Bartsocas-Papas Syndrome

A number sign (#) is used with this entry because of evidence that Bartsocas-Papas syndrome (BPS), also known as the lethal type of popliteal pterygium syndrome, is caused by homozygous mutation in the RIPK4 gene (605706) on chromosome 21q22.

Biallelic mutation in the RIPK4 gene can also cause CHAND syndrome (CHANDS; 214350), a less severe disorder with overlapping features.

Description

Bartsocas-Papas syndrome (lethal popliteal pterygium syndrome) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (summary by Mitchell et al., 2012).

A less severe form of popliteal pterygium syndrome (119500) is caused by mutation in the IRF6 gene (607199).

Clinical Features

Bartsocas and Papas (1972) reported a family in which the parents were third cousins and 4 sibs were severely affected. In addition to marked popliteal pterygium with a cord containing nerves and vessels, synostosis of hand and foot bones with digital hypoplasia and syndactyly occur. Facial clefts, ankyloblepharon and filiform bands between the jaws have been observed.

Hall (1984) gave a classification of the lethal pterygium syndromes. In addition to the lethal popliteal pterygium syndrome of Bartsocas and Papas, Hall (1984) recognized 3 lethal multiple pterygium syndromes. Cases of the Bartsocas-Papas syndrome were reported by Hall et al. (1982) and by Di Stefano and Romeo (1974).

Papadia et al. (1984) described a case in the offspring of third-cousin parents. Facial cleft and fusion deformity in the hands and feet were also present. Papadia and Longo (1988) insisted that there are numerous nosologic differences between Bartsocas-Papas syndrome and lethal multiple pterygium syndrome (253290), 'so that confusion between them is not possible.'

In a Spanish family, Martinez-Frias et al. (1991) described 3 affected sibs and pointed out that all but 1 of the 7 families that have been reported are of Mediterranean origin; 1 case was born to a couple of East Indian ancestry (Hall et al., 1982). The index case in the family of Martinez-Frias et al. (1991) had ankyloblepharon filiforme, absent eyebrows and eyelashes, and hypoplastic nose; bilateral clefts of the upper lip; fusion syndactyly of the hands and feet with bilateral aplasia of the thumb and phalangeal hypoplasia as well as absent nails. Thumb aplasia and fusion syndactyly of the fingers were present also in the proposita reported by Bartsocas and Papas (1972).

Giannotti et al. (1992) described an infant who was still alive at the age of 20 months. They pointed to other cases in which the condition had not been neonatally lethal. The clustering of cases among persons of Mediterranean ancestry was again emphasized. Striking synostosis of the hands and feet was illustrated.

Massoud et al. (1998) described BPS in 4 sibs in an Arab family. The phenotypically normal parents were unrelated; the father and mother were from Qatar and United Arab Emirates, respectively. The patients showed oral cleft, filiform bands between the jaws, ankyloblepharon, popliteal pterygium, syndactyly of fingers and toes, phalangeal anomalies with synostosis, clubfeet, nail hypoplasia, and genital anomalies. Additional traits included cutis aplasia, widely spaced nipples, low-set umbilicus, and unilateral renal hypoplasia. One of the sibs were stillborn; the other 3 children lived 10 to 17 months.

Aslan et al. (2000) described a female infant who presented with pterygia of the inguinal, intercrural, and popliteal areas, flexion contractures and arthrogryposis of some joints, craniofacial anomalies including ectropion, medial canthal web, blepharophimosis, hypoplasia of nose, oral and nasopharyngeal cavities, vocal cords, and tongue, micrognathia, orolabial synechiae secondary to pterygia, low-set ears, alopecia, sad and expressionless face, short neck, asymmetric nipples, anal stenosis, rectal polyp, hypoplastic labia majora, complete syndactyly of all fingers and toes, phalangeal-palmar creases, pes equinovarus, band-like web between feet, and absence of nails. Radiologic examination showed synostosis, absence or hypoplasia of metacarpal, metatarsal, and phalangeal bones of feet and hands, and hypoplasia of pelvic bones and scapulae. Autosomal recessive inheritance was considered likely because 3 sibs were similarly affected and the parents were normal. Teebi (2001) suggested that the disorder in the family reported by Aslan et al. (2000), initially believed to represent a distinct disorder, was the Bartsocas-Papas syndrome because of a strong resemblance to cases that he had reported with Massoud et al. (1998) in an Arab family from Qatar.

Kalay et al. (2012) provided follow-up on the consanguineous Turkish family with popliteal pterygium syndrome originally studied by Aslan et al. (2000). Of 6 affected children from 3 sibships, 2 boys and 2 girls died within a week after birth, and 2 female cousins were alive at ages 13 years and 1.5 years. Present in both were alopecia, ankyloblepharon filaforme adnatum, hypoplastic oral cavity and filiform bands between the jaws, limb abnormalities including digital hypoplasia, syndactyly, nail hypoplasia, arthrogryposis, clubfeet, and politeal, axillary, and inguinal pterygia, and hypoplastic labia majora. In addition to classic Bartsocas-Papas syndrome findings, the older girl also had medial canthal webbing, hypoplasia of the iliac wing and scapulae, short stature, anal stenosis, and a rectal polyp.

Veenstra-Knol et al. (2003) reported 2 Dutch families with 6 affected children. One of the patients was diagnosed prenatally by ultrasound examination. Previously unreported findings included omphalocele and aplasia of the urethra.

Shanske et al. (2004) described a male infant, born of consanguineous Gambian parents, who had large bilateral popliteal pterygia extending from the crurae to the great toes. In addition, he had right-sided cleft lip and palate, abortive left-sided cleft, symblepharon, and synechiae between the upper and lower alveolar ridges. He had normal eyelashes and eyebrows. There was syndactyly of the second, third, and fourth fingers bilaterally, with hypoplasia of the phalanges and fingernails of those digits, and he had bilateral cryptorchidism. He underwent tracheostomy and gastrostomy due to the ankylosed mandible, and the oral synechiae and ocular filiform adhesions were lysed and the cleft lip repaired. A 3-D CT scan of the head demonstrated probable fusion between the left coronoid process and zygoma as well as between the condylar head and the temporomandibular fossa. At 3 years of age, he was developmentally appropriate except for gross physical limitations; his palate remained unrepaired and the jaw was ankylosed. He was evaluated for release of the popliteal pterygia, but because the neurovascular bundles could not be preserved, he underwent bilateral below-the-knee amputations. His mother experienced fetal demise 14 months after the birth of the proband, with delivery of a 33-week gestation female fetus with low-set pinnae, cleft between the eyes, absence of eyebrows and eyelashes, flattened nose, and filiform bands of thickened collagen fibers fusing the eyelids and connecting the lower lip to the maxilla. There were also large pterygia in both popliteal fossae and synostosis of the bones of the second and third fingers of the right hand and of the digits of both feet except for the great toes; no fingernails or toenails were present.

Abdalla and Morsy (2011) reported an Egyptian family with Bartsocas-Papas syndrome. The proband was a 3-month-old girl who had striking craniofacial anomalies, including a severely malformed nose with clefting and 2 symmetrical indentations over the nasal root, hypertelorism with major eye anomalies including microphthalmia, small hazy corneas, left ankyloblepharon with filiform bands, multiple right eyelid colobomas, short palpebral fissures with marked upward slanting, and total absence of eyebrows, eyelashes, and scalp hair. No mouth or lips were present, although 2 salivary pits could be identified, and there was a bilateral orofacial cleft extending into the alae nasi and connecting with a bilateral cleft palate. The mandible and maxilla were severely hypoplastic, with a transverse groove over the chin, whereas the ears were relatively large, cupped, and low set. In addition, she had major pterygia of almost all joints, including the shoulders, elbows, wrists, hips, knees, and ankles, but sparing the neck. There was complete syndactyly between all fingers of both hands, flexed fingers, and absent thumbs, and there was adactyly of both feet with dorsiflexion and pes planus. Nails were absent in all fingers and toes. Other anomalies included a very short sternum, widely spaced nipples, low-set umbilicus, and prominent veins over the chest and abdomen, with skin tags over the chest as well as the right palm and right labia minora. She also had ambiguous genitalia with absent clitoris and hypoplastic labia majora, anal stenosis, and sacral dimple. The infant died shortly after examination, and the parents reported a similarly affected older female sib with genital ambiguity who had died in utero after a 26-week gestation complicated by intrauterine growth retardation. In addition, there was a 16-year-old maternal uncle who had mental retardation and ocular, cutaneous, and limb anomalies, including microphthalmia with short and narrow palpebral fissures, sparse lower eyelashes, hypoplastic thumbs, and complete syndactyly. He also had truncal obesity and hypoplastic external genitalia. However, he had no pterygia and displayed multiple cafe-au-lait spots, a feature not previously reported in BPS.

Mitchell et al. (2012) studied a 6-year-old boy, the second child of consanguineous parents, who was born with alopecia totalis with only sparse scalp hair, partial ankyloblepharon, oral synechia resulting in partial occlusion of the oral cavity, hypertelorism, cloudy corneas, absent thumbs, finger and toe oligosyndactyly, hypoplastic genitalia, extensive popliteal pterygia, multiple skin tags, and unusual fibrous tethers between the feet and suprapubic region. Intellectual development appeared to be normal. On the basis of these features, a diagnosis of Bartsocas-Papas syndrome was made.

Busa et al. (2017) reported a male fetus (patient 1), conceived of consanguineous Moroccan parents, with features of BPS. Autopsy showed a typical facial appearance with absent eyelids, bilateral labio-maxillo-palatal cleft, nasal hypoplasia, and small ears attached to the scalp. There was also a small omphalocele, multiple pterygia of the upper and lower limbs, syndactyly of hands and feet, clubfeet, anal atresia, and absence of external genitalia.

Mapping

In 2 affected and 10 unaffected members of a consanguineous Turkish family with lethal popliteal pterygium syndrome, originally reported by Aslan et al. (2000), Kalay et al. (2012) performed genomewide homozygosity mapping and observed a single homozygous segment on chromosome 21q22. Within that region, haplotypes between SNP markers rs2838045 and rs225444 were identical in both affected individuals, indicating homozygosity by descent. Microsatellite-marker genotyping in all family members confirmed the 21q22.3 locus, and recombination events narrowed the critical region to an approximately 0.71-Mb interval containing 7 genes and 3 expressed sequence tags.

Molecular Genetics

In a 6-year-old boy with features consistent with Bartsocas-Papas syndrome who was born of consanguineous parents, Mitchell et al. (2012) performed exome sequencing and identified homozygosity for a nonsense mutation in the RIPK4 gene (S376X; 605706.0001), located within a 9.3-Mb region of homozygosity between SNPs rs1053808 and rs1044998. Both parents were heterozygous for the mutation. Sequencing of RIPK4 in a DNA sample from the 3-year-old boy with Bartsocas-Papas syndrome previously studied by Shanske et al. (2004) revealed homozygosity for a missense mutation (I81N; 605706.0002); although no DNA from his parents was available, the mutation was not found in dbSNP, the 1000 Genomes Database, or in over 4,000 chromosomes from the National Heart, Lung, and Blood Institute Exome Sequencing Project.

In a consanguineous Turkish family with lethal popliteal pterygium syndrome mapping to chromosome 21q22.3, originally reported by Aslan et al. (2000), Kalay et al. (2012) analyzed the candidate RIPK4 gene and identified homozygosity for a missense mutation (I121N; 605706.0003) in the 2 surviving affected individuals, whose parents were heterozygous for the mutation. Analysis of another Turkish family with a deceased male infant who had features consistent with Bartsocas-Papas syndrome revealed that the first-cousin parents were both heterozygous for another missense mutation in RIPK4 (DNA was not available from the deceased infant). Kalay et al. (2012) also sequenced the RIPK4 gene in a consanguineous Egyptian family with an affected girl who died at 3.5 months of age, previously described by Abdalla and Morsy (2011), and found that the deceased infant had a homozygous 1-bp insertion in RIPK4 (605706.0004) for which her unaffected parents were heterozygous. Kalay et al. (2012) noted similarities between the Bartsocas-Papas phenotype and the more severe 'cocoon' syndrome (613630) caused by mutation in the CHUK gene (600664), and suggested that RIPK4 and CHUK might function via closely related pathways to promote keratinocyte differentiation and epithelial growth.

In a male fetus (patient 1), conceived of consanguineous Moroccan parents, with lethal Bartsocas-Papas syndrome, Busa et al. (2017) identified homozygosity for a single base duplication in the RIPK4 gene (605706.0007). The parents were heterozygous for the mutation.

Exclusion Studies

In a 3-year-old boy with Bartsocas-Papas popliteal pterygium syndrome, Shanske et al. (2004) sequenced exons 3 to 8 and parts of exons 9 and 10 of the IRF6 gene (607199) but found no disease-causing mutations.