

Understanding the clinical heterogeneity within the same family highlights the complexity of this neurodevelopmental syndrome and reinforces the need for an individualized approach for each patient. Additionally, it emphasizes the relevance of continuous monitoring and targeted therapeutic interventions, considering the different clinical and genetic manifestations observed.

Patient consent

The family of the patients gave written informed consent to publish this article.

Conflict of interest

None declared.