Definition, Prevalence, Etiology, and Pathogenesis

Prader, Labhart, and Willi described the first patient with this syndrome in 1956.² Prader-Willi syndrome (PWS) is the most common syndromal cause of human obesity, with an estimated prevalence of about 1 in 25,000 births and a population prevalence of 1 in 50,000.³ Prader-Willi syndrome is caused by deficiency of one or more paternally expressed imprinted transcripts within chromosome 15q11-q13, a region that includes SNURF-SNRPN and multiple small nucleolar RNAs (snoRNAs). The molecular pathophysiology of PWS remains unclear, although several candidate genes in this region have been studied and their expression has been shown to be absent in postmortem brains of PWS patients.⁴ Balanced translocations that leave the SNURF-SNRPN promoter and coding regions intact⁵ suggest that disruption of SNURF-SNRPN is less important, whereas a recently reported microdeletion of the HBII-85 snoRNAs in a child with PWS provides strong evidence that deficiency of HBII-85 snoRNAs plays a major role in the key characteristics of the PWS phenotype.⁶ However, some atypical features in the latter patient suggest that other genes in this region also may be important.

One suggested mediator of the obesity phenotype in PWS patients is the enteric hormone ghrelin, which is implicated in the regulation of meal-time hunger in rodents and humans and is also a stimulator of growth hormone (GH) secretion via the GH-secretagogue receptor (GHS-R).⁷ Fasting plasma ghrelin levels are 4.5-fold higher in PWS subjects than in equally obese controls and patients with other obesity syndromes, and thus they may be implicated in the pathogenesis of hyperphagia in these patients.^8,9

Clinical Features

The Prader-Willi syndrome (PWS) is characterized by diminished fetal activity, hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, and obesity. The diagnostic criteria arrived at by a consensus group are based on a point system; 1 point each is allowed for each of five major criteria, and one-half point each for seven minor criteria.¹⁰ A minimum of 8.5 points is considered necessary for the clinical diagnosis of PWS (Table 3-1).

In general, mild prenatal growth retardation occurs, with a mean birth weight of about 6 lb (2.8 kg) at term, hyporeflexia, and poor feeding in neonatal life due to diminished swallowing and sucking reflexes; infants often require assisted feeding for about 3 to 4 months. Feeding difficulties generally improve by the age of 6 months. From 12 to 18 months onward, hyperphagia is a dominant feature in PWS subjects, often associated with pica behavior.

Children with PWS display diminished growth, reduced muscle mass, and increased fat mass; body composition abnormalities resemble those seen in GH deficiency.¹¹ Diminished GH responses to various provocative agents, low insulin-like growth factor-1 levels, and the presence of additional evidence of hypothalamic dysfunction support the presence of true GH deficiency (GHD) in many children with PWS. Boys with PWS usually have hypoplastic external genitalia, including micropenis, whereas girls have hypoplastic labia minora. Adrenarche can occur early, but gonadal maturation usually is delayed or incomplete as the result of hypogonadotropic hypogonadism.

Recent studies have demonstrated a particular pattern of fat distribution in adult patients with PWS, with large amounts of subcutaneous fat, in the presence of relatively normal intraabdominal fat stores. This is associated with relative protection from the insulin resistance and metabolic syndrome usually associated with morbid obesity.¹²

Diagnosis

Loss of the paternal chromosomal segment 15q11.2-q12 (usually de novo) is principally responsible for PWS. Such a loss can occur by either of two mechanisms: through deletion of the paternal “critical” segment (75%), or through loss of the entire paternal chromosome 15 with the presence of two maternal homologues (uniparental maternal disomy) in approximately 22% of patients.¹³ The opposite (i.e., maternal deletion or paternal uniparental disomy) causes another characteristic phenotype, the Angelman syndrome. In rare instances, imprinting errors due to a sporadic or inherited microdeletion in the imprinting center (3% of patients) or a paternal imprinted translocation (<1%) is observed.¹³

Deletions account for 70% to 80% of cases, many of which can be visualized by standard prometaphase banding examination. A minority consist of unbalanced translocations, which are detected easily by routine chromosome examination. Remaining cases are the result of maternal uniparental disomy wherein cytogenetic examinations yield normal results. However, distinct differences in DNA methylation are noted at the D15S9 locus on 15q11-q13, according to the parent of origin; thus DNA methylation can be used as a reliable postnatal diagnostic tool in PWS patients with a normal karyotype.¹⁴

Treatment

Traditionally, the mainstay of management has centered on early institution of a low-calorie diet with regular exercise, rigorous supervision, restriction of food and money, and appropriate psychological and behavioral counseling for the patient and family, often in the context of group homes for PWS adolescents and adults. Pharmacologic treatment, including anorexigenic agents that act through central monoamine and serotoninergic pathways, is not always beneficial in treating hyperphagia and obesity, although a few published controlled studies can be found in the literature. The choice and the use of specific antidiabetic, antihypertensive, and lipid-lowering agents will be guided by those in the general population with obesity, but possible differences in PWS have not been addressed systematically.¹⁵

In PWS children, therapy with GH significantly improves the rate of growth and final height. Long-term studies show that final height is in the average range for age, and GH is now licensed for use in PWS. GH treatment in PWS children also decreases body fat and increases muscle mass, fat oxidation, and energy expenditure.¹⁶ Physical strength and agility are also improved. These improvements are most dramatic during the first year of GH therapy, although prolonged treatment does not completely normalize these parameters.¹⁷ Although increases in fasting insulin and reduced glucose elimination rates have been seen during GH therapy, the development of glucose intolerance and diabetes mellitus does not appear to be a problem to date.

Treatment with clomiphene citrate has been shown to raise plasma luteinizing hormone, testosterone, and urinary gonadotropin levels to normal and to result in normal spermatogenesis and physical signs of puberty.¹⁸ The prescription of testosterone therapy for PWS males has been complicated by anecdotal reports of increased aggressive behavior.

Definition, Prevalence, Etiology, and Pathogenesis

The fragile X syndrome is the most common cause of inherited mental retardation. Recent epidemiologic studies indicate that it is responsible for moderate to severe mental retardation in 1 in 4000 to 6000 males of European descent and is responsible for mild to moderate mental retardation in 1 in 7000 to 10,000 females, with frequency of disease thought to be higher in some ethnic groups (e.g., Tunisian Jews, African Americans). In affected families, there are often clinically normal, transmitting males whose daughters, who are also clinically normal, have a high risk of having clinically affected children.¹⁹ In 1991, the molecular cloning of the fragile X locus revealed unstable expansions of a CGG trinucleotide repeat, located in the FMR1 (fragile X mental retardation 1) gene, which lead to transcriptional silencing. FMR1 encodes a specific RNA-binding protein, FMRP, that negatively regulates local protein synthesis in neuronal dendrites. In its absence, the transcripts normally regulated by FMRP are overtranslated. The resulting overabundance of certain proteins results in reduced synaptic strength and synaptic plasticity.²⁰

Clinical Features

Fragile X syndrome is characterized by moderate to severe mental retardation, macroorchidism, large ears, macrocephaly, prominent jaw (mandibular prognathism), and high-pitched jocular speech. In affected boys, delay in language acquisition and/or behavioral problems are often the presenting symptoms. A Prader-Willi–like subphenotype of the fragile X syndrome has been described in a subset of patients with extreme obesity with a full, round face, small, broad hands and feet, and regional skin hyperpigmentation.²¹ Unlike with Prader-Willi syndrome, patients lack neonatal hypotonia and feeding problems during infancy followed by hyperphagia during toddlerhood.

Diagnosis and Treatment

The discovery of the fragile X expansion mutation has produced efficient and reliable tools for diagnosis, genetic counseling, and prenatal diagnosis.²² Approaches used in the management of the behavioral disturbance of these children include the use of clonidine and anticonvulsants, especially carbamazepine and valproate, which may have behavior-modifying effects in addition to their antiseizure actions, and some forms of behavioral therapy.²³

Definition, Prevalence, Etiology, and Pathogenesis

The earliest formal description of this syndrome was provided in 1920 by George Bardet, who described patients with polydactyly, retinitis pigmentosa, and obesity. In 1922, Artur Biedl, an Austrian professor of pathology and endocrinology, published a short independent account of two siblings with “congenital deformations (retinitis pigmentosa and polydactyly) and an intellectual torpidity.” Bardet-Biedl syndrome (BBS) is a rare (prevalence <1/100,000), genetically highly heterogeneous, autosomal recessive syndrome characterized by central obesity (in 75% of patients), mental retardation, dysphormic extremities (syndactyly, brachydactyly, or polydactyly), retinal dystrophy or pigmentary retinopathy, hypogonadism or hypogenitalism (limited to male patients), and structural abnormalities of the kidney or functional renal impairment. Some overlap has been noted with the syndrome described by John Laurence (an ophthalmic surgeon) and his house surgeon Robert Moon in the late 1800s, which was characterized by retinal pigmentary degeneration, mental retardation, and hypogonadism in conjunction with progressive spastic paraparesis and distal muscle weakness, but without polydactyly.²⁴

Bardet-Biedl syndrome is a genetically heterogeneous disorder that now is known to map to at least twelve loci, many of which have now been identified at the molecular level.25–27 Although BBS is usually transmitted as a recessive disorder, some families have exhibited so called “tri-allelic” inheritance, where the clinical manifestation of the syndrome requires two mutations in one BBS gene plus an additional mutation in a second, unlinked BBS gene.²⁸

Recent studies strongly indicate that most of the genes involved in the BBS are involved in the structure and/or function of the basal body, a modified centriole that is essential for the function of nonmotile cilia,29,30 subcellular organelles whose importance for intercellular communication is becoming increasingly evident. Some BBS proteins are involved in non-canonical Wnt and Sonic Hedgehog signaling within the cilium, suggesting that BBS proteins may contribute to disease pathogenesis through multiple molecular mechanisms.³¹

Genotype-Phenotype Correlations

The clinical manifestations of BBS have been compared in three unrelated, extended Arab-Bedouin kindreds in which linkage to chromosomes 3 (BBS3), 15 (BBS4), and 16 (BBS2) had been demonstrated. Observed differences included the limb distribution of the postaxial polydactyly and the extent and age association of obesity. It appeared that the BBS3 locus is associated with polydactyly of all four limbs, and that polydactyly of the chromosome 15 type (BBS4) is mostly confined to the hands. The chromosome 15 type is associated with early-onset morbid obesity, and the chromosome 16 (BBS2) type appears to present the “leanest” BBS phenotype.

Diagnosis and Treatment

Currently, a diagnosis of BBS is made on clinical grounds, although it is envisaged that prenatal and postnatal molecular genetic testing soon will reach routine clinical practice. Patients with BBS are managed best in specialist centers with access to a wide range of specialists with experience with the disorder. Ophthalmologic advice is crucial, although no established treatments prevent or alleviate the deterioration in vision. However, support can be given to prepare the patient for a life with low vision. Learning difficulties should be assessed early, if possible before visual impairment hampers potentially beneficial speech and language therapy. Accessory digits often are nonfunctional and are excised within the first year of life by orthopedic or plastic surgeons. Bony deformation in already wide feet can lead to ill-fitting shoes, and podiatric advice and special fitting of shoes are important. Oral hypoglycemics and insulin have been used in patients who develop type 2 diabetes. No evidence suggests that testosterone therapy or growth hormone therapy is particularly beneficial.