A 5 year old girl with Prader-Willi syndrome and worsening snoring during growth hormone therapy
Case Editor - Kamyar Afshar
Reviewed By Clinical Problems Assembly
Camilla K. B. Matthews, MD
Department of Pediatrics
Wisconsin Sleep Center, University of Wisconsin School of Medicine and Public Health
Mihaela Teodorescu, MD, MS
Department of Medicine
Wisconsin Sleep Center, University of Wisconsin School of Medicine and Public Health
On exam, the patient had a blood pressure of 102/84 mm Hg and pulse of 111 beats/min. Her BMI was 28 kg/m2, compared to 20 kg/m2 one year previously. Her general appearance was notable for obesity and the general facies of a child with PWS, including almond-shaped eyes, thin upper lip, and down turned corners of the mouth. HEENT exam showed no thyromegaly, however, her tonsils were 4+. Her lungs were clear to auscultation. The cardiac exam showed a regular heart rate without murmur or gallop. Musculoskeletal exam revealed subtle scoliosis. Her gait was broad based. The skin exam revealed well healed scars on the hips from osteotomies for bilateral hip dysplasia. The neurological exam was notable for diffuse hypotonia. Her skin exam was normal.
The patient was referred for a nocturnal polysomnogram (PSG). As depicted below (Fig 1), she was found to have severe OSA with an apnea-hypopnea index (AHI) of 24 events/hour and a REM sleep AHI of 38 events/hour and a lowest oxygen saturation of 81% (Fig 2).
LEOG AND REOG, left and respectively right outer cantus electro-oculography electrodes; F3-M2, C3-M2 and O1-M2, left frontal, central and respectively, occipital electroencephalography electrodes; F4-M1, C4-M1 and O2-M1, right frontal, central and respectively, occipital electroencephalography electrodes; Chin EMG, submental electromyography signal; INT EMG, intercostals electromyography signal; ECG II, one standard electrocardiogram lead; RTibial and LTibial, right and respectively left lower limbs electromyography electrodes; SNORE, the snoring sound via microphone; TFLOW, the airflow via nasal/oral thermocouples; PFLOW, the airflow via nasal air pressure transducer; CHEST and ABDO, chest and respectively abdominal walls motion via inductive plethysmography; SpO2, the pulse oximetry by finger probe; PLETH, phlethysmographic waveform; POSITION, S=Supine; PCO2 and ETCO2, end tidal CO2 monitoring with accompanying waveform.
Hypnogram from baseline PSG depicting multiple respiratory events, more frequent and with lower oxygen desaturations during supine-REM sleep
Figure 3: Hypnogram from follow-up PSG showing significant improvement in sleep-disordered breathing.
Figure 4: Follow-up PSG showing hypopnea and variability in airflow (see arrows) during supine REM sleep.
Figure 5: Follow-up PSG continued to show variability in the plethysmographic waveform (see arrows) during NREM sleep suggesting increased upper airway resistance.
PWS is a genetic neuro-developmental disorder that arises from failure to express paternal genes in the 15q11.2-13 domain. The syndrome is characterized by short stature, infantile hypotonia, hyperphagia, early onset childhood obesity, hypogonadism, temperature instability and impaired cognitive ability. Its prevalence is estimated to be 1:12,000 to 1:25,000 live births (both sexes, all races). Current evidence indicates that dysregulation of the GH/insulin-like growth factor (IGF)-1 axis is the primary abnormality of PWS, and in 2000, the Food and Drug Administration approved GH therapy for these patients.
There is an increased prevalence of sleep-disordered breathing among children with PWS. Its spectrum can include sleep-related hypoxemia/hypoventilation related to reduced ventilatory response to hypoxia and hypercapnia (1), central sleep apnea related to the hypothalamic dysfunction noted in other aspects of the syndrome, and overt OSA, with prevalence estimates for the latter varying from 57% to 100%. Therefore, evaluation for these conditions has been recommended (2,3).
OSA in PWS patients can be attributed to a number of factors, including facial dysmorphism and sticky secretions, obesity, adenotonsillar hypertrophy which may be related to upper respiratory infections, GH therapy and restrictive chest disease due to respiratory muscle hypotonia or scoliosis (4-6). As in this case, combinations of such factors contribute to the condition in an individual with PWS.
The use of GH has been linked potentially to an increased incidence of OSA, especially early on in the course of therapy. Two theories have been proposed (7,8). One relates to IGF-1-mediated hypertrophy of the tonsillar and adenoidal tissues, with further narrowing of the upper airway. Especially in children in the 2-6 years age group when these tissues tend to be enlarged relative to the airway diameter, this further increase in size in a susceptible patient may significantly worsen sleep apnea. In this patient, the rise in IGF-1 levels during GH therapy, though concurrent with her recent weight gain, provide evidence in support of such a mechanism. Additionally, some patients have concurrent upper respiratory infections, which would further worsen the lymphoidal enlargement. In fact, fatalities have been attributed to worsening of OSA in the setting of upper airway inflammation during GH therapy. Another mechanism leading to worsening of respiratory responses is an augmented volume load. Short- term GH therapy can cause sodium retention with secondary water retention, due to an inappropriate increase in plasma renin activity. In light of these possibilities, one recommendation has been to have a baseline sleep study prior to initiation of GH, with a repeat PSG approximately 6 weeks after initiation of GH therapy. Also, if patients develop symptoms of sleep apnea, regardless of the duration of GH therapy and particularly during inter-current upper respiratory tract infections, a PSG and otorhinolaryngological evaluation should be initiated (7,8).
As with other children with OSA, adenotonsillectomy remains the first line therapy for OSA in children with PWS. However, children with PWS may be at increased risk of postoperative complications. Contributing factors to these complications can include age below 3 years, failure to thrive, obesity, cardiac complications such as right ventricular hypertrophy, craniofacial anomalies, hypotonia, severe OSA, and oxygen desaturations to less than 80% (4). Preoperative evaluation with a PSG may be helpful in predicting which patients are more at risk for postoperative complications. Additionally, weight loss and weight management in obese children with OSA may significantly improve their sleep-disordered breathing in addition to other health outcomes.
It has been proposed that OSA can contribute to neurocognitive deficits in children with PWS since the treatment of OSA either with adenotonsillectomy and / or CPAP can produce gains not only in sleep quality but also improvements in daytime behavioral issues, in these children. Children with PWS are known to have increased difficulty with behavior regulation, tantrums, stubbornness, poor attention and frustration (3).
CLINICAL COURSE: The patient was referred for adeno-tonsillectomy and GH therapy was temporarily discontinued until a repeat PSG could be performed post-operatively, to reassess her respiratory status. She had significant improvement in her snoring although the mother still described loud breathing at night and restless sleep.
Repeat PSG found continued but mild sleep-disordered breathing. The overall AHI was 1.8 events/ hour (Fig 3) and her REM AHI was 8.4 events/ hour with a lowest oxygen desaturation of 94%. Mild snoring was noted along with variability of airflow (Fig 4), and of the plethysmographic waveform (Fig 5) which was concerning for increased upper airway resistance. No sleep-associated hypoventilation was noted, since end-tidal CO2 and transcutaneous CO2 values were in the normal range, in the mid 40's mmHg.
Because the sleep study indicated sleep-disordered breathing in combination with the parental report of heavy breathing and restless sleep, CPAP therapy with acclimation to the mask prior to in lab titration was recommended. The patient was evaluated by a respiratory therapist and a health psychologist prior to in lab titration. Initially, she was started on an empiric CPAP pressure of 4 cm H2O. She was brought back for CPAP titration and titrated to CPAP of 8 cm H20. She has been doing fairly well with a compliance rate of 70% of nights with greater than 4 hours of usage. Her mother reported that the snoring was controlled with the use of CPAP, and that the patient's daytime behavior had also improved with greater attention during the daytime. She had resumed GH therapy after the follow-up PSG noted improved sleep-disordered breathing and continued it through CPAP initiation and therapy. Her family is having more success on weight loss strategies as the daytime attention and physical activity level have improved.
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