Familial Sleep Disorders in Unknown Genetic Syndrome

Abstract

Sleep-disordered breathing (SDB) is common in children, especially in those with congenital or genetic diseases. The factors involved include obstructive sleep apnea, disrupted rapid eye movement sleep, and central hypoventilation. Diagnosing and treating SDB in these children have a positive impact on the quality of life of them and their families, reducing the risk of both further impairment of cognitive abilities and cardiopulmonary complications. We report a familial case of SDB with central hypoventilation, in which identification of the disorder in the younger sister led to the unfortunately late diagnosis and treatment of the same condition in the older sister.

Introduction

Sleep-disordered breathing (SDB) is a common problem in children, especially in those with congenital and/or genetic diseases. A recent review reported a prevalence of sleep disorders of up to 80% in children with neurodevelopmental disorders and genetic syndromes. ¹ Several factors may contribute to sleep disturbance in these patients, including obstructive sleep apnea (OSA), disrupted rapid eye movement (REM) sleep pattern, central sleep apnea (CSA), and hypoventilation. According to the American Association of Sleep Medicine, OSA is defined as a drop in nasal flow amplitude by 90% of baseline for at least two respiratory cycles with continued or increased inspiratory effort, whereas CSA is the absence of chest and abdominal movements associated with a cessation of airflow (more than 20 seconds or more than two baseline respiratory cycles in association with an arousal or an awakening or an oxygen desaturation of at least 3%). A hypoventilation is defined as a carbon dioxide (CO ₂ ) level greater than 50 mm Hg for at least 25% of total sleep time, as measured by either the arterial PCO ₂ or surrogate. ² OSA is the most frequent sleep disorder in children, while CSA and hypoventilation are less common, although their real prevalence is unknown and is probably underestimated, including in high-risk categories. Several conditions may play a role in exacerbating SDB. Although infancy enlarged adenotonsillar tissue becomes the principal cause of OSA, craniofacial disorders, macroglossia, narrow nasopharynx and/or oropharynx, obesity and hypotonia, common features in many genetic disorders, are predisposing factors for OSA. Prematurity, inherited disorders, such as Prader–Willi syndrome (PWS) or acquired conditions such as foramen magnum compression in achondroplasic patients or an Arnold–Chiari malformation, are more often associated to an increased risk of CSA. ³ Many sleep disorders have a familial occurrence, suggesting an underlying genetic basis. However, while no specific risk loci have been found for OSA, in 2003 Wees-Mayer et al identified a variant of the paired-like homeobox 2B (PHOX2B) gene on chromosome 4p12 as the cause of approximately 90% of cases of congenital central hypoventilation syndrome (CCHS). The transmission of this condition is mostly autosomal dominant, but some cases are heterozygous for a de novo mutation or caused by inherited mosaicism from an asymptomatic parent. ⁴ Children with sleep disorders should be identified early and treated appropriately, as a late diagnosis can have detrimental effects on neurocognitive development and growth, leading to a worse quality of life for the children and their families. We describe a case of SDB with central hypoventilation in two sisters with an unknown genetic syndrome, in which the identification of the disease in the younger sister led to an unfortunately late diagnosis of the same condition in the older sister.

Case Report

Two sisters aged 8 and 3 years were followed up in the Pediatric Outpatient Department of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, for a suspected genetic disease of unknown origin. The eldest sister was born at term via spontaneous vaginal delivery and had a birth weight of 3,240 g. Immediately after birth she was admitted to the Neonatal Intensive Care Unit (NICU) of another hospital for global hypotonia and sucking difficulties. During hospitalization she underwent a cerebral ultrasound, which was normal. After discharge, she presented a normal growth pattern but persistent hypotonia, while there was a progressive lag in the acquisition of the milestones of psychomotor development: head control was achieved at 7 months, sitting and first words at around 12 months, and independent walking at around 30 months. Episodes of sleep apnea were observed by her parents in her first months of life, with apparent later resolution. No polysomnography was performed at that time. Brain magnetic resonance imaging (MRI) at 1 year of age showed a thinning of the corpus callosum and asymmetry of the lateral ventricles. The first neurological examination in our hospital, which took place when she was 5 years 9 months old, revealed global hypotonia, divergent strabismus, a dysmorphic triangular and masked facies, pes valgus, clumsy movements, wide-based gait, a slow run, language delay and intellectual impairment ( Fig. 1 ). An electroencephalogram (EEG) did not show any significant alterations, except for modest generalized slow abnormalities and a monomorphic morphology. Measurement of plasma and urinary amino acids, urinary organic acids and mucopolysaccharides, blood lactate and pyruvate and sialotransferrin levels by isoelectric focusing produced normal results. The results of karyotype and CGH-array analyses were normal, as were molecular tests for Fragile X syndrome, PLOD1-related Ehlers Danlos syndrome, and Coffin Lowry syndrome, associated with the RSK2 gene. Finally, whole-exome sequencing (WES) analysis did not identify any variants of pathogenic significance. An additional brain MRI confirmed a slightly thinned appearance of the corpus callosum and a modest asymmetry of the lateral ventricles (right greater than left). The younger sister was born at 36 weeks of gestation via an urgent caesarean section due to suspected fetal distress and heart abnormalities detected by cardiotocography. She was hospitalized for 40 days in our NICU because of sucking difficulties, dyspnea, recurrent episodes of desaturation with bradycardia, and sleep apnea. At 15 days she underwent a brain MRI, which revealed dilated and dysmorphic lateral ventricles and small subependymal heterotopias. Metabolic screening of plasma and urinary amino acids, urinary levels of organic acids and mucopolysaccharides, and blood levels of lactate and pyruvate produced normal results. An EEG performed at 1 month of age showed slight alterations in general electrocortical activity with excessive generalized slow activity and reduced presence of neonatal physiological graphic elements, while the visual evoked potentials were normal. Intraluminal impedance-pH monitoring revealed findings consistent with gastroesophageal reflux. A genetic examination in the first month of life highlighted a phenotype similar to that described in the older sister, so a genetic autosomal recessive transmission condition was suspected. As in her sister, WES analysis was negative. Due to the detection of daytime bradypnea (respiratory rate 15–20 cycles/min), continuous home cardiorespiratory monitoring was implemented after discharge from the NICU. This revealed periodic episodes of central apnea, subsequently confirmed by home sleep apnea testing, which documented a respiratory event index (REI, defined as total number of respiratory events scored × 60 divided by monitoring time, as defined in the AASM [American Academy of Sleep Medicine] Scoring Manual Version 2.2) of 80.7/h (99.3% due to central events), a desaturation index (ODI, defined as the number of ≥3% arterial oxygen desaturations per hour of sleep) of 40.5/h, an average oxygen saturation of 92.8% and a typical periodic pattern of Cheyne-Stokes breathing characterized by cyclical alternation of increases and decreases in breathing followed by a period of apnea. ² Continuous overnight transcutaneous pCO ₂ measurement (TcpCO ₂ ) showed a mean value of 62 mm Hg, providing an alveolar hypoventilation diagnosis. A bilevel positive airway pressure therapy (BPAP) was used to deliver nocturnal noninvasive ventilation (NIV) through a nasal mask, with good tolerance. A subsequent home sleep apnea testing during nocturnal BPAP revealed that her breathing had significantly improved (REI: 1.3/h, 33.3% due to central events, ODI: 9/h, average oxygen saturation 94.9%), with nocturnal TcpCO ₂ of 48 mm Hg ( Table 1 ). As the two sisters had the same phenotype, a home sleep apnea testing and noninvasive gas analysis were also performed in the older sister, when she was 6 years old. The home sleep apnea testing revealed an REI of 4/h (85.2% due to central events), ODI of 6.6/h, and an average oxygen saturation of 93.1%, with no pathological pattern of respiration, while nocturnal TcpCO ₂ was slightly increased (53 mm Hg). Due to the increased number of central events and nocturnal hypercapnia, NIV through a BPAP machine and nasal mask was also used in the older sister. After 1 month of NIV, her home sleep apnea testing features and TcpCO ₂ had normalized.

Fig. 1.

Phenotype of the two sisters.

Table 1. Home sleep apnea testing results of the younger sister: before beginning BPAP therapy (top) and during BPAP (bottom).

Apnea/Hypopnea statistics
Respiration	Number	%	A or H/h	Supine	Nonsupine	Mean (s)	Longest (s)
Apnea	707	99.4	80.2	707	0	9.5	81.0
Obstructive	1	0.1	0.1	1	0	81.0	81.0
Central	706	99.3	80.1	706	0	9.4	18.9
Mixed	0	0.0	0.0	0	0	0.0	0.0
Hypopnea (All)	4	0.6	0.5	4	0	13.7	19.0
Obstructive	–	–	–	–	–	–	–
Central	–	–	–	–	–	–	–
Mixed	–	–	–	–	–	–	–
RDI				–	–
Total	711		80.7	711	0	9.5	81.0
Respiration	Number	%	A or H/h	Supine	Nonsupine	Mean (s)	Longest (s)
Apnea	4	33.3	0.4	0	4	5.1	6.8
Obstructive	0	0.0	0.0	0	0	0.0	0.0
Central	4	33.3	0.4	0	4	5.1	6.8
Mixed	0	0.0	0.4	0	0	0.0	0.0
Hypopnea (All)	8	66.7	0.9	0	8	32.2	111.6
Obstructive	–	–	–	–	–	–	–
Central	–	–	–	–	–	–	–
Mixed	–	–	–	–	–	–	–
RDI				–	–
Total	12		1.3	0	12	23.1	111.6

Abbreviations: BPAP, bilevel positive airway pressure therapy; RDI, Respiratory Disturbance Index.

Discussion

SDB is a general term for breathing difficulties occurring during sleep. It is quite common in the pediatric population but its frequency and the severity of its clinical presentation in children with genetic syndromes may be particularly significant. In any case, the prevalence of this condition is generally underestimated. Consequently, diagnosis and appropriate treatment are often delayed, as exemplified in our familial case, in which SDB in the older girl was only recognized after it was suspected and evaluated instrumentally in her younger sister. The pathogenesis of SDB is generally multifactorial, but increasing evidence suggests a familial and/or genetic influence on predisposition to SDB, particularly in neurogenetic diseases, in which the prevalence of sleep disorders may be as high as 80%. ¹ In children with neurological impairment, sleep disturbances tend to be more chronic and there may be multiple types of sleep disorder simultaneously. The risk of SDB in specific genetic syndromes such as Down syndrome (DS), PWS, or achondroplasia is well known, and diagnostic screening protocols involving sleep polysomnography have already been proposed by some authors. ⁵ SDB in DS is common at all ages. It seems to be more severe in patients with increased learning disabilities, while at the same time, sleep disorders could exacerbate cognitive and psychological dysfunction. Midface hypoplasia, macroglossia, narrow nasopharynx and oropharynx, hypothyroidism, obesity and global hypotonia are common features in DS and are predisposing conditions for OSA. However, patients with DS also have a high prevalence of CSA, nocturnal hypoventilation, and low overnight oxygen saturation compared with the general population. ⁶ The presence of SDB in patients with PWS is equally well recognized. CSA and hypoventilation are mainly seen in infants, while OSA is significantly more prevalent in older children (>2 years). In PWS patients, OSA is due to a combination of minor facial anomalies, narrowing of the upper airways, adenotonsillar hypertrophy and, in many cases, obesity. Global muscle hypotonia and scoliosis of these patients can lead to restrictive lung diseases and sleep-related hypoventilation, which, in association with hypothalamic dysfunction and abnormal chemoreceptor sensitivity, could exacerbate CSA. ⁷ SDB is also common in infants with achondroplasia, especially in the first months/years of life, and is mainly related to a combination of the different clinical features typical in this condition: midface hypoplasia leading to relative adenotonsillar hypertrophy and to OSA, and dysplasia of the basal skull and craniovertebral junction, resulting in foramen magnum compression and hypoglossal canal stenosis with a consequent risk of CSA, muscular obstruction of the upper airways, and hydrocephalus. ⁸ SDB is also common in many other genetic syndromes. From 20 to 80% of the patients with Angelman syndrome present SDB, although polysomnographic data are rarely reported in this group, due to their low tolerance of this type of examination. ⁹ Previous studies also showed a high prevalence of SDB in children with Ehlers-Danlos syndrome, related to cartilaginous defects in oral and facial growth. In this group, OSA is the most common type of SDB, with up to 26% of the children affected. ¹⁰ Given the high prevalence of SDB in children with known genetic syndromes, we emphasize the importance of extending early routine sleep surveillance also to a larger population with nonspecific genetic conditions in the presence of any clinical features that might increase the risk of SDB. In the case of the older sister discussed herein, the observation of marked hypotonia with poor sucking and delayed neurocognitive development from an early age should have been considered highly suggestive of SDB. Central CSA may be a common finding in children with decreased muscle tone and respiratory muscle weakness, as is known in neuromuscular disorders. Respiratory muscle impairment can result in a decrease in functional residual capacity, an increase of respiratory rate, and nocturnal hypoventilation with hypercapnia. With diaphragmatic involvement there is a loss of ventilatory efforts, that mimic CSA. Furthermore, in neuromuscular diseases a decrease in chemosensitivity with chronic hypercapnia is also described. ¹¹ However, the same clinical phenotype in the two sisters, mild and similar structural cerebral malformations, persistent low respiratory rate, and polysomnographic findings, suggested a case of innate CSA upon a genetic basis, rather than a neuromuscular disorder. The presence of central hypoventilation during sleep associated with hypotonia and delayed neurocognitive development could suggest pathogenic variants in the PHOX2B gene or in the sodium leak channel nonselective protein (NACLN). PHOX2B encodes a transcription factor involved in the regulation of neural crest migration and development of the autonomic nervous system, and its mutation causes CCHS, previously known as Ondine's curse. SDB in CCHS may range from alveolar hypoventilation during non-REM sleep and normal ventilation during wakefulness to severe complete central apneas during sleep and severe hypoventilation while awake. ⁴ NACLN is a transmembrane protein that facilitates the intracellular movement of sodium and is widely expressed in the central nervous system. To date, a handful of studies have described NACLN mutations in humans as causes of hypotonia, developmental delay, subtle facial abnormalities, constipation, strabismus, and poor weight gain. Two of these studies also described dysrhythmic breathing. ¹² In our cases, WES did not show any mutations of these two suspected loci, however, a different genetic background could be involved and the absence of mutations in those specific loci does not fully exclude the presence of a different form of complicated congenital central hypoventilation. Unfortunately, the lack of an underlying genetic pathogenic variant impeded the prompt scheduling of appropriate clinical investigations. In this case an early sleep study could have provided additional data that would have guided the clinicians to the earlier recognition and treatment of the CSA. The mild CSA features in the older sister at 5 years of age could be related to the late diagnosis, suggesting that, as in CCHS, CSA tends to improve over time in this unknown genetic syndrome. Certainly, the significant intellectual impairment observed in the older sister could be either due to the underlying genetic disorder itself or to the chronic persistent hypoxemia/hypercapnia caused by untreated CSA. Only the clinical course in the younger sister, whose CSA was precociously corrected by noninvasive ventilation, will allow the natural history of this genetic disorder to be established, hence enabling better targeting of the therapeutic intervention.

Conclusion

Early diagnosis and treatment of SDB in children with a genetic syndrome may have a positive impact on their quality of life, reducing the risk of both further impairment of cognitive abilities and further cardiopulmonary and metabolic complications. Our case shows that SDB, and, in particular CSA, should be suspected also in children with unknown genetic syndromes that affect CNS and muscle tone and that early sleep surveillance should be considered even when the precise genetic syndrome involved has not been identified. Although the literature is generally focused on SDB related to renowned genetic conditions and we do not have sufficient data to provide a guideline, our opinion is that in children with neurological and muscular tone impairment it would be prudent, besides neurodevelopmental assessment, to include home sleep apnea testing in the first year of life to recognize underlying sleep disorders and to manage an individualized follow-up, if pathological findings are detected. This will result in an improvement in CSA and better life expectancy in most of these patients.