Headache and Sleep-Related Breathing Disorders Among Patients With Sclerosteosis and Disease Carriers: The First Family in Italy

doi:10.21203/rs.3.rs-80061/v1

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Headache and Sleep-Related Breathing Disorders Among Patients With Sclerosteosis and Disease Carriers: The First Family in Italy

https://doi.org/10.21203/rs.3.rs-80061/v1

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Background

Headache and sleep-related breathing disorders among patients with sclerosteosis and disease carriers has been little studied. We investigated the neurological and neuroimaging features of patients and gene carriers of a large Italian family with sclerosteosis.

Main body

In this Italian family with sclerosteosis, genetic tests detected the homozygous mutation p.Gln24X (c.70C>T) of the SOST gene in the proband, and a heterozygous mutation between 9 siblings. Severe hyperostosis of the skull caused chronic headache secondary to intracranial hypertension due to venous hypertension and obstructive sleep apnea syndrome in adult homozygotes. There was transosseous intracranial-extracranial occipital venous drainage which indicated a compensatory mechanism for intracranial venous hypertension, one of the causative factors of increased CSF pressure in sclerosteosis. While mild hyperostosis of the skull was associated with headache and snoring in heterozygotes.

Conclusions

Headache and sleep-related breathing disorders are the most common clinical manifestations among patients with sclerosteosis and disease carriers. Cerebral venous hypertension leading to intracranial hypertension and facial deformities are the causative factors of headache and sleep-related breathing disorders. These data suggest that venous stenting to accommodate cerebral venous drainage could be useful in the treatment of intracranial hypertension, and correction of facial deformities to relieve obstructive sleep apnea may play a role in the treatment of patients with sclerosteosis. The data highlight that it is reasonable to extend neurological evaluation and radiological study to gene carriers.

Neurology

sclerosteosis

headache

intracranial venous hypertension

intracranial hypertension

obstructive sleep apnea

Sclerosteosis is a rare cause of hyperostosis of the skull, manifested in particular by facial dysmorphism, enlargement of the jaw and frontal bossing [1]. It is transmitted as an autosomal recessive trait, and is caused by the mutation of the loss of function of the SOST gene in the chromosome 17q12-q21 [2]. Due to the limited number of affected individuals by sclerosteosis described mainly from South Africa, the neurological features of patients have been little studied and the presence of clinical manifestations of the disease among carriers remains still uncertain [3]. We report the clinical features and neuroimaging results in patients and gene carriers of an Italian family with sclerosteosis.

Participants

The Calabrian family of Southern Italy included living subjects of 3 different generations. All participants made a careful general and neurological evaluation. The neuroimaging study included computed tomography (CT) of the head, brain magnetic resonance imaging (MRI), and cerebral MRI venography. CSF pressure was assessed through 1-hour CSF monitoring by spinal needle, as described elsewhere [4]. Polysomnography was used to diagnose obstructive sleep apnea syndrome (OSAS).

DNA analysis

DNA was tested for SOST gene mutations in all participants. Genomic DNA was extracted from peripheral blood using standard methods. The primers alongside all 2 exons and the intron-exon boundaries of SOST were designed using the Primer 3 website (http://bioinfo.ut.ee/primer3-0.4.0/). The purified PCR products were analyzed on 3500 Genetic Analyzer.

The family consisted of 13 subjects, 9 males and 4 females. Pedigree analysis revealed autosomal recessive inheritance. Molecular screening of SOST gene detected a nonsense homozygous mutation p.Gln24X (c.70C>T) in the proband, and a heterozygous mutation in 9 siblings (Figure 1).

Patients

Clinical characteristics of patients and disease carriers are summarized in Table 1. The proband, a middle age male, complained of chronic refractory headaches associated with transient visual disturbances, tinnitus, dizziness, snoring and daytime sleepiness from the age of 20. At the age of 5 he suffered from bilateral facial nerve paralysis. Neurosensory hearing loss and left eye blindness occurred a few years later. The clinical evaluation indicated a height of 1.70 m and a weight of 97.1 kg with a body mass index of 33.6 kg/m². It also showed bilateral exophthalmos, marked enlargement of the mandible and a frontal bossing. Routine serum analysis, electrolytes, hormonal evaluation were all normal.

Another middle age male had facial deformities and complained of similar disorders. He reported unilateral hearing loss and bilateral paralysis of the facial nerve since childhood. From the age of 20 he complained of severe chronic headache and night snoring.

CT images of the skull obtained with high-spatial-resolution bone algorithm revealed thickening of the calvarium, skull base and mandible, and narrowing of the optic canals, internal auditory meatus, facial nerve canals, and vascular foramina. The mastoid cells were not aerated (Figure 2 C). Hyperostosis of the orbital walls reduced intraorbital volume and led to a slight proptosis. Brain MRI displayed depletion of subarachnoid spaces, empty sella turcica, flattening of posterior aspect of the globes, distension of the optic nerve sheaths, and cerebellar tonsillar descent below the level of the foramen magnum. Cerebral MRI venography showed a global engorgement of the suboccipital plexus with evidence of superficial temporal and retromandibular temporal veins, absence of right transverse sinus and left transverse sinus flow gap, suggesting an intracranial venous hypertension; 3D Volume Rendering of MR venography exhibited the presence of transosseous occipital venous collateral indicating an intracranial-extracranial cerebral venous drainage. (Figure 2 B and D).

One-hour lumbar CSF pressure monitoring through spinal needle revealed an elevated CSF pressure (opening pressure 370 mmH₂O, mean pressure 264 mmH₂O) indicating an intracranial hypertension (IH). At the end of the short pressure monitoring a CSF subtraction of about 20 ml was carried out which produced a normalization of the closing pressure. Polysomnographic testing confirmed an obstructive pattern of sleep apnea (apnea-hypopnea index of 15). The patient began therapy with acetazolamide 1000 mg/day, and ventilatory therapy with the Continuous Positive Airway Pressure Device (CPAP), which produced an improvement of symptoms.

Disease carriers

Facial alterations such as enlarged jaw and frontal bossing were present in 6 of 9 disease carriers, and were more pronounced in adults. In addition, two had a radial deviation of the phalanges of the last two fingers. Seven individuals complained of severe episodic or chronic headaches. Five out of nine also had night snoring from early childhood. Headache and snoring had become more severe in adulthood.

CT scans of the skull in the bone window of 2 symptomatic heterozygotes showed a slight thickening of the calvarium mainly in the occipital region with a prominence of the external occipital protuberance in the adult individual, while the child had normal CT results (Figure 3 B and C).

Table 1. Neurologic features of patients with sclerosteosis and disease carriers.

Subjects Sex/ years	Genetic status	Age at Onset and first clinical manifestation	Clinical features	Progression	Findings
F/ 66	Heterozygous	20 years Headache	Enlarged mandible, radial deviation of phalanges, chronic headache, snoring	stable	Snoring
M/ 67	Heterozygous	30 years Headache	Enlarged mandible, frontal bossing, episodic headache, snoring	stable	Snoring
M/ 43	Refused genetic test	4 years Bilateral facial nerve palsy	Bilateral exophthalmos, enlarged mandible, frontal bossing, unilateral hearing loss, bilateral facial nerve palsy, chronic headache with postural variations, tinnitus, transient visual disturbances, vertigo, snoring	Multiple cranial nerve palsy onset in the first 2 decades, chronic headache and snoring since the III decade, stable since the IV decade	Snoring
M/ 40	Heterozygous	30 years Chronic headache	Enlarged mandible, frontal bossing, chronic headache	stable	Unknown
F/ 41	Heterozygous	NA	Enlarged mandible, radial deviation of phalanges	stable	Unknown
M/ 39	Homozygous	5 years Bilateral facial nerve palsy	Bilateral exophthalmos, enlarged mandible, frontal bossing, unilateral blindness, unilateral sensorineural hearing loss, bilateral facial nerve palsy, chronic headache with postural variations, tinnitus, transient visual disturbances, vertigo, snoring	Multiple cranial nerve palsy onset in the first 2 decades, chronic headache and snoring progressive worsening up to time of observation, stable since the age of 37	Intracranial hypertension, OSAS, cerebral venous hypertension
M/ 28	Heterozygous	12 years headache and snoring	Enlarged mandible, chronic headache, snoring	Worsening of headache	Snoring
F/ 31	Wild-type	NA	Normal appearance of the skull	NA	NA
M/ 5	Wild-type	NA	Normal appearance of the skull	NA	NA
M/ 15	Heterozygous	8 years Headache	Episodic headache	stable	Unknown
M/ 6	Heterozygous	5 years Headache and snoring	Episodic headache, snoring	stable	Snoring
F/ 4 months	Heterozygous	NA	Normal appearance of the skull	NA	NA
M/ 5	Heterozygous	5 years snoring	Enlarged mandible, episodic headache, snoring	Worsening of snoring	Snoring

NA: not applicable

Headache and sleep-related breathing disorders were the most common clinical manifestations among patients with sclerosteosis and disease carriers. Skull hyperostosis was the cause of intracranial hypertension (IH) and of facial deformities which in turn caused headache and sleep-related breathing disorders in patients and carriers of sclerosteosis. These data suggest that venous stenting to accommodate venous outflow, and correction of facial deformities to relieve obstructive sleep apnea may play a role in the treatment of headache secondary to IH in patients with sclerosteosis.

Nocturnal headache and chronic morning headache aggravated by postural changes and Valsalva-like maneuvers were common among patients and disease carriers of this Italian family with sclerosteosis. The onset of nocturnal attacks of pulsating pain and persistent headache in the morning, exacerbated by postural changes and coughing, can be explained by the presence of abnormal CSF pulsations occurring during sleep and the posture changes in patients with intracranial hypertension [5]. One possible basis for increased intracranial pressure in patients with sclerosteosis is a reduction of the intracranial diameter due to overgrowth of the calvarium and of skull base [6]. However, IH cannot be entirely attributed to reduction of the intracranial diameter. A possible contributory factor to IH may be the presence of intracranial venous hypertension due to venous outflow disturbances caused by vascular foramen narrowing. Consistent with this hypothesis, we detected transosseous intracranial extracranial venous drainage which indicated a compensatory mechanism for intracranial venous hypertension which in turn resulted in increased intracranial pressure in the patient with sclerosteosis. This fact suggests that improved cerebral venous drainage using venous stenting [7] could be useful in the treatment of intracranial hypertension in patients with sclerosteosis.

The presence of sleep-related breathing disorders has never been reported in patients with sclerosteosis. To explain this finding, we hypothesize that excessive growth of skull bones alters the structure of the upper airway causing obstructive sleep apnea in patients with sclerosteosis. The role of craniomandibular anatomical abnormalities in the development of obstructive sleep apnea is well recognized [8]. Increased inspiratory effort against the closed airways during obstructive sleep apnea causes hypercapnia and hypoxia, which in turn induce changes in brain perfusion pressure and increased intracranial pressure [9], In accordance with this pathogenetic mechanism, the association between breath-related sleep disorders and chronic headache has been observed in OSAS patients [10, 11]. Similar mechanism could be the cause of nocturnal snoring and chronic headache in heterozygotes with mild skull hyperostosis. Overall, these data suggest that correction of facial deformities to relieve airway obstruction could play a role in the treatment of sleep-related breathing disorders in patients with sclerosteosis.

Although it is recognized [3] that heterozygotes have no manifestations of disease 6 gene carriers had headaches and mild cranial hyperostosis in this family. In fact, characteristic facial dysmorphic aspects were detected in heterozygotes, with more marked alterations in adult individuals. In addition, we also found the presence of mild abnormalities of the limbs in adult disease carriers. Consistent with these results, a previous study [12] reported a significant reduction in sclerostin activity in heterozygotes, which caused an increase in bone density compared to healthy controls. The latter data indicate a gene-dose effect of the SOST mutation on circulating sclerostin. The presence of disease manifestations in heterozygous individuals in this Italian family provides evidence that sclerostin, which has been reported to be transmitted as an autosomal recessive trait [2], may instead be a co-dominant autosomal condition. Overall, the results suggest that it is reasonable to extend neurological evaluation and radiological study to disease carriers.

In this Italian family we found a homozygous and heterozygous mutation without sense p.Gln24X (c.70C>T) in exon 1 of the SOST gene. This mutation without sense which, according to the predictions of Mutation TasterServer (http://www.mutationtaster.org), exerts a deleterious effect and leads to the premature cessation of the protein. The same mutation has been previously reported in an African family [2]. The identification of the same mutation in this family from southern Italy, considering the geographical proximity that facilitates migration from that continent to southern Italy, suggests the potential founding effect.

Severe hyperostosis of the skull manifests with chronic headache secondary to intracranial hypertension due to intracranial venous hypertension and OSAS in affected adults by sclerosteosis. Mild hyperostosis of the skull manifests with headache and snoring in gene carriers. Our study expandes the clinical spectrum of hyperostosis of the skull due to sclerosteosis.

CSF: cerebrospinal fluid; CPAP: Continuous Positive Airway Pressure Device; CT: computed tomography; IH: intracranial hypertension; MRI: magnetic resonance imaging; OSAS: obstructive sleep apnea syndrome.

Acknowledgements: not applicable

Contributors: Study concept and design: FB; LR, FB, collected, analyzed and interpreted data; LR, MG, CB, GA, GD FB drafted the manuscript; FB revised the manuscript for intellectual content. All authors read and approved the final manuscript.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Availability of data: all relevant data are included in the article.

Ethics approval and consent: Approval from the Internal Institutional Review Board of the Magna Graecia University of Catanzaro was obtained for this study.

Consent for publication: Written informed consent was obtained from all adult participants and parents of the children included in the study.

Competing interests: The authors declared they have no competing interests.

Truswell AS. Osteopetrosis with syndactyly; a morphological variant of Albers-Schönberg's disease. J Bone Joint Surg Br. 1958; 40-B(2):209-18.
Brunkow ME, Gardner JC, Van Ness J et al., Bone dysplasia Sclerosteosis results from loss of the SOST gene product, a novel cystine k not-containing protein. Am. J. Hum. Genet, 2001; 68:577-589.
Hamersma H, Gardner J, Beighton P, The natural history of sclerosteosis. Clin Genet 2003; 63:192-197.
Bono F, Salvino D, Tallarico T, et al. Abnormal pressure waves in headache sufferers with bilateral transverse sinus stenosis. Cephalalgia 2010; 30:1419–1425.
Bono F, Curcio M, Rapisarda L, et al. Cerebrospinal fluid pressure-related features in chronic headache: a prospective study and potential diagnostic implications. Front Neurol. 2018 Dec 18;9:1090.
Van Lierop AH, Appelman-Dijkstra NM, Papapoulos SE, Sclerostin deficiency in humans. Bone 2017; 96:51-62.
Higgins J, Cousins C, Owler B, et al. Idiopathic intracranial hypertension: 12 cases treated by venous sinus stenting. J Neurol Neurosurg Psychiatry 2003;74(12):1662–1666.
Zucconi M, Ferini-Strambi L, Palazzi S, Orena C et al. Habitual snoring with and without obstructive sleep apnoea: the importance of cephalometric variables. Thorax 1992 Mar; 47(3):157–161.
Lee AG, Golnik K, Kardon R et al. Sleep apnea and intracranial hypertension in men. Ophthalmology 2002; 109(3):482-5.
Ferini-Strambi L, Galbiati A, Combi R. Sleep Disorder-Related Headaches. Neurol Sci 2019 May;40(Suppl 1):107-113.
Ohayon MM. Prevalence and risk factors of morning headaches in the general population. Arch Intern Med 2004;164(1):97-102.
Gardner JC, van Benzooijen RL, Mervis B et al. Bone mineral density in Sclerosteosis, affected individuals and gene carriers. J Clin Endocrinol Metab. 2005; 90(12):6392-6395.

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Headache and Sleep-Related Breathing Disorders Among Patients With Sclerosteosis and Disease Carriers: The First Family in Italy

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