Bardet Biedl Syndrome, McKusick-Kaufman Syndrome, Borjeson-Forssman-Lehmann Syndrome, Alström Syndrome, Albright Hereditary Osteodystrophy
McKusick-Kaufman Syndrome is characterized by postaxial polydactyly, congenital heart disease and hydrometrocolpos in females and genital malformations (hypospadias, cryptorchidism, chordee) in males. Hydrometrocolpos develops in the female fetus as a result of accumulation of secretions in the vagina and uterus due to a congenital obstruction. McKusick-Kaufman Syndrome (MKKS) is inherited in an autosomal recessive manner. MKS is concentrated in the Amish population, where it affects an estimated 1 in 10,000 people. The disease is caused by mutations in MKKS (BBS6) gene, which encodes a protein with similarity to members of the chaperonin family. Some mutations in MKKS gene are associated with McKusick-Kaufman Syndrome, most mutations cause one of the forms of Bardet-Biedl Syndrome (BBS). There are also several symptoms of MKS that overlap significantly with BBS.
Bardet-Biedl Syndrome is characterized by male hypogenitalism, complex female genitourinary malformations, postaxial polydactyly, cone-rod dystrophy, obesity, cognitive impairment, and renal abnormalities. Renal abnormalities are major cause of morbidity and mortality. The first symbol of retinal degeneration is night blindness, which later evolves into a progressive loss of peripheral vision. Patients with Bardet-Biedl also experience central vision loss during childhood or adolescence. Bardet-Biedl Syndrome is inherited in an autosomal recessive manner. BBS prevalence in Europe is estimated at between 1/125,000 and 1/175,000. BBS is associated with mutations in 18 different genes, that encode proteins involved in the development and function of primary cilia.
This phenotypic overlap between McKusick-Kaufman Syndrome and Bardet-Biedl Syndrome in infancy may lead to diagnostic errors, and all children who have been diagnosed with McKusick-Kaufman Syndrome in infancy should be reevaluated for retinitis pigmentosa and other signs of Bardet-Biedl Syndrome in later childhood.
Borjeson-Forssman-Lehmann Syndrome is characterised by the association of intellectual deficit with endocrine anomalies, epilepsy, hypogonadism and facial dysmorphism. The main clinical features evolve with age and show considerable variation both within and between families. Newborns have small genitalia and large ears and many infants have generalized hypotonia. Developmental delay is usually evident before the first birthday; the eventual degree of mental handicap is mild to moderate. Truncal obesity emerges in late childhood and gynaecomastia in adolescence. In late adolescence and adult life, the classically described heavy facial appearance emerges. Frequent visual problems have also been associated with syndrome. The pattern of inheritance is X linked. Borjeson-Forssman-Lehmann Syndrome is caused by mutations in the PHF6 gene. The differential diagnosis of obesity related syndromes includes the Prader-Willi, Bardet-Biedl, or Wilson-Turner Syndromes.
Alström Syndrome is characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated cardiomyopathy, the insulin resistance syndrome, developmental delay and progressive hepatic and renal dysfunction. The cone-rod retinal dystrophy usually develops within a few weeks after birth, the first symptoms are nystagmus and extreme photodysphoria or light sensitivity. It is progressive and leads to blindness, usually by the second decade of life. Progressive sensorineural hearing loss presents in the first decade in as many as 70% of individuals. Males may have hypogonadotrophic hypogonadism. Obesity, insulin resistance and hyperinsulinemia are early and consistent features.
In contrast to BBS, Alström Syndrome is characterized by relative preservation of cognitive function and the absence of polydactyly. Approximately 450 cases of Alström Syndrome have been identified worldwide. Alström Syndrome is caused by mutations in the gene ALMS1 and is inherited in an autosomal recessive manner. Differential diagnosis includes Bardet-Biedl Syndrome, Biemond II Syndrome, Wolfram Syndrome, Cohen Syndrome, sporadic infantile dilated cardiomyopathy, and mitochondrial disorders.
Albright Hereditary Osteodystrophy (AHO) is characterised by a wide range of features including short stature in adulthood, a tendency for obesity and brachydactyly (shortening of the bones in the hands and feet). Other features may include a rounded face, wide neck and small subcutaneous ossifications (hard lumps under the skin). Mental retardation was less frequently described. There are different types of AHO. These are AHO with Pseudo Hypoparathyroidism (PHP) and AHO with Pseudo Pseudo Hypoparathyroidism (PPHP).
PHP is associated with resistance to parathyroid hormone (PTH) and to other hormones (thyroid-stimulation hormone – TSH, in particular). PHP1a is characterized by AHO features, hypoparathyroid manifestations (hypocalcemia, hyperphosphoremia), elevated PTH levels and decreased erythrocyte Gs activity. Individuals with PHP-1b have PTH resistance and normal levels of erythrocyte Gs activity. Classically, patients do not have features of AHO. PHP Ic is characterized by PTH resistance, generalized hormone resistance, features of AHO and normal Gs activity.
Patients with pseudopseudohypoparathyroidism (PPHP) have physical findings of AHO with Gs deficiency but without hormone resistance.
Condition characterized by AHO features and decreased Gs activity is caused by heterozygous inactivating mutations of the GNAS gene. GNAS encodes the alpha subunit of the stimulatory G protein (Gs). Resistance to hormones is determined by the parental origin of the mutation, a functional maternal GNAS allele has a predominant role in preventing hormone resistance.
PHP with AHO features is inherited in an autosomal dominant manner.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation