Prader-Labhart-Willi Syndrome

Infantile hypotonia, early childhood-onset obesity, hypogonadism, and mental retardation.

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Prader-Willi Syndrome; Willi-Prader Syndrome.

First described in 1956 by A. Prader, A. Labhart, and H. Willi, all three Swiss pediatricians and internists, on the basis of observation obtained from nine children with the tetrad of short stature, mental retardation, severe obesity, and small hands and feet. In 1961, muscle hypotonia in infancy was added to the phenotype. Diabetes mellitus usually develops in childhood.

In the United States, most cases are sporadic in occurrence. Rate of prevalence is reported to be 1:16,062 live births by Burd et al., whereas Butler et al. reports a prevalence of 1:25,000 live births. Internationally, the reported prevalence range from 1:8,000 in rural Sweden to 1:16,000 in western Japan.

Syndrome results from the loss of the paternal copy of chromosome 15q11.2-13. It is described as a microdeletion/disomy disorder. However, most cases arise sporadically. More than 70% of patients have a deletion of the paternal copy. Approximately 25% of patients have maternal uniparental disomy for chromosome 15. The remainder present with translocation or other structural aberration in chromosome 15.

Reduction in lung volumes, including expiratory reserve volume, vital capacity, and functional residual capacity; closing capacity is increased, leading to airway closure in the dependent areas of the lung and V/Q mismatch; reduced chest and diaphragmatic excursions; decreased alveolar ventilation; diminished sensitivity of the respiratory center to hypoxia and hypercarbia—all contributing to hypoxia and hypercarbia. Intermittent upper airway obstruction and hypoxia during sleep with resultant chronic sleep deprivation and daytime somnolence; severe and chronic hypoxia leading to polycythemia, pulmonary hypertension, right ventricular hypertrophy, and failure.

Neonatal hypotonia is one hallmark feature of this disorder and is a valuable clue to initiate diagnostic testing. Clinical features; biochemical (polycythemia, hypoxia, hypercarbia); lung function tests (reduced lung volumes including total lung capacity, functional residual capacity, vital capacity, and expiratory reserve volume); ECG (right axis deviation); chest radiograph or echocardiography (cardiomegaly); sleep studies (obstructive sleep apnea).

The syndrome is biphasic; initially the picture is one of hypotonia and later changes to hyperphagia leading to obesity.

Antenatal: delayed onset and reduced fetal activity during pregnancy; often breech presentation at birth.

Neonatal and infancy: low birth weight, infantile hypotonia (“floppy infant”), neonatal asphyxia, poor feeding, and failure to thrive; gross motor developmental delay, weak cry and cough, hypogonadism with genital hypoplasia. Neonates may require tube feeding for 3 to 4 months, although this usually improves by 6 months and by 12 to 18 months, uncontrollable hyperphagia occurs.

Childhood: endocrine (polyphagia, insatiable hunger, hypoglycemia, rapid weight gain after 1 year of age, morbid obesity, short stature, hypogenitalism, and hypogonadism); craniofacial (narrow bitemporal head dimension, almond-shaped eyes with strabismus and myopia, thin upper lips with down-turned corners, dental enamel hypoplasia and early caries, viscous saliva); neurological (global developmental delay, skin picking, high pain threshold, behavioral and personality problems, sleep disturbances, speech problems, hyporeflexia, seizures); musculoskeletal (small hands and feet with tapered fingers, hypermobile joints, scoliosis, kyphosis); respiratory (poor cough, hypoventilation, sleep apnea, restrictive lung disease, recurrent chest infections, hypoxia); cardiovascular system (pulmonary hypertension and cor pulmonale secondary to chronic hypoxia, cardiac failure and arrhythmias, primarily premature ventricular contractions); other (skin hypopigmentation, defective temperature regulation, ischemic gastroenteritis, and gastric dilatation). Diabetes mellitus most often is diagnosed at that time because of high calorie intake.

Adolescence: delayed puberty, alimentary diabetes because of high caloric intake, emotional lability (temper tantrums and obsessive-compulsive behavior), poor gross motor and cognitive skills, signs of cardiac failure. Ventilatory control: abnormal responses to hyperoxia, hypoxia, and hypercarbia whether awake or asleep. Because growth hormone therapy seems to increase respiratory drive in these patients, both a peripheral (nearly absent chemoreceptor activity) and a central mechanism (hypothalamus) must be involved. Arrhythmias, conduction abnormalities, hypertension, and cardiac failure may occur. Truncal obesity may result in a restrictive defect in pulmonary function and there may also be a respiratory muscle weakness. Type II diabetes mellitus is common. Sleep apnea, thermoregulatory disturbance, and convulsions may occur. There may be abnormally thick, viscous saliva. Death usually occurs in the third decade of life from complications of diabetes, respiratory failure, and cardiac failure.

Detailed preoperative cardiac and respiratory assessment is required; although weight loss might be advisable prior to elective surgery. It is most often impossible to achieve for the patient. Infancy: history relating to episodes of neonatal aspiration, severe hypotonia, and associated pneumonia. Childhood and adolescence: history relating to sleep apnea. Evaluate respiratory function tests. Obtain full cardiac history with attention to ECG, hypertension, and signs of cardiac failure (echocardiography to rule out cor pulmonale). Ensure appropriate perioperative blood glucose control if diabetic. The recommendations from the patient's endocrinologist must be followed. Strict consideration for feeding guidelines must be assessed. Make sure the patient has no access to food, otherwise nil per os instructions will not be followed.

Difficult child because of behavioral problems and mental retardation. Because of obesity, venous access and identification of landmarks for regional anesthesia may be difficult. Difficulty in maintaining patent airway during face-mask ventilation. Direct laryngoscopy and tracheal intubations could be difficult because of morbid obesity. The risk of gastric aspiration is increased because of obesity, gastric dilatation, rumination, and/or stealing of food. The stomach should never be considered empty. Airway obstruction during induction and awakening; reduced functional residual capacity and higher closing capacity result in poor respiratory reserve with rapid oxygen desaturation. High risk of postoperative hypoventilation and obstructive sleep apnea. Intraoperative hypertension and arrhythmias may require specific management. Close perioperative monitoring of blood glucose levels is mandatory and patients may need glucose-containing intravenous fluids. Intraoperative temperature monitoring is mandatory because hypothermia or hyperthermia may occur. Obese patients require lower drug doses on a per-kilogram basis. Succinylcholine has been used without complications but must be used only if face-mask positive-pressure ventilation is confirmed. Cautious use of respiratory depressants is advisable. Preoperative premedication may not be advisable in most patients. Postoperative apnea monitoring is required. Supine position is associated with a drop in PaO2 and is to be avoided postoperatively; nasal continuous positive airway pressure or continuous positive airway pressure mask recommended for obstructive sleep apnea. Polycythemia may predispose to deep venous thrombosis in the postoperative period, although pulmonary embolism is extremely rare in children.

Preoperative sedation should be avoided because of the risk of hypoventilation and apnea. Use of prophylaxis against gastric aspiration recommended; require lower drug doses on a per-kilogram basis; increased sensitivity to respiratory depressants, including opioids; increased incidence of postoperative respiratory complications.

Bardet-Biedl Syndrome: Mental retardation, pigmentary retinopathy, polydactyly, obesity, renal anomalies, and hypogenitalism.

Albright Hereditary Osteodystrophy: Round face, short stature and neck, and obesity. Intracranial and subcutaneous calcification; neuromuscular problems such as fatigue and muscle cramps; seizures; pseudohypoparathyroidism and hypocalcemia; hypertension. Correction of chronic hypocalcemia is treated by oral calcium and vitamin D. Avoid respiratory or metabolic alkalosis. If surgery cannot be delayed, intravenous calcium therapy must be given with continuous ECG monitoring.

Chudley Mental Retardation Syndrome: Extremely rare disorder characterized by mental retardation, distinctive mouth, obesity, and hypogonadism.