Filippi Syndrome

A number sign (#) is used with this entry because of evidence that Filippi syndrome (FLPIS) is caused by homozygous or compound heterozygous mutation in the CKAP2L gene (616174) on chromosome 2q13.

Description

Filippi syndrome is characterized by short stature, microcephaly, syndactyly, intellectual disability, and facial dysmorphism consisting of bulging forehead, broad and prominent nasal bridge, and diminished alar flare. Common features include cryptorchidism, speech impairment, and clinodactyly of the fifth finger, Some patients exhibit visual disturbances, polydactyly, seizures, and/or ectodermal abnormalities, such as nail hypoplasia, long eyelashes, hirsutism, and microdontia (summary by Hussain et al., 2014).

Clinical Features

Scott et al. (1971) described a craniodigital syndrome with mental retardation in 3 brothers. The mother and the maternal grandmother had soft tissue syndactyly between toes 2 and 3. The father and mother were 46 and 31 years old, respectively, at the birth of their first child. Somatic and mental development was delayed. From birth the facies were abnormal with brachycephaly, small and narrow nose, 'startled' appearance, thick head hair with extension of the hair unusually far on the temples and sideburn areas, long eyelashes, thick eyebrows, and somewhat short mandible. The digital anomalies were soft-tissue syndactyly between toes 2 and 3 and between fingers 2, 3, and 4. The dermatoglyphic patterns on the hands were considered unusual. Because the disorder occurred in 3 brothers, Scott et al. (1971) suggested X-linked inheritance.

Filippi (1985) described an apparently distinct syndrome in 3 (2 boys, 1 girl) of 8 sibs with healthy, unrelated parents. The affected individuals had striking syndactyly of fingers 3 and 4, clinodactyly of the fifth finger, and syndactyly of toes 2, 3 and 4. There was microcephaly and severe physical and mental retardation. The nose had a broad base resembling that in Waardenburg syndrome.

Lorenz et al. (1990) reported what they designated the craniofacial digital syndrome of Scott in a boy whose mother had bilateral cutaneous syndactyly of toes 2 and 3. Photographs of the hands in the boy showed syndactyly of fingers 2, 3, and 4 (especially 3 and 4) and syndactyly of toes 2-4. The syndactyly of the toes in the mother appeared in a photograph to have been very mild.

Zerres et al. (1992) described a 2-year-old boy with mental retardation, postnatal short stature, postnatal microcephaly, a small atrial septal defect, dysmorphic face, syndactyly 2/5 of the hands and 1/4 of the feet, and brachymesophalangy of fingers 2 and 5.

Meinecke (1993) described an 18-year-old boy and his 15-year-old sister with the same syndrome. They showed pre- and postnatal short stature, microcephaly, moderate to severe mental retardation, and cutaneous syndactyly of hands and feet. In addition, they showed a mildly dysmorphic but apparently characteristic face. Radiologically, the hands and feet showed brachydactyly, the metacarpals and metatarsals being the most severely affected.

Toriello and Higgins (1995) concluded that the appropriate diagnosis was Filippi syndrome in a boy who showed low birth weight, congenital microcephaly, multiple minor facial anomalies, cleft palate, soft tissue syndactyly of fingers and toes, and moderate to severe mental retardation.

Heron et al. (1995) reported the case of a 9-year-old girl, born to first-cousin Tunisian parents, with microcephaly, cutaneous syndactyly of the toes, and moderate mental retardation with marked speech involvement. The face showed high nasal root and skeletal anomalies were demonstrated radiologically: hypoplasia of radial heads and dislocation of the elbows; synostosis of 2 carpal bones, and brachymesophalangism of the fifth fingers.

Fryer (1996) described 2 brothers with pre- and postnatal growth retardation, microcephaly, syndactyly of fingers and toes (only feet were affected in the younger brother), cryptorchidism, and only minimal learning difficulties.

Williams et al. (1999) described 3 unrelated patients with Filippi syndrome. All had microcephaly, minor facial anomalies, variable syndactyly of the digits, growth impairment, and developmental delay. One patient also had polydactyly, which had not previously been reported in Filippi syndrome.

Franceschini et al. (2002) reported a patient with the characteristic features of Filippi syndrome. They compared her features with those of other reported patients, including 11 males and 5 females, and underscored the peculiar and specific shape of the nasal bridge. A high nasal bridge was found to be present from an early age. The metacarpophalangeal profile showed a peculiar shortness of all metacarpals and of the proximal first phalanx. Franceschini et al. (2002) also compared the clinical findings in all 17 cases of Filippi syndrome with those in other 'craniodigital syndromes.'

Schorderet et al. (2002) described 2 brothers of Bosniak origin with syndactyly of the fingers and/or toes, cerebellar atrophy, axial hypotonia, limb hypertonia, and severe mental retardation.

Sharif and Donnai (2004) reported 2 unrelated children with Filippi syndrome. Both showed typical facial dysmorphism, syndactyly of fingers and toes, growth retardation, postnatal microcephaly and developmental delay, particularly involving speech. In addition, both children had unusual teeth and hair. The authors proposed that neurologic and ectodermal involvement may be underrecognized features of the syndrome.

Milani et al. (2007) reported a girl, born of unrelated Italian patients, with a phenotype most reminiscent of Scott syndrome. She showed intrauterine growth retardation during the second semester and had microsomia with small body and microcephaly at age 3 years. She had severely delayed psychomotor development, learned to walk at 3.5 years, and showed poor social interaction and stereotyped movements. Dysmorphic features included fine hair, synophrys, long eyelashes, hypertelorism, bulbous nasal tip, anteverted ears with hyperconvoluted helix, shallow philtrum, thin lips, small and widely spaced teeth, and generalized hirsutism. Severe syndactyly of toes 2 and 3 was present bilaterally, which was also found in the mother and paternal grandfather. Brain MRI showed Chiari type I malformation. She had a single seizure at age 4 years. In addition, her bone age was delayed, and Milani et al. (2007) noted that the patient reported by Lorenz et al. (1990) also had delayed bone age. Although Milani et al. (2007) favored dominant inheritance of the disorder with variable expressivity, the occurrence of the disorder in a female argues against this (Sobreira, 2013).

Battaglia et al. (2008) published MRI images of a child with Filippi syndrome, the offspring of healthy nonconsanguineous parents, which showed diffuse enlargement of subarachnoid spaces and lateral ventricles and the presence of a megacisterna magna.

For similar craniodigital syndromes, see 251255 and 615236.

Inheritance

In a review of 17 cases of Filippi syndrome, Franceschini et al. (2002) found at least 3 reports of families with both affected males and females and a pedigree pattern consistent with autosomal recessive inheritance.

Mapping

In a Sardinian family with Filippi syndrome, originally reported by Battaglia et al. (2008), Hussain et al. (2014) performed genomewide linkage analysis and identified several regions of homozygosity by descent with a maximum parametric lod score of 2.4 on chromosomes 1, 2, 5, 7, and 16. Haplotype analysis revealed a 0.93-Mb region of homozygosity on chromosome 2q13.

Molecular Genetics

Using DNA from 2 affected brothers from a Sardinian family with Filippi syndrome, originally reported by Battaglia et al. (2008), Hussain et al. (2014) performed whole-exome sequencing and identified homozygosity for a 1-bp insertion in the CKAP2L gene on chromosome 2q13 (616174.0001); Sanger sequencing confirmed the mutation and demonstrated segregation with disease in the family. Sequencing of CKAP2L in 8 additional probands with Filippi syndrome revealed homozygosity or compound heterozygosity for truncating mutations in the probands from 4 families (616174.0002-616174.0006), including the Pakistani boy originally described by Sharif and Donnai (2004) and the English family previously reported by Fryer (1996). The mutations segregated with disease in each family. All affected individuals exhibited microcephaly, short stature, typical facial dysmorphism, syndactyly, and intellectual disability. However, intrauterine growth restriction as well as significant microcephaly at birth appeared to be features characteristic of individuals with biallelic mutations in the CKAP2L gene.