Ischiocoxopodopatellar Syndrome With Or Without Pulmonary Arterial Hypertension

A number sign (#) is used with this entry because ischiocoxopodopatellar syndrome (ICPPS), also known as small patella syndrome, is caused by heterozygous mutation in the TBX4 gene (601719) on chromosome 17q23.

Description

Ischiocoxopodopatellar syndrome (ICPPS) is a rare autosomal dominant disorder characterized by a/hypoplasia of the patellas and various anomalies of the pelvis and feet. Pelvic anomalies include bilateral absent or delayed ossification of the ischiopubic junction and infraacetabular axe cut notches. Other major signs are a wide gap between the first and second toes, short fourth and fifth rays of the feet, and pes planus (summary by Bongers et al., 2001). Pediatric-onset pulmonary arterial hypertension may be seen in association with ICPPS (Kerstjens-Frederikse et al., 2013 and Levy et al., 2016).

Clinical Features

Scott and Taor (1979) described a family in which 12 members in an autosomal dominant pedigree pattern were found to have small or absent patellas. Seven of these persons also had abnormalities of the pelvic girdle and upper femurs. Recurrent dislocation of the patella was a complication in several members of the family. Familial recurrent dislocation of the patella (169000) and the nail-patella syndrome (161200) are separate conditions. Renwick (1956) had studied the family reported by Scott and Taor (1979) while investigating the genetics of the nail-patella syndrome. Iliac horns are absent in this condition but other changes occur in the pelvis, the most striking being defective ossification at the ischiopubic junction. Vanek (1981) reported a second family with affected members in 3 generations and pointed out that there are no changes in the fingernails in this condition.

Morin et al. (1985) reported a family with 15 affected members under the designation coxo-podo-patellar syndrome. All 11 patients whose feet had been examined showed an increased space between the first and second toes. In most of them, short fourth and fifth toes and flat feet were also noted. Burckhardt (1988) reported 3 unrelated patients, 1 of whom had a femoropatellar pain syndrome. Radiographs showed striking hypoplasia of the ischium.

Kozlowski and Nelson (1995) reported 2 sporadic cases thought to represent new mutations.

Bongers et al. (2001) described 5 cases from 3 previously undescribed families. Based on the clinical features found in the affected individuals in these families and those of 46 other individuals and information found in the medical literature, Bongers et al. (2001) identified diagnostic criteria for this condition. They suggested that aplasia or hypoplasia of the patellae and absent, delayed, or irregular ossification of the ischiopubic junctions or infraacetabular axe-cut notches were minimal criteria for the diagnosis of ischiopatellar syndrome. In addition, major signs were an increased space between the first and second toes and short fourth and fifth rays of the feet with pes planus.

Bongers et al. (2005) provided a comprehensive review of human syndromes with congenital patella anomalies and discussed the underlying gene defects.

Goeminne (2011) suggested that the patients reported by Scott and Taor (1979) had the same syndrome reported by Goeminne and Dujardin (1970) as 'patella aplasia, coxa vara, and tarsal synostosis' in 3 members of a family. In addition to absent patellas, the mother had severe coxa vara, hypoplasia of 'descending parts of the pubic arches' in the osseous pelvis, talocalcaneal synostosis, and absence of one metatarsal bilaterally. Her daughter had the full syndrome except for the tarsal synostosis and her son had only patella aplasia. Goeminne (2011) reviewed other reported cases and suggested that the syndrome be called familial ischio-coxo-podo-patellar syndrome (ICPPS).

Kerstjens-Frederikse et al. (2013) studied 20 consecutive cases with idiopathic or heritable pulmonary arterial hypertension (PAH; see 612349). Six had accompanying mental retardation and dysmorphic features. These 6 underwent array CGH and 3 were found to have 17q23 deletions of a region including the TBX2 (600767) and TBX4 genes (see 613355). Screening of both genes in the rest of the cohort identified heterozygous mutations in 3 unrelated patients with normal intelligence and without previously detected ICPPS features. Two of the 3 patients had parents available for testing and the mutations were found to be inherited. A clinical geneticist evaluated the 5 living patients and the 2 carrier parents and found that all had skeletal malformations characteristic for ICPPS, including patellar luxation, hypoplastic or absent patellas, sandal gap toes, and relatively long rays of the second and third feet. On x-ray, there was absent or irregular ossification of the ischiopubic junction of the pelvis, axe-cut notches of the acetabulum, and a broad neck of the talus. In one of the patients with a TBX4 mutation, postmortem examination revealed features of pulmonary venoocclusive disease (PVOD; see 265450). Kerstjens-Frederikse et al. (2013) also evaluated 23 adults with ICPPS and a mutation in the TBX4 gene and found that none had evidence of PAH.

Inheritance

Small patella syndrome is an autosomal dominant disorder (Bongers et al., 2001).

Mapping

Bongers et al. (2001) carried out haplotype analysis at the 9q34 locus with the LMX1B gene, mutations in which are responsible for nail-patella syndrome (161200), and the locus at 17q21-q22, associated with the patella aplasia-hypoplasia phenotype (168860). Their analysis excluded the 9q34 locus but not the 17q21-q22 locus.

By haplotype analysis, Bongers et al. (2004) identified a critical region of 5.6 cM on 17q22 for small patella syndrome.

Molecular Genetics

In 6 families with small patella syndrome, Bongers et al. (2004) identified heterozygous mutations in the TBX4 gene, including 2 missense, 1 nonsense, 1 frameshift and 1 splice site mutation (see, e.g., 601719.0001-601719.0003). TBX4 encodes a transcription factor with a strongly conserved DNA-binding T-box domain that plays a crucial role in lower limb development in chickens and mice. Thus, the importance of TBX4 was established in the developmental pathways of the lower limbs and pelvis in humans.

In a study of 20 consecutive patients with childhood-onset pulmonary arterial hypertension, Kerstjens-Frederikse et al. (2013) found that 3 patients had mutations (2 frameshift and 1 missense) in the TBX4 gene (see, e.g., 601719.0004) and 3 others had TBX4-containing deletions. All 3 mutations were inherited. In the 5 patients still alive, and in the 2 carrier parents tested, skeletal malformations characteristic of ICPPS were found.

Levy et al. (2016) studied a cohort of 40 patients with idiopathic or familial pulmonary hypertension and identified heterozygous TBX4 mutations in 3 patients (7.5%). All of the mutations were inherited from parents with ICPPS and without PAH.