Genitopatellar Syndrome

A number sign (#) is used with this entry because of evidence that genitopatellar syndrome (GTPTS) can be caused by heterozygous mutation in the KAT6B gene (605880) on chromosome 10q22.

Description

Genitopatellar syndrome is a rare disorder consisting of microcephaly, severe psychomotor retardation, and characteristic coarse facial features, including broad nose and small or retracted chin, associated with congenital flexion contractures of the lower extremities, abnormal or missing patellae, and urogenital anomalies (summary by Penttinen et al., 2009).

The SBBYS variant of Ohdo syndrome (603736) is an allelic disorder with overlapping features.

Clinical Features

Cormier-Daire et al. (2000) reported the association of absent patellae, genital and renal anomalies, dysmorphic features, and mental retardation in 6 boys and 1 girl belonging to 5 unrelated families. Flexion deformities of the knees and hips with clubfeet and absent patellae were consistently observed, and scrotal hypoplasia and cryptorchidism were present in all boys. Dysmorphic features included coarse facies, prominent nose with a high nasal bridge, and microcephaly. Multicystic kidneys or hydronephrosis were present in all cases. Agenesis of the corpus callosum was present in 4 cases. Micrognathia was found in 4 cases and pulmonary hypoplasia in 3. Other radiographic features included bilateral hypoplasia of the ischia and brachydactyly. Two of the 7 cases were detected by prenatal ultrasound and resulted in termination of pregnancy. Three of the remaining 5 children died within the first 3 years of life; 2 died within the first 6 months. The remaining children were alive at 10 and 12 years, respectively, but neither had achieved walking or had any speech. Cytogenetic analysis was normal in all cases. Cormier-Daire et al. (2000) noted the report of a similar association by Goldblatt et al. (1988) of a 4-year-old boy who presented with hypoplastic patellae, mental retardation, scrotal hypospadias, skeletal deformities, fused renal ectopia, flattened nasal bridge, and short stature.

Cormier-Daire et al. (2000) reported the first female patient with genitopatellar syndrome, who had clitoral hypertrophy and prominent labia minora. Lammer and Abrams (2002) reported the second female patient with the syndrome; she had a small clitoris, and underdeveloped labia minora with anteriorly displaced anus. The patient also had severe mental retardation and microcephaly with absence of the corpus callosum, absent/hypoplastic patellae, and hydronephrosis. In a male patient reported by Reardon (2002), arthrogryposis of the hips and knees, talipes calcaneovalgus, and absent scrotum were noted at birth. The facies showed prominent nasal bridge and broad nose. Lammer and Abrams (2002) commented that positioning of the legs with flexion contractures at the hips and knees, with the feet hyperflexed and varus, seemed to be characteristic for the syndrome.

Armstrong and Clarke (2002) described a 3-month-old male patient with genitopatellar syndrome, born to nonconsanguineous parents. He had an abnormal neurologic examination, microcephaly, agenesis of the corpus callosum, and neuronal heterotopia. He had dysmorphic features, congenital heart disease, 11 thoracic ribs, cryptorchidism, scrotal hypoplasia, ureterohydronephrosis, and a multicystic kidney. His legs were relatively short, with flexion contractures of the knees and bilateral clubfeet. The extensor surfaces of the knees were dimpled and the patellae could not be palpated, but dislocated patellae were seen on ultrasound. Armstrong and Clarke (2002) suggested that this patient challenged the importance of absent patellae as a defining feature. They noted the observation of Goldblatt et al. (1988) that absent patellae had been associated with multiple joint contracture syndromes, suggesting that maldevelopment of the patellae may be secondary to intrauterine knee contractures. Thus flexion deformities may be the primary knee problem in genitopatellar syndrome, not absence of the patellae.

Lifchez et al. (2003) described another patient who, in addition to previously described features of genitopatellar syndrome, had a congenital heart defect, anal anomalies, and features of an ectodermal dysplasia. Cardiac defect and anal anomaly had been observed previously by Lammer and Abrams (2002). Furthermore, sparse scalp hair was present in both cases.

Abdul-Rahman et al. (2006) reported 2 unrelated patients with a clinical phenotype consistent with genitopatellar syndrome. In addition, both patients showed mild bilateral hearing loss, and 1 had radioulnar synostosis. Mutation screening excluded mutations in the LMX1B (602575) and TBX4 (601719) genes.

Penttinen et al. (2009) reported a 17-year-old Finnish girl with a phenotype consistent with genitopatellar syndrome who also had symptomatic osteoporosis with severe kyphoscoliosis and anterior wedging of osteopenic vertebrae, abnormal bone structure with undertubulation of long bones, primary hypothyroidism, and delayed puberty. The authors stated that this was the oldest reported patient with genitopatellar syndrome, and suggested that her severe osteoporosis and endocrine abnormalities were manifestations of the syndrome.

Brugha et al. (2011) reported a 16-month-old girl with severe genitopatellar syndrome, the fourth daughter of consanguineous parents, who had 3 healthy older sisters. Examination at 16 months of age showed microcephaly and developmental delay: she was unable to sit unsupported and had marked head lag; she had very little visual attention but normal hearing. She had constant tongue thrusting, poor swallowing, and required frequent suctioning of the upper airways; she had a primitive palmar grasp and generalized hypotonia. At 6 weeks of age she had developed upper airway edema secondary to severe gastroesophageal reflux and had undergone tracheostomy; she later underwent tracheal reconstruction after resection of a subglottic cartilaginous ridge, which was believed to be the primary pathology contributing to her being tracheostomy-dependent. Her face was long, with bitemporal narrowing, slightly upslanting palpebral fissures, broad nose with short columella, full cheeks, and downturned corners of the mouth. MRI of the brain at 2 weeks of age showed absent corpus callosum with ventriculomegaly. She had multiple urinary tract infections and bilateral hydronephrosis; she had clitoromegaly at birth but by 6 months of age the appearance was of hypoplastic labia majora. Echocardiography initially showed an atrial septal defect, ventricular septal defect (VSD), and patent ductus arteriosus (PDA); the VSD and PDA subsequently resolved. She had flexion deformity of the right knee with no palpable patella; knee ultrasound showed normal left knee, but no extensor tendon or patella on the right side. Radiographs of the upper limbs also showed bilateral radioulnar synostosis, and Brugha et al. (2011) noted that this feature had been reported in 2 earlier cases (Abdul-Rahman et al., 2006; Bergmann et al., 2011).

Molecular Genetics

Campeau et al. (2012) performed whole-exome sequencing in 3 patients with genitopatellar syndrome, including 1 patient ('patient 2') previously reported by Abdul-Rahman et al. (2006) and 1 patient previously reported by Lifchez et al. (2003), and identified heterozygosity for 3 different frameshift mutations in the KAT6B gene (605880.0005-605880.0007). After confirmation of the variants by Sanger sequencing, the KAT6B gene was sequenced in 3 additional patients with genitopatellar syndrome, including 'patient 1' of Abdul-Rahman et al. (2006) and a patient previously reported by Lammer and Abrams (2002), with identification of heterozygous mutations in all 3 (605880.0006 and 605880.0008-605880.0009). Campeau et al. (2012) noted that mutations in the KAT6B gene can also cause the Say-Barber-Biesecker variant of Ohdo syndrome (SBBYSS; 603736), a disorder with features overlapping those of genitopatellar syndrome, but with clinical differences: structural brain defects, skeletal defects, anogenital anomalies, and renal defects are more severe or frequent in genitopatellar syndrome, whereas ocular, dental, palatal, and thyroid defects are more severe or frequent in SBBYSS.

Simpson et al. (2012) performed whole-exome sequencing in 6 unrelated patients with genitopatellar syndrome, including 1 patient originally reported by Reardon (2002) and 1 patient reported by Brugha et al. (2011), and identified 4 different truncating mutations in the KAT6B gene in 5 of them (see, e.g., 605880.0006 and 605880.0010). The patient of Brugha et al. (2011) did not show variation in KAT6B by exome or Sanger sequencing, and high-resolution CGH microarray analysis did not reveal any CNVs affecting KAT6B or any other genomic abnormalities that might explain the phenotype, suggesting that the case might represent a phenocopy or genetic heterogeneity of genitopatellar syndrome. Simpson et al. (2012) also stated that the form of Ohdo syndrome (SBBYS) in which mutations in KAT6B had been found is phenotypically distinct from genitopatellar syndrome.

Inheritance

Cormier-Daire et al. (2000) proposed recessive inheritance for this disorder. However, the finding of heterozygous mutations by Campeau et al. (2012) and Simpson et al. (2012) demonstrated autosomal dominant inheritance.