Novel phenotype of SIN3A-related disorder diagnosed in adulthood with multi-system involvement

Introduction

In response to the study by Balasubramanian et al., of 28 individuals with variants in SIN3A, we present the first Irish cases of SIN3A-related disorder diagnosed in adulthood with mild neurodevelopmental phenotype and multisystem involvement [1]. We believe the features in our cases expand the phenotype of this rare condition to include congenital myopathy, hypogonadotropic hypogonadism and skin involvement. Written consent was obtained for publication of cases and included pictures.

Case 1

A 34-year male was referred to neurology outpatients with whole body pain and headaches. There were no craniofacial abnormalities noted as a neonate. Motor developmental delay was evident with ataxia and hypotonia in early childhood. Additionally, speech delay required input from speech therapy. Intellectual development was normal, with completion of mainstream schooling and third level qualification.

A widespread rash occurred with small papules confluencing into plaques covering over 50% of his body, diagnosed as pitrysis rubra pilaris (Fig. 1D). Skin biopsy showed a perivascular lymphocytic infiltrate. Photosensitivity and recurrent urticarial rashes have reoccurred (Fig. 1E), which have not previously been described in this disease. There was also a history of severe sleep apnoea and chronic rhinitis. Clinical features are summarised in Table 1.

Fig. 1. Representative images of the phenotypic features in this case of a patient with a variant in SIN3A.

A and B showing facial features of small mouth and enlargement of forehead, C axial T2-weighted MRI brain with enlargement of the lateral ventricles and preservation of the corpus callosum, D and E representative images of photosensitive rash diagnosed on biopsy as pitrysis rubra pilaris, F brachydactyly.

Table 1.

Clinical features in previously reported cases of SIN3A-related disorder, with expanded phenotype highlighted in our cases.

Clinical features	Case 1	Case 2
Motor + language delay	+	+
Intellectual disability	–	+
Hypotonia	+	+
Feeding difficulties	–	+
Epilepsy	–	–
ASD	–	–
Short stature	+	+
Ophthalmic abnormalities (anterior segment)	+	–
Dysmorphic facial features	+	+
Hearing impairment	–	–
Recurrent infections	+	–
Joint laxity	+	–
Sleep apnoea	+	–
Multiple dental caries	+	–
Dermatological abnormalities	+	–
GAVE	+	–
Myopathy	–	+
Hypogonadotropic hypogonadism	–	+

ASD Autism Spectrum Disorder, GAVE Gastric Antral Vascular Ectasia.

Family history revealed a paternal history of cardiac death and no maternal history. He has one sister diagnosed with ankylosing spondylitis, chronic rhinitis and migraines, and her four children have a range of medical issues including, but not limited to dyspraxia, mild autism spectrum disorder, selective mutism, constipation, lactose intolerance, and photosensitivity. No prior familial genomic testing or formal phenotyping had taken place at the time of consultation. A neurogenetic disorder was suspected based on features of developmental delay, family history, and dysmorphology.

On examination, we recorded short stature (height 165 cm), head circumference of 59 cm (50^th percentile). There was a broad, tall forehead, small mouth with a pointed chin, (Fig. 1A, B), as well as brachydactyly (Fig. 1F), and flattening of his feet. He had multiple dental caries. There was no evidence of hearing loss on audiology testing. On ocular exam, he has astigmatism and myopia, with normal OCT. Retinal imaging (colour fundus photograph and fundus autofluorescence) was also normal. Neurophysiology had normal electroretinography (ERG), pattern ERG, Goldmann visual field, and visual evoked potentials.

MRI brain demonstrated ventriculomegaly involving the lateral ventricles with disproportionate involvement of posterior horns, with normal third and fourth ventricles. Congenital cavum septum pellucidum was noted, the corpus callosum appeared normal (Fig. 1C). EMG/NCS was normal.

WES revealed a novel pathogenic variant in SIN3A NM_ c.3025C>T p.Gln1009*, NM_001145358.2 in a heterozygous state, resulting in a premature stop codon, predicting to cause nonsense-mediated decay of mRNA transcript and loss of protein which is a known mechanism for SIN3A-associated disease. This variant is absent from the global population dataset and has not previously been described in SIN3A-associated disease.

Case 2

A 28-year female was referred for neurological assessment due to non-progressive weakness present since childhood. She was born at 37 weeks gestation with no perinatal complications. Head circumference was small and there were difficulties establishing feeding due to hypersomnolence. She was noted to be floppy with hypotonia. There was motor developmental delay, and mild intellectual disability was detected during schooling, although she attended and completed mainstream school. At age 17, she was diagnosed with hypogonadotropic hypogonadism with primary amenorrhoea, growth hormone deficiency and hypothyroidism.

There was no relevant family history.

Examination revealed proximal weakness in the upper and lower limbs, affecting neck, shoulder, elbow, hip and knee flexion and extension (grade 4 to 4⁺/5 on MRC muscle scale). A modified Gower’s technique was used to rise from the floor. Dysmorphic features consistent with SIN3A-related disorder included high forehead, small pointed chin, down-slanting palpebral fissures, short stature and small hands.

Neurophysiology demonstrated normal sensory and motor nerve conduction studies. EMG revealed myopathic changes that were most evident in brachioradialis, biceps and deltoid, supporting a proximal congenital myopathy. Creatine kinase was normal. Muscle biopsy and MRI brain were unremarkable.

Given the clinical findings of dysmorphism, endocrinopathy and myopathy, WES was performed. A novel pathogenic heterozygous frameshift variant in SIN3A,NM_001145357.1, c.1357del;p.(Ala453Glnfs*42) was identified resulting in a premature stop codon in exon 9. Familial segregation analysis confirmed the variant occurred de novo. This variant was absent from population databases including gnomAD, and has not previously been described in Witteveen-Kolk syndrome. There were no other gene variants identified, specifically none linked to hypogonadism. Thus this case demonstrates that congenital myopathy and hypogonadotropic hypogonadism expand the phenotype of SIN3A-related disorder.

Conclusion

In summary, we present the first Irish cases of SIN3A-related disorder diagnosed in adulthood, due to two novel pathogenic variants in SIN3A, which adds to the phenotype associated with this rare condition.

Both cases displayed a mild neurodevelopmental phenotype. Short stature and characteristic facial features were common to both cases, with case one also demonstrating MRI abnormalities consistent with SIN3A-related disorder.

Of particular interest, we believe these two cases expand the phenotype of SIN3A-related disorder through identification of: (i) an inflammatory skin disorder, (ii) congenital myopathy, and (iii) hypogonadotropic hypogonadism. Lastly, we provide evidence of deep-phenotyping of the retina for the first time.

Eczema is the only skin manifestation previously reported in SIN3A-related-disorder, we now demonstrate biopsy proven photosensitive rash that extends this previously documented skin disease [1].

Congenital myopathy has not been reported in this condition, however, hypotonia is common [1, 2]. In our case we provide neurophysiological and clinical evidence of a myopathy as part of the phenotype.

Although hypogonadotropic hypogonadism has not previously been reported, SIN3A is a corepressor with HESX1, which has a crucial role in pituitary gland determination and differentiation [3].

Furthermore, we demonstrate a normal OCT examination for the first time – this may be of future importance in characterising the phenotype in suspected cases as the abnormality appears to be confined to the anterior segment. Previously reported ophthalmic findings include strabismus, nystagmus secondary to ocular albinism, bilateral colobomas and megalophthalmus [1, 4, 5].

Finally, our cases underline the importance of considering syndromes that may characteristically have a severe childhood onset, but which present with milder phenotype to an adult clinic.

Author contributions

MB: Clinical phenotyping of patient 1 and writing of the manuscript. RF: Clinical phenotyping of patient 2 and writing of the manuscript. SM: clinical overview of patient 2 and editing of manuscript. HK: clinical overview of patient 1 and editing of manuscript.

Funding

No specific funding was received for this study.

Data availability

Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Case one variant ClinVar; accession number VCV002498622.5, https://www.ncbi.nlm.nih.gov/clinvar/variation/2498622/?oq=sin3a[gene]+NM_001145358.2:c.3025C%3ET&m=NM_001145358.2(SIN3A):c.3025C%3ET%20(p.Gln1009Ter). Case two variant LOVD; variant ID is #0000935135, https://databases.lovd.nl/shared/variants/0000935135#00025859.

Competing interests

The authors declare no competing interests.

Ethical approval

Ethical approval was not required for case reporting. Written informed consent for blood sampling for genetic testing was obtained as part of the diagnostic protocol. Written informed consent for scientific publication including of pictures was also obtained.

Supplementary information

The online version contains supplementary material available at 10.1038/s41431-023-01506-6.