Exome sequence identifies RIPK4 as the Bartsocas-Papas syndrome locus.

Pterygium syndromes are complex congenital disorders that encompass several distinct clinical conditions characterized by multiple skin webs affecting the flexural surfaces often accompanied by craniofacial anomalies. In severe forms, such as in the autosomal-recessive Bartsocas-Papas syndrome, early lethality is common, complicating the identification of causative mutations. Using exome sequencing in a consanguineous family, we identified the homozygous mutation c.1127C>A in exon 7 of RIPK4 that resulted in the introduction of the nonsense mutation p.Ser376X into the encoded ankyrin repeat-containing kinase, a protein that is essential for keratinocyte differentiation. Subsequently, we identified a second mutation in exon 2 of RIPK4 (c.242T>A) that resulted in the missense variant p.Ile81Asn in the kinase domain of the protein. We have further demonstrated that RIPK4 is a direct transcriptional target of the protein p63, a master regulator of stratified epithelial development, which acts as a nodal point in the cascade of molecular events that prevent pterygium syndromes.

Mutations in RIPK4 cause the autosomal-recessive form of popliteal pterygium syndrome.

The autosomal-recessive form of popliteal pterygium syndrome, also known as Bartsocas-Papas syndrome, is a rare, but frequently lethal disorder characterized by marked popliteal pterygium associated with multiple congenital malformations. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this malformation syndrome to chromosomal region 21q22.3. Direct sequencing of RIPK4 (receptor-interacting serine/threonine kinase protein 4) showed a homozygous transversion (c.362T>A) that causes substitution of a conserved isoleucine with asparagine at amino acid position 121 (p.Ile121Asn) in the serine/threonine kinase domain of the protein. Additional pathogenic mutations-a homozygous transition (c.551C>T) that leads to a missense substitution (p.Thr184Ile) at a conserved position and a homozygous one base-pair insertion mutation (c.777_778insA) predicted to lead to a premature stop codon (p.Arg260ThrfsX14) within the kinase domain-were observed in two families. Molecular modeling of the kinase domain showed that both the Ile121 and Thr184 positions are critical for the protein's stability and kinase activity. Luciferase reporter assays also demonstrated that these mutations are critical for the catalytic activity of RIPK4. RIPK4 mediates activation of the nuclear factor-κB (NF-κB) signaling pathway and is required for keratinocyte differentiation and craniofacial and limb development. The phenotype of Ripk4(-/-) mice is consistent with the human phenotype presented herein. Additionally, the spectrum of malformations observed in the presented families is similar, but less severe than the conserved helix-loop-helix ubiquitous kinase (CHUK)-deficient human fetus phenotype; known as Cocoon syndrome; this similarity indicates that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.

Multicore myopathy associated with multiple pterygium syndrome and hypertrophic cardiomyopathy.

A boy with multicore myopathy associated with multiple pterygium syndrome and hypertrophic cardiomyopathy is described. Light microscopy of biopsy samples from the skeletal muscle and myocardium revealed multiple cores in the muscle fibers in the former but their absence in the latter. These results suggest that the pathogenesis of the histologic changes might differ between skeletal muscle and myocardium, and that further electron microscopic examination be done on both types of specimen. The prognosis of multicore myopathy is not usually good when cardiac involvement is present.

Otolaryngologic manifestations of multiple pterygium syndrome.

Escobar Syndrome, or Multiple Pterygium Syndrome (MPS), is a rare syndrome with multiple congenital anomalies involving the head and neck area and limbs. Affected individuals have multiple pterygia, camptodactyly and/or syndactyly as the main features of this syndrome. Patients with MPS have a characteristic facies, including ptosis, antimongoloid slant of the palpebral fissures, hypertelorism, micrognathia, neck pterygia, and a sad flat, emotionless look to the face. We present a case of MPS recently treated at our institution for the purpose of further describing the clinical features of this syndrome, emphasizing the otolaryngologic manifestations. Increased awareness of MPS will facilitate appropriate management of this syndrome.

Multiple pterygium syndrome with body asymmetry.

We report on a fetus with multiple pterygia in the popliteal, antecubital, intercrural, axillary, and nuchal region, arthrogryposis, camptodactyly, anal atresia, hypospadias, ambiguous genitalia, and neonatal death. Arthrogryposis was much more pronounced at the left than at the right side. Moreover, there was gross body asymmetry with hypoplasia of the left arm, leg, pelvis, and kidney. As this spectrum of anomalies does not fit any of the known multiple pterygium syndromes, this patient adds another clinical entity to the already wide spectrum of multiple pterygium syndromes.

Lethal multiple pterygium syndrome: report of a case with neurological anomalies.

We report on a 22-week female fetus with multiple pterygia, congenital joint contractures, muscle hypoplasia, cystic hygroma, hydrops, pulmonary and cardiac hypoplasia, facial anomalies, and growth retardation. Examination also documented microcephaly, brain immaturity, and severe cerebellar and pontine hypoplasia with absence of the pyramidal tracts. The spinal cord showed a marked decrease in size of all white matter tracts. The muscles were markedly hypoplastic. The relation of the neurological findings to the development of the syndrome is discussed.

Primary epitarsus: a case report.

Epitarsus is a rare congenital anomaly or may be acquired following severe conjunctivitis, usually of a cicatrising nature. The terms primary and secondary epitarsus are suggested to denote the two different aetiological varieties. On its clinical and histopathological features the present case conforms to the interfornix variety of primary epitarsus.

Mental retardation with pterygia, shortness and distinct facial appearance. A new MCA/MR syndrome.

During a systematic survey of the mentally retarded, 3 related females were seen with a similar syndrome of shortness, unusual combination of craniofacial anomalies (trigonocephaly; bulging forehead; flat face; posteriorly angulated, lowset ears and microretrognathia), and genital hypoplasia in all 3 cases, and multiple pterygia in one. The facial changes were also noted in 2 grandmothers and may indicate autosomal dominant inheritance of this presently "private" MCA/MR syndrome.